U.S. patent application number 15/920336 was filed with the patent office on 2018-07-26 for therapeutic combinations of a btk inhibitor, a pi3k inhibitor and/or a jak-2 inhibitor.
The applicant listed for this patent is Acerta Pharma B.V.. Invention is credited to Tjeerd Barf, Todd Covey, Ahmed Hamdy, Raquel Izumi, Dave Johnson, Allard Kaptein, Brian Lannutti, Wayne Rothbaum, Roger Ulrich.
Application Number | 20180207154 15/920336 |
Document ID | / |
Family ID | 54695758 |
Filed Date | 2018-07-26 |
United States Patent
Application |
20180207154 |
Kind Code |
A1 |
Hamdy; Ahmed ; et
al. |
July 26, 2018 |
Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor
and/or a JAK-2 Inhibitor
Abstract
Therapeutic combinations of a Janus kinase-2 (JAK-2) inhibitor,
a Bruton's tyrosine kinase (BTK) inhibitor, and/or a
phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K
inhibitors selective for the .gamma.- and .delta.-isoforms and
selective for both .gamma.- and .delta.-isoforms, are described. In
some embodiments, the invention provides pharmaceutical
compositions comprising combinations of (1) a PI3K-.delta.inhibitor
and a BTK inhibitor, (2) a JAK-2 inhibitor and a BTK inhibitor, or
(3) a JAK-2 inhibitor, PI3K-.delta. inhibitor, and BTK inhibitor,
and methods of using the pharmaceutical compositions for treating a
disease, in particular a cancer.
Inventors: |
Hamdy; Ahmed; (Santa Cruz,
CA) ; Rothbaum; Wayne; (Delray Beach, FL) ;
Izumi; Raquel; (San Carlos, CA) ; Lannutti;
Brian; (Solana Beach, CA) ; Covey; Todd; (San
Carlos, CA) ; Ulrich; Roger; (Sammamish, WA) ;
Johnson; Dave; (Aptos, CA) ; Barf; Tjeerd;
(Ravenstein, NL) ; Kaptein; Allard; (Zaltbommel,
NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Acerta Pharma B.V. |
Oss |
|
NL |
|
|
Family ID: |
54695758 |
Appl. No.: |
15/920336 |
Filed: |
March 13, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15319740 |
Dec 16, 2016 |
9949971 |
|
|
PCT/IB2015/001811 |
Jun 17, 2015 |
|
|
|
15920336 |
|
|
|
|
62013506 |
Jun 17, 2014 |
|
|
|
62035785 |
Aug 11, 2014 |
|
|
|
62087975 |
Dec 5, 2014 |
|
|
|
62115493 |
Feb 12, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/454 20130101;
A61P 35/00 20180101; A61K 31/52 20130101; A61K 31/519 20130101;
A61K 45/06 20130101; A61K 31/529 20130101; A61K 31/517 20130101;
A61K 31/337 20130101; A61K 31/4985 20130101; C07K 16/2887 20130101;
A61K 39/39558 20130101; A61K 31/7068 20130101; C07K 2317/732
20130101; A61P 35/02 20180101; A61K 31/506 20130101; A61K 31/519
20130101; A61K 2300/00 20130101; A61K 31/517 20130101; A61K 2300/00
20130101; A61K 31/4985 20130101; A61K 2300/00 20130101; A61K 31/454
20130101; A61K 2300/00 20130101; A61K 31/7068 20130101; A61K
2300/00 20130101; A61K 31/337 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61K 39/395 20060101 A61K039/395; C07K 16/28 20060101
C07K016/28; A61K 31/519 20060101 A61K031/519; A61K 31/529 20060101
A61K031/529; A61K 31/52 20060101 A61K031/52 |
Claims
1. A method of treating a hyperproliferative disease, comprising
co-administering, to a mammal in need thereof, therapeutically
effective amounts of (1) a Janus kinase-2 (JAK-2) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, and (2) a Bruton's tyrosine kinase (BTK) inhibitor
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug thereof.
2. The method of claim 1, wherein the JAK-2 inhibitor is
administered to the mammal before administration of the BTK
inhibitor.
3. The method of claim 1, wherein the JAK-2 inhibitor is
administered to the mammal simultaneously with the administration
of the BTK inhibitor.
4. The method of claim 1, wherein the JAK-2 inhibitor is
administered to the mammal after administration of the BTK
inhibitor.
5. The method of any one of claims 1-4, wherein the BTK inhibitor
is selected from the group consisting of: ##STR00215## ##STR00216##
and pharmaceutically-acceptable salts, cocrystals, hydrates,
solvates, and prodrugs thereof.
6. The method of any one of claims 1-4, wherein the BTK inhibitor
is selected from the group consisting of: ##STR00217## and
pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,
and prodrugs thereof.
7. The method of any one of claims 1-6, wherein the JAK-2 inhibitor
is selected from the group consisting of: ##STR00218## and
pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,
or prodrugs thereof.
8. The method of any one of claims 1-7, further comprising the step
of administering a therapeutically effective amount of an anti-CD20
antibody selected from the group consisting of rituximab,
obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and
fragments, derivatives, conjugates, variants, radioisotope-labeled
complexes, biosimilars thereof, and combinations thereof.
9. The method of any one of claims 1-8, further comprising the step
of administering a phosphoinositide 3-kinase (PI3K) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
10. The method of claim 9, wherein the PI3K inhibitor is a
PI3K-.delta. inhibitor.
11. The method of any one of claims 9-10, wherein the PI3K
inhibitor is administered to the mammal before administration of
the BTK inhibitor.
12. The method of any one of claims 9-10, wherein the PI3K
inhibitor is administered to the mammal concurrently with the
administration of the BTK inhibitor.
13. The method of any one of claims 9-10, wherein the PI3K
inhibitor is administered to the mammal after administration of the
BTK inhibitor.
14. The method of any one of claims 9-13, wherein the PI3K
inhibitor is selected from the group consisting of: ##STR00219##
and pharmaceutically acceptable salts, solvates, hydrates,
cocrystals, and prodrugs thereof.
15. The method of any one of claims 1-14, wherein the
hyperproliferative disease is a cancer, and the cancer is a B cell
hematological malignancy, and wherein the B cell hematological
malignancy is selected from the group consisting of chronic
lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL),
non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma
(DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL),
Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL),
Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's
lymphoma, multiple myeloma, and myelofibrosis.
16. The method of any one of claims 1-14, wherein the
hyperproliferative disease is a cancer, and wherein the cancer is a
solid tumor cancer, and wherein the solid tumor cancer is selected
from the group consisting of bladder cancer, non-small cell lung
cancer, cervical cancer, anal cancer, pancreatic cancer, squamous
cell carcinoma including head and neck cancer, renal cell
carcinoma, melanoma, ovarian cancer, small cell lung cancer,
glioblastoma, gastrointestinal stromal tumor, breast cancer, lung
cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach
cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer,
kidney cancer, liver cancer, prostate cancer, esophageal cancer,
testicular cancer, gynecological cancer, colon cancer, and brain
cancer.
17. The method of claim 16, further comprising the step of
administering a therapeutically effective amount of
gemcitabine.
18. The method of claim 16, further comprising the step of
administering a therapeutically effective amount of albumin-bound
paclitaxel.
19. A method of treating a cancer in a human comprising the step of
co-administering (1) a therapeutically effective amount of a Janus
kinase-2 (JAK-2) inhibitor or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof, and (2) a
therapeutically effective amount of a Bruton's tyrosine kinase
(BTK) inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein the therapeutically
effective amount is effective to inhibit signaling between a tumor
cell of the cancer and at least one tumor microenvironment selected
from the group consisting of macrophages, monocytes, mast cells,
helper T cells, cytotoxic T cells, regulatory T cells, natural
killer cells, myeloid-derived suppressor cells, regulatory B cells,
neutrophils, dendritic cells, and fibroblasts.
20. The method of claim 19, wherein the cancer is a solid tumor
cancer selected from the group consisting of bladder cancer,
non-small cell lung cancer, cervical cancer, anal cancer,
pancreatic cancer, squamous cell carcinoma including head and neck
cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell
lung cancer, glioblastoma, gastrointestinal stromal tumor, breast
cancer, lung cancer, colorectal cancer, thyroid cancer, bone
sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer,
gastric cancer, kidney cancer, liver cancer, prostate cancer,
esophageal cancer, testicular cancer, gynecological cancer, colon
cancer, and brain cancer.
21. The method of claim 19 or 20, wherein the therapeutically
effective amount is further effective to increase immune system
recognition and rejection of the solid tumor by the human.
22. The method of any one of claims 19-21, wherein the BTK
inhibitor is selected from the group consisting of: ##STR00220##
##STR00221## and pharmaceutically-acceptable salts, cocrystals,
hydrates, solvates, or prodrugs thereof.
23. The method of any one of claims 19-22, wherein the JAK-2
inhibitor is selected from the group consisting of: ##STR00222##
and pharmaceutically-acceptable salts, cocrystals, hydrates,
solvates, and prodrugs thereof.
24. The method of any one of claims 19-23, further comprising the
step of administering a therapeutically effective amount of a
phosphoinositide 3-kinase (PI3K) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug
thereof.
25. The method of claim 24, wherein the PI3K inhibitor is selected
from the group consisting of: ##STR00223## and
pharmaceutically-acceptable salts, solvates, hydrates, cocrystals,
and prodrugs thereof.
26. A method of treating a cancer in a human intolerant to a
bleeding event comprising the step of administering (1) a
therapeutically effective amount of a Janus kinase-2 (JAK-2)
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof, and (2) a therapeutically effective
amount of a Bruton's tyrosine kinase (BTK) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, wherein the BTK inhibitor is selected from the
group consisting of: ##STR00224## ##STR00225## and
pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,
or prodrugs thereof.
27. The method of claim 26, wherein the bleeding event is selected
from the group consisting of subdural hematoma, gastrointestinal
bleeding, hematuria, post-procedural hemorrhage, bruising,
petechiae, and combinations thereof.
28. The method of claim 26 or 27, wherein the JAK-2 inhibitor is
selected from the group consisting of: ##STR00226## and
pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,
and prodrugs thereof.
29. The method of any one of any of claims 26-28, further
comprising the step of administering a therapeutically effective
amount of an anticoagulant or antiplatelet active pharmaceutical
ingredient.
30. The method of claim 29, wherein the anticoagulant or
antiplatelet active pharmaceutical ingredient is selected from the
group consisting of acenocoumarol, anagrelide, anagrelide
hydrochloride, abciximab, aloxiprin, antithrombin, apixaban,
argatroban, aspirin, aspirin with extended-release dipyridamole,
beraprost, betrixaban, bivalirudin, carbasalate calcium,
cilostazol, clopidogrel, clopidogrel bisulfate, cloricromen,
dabigatran etexilate, darexaban, dalteparin, dalteparin sodium,
defibrotide, dicumarol, diphenadione, dipyridamole, ditazole,
desirudin, edoxaban, enoxaparin, enoxaparin sodium, eptifibatide,
fondaparinux, fondaparinux sodium, heparin, heparin sodium, heparin
calcium, idraparinux, idraparinux sodium, iloprost, indobufen,
lepirudin, low molecular weight heparin, melagatran, nadroparin,
otamixaban, parnaparin, phenindione, phenprocoumon, prasugrel,
picotamide, prostacyclin, ramatroban, reviparin, rivaroxaban,
sulodexide, terutroban, terutroban sodium, ticagrelor, ticlopidine,
ticlopidine hydrochloride, tinzaparin, tinzaparin sodium,
tirofiban, tirofiban hydrochloride, treprostinil, treprostinil
sodium, triflusal, vorapaxar, warfarin, warfarin sodium,
ximelagatran, salts thereof, solvates thereof, hydrates thereof,
and combinations thereof.
31. The method of any one of claims 26-30, wherein the cancer is
selected from the group consisting of bladder cancer, squamous cell
carcinoma including pancreatic ductal adenocarcinoma (PDA),
pancreatic cancer, colon carcinoma, mammary carcinoma, breast
cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung
carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian
cancer, acute myeloid leukemia, thymus cancer, brain cancer,
squamous cell cancer, skin cancer, eye cancer, retinoblastoma,
melanoma, intraocular melanoma, oral cavity and oropharyngeal
cancers, gastric cancer, stomach cancer, cervical cancer, head and
neck cancer, renal cancer, kidney cancer, liver cancer, ovarian
cancer, esophageal cancer, testicular cancer, gynecological cancer,
thyroid cancer, acquired immune deficiency syndrome (AIDS)-related
cancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced
cancer, glioblastoma, esophageal tumors, hematological neoplasms,
non-small-cell lung cancer, chronic myelocytic leukemia, diffuse
large B-cell lymphoma, esophagus tumor, follicle center lymphoma,
head and neck tumor, hepatitis C virus infection, hepatocellular
carcinoma, Hodgkin's disease, metastatic colon cancer, multiple
myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma,
ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung
cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell
acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular
lymphoma, mantle cell lymphoma, Burkitt's lymphoma, and
myelofibrosis.
32. A composition comprising therapeutically effective amounts of
(1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, for use in the treatment of cancer.
33. The composition of claim 32, for use as a medicament.
34. The composition of claim 32 or 33, for use in the treatment of
cancer.
35. The composition of any one of claims 32-34, wherein the BTK
inhibitor is selected from the group consisting of: ##STR00227##
##STR00228## and pharmaceutically-acceptable salts, cocrystals,
hydrates, solvates, and prodrugs thereof.
36. The composition of any one of claims 32-35, wherein the BTK
inhibitor is selected from the group consisting of: ##STR00229##
and pharmaceutically-acceptable salts, cocrystals, hydrates,
solvates, and prodrugs thereof.
37. The composition of any one of claims 32-36, wherein the JAK-2
inhibitor is selected from the group consisting of: ##STR00230##
and pharmaceutically-acceptable salts, cocrystals, hydrates,
solvates, and prodrugs thereof.
38. The composition of any one of claims 32-37, further comprising
a therapeutically effective amount of an anti-CD20 antibody
selected from the group consisting of rituximab, obinutuzumab,
ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,
derivatives, conjugates, variants, radioisotope-labeled complexes,
and biosimilars thereof.
39. The composition of any one of claims 32-38, further comprising
a phosphoinositide 3-kinase (PI3K) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug
thereof.
40. The composition of claim 39, wherein the PI3K inhibitor is a
PI3K-.delta. inhibitor.
41. The composition of claim 40, wherein the PI3K-.delta. inhibitor
is selected from the group consisting of: ##STR00231## and
pharmaceutically acceptable salts, solvates, hydrates, cocrystals,
and prodrugs thereof.
42. The composition of any one of claims 32-39, for use in the
treatment of cancer, wherein the cancer is a B cell hematological
malignancy, and wherein the B cell hematological malignancy is
selected from the group consisting of chronic lymphocytic leukemia
(CLL), small lymphocytic leukemia (SLL), non-Hodgkin's lymphoma
(NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma
(FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute
lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's
macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, or
myelofibrosis.
43. The composition of any one of claims 32-39, for use in the
treatment of cancer, wherein the cancer is a solid tumor cancer,
and wherein the solid tumor cancer is selected from the group
consisting of bladder cancer, non-small cell lung cancer, cervical
cancer, anal cancer, pancreatic cancer, squamous cell carcinoma
including head and neck cancer, renal cell carcinoma, melanoma,
ovarian cancer, small cell lung cancer, glioblastoma,
gastrointestinal stromal tumor, breast cancer, lung cancer,
colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer,
oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney
cancer, liver cancer, prostate cancer, esophageal cancer,
testicular cancer, gynecological cancer, colon cancer, and brain
cancer.
44. The composition of any one of claims 41-43, further comprising
a therapeutically effective amount of gemcitabine.
45. The composition of any one of claims 41-44, further comprising
a therapeutically effective amount of albumin-bound paclitaxel.
46. A composition comprising (1) a therapeutically effective amount
of a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
and (2) a therapeutically effective amount of a Bruton's tyrosine
kinase (BTK) inhibitor or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof, for use in
treating a solid tumor cancer, wherein the therapeutically
effective amount is effective to inhibit signaling between the
cells of the solid tumor cancer and at least one tumor
microenvironment selected from the group consisting of macrophages,
monocytes, mast cells, helper T cells, cytotoxic T cells,
regulatory T cells, natural killer cells, myeloid-derived
suppressor cells, regulatory B cells, neutrophils, dendritic cells,
and fibroblasts.
47. The composition of claim 46, wherein the solid tumor cancer is
selected from the group consisting of bladder cancer, non-small
cell lung cancer, cervical cancer, anal cancer, pancreatic cancer,
squamous cell carcinoma including head and neck cancer, renal cell
carcinoma, melanoma, ovarian cancer, small cell lung cancer,
glioblastoma, gastrointestinal stromal tumor, breast cancer, lung
cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach
cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer,
kidney cancer, liver cancer, prostate cancer, esophageal cancer,
testicular cancer, gynecological cancer, colon cancer, and brain
cancer.
48. The composition of any one of claims 46-47, wherein the dose is
further effective to increase immune system recognition and
rejection of the solid tumor by the human.
49. The composition of any one of claims 46-48, wherein the BTK
inhibitor is selected from the group consisting of: ##STR00232##
##STR00233## and pharmaceutically-acceptable salts, cocrystals,
hydrates, solvates, and prodrugs thereof.
50. The composition of any one of claims 46-49, wherein the JAK-2
inhibitor is selected from the group consisting of: ##STR00234##
and pharmaceutically-acceptable salts, cocrystals, hydrates,
solvates, and prodrugs thereof.
51. The composition of any one of claims 46-50, further comprising
a therapeutically effective amount of a phosphoinositide 3-kinase
(PI3K) inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof.
52. The composition of claim 51, wherein the PI3K inhibitor is
selected from the group consisting of: ##STR00235## and
pharmaceutically acceptable salts, solvates, hydrates, cocrystals,
or prodrugs thereof.
53. A composition comprising (1) a therapeutically effective amount
of a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
and (2) a therapeutically effective amount of a Bruton's tyrosine
kinase (BTK) inhibitor or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof, wherein the BTK
inhibitor is selected from the group consisting of: ##STR00236##
##STR00237## and pharmaceutically-acceptable salts, cocrystals,
hydrates, solvates, and prodrugs thereof, for use in the treatment
of a cancer in a human intolerant to a bleeding event.
54. The composition of claim 53, wherein the bleeding event is
selected from the group consisting of subdural hematoma,
gastrointestinal bleeding, hematuria, post-procedural hemorrhage,
bruising, petechiae, and combinations thereof.
55. The composition of any one of claims 53-54, wherein the JAK-2
inhibitor is selected from the group consisting of: ##STR00238##
and pharmaceutically-acceptable salts, cocrystals, hydrates,
solvates, and prodrugs thereof.
56. The composition of any one of claims 51-53, further comprising
a therapeutically effective dose of an anticoagulant or
antiplatelet active pharmaceutical ingredient.
57. The composition of claim 56, wherein the anticoagulant or
antiplatelet active pharmaceutical ingredient is selected from the
group consisting of acenocoumarol, anagrelide, anagrelide
hydrochloride, abciximab, aloxiprin, antithrombin, apixaban,
argatroban, aspirin, aspirin with extended-release dipyridamole,
beraprost, betrixaban, bivalirudin, carbasalate calcium,
cilostazol, clopidogrel, clopidogrel bisulfate, cloricromen,
dabigatran etexilate, darexaban, dalteparin, dalteparin sodium,
defibrotide, dicumarol, diphenadione, dipyridamole, ditazole,
desirudin, edoxaban, enoxaparin, enoxaparin sodium, eptifibatide,
fondaparinux, fondaparinux sodium, heparin, heparin sodium, heparin
calcium, idraparinux, idraparinux sodium, iloprost, indobufen,
lepirudin, low molecular weight heparin, melagatran, nadroparin,
otamixaban, parnaparin, phenindione, phenprocoumon, prasugrel,
picotamide, prostacyclin, ramatroban, reviparin, rivaroxaban,
sulodexide, terutroban, terutroban sodium, ticagrelor, ticlopidine,
ticlopidine hydrochloride, tinzaparin, tinzaparin sodium,
tirofiban, tirofiban hydrochloride, treprostinil, treprostinil
sodium, triflusal, vorapaxar, warfarin, warfarin sodium,
ximelagatran, salts thereof, solvates thereof, hydrates thereof,
and combinations thereof.
58. The composition of any one of claims 53-57, wherein the cancer
is selected from the group consisting of bladder cancer, squamous
cell carcinoma including pancreatic ductal adenocarcinoma (PDA),
pancreatic cancer, colon carcinoma, mammary carcinoma, breast
cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung
carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian
cancer, acute myeloid leukemia, thymus cancer, brain cancer,
squamous cell cancer, skin cancer, eye cancer, retinoblastoma,
melanoma, intraocular melanoma, oral cavity and oropharyngeal
cancers, gastric cancer, stomach cancer, cervical cancer, head and
neck cancer, renal cancer, kidney cancer, liver cancer, ovarian
cancer, esophageal cancer, testicular cancer, gynecological cancer,
thyroid cancer, acquired immune deficiency syndrome (AIDS)-related
cancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced
cancer, glioblastoma, esophageal tumors, hematological neoplasms,
non-small-cell lung cancer, chronic myelocytic leukemia, diffuse
large B-cell lymphoma, esophagus tumor, follicle center lymphoma,
head and neck tumor, hepatitis C virus infection, hepatocellular
carcinoma, Hodgkin's disease, metastatic colon cancer, multiple
myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma,
ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung
cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell
acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular
lymphoma, mantle cell lymphoma, and Burkitt's lymphoma.
59. A JAK-2 inhibitor in combination with a BTK inhibitor and/or in
combination with a PI3K inhibitor, for use in treating a
hyperproliferative disorder.
60. A pharmaceutical composition comprising a JAK-2 inhibitor in
combination with a BTK inhibitor and/or in combination with a PI3K
inhibitor, and at least one pharmaceutically acceptable
excipient.
61. The pharmaceutical composition of claim 60, for use in treating
a hyperproliferative disorder.
62. A kit comprising a pharmaceutical composition comprising a
JAK-2 inhibitor, a pharmaceutical composition comprising a PI3K
inhibitor and a pharmaceutical composition comprising a BTK
inhibitor, for co-administration of the JAK-2 inhibitor and the BTK
inhibitor and/or the PI3K inhibitor, either simultaneously or
separately.
63. The kit of claim 62, for use in treating a hyperproliferative
disorder.
64. A JAK-2 inhibitor in combination with a BTK inhibitor for use
in treating a hyperproliferative disorder.
65. A pharmaceutical composition comprising a JAK-2 inhibitor in
combination with a BTK inhibitor and at least one pharmaceutically
acceptable excipient.
66. The pharmaceutical composition of claim 65, for use in treating
a hyperproliferative disorder.
67. A kit comprising a pharmaceutical composition comprising a
JAK-2 inhibitor and a pharmaceutical composition comprising a BTK
inhibitor, for co-administration of the JAK-2 inhibitor and the BTK
inhibitor, either simultaneously or separately.
68. The kit of claim 67, for use in treating a hyperproliferative
disorder.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/013,506 filed on Jun. 17, 2014; U.S. Provisional
Application No. 62/035,785 filed on Aug. 11, 2014; U.S. Provisional
Application No. 62/087,975 filed on Dec. 5, 2014; and U.S.
Provisional Application No. 62/115,493 filed on Feb. 12, 2015, all
of which are herein incorporated by reference in their
entireties.
FIELD OF THE INVENTION
[0002] Therapeutic combinations of a phosphoinositide 3-kinase
(PI3K) inhibitor, a Janus kinase-2 (JAK-2) inhibitor, and a
Bruton's tyrosine kinase (BTK) inhibitor and uses of the
therapeutic combinations are disclosed herein. In particular, a
combination of a BTK inhibitor and a JAK-2 inhibitor and uses
thereof are disclosed.
BACKGROUND OF THE INVENTION
[0003] PI3K kinases are members of a unique and conserved family of
intracellular lipid kinases that phosphorylate the 3'-OH group on
phosphatidylinositols or phosphoinositides. PI3K kinases are key
signaling enzymes that relay signals from cell surface receptors to
downstream effectors. The PI3K family comprises 15 kinases with
distinct substrate specificities, expression patterns, and modes of
regulation. The class I PI3K kinases (p110.alpha., p110.beta.,
p110.delta., and p110.gamma.) are typically activated by tyrosine
kinases or G-protein coupled receptors to generate PIP3, which
engages downstream effectors such as those in the Akt/PDK1 pathway,
mTOR, the Tec family kinases, and the Rho family GTPases.
[0004] The PI3K signaling pathway is known to be one of the most
highly mutated in human cancers. PI3K signaling is also a key
factor in disease states including hematologic malignancies,
non-Hodgkin lymphoma (such as diffuse large B-cell lymphoma),
allergic contact dermatitis, rheumatoid arthritis, osteoarthritis,
inflammatory bowel diseases, chronic obstructive pulmonary
disorder, psoriasis, multiple sclerosis, asthma, disorders related
to diabetic complications, and inflammatory complications of the
cardiovascular system such as acute coronary syndrome. The role of
PI3K in cancer has been discussed, for example, in J. A. Engleman,
Nat. Rev. Cancer 2009, 9, 550-562. The PI3K-.delta. and
PI3K-.gamma. isoforms are preferentially expressed in normal and
malignant leukocytes.
[0005] The delta (.delta.) isoform of class I PI3K (PI3K-.delta.)
is involved in mammalian immune system functions such as T-cell
function, B-cell activation, mast cell activation, dendritic cell
function, and neutrophil activity. Due to its role in immune system
function, PI3K-.delta. is also involved in a number of diseases
related to undesirable immune response such as allergic reactions,
inflammatory diseases, inflammation mediated angiogenesis,
rheumatoid arthritis, auto-immune diseases such as lupus, asthma,
emphysema and other respiratory diseases. The gamma (.gamma.)
isoform of class I PI3K (PI3K-.gamma.) is also involved in immune
system functions and plays a role in leukocyte signaling and has
been implicated in inflammation, rheumatoid arthritis, and
autoimmune diseases such as lupus.
[0006] Downstream mediators of the PI3K signal transduction pathway
include Akt and mammalian target of rapamycin (mTOR). One important
function of Akt is to augment the activity of mTOR, through
phosphorylation of TSC2 and other mechanisms. mTOR is a
serine-threonine kinase related to the lipid kinases of the PI3K
family and has been implicated in a wide range of biological
processes including cell growth, cell proliferation, cell motility
and survival. Disregulation of the mTOR pathway has been reported
in various types of cancer.
[0007] In view of the above, PI3K inhibitors are prime targets for
drug development, as described in J. E. Kurt and I. Ray-Coquard,
Anticancer Res. 2012, 32, 2463-70. Several PI3K inhibitors are
known, including those that are PI3K-.delta. or PI3K-.gamma.
inhibitors and those that are PI3K-.delta.,.gamma. inhibitors.
[0008] Bruton's Tyrosine Kinase (BTK) is a Tec family non-receptor
protein kinase expressed in B cells and myeloid cells. The function
of BTK in signaling pathways activated by the engagement of the B
cell receptor (BCR) and FCER1 on mast cells is well established.
Functional mutations in BTK in humans result in a primary
immunodeficiency disease characterized by a defect in B cell
development with a block between pro- and pre-B cell stages. The
result is an almost complete absence of B lymphocytes, causing a
pronounced reduction of serum immunoglobulin of all classes. These
findings support a key role for BTK in the regulation of the
production of auto-antibodies in autoimmune diseases.
[0009] Other diseases with an important role for dysfunctional B
cells are B cell malignancies. The reported role for BTK in the
regulation of proliferation and apoptosis of B cells indicates the
potential for BTK inhibitors in the treatment of B cell lymphomas.
BTK inhibitors have thus been developed as potential therapies, as
described in O. J. D'Cruz and F. M. Uckun, OncoTargets and Therapy
2013, 6, 161-176.
[0010] Janus kinase-2 (JAK-2) is an enzyme that is a member of the
Janus kinase family of four cytoplasmic tyrosine kinases that also
includes JAK-1, JAK-3, and Tyk2 (tyrosine kinase 2). The Janus
kinase family transduces cytokine-mediated signals as part of the
JAK-STAT signalling pathway (where STAT is an acronym for "signal
transducer and activator of transcription"), as described in K.
Ghoreschi, A. Laurence, J. J. O'Shea, Janus kinases in immune cell
signaling. Immunol. Rev. 2009, 228, 273-287. The JAK-STAT pathway
mediates signalling by cytokines that affects proliferation,
differentiation, and survival in many cell types, and is commonly
expressed in leukocytes. The Janus kinase family of enzymes is
required for signaling by cytokine and growth factor receptors that
lack intrinsic kinase activity. JAK-2 is implicated in signaling
processes by members of the type II cytokine receptor family (such
as interferon receptors), the GM-CSF receptor family (IL-3R, IL-5R
and GM-CSF-R), the gp130 receptor family (e.g. IL-6R), and the
single chain receptors (e.g. Epo-R, Tpo-R, GH-R, PRL-R), as
described in U.S. Patent Application Publication No. 2012/0157500,
the disclosure of which is incorporated herein by reference. JAK-2
signaling is activated downstream from the prolactin receptor.
JAK-2 inhibitors were developed after discovery of an activating
tyrosine kinase mutation (the V617F mutation) in myeloproliferative
cancers and disorders. JAK-2 inhibitors have been developed as
potential therapies for myeloproliferative neoplasms, polycythemia
vera, essential thrombocythemia, and primary myelofibrosis, as
discussed in S. Verstovsek, Therapeutic potential of JAK2
inhibitors, Hematology (American Society of Hematology Education
Book), 2009, 636-642. JAK-2 inhibitorsmay reverse
hyperphosphorylation of JAK-2 and effectively treat
myeloproliferative cancers and disorders.
[0011] In many solid tumors, the supportive microenvironment (which
may make up the majority of the tumor mass) is a dynamic force that
enables tumor survival. The tumor microenvironment is generally
defined as a complex mixture of "cells, soluble factors, signaling
molecules, extracellular matrices, and mechanical cues that promote
neoplastic transformation, support tumor growth and invasion,
protect the tumor from host immunity, foster therapeutic
resistance, and provide niches for dominant metastases to thrive,"
as described in Swartz, et al., Cancer Res., 2012, 72, 2473.
Although tumors express antigens that should be recognized by T
cells, tumor clearance by the immune system is rare because of
immune suppression by the microenvironment. Addressing the tumor
cells themselves with e.g. chemotherapy has also proven to be
insufficient to overcome the protective effects of the
microenvironment. New approaches are thus urgently needed for more
effective treatment of solid tumors that take into account the role
of the microenvironment.
[0012] The CD20 antigen, also called human B-lymphocyte-restricted
differentiation antigen Bp35, or B1), is found on the surface of
normal "pre-B" and mature B lymphocytes, including malignant B
lymphocytes. Nadler, et al., J. Clin. Invest. 1981, 67, 134-40;
Stashenko, et al., J. Immunol. 1980, 139, 3260-85. The CD20 antigen
is a glycosylated integral membrane protein with a molecular weight
of approximately 35 kD. Tedder, et al., Proc. Natl. Acad. Sci. USA,
1988, 85, 208-12. CD20 is also expressed on most B cell
non-Hodgkin's lymphoma cells, but is not found on hematopoietic
stem cells, pro-B cells, normal plasma cells, or other normal
tissues. Anti-CD20 antibodies are currently used as therapies for
many B cell hematological malignancies, including indolent
non-Hodgkin's lymphoma (NHL), aggressive NHL, and chronic
lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL). Lim,
et. al., Haematologica 2010, 95, 135-43; Beers, et. al., Sem.
Hematol. 2010, 47, 107-14; Klein, et al., mAbs 2013, 5, 22-33.
However, there is an urgent need to provide for more efficacious
therapies in many B cell hematological malignancies.
[0013] The present invention provides the unexpected finding that
the combination of a JAK-2 inhibitor and a BTK inhibitor is
synergistically effective in the treatment of any of several types
of cancers such as leukemia, lymphoma, and solid tumor cancers. The
present invention also provides the unexpected finding that a
combination of a PI3K inhibitor, a JAK-2 inhibitor, and a BTK
inhibitor is synergistically effective in the treatment of any of
several types of cancers such as leukemia, lymphoma, and solid
tumor cancers. The present invention further provides the
unexpected finding that the combination of a JAK-2 inhibitor and a
PI3K inhibitor is synergistically effective in the treatment of any
of several types of cancers such as leukemia, lymphoma, and solid
tumor cancers. The present invention further provides the
unexpected finding that the combination of a PI3K inhibitor and a
BTK inhibitor is synergistically effective in the treatment of any
of several types of cancers such as leukemia, lymphoma, and solid
tumor cancers. The present invention further provides the
unexpected finding that the combination of an anti-CD20 antibody
with a BTK inhibitor, a PI3K inhibitor, and/or a JAK-2 inhibitor,
is synergistically effective in the treatment of any of several
types of cancers such as leukemia, lymphoma, and solid tumor
cancers.
SUMMARY OF THE INVENTION
[0014] In an embodiment, the invention provides a method of
treating a hyperproliferative disease, comprising co-administering,
to a mammal in need thereof, therapeutically effective amounts of
(1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. In an embodiment, the JAK-2 inhibitor is
administered to the mammal before administration of the BTK
inhibitor. In an embodiment, the JAK-2 inhibitor is administered to
the mammal simultaneously with the administration of the BTK
inhibitor. In an embodiment, the JAK-2 inhibitor is administered to
the mammal after administration of the BTK inhibitor.
[0015] In an embodiment, the invention provides a method of
treating a hyperproliferative disease, comprising co-administering,
to a mammal in need thereof, therapeutically effective amounts of
(1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, wherein the BTK inhibitor is selected from the
group consisting of:
##STR00001## ##STR00002## [0016] and pharmaceutically-acceptable
salts, cocrystals, hydrates, solvates, and prodrugs thereof.
[0017] In an embodiment, the invention provides a method of
treating a hyperproliferative disease, comprising co-administering,
to a mammal in need thereof, therapeutically effective amounts of
(1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, wherein the BTK inhibitor is selected from the
group consisting of:
##STR00003## [0018] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof.
[0019] In an embodiment, the invention provides a method of
treating a hyperproliferative disease, comprising co-administering,
to a mammal in need thereof, therapeutically effective amounts of
(1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, wherein the JAK-2 inhibitor is selected from the
group consisting of:
##STR00004## [0020] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, or prodrugs thereof.
[0021] In an embodiment, the invention provides a method of
treating a hyperproliferative disease, comprising co-administering,
to a mammal in need thereof, therapeutically effective amounts of
(1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, further comprising the step of administering a
therapeutically effective amount of an anti-CD20 antibody selected
from the group consisting of rituximab, obinutuzumab, ofatumumab,
veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,
conjugates, variants, radioisotope-labeled complexes, biosimilars
thereof, and combinations thereof.
[0022] In an embodiment, the invention provides a method of
treating a hyperproliferative disease, comprising co-administering,
to a mammal in need thereof, therapeutically effective amounts of
(1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, further comprising the step of administering a
phosphoinositide 3-kinase (PI3K) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
In an embodiment, the PI3K inhibitor is a PI3K-.delta. inhibitor.
In an embodiment, the PI3K inhibitor is administered to the mammal
before administration of the BTK inhibitor. In an embodiment,
wherein the PI3K inhibitor is administered to the mammal
concurrently with the administration of the BTK inhibitor. In an
embodiment, the PI3K inhibitor is administered to the mammal after
administration of the BTK inhibitor. In an embodiment, the PI3K
inhibitor is selected from the group consisting of:
##STR00005## [0023] and pharmaceutically acceptable salts,
solvates, hydrates, cocrystals, and prodrugs thereof.
[0024] In an embodiment, the invention provides a method of
treating a hyperproliferative disease, wherein the
hyperproliferative disease is a cancer, comprising
co-administering, to a mammal in need thereof, therapeutically
effective amounts of (1) a Janus kinase-2 (JAK-2) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, and (2) a Bruton's tyrosine kinase (BTK) inhibitor
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug thereof, wherein the cancer is a B cell hematological
malignancy, and wherein the B cell hematological malignancy is
selected from the group consisting of chronic lymphocytic leukemia
(CLL), small lymphocytic leukemia (SLL), non-Hodgkin's lymphoma
(NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma
(FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute
lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's
macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, and
myelofibrosis. In an embodiment, the cancer is a solid tumor
cancer, wherein the solid tumor cancer is selected from the group
consisting of bladder cancer, non-small cell lung cancer, cervical
cancer, anal cancer, pancreatic cancer, squamous cell carcinoma
including head and neck cancer, renal cell carcinoma, melanoma,
ovarian cancer, small cell lung cancer, glioblastoma,
gastrointestinal stromal tumor, breast cancer, lung cancer,
colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer,
oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney
cancer, liver cancer, prostate cancer, esophageal cancer,
testicular cancer, gynecological cancer, colon cancer, and brain
cancer.
[0025] In an embodiment, the invention provides a method of
treating a hyperproliferative disease, comprising co-administering,
to a mammal in need thereof, therapeutically effective amounts of
(1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, further comprising the step of administering a
therapeutically effective amount of gemcitabine or albumin-bound
paclitaxel.
[0026] In an embodiment, the invention provides a method of
treating a cancer in a human comprising the step of
co-administering (1) a therapeutically effective amount of a Janus
kinase-2 (JAK-2) inhibitor or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof, and (2) a
therapeutically effective amount of a Bruton's tyrosine kinase
(BTK) inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein the therapeutically
effective amount is effective to inhibit signaling between the
tumor cells of the cancer and at least one tumor microenvironment
selected from the group consisting of macrophages, monocytes, mast
cells, helper T cells, cytotoxic T cells, regulatory T cells,
natural killer cells, myeloid-derived suppressor cells, regulatory
B cells, neutrophils, dendritic cells, and fibroblasts. In an
embodiment, the cancer is a solid tumor cancer selected from the
group consisting of bladder cancer, non-small cell lung cancer,
cervical cancer, anal cancer, pancreatic cancer, squamous cell
carcinoma including head and neck cancer, renal cell carcinoma,
melanoma, ovarian cancer, small cell lung cancer, glioblastoma,
gastrointestinal stromal tumor, breast cancer, lung cancer,
colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer,
oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney
cancer, liver cancer, prostate cancer, esophageal cancer,
testicular cancer, gynecological cancer, colon cancer, and brain
cancer. In an embodiment, the BTK inhibitor is selected from the
group consisting of:
##STR00006## ##STR00007## [0027] and pharmaceutically-acceptable
salts, cocrystals, hydrates, solvates, or prodrugs thereof. In an
embodiment, the JAK-2 inhibitor is selected from the group
consisting of:
[0027] ##STR00008## [0028] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof.
[0029] In an embodiment, the invention provides a method of
treating a cancer in a human intolerant to a bleeding event
comprising the step of administering (1) a therapeutically
effective amount of a Janus kinase-2 (JAK-2) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, and (2) a therapeutically effective amount of a
Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
wherein the BTK inhibitor is selected from the group consisting
of:
##STR00009## ##STR00010## [0030] and pharmaceutically-acceptable
salts, cocrystals, hydrates, solvates, or prodrugs thereof. In an
embodiment, the bleeding event is selected from the group
consisting of subdural hematoma, gastrointestinal bleeding,
hematuria, post-procedural hemorrhage, bruising, petechiae, and
combinations thereof. In an embodiment, the JAK-2 inhibitor is
selected from the group consisting of:
[0030] ##STR00011## [0031] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof.
[0032] In an embodiment, the invention provides a method of
treating a cancer in a human intolerant to a bleeding event
comprising the step of administering (1) a therapeutically
effective amount of a Janus kinase-2 (JAK-2) inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, and (2) a therapeutically effective amount of a
Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,
further comprising the step of administering a therapeutically
effective amount of an anticoagulant or antiplatelet active
pharmaceutical ingredient. In an embodiment, the anticoagulant or
antiplatelet active pharmaceutical ingredient is selected from the
group consisting of acenocoumarol, anagrelide, anagrelide
hydrochloride, abciximab, aloxiprin, antithrombin, apixaban,
argatroban, aspirin, aspirin with extended-release dipyridamole,
beraprost, betrixaban, bivalirudin, carbasalate calcium,
cilostazol, clopidogrel, clopidogrel bisulfate, cloricromen,
dabigatran etexilate, darexaban, dalteparin, dalteparin sodium,
defibrotide, dicumarol, diphenadione, dipyridamole, ditazole,
desirudin, edoxaban, enoxaparin, enoxaparin sodium, eptifibatide,
fondaparinux, fondaparinux sodium, heparin, heparin sodium, heparin
calcium, idraparinux, idraparinux sodium, iloprost, indobufen,
lepirudin, low molecular weight heparin, melagatran, nadroparin,
otamixaban, parnaparin, phenindione, phenprocoumon, prasugrel,
picotamide, prostacyclin, ramatroban, reviparin, rivaroxaban,
sulodexide, terutroban, terutroban sodium, ticagrelor, ticlopidine,
ticlopidine hydrochloride, tinzaparin, tinzaparin sodium,
tirofiban, tirofiban hydrochloride, treprostinil, treprostinil
sodium, triflusal, vorapaxar, warfarin, warfarin sodium,
ximelagatran, salts thereof, solvates thereof, hydrates thereof,
and combinations thereof. In an embodiment, the cancer is selected
from the group consisting of bladder cancer, squamous cell
carcinoma including head and neck cancer, pancreatic ductal
adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary
carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell
carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal
cancer, ovarian cancer, acute myeloid leukemia, thymus cancer,
brain cancer, squamous cell cancer, skin cancer, eye cancer,
retinoblastoma, melanoma, intraocular melanoma, oral cavity and
oropharyngeal cancers, gastric cancer, stomach cancer, cervical
cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer,
esophageal cancer, testicular cancer, gynecological cancer, thyroid
cancer, acquired immune deficiency syndrome (AIDS)-related cancers
(e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer,
glioblastoma, esophageal tumors, hematological neoplasms,
non-small-cell lung cancer, chronic myelocytic leukemia, diffuse
large B-cell lymphoma, esophagus tumor, follicle center lymphoma,
head and neck tumor, hepatitis C virus infection, hepatocellular
carcinoma, Hodgkin's disease, metastatic colon cancer, multiple
myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma,
ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung
cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell
acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular
lymphoma, mantle cell lymphoma, Burkitt's lymphoma, and
myelofibrosis.
[0033] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; and (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, for use in the treatment of cancer. This
composition is typically a pharmaceutical composition.
[0034] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
This composition is typically a pharmaceutical composition.
[0035] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K-.delta. inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. This composition is typically a pharmaceutical
composition.
[0036] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K-.gamma. inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. This composition is typically a pharmaceutical
composition.
[0037] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K-.gamma.,.delta. inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. This composition is typically a pharmaceutical
composition.
[0038] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, for use in the treatment of cancer; and (3) a
therapeutically effective amount of an anti-CD20 antibody selected
from the group consisting of rituximab, obinutuzumab, ofatumumab,
veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,
conjugates, variants, radioisotope-labeled complexes, and
biosimilars thereof. This composition is typically a pharmaceutical
composition.
[0039] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a PI3K inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
and (4) a therapeutically effective amount of an anti-CD20 antibody
selected from the group consisting of rituximab, obinutuzumab,
ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,
derivatives, conjugates, variants, radioisotope-labeled complexes,
and biosimilars thereof. This composition is typically a
pharmaceutical composition.
[0040] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof any of the
foregoing compositions.
[0041] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof a
therapeutically effective amount of a PI3K inhibitor and a BTK
inhibitor.
[0042] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof a
therapeutically effective amount of a PI3K-.gamma. inhibitor and a
BTK inhibitor.
[0043] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof a
therapeutically effective amount of a PI3K-.delta. inhibitor and a
BTK inhibitor.
[0044] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof a
therapeutically effective amount of a PI3K-.gamma.,.delta.
inhibitor and a BTK inhibitor.
[0045] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof a
therapeutically effective amount of a JAK-2 inhibitor and a BTK
inhibitor.
[0046] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof a
therapeutically effective amount of a PI3K inhibitor, a JAK-2
inhibitor, and a BTK inhibitor.
[0047] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof a
therapeutically effective amount of a PI3K-.gamma. inhibitor, a
JAK-2 inhibitor, and a BTK inhibitor.
[0048] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof a
therapeutically effective amount of a PI3K-.delta. inhibitor, a
JAK-2 inhibitor, and a BTK inhibitor.
[0049] In some embodiments, the invention provides a method of
treating leukemia, lymphoma or a solid tumor cancer in a subject,
comprising co-administering to a mammal in need thereof a
therapeutically effective amount of a PI3K-.gamma.,.delta.
inhibitor, a JAK-2 inhibitor, and a BTK inhibitor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0050] The foregoing summary, as well as the following detailed
description of the invention, will be better understood when read
in conjunction with the appended drawings.
[0051] FIG. 1 illustrates the sensitivity of the TMD8 diffuse large
B cell lymphoma (DLBCL) cell line to individual treatment with the
BTK inhibitor of Formula (XVIII) ("Tested Btk Inhibitor") and the
PI3K inhibitor of Formula (IX) ("Tested PI3K Inhibitor") and
combined treatment with Formula (XVIII) and Formula (IX)
("Btki+PI3Ki") at different concentrations. The concentration of
the first active pharmaceutical ingredient in the combination (the
BTK inhibitor) and the concentration of the individual active
pharmaceutical ingredients is given on the x-axis, and the
concentration of the added PI3K inhibitor in combination with the
BTK inhibitor is given in the legend.
[0052] FIG. 2 illustrates the sensitivity of the MINO mantle cell
lymphoma cell to individual treatment with the BTK inhibitor of
Formula (XVIII) ("Tested Btk Inhibitor") and the PI3K inhibitor of
Formula (IX) ("Tested PI3K Inhibitor") and combined treatment with
Formula (XVIII) and Formula (IX) ("Btki+PI3Ki") at different
concentrations. The concentration of the first active
pharmaceutical ingredient in the combination (the BTK inhibitor)
and the concentration of the individual active pharmaceutical
ingredients is given on the x-axis, and the concentration of the
added PI3K inhibitor in combination with the BTK inhibitor is given
in the legend.
[0053] FIG. 3 illustrates the activity in primary mantle cell
lymphoma cells of Formula (XVIII) ("Tested Btki") and Formula (IX)
("Tested PI3Ki"). The percentage viability of cells ("% viability",
y-axis) is plotted versus the concentration of the active
pharmaceutical ingredient(s). Treatment with single BTK ("Tested
Btki") or PI3K inhibitors ("Tested PI3Ki") is compared to four
combinations of Formula (XVIII) and Formula (IX) ("(10 .mu.M)
Tested PI3Ki", "(1.0 .mu.M) Tested PI3Ki," "(0.1 .mu.M) Tested
PI3Ki," "(0.01 .mu.M) Tested PI3Ki").
[0054] FIG. 4 illustrates the interaction index of the combination
of the BTK inhibitor of Formula (XVIII) and the PI3K inhibitor of
Formula (IX) in primary mantle cell lymphoma cells from different
patients (MCL-1 to MCL-5). Each symbol represents a concentration
from 10 .mu.M to 0.1 nM.
[0055] FIG. 5 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the
PI3K-.delta. inhibitor of Formula (IX) are combined. The tested
cell lines include Maver-1 (B cell lymphoma, mantle), Jeko (B cell
lymphoma, mantle), CCRF (B lymphoblast, acute lymphoblastic
leukemia), and SUP-B15 (B lymphoblast, acute lymphoblastic
leukemia). The dose-effect curves for these cell lines are given in
FIG. 6, FIG. 7, FIG. 8, and FIG. 9. ED25, ED50, ED75, and ED90
refer to the effective doses causing 25%, 50%, 75%, and 90% of the
maximum biological effect (proliferation).
[0056] FIG. 6 illustrates the dose-effect curves obtained for the
tested Maver-1 cell line (B cell lymphoma, mantle) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0057] FIG. 7 illustrates the dose-effect curves obtained for the
tested Jeko cell line (B cell lymphoma, mantle) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0058] FIG. 8 illustrates the dose-effect curves obtained for the
tested CCRF cell line (B lymphoblast, acute lymphoblastic leukemia)
using combined dosing of the BTK inhibitor of Formula (XVIII)
("Inh.1") and the PI3K-.delta. inhibitor of Formula (IX) ("Inh.3").
The y-axis ("Effect") is given in units of Fa (fraction affected)
and the x-axis ("Dose") is given in linear units of .mu.M.
[0059] FIG. 9 illustrates the dose-effect curves obtained for the
tested SUP-B15 cell line (B lymphoblast, acute lymphoblastic
leukemia) using combined dosing of the BTK inhibitor of Formula
(XVIII) ("Inh.1") and the PI3K-.delta. inhibitor of Formula (IX)
("Inh.3"). The y-axis ("Effect") is given in units of Fa (fraction
affected) and the x-axis ("Dose") is given in linear units of
.mu.M.
[0060] FIG. 10 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the
PI3K-.delta. inhibitor of Formula (IX) are combined. The tested
cell lines include Jeko (B cell lymphoma, mantle cell lymphoma) and
SU-DHL-4 (activated B cell like (ABC) diffuse large B cell
lymphoma). The dose-effect curves for these cell lines are given in
FIG. 11 and FIG. 12.
[0061] FIG. 11 illustrates the dose-effect curves obtained for the
tested Jeko cell line (B cell lymphoma, mantle) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0062] FIG. 12 illustrates the dose-effect curves obtained for the
tested SU-DHL-4 cell line (diffuse large B cell lymphoma, ABC)
using combined dosing of the BTK inhibitor of Formula (XVIII)
("Inh.1") and the PI3K-.delta. inhibitor of Formula (IX) ("Inh.3").
The y-axis ("Effect") is given in units of Fa (fraction affected)
and the x-axis ("Dose") is given in linear units of .mu.M.
[0063] FIG. 13 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the
PI3K-.delta. inhibitor of Formula (IX) are combined. The tested
cell lines include CCRF (B lymphoblast, acute lymphoblastic
leukemia), SUP-B15 (B lymphoblast, acute lymphoblastic leukemia),
JVM-2 (prolymphocytic leukemia), Ramos (Burkitt's lymphoma), and
Mino (mantle cell lymphoma). The dose-effect curves for these cell
lines are given in FIG. 14, FIG. 15, FIG. 16, and FIG. 17. No
dose-effect curve is given for Ramos (Burkitt's lymphoma) because
of negative slope.
[0064] FIG. 14 illustrates the dose-effect curves obtained for the
tested CCRF cell line (B lymphoblast, acute lymphoblastic leukemia)
using combined dosing of the BTK inhibitor of Formula (XVIII)
("Inh.1") and the PI3K-.delta. inhibitor of Formula (IX) ("Inh.3").
The y-axis ("Effect") is given in units of Fa (fraction affected)
and the x-axis ("Dose") is given in linear units of .mu.M.
[0065] FIG. 15 illustrates the dose-effect curves obtained for the
tested SUP-B15 cell line (B lymphoblast, acute lymphoblastic
leukemia) using combined dosing of the BTK inhibitor of Formula
(XVIII) ("Inh.1") and the PI3K-.delta. inhibitor of Formula (IX)
("Inh.3"). The y-axis ("Effect") is given in units of Fa (fraction
affected) and the x-axis ("Dose") is given in linear units of
.mu.M.
[0066] FIG. 16 illustrates the dose-effect curves obtained for the
tested JVM-2 cell line (prolymphocytic leukemia) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0067] FIG. 17 illustrates the dose-effect curves obtained for the
tested Mino cell line (mantle cell lymphoma) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0068] FIG. 18 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the
PI3K-.delta. inhibitor of Formula (IX) are combined. The tested
cell lines include Raji (B lymphocyte, Burkitt's lymphoma),
SU-DHL-1 (DLBCL-ABC), and Pfeiffer (follicular lymphoma). The
dose-effect curves for these cell lines are given in FIG. 19, FIG.
20, and FIG. 21.
[0069] FIG. 19 illustrates the dose-effect curves obtained for the
tested Raji cell line (B lymphocyte, Burkitt's lymphoma) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0070] FIG. 20 illustrates the dose-effect curves obtained for the
tested SU-DHL-1 cell line (DLBCL-ABC) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the PI3K-.delta.
inhibitor of Formula (IX) ("Inh.3"). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0071] FIG. 21 illustrates the dose-effect curves obtained for the
tested Pfeiffer cell line (follicular lymphoma) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0072] FIG. 22 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the
PI3K-.delta. inhibitor of Formula (IX) are combined. The tested
cell lines include Ly1 (Germinal center B-cell like diffuse large
B-cell lymphoma, DLBCL-GCB), Ly7 (DLBCL-GCB), Ly19 (DLBCL-GCB),
SU-DHL-2 (Activated B-cell like diffuse large B-cell lymphoma,
DLBCL-ABC), and DOHH2 (follicular lymophoma, FL). The dose-effect
curves for these cell lines are given in FIG. 23, FIG. 24, FIG. 25,
and FIG. 26, except for the Ly19 cell line, which is not graphed
because of a negative slope.
[0073] FIG. 23 illustrates the dose-effect curves obtained for the
tested Ly1 cell line (DLBCL-GCB) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the PI3K-.delta.
inhibitor of Formula (IX) ("Inh.3"). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0074] FIG. 24 illustrates the dose-effect curves obtained for the
tested Ly7 cell line (DLBCL-GCB) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the PI3K-.delta.
inhibitor of Formula (IX) ("Inh.3"). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0075] FIG. 25 illustrates the dose-effect curves obtained for the
tested DOHH2 cell line (FL) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the PI3K-.delta.
inhibitor of Formula (IX) ("Inh.3"). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0076] FIG. 26 illustrates the dose-effect curves obtained for the
tested SU-DHL-2 cell line (DLBCL-ABC) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the PI3K-.delta.
inhibitor of Formula (IX) ("Inh.3"). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0077] FIG. 27 illustrates the synergy observed in certain cell
lines when Formula (XVIII) and Formula (IX) are combined. The
tested cell lines include U937 (histiocytic lymphoma and/or
myeloid), K562 (leukemia, myeloid, and/or chronic myelogenous
leukemia), Daudi (human Burkitt's lymphoma), and SU-DHL-6
(DLBCL-GCB and/or peripheral T-cell lymphoma, PTCL). The
dose-effect curves for these cell lines are given in FIG. 28, FIG.
29, FIG. 30, and FIG. 31.
[0078] FIG. 28 illustrates the dose-effect curves obtained for the
tested U937 cell line (histiocytic lymphoma and/or myeloid) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0079] FIG. 29 illustrates the dose-effect curves obtained for the
tested K562 cell line (leukemia, myeloid, and/or chronic
myelogenous leukemia) using combined dosing of the BTK inhibitor of
Formula (XVIII) ("Inh.1") and the PI3K-.delta. inhibitor of Formula
(IX) ("Inh.3"). The y-axis ("Effect") is given in units of Fa
(fraction affected) and the x-axis ("Dose") is given in linear
units of .mu.M.
[0080] FIG. 30 illustrates the dose-effect curves obtained for the
tested Daudi cell line (human Burkitt's lymphoma) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0081] FIG. 31 illustrates the dose-effect curves obtained for the
tested SU-DHL-6 cell line (DLBCL-GCB and/or PTCL) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0082] FIG. 32 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the
PI3K-.delta. inhibitor of Formula (IX) are combined. The tested
cell lines include SU-DHL-6 (DLBCL-GCB or PTCL), TMD-8 (DLBCL-ABC),
HBL-1 (DLBCL-ABC), and Rec-1 (follicular lymphoma). The dose-effect
curves for these cell lines are given in FIG. 34, FIG. 35, FIG. 36,
and FIG. 37.
[0083] FIG. 33 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the
PI3K-.delta. inhibitor of Formula (IX) are combined. The tested
cell lines include SU-DHL-6 (DLBCL-GCB or PTCL), TMD-8 (DLBCL-ABC),
HBL-1 (DLBCL-ABC), and Rec-1 (follicular lymphoma). All
corresponding CIs are shown for each of the combinations tested as
listed on the x axis.
[0084] FIG. 34 illustrates the dose-effect curves obtained for the
tested SU-DHL-6 cell line (DLBCL-GCB or PTCL) cell line using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0085] FIG. 35 illustrates the dose-effect curves obtained for the
tested TMD-8 cell line (DLBCL-ABC) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the PI3K-.delta.
inhibitor of Formula (IX) ("Inh.3"). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0086] FIG. 36 illustrates the dose-effect curves obtained for the
tested HBL-1 cell line (DLBCL-ABC) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the PI3K-.delta.
inhibitor of Formula (IX) ("Inh.3"). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0087] FIG. 37 illustrates the dose-effect curves obtained for the
tested Rec-1 cell line (follicular lymphoma) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
PI3K-.delta. inhibitor of Formula (IX) ("Inh.3"). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0088] FIG. 38 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula XXX (ruxolitinib) are combined. The tested
cell lines included Maver-1 (B cell lymphoma, mantle), Jeko (B cell
lymphoma, mantle), SUP-B15 (B lymphoblast, acute lymphoblastic
leukemia), and CCRF (B lymphoblast, acute lymphoblastic leukemia).
The dose-effect curves for these cell lines are given in FIG. 39,
FIG. 40, FIG. 41, and FIG. 42.
[0089] FIG. 39 illustrates the dose-effect curves obtained for the
tested Maver-1 cell line (B cell lymphoma, mantle) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0090] FIG. 40 illustrates the dose-effect curves obtained for the
tested Jeko cell line (B cell lymphoma, mantle) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0091] FIG. 41 illustrates the dose-effect curves obtained for the
tested SUP-B15 cell line (B lymphoblast, acute lymphoblastic
leukemia) using combined dosing of the BTK inhibitor of Formula
(XVIII) ("Inh.1") and the JAK-2 inhibitor of Formula XXX ("Inh.2")
(ruxolitinib). The y-axis ("Effect") is given in units of Fa
(fraction affected) and the x-axis ("Dose") is given in linear
units of .mu.M.
[0092] FIG. 42 illustrates the dose-effect curves obtained for the
tested CCRF cell line (B lymphoblast, acute lymphoblastic leukemia)
using combined dosing of the BTK inhibitor of Formula (XVIII)
("Inh.1") and the JAK-2 inhibitor of Formula XXX ("Inh.2")
(ruxolitinib). The y-axis ("Effect") is given in units of Fa
(fraction affected) and the x-axis ("Dose") is given in linear
units of .mu.M.
[0093] FIG. 43 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula XXX (ruxolitinib) are combined. Repeat
experiments for two of the cell lines previously shown in FIG. 38
are shown, including SUP-B15 (B lymphoblast, acute lymphoblastic
leukemia) and CCRF (B lymphoblast, acute lymphoblastic
leukemia).
[0094] FIG. 44 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula XXX (ruxolitinib) are combined. The tested
cell lines included JVM-2 (prolymphocytic leukemia), Raji (B
lymphocyte, Burkitt's lymphoma), Ramos (B lymphocyte, Burkitt's
lymphoma), and Mino (mantle cell lymphoma). The dose-effect curves
for these cell lines are given in FIG. 45, FIG. 46, FIG. 47, and
FIG. 48.
[0095] FIG. 45 illustrates the dose-effect curves obtained for the
tested JVM-2 cell line (prolymphocytic leukemia) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0096] FIG. 46 illustrates the dose-effect curves obtained for the
tested Raji cell line (B lymphocyte, Burkitt's lymphoma) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the JAK-2 inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0097] FIG. 47 illustrates the dose-effect curves obtained for the
tested Ramos cell line (B lymphocyte, Burkitt's lymphoma) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the JAK-2 inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0098] FIG. 48 illustrates the dose-effect curves obtained for the
tested Mino cell line (mantle cell lymphoma) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2
inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0099] FIG. 49 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula XXX (ruxolitinib) are combined. The tested
cell lines included Pfeiffer (follicular lymphoma) and SU-DHL-1
(DLBCL-ABC). The dose-effect curves for these cell lines are given
in FIG. 50 and FIG. 51.
[0100] FIG. 50 illustrates the dose-effect curves obtained for the
tested Pfeiffer cell line (follicular lymphoma) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0101] FIG. 51 illustrates the dose-effect curves obtained for the
tested SU-DHL-1 cell line (follicular lymphoma) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0102] FIG. 52 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula XXX (ruxolitinib) are combined. The tested
cell lines included DOHH2 (follicular lymphoma), SU-DHL-1
(DLBCL-ABC), Ly1 (DLBCL-GCB), Ly7 (DLBCL-GCB), and Ly19
(DLBCL-GCB). The dose-effect curves for these cell lines are given
in FIG. 53, FIG. 54, FIG. 55, and FIG. 56, except for the Ly19 cell
line, which is not graphed because of a negative slope.
[0103] FIG. 53 illustrates the dose-effect curves obtained for the
tested DOHH2 cell line (follicular lymphoma) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2
inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0104] FIG. 54 illustrates the dose-effect curves obtained for the
tested SU-DHL-1 cell line (DLBCL-ABC) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor
of Formula XXX ("Inh.2") (ruxolitinib). The y-axis ("Effect") is
given in units of Fa (fraction affected) and the x-axis ("Dose") is
given in linear units of .mu.M.
[0105] FIG. 55 illustrates the dose-effect curves obtained for the
tested Ly1 cell line (DLBCL-GCB) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor of
Formula XXX ("Inh.2") (ruxolitinib). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0106] FIG. 56 illustrates the dose-effect curves obtained for the
tested Ly7 cell line (DLBCL-GCB) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor of
Formula XXX ("Inh.2") (ruxolitinib). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0107] FIG. 57 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula XXX (ruxolitinib) are combined. The tested
cell lines included U937 (histiocytic lymphoma), Daudi (human
Burkitt's lymphoma), and K562 (leukemia, myeloid, and/or chronic
myelogenous leukemia). The dose-effect curves for these cell lines
are given in FIG. 58, FIG. 59, and FIG. 60.
[0108] FIG. 58 illustrates the dose-effect curves obtained for the
tested U937 cell line (histiocytic lymphoma) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2
inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0109] FIG. 59 illustrates the dose-effect curves obtained for the
tested Daudi cell line (human Burkitt's lymphoma) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0110] FIG. 60 illustrates the dose-effect curves obtained for the
tested K562 cell line (leukemia, myeloid, and/or chronic
myelogenous leukemia) using combined dosing of the BTK inhibitor of
Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor of Formula XXX
("Inh.2") (ruxolitinib). The y-axis ("Effect") is given in units of
Fa (fraction affected) and the x-axis ("Dose") is given in linear
units of .mu.M.
[0111] FIG. 61 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula XXX (ruxolitinib) are combined. The tested
cell lines include SU-DHL-6 (DLBCL-GCB or PTCL), TMD-8 (DLBCL-ABC),
HBL-1 (DLBCL-ABC), and Rec-1 (follicular lymphoma). The dose-effect
curves for these cell lines are given in FIG. 62, FIG. 63, FIG. 64,
and FIG. 65.
[0112] FIG. 62 illustrates the dose-effect curves obtained for the
tested SU-DHL-6 cell line (DLBCL-GCB or PTCL) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2
inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0113] FIG. 63 illustrates the dose-effect curves obtained for the
tested TMD-8 cell line (DLBCL-ABC) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor of
Formula XXX ("Inh.2") (ruxolitinib). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0114] FIG. 64 illustrates the dose-effect curves obtained for the
tested HBL-1 cell line (DLBCL-ABC) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor of
Formula XXX ("Inh.2") (ruxolitinib). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0115] FIG. 65 illustrates the dose-effect curves obtained for the
tested Rec-1 cell line (follicular lymphoma) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2
inhibitor of Formula XXX ("Inh.2") (ruxolitinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0116] FIG. 66 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula LIV (pacritinib) are combined. The tested cell
lines include Mino (mantle cell lymphoma), Maver-1 (B cell
lymphoma, mantle cell lymophoma), Raji (B lymphocyte, Burkitt's
lymphoma), JVM-2 (prolymphocytic leukemia), Daudi (Human Burkitt's
lymphoma), Rec-1 (follicular lymphoma), SUP-B15 (B lymphoblast,
acute lymphoblastic leukemia), CCRF (B lymphoblast, acute
lymphoblastic leukemia), and SU-DHL-4 (DLBCL-ABC). The dose-effect
curves for these cell lines are given in FIG. 67, FIG. 68, FIG. 69,
FIG. 70, FIG. 71, FIG. 72, FIG. 73, FIG. 74, and FIG. 75.
[0117] FIG. 67 illustrates the dose-effect curves obtained for the
tested Mino cell line (mantle cell lymphoma) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2
inhibitor of Formula LIV ("Inh.4") (pacritinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0118] FIG. 68 illustrates the dose-effect curves obtained for the
tested Maver-1 cell line (B cell lymphoma, mantle cell lymophoma)
using combined dosing of the BTK inhibitor of Formula (XVIII)
("Inh.1") and the JAK-2 inhibitor of Formula LIV ("Inh.4")
(pacritinib). The y-axis ("Effect") is given in units of Fa
(fraction affected) and the x-axis ("Dose") is given in linear
units of .mu.M.
[0119] FIG. 69 illustrates the dose-effect curves obtained for the
tested Raji cell line (B lymphocyte, Burkitt's lymphoma) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0120] FIG. 70 illustrates the dose-effect curves obtained for the
tested JVM-2 cell line (prolymphocytic leukemia) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0121] FIG. 71 illustrates the dose-effect curves obtained for the
tested Daudi cell line (Human Burkitt's lymphoma) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0122] FIG. 72 illustrates the dose-effect curves obtained for the
tested Rec-1 cell line (follicular lymphoma) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2
inhibitor of Formula LIV ("Inh.4") (pacritinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0123] FIG. 73 illustrates the dose-effect curves obtained for the
tested SUP-B15 cell line (B lymphoblast, acute lymphoblastic
leukemia) using combined dosing of the BTK inhibitor of Formula
(XVIII) ("Inh.1") and the JAK-2 inhibitor of Formula LIV ("Inh.4")
(pacritinib). The y-axis ("Effect") is given in units of Fa
(fraction affected) and the x-axis ("Dose") is given in linear
units of .mu.M.
[0124] FIG. 74 illustrates the dose-effect curves obtained for the
tested CCRF cell line (B lymphoblast, acute lymphoblastic leukemia)
using combined dosing of the BTK inhibitor of Formula (XVIII)
("Inh.1") and the JAK-2 inhibitor of Formula LIV ("Inh.4")
(pacritinib). The y-axis ("Effect") is given in units of Fa
(fraction affected) and the x-axis ("Dose") is given in linear
units of .mu.M.
[0125] FIG. 75 illustrates the dose-effect curves obtained for the
tested SU-DHL-4 cell line (DLBCL-ABC) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor
of Formula LIV ("Inh.4") (pacritinib). The y-axis ("Effect") is
given in units of Fa (fraction affected) and the x-axis ("Dose") is
given in linear units of .mu.M.
[0126] FIG. 76 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula LIV (pacritinib) are combined. The tested cell
lines include EB3 (B lymphocyte, Burkitt's lymphoma), CA46 (B
lymphocyte, Burkitt's lymphoma), DB (B cell lymphoma, mantle cell
lymphoma), Pfeiffer (follicular lymphoma), DOHH2 (follicular
lymphoma), Namalwa (B lymphocyte, Burkitt's lymphoma), JVM-13 (B
cell lymphoma, mantle cell lymphoma), SU-DHL-1 (DLBCL-ABC), and
SU-DHL-2 (DLBCL-ABC). The dose-effect curves for these cell lines
are given in FIG. 77, FIG. 78, FIG. 79, FIG. 80, FIG. 81, FIG. 82,
FIG. 83, FIG. 84, and FIG. 85.
[0127] FIG. 77 illustrates the dose-effect curves obtained for the
tested EB3 cell line (B lymphocyte, Burkitt's lymphoma) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0128] FIG. 78 illustrates the dose-effect curves obtained for the
tested CA46 cell line (B lymphocyte, Burkitt's lymphoma) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0129] FIG. 79 illustrates the dose-effect curves obtained for the
tested DB cell line (B cell lymphoma, mantle cell lymphoma) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0130] FIG. 80 illustrates the dose-effect curves obtained for the
tested Pfeiffer cell line (follicular lymphoma) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0131] FIG. 81 illustrates the dose-effect curves obtained for the
tested DOHH2 cell line (follicular lymphoma) using combined dosing
of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2
inhibitor of Formula LIV ("Inh.4") (pacritinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0132] FIG. 82 illustrates the dose-effect curves obtained for the
tested Namalwa cell line (B lymphocyte, Burkitt's lymphoma) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0133] FIG. 83 illustrates the dose-effect curves obtained for the
tested JVM-13 cell line (B cell lymphoma, mantle cell lymphoma)
using combined dosing of the BTK inhibitor of Formula (XVIII)
("Inh.1") and the JAK-2 inhibitor of Formula LIV ("Inh.4")
(pacritinib). The y-axis ("Effect") is given in units of Fa
(fraction affected) and the x-axis ("Dose") is given in linear
units of .mu.M.
[0134] FIG. 84 illustrates the dose-effect curves obtained for the
tested SU-DHL-1 cell line (DLBCL-ABC) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor
of Formula LIV ("Inh.4") (pacritinib). The y-axis ("Effect") is
given in units of Fa (fraction affected) and the x-axis ("Dose") is
given in linear units of .mu.M.
[0135] FIG. 85 illustrates the dose-effect curves obtained for the
tested SU-DHL-2 cell line (DLBCL-ABC) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor
of Formula LIV ("Inh.4") (pacritinib). The y-axis ("Effect") is
given in units of Fa (fraction affected) and the x-axis ("Dose") is
given in linear units of .mu.M.
[0136] FIG. 86 illustrates the synergy observed in certain cell
lines when the BTK inhibitor of Formula (XVIII) and the JAK-2
inhibitor of Formula LIV (pacritinib) are combined. The tested cell
lines include Jeko (B cell lymphoma, mantle cell lymphoma), TMD-8
(DLBCL-ABC), SU-DHL6 (DLBCL-GCB), Ramos (human Burkitt's lymphoma),
HBL-1 (DLBCL-ABC), SU-DHL-10 (DLBCL-GCB), OCI-Ly7 (DLBCL-ABC), and
OCI-Ly3 (DLBCL-ABC). The dose-effect curves for these cell lines
are given in FIG. 87, FIG. 88, FIG. 89, FIG. 90, FIG. 91, FIG. 92,
FIG. 93, and FIG. 94.
[0137] FIG. 87 illustrates the dose-effect curves obtained for the
tested Jeko cell line (B cell lymphoma, mantle cell lymphoma) using
combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1")
and the JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The
y-axis ("Effect") is given in units of Fa (fraction affected) and
the x-axis ("Dose") is given in linear units of .mu.M.
[0138] FIG. 88 illustrates the dose-effect curves obtained for the
tested TMD-8 cell line (DLBCL-ABC) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor of
Formula LIV ("Inh.4") (pacritinib). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0139] FIG. 89 illustrates the dose-effect curves obtained for the
tested SU-DHL6 cell line (DLBCL-GCB) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor
of Formula LIV ("Inh.4") (pacritinib). The y-axis ("Effect") is
given in units of Fa (fraction affected) and the x-axis ("Dose") is
given in linear units of .mu.M.
[0140] FIG. 90 illustrates the dose-effect curves obtained for the
tested Ramos cell line (human Burkitt's lymphoma) using combined
dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1") and the
JAK-2 inhibitor of Formula LIV ("Inh.4") (pacritinib). The y-axis
("Effect") is given in units of Fa (fraction affected) and the
x-axis ("Dose") is given in linear units of .mu.M.
[0141] FIG. 91 illustrates the dose-effect curves obtained for the
tested HBL-1 cell line (DLBCL-ABC) using combined dosing of the BTK
inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor of
Formula LIV ("Inh.4") (pacritinib). The y-axis ("Effect") is given
in units of Fa (fraction affected) and the x-axis ("Dose") is given
in linear units of .mu.M.
[0142] FIG. 92 illustrates the dose-effect curves obtained for the
tested SU-DHL-10 cell line (DLBCL-GCB) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor
of Formula LIV ("Inh.4") (pacritinib). The y-axis ("Effect") is
given in units of Fa (fraction affected) and the x-axis ("Dose") is
given in linear units of .mu.M.
[0143] FIG. 93 illustrates the dose-effect curves obtained for the
tested OCI-Ly7 cell line (DLBCL-ABC) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor
of Formula LIV ("Inh.4") (pacritinib). The y-axis ("Effect") is
given in units of Fa (fraction affected) and the x-axis ("Dose") is
given in linear units of .mu.M.
[0144] FIG. 94 illustrates the dose-effect curves obtained for the
tested OCI-Ly3 cell line (DLBCL-ABC) using combined dosing of the
BTK inhibitor of Formula (XVIII) ("Inh.1") and the JAK-2 inhibitor
of Formula LIV ("Inh.4") (pacritinib). The y-axis ("Effect") is
given in units of Fa (fraction affected) and the x-axis ("Dose") is
given in linear units of .mu.M.
[0145] FIG. 95 illustrates tumor growth suppression in an
orthotopic pancreatic cancer model. Mice were dosed orally with 15
mg/kg of the BTK inhibitor of Formula (XVIII), 15 mg/kg of the
phosphoinositide 3-kinase .delta. (PI3K-.delta.) inhibitor of
Formula (IX) (denoted "p110d"), or a combination of both drugs. The
statistical p-value (presumption against null hypothesis) is shown
for each tested single active pharmaceutical ingredient and for the
combination against the vehicle.
[0146] FIG. 96 illustrates the effects of oral dosing with 15 mg/kg
of the BTK inhibitor of Formula (XVIII), 15 mg/kg of the
phosphoinositide 3-kinase .delta. (PI3K-.delta.) inhibitor of
Formula (IX) (denoted "p110d"), or a combination of both inhibitors
on myeloid tumor-associated macrophages (TAMs) in pancreatic
tumor-bearing mice.
[0147] FIG. 97 illustrates the effects of oral dosing with 15 mg/kg
of the BTK inhibitor of Formula (XVIII), 15 mg/kg of the
phosphoinositide 3-kinase .delta. (PI3K-.delta.) inhibitor of
Formula (IX) (denoted "p110d"), or a combination of both inhibitors
on myeloid-derived suppressor cells (MDSCs) in pancreatic
tumor-bearing mice.
[0148] FIG. 98 illustrates the effects of oral dosing with 15 mg/kg
of the BTK inhibitor of Formula (XVIII), 15 mg/kg of the
phosphoinositide 3-kinase .delta. (PI3K-.delta.) inhibitor of
Formula (IX), or a combination of both inhibitors on regulatory T
cells (Tregs) in pancreatic tumor-bearing mice.
[0149] FIG. 99 illustrates the effects of vehicle on flux at two
timepoints, as a control for comparison with FIG. 100, in the ID8
syngeneic orthotropic ovarian cancer model.
[0150] FIG. 100 illustrates the effects of the BTK inhibitor of
Formula (XVIII) on flux at two timepoints, for comparison with FIG.
99, in the ID8 syngeneic orthotropic ovarian cancer model.
[0151] FIG. 101 illustrates tumor response to treatment with the
BTK inhibitor of Formula (XVIII) correlates with a significant
reduction in immunosuppressive tumor associated lymphocytes in
tumor-bearing mice, in comparison to a control (vehicle).
[0152] FIG. 102 illustrates that treatment with the BTK inhibitor
of Formula (XVIII) impairs ID8 ovarian cancer growth in the
syngeneic murine model in comparison to a control (vehicle).
[0153] FIG. 103 illustrates that treatment with the BTK inhibitor
of Formula (XVIII) induces a tumor response that correlates with a
significant reduction in total B cells in tumor-bearing mice.
[0154] FIG. 104 illustrates that treatment with the BTK inhibitor
of Formula (XVIII) induces a tumor response that correlates with a
significant reduction in B regulatory cells (Bregs) in
tumor-bearing mice.
[0155] FIG. 105 illustrates that treatment with the BTK inhibitor
of Formula (XVIII) induces a tumor response that correlates with a
significant reduction in immunosuppressive tumor associated
Tregs.
[0156] FIG. 106 illustrates that treatment with the BTK inhibitor
of Formula (XVIII) induces a tumor response that correlates with an
increase in CD8.sup.+ T cells.
[0157] FIG. 107 illustrates the effects on tumor volume of vehicle
(measured in mm.sup.3) of the BTK inhibitor of Formula (XVIII), a
combination of the BTK inhibitor of Formula (XVIII) and gemcitabine
("Gem"), and gemcitabine alone.
[0158] FIG. 108 illustrates the effects on the amount of CD8.sup.+
T cells, given as a percentage of cells expressing the T cell
receptor (CD3), of the BTK inhibitor of Formula (XVIII), a
combination of the BTK inhibitor of Formula (XVIII) and gemcitabine
("Gem"), and gemcitabine alone.
[0159] FIG. 109 illustrates the effects on the percentage of
CD4.sup.+, CD25.sup.+, and FoxP3.sup.+ T regulatory cells
("Tregs"), given as a percentage of cells expressing the T cell
receptor (CD3), of the BTK inhibitor of Formula (XVIII), a
combination of the BTK inhibitor of Formula (XVIII) and gemcitabine
("Gem"), and gemcitabine alone.
[0160] FIG. 110 illustrates the effects on the percentage of
CD11b.sup.+, LY6C.sup.low, F4/80.sup.+, and Csflr.sup.+
tumor-associated macrophages ("TAMs"), given as a percentage of
cells expressing the T cell receptor (CD3), of the BTK inhibitor of
Formula (XVIII), a combination of the BTK inhibitor of Formula
(XVIII) and gemcitabine ("Gem"), and gemcitabine alone.
[0161] FIG. 111 illustrates the effects on the percentage of
Gr1.sup.+ and LY6C.sup.hi, F4/80.sup.+, and Csflr.sup.+
myeloid-derived suppressor cells ("MDSCs"), given as a percentage
of cells expressing the T cell receptor (CD3), of the BTK inhibitor
of Formula (XVIII), a combination of the BTK inhibitor of Formula
(XVIII) and gemcitabine ("Gem"), and gemcitabine alone.
[0162] FIG. 112 illustrates representative photomicrographs and
comparison of maximal thrombus size in laser injured arterioles of
VWF HA1 mutant mice infused with human platelets in the absence or
presence of various BTK inhibitors. Representative photomicrographs
are given as a comparison of maximal thrombus size in laser-injured
arterioles (1 .mu.M concentrations shown).
[0163] FIG. 113 illustrates a quantitative comparison obtained by
in vivo analysis of early thrombus dynamics in a humanized mouse
laser injury model using three BTK inhibitors at a concentration 1
.mu.M.
[0164] FIG. 114 illustrates the effect of the tested BTK inhibitors
on thrombus formation. The conditions used were N=4, 3 mice per
drug; anti-clotting active pharmaceutical ingredients <2000
.mu.M.sup.2. In studies with ibrutinib, 48% MCL bleeding events
were observed with 560 mg QD and 63% CLL bleeding events were
observed with 420 mg QD, where bleeding event is defined as
subdural hematoma, ecchymoses, GI bleeding, or hematuria.
[0165] FIG. 115 illustrates the effect of the concentration of the
tested BTK inhibitors on thrombus formation.
[0166] FIG. 116 illustrates the results of GPVI platelet
aggregation studies of Formula XVIII (IC50=1.15 .mu.M) and Formula
XX-A (ibrutinib, IC50=0.13 .mu.M).
[0167] FIG. 117 illustrates the results of GPVI platelet
aggregation studies of Formula XVIII and Formula XX-A
(ibrutinib).
[0168] FIG. 118 illustrates the effects of treatment with the
active pharmaceutical ingredient of Formula (XVIII) on tumor
volumes in the KPC pancreatic cancer model.
[0169] FIG. 119 illustrates the results of analysis of tumor
tissues showing that immunosuppressive TAMs
(CD11b.sup.+Ly6ClowF4/80.sup.+Csflr.sup.+) were significantly
reduced with Formula (XVIII) treatment in the KPC pancreatic cancer
model.
[0170] FIG. 120 illustrates the results of analysis of tumor
tissues showing that immunosuppressive MDSCs (Gr1.sup.+Ly6CHi) were
significantly reduced with Formula (XVIII) treatment in the KPC
pancreatic cancer model.
[0171] FIG. 121 illustrates the results of analysis of tumor
tissues showing that immunosuppressive Tregs
(CD4.sup.+CD25.sup.+FoxP3.sup.+) were significantly reduced with
Formula (XVIII) treatment in the KPC pancreatic cancer model.
[0172] FIG. 122 illustrates that the decrease in immunosuppressive
TAMs, MDSCs, and Tregs in the KPC pancreatic cancer model
correlated with a significant increase in CD8.sup.+ cells (FIG.
122).
[0173] FIG. 123 shows in vitro analysis of antibody-dependent NK
cell-mediated IFN-.gamma. release with BTK inhibitors. To evaluate
NK cell function, purified NK cells were isolated from healthy
peripheral blood mononuclear cells and cultured with 0.1 or 1 .mu.M
of ibrutinib or 1 .mu.M of Formula (XVIII) for 4 hours together
with rituximab-coated (10 .mu.g/mL) lymphoma cells, DHL4, or
trastuzumab-coated (10 .mu.g/mL) HER2+ breast cancer cells, HER18,
and supernatant was harvested and analyzed by enzyme-linked
immunosorbent assay for interferon-.gamma. (IFN-.gamma.). All in
vitro experiments were performed in triplicate. Labels are defined
as follows: *p=0.018, **p=0.002, ***p=0.001.
[0174] FIG. 124 shows in vitro analysis of antibody-dependent NK
cell-mediated degranulation with BTK inhibitors. To evaluate NK
cell function, purified NK cells were isolated from healthy
peripheral blood mononuclear cells and cultured with 0.1 or 1 .mu.M
of ibrutinib or 1 .mu.M of Formula (XVIII) for 4 hours together
with rituximab-coated (10 .mu.g/mL) lymphoma cells, DHL4, or
trastuzumab-coated (10 .mu.g/mL) HER2+ breast cancer cells, HER18,
and NK cells isolated and analyzed for degranulation by flow
cytometry for CD107a mobilization. All in vitro experiments were
performed in triplicate. Labels are defined as follows: *p=0.01,
**p=0.002, ***p=0.003, ****p=0.0005.
[0175] FIG. 125 shows that ibrutinib antagonizes antibody-dependent
NK cell-mediated cytotoxicity using the Raji cell line. NK cell
cytotoxicity as percent lysis of tumor cells was analyzed in
chromium release assays with purified NK cells incubated with
chromium-labeled Raji for 4 hours at variable rituximab
concentrations at a constant effector:target ratio of 25:1 and
ibrutinib (1 .mu.M), Formula (XVIII) (1 .mu.M), or other ITK
sparing BTK inhibitors CGI-1746, inhibA (1 .mu.M) and BGB-3111
("inhibB," 1 .mu.M). All in vitro experiments were performed in
triplicate. Labels are defined as follows: *p=0.001.
[0176] FIG. 126 shows that ibrutinib antagonizes antibody-dependent
NK cell-mediated cytotoxicity in primary CLL cells. NK cell
cytotoxicity as percent lysis of tumor cells was analyzed in
chromium release assays with purified NK cells incubated with
chromium-labeled Raji for 4 hours at variable rituximab
concentrations at a constant effector:target ratio of 25:1 and
ibrutinib (1 .mu.M), Formula (XVIII) (1 .mu.M), or other ITK
sparing BTK inhibitors CGI-1746, inhibA (1 .mu.M) and BGB-3111
("inhibB," 1 .mu.M). All in vitro experiments were performed in
triplicate. Labels are defined as follows: *p=0.001.
[0177] FIG. 127 shows a summary of the results given in FIG. 125 at
the highest concentration of rituximab ("Ab") (10 .mu.g/mL).
[0178] FIG. 128 shows NK cell degranulation results. The percentage
of CD56.sup.+/CD107a.sup.+ NK cells observed in whole blood after
pretreatment for 1 hour with the BTK inhibitors and stimulatation
with MEC-1 cells opsonised with obinutuzumab at 1 .mu.g/mL for 4
hours (n=3) is shown.
[0179] FIG. 129 shows the effects of BTK inhibition on generalized
NK cell mediated cytotoxicity.
[0180] FIG. 130 shows that Formula (XVIII) has no adverse effect on
T helper 17 (Th17) cells, which are a subset of T helper cells that
produce interleukin 17 (IL-17), while ibrutinib strongly inhibits
Th17 cells.
[0181] FIG. 131 shows that Formula (XVIII) has no effect on
regulatory T cell (Treg) development, while ibrutinib strongly
increases Treg development.
[0182] FIG. 132 shows that Formula (XVIII) has no effect on
CD8.sup.+ T cell viability, development, while ibrutinib strongly
affects CD8.sup.+ T cell viability at higher doses.
[0183] FIG. 133 illustrates in vivo potency of Formula (XVIII)
(labeled "BTK inhibitor") and ibrutinib. Mice were gavaged at
increasing drug concentration and sacrificed at one time point (3
hours post-dose). BCR is stimulated with IgM and the expression of
activation markers CD69 and CD86 are monitored by flow cytometry to
determine EC.sub.50 values. The results show that Formula (XVIII)
is more potent at inhibiting expression of activation makers than
ibrutinib.
[0184] FIG. 134 illustrates in vitro potency in whole blood of
Formula (XVIII), ibrutinib and CC-292 in inhibition of signals
through the B cell receptor.
[0185] FIG. 135 illustrates EGF receptor phosphorylation in vitro
for Formula (XVIII) and ibrutinib.
[0186] FIG. 136 illustrates the results of the clinical study of
Formula (XVIII) (labeled "BTK inhibitor") in CLL, which are shown
in comparison to the results reported for ibrutinib in FIG. 1A of
Byrd, et al., N. Engl. J. Med. 2013, 369, 32-42. The results show
that the BTK inhibitor of Formula (XVIII) causes a much smaller
relative increase and much faster decrease in absolute lymphocyte
count (ALC) relative to the BTK inhibitor ibrutinib. The sum of the
product of greatest diameters (SPD) also decreases more rapidly
during treatment with the BTK inhibitor than with the BTK inhibitor
ibrutinib.
[0187] FIG. 137 shows overall response data shown by SPD of
enlarged lymph nodes in CLL patients as a function of dose of the
BTK inhibitor of Formula (XVIII).
[0188] FIG. 138 shows a comparison of progression-free survival
(PFS) in CLL patients treated with the BTK inhibitor ibrutinib or
the BTK inhibitor of Formula (XVIII). The ibrutinib data is taken
from Byrd, et al., N. Engl. J. Med. 2013, 369, 32-42. CLL patients
treated with Formula (XVIII) for at least 8 days are included.
[0189] FIG. 139 shows a comparison of number of patients at risk in
CLL patients treated with the BTK inhibitor ibrutinib or the BTK
inhibitor of Formula (XVIII). CLL patients treated with Formula
(XVIII) for at least 8 days are included.
[0190] FIG. 140 shows a comparison of progression-free survival
(PFS) in CLL patients exhibiting the 17p deletion and treated with
the BTK inhibitor ibrutinib or the BTK inhibitor of Formula
(XVIII). The ibrutinib data is taken from Byrd, et al., N. Engl. J.
Med. 2013, 369, 32-42.
[0191] FIG. 141 shows a comparison of number of patients at risk in
CLL patients exhibiting the 17p deletion and treated with the BTK
inhibitor ibrutinib or the BTK inhibitor of Formula (XVIII). The
ibrutinib data is taken from Byrd, et al., N. Engl. J. Med. 2013,
369, 32-42. CLL patients treated with Formula (XVIII) for at least
8 days are included.
[0192] FIG. 142 shows improved BTK target occupancy of Formula
(XVIII) at lower dosage versus ibrutinib in relapsed/refractory CLL
patients.
[0193] FIG. 143 shows the % change in myeloid-derived suppressor
cell (MDSC) (monocytic) level over 28 days versus % ALC change at
Cycle 1, day 28 (C1D28) with trendlines.
[0194] FIG. 144 shows the % change in MDSC (monocytic) level over
28 days versus % ALC change at Cycle 2, day 28 (C2D28) with
trendlines.
[0195] FIG. 145 shows the % change in natural killer (NK) cell
level over 28 days versus % ALC change at Cycle 1, day 28 (C2D28)
with trendlines.
[0196] FIG. 146 shows the % change in NK cell level over 28 days
versus % ALC change at Cycle 2, day 28 (C2D28) with trendlines.
[0197] FIG. 147 compares the % change in MDSC (monocytic) level and
% change in NK cell level over 28 days versus % ALC change with the
% change in level of CD4.sup.+ T cells, CD8.sup.+ T cells,
CD4+/CD8.sup.+ T cell ratio, NK-T cells, PD-1.sup.+ CD4.sup.+ T
cells, and PD-1.sup.+CD8.sup.+ T cells, also versus % ALC change,
at Cycle 1 day 28 (C1D28). Trendlines are shown for % change in
MDSC (monocytic) level and % change in NK cell level.
[0198] FIG. 148 compares the % change in MDSC (monocytic) level and
% change in NK cell level over 28 days versus % ALC change with the
% change in level of CD4.sup.+ T cells, CD8.sup.+ T cells,
CD4+/CD8.sup.+ T cell ratio, NK-T cells, PD-1.sup.+ CD4.sup.+ T
cells, and PD-1.sup.+ CD8.sup.+ T cells, also versus % ALC change,
at Cycle 2 day 28 (C2D28). Trendlines are shown for % change in
MDSC (monocytic) level and % change in NK cell level.
[0199] FIG. 149 shows an update of the data presented in FIG.
136.
[0200] FIG. 150 shows an update of the data presented in FIG. 142,
and includes BID dosing results.
[0201] FIG. 151 illustrates PFS for patients with 1 lip
deletion.
[0202] FIG. 152 illustrates PFS across relapsed/refractory patients
with 1 lip deletion and with 17q deletion and no 1 lip
deletion.
[0203] FIG. 153 illustrates PFS for patients with 17q deletion and
no 1 lip deletion.
[0204] FIG. 154 illustrates updated SPD results from the clinical
study of Formula (XVIII) in relapsed/refractory CLL patients.
[0205] FIG. 155 illustrates that treatment of CLL patients with
Formula (XVIII) resulted in increased apoptosis.
[0206] FIG. 156 illustrates a decrease in CXCL12 levels observed in
patients treated with Formula (XVIII).
[0207] FIG. 157 illustrates a decrease in CCL2 levels observed in
patients treated with Formula (XVIII).
[0208] FIG. 158 illustrates BTK inhibitory effects on MDSCs.
[0209] FIG. 159 illustrates the dosing schema used with the KrasLA2
non-small cell lung cancer (NSCLC) model.
[0210] FIG. 160 illustrates tumor volume variation from baseline as
assessed by microcomputerized tomography (microCT) in the KrasL2
NSCLC model.
[0211] FIG. 161 illustrates TAMs in the KrasL2 NSCLC model, and
indicates that Formula (XVIII) induces a tumor response that
correlates with a significant reduction in immunosuppressive tumor
associated TAMs.
[0212] FIG. 162 illustrates MDSCs in the KrasL2 NSCLC model, and
indicates that Formula (XVIII) induces a tumor response that
correlates with a significant reduction in immunosuppressive tumor
associated MDSCs.
[0213] FIG. 163 illustrates Tregs in the KrasL2 NSCLC model, and
indicates that Formula (XVIII) induces a tumor response that
correlates with a significant reduction in immunosuppressive tumor
associated Tregs.
[0214] FIG. 164 illustrates CD8.sup.+ T cells in the KrasL2 NSCLC
model.
BRIEF DESCRIPTION OF THE SEQUENCE LISTING
[0215] SEQ ID NO:1 is the heavy chain amino acid sequence of the
anti-CD20 monoclonal antibody rituximab.
[0216] SEQ ID NO:2 is the light chain amino acid sequence of the
anti-CD20 monoclonal antibody rituximab.
[0217] SEQ ID NO:3 is the heavy chain amino acid sequence of the
anti-CD20 monoclonal antibody obinutuzumab.
[0218] SEQ ID NO:4 is the light chain amino acid sequence of the
anti-CD20 monoclonal antibody obinutuzumab.
[0219] SEQ ID NO:5 is the variable heavy chain amino acid sequence
of the anti-CD20 monoclonal antibody ofatumumab.
[0220] SEQ ID NO:6 is the variable light chain amino acid sequence
of the anti-CD20 monoclonal antibody ofatumumab.
[0221] SEQ ID NO:7 is the Fab fragment heavy chain amino acid
sequence of the anti-CD20 monoclonal antibody ofatumumab.
[0222] SEQ ID NO:8 is the Fab fragment light chain amino acid
sequence of the anti-CD20 monoclonal antibody ofatumumab.
[0223] SEQ ID NO:9 is the heavy chain amino acid sequence of the
anti-CD20 monoclonal antibody veltuzumab.
[0224] SEQ ID NO:10 is the light chain amino acid sequence of the
anti-CD20 monoclonal antibody veltuzumab.
[0225] SEQ ID NO:11 is the heavy chain amino acid sequence of the
anti-CD20 monoclonal antibody tositumomab.
[0226] SEQ ID NO:12 is the light chain amino acid sequence of the
anti-CD20 monoclonal antibody tositumomab.
[0227] SEQ ID NO:13 is the heavy chain amino acid sequence of the
anti-CD20 monoclonal antibody ibritumomab.
[0228] SEQ ID NO:14 is the light chain amino acid sequence of the
anti-CD20 monoclonal antibody ibritumomab.
DETAILED DESCRIPTION OF THE INVENTION
[0229] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which this invention belongs. All patents
and publications referred to herein are incorporated by reference
in their entireties.
[0230] The terms "co-administration," "co-administering,"
"administered in combination with," "administering in combination
with," "simultaneous," and "concurrent," as used herein, encompass
administration of two or more active pharmaceutical ingredients (in
a preferred embodiment of the present invention, for example, at
least one JAK-2 inhibitor and at least one BTK inhibitor) to a
subject so that both active pharmaceutical ingredients and/or their
metabolites are present in the subject at the same time.
Co-administration includes simultaneous administration in separate
compositions, administration at different times in separate
compositions, or administration in a composition in which two or
more active pharmaceutical ingredients are present. Simultaneous
administration in separate compositions and administration in a
composition in which both agents are present are preferred.
[0231] The term "in vivo" refers to an event that takes place in a
subject's body.
[0232] The term "in vitro" refers to an event that takes places
outside of a subject's body. In vitro assays encompass cell-based
assays in which cells alive or dead are employed and may also
encompass a cell-free assay in which no intact cells are
employed.
[0233] The term "effective amount" or "therapeutically effective
amount" refers to that amount of a compound or combination of
compounds as described herein that is sufficient to effect the
intended application including, but not limited to, disease
treatment. A therapeutically effective amount may vary depending
upon the intended application (in vitro or in vivo), or the subject
and disease condition being treated (e.g., the weight, age and
gender of the subject), the severity of the disease condition, the
manner of administration, etc. which can readily be determined by
one of ordinary skill in the art. The term also applies to a dose
that will induce a particular response in target cells (e.g., the
reduction of platelet adhesion and/or cell migration). The specific
dose will vary depending on the particular compounds chosen, the
dosing regimen to be followed, whether the compound is administered
in combination with other compounds, timing of administration, the
tissue to which it is administered, and the physical delivery
system in which the compound is carried.
[0234] A "therapeutic effect" as that term is used herein,
encompasses a therapeutic benefit and/or a prophylactic benefit. A
prophylactic effect includes delaying or eliminating the appearance
of a disease or condition, delaying or eliminating the onset of
symptoms of a disease or condition, slowing, halting, or reversing
the progression of a disease or condition, or any combination
thereof.
[0235] The terms "QD," "qd," or "q.d." mean quaque die, once a day,
or once daily. The terms "BID," "bid," or "b.i.d." mean bis in die,
twice a day, or twice daily. The terms "TID," "tid," or "t.i.d."
mean ter in die, three times a day, or three times daily. The terms
"QID," "qid," or "q.i.d." mean quater in die, four times a day, or
four times daily.
[0236] The term "pharmaceutically acceptable salt" refers to salts
derived from a variety of organic and inorganic counter ions known
in the art. Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids. Preferred inorganic
acids from which salts can be derived include, for example,
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and
phosphoric acid. Preferred organic acids from which salts can be
derived include, for example, acetic acid, propionic acid, glycolic
acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,
succinic acid, fumaric acid, tartaric acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
Pharmaceutically acceptable base addition salts can be formed with
inorganic and organic bases. Inorganic bases from which salts can
be derived include, for example, sodium, potassium, lithium,
ammonium, calcium, magnesium, iron, zinc, copper, manganese and
aluminum. Organic bases from which salts can be derived include,
for example, primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic
amines and basic ion exchange resins. Specific examples include
isopropylamine, trimethylamine, diethylamine, triethylamine,
tripropylamine, and ethanolamine. In some embodiments, the
pharmaceutically acceptable base addition salt is chosen from
ammonium, potassium, sodium, calcium, and magnesium salts. The term
"cocrystal" refers to a molecular complex derived from a number of
cocrystal formers known in the art. Unlike a salt, a cocrystal
typically does not involve hydrogen transfer between the cocrystal
and the drug, and instead involves intermolecular interactions,
such as hydrogen bonding, aromatic ring stacking, or dispersive
forces, between the cocrystal former and the drug in the crystal
structure.
[0237] "Pharmaceutically acceptable carrier" or "pharmaceutically
acceptable excipient" is intended to include any and all solvents,
dispersion media, coatings, antibacterial and antifungal agents,
isotonic and absorption delaying agents, and inert ingredients. The
use of such pharmaceutically acceptable carriers or
pharmaceutically acceptable excipients for active pharmaceutical
ingredients is well known in the art. Except insofar as any
conventional pharmaceutically acceptable carrier or
pharmaceutically acceptable excipient is incompatible with the
active pharmaceutical ingredient, its use in the therapeutic
compositions of the invention is contemplated. Additional active
pharmaceutical ingredients, such as other drugs, can also be
incorporated into the described compositions and methods.
[0238] "Prodrug" is intended to describe a compound that may be
converted under physiological conditions or by solvolysis to a
biologically active compound described herein. Thus, the term
"prodrug" refers to a precursor of a biologically active compound
that is pharmaceutically acceptable. A prodrug may be inactive when
administered to a subject, but is converted in vivo to an active
compound, for example, by hydrolysis. The prodrug compound often
offers the advantages of solubility, tissue compatibility or
delayed release in a mammalian organism (see, e.g., Bundgaard, H.,
Design of Prodrugs (1985) (Elsevier, Amsterdam). The term "prodrug"
is also intended to include any covalently bonded carriers, which
release the active compound in vivo when administered to a subject.
Prodrugs of an active compound, as described herein, may be
prepared by modifying functional groups present in the active
compound in such a way that the modifications are cleaved, either
in routine manipulation or in vivo, to yield the active parent
compound. Prodrugs include, for example, compounds wherein a
hydroxy, amino or mercapto group is bonded to any group that, when
the prodrug of the active compound is administered to a mammalian
subject, cleaves to form a free hydroxy, free amino or free
mercapto group, respectively. Examples of prodrugs include, but are
not limited to, acetates, formates and benzoate derivatives of an
alcohol, various ester derivatives of a carboxylic acid, or
acetamide, formamide and benzamide derivatives of an amine
functional group in the active compound.
[0239] As used herein, the term "warhead" or "warhead group" refers
to a functional group present on a compound of the present
invention wherein that functional group is capable of covalently
binding to an amino acid residue present in the binding pocket of
the target protein (such as cysteine, lysine, histidine, or other
residues capable of being covalently modified), thereby
irreversibly inhibiting the protein.
[0240] Unless otherwise stated, the chemical structures depicted
herein are intended to include compounds which differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds where one or more hydrogen atoms is replaced by deuterium
or tritium, or wherein one or more carbon atoms is replaced by
.sup.13C- or .sup.14C-enriched carbons, are within the scope of
this invention.
[0241] When ranges are used herein to describe, for example,
physical or chemical properties such as molecular weight or
chemical formulae, all combinations and subcombinations of ranges
and specific embodiments therein are intended to be included. Use
of the term "about" when referring to a number or a numerical range
means that the number or numerical range referred to is an
approximation within experimental variability (or within
statistical experimental error), and thus the number or numerical
range may vary. The variation is typically from 0% to 15%,
preferably from 0% to 10%, more preferably from 0% to 5% of the
stated number or numerical range. The term "comprising" (and
related terms such as "comprise" or "comprises" or "having" or
"including") includes those embodiments such as, for example, an
embodiment of any composition of matter, method or process that
"consist of" or "consist essentially of" the described
features.
[0242] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to ten carbon atoms (e.g.,
(C.sub.1-10)alkyl or C.sub.1-10 alkyl). Whenever it appears herein,
a numerical range such as "1 to 10" refers to each integer in the
given range--e.g., "1 to 10 carbon atoms" means that the alkyl
group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms,
etc., up to and including 10 carbon atoms, although the definition
is also intended to cover the occurrence of the term "alkyl" where
no numerical range is specifically designated. Typical alkyl groups
include, but are in no way limited to, methyl, ethyl, propyl,
isopropyl, n-butyl, isobutyl, sec-butyl isobutyl, tertiary butyl,
pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and
decyl. The alkyl moiety may be attached to the rest of the molecule
by a single bond, such as for example, methyl (Me), ethyl (Et),
n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl,
1,1-dimethylethyl (t-butyl) and 3-methylhexyl. Unless stated
otherwise specifically in the specification, an alkyl group is
optionally substituted by one or more of substituents which are
independently heteroalkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2 where each R.sup.a is independently
hydrogen, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0243] "Alkylaryl" refers to an -(alkyl)aryl radical where aryl and
alkyl are as disclosed herein and which are optionally substituted
by one or more of the substituents described as suitable
substituents for aryl and alkyl respectively.
[0244] "Alkylhetaryl" refers to an -(alkyl)hetaryl radical where
hetaryl and alkyl are as disclosed herein and which are optionally
substituted by one or more of the substituents described as
suitable substituents for aryl and alkyl respectively.
[0245] "Alkylheterocycloalkyl" refers to an -(alkyl) heterocycyl
radical where alkyl and heterocycloalkyl are as disclosed herein
and which are optionally substituted by one or more of the
substituents described as suitable substituents for
heterocycloalkyl and alkyl respectively.
[0246] An "alkene" moiety refers to a group consisting of at least
two carbon atoms and at least one carbon-carbon double bond, and an
"alkyne" moiety refers to a group consisting of at least two carbon
atoms and at least one carbon-carbon triple bond. The alkyl moiety,
whether saturated or unsaturated, may be branched, straight chain,
or cyclic.
[0247] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one double bond, and having from two to ten
carbon atoms (i.e., (C.sub.2-10)alkenyl or C.sub.2-10 alkenyl).
Whenever it appears herein, a numerical range such as "2 to 10"
refers to each integer in the given range--e.g., "2 to 10 carbon
atoms" means that the alkenyl group may consist of 2 carbon atoms,
3 carbon atoms, etc., up to and including 10 carbon atoms. The
alkenyl moiety may be attached to the rest of the molecule by a
single bond, such as for example, ethenyl (i.e., vinyl),
prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and
penta-1,4-dienyl. Unless stated otherwise specifically in the
specification, an alkenyl group is optionally substituted by one or
more substituents which are independently alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0248] "Alkenyl-cycloalkyl" refers to an -(alkenyl)cycloalkyl
radical where alkenyl and cycloalkyl are as disclosed herein and
which are optionally substituted by one or more of the substituents
described as suitable substituents for alkenyl and cycloalkyl
respectively.
[0249] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one triple bond, having from two to ten carbon
atoms (i.e., (C.sub.2-10)alkynyl or C.sub.2-10 alkynyl). Whenever
it appears herein, a numerical range such as "2 to 10" refers to
each integer in the given range--e.g., "2 to 10 carbon atoms" means
that the alkynyl group may consist of 2 carbon atoms, 3 carbon
atoms, etc., up to and including 10 carbon atoms. The alkynyl may
be attached to the rest of the molecule by a single bond, for
example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless
stated otherwise specifically in the specification, an alkynyl
group is optionally substituted by one or more substituents which
independently are: alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0250] "Alkynyl-cycloalkyl" refers to an -(alkynyl)cycloalkyl
radical where alkynyl and cycloalkyl are as disclosed herein and
which are optionally substituted by one or more of the substituents
described as suitable substituents for alkynyl and cycloalkyl
respectively.
[0251] "Carboxaldehyde" refers to a --(C.dbd.O)H radical.
[0252] "Carboxyl" refers to a --(C.dbd.O)OH radical.
[0253] "Cyano" refers to a --CN radical.
[0254] "Cycloalkyl" refers to a monocyclic or polycyclic radical
that contains only carbon and hydrogen, and may be saturated, or
partially unsaturated. Cycloalkyl groups include groups having from
3 to 10 ring atoms (i.e. (C.sub.3-10)cycloalkyl or C.sub.3-10
cycloalkyl). Whenever it appears herein, a numerical range such as
"3 to 10" refers to each integer in the given range--e.g., "3 to 10
carbon atoms" means that the cycloalkyl group may consist of 3
carbon atoms, etc., up to and including 10 carbon atoms.
Illustrative examples of cycloalkyl groups include, but are not
limited to the following moieties: cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless
stated otherwise specifically in the specification, a cycloalkyl
group is optionally substituted by one or more substituents which
independently are: alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0255] "Cycloalkyl-alkenyl" refers to a -(cycloalkyl)alkenyl
radical where cycloalkyl and alkenyl are as disclosed herein and
which are optionally substituted by one or more of the substituents
described as suitable substituents for cycloalkyl and alkenyl,
respectively.
[0256] "Cycloalkyl-heterocycloalkyl" refers to a
-(cycloalkyl)heterocycloalkyl radical where cycloalkyl and
heterocycloalkyl are as disclosed herein and which are optionally
substituted by one or more of the substituents described as
suitable substituents for cycloalkyl and heterocycloalkyl,
respectively.
[0257] "Cycloalkyl-heteroaryl" refers to a -(cycloalkyl)heteroaryl
radical where cycloalkyl and heteroaryl are as disclosed herein and
which are optionally substituted by one or more of the substituents
described as suitable substituents for cycloalkyl and heteroaryl,
respectively.
[0258] The term "alkoxy" refers to the group --O-alkyl, including
from 1 to 8 carbon atoms of a straight, branched, cyclic
configuration and combinations thereof attached to the parent
structure through an oxygen. Examples include, but are not limited
to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and
cyclohexyloxy. "Lower alkoxy" refers to alkoxy groups containing
one to six carbons.
[0259] The term "substituted alkoxy" refers to alkoxy wherein the
alkyl constituent is substituted (i.e., --O-(substituted alkyl)).
Unless stated otherwise specifically in the specification, the
alkyl moiety of an alkoxy group is optionally substituted by one or
more substituents which independently are: alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0260] The term "alkoxycarbonyl" refers to a group of the formula
(alkoxy)(C.dbd.O)-- attached through the carbonyl carbon wherein
the alkoxy group has the indicated number of carbon atoms. Thus a
(C.sub.1-6)alkoxycarbonyl group is an alkoxy group having from 1 to
6 carbon atoms attached through its oxygen to a carbonyl linker.
"Lower alkoxycarbonyl" refers to an alkoxycarbonyl group wherein
the alkoxy group is a lower alkoxy group.
[0261] The term "substituted alkoxycarbonyl" refers to the group
(substituted alkyl)-O--C(O)-- wherein the group is attached to the
parent structure through the carbonyl functionality. Unless stated
otherwise specifically in the specification, the alkyl moiety of an
alkoxycarbonyl group is optionally substituted by one or more
substituents which independently are: alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0262] "Acyl" refers to the groups (alkyl)-C(O)--, (aryl)-C(O)--,
(heteroaryl)-C(O)--, (heteroalkyl)-C(O)-- and
(heterocycloalkyl)-C(O)--, wherein the group is attached to the
parent structure through the carbonyl functionality. If the R
radical is heteroaryl or heterocycloalkyl, the hetero ring or chain
atoms contribute to the total number of chain or ring atoms. Unless
stated otherwise specifically in the specification, the alkyl, aryl
or heteroaryl moiety of the acyl group is optionally substituted by
one or more substituents which are independently alkyl,
heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0263] "Acyloxy" refers to a R(C.dbd.O)O-- radical wherein R is
alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl, which are
as described herein. If the R radical is heteroaryl or
heterocycloalkyl, the hetero ring or chain atoms contribute to the
total number of chain or ring atoms. Unless stated otherwise
specifically in the specification, the R of an acyloxy group is
optionally substituted by one or more substituents which
independently are: alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0264] "Amino" or "amine" refers to a --N(R.sup.a).sub.2 radical
group, where each R.sup.a is independently hydrogen, alkyl,
fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,
heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl, unless stated otherwise specifically in the
specification. When a --N(R.sup.a).sub.2 group has two R.sup.a
substituents other than hydrogen, they can be combined with the
nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example,
--N(R.sup.a).sub.2 is intended to include, but is not limited to,
1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise
specifically in the specification, an amino group is optionally
substituted by one or more substituents which independently are:
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0265] The term "substituted amino" also refers to N-oxides of the
groups --NHR.sup.d, and NR.sup.dR.sup.d each as described above.
N-oxides can be prepared by treatment of the corresponding amino
group with, for example, hydrogen peroxide or m-chloroperoxybenzoic
acid.
[0266] "Amide" or "amido" refers to a chemical moiety with formula
--C(O)N(R).sub.2 or --NHC(O)R, where R is selected from the group
consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded
through a ring carbon) and heteroalicyclic (bonded through a ring
carbon), each of which moiety may itself be optionally substituted.
The R.sub.2 of --N(R).sub.2 of the amide may optionally be taken
together with the nitrogen to which it is attached to form a 4-,
5-, 6- or 7-membered ring. Unless stated otherwise specifically in
the specification, an amido group is optionally substituted
independently by one or more of the substituents as described
herein for alkyl, cycloalkyl, aryl, heteroaryl, or
heterocycloalkyl. An amide may be an amino acid or a peptide
molecule attached to a compound disclosed herein, thereby forming a
prodrug. The procedures and specific groups to make such amides are
known to those of skill in the art and can readily be found in
seminal sources such as Greene and Wuts, Protective Groups in
Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York,
N.Y., 1999, which is incorporated herein by reference in its
entirety.
[0267] "Aromatic" or "aryl" or "Ar" refers to an aromatic radical
with six to ten ring atoms (e.g., C.sub.6-C.sub.10 aromatic or
C.sub.6-C.sub.10 aryl) which has at least one ring having a
conjugated pi electron system which is carbocyclic (e.g., phenyl,
fluorenyl, and naphthyl). Bivalent radicals formed from substituted
benzene derivatives and having the free valences at ring atoms are
named as substituted phenylene radicals. Bivalent radicals derived
from univalent polycyclic hydrocarbon radicals whose names end in
"-yl" by removal of one hydrogen atom from the carbon atom with the
free valence are named by adding "-idene" to the name of the
corresponding univalent radical, e.g., a naphthyl group with two
points of attachment is termed naphthylidene. Whenever it appears
herein, a numerical range such as "6 to 10" refers to each integer
in the given range; e.g., "6 to 10 ring atoms" means that the aryl
group may consist of 6 ring atoms, 7 ring atoms, etc., up to and
including 10 ring atoms. The term includes monocyclic or fused-ring
polycyclic (i.e., rings which share adjacent pairs of ring atoms)
groups. Unless stated otherwise specifically in the specification,
an aryl moiety is optionally substituted by one or more
substituents which are independently alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0268] "Aralkyl" or "arylalkyl" refers to an (aryl)alkyl-radical
where aryl and alkyl are as disclosed herein and which are
optionally substituted by one or more of the substituents described
as suitable substituents for aryl and alkyl respectively.
[0269] "Ester" refers to a chemical radical of formula --COOR,
where R is selected from the group consisting of alkyl, cycloalkyl,
aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic
(bonded through a ring carbon). The procedures and specific groups
to make esters are known to those of skill in the art and can
readily be found in seminal sources such as Greene and Wuts,
Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley
& Sons, New York, N.Y., 1999, which is incorporated herein by
reference in its entirety. Unless stated otherwise specifically in
the specification, an ester group is optionally substituted by one
or more substituents which independently are: alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0270] "Fluoroalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more fluoro radicals, as defined
above, for example, trifluoromethyl, difluoromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
The alkyl part of the fluoroalkyl radical may be optionally
substituted as defined above for an alkyl group.
[0271] "Halo," "halide," or, alternatively, "halogen" is intended
to mean fluoro, chloro, bromo or iodo. The terms "haloalkyl,"
"haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl,
alkenyl, alkynyl and alkoxy structures that are substituted with
one or more halo groups or with combinations thereof. For example,
the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and
haloalkoxy groups, respectively, in which the halo is fluorine.
[0272] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to
optionally substituted alkyl, alkenyl and alkynyl radicals and
which have one or more skeletal chain atoms selected from an atom
other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or
combinations thereof. A numerical range may be given--e.g.,
C.sub.1-C.sub.4 heteroalkyl which refers to the chain length in
total, which in this example is 4 atoms long. A heteroalkyl group
may be substituted with one or more substituents which
independently are: alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0273] "Heteroalkylaryl" refers to an -(heteroalkyl)aryl radical
where heteroalkyl and aryl are as disclosed herein and which are
optionally substituted by one or more of the substituents described
as suitable substituents for heteroalkyl and aryl,
respectively.
[0274] "Heteroalkylheteroaryl" refers to an
-(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl
are as disclosed herein and which are optionally substituted by one
or more of the substituents described as suitable substituents for
heteroalkyl and heteroaryl, respectively.
[0275] "Heteroalkylheterocycloalkyl" refers to an
-(heteroalkyl)heterocycloalkyl radical where heteroalkyl and
heterocycloalkyl are as disclosed herein and which are optionally
substituted by one or more of the substituents described as
suitable substituents for heteroalkyl and heterocycloalkyl,
respectively.
[0276] "Heteroalkylcycloalkyl" refers to an
-(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl
are as disclosed herein and which are optionally substituted by one
or more of the substituents described as suitable substituents for
heteroalkyl and cycloalkyl, respectively.
[0277] "Heteroaryl" or "heteroaromatic" or "HetAr" refers to a 5-
to 18-membered aromatic radical (e.g., C.sub.5-C.sub.13 heteroaryl)
that includes one or more ring heteroatoms selected from nitrogen,
oxygen and sulfur, and which may be a monocyclic, bicyclic,
tricyclic or tetracyclic ring system. Whenever it appears herein, a
numerical range such as "5 to 18" refers to each integer in the
given range--e.g., "5 to 18 ring atoms" means that the heteroaryl
group may consist of 5 ring atoms, 6 ring atoms, etc., up to and
including 18 ring atoms. Bivalent radicals derived from univalent
heteroaryl radicals whose names end in "-yl" by removal of one
hydrogen atom from the atom with the free valence are named by
adding "-idene" to the name of the corresponding univalent
radical--e.g., a pyridyl group with two points of attachment is a
pyridylidene. A N-containing "heteroaromatic" or "heteroaryl"
moiety refers to an aromatic group in which at least one of the
skeletal atoms of the ring is a nitrogen atom. The polycyclic
heteroaryl group may be fused or non-fused. The heteroatom(s) in
the heteroaryl radical are optionally oxidized. One or more
nitrogen atoms, if present, are optionally quaternized. The
heteroaryl may be attached to the rest of the molecule through any
atom of the ring(s). Examples of heteroaryls include, but are not
limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl,
1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl,
benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl,
benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl,
benzothiazolyl, benzothienyl(benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,
cyclopenta[d]pyrimidinyl,
6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl,
furo[3,2-c]pyridinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl,
imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl,
thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl,
thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,
thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless
stated otherwise specifically in the specification, a heteroaryl
moiety is optionally substituted by one or more substituents which
are independently: alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0278] Substituted heteroaryl also includes ring systems
substituted with one or more oxide (--O--) substituents, such as,
for example, pyridinyl N-oxides.
[0279] "Heteroarylalkyl" refers to a moiety having an aryl moiety,
as described herein, connected to an alkylene moiety, as described
herein, wherein the connection to the remainder of the molecule is
through the alkylene group.
[0280] "Heterocycloalkyl" refers to a stable 3- to 18-membered
non-aromatic ring radical that comprises two to twelve carbon atoms
and from one to six heteroatoms selected from nitrogen, oxygen and
sulfur. Whenever it appears herein, a numerical range such as "3 to
18" refers to each integer in the given range--e.g., "3 to 18 ring
atoms" means that the heterocycloalkyl group may consist of 3 ring
atoms, 4 ring atoms, etc., up to and including 18 ring atoms.
Unless stated otherwise specifically in the specification, the
heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, which may include fused or bridged ring
systems. The heteroatoms in the heterocycloalkyl radical may be
optionally oxidized. One or more nitrogen atoms, if present, are
optionally quaternized. The heterocycloalkyl radical is partially
or fully saturated. The heterocycloalkyl may be attached to the
rest of the molecule through any atom of the ring(s). Examples of
such heterocycloalkyl radicals include, but are not limited to,
dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,
imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,
morpholinyl, octahydroindolyl, octahydroisoindolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl,
pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,
tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,
thiamorpholinyl, 1-oxo-thiomorpholinyl, and
1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in
the specification, a heterocycloalkyl moiety is optionally
substituted by one or more substituents which independently are:
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
nitro, oxo, thioxo, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0281] "Heterocycloalkyl" also includes bicyclic ring systems
wherein one non-aromatic ring, usually with 3 to 7 ring atoms,
contains at least 2 carbon atoms in addition to 1-3 heteroatoms
independently selected from oxygen, sulfur, and nitrogen, as well
as combinations comprising at least one of the foregoing
heteroatoms; and the other ring, usually with 3 to 7 ring atoms,
optionally contains 1-3 heteroatoms independently selected from
oxygen, sulfur, and nitrogen and is not aromatic.
[0282] "Nitro" refers to the --NO.sub.2 radical.
[0283] "Oxa" refers to the --O-- radical.
[0284] "Oxo" refers to the .dbd.O radical.
[0285] "Isomers" are different compounds that have the same
molecular formula.
[0286] "Stereoisomers" are isomers that differ only in the way the
atoms are arranged in space--i.e., having a different
stereochemical configuration. "Enantiomers" are a pair of
stereoisomers that are non-superimposable mirror images of each
other. A 1:1 mixture of a pair of enantiomers is a "racemic"
mixture. The term "(.+-.)" is used to designate a racemic mixture
where appropriate. "Diastereoisomers" are stereoisomers that have
at least two asymmetric atoms, but which are not mirror-images of
each other. The absolute stereochemistry is specified according to
the Cahn-Ingold-Prelog R--S system. When a compound is a pure
enantiomer the stereochemistry at each chiral carbon can be
specified by either (R) or (S). Resolved compounds whose absolute
configuration is unknown can be designated (+) or (-) depending on
the direction (dextro- or levorotatory) which they rotate plane
polarized light at the wavelength of the sodium D line. Certain of
the compounds described herein contain one or more asymmetric
centers and can thus give rise to enantiomers, diastereomers, and
other stereoisomeric forms that can be defined, in terms of
absolute stereochemistry, as (R) or (S). The present chemical
entities, pharmaceutical compositions and methods are meant to
include all such possible isomers, including racemic mixtures,
optically pure forms and intermediate mixtures. Optically active
(R)- and (S)-isomers can be prepared using chiral synthons or
chiral reagents, or resolved using conventional techniques. When
the compounds described herein contain olefinic double bonds or
other centers of geometric asymmetry, and unless specified
otherwise, it is intended that the compounds include both E and Z
geometric isomers.
[0287] "Enantiomeric purity" as used herein refers to the relative
amounts, expressed as a percentage, of the presence of a specific
enantiomer relative to the other enantiomer. For example, if a
compound, which may potentially have an (R)- or an (S)-isomeric
configuration, is present as a racemic mixture, the enantiomeric
purity is about 50% with respect to either the (R)- or (S)-isomer.
If that compound has one isomeric form predominant over the other,
for example, 80% (S)-isomer and 20% (R)-isomer, the enantiomeric
purity of the compound with respect to the (S)-isomeric form is
80%. The enantiomeric purity of a compound can be determined in a
number of ways known in the art, including but not limited to
chromatography using a chiral support, polarimetric measurement of
the rotation of polarized light, nuclear magnetic resonance
spectroscopy using chiral shift reagents which include but are not
limited to lanthanide containing chiral complexes or Pirkle's
reagents, or derivatization of a compounds using a chiral compound
such as Mosher's acid followed by chromatography or nuclear
magnetic resonance spectroscopy.
[0288] In preferred embodiments, the enantiomerically enriched
composition has a higher potency with respect to therapeutic
utility per unit mass than does the racemic mixture of that
composition. Enantiomers can be isolated from mixtures by methods
known to those skilled in the art, including chiral high pressure
liquid chromatography (HPLC) and the formation and crystallization
of chiral salts; or preferred enantiomers can be prepared by
asymmetric syntheses. See, for example, Jacques, et al.,
Enantiomers, Racemates and Resolutions, Wiley Interscience, New
York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds,
McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen,
Stereochemistry of Organic Compounds, Wiley-Interscience, New York
(1994).
[0289] The terms "enantiomerically enriched" and "non-racemic," as
used herein, refer to compositions in which the percent by weight
of one enantiomer is greater than the amount of that one enantiomer
in a control mixture of the racemic composition (e.g., greater than
1:1 by weight). For example, an enantiomerically enriched
preparation of the (S)-enantiomer, means a preparation of the
compound having greater than 50% by weight of the (S)-enantiomer
relative to the (R)-enantiomer, such as at least 75% by weight, or
such as at least 80% by weight. In some embodiments, the enrichment
can be significantly greater than 80% by weight, providing a
"substantially enantiomerically enriched" or a "substantially
non-racemic" preparation, which refers to preparations of
compositions which have at least 85% by weight of one enantiomer
relative to other enantiomer, such as at least 90% by weight, or
such as at least 95% by weight. The terms "enantiomerically pure"
or "substantially enantiomerically pure" refers to a composition
that comprises at least 98% of a single enantiomer and less than 2%
of the opposite enantiomer.
[0290] "Moiety" refers to a specific segment or functional group of
a molecule. Chemical moieties are often recognized chemical
entities embedded in or appended to a molecule.
[0291] "Tautomers" are structurally distinct isomers that
interconvert by tautomerization. "Tautomerization" is a form of
isomerization and includes prototropic or proton-shift
tautomerization, which is considered a subset of acid-base
chemistry. "Prototropic tautomerization" or "proton-shift
tautomerization" involves the migration of a proton accompanied by
changes in bond order, often the interchange of a single bond with
an adjacent double bond. Where tautomerization is possible (e.g.,
in solution), a chemical equilibrium of tautomers can be reached.
An example of tautomerization is keto-enol tautomerization. A
specific example of keto-enol tautomerization is the
interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one
tautomers. Another example of tautomerization is phenol-keto
tautomerization. A specific example of phenol-keto tautomerization
is the interconversion of pyridin-4-ol and pyridin-4(1H)-one
tautomers.
[0292] A "leaving group or atom" is any group or atom that will,
under selected reaction conditions, cleave from the starting
material, thus promoting reaction at a specified site. Examples of
such groups, unless otherwise specified, include halogen atoms and
mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.
[0293] "Protecting group" is intended to mean a group that
selectively blocks one or more reactive sites in a multifunctional
compound such that a chemical reaction can be carried out
selectively on another unprotected reactive site and the group can
then be readily removed or deprotected after the selective reaction
is complete. A variety of protecting groups are disclosed, for
example, in T. H. Greene and P. G. M. Wuts, Protective Groups in
Organic Synthesis, Third Edition, John Wiley & Sons, New York
(1999).
[0294] "Solvate" refers to a compound in physical association with
one or more molecules of a pharmaceutically acceptable solvent.
[0295] "Substituted" means that the referenced group may have
attached one or more additional groups, radicals or moieties
individually and independently selected from, for example, acyl,
alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate,
carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy,
mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester,
thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo,
perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl,
sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono-
and di-substituted amino groups, and protected derivatives thereof.
The substituents themselves may be substituted, for example, a
cycloalkyl substituent may itself have a halide substituent at one
or more of its ring carbons. The term "optionally substituted"
means optional substitution with the specified groups, radicals or
moieties.
[0296] "Sulfanyl" refers to groups that include --S-(optionally
substituted alkyl), --S-(optionally substituted aryl),
--S-(optionally substituted heteroaryl) and --S-(optionally
substituted heterocycloalkyl).
[0297] "Sulfinyl" refers to groups that include --S(O)--H,
--S(O)-(optionally substituted alkyl), --S(O)-(optionally
substituted amino), --S(O)-(optionally substituted aryl),
--S(O)-(optionally substituted heteroaryl) and --S(O)-(optionally
substituted heterocycloalkyl).
[0298] "Sulfonyl" refers to groups that include --S(O.sub.2)--H,
--S(O.sub.2)-(optionally substituted alkyl),
--S(O.sub.2)-(optionally substituted amino),
--S(O.sub.2)-(optionally substituted aryl),
--S(O.sub.2)-(optionally substituted heteroaryl), and
--S(O.sub.2)-(optionally substituted heterocycloalkyl).
[0299] "Sulfonamidyl" or "sulfonamido" refers to a
--S(.dbd.O).sub.2--NRR radical, where each R is selected
independently from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
heteroalicyclic (bonded through a ring carbon). The R groups in
--NRR of the --S(.dbd.O).sub.2--NRR radical may be taken together
with the nitrogen to which it is attached to form a 4-, 5-, 6- or
7-membered ring. A sulfonamido group is optionally substituted by
one or more of the substituents described for alkyl, cycloalkyl,
aryl, heteroaryl, respectively.
[0300] "Sulfoxyl" refers to a --S(.dbd.O).sub.2OH radical.
[0301] "Sulfonate" refers to a --S(.dbd.O).sub.2--OR radical, where
R is selected from the group consisting of alkyl, cycloalkyl, aryl,
heteroaryl (bonded through a ring carbon) and heteroalicyclic
(bonded through a ring carbon). A sulfonate group is optionally
substituted on R by one or more of the substituents described for
alkyl, cycloalkyl, aryl, heteroaryl, respectively.
[0302] Compounds of the invention also include crystalline and
amorphous forms of those compounds, including, for example,
polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated
polymorphs (including anhydrates), conformational polymorphs, and
amorphous forms of the compounds, as well as mixtures thereof.
"Crystalline form" and "polymorph" are intended to include all
crystalline and amorphous forms of the compound, including, for
example, polymorphs, pseudopolymorphs, solvates, hydrates,
unsolvated polymorphs (including anhydrates), conformational
polymorphs, and amorphous forms, as well as mixtures thereof,
unless a particular crystalline or amorphous form is referred
to.
Co-Administration of Compounds
[0303] An aspect of the invention is a composition, such as a
pharmaceutical composition, comprising a combination of a PI3K
inhibitor, a BTK inhibitor, and/or a JAK-2 inhibitor. Preferably,
said composition comprises a combination of a BTK inhibitor and a
JAK-2 inhibitor.
[0304] Another aspect is a kit containing any two or all three of a
PI3K inhibitor, a BTK inhibitor, and a JAK-2 inhibitor, wherein
each of the inhibitors is formulated into a separate pharmaceutical
composition, and wherein said separate pharmaceutical compositions
are formulated for co-administration. Preferably, said kit contains
a BTK inhibitor and a JAK-2 inhibitor.
[0305] Another aspect of the invention is a method of treating a
disease or condition in a subject, in particular a
hyperproliferative disorder such as leukemia, lymphoma or a solid
tumor cancer in a subject, comprising co-administering to the
subject in need thereof a therapeutically effective amount of a
combination of a PI3K inhibitor, a BTK inhibitor, and/or a JAK-2
inhibitor. In an embodiment, the foregoing method exhibits
synergistic effects that may result in greater efficacy, less side
effects, the use of less active pharmaceutical ingredient to
achieve a given clinical result, or other synergistic effects. A
combination of a BTK inhibitor and a JAK-2 inhibitor is a preferred
embodiment. The pharmaceutical composition comprising the
combination, and the kit, are both for use in treating such disease
or condition.
[0306] In a preferred embodiment, the solid tumor cancer is
selected from the group consisting of breast, lung, colorectal,
thyroid, bone sarcoma, and stomach cancers.
[0307] In a preferred embodiment, the leukemia is selected from the
group consisting of acute myelogenous leukemia (AML), chronic
myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), B
cell chronic lymphocytic leukemia (B-CLL), and chronic lymphoid
leukemia (CLL).
[0308] In a preferred embodiment, the lymphoma is selected from the
group consisting of Burkitt's lymphoma, mantle cell lymphoma,
follicular lymphoma, indolent B-cell non-Hodgkin's lymphoma,
histiocytic lymphoma, activated B-cell like diffuse large B cell
lymphoma (DLBCL-ABC), germinal center B-cell like diffuse large B
cell lymphoma (DLBCL-GCB), and diffuse large B cell lymphoma
(DLBCL).
[0309] In an embodiment, the PI3K inhibitor is a PI3K-.gamma.
inhibitor.
[0310] In a preferred embodiment, the PI3K inhibitor is a
PI3K-.delta. inhibitor.
[0311] In a preferred embodiment, the PI3K inhibitor is a
PI3K-.gamma.,.delta. inhibitor.
[0312] In an embodiment, the PI3K inhibitor is a selective PI3K
inhibitor.
[0313] In an embodiment, the combination of the the PI3K inhibitor,
PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor with the BTK inhibitor is
administered by oral, intravenous, intramuscular, intraperitoneal,
subcutaneous or transdermal means.
[0314] In an embodiment, the PI3K inhibitor, PI3K-.gamma.
inhibitor, PI3K-.delta. inhibitor, or PI3K-.gamma.,.delta.
inhibitor is in the form of a pharmaceutically acceptable salt,
solvate, hydrate, complex, derivative, prodrug (such as an ester or
phosphate ester), or cocrystal.
[0315] In an embodiment, the BTK inhibitor is in the form of a
pharmaceutically acceptable salt, solvate, hydrate, complex,
derivative, prodrug (such as an ester or phosphate ester), or
cocrystal.
[0316] In an embodiment, the JAK-2 inhibitor is in the form of a
pharmaceutically acceptable salt, solvate, hydrate, complex,
derivative, prodrug (such as an ester or phosphate ester), or
cocrystal.
[0317] In an embodiment, the PI3K inhibitor, which is preferably
selected from the group consisting of a PI3K-.gamma. inhibitor, a
PI3K-.delta. inhibitor, and a PI3K-.gamma.,.delta. inhibitor, is
administered to the subject before administration of the BTK
inhibitor.
[0318] In an embodiment, the PI3K inhibitor, which is preferably
selected from the group consisting of a PI3K-.gamma. inhibitor, a
PI3K-.delta. inhibitor, and a PI3K-.gamma.,.delta. inhibitor is
administered concurrently with the administration of the BTK
inhibitor.
[0319] In an embodiment, the PI3K inhibitor, which is preferably
selected from the group consisting of a PI3K-.gamma. inhibitor, a
PI3K-.delta. inhibitor, and a PI3K-.gamma.,.delta. inhibitor is
administered to the subject after administration of the BTK
inhibitor.
[0320] In an embodiment, the JAK-2 inhibitor is administered to the
subject before administration of the BTK inhibitor.
[0321] In an embodiment, the JAK-2 inhibitor is administered
concurrently with the administration of the BTK inhibitor.
[0322] In an embodiment, the JAK-2 inhibitor is administered to the
subject after administration of the BTK inhibitor.
[0323] In an embodiment, the JAK-2 inhibitor is administered to the
subject after administration of the BTK inhibitor.
[0324] In an embodiment, the JAK-2 inhibitor is administered to the
subject before administration of the PI3K inhibitor.
[0325] In an embodiment, the JAK-2 inhibitor is administered
concurrently with the administration of the PI3K inhibitor.
[0326] In a preferred embodiment, the BTK inhibitor, JAK-2
inhibitor, and/or PI3K inhibitor are administered concurrently.
[0327] In a preferred embodiment, the subject is a mammal, such as
a human. In an embodiment, the subject is a human. In an
embodiment, the subject is a companion animal. In an embodiment,
the subject is a canine, feline, or equine.
PI3K Inhibitors
[0328] The PI3K inhibitor may be any PI3K inhibitor known in the
art. In particular, it is one of the PI3K inhibitors described in
more detail in the following paragraphs. Preferably, it is a PI3K
inhibitor selected from the group consisting of a PI3K-.gamma.
inhibitor, a PI3K-.delta. inhibitor, and a PI3K-.gamma.,.delta.
inhibitor. In one specific embodiment, it is a PI3K-.delta.
inhibitor.
[0329] In an embodiment, the PI3K inhibitor, which is preferably
selected from the group consisting of a PI3K-.gamma. inhibitor, a
PI3K-.delta. inhibitor, and a PI3K-.gamma.,.delta. inhibitor, is a
compound selected from the structures disclosed in U.S. Pat. Nos.
8,193,182 and 8,569,323, and U.S. Patent Application Publication
Nos. 2012/0184568 A1, 2013/0344061 A1, and 2013/0267521 A1, the
disclosures of which are incorporated by reference herein. In an
embodiment, the PI3K inhibitor (which may be a PI3K-.gamma.
inhibitor, PI3K-.delta. inhibitor, or PI3K-.gamma.,.delta.
inhibitor) is a compound of Formula (I):
##STR00012## [0330] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal or prodrug thereof, wherein: [0331] Cy is aryl
or heteroaryl substituted by 0 or 1 occurrences of R.sup.3 and 0,
1, 2, or 3 occurrences of R.sup.5; [0332] W.sub.b5 is CR.sup.8,
CHR.sup.8, or N; [0333] R.sup.8 is hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl,
acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro; [0334] B is
hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,
aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3,
or 4 occurrences of R.sup.2; [0335] each R.sup.2 is independently
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino,
acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,
nitro, phosphate, urea, or carbonate; [0336] X is
--(CH(R.sup.9)).sub.z--; [0337] Y is --N(R.sup.9)--C(.dbd.O)--,
--C(.dbd.O)--N(R.sup.9)--, --C(.dbd.O)--N(R.sup.9)--(CHR.sup.9)--,
--N(R.sup.9)--S(.dbd.O)--, --S(.dbd.O)--N(R.sup.9)--,
S(.dbd.O).sub.2--N(R.sup.9)--, --N(R.sup.9)--C(.dbd.O)--N(R.sup.9)
or --N(R.sup.9)S(.dbd.O).sub.2--; [0338] z is an integer of 1, 2,
3, or 4; [0339] R.sup.3 is alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,
acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,
cyano, aryl, heteroaryl, hydroxyl, or nitro; [0340] each R.sup.5 is
independently alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,
alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano,
hydroxyl, or nitro; [0341] each R.sup.9 is independently hydrogen,
alkyl, cycloalkyl, heterocyclyl, or heteroalkyl; or two adjacent
occurrences of R.sup.9 together with the atoms to which they are
attached form a 4- to 7-membered ring; [0342] W.sub.d is
heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which is
substituted with one or more R.sup.10, R.sup.11, R.sup.12 or
R.sup.13, and [0343] R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are
each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl,
acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro,
phosphate, urea, carbonate or NR'R'' wherein R' and R'' are taken
together with nitrogen to form a cyclic moiety.
[0344] In an embodiment, the PI3K inhibitor (which may be a
PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (I-1):
##STR00013## [0345] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0346] B is a
moiety of Formula (II-A):
[0346] ##STR00014## [0347] W.sub.c is aryl, heteroaryl,
heterocycloalkyl, or cycloalkyl; [0348] q is an integer of 0, 1, 2,
3, or 4; [0349] X is a bond or --(CH(R.sup.9)).sub.z--, and z is an
integer of 1, 2, 3 or 4; [0350] Y is a bond, --N(R.sup.9)--, --O--,
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2, --C(.dbd.O)--,
--C(.dbd.O)(CHR.sup.9).sub.z--, --N(R.sup.9)--C(.dbd.O)--,
--N(R.sup.9)--C(.dbd.O)NH-- or --N(R.sup.9)C(R.sup.9).sub.2--;
[0351] z is an integer of 1, 2, 3, or 4; [0352] W.sub.d is:
[0352] ##STR00015## ##STR00016## [0353] X.sub.1, X.sub.2 and
X.sub.3 are each independently C, CR.sup.13 or N; and X.sub.4,
X.sub.5 and X.sub.6 are each independently N, NH, CR.sup.13, S or
O; [0354] R.sup.1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro; [0355]
R.sup.2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano,
hydroxy or nitro; [0356] R.sup.3 is hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino,
alkoxycarbonyl sulfonamido, halo, cyano, hydroxy or nitro; and each
instance of R.sup.9 is independently hydrogen, alkyl, or
heterocycloalkyl.
[0357] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (III):
##STR00017## [0358] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, where B is a moiety of
Formula (II-A), [0359] R.sup.2 is alkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl,
alkoxy, amino, halo, cyano, hydroxy or nitro; and [0360] R.sup.9 is
hydrogen, alkyl, or heterocycloalkyl.
[0361] In a preferred embodiment, the PI3K-.gamma.,.delta.
inhibitor is a compound of Formula (III-A):
##STR00018## [0362] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. Formula (III-A) is also
known as IPI-145 or duvelisib (Infinity Pharmaceuticals) and has
been studied at doses of 5 mg and 25 mg in clinical trials,
including those described in Flinn, et al., Blood, 2014, 124, 802,
and O'Brien, et al., Blood, 2014, 124, 3334.
[0363] In a preferred embodiment, the PI3K inhibitor is a compound
of Formula (IV):
##STR00019## [0364] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof.
[0365] In a preferred embodiment, the PI3K inhibitor is
(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinoline-1(2H)-
-one or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[0366] In a preferred embodiment, the PI3K inhibitor is
(S)-3-amino-N-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethy-
l)pyrazine-2-carboxamide or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof.
[0367] In an embodiment, the PI3K inhibitor (which may be a
PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound selected from the
structures disclosed in U.S. Pat. Nos. 8,193,199, 8,586,739, and
8,901,135, the disclosure of each of which is incorporated by
reference herein. In an embodiment, the PI3K inhibitor or
PI3K-.delta. inhibitor is a compound of Formula (V):
##STR00020## [0368] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0369] X.sup.1 is
C(R.sup.9) or N; [0370] X.sup.2 is C(R.sub.10) or N; [0371] Y is
N(R.sup.11), O or S; [0372] Z is CR.sup.8 or N; [0373] n is 0, 1, 2
or 3; [0374] R.sup.1 is a direct-bonded or oxygen-linked saturated,
partially saturated or unsaturated 5-, 6- or 7-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one 0 or S, wherein the available carbon
atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo
groups, wherein the ring is substituted by 0 or 1 R.sup.2
substituents, and the ring is additionally substituted by 0, 1, 2
or 3 substituents independently selected from halo, nitro, cyano,
(C.sub.1-4)alkyl, O(C.sub.1-4)alkyl, O(C.sub.1-4)haloalkyl,
NHC.sub.1-4, N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl and
(C.sub.1-4)haloalkyl; [0375] R.sup.2 is selected from halo,
(C.sub.1-4)haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a.
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylNR.sup.aR.sup.a, --O(C.sub.2-6)alkylOR.sup.a,
--SR.sup.a, OS(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.a(C.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.a(C.sub.2-6)alkylOR.sup.a; or
R.sup.2 is selected from (C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl, heterocycle, --((C.sub.1-3)alkyl)heteroaryl,
--((C.sub.1-3)alkyl)heterocycle, --O((C.sub.1-3)alkyl)heteroaryl,
--O((C.sub.1-3)alkyl)heterocycle,
--NR.sup.a((C.sub.1-3)alkyl)heteroaryl,
--NR.sup.a((C.sub.1-3)alkyl)heterocycle, --(C.sub.1-3)alkyl)phenyl,
--O((C.sub.1-3)alkyl)phenyl and --NR.sup.a((C.sub.1-3)alkyl)phenyl
all of which are substituted by 0, 1, 2 or 3 substituents selected
from (C.sub.1-4)haloalkyl, O(C.sub.1-4)alkyl, Br, Cl, F, I and
(C.sub.1-4)alkyl; [0376] R.sup.3 is selected from H, halo,
(C.sub.1-4)haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)R.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.2,
--O(C.sub.2-6)alkylNR.sup.aR.sup.a, --O(C.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aNR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a, (C.sub.1-6)alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the (C.sub.1-6)alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from
(C.sub.1-6)haloalkyl, O(C.sub.1-6)alkyl, Br, Cl, F, I and
(C.sub.1-6)alkyl; [0377] R.sup.4 is, independently, in each
instance, halo, nitro, cyano, (C.sub.1-4)alkyl, O(C.sub.1-4)alkyl,
O(C.sub.1-4)haloalkyl, NH(C.sub.1-4)alkyl,
N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl or (C.sub.1-4)haloalkyl; [0378]
R.sup.5 is, independently, in each instance, H, halo,
(C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl, or (C.sub.1-6)alkyl
substituted by 1, 2 or 3 substituents selected from halo, cyano,
OH, O(C.sub.1-4)alkyl, (C.sub.1-4)alkyl, (C.sub.1-3)haloalkyl,
O(C.sub.1-4)alkyl, NH.sub.2, NHC.sub.1-4)alkyl,
N(C.sub.1-4)alkyl(C.sub.1-4)alkyl; or both R.sup.5 groups together
form a (C.sub.3-6)spiroalkyl substituted by 0, 1, 2 or 3
substituents selected from halo, cyano, OH, O(C.sub.1-4)alkyl,
(C.sub.1-4)alkyl, (C.sub.1-3)haloalkyl, O(C.sub.1-4)alkyl,
NH.sub.2, NH(C.sub.1-4)alkyl, N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl;
[0379] R.sup.6 is selected from H, halo, (C.sub.1-6)alkyl,
(C.sub.1-4)haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [0380] R.sup.7
is selected from H, halo, (C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [0381] R.sup.8
is selected from H, (C.sub.1-6)haloalkyl, Br, Cl, F, I, OR.sup.a,
NR.sup.aR.sup.a, (C.sub.1-6)alkyl, phenyl, benzyl, heteroaryl and
heterocycle, wherein the (C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl and heterocycle are additionally substituted by 0, 1, 2
or 3 substituents selected from (C.sub.1-6)haloalkyl,
O(C.sub.1-6)alkyl, Br, Cl, F, I and (C.sub.1-6)alkyl; [0382]
R.sup.9 is selected from H, halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(O)NR.sup.aR.sup.aN(R.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.a(C.sub.2-6
alkylNR.sup.aR.sup.a, --NR.sup.a(C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the (C.sub.1-6 alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, (C.sub.1-4)haloalkyl,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylNR.sup.aR.sup.a, --O(C.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a; or R.sup.9 is a saturated,
partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the available carbon
atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo
groups, wherein the ring is substituted by 0, 1, 2, 3 or 4
substituents selected from halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylNR.sup.aR.sup.a, --O(C.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylNR.sup.aR.sup.a and
--NR.sup.a(C.sub.2-6)alkylOR.sup.a; [0383] R.sup.10 is H,
(C.sub.1-3)alkyl, (C.sub.1-3)haloalkyl, cyano, nitro,
CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a; [0384] R.sup.11 is H or
(C.sub.1-4)alkyl; [0385] R.sup.a is independently, at each
instance, H or R.sup.b; and [0386] R.sup.b is independently, at
each instance, phenyl, benzyl or (C.sub.1-6)alkyl, the phenyl,
benzyl and (C.sub.1-6)alkyl being substituted by 0, 1, 2 or 3
substituents selected from halo, (C.sub.1-4)alkyl,
(C.sub.1-3)haloalkyl, --O(C.sub.1-4)alkyl, --NH.sub.2,
--NHC.sub.1-4)alkyl, --N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl.
[0387] In another embodiment, the PI3K inhibitor (which may be a
PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VI):
##STR00021## [0388] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0389] X.sup.1 is
C(R.sup.9) or N; [0390] X.sup.2 is C(R.sup.10) or N; [0391] Y is
N(R.sup.11), O or S; [0392] Z is CR.sup.8 or N; [0393] R.sup.1 is a
direct-bonded or oxygen-linked saturated, partially-saturated or
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0 or 1 R.sup.2 substituents, and the ring is
additionally substituted by 0, 1, 2 or 3 substituents independently
selected from halo, nitro, cyano, (C.sub.1-4)alkyl,
O(C.sub.1-4)alkyl, O(C.sub.1-4)haloalkyl, (NHC.sub.1-4)alkyl,
N(C.sub.1-4 alkyl)(C.sub.1-4)alkyl and (C.sub.1-4)haloalkyl; [0394]
R.sup.2 is selected from halo, (C.sub.1-4)haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylNR.sup.aR.sup.a, --O(C.sub.2-6)alkylOR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.a(C.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.a(C.sub.2-6)alkylOR.sup.a; or
R.sup.2 is selected from (C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl, heterocycle, --((C.sub.1-3)alkyl)heteroaryl,
--((C.sub.1-3)alkyl)heterocycle, --O((C.sub.1-3)alkyl)heteroaryl,
--O((C.sub.1-3)alkyl)heterocycle,
--NR.sup.a((C.sub.1-3)alkyl)heteroaryl,
--NR.sup.a((C.sub.1-3)alkyl)heterocycle,
--((C.sub.1-3)alkyl)phenyl, --O((C.sub.1-3)alkyl)phenyl and
--NR.sup.a(C.sub.1-3 alkyl)phenyl all of which are substituted by
0, 1, 2 or 3 substituents selected from (C.sub.1-4)haloalkyl,
O(C.sub.1-4)alkyl, Br, Cl, F, I and (C.sub.1-4)alkyl; [0395]
R.sup.3 is selected from H, halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
C(.dbd.O)NR.sup.aR.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylNR.sup.aR.sup.a, --O(C.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a, (C.sub.1-6)alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the (C.sub.1-6)alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from
(C.sub.1-6)haloalkyl, O(C.sub.1-6)alkyl, Br, Cl, F, I and
(C.sub.1-6)alkyl; R.sup.5 is, independently, in each instance, H,
halo, (C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl, or (C.sub.1-6)alkyl
substituted by 1, 2 or 3 substituents selected from halo, cyano,
OH, O(C.sub.1-4)alkyl, (C.sub.1-4)alkyl, (C.sub.1-3)haloalkyl,
O(C.sub.1-4)alkyl, NH.sub.2, (NHC.sub.1-4)alkyl,
N(C.sub.1-4)alkyl(C.sub.1-4)alkyl; or both R.sup.5 groups together
form a C.sub.3-6-spiroalkyl substituted by 0, 1, 2 or 3
substituents selected from halo, cyano, OH, O(C.sub.1-4)alkyl,
(C.sub.1-4)alkyl, (C.sub.1-3)haloalkyl, O(C.sub.1-4)alkyl,
NH.sub.2, (NHC.sub.1-4)alkyl, N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl;
[0396] R.sup.6 is selected from H, halo, (C.sub.1-6)alkyl,
(C.sub.1-4)haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [0397] R.sup.7
is selected from H, halo, (C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.aS(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [0398] R.sup.8
is selected from H, (C.sub.1-6)haloalkyl, Br, Cl, F, I, OR.sup.a,
NR.sup.aR.sup.a, (C.sub.1-6)alkyl, phenyl, benzyl, heteroaryl and
heterocycle, wherein the (C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl and heterocycle are additionally substituted by 0, 1, 2
or 3 substituents selected from (C.sub.1-6)haloalkyl, O(C.sub.1-6
alkyl, Br, Cl, F, I and (C.sub.1-6)alkyl; [0399] R.sup.9 is
selected from H, halo, (C.sub.1-4)haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylNR.sup.aR.sup.a, --O(C.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylNR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a, (C.sub.1-6)alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the (C.sub.1-6)alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from halo,
(C.sub.1-4)haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylNR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a; or R.sup.9 is a saturated,
partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the available carbon
atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo
groups, wherein the ring is substituted by 0, 1, 2, 3 or 4
substituents selected from halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.a(C.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.a(C.sub.2-6)alkylOR.sup.a; [0400]
R.sup.10 is H, (C.sub.1-3)alkyl, (C.sub.1-3)haloalkyl, cyano,
nitro, CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a; --R.sup.11 is H or
(C.sub.1-4)alkyl; [0401] R.sup.a is independently, at each
instance, H or R.sup.b; and [0402] R.sup.b is independently, at
each instance, phenyl, benzyl or (C.sub.1-6)alkyl, the phenyl,
benzyl and (C.sub.1-6)alkyl being substituted by 0, 1, 2 or 3
substituents selected from halo, (C.sub.1-4)alkyl, (C.sub.1-3)
haloalkyl, --O(C.sub.1-4)alkyl, --NH.sub.2, --NH(C.sub.1-4)alkyl,
--N(C.sub.1-4)alkyl(C.sub.1-4)alkyl.
[0403] In another embodiment, the the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VII):
##STR00022## [0404] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0405] X.sup.1 is
C(R.sup.9) or N; [0406] X.sup.2 is C(R.sup.10) or N; [0407] Y is
N(R.sup.11), O or S; [0408] Z is CR.sup.8 or N; [0409] R.sup.1 is a
direct-bonded or oxygen-linked saturated, partially-saturated or
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0 or 1 R.sup.2 substituents, and the ring is
additionally substituted by 0, 1, 2 or 3 substituents independently
selected from halo, nitro, cyano, (C.sub.1-4)alkyl,
O(C.sub.1-4)alkyl, O(C.sub.1-4)haloalkyl, NH(C.sub.1-4)alkyl,
N(C.sub.1-4)alkyl(C.sub.1-4)alkyl and (C.sub.1-4)haloalkyl; [0410]
R.sup.2 is selected from halo, (C.sub.1-4)haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6)alkylNR.sup.aR.sup.a, --OC.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.a(C.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.a(C.sub.2-6)alkylOR.sup.a; or
R.sup.2 is selected from (C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl, heterocycle, --(C.sub.1-3 alkyl)heteroaryl,
--(C.sub.1-3 alkyl)heterocycle, --O(C.sub.1-3 alkyl)heteroaryl,
--O((C.sub.1-3)alkyl)heterocycle, --NR.sup.a(C.sub.1-3
alkyl)heteroaryl, --NR.sup.a(C.sub.1-3 alkyl)heterocycle,
--(C.sub.1-3 alkyl)phenyl, --O(C.sub.1-3 alkyl)phenyl and
--NR.sup.a(C.sub.1-3 alkyl)phenyl all of which are substituted by
0, 1, 2 or 3 substituents selected from (C.sub.1-4)haloalkyl,
O(C.sub.1-4)alkyl, Br, Cl, F, I and (C.sub.1-4)alkyl; [0411]
R.sup.3 is selected from H, halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6)alkylNR.sup.aR.sup.a, --OC.sub.2-6)alkylOR.sup.1,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylNR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a, (C.sub.1-6)alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the (C.sub.1-6)alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from
(C.sub.1-6)haloalkyl, O(C.sub.1-6)alkyl, Br, Cl, F, I and
(C.sub.1-6)alkyl; [0412] R.sup.5 is, independently, in each
instance, H, halo, (C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl, or
(C.sub.1-6)alkyl substituted by 1, 2 or 3 substituents selected
from halo, cyano, OH, O(C.sub.1-4)alkyl, (C.sub.1-4)alkyl,
(C.sub.1-3)haloalkyl, O(C.sub.1-4)alkyl, NH.sub.2,
NHC.sub.1-4)alkyl, N(C.sub.1-4)alkyl(C.sub.1-4)alkyl; or both
R.sup.5 groups together form a C.sub.3-6-spiroalkyl substituted by
0, 1, 2 or 3 substituents selected from halo, cyano, OH,
O(C.sub.1-4)alkyl, (C.sub.1-4)alkyl, (C.sub.1-3)haloalkyl,
O(C.sub.1-4)alkyl, NH.sub.2, NHC.sub.1-4)alkyl,
N(C.sub.1-4)alkyl)C.sub.1-4)alkyl; [0413] R.sup.6 is selected from
H, halo, (C.sub.1-6)alkyl, (C.sub.1-4haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.aS(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [0414] R.sup.7
is selected from H, halo, (C.sub.1-6)alkyl, (C.sub.1-4haloalkyl,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.aS(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [0415] R.sup.8
is selected from H, (C.sub.1-6)haloalkyl, Br, Cl, F, I, OR.sup.a,
NR.sup.aR.sup.a, (C.sub.1-6)alkyl, phenyl, benzyl, heteroaryl and
heterocycle, wherein the (C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl and heterocycle are additionally substituted by 0, 1, 2
or 3 substituents selected from (C.sub.1-6)haloalkyl,
O(C.sub.1-6)alkyl, Br, Cl, F, I and (C.sub.1-6)alkyl; [0416]
R.sup.9 is selected from H, halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6)alkylNR.sup.aR.sup.a, --OC.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a, (C.sub.1-6)alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the (C.sub.1-6)alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from halo,
(C.sub.1-4)haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.8,
--OC(.dbd.O)NR.sup.2R.sup.8,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6)alkylNR.sup.aR.sup.a, --OC.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.8,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylNR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a; or R.sup.9 is a saturated,
partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the available carbon
atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo
groups, wherein the ring is substituted by 0, 1, 2, 3 or 4
substituents selected from halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6)alkylNR.sup.aR.sup.a, --OC.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylNR.sup.aR.sup.a and
--NR.sup.a(C.sub.2-6)alkylOR.sup.a; [0417] R.sup.10 is H,
(C.sub.1-3 alkyl, (C.sub.1-3)haloalkyl, cyano, nitro,
CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a; [0418] R.sup.11 is H or
(C.sub.1-4)alkyl; [0419] R.sup.a is independently, at each
instance, H or R.sup.b; and [0420] R.sup.b is independently, at
each instance, phenyl, benzyl or (C.sub.1-6)alkyl, the phenyl,
benzyl and (C.sub.1-6)alkyl being substituted by 0, 1, 2 or 3
substituents selected from halo, (C.sub.1-4)alkyl,
(C.sub.1-3)haloalkyl, --O(C.sub.1-4)alkyl, --NH.sub.2,
--NHC.sub.1-4)alkyl, --N(C.sub.1-4)alkyl(C.sub.1-4)alkyl.
[0421] In another embodiment, the PI3K inhibitor (which may be a
PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula
(VIII):
##STR00023## [0422] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0423] X.sup.1 is
C(R.sup.9) or N; [0424] X.sup.2 is C(R.sup.10) or N; [0425] Y is
N(R.sup.11), O or S; [0426] Z is CR.sup.8 or N; [0427] R.sup.1 is a
direct-bonded or oxygen-linked saturated, partially-saturated or
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0 or 1 R.sup.2 substituents, and the ring is
additionally substituted by 0, 1, 2 or 3 substituents independently
selected from halo, nitro, cyano, (C.sub.1-4)alkyl,
O(C.sub.1-4)alkyl, O(C.sub.1-4)haloalkyl, NH(C.sub.1-4)alkyl,
N(C.sub.1-4 alkyl)C.sub.1-4)alkyl and (C.sub.1-4)haloalkyl; [0428]
R.sup.2 is selected from halo, (C.sub.1-4)haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a
C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.a(C.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.a(C.sub.2-6alkylOR.sup.a; or
R.sup.2 is selected from (C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl, heterocycle, --(C.sub.1-3 alkyl)heteroaryl,
--(C.sub.1-3 alkyl)heterocycle, --O(C.sub.1-3 alkyl)heteroaryl,
--O(C.sub.1-3 alkyl)heterocycle, --NR.sup.a(C.sub.1-3
alkyl)heteroaryl, --NR.sup.a(C.sub.1-3 alkyl)heterocycle,
--(C.sub.1-3 alkyl)phenyl, --O(C.sub.1-3 alkyl)phenyl and
--NR.sup.a(C.sub.1-3 alkyl)phenyl all of which are substituted by
0, 1, 2 or 3 substituents selected from (C.sub.1-4 haloalkyl,
O(C.sub.1-4)alkyl, Br, Cl, F, I and (C.sub.1-4)alkyl; [0429]
R.sup.3 is selected from H, halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aNR.sup.a, --NR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a, (C.sub.1-6)alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the (C.sub.1-6)alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from
(C.sub.1-6)haloalkyl, O(C.sub.1-6)alkyl, Br, Cl, F, I and
(C.sub.1-6)alkyl; [0430] R.sup.5 is, independently, in each
instance, H, halo, (C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl, or
(C.sub.1-6)alkyl substituted by 1, 2 or 3 substituents selected
from halo, cyano, OH, O(C.sub.1-4)alkyl, (C.sub.1-4)alkyl,
(C.sub.1-3)haloalkyl, O(C.sub.1-4)alkyl, NH.sub.2,
NH(C.sub.1-4)alkyl, N(C.sub.1-4)alkyl(C.sub.1-4)alkyl; or both
R.sup.5 groups together form a C.sub.3-6-spiroalkyl substituted by
0, 1, 2 or 3 substituents selected from halo, cyano, OH,
O(C.sub.1-4)alkyl, (C.sub.1-4)alkyl, (C.sub.1-3)haloalkyl,
O(C.sub.1-4)alkyl, NH.sub.2, NH(C.sub.1-4)alkyl,
N(C.sub.1-4)alkyl(C.sub.1-4)alkyl; [0431] R.sup.6 is selected from
H, halo, (C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, S(.dbd.O).sub.2R.sup.a,
S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [0432] R.sup.7
is selected from H, halo, (C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, S(.dbd.O).sub.2R.sup.a,
S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [0433] R.sup.8
is selected from H, (C.sub.1-6)haloalkyl, Br, Cl, F, I, OR.sup.a,
NR.sup.aR.sup.a, (C.sub.1-6alkyl, phenyl, benzyl, heteroaryl and
heterocycle, wherein the (C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl and heterocycle are additionally substituted by 0, 1, 2
or 3 substituents selected from (C.sub.1-6)haloalkyl, OC.sub.1-6
alkyl, Br, Cl, F, I and (C.sub.1-6)alkyl; [0434] R.sup.9 is
selected from H, halo, (C.sub.1-4)haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylNR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylOR.sup.a, (C.sub.1-6)alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the (C.sub.1-6)alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from halo,
(C.sub.1-4)haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylNR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylOR.sup.a; or R.sup.9 is a saturated,
partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the available carbon
atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo
groups, wherein the ring is substituted by 0, 1, 2, 3 or 4
substituents selected from halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.a(C.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.a(C.sub.2-6alkylOR.sup.a; [0435]
R.sup.10 is H, (C.sub.1-3 alkyl, (C.sub.1-3)haloalkyl, cyano,
nitro, CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a; [0436] R.sup.11 is H or
(C.sub.1-4)alkyl; [0437] R.sup.a is independently, at each
instance, H or R.sup.b; and [0438] R.sup.b is independently, at
each instance, phenyl, benzyl or (C.sub.1-6)alkyl, the phenyl,
benzyl and (C.sub.1-6) alkyl being substituted by 0, 1, 2 or 3
substituents selected from halo, (C.sub.1-4)alkyl, (C.sub.1-3
haloalkyl, --O(C.sub.1-4)alkyl, --NH.sub.2, --NH(C.sub.1-4)alkyl,
--N(C.sub.1-4)alkyl(C.sub.1-4)alkyl.
[0439] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein X.sup.1 is C(R.sup.9) and X.sup.2 is N.
[0440] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein X.sup.1 is C(R.sup.9) and X.sup.2 is C(R.sup.10).
[0441] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.1 is phenyl substituted by 0, 1, 2, or 3
independently selected R.sup.2 substituents.
[0442] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.1 is phenyl.
[0443] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.1 is selected from 2-methylphenyl, 2-chlorophenyl,
2-trifluoromethylphenyl, 2-fluorophenyl and 2-methoxyphenyl.
[0444] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.1 is phenoxy.
[0445] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.1 is a direct-bonded or oxygen-linked saturated,
partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic
ring containing 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the available carbon
atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo
groups, wherein the ring is substituted by 0 or 1 R.sup.2
substituents, and the ring is additionally substituted by 0, 1, 2
or 3 substituents independently selected from halo, nitro, cyano,
C.sub.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl and
C.sub.1-4haloalkyl.
[0446] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.1 is an unsaturated 5- or 6-membered monocyclic ring
containing 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the ring is substituted
by 0 or 1 R.sup.2 substituents, and the ring is additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitro, cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl,
OC.sub.1-4haloalkyl, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl and C.sub.1-4haloalkyl.
[0447] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.1 is an unsaturated 5- or 6-membered monocyclic ring
containing 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the ring is substituted
by 0 or 1 R.sup.2 substituents, and the ring is additionally
substituted by 1, 2 or 3 substituents independently selected from
halo, nitro, cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl,
OC.sub.1-4haloalkyl, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl and C.sub.1-4haloalkyl.
[0448] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.1 is an unsaturated 5- or 6-membered monocyclic ring
containing 1, 2, 3 or 4 atoms selected from N, O and S.
[0449] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.1 is selected from pyridyl and pyrimidinyl.
[0450] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.3 is selected from halo, C.sub.1-4haloalkyl, cyano,
nitro, --C(O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O)NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylNR.sup.aR.sup.a, --NR.sup.a,
C.sub.1-6alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein
the C.sub.1-6alkyl, phenyl, benzyl, heteroaryl and heterocycle are
additionally substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-6)haloalkyl, OC.sub.1-6alkyl, Br, Cl, F, I and
C.sub.1-6alkyl.
[0451] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.3 is H.
[0452] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.3 is selected from F, Cl, C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the C.sub.1-6alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-6)haloalkyl, OC.sub.1-6alkyl, Br, Cl, F, I and
C.sub.1-6alkyl.
[0453] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alkyl, C.sub.1-4haloalkyl, or C.sub.1-6alkyl substituted
by 1, 2 or 3 substituents selected from halo, cyano, OH,
OC.sub.1-4)alkyl, C.sub.1-4)alkyl, C.sub.1-3)haloalkyl,
OC.sub.1-4)alkyl, NH.sub.2, NHC.sub.1-4)alkyl,
N(C.sub.1-4)alkyl)C.sub.1-4)alkyl; or both R.sup.5 groups together
form a C.sub.3-6spiroalkyl substituted by 0, 1, 2 or 3 substituents
selected from halo, cyano, OH, OC.sub.1-4)alkyl, C.sub.1-4)alkyl,
C.sub.1-3)haloalkyl, OC.sub.1-4)alkyl, NH.sub.2, NHC.sub.1-4)alkyl,
N(C.sub.1-4)alkyl)C.sub.1-4)alkyl.
[0454] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.5 is H.
[0455] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein one R.sup.5 is S-methyl, the other is H.
[0456] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein at least one R.sup.5 is halo, C.sub.1-6alkyl,
C.sub.1-4haloalkyl, or C.sub.1-6alkyl substituted by 1, 2 or 3
substituents selected from halo, cyano, OH, OC.sub.1-4)alkyl,
C.sub.1-4)alkyl, C.sub.1-3)haloalkyl, OC.sub.1-4)alkyl, NH.sub.2,
NHC.sub.1-4)alkyl, N(C.sub.1-4)alkyl)C.sub.1-4)alkyl.
[0457] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.6 is H.
[0458] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.6 is F, Cl, cyano or nitro.
[0459] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.7 is H.
[0460] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.7 is F, Cl, cyano or nitro.
[0461] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.8 is selected from H, CF.sub.3, C.sub.1-3 alkyl, Br,
Cl and F.
[0462] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.8 is selected from H.
[0463] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.8 is selected from CF.sub.3, C.sub.1-3 alkyl, Br, Cl
and F.
[0464] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.9 is H.
[0465] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.9 is selected from halo, C.sub.1-4haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylNR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, C.sub.1-4haloalkyl,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylNR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylOR.sup.a.
[0466] In a preferred embodiment the PI3K inhibitor (which may be a
PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.9 is a saturated, partially-saturated or unsaturated
5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4
atoms selected from N, O and S, but containing no more than one O
or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0, 1, 2, 3 or 4 substituents selected from halo,
C.sub.1-4haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.a(C.sub.2-6alkylOR.sup.a.
[0467] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.10 is H.
[0468] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.10 is cyano, nitro, --CO.sub.2R.sup.a,
C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a.
[0469] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is a compound of Formula (VIII)
wherein R.sup.11 is H.
[0470] In a preferred embodiment, the PI3K-.delta. inhibitor is a
compound of Formula (IX):
##STR00024## [0471] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof.
[0472] In a preferred embodiment, the PI3K inhibitor or
PI3K-.delta. inhibitor is
(S)--N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug thereof.
[0473] In a preferred embodiment, the PI3K-.delta. inhibitor is a
compound of Formula (X):
##STR00025## [0474] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof.
[0475] In a preferred embodiment, the PI3K inhibitor or
PI3K-.delta. inhibitor is
(S)--N-(1-(6-fluoro-3-(pyridin-2-yl)quinoxalin-2-yl)ethyl)-9H-purin-6-ami-
ne or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[0476] In a preferred embodiment, the PI3K-.delta. inhibitor is a
compound of Formula (XI):
##STR00026## [0477] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof.
[0478] In a preferred embodiment, the PI3K-.delta. inhibitor is
(S)--N-(1-(2-(3,5-difluorophenyl)-8-fluoroquinolin-3-yl)ethyl)-9H-purin-6-
-amine or a pharmaceutically-acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[0479] In a preferred embodiment, the PI3K-.delta. inhibitor is a
compound of Formula (XII):
##STR00027## [0480] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof.
[0481] In a preferred embodiment, the PI3K-.delta. inhibitor is
(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-2-(pyridin-2-yl)quinoline-8-carboni-
trile or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[0482] In a preferred embodiment, the PI3K-.delta. inhibitor is a
compound of Formula (XIII):
##STR00028## [0483] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof.
[0484] In a preferred embodiment, the PI3K-.delta. inhibitor is
(S)--N-(1-(5,7-difluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-a-
mine or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[0485] In an embodiment, the PI3K inhibitor or PI3K-.delta.
inhibitor is a compound selected from the structures disclosed in
U.S. Pat. Nos. 7,932,260 and 8,207,153, the disclosure of which is
incorporated by reference herein. In an embodiment, the PI3K
inhibitor or PI3K-.delta. inhibitor is a compound of Formula
(XIV):
##STR00029## [0486] wherein [0487] X and Y, independently, are N or
CH; [0488] Z is N--R.sup.7 or O; [0489] R.sup.1 are the same and
are hydrogen, halo, or C.sub.1-3 alkyl; [0490] R.sup.2 and R.sup.3,
independently, are hydrogen, halo, or C.sub.1-3 alkyl; [0491]
R.sup.4 is hydrogen, halo, OR.sup.a, CN, C.sub.2-6alkynyl,
C(.dbd.O)R.sup.a, C(.dbd.O)NR.sup.aR.sup.b,
C.sub.3-6heterocycloalkyl, C.sub.1-3
alkyleneC.sub.3-6heterocycloalkyl, O(C.sub.1-3)alkyleneOR.sup.a,
O(C.sub.1-3)alkyleneNR.sup.aR.sup.b, O(C.sub.1-3)alkyleneC.sub.3-6
cycloalkyl, OC.sub.3-6heterocycloalkyl,
O(C.sub.1-3)alkyleneC.ident.H, or
O(C.sub.1-3)alkyleneC(.dbd.O)NR.sup.aR.sup.b; [0492] R.sup.5 is
(C.sub.1-3)alkyl, CH.sub.2CF.sub.3, phenyl, CH.sub.2C.ident.CH,
(C.sub.1-3)alkyleneOR.sup.e, (C.sub.1-4)alkyleneNR.sup.aR.sup.b, or
C.sub.1-4 alkyleneNHC(.dbd.O)OR.sup.a, [0493] R.sup.6 is hydrogen,
halo, or NR.sup.aR.sup.b; [0494] R.sup.7 is hydrogen or R.sup.5 and
R.sup.7 are taken together with the atoms to which they are
attached to form a five- or six-membered saturated ring; [0495]
R.sup.8 is C.sub.1-3 alkyl, halo, CF.sub.3, or
CH.sub.2C.sub.3-6heterocycloalkyl; [0496] n is 0, 1, or 2; [0497]
R.sup.a is hydrogen, (C.sub.1-4)alkyl, or CH.sub.2C.sub.6H.sub.5;
[0498] R.sup.b is hydrogen or C.sub.1-3 alkyl; and [0499] R.sup.c
is hydrogen, C.sub.1-3 alkyl, or halo, [0500] wherein when the
R.sup.1 groups are different from hydrogen, R.sup.2 and R.sup.4 are
the same; or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[0501] In a preferred embodiment, the PI3K inhibitor or
PI3K-.delta. inhibitor is an enantiomer of Formula (XIV), as shown
in Formula (XV):
##STR00030## [0502] wherein X, Y, Z, R.sup.1 through R.sup.8,
R.sup.a, R.sup.b, R.sup.c, and n are as defined above for Formula
(XIV).
[0503] In various embodiments exhibiting increased potency relative
to other compounds, n=1, 2, or 3 and R.sup.8 is C.sub.1-3alkyl, F,
Cl, or CF.sub.3. Alternatively, in such embodiments, n is 0 (such
that there is no R.sup.8 substituent).
[0504] In further embodiments exhibiting increased potency, X is N
and Y is CH. Alternatively, X and Y may also both be CH.
[0505] In further embodiments exhibiting increased potency, R.sup.6
is hydrogen, halo, or NH.sub.2. Preferably, R.sup.6 is
hydrogen.
[0506] In preferred embodiments exhibiting increased potency, n is
0 or 1; R.sup.8 (if n is 1) is C.sub.1-3alkyl, F, Cl, or CF.sub.3;
R.sup.6 is hydrogen; X is N and Y is CH or X and Y are both CH; Z
is NH; R.sup.1 are the same and are hydrogen, halo, or
C.sub.1-3alkyl; and R.sup.2 and R.sup.3, independently, are
hydrogen, halo, or C.sub.1-3alkyl. Preferably, R.sup.1, R.sup.2,
and R.sup.3 are hydrogen.
[0507] Unexpectedly, potency against PI3K-.delta. is conserved when
R.sup.1 is the same. In structural formulae (I) and (II), R.sup.2
and R.sup.4 may differ provided that R.sup.1 is H. When R.sup.1 is
H, free rotation is unexpectedly permitted about the bond
connecting the phenyl ring substituent to the quinazoline ring, and
the compounds advantageously do not exhibit atropisomerism (i.e.,
multiple diasteromer formation is avoided). Alternatively, R.sup.2
and R.sup.4 can be the same such that the compounds advantageously
do not exhibit atropisomerism.
[0508] In preferred embodiments, Z is N--R.sup.7, and the bicyclic
ring system containing X and Y is:
##STR00031##
[0509] In other preferred embodiments of Formula (XIV) or Formula
(XV), X, Y, Z, R.sup.a, R.sup.b, and R.sup.c are as defined above
for Formula (XIV), and R.sup.1 is hydrogen, fluoro, chloro, methyl,
or
##STR00032## [0510] and R.sup.2 is hydrogen, methyl, chloro, or
fluoro; R.sup.3 is hydrogen or fluoro; R.sup.6 is NH.sub.2,
hydrogen, or fluoro; R.sup.7 is hydrogen or R.sup.5 and R.sup.7 are
taken together to form
[0510] ##STR00033## [0511] R.sup.8 is methyl, trifluoromethyl,
chloro, or fluoro; R.sup.4 is hydrogen, fluoro, chloro, OH,
OCH.sub.3, OCH.sub.2C.ident.CH, O(CH.sub.2).sub.2N(CH.sub.3).sub.2,
C(.dbd.O)CH.sub.3, C.ident.CH, CN, C(.dbd.O)NH.sub.2,
OCH.sub.2C(.dbd.O)NH.sub.2, O(CH.sub.2).sub.2OCH.sub.3,
O(CH.sub.2).sub.2N(CH.sub.3).sub.2,
[0511] ##STR00034## [0512] and R.sup.5 is methyl, ethyl, propyl,
phenyl, CH.sub.2OH, CH.sub.2OCH.sub.2C.sub.6H.sub.5,
CH.sub.2CF.sub.3, CH.sub.2OC(CH.sub.3).sub.3, CH.sub.2C.ident.CH,
(CH.sub.2).sub.3N(C.sub.2H.sub.5).sub.2, (CH.sub.2).sub.3NH.sub.2,
(CH.sub.2).sub.4NH.sub.2,
(CH.sub.2).sub.3NHC(.dbd.O)OCH.sub.2C.sub.6H.sub.5, or
(CH.sub.2).sub.4NHC(.dbd.O)OCH.sub.2C6H.sub.5; R.sup.c is hydrogen,
methyl, fluoro, or bromo; and n is 0 or 1.
[0513] As used with respect to Formula (XIV) and Formula (XV), the
term "alkyl" is defined as straight chained and branched
hydrocarbon groups containing the indicated number of carbon atoms,
e.g., methyl, ethyl, and straight chain and branched propyl and
butyl groups. The terms "(C.sub.1-3)alkylene" and
"(C.sub.1-4)alkylene" are defined as hydrocarbon groups containing
the indicated number of carbon atoms and one less hydrogen than the
corresponding alkyl group. The term "(C.sub.2-6)alkynyl" is defined
as a hydrocarbon group containing the indicated number of carbon
atoms and a carbon-carbon triple bond. The term
"(C.sub.3-6)cycloalkyl" is defined as a cyclic hydrocarbon group
containing the indicated number of carbon atoms. The term
"(C.sub.2-6)heterocycloalkyl" is defined similarly as cycloalkyl
except the ring contains one or two heteroatoms selected from the
group consisting of O, NR.sup.a, and S. The term "halo" is defined
as fluoro, bromo, chloro, and iodo.
[0514] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is idelalisib. In a preferred
embodiment, the PI3K inhibitor (which may be a PI3K-.gamma.
inhibitor, PI3K-.delta. inhibitor, or PI3K-.gamma.,.delta.
inhibitor) is the compound of Formula (XVI):
##STR00035## [0515] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof.
[0516] In a preferred embodiment, the PI3K inhibitor (which may be
a PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is
(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)--
one or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[0517] In an embodiment, the PI3K inhibitor (which may be a
PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is 4(3H)-quinazolinone,
5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-5-fluoro-3-phenyl-
-2-{(1S)-1-[(7H-purin-6-yl)amino]propyl}quinazolin-4(3H)-one or or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[0518] In an embodiment, the PI3K inhibitor (which may be a
PI3K-.gamma. inhibitor, PI3K-.delta. inhibitor, or
PI3K-.gamma.,.delta. inhibitor) is GS-9901. Other PI3K inhibitors
suitable for use in the described combination with a BTK inhibitor
also include, but are not limited to, those described in, for
example, U.S. Pat. No. 8,193,182 and U.S. Published Application
Nos. 2013/0267521; 2013/0053362; 2013/0029984; 2013/0029982;
2012/0184568; and 2012/0059000, the disclosures of each of which
are incorporated by reference in their entireties.
BTK Inhibitors
[0519] The BTK inhibitor may be any BTK inhibitor known in the art.
In particular, it is one of the BTK inhibitors described in more
detail in the following paragraphs.
[0520] In an embodiment, the BTK inhibitor is a compound of Formula
(XVII):
##STR00036## [0521] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0522] X is CH, N,
O or S; [0523] Y is C(R.sub.6), N, O or S; [0524] Z is CH, N or
bond; [0525] A is CH or N; [0526] B.sub.1 is N or C(R.sub.7);
[0527] B.sub.2 is N or C(R.sub.8); [0528] B.sub.3 is N or
C(R.sub.9); [0529] B.sub.4 is N or C(R.sub.10); [0530] R.sub.1 is
R.sub.11C(.dbd.O), R.sub.12S(.dbd.O), R.sub.13S(.dbd.O).sub.2 or
(C.sub.1-6)alkyl optionally substituted with R.sub.14; [0531]
R.sub.2 is H, (C.sub.1-3)alkyl or (C.sub.3-7)cycloalkyl; [0532]
R.sub.3 is H, (C.sub.1-6)alkyl or (C.sub.3-7)cycloalkyl); or [0533]
R.sub.2 and R.sub.3 form, together with the N and C atom they are
attached to, a (C.sub.3-7)heterocycloalkyl optionally substituted
with one or more fluorine, hydroxyl, (C.sub.1-3)alkyl,
(C.sub.1-3)alkoxy or oxo; [0534] R.sub.4 is H or (C.sub.1-3)alkyl;
[0535] R.sub.5 is H, halogen, cyano, (C.sub.1-4)alkyl,
(C.sub.1-3)alkoxy, (C.sub.3-6)cycloalkyl, any alkyl group of which
is optionally substituted with one or more halogen; or R.sub.5 is
(C.sub.6-10)aryl or (C.sub.2-6)heterocycloalkyl; [0536] R.sub.6 is
H or (C.sub.1-3)alkyl; or [0537] R.sub.5 and R.sub.6 together may
form a (C.sub.3-7)cycloalkenyl or (C.sub.2-6)heterocycloalkenyl,
each optionally substituted with (C.sub.1-3)alkyl or one or more
halogens; [0538] R.sub.7 is H, halogen, CF.sub.3, (C.sub.1-3)alkyl
or (C.sub.1-3)alkoxy; [0539] R.sub.8 is H, halogen, CF.sub.3,
(C.sub.1-3)alkyl or (C.sub.1-3)alkoxy; or [0540] R.sub.7 and
R.sub.8 together with the carbon atoms they are attached to, form
(C.sub.6-10)aryl or (C.sub.1-9)heteroaryl; [0541] R.sub.9 is H,
halogen, (C.sub.1-3)alkyl or (C.sub.1-3)alkoxy; [0542] R.sub.10 is
H, halogen, (C.sub.1-3)alkyl or (C.sub.1-3)alkoxy; [0543] R.sub.11
is independently selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl and (C.sub.2-6)alkynyl, where
each alkyl, alkenyl or alkynyl is optionally substituted with one
or more substituents selected from the group consisting of
hydroxyl, (C.sub.1-4)alkyl, (C.sub.3-7)cycloalkyl,
[(C.sub.1-4)alkyl]amino, di[(C.sub.1-4)alkyl]amino,
(C.sub.1-3)alkoxy, (C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl and
(C.sub.3-7)heterocycloalkyl; or R.sub.11 is
(C.sub.1-3)alkyl-C(O)--S--(C.sub.1-3)alkyl; or [0544] R.sub.11 is
(C.sub.1-5)heteroaryl optionally substituted with one or more
substituents selected from the group consisting of halogen or
cyano; [0545] R.sub.12 and R.sub.13 are independently selected from
the group consisting of (C.sub.2-6)alkenyl or (C.sub.2-6)alkynyl,
both optionally substituted with one or more substituents selected
from the group consisting of hydroxyl, (C.sub.1-4)alkyl,
(C.sub.3-7)cycloalkyl, [(C.sub.1-4)alkyl]amino,
di[(C.sub.1-4)alkyl]amino, (C.sub.1-3)alkoxy,
(C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl and
(C.sub.3-7)heterocycloalkyl; or a (C.sub.1-5)heteroaryl optionally
substituted with one or more substituents selected from the group
consisting of halogen and cyano; and [0546] R.sub.14 is
independently selected from the group consisting of halogen, cyano,
(C.sub.2-6)alkenyl and (C.sub.2-6)alkynyl, both optionally
substituted with one or more substituents selected from the group
consisting of hydroxyl, (C.sub.1-4)alkyl, (C.sub.3-7)cycloalkyl,
(C.sub.1-4)alkylamino, di[(C.sub.1-4)alkyl]amino,
(C.sub.1-3)alkoxy, (C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl,
(C.sub.1-5)heteroaryl and (C.sub.3-7)heterocycloalkyl; with the
proviso that: [0547] 0 to 2 atoms of X, Y, Z can simultaneously be
a heteroatom; [0548] when one atom selected from X, Y is O or S,
then Z is a bond and the other atom selected from X, Y can not be O
or S; [0549] when Z is C or N then Y is C(R.sub.6) or N and X is C
or N; [0550] 0 to 2 atoms of B.sub.1, B.sub.2, B.sub.3 and B.sub.4
are N; [0551] with the terms used having the following meanings:
[0552] (C.sub.1-2)alkyl means an alkyl group having 1 to 2 carbon
atoms, being methyl or ethyl, [0553] (C.sub.1-3)alkyl means a
branched or unbranched alkyl group having 1-3 carbon atoms, being
methyl, ethyl, propyl or isopropyl; [0554] (C.sub.1-4)alkyl means a
branched or unbranched alkyl group having 1-4 carbon atoms, being
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and
tert-butyl, (C.sub.1-3)alkyl groups being preferred; [0555]
(C.sub.1-5)alkyl means a branched or unbranched alkyl group having
1-5 carbon atoms, for example methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl and isopentyl,
(C.sub.1-4)alkyl groups being preferred. (C.sub.1-6)Alkyl means a
branched or unbranched alkyl group having 1-6 carbon atoms, for
example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,
n-pentyl and n-hexyl. (C.sub.1-6)alkyl groups are preferred,
(C.sub.1-4)alkyl being most preferred; [0556] (C.sub.1-2)alkoxy
means an alkoxy group having 1-2 carbon atoms, the alkyl moiety
having the same meaning as previously defined; [0557]
(C.sub.1-3)alkoxy means an alkoxy group having 1-3 carbon atoms,
the alkyl moiety having the same meaning as previously defined.
(C.sub.1-2)alkoxy groups are preferred; [0558] (C.sub.1-4)alkoxy
means an alkoxy group having 1-4 carbon atoms, the alkyl moiety
having the same meaning as previously defined. (C.sub.1-3)alkoxy
groups are preferred, (C.sub.1-2)alkoxy groups being most
preferred; [0559] (C.sub.2-4)alkenyl means a branched or unbranched
alkenyl group having 2-4 carbon atoms, such as ethenyl, 2-propenyl,
isobutenyl or 2-butenyl; [0560] (C.sub.2-6)alkenyl means a branched
or unbranched alkenyl group having 2-6 carbon atoms, such as
ethenyl, 2-butenyl, and n-pentenyl, (C.sub.2-4)alkenyl groups being
most preferred; [0561] (C.sub.2-4)alkynyl means a branched or
unbranched alkynyl group having 2-4 carbon atoms, such as ethynyl,
2-propynyl or 2-butynyl; [0562] (C.sub.2-6)alkynyl means a branched
or unbranched alkynyl group having 2-6 carbon atoms, such as
ethynyl, propynyl, n-butynyl, n-pentynyl, isopentynyl, isohexynyl
or n-hexynyl. (C.sub.2-4)alkynyl groups are preferred;
(C.sub.3-6)cycloalkyl means a cycloalkyl group having 3-6 carbon
atoms, being cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
[0563] (C.sub.3-7)cycloalkyl means a cycloalkyl group having 3-7
carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl or cycloheptyl; [0564] (C.sub.2-6)heterocycloalkyl means
a heterocycloalkyl group having 2-6 carbon atoms, preferably 3-5
carbon atoms, and one or two heteroatoms selected from N, O and/or
S, which may be attached via a heteroatom if feasible, or a carbon
atom; preferred heteroatoms are N or O; also preferred are
piperidine, morpholine, pyrrolidine and piperazine; with the most
preferred (C.sub.2-6)heterocycloalkyl being pyrrolidine; the
heterocycloalkyl group may be attached via a heteroatom if
feasible; [0565] (C.sub.3-7)heterocycloalkyl means a
heterocycloalkyl group having 3-7 carbon atoms, preferably 3-5
carbon atoms, and one or two heteroatoms selected from N, O and/or
S. Preferred heteroatoms are N or O; preferred (C.sub.3-7)
heterocycloalkyl groups are azetidinyl, pyrrolidinyl, piperidinyl,
homopiperidinyl or morpholinyl; more preferred
(C.sub.3-7)heterocycloalkyl groups are piperidine, morpholine and
pyrrolidine; and the heterocycloalkyl group may be attached via a
heteroatom if feasible; [0566] (C.sub.3-7)cycloalkoxy means a
cycloalkyl group having 3-7 carbon atoms, with the same meaning as
previously defined, attached via a ring carbon atom to an exocyclic
oxygen atom; [0567] (C.sub.6-10)aryl means an aromatic hydrocarbon
group having 6-10 carbon atoms, such as phenyl, naphthyl,
tetrahydronaphthyl or indenyl; the preferred (C.sub.6-10)aryl group
is phenyl; [0568] (C.sub.1-5)heteroaryl means a substituted or
unsubstituted aromatic group having 1-5 carbon atoms and 1-4
heteroatoms selected from N, O and/or S; the (C.sub.1-5)heteroaryl
may optionally be substituted; preferred (C.sub.1-5)heteroaryl
groups are tetrazolyl, imidazolyl, thiadiazolyl, pyridyl,
pyrimidyl, triazinyl, thienyl or furyl, a more preferred
(C.sub.1-5)heteroaryl is pyrimidyl; [0569] (C.sub.1-9)heteroaryl
means a substituted or unsubstituted aromatic group having 1-9
carbon atoms and 1-4 heteroatoms selected from N, O and/or S; the
(C.sub.1-9)heteroaryl may optionally be substituted; preferred
(C.sub.1-9)heteroaryl groups are quinoline, isoquinoline and
indole; [0570] [(C.sub.1-4)alkyl]amino means an amino group,
monosubstituted with an alkyl group containing 1-4 carbon atoms
having the same meaning as previously defined; preferred
[(C.sub.1-4)alkyl]amino group is methylamino; [0571]
di[(C.sub.1-4)alkyl]amino means an amino group, disubstituted with
alkyl group(s), each containing 1-4 carbon atoms and having the
same meaning as previously defined; preferred
di[(C.sub.1-4)alkyl]amino group is dimethylamino; [0572] halogen
means fluorine, chlorine, bromine or iodine; [0573]
(C.sub.1-3)alkyl-C(O)--S--(C.sub.1-3)alkyl means an
alkyl-carbonyl-thio-alkyl group, each of the alkyl groups having 1
to 3 carbon atoms with the same meaning as previously defined;
[0574] (C.sub.3-7)cycloalkenyl means a cycloalkenyl group having
3-7 carbon atoms, preferably 5-7 carbon atoms; preferred
(C.sub.3-7)cycloalkenyl groups are cyclopentenyl or cyclohexenyl;
cyclohexenyl groups are most preferred; [0575]
(C.sub.2-6)heterocycloalkenyl means a heterocycloalkenyl group
having 2-6 carbon atoms, preferably 3-5 carbon atoms; and 1
heteroatom selected from N, O and/or S; preferred
(C.sub.2-6)heterocycloalkenyl groups are oxycyclohexenyl and
azacyclohexenyl group.
[0576] In the above definitions with multifunctional groups, the
attachment point is at the last group.
[0577] When, in the definition of a substituent, it is indicated
that "all of the alkyl groups" of said substituent are optionally
substituted, this also includes the alkyl moiety of an alkoxy
group.
[0578] A circle in a ring of Formula (XVII) indicates that the ring
is aromatic.
[0579] Depending on the ring formed, the nitrogen, if present in X
or Y, may carry a hydrogen.
[0580] In a preferred embodiment, the BTK inhibitor is a compound
of Formula (XVII) or a pharmaceutically acceptable salt thereof,
wherein: [0581] X is CH or S; [0582] Y is C(R.sub.6); [0583] Z is
CH or bond; [0584] A is CH; [0585] B.sub.1 is N or C(R.sub.7);
[0586] B.sub.2 is N or C(R.sub.8); [0587] B.sub.3 is N or CH;
[0588] B.sub.4 is N or CH; [0589] R.sub.1 is R.sub.11C(.dbd.O),
[0590] R.sub.2 is (C.sub.1-3)alkyl; [0591] R.sub.3 is
(C.sub.1-3)alkyl; or [0592] R.sub.2 and R.sub.3 form, together with
the N and C atom they are attached to, a
(C.sub.3-7)heterocycloalkyl ring selected from the group consisting
of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl,
optionally substituted with one or more fluorine, hydroxyl,
(C.sub.1-3)alkyl, or (C.sub.1-3)alkoxy; [0593] R.sup.4 is H; [0594]
R.sub.5 is H, halogen, cyano, (C.sub.1-4)alkyl, (C.sub.1-3)alkoxy,
(C.sub.3-6)cycloalkyl, or an alkyl group which is optionally
substituted with one or more halogen; [0595] R.sub.6 is H or
(C.sub.1-3)alkyl; [0596] R.sub.7 is H, halogen or
(C.sub.1-3)alkoxy; [0597] R.sub.8 is H or (C.sub.1-3)alkyl; or
[0598] R.sub.7 and R.sub.8 form, together with the carbon atom they
are attached to a (C.sub.6-10)aryl or (C.sub.1-9)heteroaryl; [0599]
R.sub.5 and R.sub.6 together may form a (C.sub.3-7)cycloalkenyl or
(C.sub.2-6)heterocycloalkenyl, each optionally substituted with
(C.sub.1-3)alkyl or one or more halogen; [0600] R.sub.11 is
independently selected from the group consisting of
(C.sub.2-6)alkenyl and (C.sub.2-6)alkynyl, where each alkenyl or
alkynyl is optionally substituted with one or more substituents
selected from the group consisting of hydroxyl, (C.sub.1-4)alkyl,
(C.sub.3-7)cycloalkyl, [(C.sub.1-4)alkyl]amino,
di[(C.sub.1-4)alkyl]amino, (C.sub.1-3)alkoxy,
(C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl and
(C.sub.3-7)heterocycloalkyl; with the proviso that 0 to 2 atoms of
B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are N.
[0601] In an embodiment of Formula (XVII), B.sub.1 is C(R.sub.7);
B.sub.2 is C(R.sub.9); B.sub.3 is C(R.sub.9); B.sub.4 is
C(R.sub.10); R.sub.7, R.sub.9, and R.sub.10 are each H; and R.sub.8
is hydrogen or methyl.
[0602] In an embodiment of Formula (XVII), the ring containing X, Y
and Z is selected from the group consisting of pyridyl, pyrimidyl,
pyridazyl, triazinyl, thiazolyl, oxazolyl and isoxazolyl.
[0603] In an embodiment of Formula (XVII), the ring containing X, Y
and Z is selected from the group consisting of pyridyl, pyrimidyl
and pyridazyl.
[0604] In an embodiment of Formula (XVII), the ring containing X, Y
and Z is selected from the group consisting of pyridyl and
pyrimidyl.
[0605] In an embodiment of Formula (XVII), the ring containing X, Y
and Z is pyridyl.
[0606] In an embodiment of Formula (XVII), R.sub.5 is selected from
the group consisting of hydrogen, fluorine, methyl, methoxy and
trifluoromethyl.
[0607] In an embodiment of Formula (XVII), R.sub.5 is hydrogen.
[0608] In an embodiment of Formula (XVII), R.sub.2 and R.sub.3
together form a heterocycloalkyl ring selected from the group
consisting of azetidinyl, pyrrolidinyl, piperidinyl,
homopiperidinyl and morpholinyl, optionally substituted with one or
more of fluoro, hydroxyl, (C.sub.1-3)alkyl and
(C.sub.1-3)alkoxy.
[0609] In an embodiment of Formula (XVII), R.sub.2 and R.sub.3
together form a heterocycloalkyl ring selected from the group
consisting of azetidinyl, pyrrolidinyl and piperidinyl.
[0610] In an embodiment of Formula (XVII), R.sub.2 and R.sub.3
together form a pyrrolidinyl ring.
[0611] In an embodiment of Formula (XVII), R.sub.1 is independently
selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl or (C.sub.2-6)alkynyl, each optionally
substituted with one or more substituents selected from the group
consisting of hydroxyl, (C.sub.1-4)alkyl, (C.sub.3-7)cycloalkyl,
[(C.sub.1-4)alkyl]amino, di[(C.sub.1-4)alkyl]amino,
(C.sub.1-3)alkoxy, (C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl and
(C.sub.3-7)heterocycloalkyl.
[0612] In an embodiment of Formula (XVII), B.sub.1, B.sub.2,
B.sub.3 and B.sub.4 are CH; X is N; Y and Z are CH; R.sub.5 is
CH.sub.3; A is N; R.sub.2, R.sub.3 and R.sub.4 are H; and R.sub.1
is CO--CH.sub.3.
[0613] In an embodiment of Formula (XVII), B.sub.1, B.sub.2,
B.sub.3 and B.sub.4 are CH; X and Y are N; Z is CH; R.sub.5 is
CH.sub.3; A is N; R.sub.2, R.sub.3 and R.sub.4 are H; and R.sub.1
is CO--CH.sub.3.
[0614] In an embodiment of Formula (XVII), B.sub.1, B.sub.2,
B.sub.3 and B.sub.4 are CH; X and Y are N; Z is CH; R.sub.5 is
CH.sub.3; A is CH; R.sub.2 and R.sub.3 together form a piperidinyl
ring; R.sub.4 is H; and R.sub.1 is CO-ethenyl.
[0615] In an embodiment of Formula (XVII), B.sub.1, B.sub.2,
B.sub.3 and B.sub.4 are CH; X, Y and Z are CH; R.sub.5 is H; A is
CH; R.sub.2 and R.sub.3 together form a pyrrolidinyl ring; R.sub.4
is H; and R.sub.1 is CO-propynyl.
[0616] In an embodiment of Formula (XVII), B.sub.1, B.sub.2,
B.sub.3 and B.sub.4 are CH; X, Y and Z are CH; R.sub.5 is CH.sub.3;
A is CH; R.sub.2 and R.sub.3 together form a piperidinyl ring;
R.sub.4 is H; and R.sub.1 is CO-propynyl.
[0617] In an embodiment of Formula (XVII), B.sub.1, B.sub.2,
B.sub.3 and B.sub.4 are CH; X and Y are N; Z is CH; R.sub.5 is H; A
is CH; R.sub.2 and R.sub.3 together form a morpholinyl ring;
R.sub.4 is H; and R.sub.1 is CO-ethenyl.
[0618] In an embodiment of Formula (XVII), B.sub.1, B.sub.2,
B.sub.3 and B.sub.4 are CH; X and Y are N; Z is CH; R.sub.5 is
CH.sub.3; A is CH; R.sub.2 and R.sub.3 together form a morpholinyl
ring; R.sub.4 is H; and R.sub.1 is CO-propynyl.
[0619] In a preferred embodiment, the BTK inhibitor is a compound
of Formula (XVIII):
##STR00037## [0620] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in International Patent Application
Publication No. WO 2013/010868, the disclosure of which is
incorporated herein by reference.
[0621] In a preferred embodiment, the BTK inhibitor is
(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1--
yl)-N-(pyridin-2-yl)benzamide or pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof.
[0622] In a preferred embodiment, the BTK inhibitor is a compound
of Formula (XVIII-A):
##STR00038## [0623] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in International Patent Application
Publication No. WO 2013/010868, the disclosure of which is
incorporated herein by reference.
[0624] In a preferred embodiment, the BTK inhibitor is a compound
of Formula (XVIII-B):
##STR00039## [0625] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in International Patent Application
Publication No. WO 2013/010868, the disclosure of which is
incorporated herein by reference.
[0626] In a preferred embodiment, the BTK inhibitor is a compound
of Formula (XVIII-C):
##STR00040## [0627] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in International Patent Application
Publication No. WO 2013/010868, the disclosure of which is
incorporated herein by reference.
[0628] In a preferred embodiment, the BTK inhibitor is a compound
of Formula (XVIII-D):
##STR00041## [0629] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in International Patent Application
Publication No. WO 2013/010868, the disclosure of which is
incorporated herein by reference.
[0630] In a preferred embodiment, the BTK inhibitor is a compound
of Formula (XVIII-E):
##STR00042## [0631] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in International Patent Application
Publication No. WO 2013/010868, the disclosure of which is
incorporated herein by reference.
[0632] In other embodiments, the BTK inhibitors include, but are
not limited to, those compounds described in International Patent
Application Publication No. WO 2013/010868, the disclosures of each
of which are specifically incorporated by reference herein.
[0633] In an embodiment, the BTK inhibitor is a compound of Formula
(XIX) or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug of a compound of Formula (XIX):
##STR00043##
[0634] In Formula (XIX) the substituents are defined as [0635] X is
CH, N, O or S; [0636] Y is C(R.sub.6), N, O or S; [0637] Z is CH, N
or bond; [0638] A is CH or N; [0639] B.sub.1 is N or C(R.sub.7);
[0640] B.sub.2 is N or C(R.sub.8); [0641] B.sub.3 is N or
C(R.sub.9); [0642] B.sub.4 is N or C(R.sub.10); [0643] R.sub.1 is
R.sub.11C(O), R.sub.12S(O), R.sub.13SO.sub.2 or (C.sub.1-6)alkyl
optionally substituted with R.sub.14; [0644] R.sub.2 is H,
(C.sub.1-3)alkyl or (C.sub.3-7)cycloalkyl; [0645] R.sub.3 is H,
(C.sub.1-6)alkyl or (C.sub.3-7)cycloalkyl); or [0646] R.sub.2 and
R.sub.3 form, together with the N and C atom they are attached to,
a (C.sub.3-7)heterocycloalkyl optionally substituted with one or
more fluorine, hydroxyl, (C.sub.1-3)alkyl, (C.sub.1-3)alkoxy or
oxo; [0647] R.sub.4 is H or (C.sub.1-3)alkyl; [0648] R.sub.5 is H,
halogen, cyano, (C.sub.1-4)alkyl, (C.sub.1-3)alkoxy,
(C.sub.3-6)cycloalkyl; all alkyl groups of R5 are optionally
substituted with one or more halogen; or R.sub.5 is
(C.sub.6-10)aryl or (C.sub.2-6)heterocycloalkyl; [0649] R.sub.6 is
H or (C.sub.1-3)alkyl; or R.sub.5 and R.sub.6 together may form a
(C.sub.3-7)cycloalkenyl, or (C.sub.2-6)heterocycloalkenyl; each
optionally substituted with (C.sub.1-3)alkyl, or one or more
halogen; [0650] R.sub.7 is H, halogen, CF.sub.3, (C.sub.1-3)alkyl
or (C.sub.1-3)alkoxy; [0651] R.sub.8 is H, halogen, CF.sub.3,
(C.sub.1-3)alkyl or (C.sub.1-3)alkoxy; or [0652] R.sub.7 and
R.sub.8 together with the carbon atoms they are attached to, form
(C.sub.6-10)aryl or (C.sub.1-5)heteroaryl; [0653] R.sub.9 is H,
halogen, (C.sub.1-3)alkyl or (C.sub.1-3)alkoxy; [0654] R.sub.10 is
H, halogen, (C.sub.1-3)alkyl or (C.sub.1-3)alkoxy; [0655] R.sub.11
is independently selected from a group consisting of
(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl and (C.sub.2-6)alkynyl each
alkyl, alkenyl or alkynyl optionally substituted with one or more
groups selected from hydroxyl, (C.sub.1-4)alkyl,
(C.sub.3-7)cycloalkyl, [(C.sub.1-4)alkyl]amino,
di[(C.sub.1-4)alkyl]amino, (C.sub.1-3)alkoxy,
(C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl or
(C.sub.3-7)heterocycloalkyl, or [0656] R.sub.11 is
(C.sub.1-3)alkyl-C(O)--S--(C.sub.1-3)alkyl; or [0657] R.sub.11 is
(C.sub.1-5)heteroaryl optionally substituted with one or more
groups selected from halogen or cyano.
[0658] R.sub.12 and R.sub.13 are independently selected from a
group consisting of (C.sub.2-6)alkenyl or (C.sub.2-6)alkynyl both
optionally substituted with one or more groups selected from
hydroxyl, (C.sub.1-4)alkyl, (C.sub.3-7)cycloalkyl,
[(C.sub.1-4)alkyl]amino, di[(C.sub.1-4)alkyl]amino,
(C.sub.1-3)alkoxy, (C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl, or
(C.sub.3-7)heterocycloalkyl; or [0659] (C.sub.1-5)heteroaryl
optionally substituted with one or more groups selected from
halogen or cyano; [0660] R.sub.14 is independently selected from a
group consisting of halogen, cyano or (C.sub.2-6)alkenyl or
(C.sub.2-6)alkynyl both optionally substituted with one or more
groups selected from hydroxyl, (C.sub.1-4)alkyl,
(C.sub.3-7)cycloalkyl, [(C.sub.1-4)alkyl]amino,
di[(C.sub.1-4)alkyl]amino, (C.sub.1-3)alkoxy,
(C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl, (C.sub.1-5)heteroaryl or
(C.sub.3-7)heterocycloalkyl; [0661] with the proviso that
[0662] 0 to 2 atoms of X, Y, Z can simultaneously be a
heteroatom;
[0663] when one atom selected from X, Y is O or S, then Z is a bond
and the other atom selected from X, Y can not be O or S;
[0664] when Z is C or N then Y is C(R.sub.6) or N and X is C or
N;
[0665] 0 to 2 atoms of B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are N;
[0666] with the terms used having the following meanings: [0667]
(C.sub.1-3)alkyl means a branched or unbranched alkyl group having
1-3 carbon atoms, being methyl, ethyl, propyl or isopropyl; [0668]
(C.sub.1-4)alkyl means a branched or unbranched alkyl group having
1-4 carbon atoms, being methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl and tert-butyl, (C.sub.1-3)alkyl groups being
preferred; [0669] (C.sub.1-6)alkyl means a branched or unbranched
alkyl group having 1-6 carbon atoms, for example methyl, ethyl,
propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl.
(C.sub.1-8)alkyl groups are preferred, (C.sub.1-4)alkyl being most
preferred; [0670] (C.sub.1-2)alkoxy means an alkoxy group having
1-2 carbon atoms, the alkyl moiety having the same meaning as
previously defined; [0671] (C.sub.1-3)alkoxy means an alkoxy group
having 1-3 carbon atoms, the alkyl moiety having the same meaning
as previously defined, with (C.sub.1-2)alkoxy groups preferred;
[0672] (C.sub.2-3)alkenyl means an alkenyl group having 2-3 carbon
atoms, such as ethenyl or 2-propenyl; [0673] (C.sub.2-4)alkenyl
means a branched or unbranched alkenyl group having 2-4 carbon
atoms, such as ethenyl, 2-propenyl, isobutenyl or 2-butenyl; [0674]
(C.sub.2-6)alkenyl means a branched or unbranched alkenyl group
having 2-6 carbon atoms, such as ethenyl, 2-butenyl, and
n-pentenyl, with (C.sub.2-4)alkenyl groups preferred, and
(C.sub.2-3)alkenyl groups even more preferred; [0675]
(C.sub.2-4)alkynyl means a branched or unbranched alkynyl group
having 2-4 carbon atoms, such as ethynyl, 2-propynyl or 2-butynyl;
[0676] (C.sub.2-3)alkynyl means an alkynyl group having 2-3 carbon
atoms, such as ethynyl or 2-propynyl; [0677] (C.sub.2-6)alkynyl
means a branched or unbranched alkynyl group having .sub.2-6 carbon
atoms, such as ethynyl, propynyl, n-butynyl, n-pentynyl,
isopentynyl, isohexynyl or n-hexynyl, with (C.sub.2-4)alkynyl
groups preferred, and (C.sub.2-3)alkynyl groups more preferred;
[0678] (C.sub.3-6)cycloalkyl means a cycloalkyl group having 3-6
carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl; [0679] (C.sub.3-7)cycloalkyl means a cycloalkyl group
having 3-7 carbon atoms, being cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl; [0680]
(C.sub.2-6)heterocycloalkyl means a heterocycloalkyl group having
2-6 carbon atoms, preferably 3-5 carbon atoms, and one or two
heteroatoms selected from N, O and/or S, which may be attached via
a heteroatom if feasible, or a carbon atom; preferred heteroatoms
are N or O; preferred groups are piperidine, morpholine,
pyrrolidine and piperazine; a most preferred
(C.sub.2-6)heterocycloalkyl is pyrrolidine; and the
heterocycloalkyl group may be attached via a heteroatom if
feasible; [0681] (C.sub.3-7)heterocycloalkyl means a
heterocycloalkyl group having 3-7 carbon atoms, preferably 3-5
carbon atoms, and one or two heteroatoms selected from N, O and/or
S; preferred heteroatoms are N or O; preferred (C.sub.3-7)
heterocycloalkyl groups are azetidinyl, pyrrolidinyl, piperidinyl,
homopiperidinyl or morpholinyl; more preferred
(C.sub.3-7)heterocycloalkyl groups are piperidine, morpholine and
pyrrolidine; even more preferred are piperidine and pyrrolodine;
and the heterocycloalkyl group may be attached via a heteroatom if
feasible; [0682] (C.sub.3-7)cycloalkoxy means a cycloalkyl group
having 3-7 carbon atoms, with the same meaning as previously
defined, attached via a ring carbon atom to an exocyclic oxygen
atom; [0683] (C.sub.6-10)aryl means an aromatic hydrocarbon group
having 6-10 carbon atoms, such as phenyl, naphthyl,
tetrahydronaphthyl or indenyl; the preferred (C.sub.6-10)aryl group
is phenyl; [0684] (C.sub.1-5)heteroaryl means a substituted or
unsubstituted aromatic group having 1-5 carbon atoms and 1-4
heteroatoms selected from N, O and/or S, wherein the
(C.sub.1-5)heteroaryl may optionally be substituted; preferred
(C.sub.1-5)heteroaryl groups are tetrazolyl, imidazolyl,
thiadiazolyl, pyridyl, pyrimidyl, triazinyl, thienyl or furyl, and
the more preferred (C.sub.1-5)heteroaryl is pyrimidyl; [0685]
[(C.sub.1-4)alkyl]amino means an amino group, monosubstituted with
an alkyl group containing 1-4 carbon atoms having the same meaning
as previously defined; the preferred [(C.sub.1-4)alkyl]amino group
is methylamino; [0686] di[(C.sub.1-4)alkyl]amino means an amino
group, disubstituted with alkyl group(s), each containing 1-4
carbon atoms and having the same meaning as previously defined; the
preferred di[(C.sub.1-4)alkyl]amino group is dimethylamino; [0687]
halogen means fluorine, chlorine, bromine or iodine; [0688]
(C.sub.1-3)alkyl-C(O)--S--(C.sub.1-3)alkyl means an
alkyl-carbonyl-thio-alkyl group, each of the alkyl groups having 1
to 3 carbon atoms with the same meaning as previously defined;
[0689] (C.sub.3-7)cycloalkenyl means a cycloalkenyl group having
3-7 carbon atoms, preferably 5-7 carbon atoms; preferred
(C.sub.3-7)cycloalkenyl groups are cyclopentenyl or cyclohexenyl;
and cyclohexenyl groups are most preferred; [0690]
(C.sub.2-6)heterocycloalkenyl means a heterocycloalkenyl group
having 2-6 carbon atoms, preferably 3-5 carbon atoms; and 1
heteroatom selected from N, O and/or S; the preferred
(C.sub.2-6)heterocycloalkenyl groups are oxycyclohexenyl and
azacyclohexenyl groups.
[0691] In the above definitions with multifunctional groups, the
attachment point is at the last group.
[0692] When, in the definition of a substituent, is indicated that
"all of the alkyl groups" of said substituent are optionally
substituted, this also includes the alkyl moiety of an alkoxy
group.
[0693] A circle in a ring of Formula (XIX) indicates that the ring
is aromatic.
[0694] Depending on the ring formed, the nitrogen, if present in X
or Y, may carry a hydrogen.
[0695] In a preferred embodiment, the invention relates to a
compound according to Formula (XIX) wherein B.sub.1 is C(R.sub.7);
B.sub.2 is C(R.sub.8); B.sub.3 is C(R.sub.9) and B.sub.4 is
C(R.sub.10).
[0696] In other embodiments, the BTK inhibitors include, but are
not limited to, those compounds described in International Patent
Application Publication No. WO 2013/010869, the disclosures of each
of which are specifically incorporated by reference herein.
[0697] In an embodiment, the BTK inhibitor is a compound of Formula
(XX):
##STR00044## [0698] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0699] L.sub.a is
CH.sub.2, O, NH or S; [0700] Ar is a substituted or unsubstituted
aryl, or a substituted or unsubstituted heteroaryl; [0701] Y is an
optionally substituted group selected from the group consisting of
alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl; [0702] Z is C(.dbd.O), OC(.dbd.O), NRC(.dbd.O),
C(.dbd.S), S(.dbd.O).sub.x, OS(.dbd.O).sub.x or NRS(.dbd.O).sub.x,
where x is 1 or 2; [0703] R.sup.7 and R.sup.8 are each
independently H; or R.sup.7 and R.sup.8 taken together form a bond;
[0704] R.sup.6 is H; and [0705] R is H or (C.sub.1-6)alkyl.
[0706] In an embodiment, the BTK inhibitor is ibrutinib or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. In an exemplary embodiment, the BTK inhibitor is
(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one. In an exemplary embodiment, the BTK
inhibitor is
1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]p-
iperidin-1-yl]prop-2-en-1-one. In an exemplary embodiment, the BTK
inhibitor is
(S)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one. In an exemplary embodiment, the BTK
inhibitor has the structure of Formula (XX-A), or an enantiomer
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
##STR00045##
[0707] In an exemplary embodiment, the BTK inhibitor is a compound
of Formula (XXI):
##STR00046## [0708] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0709] L.sub.a is
CH.sub.2, O, NH or S; [0710] Ar is a substituted or unsubstituted
aryl, or a substituted or unsubstituted heteroaryl; [0711] Y is an
optionally substituted group selected from the group consisting of
alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl; [0712] Z is C(.dbd.O), OC(.dbd.O), NRC(.dbd.O),
C(.dbd.S), S(.dbd.O).sub.x, OS(.dbd.O).sub.x or NRS(.dbd.O).sub.x,
where x is 1 or 2; [0713] R.sup.7 and R.sup.8 are each H; or
R.sup.7 and R.sup.8 taken together form a bond; [0714] R.sup.6 is
H; and [0715] R is H or (C.sub.1-6)alkyl.
[0716] In an embodiment, the BTK inhibitor is a compound of Formula
(XXII):
##STR00047## [0717] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0718] L.sub.a is
CH.sub.2, O, NH or S; [0719] Ar is a substituted or unsubstituted
aryl, or a substituted or unsubstituted heteroaryl; [0720] Y is an
optionally substituted group selected from the group consisting of
alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl; [0721] Z is C(.dbd.O), OC(.dbd.O), NRC(.dbd.O),
C(.dbd.S), S(.dbd.O).sub.x, OS(.dbd.O).sub.x or NRS(.dbd.O).sub.x,
where x is 1 or 2; [0722] R.sup.7 and R.sup.8 are each H; or
R.sup.7 and R.sup.8 taken together form a bond; [0723] R.sup.6 is
H; and [0724] R is H or (C.sub.1-6)alkyl.
[0725] In an embodiment, the BTK inhibitor is a compound of Formula
(XXIII):
##STR00048## [0726] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0727] L.sub.a is
CH.sub.2, O, NH or S; [0728] Ar is a substituted or unsubstituted
aryl, or a substituted or unsubstituted heteroaryl; [0729] Y is an
optionally substituted group selected from the group consisting of
alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl; [0730] Z is C(.dbd.O), OC(.dbd.O), NRC(.dbd.O),
C(.dbd.S), S(.dbd.O).sub.x, OS(.dbd.O).sub.x or NRS(.dbd.O).sub.x,
where x is 1 or 2; [0731] R.sup.7 and R.sup.8 are each H; or
R.sup.7 and R.sup.8 taken together form a bond; [0732] R.sup.6 is
H; and [0733] R is H or (C.sub.1-6)alkyl.
[0734] In an embodiment, the BTK inhibitor is a compound disclosed
in U.S. Pat. No. 7,459,554, the disclosure of which is specifically
incorporated herein by reference. In an embodiment, the BTK
inhibitor is a compound of Formula (XXIV):
##STR00049## [0735] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0736] Q.sup.1 is
aryl.sup.1, heteroaryl.sup.1, cycloalkyl, heterocyclyl,
cycloalkenyl, or heterocycloalkenyl, any of which is optionally
substituted by one to five independent G.sup.1 substituents; [0737]
R.sup.1 is alkyl, cycloalkyl, bicycloalkyl, aryl, heteroaryl,
aralkyl, heteroaralkyl, heterocyclyl, or heterobicycloalkyl, any of
which is optionally substituted by one or more independent G
substituents; [0738] G.sup.1 and G.sup.41 are each independently
halo, oxo, --CF.sub.3, --OCF.sub.3, --OR.sup.2,
--NR.sup.2R.sup.3(R.sup.3a).sub.j1, --C(O)R.sup.2,
--CO.sub.2R.sup.2, --CONR.sup.2R.sup.3, --NO.sub.2, --CN,
--S(O).sub.j1R.sup.2, --SO.sub.2NR.sup.2R.sup.3,
NR.sup.2(C.dbd.O)R.sup.3, NR.sup.2(C.dbd.O)OR.sup.3,
NR.sup.2(C.dbd.O)NR.sup.2R.sup.3, NR.sup.2S(O).sub.j1R.sup.3,
--(C.dbd.S)OR.sup.2, --(C.dbd.O)SR.sup.2,
--NR.sup.2(C.dbd.NR.sup.3)NR.sup.2aR.sup.3a,
--NR.sup.2(C.dbd.NR.sup.3)OR.sup.2a,
--NR.sup.2(C.dbd.NR.sup.3)SR.sup.3a, --O(C.dbd.O)OR.sup.2,
--O(C.dbd.O)NR.sup.2R.sup.3, --O(C.dbd.O)SR.sup.2,
--S(C.dbd.O)OR.sup.2, --S(C.dbd.O)NR.sup.2R.sup.3,
(C.sub.0-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10) alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl, cyclo(C.sub.3-8)
alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted with one or more independent halo, oxo, --CF.sub.3,
--OCF.sub.3, --OR.sup.222,
--NR.sup.222R.sup.333(R.sup.333a).sub.j1a, --C(O)R.sup.222,
--CO.sub.2R.sup.222, --CONR.sup.222R.sup.333, --NO.sub.2, --CN,
--S(O).sub.j1aR.sup.222, --SO.sub.2NR.sup.222R.sup.333,
NR.sup.222(C.dbd.O)R.sup.333, NR.sup.222(C.dbd.O)OR.sup.333,
NR.sup.222(C.dbd.O)NR.sup.222R.sup.333,
NR.sup.222S(O).sub.j1aR.sup.333, --(C.dbd.S)OR.sup.222,
--(C.dbd.O)SR.sup.222,
--NR.sup.222(C.dbd.NR.sup.333)NR.sup.222aR.sup.333a,
--NR.sup.222(C.dbd.NR.sup.333)OR.sup.222a,
--NR.sup.222(C.dbd.NR.sup.333)SR.sup.333a, --O(C.dbd.O)OR.sup.222,
--O(C.dbd.O)NR.sup.222R.sup.333, --O(C.dbd.O)SR.sup.222,
--S(C.dbd.O)OR.sup.222, or --S(C.dbd.O)NR.sup.222R.sup.333
substituents; or --(X.sup.1).sub.n--(Y.sup.1).sub.m--R.sup.4; or
aryl-(C.sub.0-10)alkyl, aryl-(C.sub.2-10)alkenyl, or
aryl-(C.sub.2-10) alkynyl, any of which is optionally substituted
with one or more independent halo, --CF.sub.3, --OCF.sub.3,
--OR.sup.222, --NR.sup.222R.sup.333(R.sup.333a).sub.j2a,
--C(O)R.sup.222, --CO.sub.2R.sup.222, --CONR.sup.222R.sup.333,
--NO.sub.2, --CN, --S(O).sub.j2aR.sup.222,
--SO.sub.2NR.sup.222R.sup.333, NR.sup.222(C.dbd.O)R.sup.333,
NR.sup.222(C.dbd.O)OR.sup.333,
NR.sup.222(C.dbd.O)NR.sup.222R.sup.333,
NR.sup.222S(O).sub.j2aR.sup.333, --(C.dbd.S)OR.sup.222,
--(C.dbd.O)SR.sup.222,
--NR.sup.222(C.dbd.NR.sup.333)NR.sup.222aR.sup.333a,
--NR.sup.222(C.dbd.NR.sup.333)OR.sup.222a,
--NR.sup.222(C.dbd.NR.sup.333)SR.sup.333a, --O(C.dbd.O)OR.sup.222,
--O(C.dbd.O)NR.sup.222R.sup.333, --O(C.dbd.O)SR.sup.222,
--S(C.dbd.O)OR.sup.222, or --S(C.dbd.O)NR.sup.222R.sup.333
substituents; or hetaryl-(C.sub.0-10)alkyl,
hetaryl-(C.sub.2-10)alkenyl, or hetaryl-(C.sub.2-10)alkynyl, any of
which is optionally substituted with one or more independent halo,
--CF.sub.3, --OCF.sub.3, --OR.sup.222, --NR.sup.222,
R.sup.333(R.sup.333a).sub.j3a, --C(O)R.sup.222,
--CO.sub.2R.sup.222, --CONR.sup.222R.sup.333, --NO.sub.2, --CN,
--S(O).sub.j3aR.sup.222, --SO.sub.2NR.sup.222R.sup.333,
NR.sup.222(C.dbd.O)R.sup.333, NR.sup.222(C.dbd.O)OR.sup.333,
NR.sup.222(C.dbd.O)NR.sup.222R.sup.333,
NR.sup.222S(O).sub.j3aR.sup.333, --(C.dbd.S)OR.sup.222,
--(C.dbd.O)SR.sup.222,
--NR.sup.222(C.dbd.NR.sup.333)NR.sup.222aR.sup.333a,
--NR.sup.222(C.dbd.NR.sup.333)OR.sup.222a,
--NR.sup.222(C.dbd.NR.sup.333)SR.sup.333a, --O(C.dbd.O)OR.sup.222,
--O(C.dbd.O)NR.sup.222R.sup.333, --O(C.dbd.O)SR.sup.222,
--S(C.dbd.O)OR.sup.222, or --S(C.dbd.O)NR.sup.222R.sup.333
substituents; [0739] G.sup.11 is halo, oxo, --CF.sub.3,
--OCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.31 (R.sup.3a1).sub.j4,
--C(O)R.sup.21, --CO.sub.2R.sup.21, --CONR.sup.21R.sup.31,
--NO.sub.2, --CN, --S(O).sub.j4R.sup.21,
--SO.sub.2NR.sup.21R.sup.31, NR.sup.21(C.dbd.O)R.sup.31,
NR.sup.21(C.dbd.O)OR.sup.31, NR.sup.21(C.dbd.O)NR.sup.21R.sup.31,
NR.sup.21S(O).sub.j4R.sup.31, --(C.dbd.S)OR.sup.21,
--(C.dbd.O)SR.sup.21, --NR.sup.21
(C.dbd.NR.sup.31)NR.sup.2a1R.sup.3a1,
--NR.sup.21(C.dbd.NR.sup.31)OR.sup.2a1,
--NR.sup.21(C.dbd.NR.sup.31)SR.sup.3a1, --O(C.dbd.O)OR.sup.21,
--O(C.dbd.O)NR.sup.21R.sup.31, --O(C.dbd.O)SR.sup.21,
--S(C.dbd.O)OR.sup.21, --S(C.dbd.O)NR.sup.21R.sup.31,
--P(O)OR.sup.21OR.sup.31, (C.sub.0-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, (C.sub.1-10) alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl, (C.sub.1-10)
alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10) alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl, cyclo(C.sub.3-8)
alkyl(C.sub.2-10) alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10) alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted with one or more independent halo, oxo, --CF.sub.3,
--OCF.sub.3, --OR.sup.2221,
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j4a, --C(O)R.sup.2221,
--CO.sub.2R.sup.2221, --CONR.sup.2221R.sup.3331, --NO.sub.2, --CN,
--S(O).sub.j4aR.sup.2221, --SO.sub.2NR.sup.2221R.sup.3331,
NR.sup.2221(C.dbd.O)R.sup.3331, NR.sup.2221(C.dbd.O)OR.sup.3331,
NR.sup.2221(C.dbd.O)NR.sup.2221R.sup.3331,
NR.sup.2221S(O).sub.j4aR.sup.3331, --(C.dbd.S)OR.sup.2221,
--(C.dbd.O)SR.sup.2221,
--NR.sup.2221(C.dbd.NR.sup.3331)NR.sup.222a1R.sup.333a1,
--NR.sup.2221(C.dbd.NR.sup.3331)OR.sup.222a1,
--NR.sup.2221(C.dbd.NR.sup.3331)SR.sup.333a1,
--O(C.dbd.O)OR.sup.2221, --O(C.dbd.O)NR.sup.2221R.sup.3331,
--O(C.dbd.O)SR.sup.2221, --S(C.dbd.O)OR.sup.2221,
--P(O)OR.sup.2221OR.sup.3331, or --S(C.dbd.O)NR.sup.2221R.sup.3331
substituents; or aryl-(C.sub.0-10)alkyl, aryl-(C.sub.2-10)alkenyl,
or aryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, --CF.sub.3, --OCF.sub.3,
--OR.sup.2221, --NR.sup.2221R.sup.3331 (R.sup.333a1).sub.j5a,
--C(O)R.sup.2221, --CO.sub.2R.sup.2221, --CONR.sup.2221R.sup.3331,
--NO.sub.2, --CN, --S(O).sub.j5aR.sup.2221,
--SO.sub.2NR.sup.2221R.sup.3331, NR.sup.2221(C.dbd.O)R.sup.3331,
NR.sup.2221(C.dbd.O)OR.sup.3331,
NR.sup.2221(C.dbd.O)NR.sup.2221R.sup.3331,
NR.sup.2221S(O).sub.j5aR.sup.3331, --(C.dbd.S)OR.sup.2221,
--(C.dbd.O)SR.sup.2221,
--NR.sup.2221(C.dbd.NR.sup.3331)NR.sup.222a1R.sup.333a1,
--NR.sup.2221(C.dbd.NR.sup.3331)OR.sup.222a1,
--NR.sup.2221(C.dbd.NR.sup.3331)SR.sup.333a1,
--O(C.dbd.O)OR.sup.2221, --O(C.dbd.O)NR.sup.2221R.sup.3331,
--O(C.dbd.O)SR.sup.2221, --S(C.dbd.O)OR.sup.2221,
--P(O)OR.sup.2221R.sup.3331, or --S(C.dbd.O)NR.sup.2221R.sup.3331
substituents; or hetaryl-(C.sub.0-10) alkyl,
hetaryl-(C.sub.2-10)alkenyl, or hetaryl-(C.sub.2-10)alkynyl, any of
which is optionally substituted with one or more independent halo,
--CF.sub.3, --OCF.sub.3, --OR.sup.2221,
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j6a, --C(O)R.sup.2221,
--CO.sub.2R.sup.221, --CONR.sup.2221R.sup.3331, --NO.sub.2, --CN,
--S(O).sub.j6aR.sup.2221, --SO.sub.2NR.sup.2221R.sup.3331,
NR.sup.2221(C.dbd.O)R.sup.3331, NR.sup.2221(C.dbd.O)OR.sup.3331,
NR.sup.2221(C.dbd.O)NR.sup.2221R.sup.3331,
NR.sup.2221S(O).sub.j6aR.sup.3331, --(C.dbd.S)OR.sup.2221,
--(C.dbd.O)SR.sup.2221,
--NR.sup.2221(C.dbd.NR.sup.3331)NR.sup.222a1R.sup.333a1,
--NR.sup.2221(C.dbd.NR.sup.3331)OR.sup.222a1,
--NR.sup.2221(C.dbd.NR.sup.333)SR.sup.333a1,
--O(C.dbd.O)OR.sup.2221, --O(C.dbd.O)NR.sup.2221R.sup.3331,
--O(C.dbd.O)SR.sup.2221, --S(C.dbd.O)OR.sup.2221,
--P(O)OR.sup.2221OR.sup.3331, or --S(C.dbd.O)NR.sup.2221R.sup.3331
substituents; or G.sup.11 is taken together with the carbon to
which it is attached to form a double bond which is substituted
with R.sup.5 and G.sup.111; [0740] R.sup.2, R.sup.2a, R.sup.3,
R.sup.3a, R.sup.222, R.sup.222a, R.sup.333, R.sup.333a, R.sup.21,
R.sup.2a1, R.sup.31, R.sup.3a1, R.sup.2221, R.sup.222a1,
R.sup.3331, and R.sup.333a1 are each independently equal to
(C.sub.0-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted by one or more G.sup.111 substituents; or
aryl-(C.sub.0-10)alkyl, aryl-(C.sub.2-10)alkenyl, or
aryl-(C.sub.2-10)alkynyl, hetaryl-(C.sub.0-10)alkyl,
hetaryl-(C.sub.2-10)alkenyl, or hetaryl-(C.sub.2-10)alkynyl, any of
which is optionally substituted by one or more G.sup.111
substituents; or in the case of --NR.sup.2R.sup.3(R.sup.3a).sub.j1
or --NR.sup.222R.sup.333(R.sup.333a).sub.j1a or
--NR.sup.222R.sup.333(R.sup.333a).sub.j2a or
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j3a or
--NR.sup.2221R.sup.3331 (R.sup.333a1).sub.j4a or
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j5a or
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j6a, R.sup.2 and R.sup.3
or R.sup.222 and R.sup.3333 or R.sup.2221 and R.sup.3331 taken
together with the nitrogen atom to which they are attached form a
3-10 membered saturated ring, unsaturated ring, heterocyclic
saturated ring, or heterocyclic unsaturated ring, wherein said ring
is optionally substituted by one or more G.sup.111 substituents;
[0741] X.sup.1 and Y.sup.1 are each independently --O--,
--NR.sup.7--, --S(O).sub.j7--, --CR.sup.5R.sup.6--,
--N(C(O)OR.sup.7)--, --N(C(O)R.sup.7)--, --N(SO.sub.2R.sup.7)--,
--CH.sub.2O--, --CH.sub.2S--, --CH.sub.2N(R.sup.7)--,
--CH(NR.sup.7)--, --CH.sub.2N(C(O)R.sup.7)--,
--CH.sub.2N(C(O)OR.sup.7)--, --CH.sub.2N(SO.sub.2R.sup.7)--,
--CH(NHR.sup.7)--, --CH(NHC(O)R.sup.7)--,
--CH(NHSO.sub.2R.sup.7)--, --CH(NHC(O)OR.sup.7)--,
--CH(OC(O)R.sup.7)--, --CH(OC(O)NHR.sup.7)--, --CH.dbd.CH--,
--C.ident.C--, --C(.dbd.NOR.sup.7)--, --C(O)--, --CH(OR.sup.7)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2-- --OC(O)N(R.sup.7)--,
--N(R.sup.7)C(O)N(R.sup.7)--, --NR.sup.7C(O)O--,
--S(O)N(R.sup.7)--, --S(O).sub.2N(R.sup.7)--,
--N(C(O)R.sup.7)S(O)--, --N(C(O)R.sup.7)S(O).sub.2--,
--N(R.sup.7)S(O)N(R.sup.7)--, --N(R.sup.7)S(O).sub.2N(R.sup.7)--,
--C(O)N(R.sup.7)C(O)--, --S(O)N(R.sup.7)C(O)--,
--S(O).sub.2N(R.sup.7)C(O)--, --OS(O)N(R.sup.7)--,
--OS(O).sub.2N(R.sup.7)--, --N(R.sup.7)S(O)O--,
--N(R.sup.7)S(O).sub.2O--, --N(R.sup.7)S(O)C(O)--,
--N(R.sup.7)S(O).sub.2C(O)--, --SON(C(O)R.sup.7)--,
--SO.sub.2N(C(O)R.sup.7)--, --N(R.sup.7)SON(R.sup.7)--,
--N(R.sup.7)SO.sub.2N(R.sup.7)--, --C(O)O--,
--N(R.sup.7)P(OR.sup.8)O--, --N(R.sup.7)P(OR.sup.8)--,
--N(R.sup.7)P(O)(OR.sup.8)O--, --N(R.sup.7)P(O)(OR.sup.8)--,
--N(C(O)R.sup.7)P(OR.sup.8)O--, --N(C(O)R.sup.7)P(OR.sup.8)--,
--N(C(O)R.sup.7)P(O)(OR.sup.8)O--, --N(C(O)R.sup.7)P(OR.sup.8)--,
--CH(R.sup.7)S(O)--, --CH(R.sup.7)S(O).sub.2--,
--CH(R.sup.7)N(C(O)OR.sup.7)--, --CH(R.sup.7)N(C(O)R.sup.7)--,
--CH(R.sup.7)N(SO.sub.2R.sup.7)--, --CH(R.sup.7)O--,
--CH(R.sup.7)S--, --CH(R.sup.7)N(R.sup.7)--,
--CH(R.sup.7)N(C(O)R.sup.7)--, --CH(R.sup.7)N(C(O)OR.sup.7)--,
--CH(R.sup.7)N(SO.sub.2R.sup.7)--,
--CH(R.sup.7)C(.dbd.NOR.sup.7)--, --CH(R.sup.7)C(O)--,
--CH(R.sup.7)CH(OR.sup.7)--, --CH(R.sup.7)C(O)N(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)C(O)--, --CH(R.sup.7)N(R.sup.7)S(O)--,
--CH(R.sup.7)N(R.sup.7)S(O).sub.2--,
--CH(R.sup.7)OC(O)N(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)C(O)N(R.sup.7)--,
--CH(R.sup.7)NR.sup.7C(O)O--, --CH(R.sup.7)S(O)N(R.sup.7)--,
--CH(R.sup.7)S(O).sub.2N(R.sup.7)--,
--CH(R.sup.7)N(C(O)R.sup.7)S(O)--,
--CH(R.sup.7)N(C(O)R.sup.7)S(O)--,
--CH(R.sup.7)N(R.sup.7)S(O)N(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)S(O).sub.2N(R.sup.7)--,
--CH(R.sup.7)C(O)N(R.sup.7)C(O)--,
--CH(R.sup.7)S(O)N(R.sup.7)C(O)--,
--CH(R.sup.7)S(O).sub.2N(R.sup.7)C(O)--,
--CH(R.sup.7)OS(O)N(R.sup.7)--,
--CH(R.sup.7)OS(O).sub.2N(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)S(O)O--,
--CH(R.sup.7)N(R.sup.7)S(O).sub.2O--,
--CH(R.sup.7)N(R.sup.7)S(O)C(O)--,
--CH(R.sup.7)N(R.sup.7)S(O).sub.2C(O)--,
--CH(R.sup.7)SON(C(O)R.sup.7)--,
--CH(R.sup.7)SO.sub.2N(C(O)R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)SON(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)SO.sub.2N(R.sup.7)--, --CH(R.sup.7)C(O)O--,
--CH(R.sup.7)N(R.sup.7)P(OR.sup.8)O--,
--CH(R.sup.7)N(R.sup.7)P(OR.sup.8)--,
--CH(R.sup.7)N(R.sup.7)P(O)(OR.sup.8)O--,
--CH(R.sup.7)N(R.sup.7)P(O)(OR.sup.8)--,
--CH(R.sup.7)N(C(O)R.sup.7)P(OR.sup.8)O--,
--CH(R.sup.7)N(C(O)R.sup.7)P(OR.sup.8)--,
--CH(R.sup.7)N(C(O)R.sup.7)P(O)(OR.sup.8)O--, or
--CH(R.sup.7)N(C(O)R.sup.7)P(OR.sup.8)--; [0742] or X.sup.1 and
Y.sup.1 are each independently represented by one of the following
structural formulas:
[0742] ##STR00050## [0743] R.sup.10, taken together with the
phosphinamide or phosphonamide, is a 5-, 6-, or 7-membered aryl,
heteroaryl or heterocyclyl ring system; [0744] R.sup.5, R.sup.6,
and G.sup.111 are each independently a (C.sub.0-10)alkyl,
(C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted with one or more independent halo, --CF.sub.3,
--OCF.sub.3, --OR.sup.77, --NR.sup.77R.sup.87, --C(O)R.sup.77,
--CO.sub.2R.sup.77, --CONR.sup.77R.sup.87, --NO.sub.2, --CN,
--S(O).sub.j5aR.sup.77, --SO.sub.2NR.sup.77R.sup.87,
NR.sup.77(C.dbd.O)R.sup.87, NR.sup.77(C.dbd.O)OR.sup.87,
NR.sup.77(C.dbd.O)NR.sup.78R.sup.87, NR.sup.77S(O).sub.j5aR.sup.87,
--(C.dbd.S)OR.sup.77, --(C.dbd.O)SR.sup.77,
--NR.sup.77(C.dbd.NR.sup.87)NR.sup.78R.sup.88,
--NR.sup.77(C.dbd.NR.sup.87)OR.sup.78,
--NR.sup.77(C.dbd.NR.sup.87)SR.sup.78, --O(C.dbd.O)OR.sup.77,
--O(C.dbd.O)NR.sup.77R.sup.87, --O(C.dbd.O)SR.sup.77,
--S(C.dbd.O)OR.sup.77, --P(O)OR.sup.77OR.sup.87, or
--S(C.dbd.O)NR.sup.77R.sup.87 substituents; or
aryl-(C.sub.0-10)alkyl, aryl-(C.sub.2-10)alkenyl, or
aryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, --CF.sub.3, --OCF.sub.3,
--OR.sup.77, --NR.sup.77R.sup.87, --C(O)R.sup.77,
--CO.sub.2R.sup.77, --CONR.sup.77R.sup.87, --NO.sub.2, --CN,
--S(O).sub.j5aR.sup.77, --SO.sub.2NR.sup.77R.sup.87,
NR.sup.77(C.dbd.O)R.sup.87, NR.sup.77(C.dbd.O)OR.sup.87,
NR.sup.77(C.dbd.O)NR.sup.78R.sup.87, NR.sup.77S(O).sub.j5aR.sup.87,
--(C.dbd.S)OR.sup.77, --(C.dbd.O)SR.sup.77,
--NR.sup.77(C.dbd.NR.sup.87)NR.sup.78R.sup.88,
--NR.sup.77(C.dbd.NR.sup.7)OR.sup.87,
--NR.sup.77(C.dbd.NR.sup.87)SR.sup.78, --O(C.dbd.O)OR.sup.77,
--O(C.dbd.O)NR.sup.77R.sup.87, --O(C.dbd.O)SR.sup.77,
--S(C.dbd.O)OR.sup.77, --P(O)OR.sup.77R.sup.87, or
--S(C.dbd.O)NR.sup.77R.sup.87 substituents; or
hetaryl-(C.sub.0-10)alkyl, hetaryl-(C.sub.2-10)alkenyl, or
hetaryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, --CF.sub.3, --OCF.sub.3,
--OR.sup.77, --NR.sup.77R.sup.87, --C(O)R.sup.77,
--CO.sub.2R.sup.77, --CONR.sup.77R.sup.87, --NO.sub.2, --CN,
--S(O).sub.j5aR.sup.77, --SO.sub.2NR.sup.77R.sup.87,
NR.sup.77(C.dbd.O)R.sup.87, NR.sup.77(C.dbd.O)OR.sup.87,
NR.sup.77(C.dbd.O)NR.sup.78R.sup.87, NR.sup.77S(O).sub.j5aR.sup.87,
--(C.dbd.S)OR.sup.77, (C.dbd.O)SR.sup.77,
--NR.sup.77(C.dbd.NR.sup.87)NR.sup.78R.sup.88,
--NR.sup.77(C.dbd.NR.sup.87)OR.sup.78,
--NR.sup.77(C.dbd.NR.sup.87)SR.sup.78, --O(C.dbd.O)OR.sup.77,
--O(C.dbd.O)NR.sup.77R.sup.87, --O(C.dbd.O)SR.sup.77,
--S(C.dbd.O)OR.sup.77, --P(O)OR.sup.77OR.sup.87, or
--S(C.dbd.O)NR.sup.77R.sup.87 substituents; or R.sup.5 with R.sup.6
taken together with the respective carbon atom to which they are
attached, form a 3-10 membered saturated or unsaturated ring,
wherein said ring is optionally substituted with R.sup.69; or
R.sup.5 with R.sup.6 taken together with the respective carbon atom
to which they are attached, form a 3-10 membered saturated or
unsaturated heterocyclic ring, wherein said ring is optionally
substituted with R.sup.69; [0745] R.sup.7 and R.sup.8 are each
independently H, acyl, alkyl, alkenyl, aryl, heteroaryl,
heterocyclyl or cycloalkyl, any of which is optionally substituted
by one or more G.sup.111 substituents; [0746] R.sup.4 is H, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,
cycloalkenyl, or heterocycloalkenyl, any of which is optionally
substituted by one or more G.sup.41 substituents; [0747] R.sup.69
is equal to halo, --OR.sup.78, --SH, --NR.sup.78R.sup.88,
--CO.sub.2R.sup.78, --CONR.sup.78R.sup.88, --NO.sub.2, --CN,
--S(O).sub.j8R.sup.78, --SO.sub.2NR.sup.78R.sup.88,
(C.sub.0-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted with one or more independent halo, cyano, nitro,
--OR.sup.778, --SO.sub.2NR.sup.778R.sup.888, or
--NR.sup.778R.sup.888 substituents; or aryl-(C.sub.0-10)alkyl,
aryl-(C.sub.2-10)alkenyl, or aryl-(C.sub.2-10)alkynyl, any of which
is optionally substituted with one or more independent halo, cyano,
nitro, --OR.sup.778, (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl, --CONR.sup.778R.sup.888,
--SO.sub.2NR.sup.778R.sup.888, or --NR.sup.778R.sup.888
substituents; or hetaryl-(C.sub.0-10)alkyl,
hetaryl-(C.sub.2-10)alkenyl, or hetaryl-(C.sub.2-10)alkynyl, any of
which is optionally substituted with one or more independent halo,
cyano, nitro, --OR.sup.778, (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl, --CONR.sup.778R.sup.888,
--SO.sub.2NR.sup.778R.sup.888, or --NR.sup.778R.sup.888
substituents; or mono(C.sub.1-6alkyl)amino(C.sub.1-6)alkyl,
di((C.sub.1-6)alkyl)amino(C.sub.1-6)alkyl,
mono(aryl)amino(C.sub.1-6)alkyl, di(aryl)amino(C.sub.1-6)alkyl, or
--N((C.sub.1-6)alkyl)-(C.sub.1-6)alkyl-aryl, any of which is
optionally substituted with one or more independent halo, cyano,
nitro, --OR.sup.778, (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl, --CONR.sup.778R.sup.888
SO.sub.2NR.sup.778R.sup.888, or --NR.sup.778R.sup.888 substituents;
or in the case of --NR.sup.78R.sup.88, R.sup.78 and R.sup.88 taken
together with the nitrogen atom to which they are attached form a
3-10 membered saturated ring, unsaturated ring, heterocyclic
saturated ring, or heterocyclic unsaturated ring, wherein said ring
is optionally substituted with one or more independent halo, cyano,
hydroxy, nitro, (C.sub.1-10)alkoxy, --SO.sub.2NR.sup.778R.sup.888,
or --NR.sup.778R.sup.888 substituents; [0748] R.sup.77, R.sup.78,
R.sup.87, R.sup.88, R.sup.778, and R.sup.888 are each independently
(C.sub.0-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxyC.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
heterocyclyl-(C.sub.2-10)alkynyl, (C.sub.1-10)alkylcarbonyl,
(C.sub.2-10)alkenylcarbonyl, (C.sub.2-10)alkynylcarbonyl,
(C.sub.1-10)alkoxycarbonyl,
(C.sub.1-10)alkoxycarbonyl(C.sub.1-10)alkyl,
mono(C.sub.1-6)alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl,
mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or
(C.sub.1-10)alkyl(aryl)aminocarbonyl, any of which is optionally
substituted with one or more independent halo, cyano, hydroxy,
nitro, (C.sub.1-10)alkoxy,
--SO.sub.2N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl), or
--N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl) substituents; or
aryl-(C.sub.0-10)alkyl, aryl-(C.sub.2-10)alkenyl, or
aryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, cyano, nitro,
--O((C.sub.0-4)alkyl), (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl,
--CON((C.sub.0-4)alkyl)((C.sub.0-10)alkyl),
--SO.sub.2N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl), or
--N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl) substituents; or
hetaryl-(C.sub.0-10)alkyl, hetaryl-(C.sub.2-10)alkenyl, or
hetaryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, cyano, nitro,
--O((C.sub.0-4)alkyl), (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl,
--CON((C.sub.0-4)alkyl)((C.sub.0-4)alkyl),
--SO.sub.2N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl), or
--N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl) substituents; or
mono((C.sub.1-6)alkyl)amino(C.sub.1-6)alkyl,
di((C.sub.1-6)alkyl)amino(C.sub.1-6)alkyl,
mono(aryl)amino(C.sub.1-6)alkyl, di(aryl)amino(C.sub.1-6)alkyl, or
--N((C.sub.1-6)alkyl)-(C.sub.1-6)alkyl-aryl, any of which is
optionally substituted with one or more independent halo, cyano,
nitro, --O((C.sub.0-4)alkyl), (C.sub.1-10)alkyl,
(C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl,
--CON((C.sub.0-4)alkyl)((C.sub.0-4)alkyl),
--SO.sub.2N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl), or
--N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl) substituents; and [0749] n,
m, j1, j1a, j2a, j3a, j4, j4a, j5a, j6a, j7, and j8 are each
independently equal to 0, 1, or 2.
[0750] In an embodiment, the BTK inhibitor is a compound selected
from the structures disclosed in U.S. Pat. Nos. 8,450,335 and
8,609,679, and U.S. Patent Application Publication Nos.
2010/0029610 A1, 2012/0077832 A1, 2013/0065879 A1, 2013/0072469 A1,
and 2013/0165462 A1, the disclosures of which are incorporated by
reference herein. In an embodiment, the BTK inhibitor is a compound
of Formula (XXV) or Formula (XXVI):
##STR00051## [0751] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0752] Ring A is
an optionally substituted group selected from phenyl, a 3-7
membered saturated or partially unsaturated carbocyclic ring, an
8-10 membered bicyclic saturated, partially unsaturated or aryl
ring, a 5-6 membered monocyclic heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 4-7 membered saturated or partially unsaturated
heterocyclic ring having 1-3 heteroatoms independently selected
from nitrogen, oxygen, or sulfur, an optionally substituted 7-10
membered bicyclic saturated or partially unsaturated heterocyclic
ring having 1-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; [0753] Ring B is an optionally substituted group
selected from phenyl, a 3-7 membered saturated or partially
unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated,
partially unsaturated or aryl ring, a 5-6 membered monocyclic
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially
unsaturated heterocyclic ring having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, an optionally
substituted 7-10 membered bicyclic saturated or partially
unsaturated heterocyclic ring having 1-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or an 8-10 membered
bicyclic heteroaryl ring having 1-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; [0754] R.sup.1 is a
warhead group; [0755] R.sup.y is hydrogen, halogen, --CN,
--CF.sub.3, C.sub.1-4 aliphatic, C.sub.1-4 haloaliphatic, --OR,
--C(O)R, or --C(O)N(R).sub.2; [0756] each R group is independently
hydrogen or an optionally substituted group selected from C.sub.1-6
aliphatic, phenyl, an optionally substituted 4-7 membered
heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; [0757] W.sup.1 and W.sup.2 are each
independently a covalent bond or a bivalent C.sub.1-3 alkylene
chain wherein one methylene unit of W.sup.1 or W.sup.2 is
optionally replaced by --NR.sup.2--, --N(R.sup.2)C(O)--,
--C(O)N(R.sup.2)--, --N(R.sup.2)SO.sub.2--, --SO.sub.2N(R.sup.2)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --SO-- or
--SO.sub.2--; [0758] R.sup.2 is hydrogen, optionally substituted
C.sub.1-6 aliphatic, or --C(O)R, or: [0759] R.sup.2 and a
substituent on Ring A are taken together with their intervening
atoms to form a 4-6 membered saturated, partially unsaturated, or
aromatic fused ring, or: [0760] R.sup.2 and R.sup.y are taken
together with their intervening atoms to form an optionally
substituted 4-7 membered partially unsaturated or aromatic fused
ring; [0761] m and p are independently 0-4; and [0762] R.sup.x and
R.sup.v are independently selected from --R, halogen, --OR,
--O(CH.sub.2).sub.qOR, --CN, --NO.sub.2, --SO.sub.2R,
--SO.sub.2N(R).sub.2, --SOR, --C(O)R, --CO.sub.2R,
--C(O)N(R).sub.2, --NRC(O)R, --NRC(O)NR.sub.2, --NRSO.sub.2R, or
--N(R).sub.2, wherein q is 1-4; or: [0763] R.sup.x and R.sup.1 when
concurrently present on Ring B are taken together with their
intervening atoms to form an optionally substituted 5-7 membered
saturated, partially unsaturated, or aryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, wherein said ring is substituted with a warhead group and
0-3 groups independently selected from oxo, halogen, --CN, or
C.sub.1-6 aliphatic; or [0764] R.sup.v and R.sup.1 when
concurrently present on Ring A are taken together with their
intervening atoms to form an optionally substituted 5-7 membered
saturated, partially unsaturated, or aryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, wherein said ring is substituted with a warhead group and
0-3 groups independently selected from oxo, halogen, --CN, or
C.sub.1-6 aliphatic.
[0765] In an embodiment, the BTK inhibitor is a compound of Formula
(XXV) or Formula (XXVI), wherein: [0766] Ring A is selected from
phenyl, a 3-7 membered saturated or partially unsaturated
carbocyclic ring, an 8-10 membered bicyclic saturated, partially
unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, an optionally substituted 4-7 membered saturated
or partially unsaturated heterocyclic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, an
optionally substituted 7-10 membered bicyclic saturated or
partially unsaturated heterocyclic ring having 1-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or an 8-10
membered bicyclic heteroaryl ring having 1-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0767]
Ring B is selected from phenyl, a 3-7 membered saturated or
partially unsaturated carbocyclic ring, an 8-10 membered bicyclic
saturated, partially unsaturated or aryl ring, a 5-6 membered
monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, an optionally
substituted 4-7 membered saturated or partially unsaturated
heterocyclic ring having 1-3 heteroatoms independently selected
from nitrogen, oxygen, or sulfur, an optionally substituted 7-10
membered bicyclic saturated or partially unsaturated heterocyclic
ring having 1-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; [0768] R.sup.1 is -L-Y, wherein: [0769] L is a
covalent bond or a bivalent C.sub.1-8 saturated or unsaturated,
straight or branched, hydrocarbon chain, wherein one, two, or three
methylene units of L are optionally and independently replaced by
cyclopropylene, --NR--, --N(R)C(O)--, --C(O)N(R)--,
--N(R)SO.sub.2--, --SO.sub.2N(R)--, --O--, --C(O)--, --OC(O)--,
--C(O)O--, --S--, --SO--, --SO.sub.2--, --C(.dbd.S)--,
--C(.dbd.NR)--, --N.dbd.N--, or --C(.dbd.N.sub.2)--; [0770] Y is
hydrogen, C.sub.1-6 aliphatic optionally substituted with oxo,
halogen, or CN, or a 3-10 membered monocyclic or bicyclic,
saturated, partially unsaturated, or aryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, and wherein said ring is substituted with at 1-4 groups
independently selected from -Q-Z, oxo, NO.sub.2, halogen, CN, or
C.sub.1-6 aliphatic, wherein: [0771] Q is a covalent bond or a
bivalent C.sub.1-6 saturated or unsaturated, straight or branched,
hydrocarbon chain, wherein one or two methylene units of Q are
optionally and independently replaced by --NR--, --S--, --O--,
--C(O)--, --SO--, or --SO.sub.2--; and [0772] Z is hydrogen or
C.sub.1-6 aliphatic optionally substituted with oxo, halogen, or
CN; [0773] R.sup.y is hydrogen, halogen, --CN, --CF.sub.3,
C.sub.1-4 aliphatic, C.sub.1-4 haloaliphatic, --OR, --C(O)R, or
--C(O)N(R).sub.2; [0774] each R group is independently hydrogen or
an optionally substituted group selected from C.sub.1-6 aliphatic,
phenyl, an optionally substituted 4-7 membered heterocylic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; W.sup.1 and W.sup.2 are each independently a
covalent bond or a bivalent C.sub.1-3 alkylene chain wherein one
methylene unit of W.sup.1 or W.sup.2 is optionally replaced by
--NR.sup.2--, --N(R.sup.2)C(O)--, --C(O)N(R.sup.2)--,
--N(R.sup.2)SO.sub.2--, --SO.sub.2N(R.sup.2)--, --O--, --C(O)--,
--OC(O)--, --C(O)O--, --S--, --SO-- or --SO.sub.2--; [0775] R.sup.2
is hydrogen, optionally substituted C.sub.1-6 aliphatic, or
--C(O)R, or: [0776] R.sup.2 and a substituent on Ring A are taken
together with their intervening atoms to form a 4-6 membered
partially unsaturated or aromatic fused ring; or [0777] R.sup.2 and
R.sup.y are taken together with their intervening atoms to form a
4-6 membered saturated, partially unsaturated, or aromatic fused
ring; [0778] m and p are independently 0-4; and [0779] R.sup.x and
R.sup.v are independently selected from --R, halogen, --OR,
--O(CH.sub.2).sub.qOR, --CN, --NO.sub.2, --SO.sub.2R,
--SO.sub.2N(R).sub.2, --SOR, --C(O)R, --CO.sub.2R,
--C(O)N(R).sub.2, --NRC(O)R, --NRC(O)NR.sub.2, --NRSO.sub.2R, or
--N(R).sub.2, wherein R is independently selected from the group
consisting of hydrogen, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
aryl, heteroaryl, and heterocycly; or: [0780] R.sup.x and R.sup.1
when concurrently present on Ring B are taken together with their
intervening atoms to form a 5-7 membered saturated, partially
unsaturated, or aryl ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, wherein said ring is
substituted with a warhead group and 0-3 groups independently
selected from oxo, halogen, --CN, or C.sub.1-6 aliphatic; or [0781]
R.sup.v and R.sup.1 when concurrently present on Ring A are taken
together with their intervening atoms to form a 5-7 membered
saturated, partially unsaturated, or aryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, wherein said ring is substituted with a warhead group and
0-3 groups independently selected from oxo, halogen, --CN, or
C.sub.1-6 aliphatic.
[0782] As defined generally above, Ring A is selected from phenyl,
a 3-7 membered saturated or partially unsaturated carbocyclic ring,
an 8-10 membered bicyclic saturated, partially unsaturated or aryl
ring, a 5-6 membered monocyclic heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, an optionally substituted 4-7 membered saturated or
partially unsaturated heterocyclic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, an
optionally substituted 7-10 membered bicyclic saturated or
partially unsaturated heterocyclic ring having 1-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or an 8-10
membered bicyclic heteroaryl ring having 1-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0783] In preferred embodiments, Ring A is an optionally
substituted phenyl group. In some embodiments, Ring A is an
optionally substituted naphthyl ring or an optionally substituted
bicyclic 8-10 membered heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In certain
other embodiments, Ring A is an optionally substituted 3-7 membered
carbocyclic ring. In yet other embodiments, Ring A is an optionally
substituted 4-7 membered heterocyclic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In
preferred embodiments, Ring B is an optionally substituted phenyl
group.
[0784] In certain embodiments, Ring A in Formula (XXV) or Formula
(XXVI) is substituted as defined herein. In some embodiments, Ring
A is substituted with one, two, or three groups independently
selected from halogen, R , or --(CH.sub.2).sub.0-4OR , or
--O(CH.sub.2).sub.0-4R , wherein each R is independently selected
from the group consisting of cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, aryl, heteroaryl, and heterocyclyl. Exemplary substituents
on Ring A include Br, I, Cl, methyl, --CF.sub.3, --C.ident.CH,
--OCH.sub.2phenyl, --OCH.sub.2(fluorophenyl), or
--OCH.sub.2pyridyl.
[0785] In a preferred embodiment, the BTK inhibitor is CC-292, or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, preferably a hydrochloride salt or a besylate salt
thereof. In a preferred embodiment, the BTK inhibitor is a compound
of Formula (XXVII):
##STR00052## [0786] which is
N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)-
phenyl)acrylamide, or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, or in an exemplary
embodiment is a hydrochloride salt or a besylate salt thereof. The
preparation of this compound is described in U.S. Patent
Application Publication No. 2010/0029610 A1 at Example 20, the
disclosure of which is incorporated by reference herein. The
preparation of the besylate salt of this compound is described in
U.S. Patent Application Publication No. 2012/0077832 A1, the
disclosure of which is incorporated by reference herein. In an
embodiment, the BTK inhibitor is a compound selected from the
structures disclosed in U.S. Patent Application Publication No.
2010/0029610 A1 or No. 2012/0077832 A1, the disclosures of which
are incorporated by reference herein.
[0787] In a preferred embodiment, the BTK inhibitor is
N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)-
phenyl)acrylamide or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, or a hydrochloride salt
thereof. The preparation of this compound is described in U.S.
Patent Application Publication Nos. 2010/0029610 A1 and
2012/0077832 A1, the disclosure of which is incorporated by
reference herein.
[0788] In a preferred embodiment, the BTK inhibitor is
(N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phe-
nyl)acrylamide), or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, or preferably a besylate
salt thereof. The preparation of this compound is described in U.S.
Patent Application Publication No. 2010/0029610 A1 at Example 20,
the disclosure of which is incorporated by reference herein. The
preparation of its besylate salt is described in U.S. Patent
Application Publication No. 2012/0077832 A1, the disclosure of
which is incorporated by reference herein.
[0789] In an embodiment, the BTK inhibitor is a compound of Formula
(XXVIII):
##STR00053## [0790] or a pharmaceutically acceptable salt, hydrate,
solvate, cocrystal, or prodrug thereof, wherein [0791] L represents
(1) --O--, (2) --S--, (3) --SO--, (4) --SO.sub.2-- (5) --NH--, (6)
--C(O)--, (7) --CH.sub.2O--, (8) --O--CH.sub.2--, (9) --CH.sub.2--,
or (10) --CH(OH)--; [0792] R.sup.1 represents (1) a halogen atom,
(2) a C.sub.1-4 alkyl group, (3) a C.sub.1-4 alkoxy group, (4) a
C.sub.1-4 haloalkyl group, or (5) a C.sub.1-4 haloalkoxy group;
[0793] ring1 represents a 4- to 7-membered cyclic group, which may
be substituted by from one to five substituents each independently
selected from the group consisting of (1) halogen atoms, (2)
C.sub.1-4 alkyl groups, (3) C.sub.1-4 alkoxy groups, (4) nitrile,
(5) C.sub.1-4 haloalkyl groups, and (6) C.sub.1-4 haloalkoxy
groups, wherein when two or more substituents are present on ring1,
these substituents may form a 4- to 7-membered cyclic group
together with the atoms in ring1 to which these substituents are
bound; [0794] ring2 represents a 4- to 7-membered saturated
heterocycle, which may be substituted by from one to three
--K--R.sup.2; K represents (1) a bond, (2) a C.sub.1-4 alkylene,
(3) --C(O)--, (4) --C(O)--CH.sub.2--, (5) --CH.sub.2--C(O)--, (6)
--C(O)O--, or (7) --SO.sub.2-- (wherein the bond on the left is
bound to the ring2); [0795] R.sup.2 represents (1) a C.sub.1-4
alkyl, (2) a C.sub.2-4 alkenyl, or (3) a C.sub.2-4 alkynyl group,
each of which may be substituted by from one to five substituents
each independently selected from the group consisting of (1)
NR.sup.3R.sup.4, (2) halogen atoms, (3) CONR.sup.5R.sup.6, (4)
CO.sub.2R.sup.7, and (5) OR.sup.8; [0796] R.sup.3 and R.sup.4 each
independently represent (1) a hydrogen atom, or (2) a C.sub.1-4
alkyl group which may be substituted by OR.sup.9 or
CONR.sup.10R.sup.11; R.sup.3 and R.sup.4 may, together with the
nitrogen atom to which they are bound, form a 4- to 7-membered
nitrogenous saturated heterocycle, which may be substituted by an
oxo group or a hydroxyl group; [0797] R.sup.5 and R.sup.6 each
independently represent (1) a hydrogen atom, (2) a C.sub.1-4 alkyl
group, or (3) a phenyl group; [0798] R.sup.7 represents (1) a
hydrogen atom or (2) a C.sub.1-4 alkyl group; [0799] R.sup.8
represents (1) a hydrogen atom, (2) a C.sub.1-4 alkyl group, (3) a
phenyl group, or (4) a benzotriazolyl group; R.sup.9 represents (1)
a hydrogen atom or (2) a C.sub.1-4 alkyl group; [0800] R.sup.10 and
R.sup.11 each independently represent (1) a hydrogen atom or (2) a
C.sub.1-4 alkyl group; [0801] n represents an integer from 0 to 4;
[0802] m represents an integer from 0 to 2; and [0803] when n is
two or more, the R's may be the same as each other or may differ
from one another).
[0804] In an exemplary embodiment, the BTK inhibitor is a compound
of Formula (XXVIII-A):
##STR00054## [0805] or a pharmaceutically acceptable salt, hydrate,
solvate, cocrystal, or prodrug thereof, wherein [0806] R.sup.1
represents (1) a halogen atom, (2) a C.sub.1-4 alkyl group, (3) a
C.sub.1-4 alkoxy group, (4) a C.sub.1-4 haloalkyl group, or (5) a
C.sub.1-4 haloalkoxy group; [0807] ring1 represents a benzene,
cyclohexane, or pyridine ring, each of which may be substituted by
from one to five substituents each independently selected from the
group consisting of (1) halogen atoms, (2) C.sub.1-4 alkyl groups,
(3) C.sub.1-4 alkoxy groups, (4) nitrile, (5) CF.sub.3; ring2
represents a 4- to 7-membered nitrogenous saturated heterocycle,
which may be substituted by from one to three --K--R.sup.2; wherein
K represents (1) a bond, (2) a C.sub.1-4 alkylene, (3) --C(O)--,
(4) --C(O)--CH.sub.2--, (5) --CH.sub.2--C(O)--, (6) --C(O)O--, or
(7) --SO.sub.2-- (wherein the bond on the left is bound to the
ring2); [0808] R.sup.2 represents (1) a C.sub.1-4 alkyl, (2) a
C.sub.2-4 alkenyl, or (3) a C.sub.2-4 alkynyl group, each of which
may be substituted by from one to five substituents each
independently selected from the group consisting of (1)
NR.sup.3R.sup.4, (2) halogen atoms, (3) CONR.sup.5R.sup.6, (4)
CO.sub.2R.sup.7, and (5) OR.sup.8; [0809] R.sup.3 and R.sup.4 each
independently represent (1) a hydrogen atom, or (2) a C.sub.1-4
alkyl group which may be substituted by OR.sup.9 or
CONR.sup.10R.sup.11; R.sup.3 and R.sup.4 may, together with the
nitrogen atom to which they are bound, form a 4- to 7-membered
nitrogenous saturated heterocycle, which may be substituted by an
oxo group or a hydroxyl group; [0810] R.sup.5 and R.sup.6 each
independently represent (1) a hydrogen atom, (2) a C.sub.1-4 alkyl
group, or (3) a phenyl group; [0811] R.sup.7 represents (1) a
hydrogen atom or (2) a C.sub.1-4 alkyl group; [0812] R.sup.8
represents (1) a hydrogen atom, (2) a C.sub.1-4 alkyl group, (3) a
phenyl group, or (4) a benzotriazolyl group; R.sup.9 represents (1)
a hydrogen atom or (2) a C.sub.1-4 alkyl group; [0813] R.sup.10 and
R.sup.11 each independently represent (1) a hydrogen atom or (2) a
C.sub.1-4 alkyl group; [0814] n represents an integer from 0 to 4;
[0815] m represents an integer from 0 to 2; and [0816] when n is
two or more, the R's may be the same as each other or may differ
from one another).
[0817] In a preferred embodiment, the BTK inhibitor is a compound
of Formula (XXVIII-B):
##STR00055## [0818] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, preferably a hydrochloride
salt thereof. The preparation of this compound is described in
International Patent Application Publication No. WO 2013/081016 A1,
the disclosure of which is incorporated by reference herein. In an
embodiment, the BTK inhibitor is
6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7,9-dihydr-
o-8H-purin-8-one or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, or preferably a
hydrochloride salt thereof. In an embodiment, the BTK inhibitor is
6-amino-9-[(3S)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-di-
hydro-8H-purin-8-one or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof, or a hydrochloride
salt thereof.
[0819] The R-enantiomer of Formula (XXVIII-B) is also known as
ONO-4059, and is given by Formula (XXVIII-R). In a preferred
embodiment, the BTK inhibitor is a compound of Formula
(XXVIII-R):
##STR00056## [0820] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, preferably a hydrochloride
salt thereof.
[0821] In an embodiment, the BTK inhibitor is
6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-di-
hydro-8H-purin-8-one or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof, preferably a
hydrochloride salt thereof.
[0822] The preparation of Formula (XXVII-R) is described in
International Patent Application Publication No. WO 2013/081016 A1,
the disclosure of which is incorporated by reference herein. In
brief, the BTK inhibitor of Formula (XXVIII-R) can be prepared by
the following procedure.
Step 1
[0823] A solution of dibenzylamine (10.2 g) in dichloromethane (30
mL) is dripped into a solution of 4,6-dichloro-5-nitropyrimidine
(10 g) in dichloromethane (70 mL) on an ice bath. Then
triethylamine (14.4 mL) is added, and the mixture is stirred for 1
hour. Water is added to the reaction mixture, the organic layer is
washed with a saturated aqueous sodium chloride solution and dried
over anhydrous sodium sulfate, and the solvent is concentrated
under reduced pressure to obtain
N,N-dibenzyl-6-chloro-5-nitropyrimidine-4-amine (19.2 g).
Step 2
[0824] The compound prepared in Step 1 (19 g) and tert-butyl
(3R)-3-aminopyrrolidine-1-carboxylate (10.5 g) are dissolved in
dioxane (58 mL). Triethylamine (8.1 mL) is added, and the mixture
is stirred for 5 hours at 50.degree. C. The reaction mixture is
returned to room temperature, the solvent is distilled off, water
is added, and extraction is performed with ethyl acetate. The
organic layer is washed with saturated aqueous sodium chloride
solution, then dried over anhydrous sodium sulfate, and the solvent
is distilled off. The residue is purified by silica gel column
chromatography to obtain tert-butyl
(3R)-3-{[6-(dibenzylamino)-5-nitropyrimidin-4-yl]amino}pyrrolid-ine-1-car-
boxylate (27.0 g).
Step 3
[0825] An ethyl acetate (360 mL) solution of the compound prepared
in Step 2 (17.5 g) is dripped into a mixture of zinc (23.3 g) and a
3.0 M aqueous ammonium chloride solution (11.4 g) on an ice bath,
and the temperature is immediately raised to room temperature.
After stirring for 2 hours, the reaction mixture is filtered
through CELITE and the solvent is distilled off. The residue is
purified by silica gel column chromatography to obtain tert-butyl
(3R)-3-{[5-amino-6-(dibenzylamino)pyrimidin-4-yl]amino}pyrrolidine-1-carb-
oxylate (12.4 g).
Step 4
[0826] The compound prepared in Step 3 (8.4 g) and 1,1'-carbonyl
diimidazole (5.9 g) are dissolved in tetrahydrofuran (120 mL) and
the solution is stirred for 15 hours at 60.degree. C. The solvent
is distilled off from the reaction mixture, water is added, and
extraction with ethyl acetate is performed. The organic layer is
washed with saturated aqueous sodium chloride solution, dried over
anhydrous sodium sulfate, and the solvent is distilled off. The
residue is purified by silica gel column chromatography to obtain
tert-butyl
(3R)-3-[6-(dibenzylamino)-8-oxo-7,8-dihydro-9H-purin-9-yl]pyrrolidin-1-ca-
rboxylate (7.8 g).
Step 5
[0827] The compound prepared in Step 4 (7.8 g) is dissolved in
methanol (240 mL) and ethyl acetate (50 mL), 20% Pearlman's
catalyst (Pd(OH).sub.2/C) (8.0 g, 100 wt %) is added, hydrogen gas
replacement is carried out, and stirring is performed for 7.5 hours
at 60.degree. C. The reaction mixture is filtered through CELITE
and the solvent is distilled off to obtain tert-butyl
(3R)-3-(6-amino-8-oxo-7,8-dihydro-9H-purin-9-yl)pyrrolidine-1-carboxylate
(5.0 g).
Step 6
[0828] At room temperature p-phenoxy phenyl boronic acid (2.1 g),
copper(II) acetate (1.48 g), molecular sieve 4 A (2.5 g), and
pyridine (0.82 mL) are added to a dichloromethane suspension (200
mL) of the compound prepared in Step 5 (2.5 g), followed by
stirring for 21 hours. The reaction mixture is filtered through
CELITE and the residue is purified by silica gel column
chromatography to obtain tert-butyl
(3R)-3-[6-amino-8-oxo-7-(4-phenoxyphenyl)-7,8-dihydro-9H-purin-9-yl]pyrro-
lidine-1-carboxylate (1.3 g).
Step 7
[0829] At room temperature 4 N HCl/dioxane (13 mL) is added to a
methanol (13 mL) suspension of the compound prepared in Step 6 (1.3
g 2.76 mmol, 1.0 equivalent), and the mixture is stirred for 1
hour. The solvent is then distilled off to obtain
(3R)-6-amino-9-pyrrolidin-3-yl-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-
-one dihydrochloride (1.5 g).
Step 8
[0830] After 2-butynoic acid (34 mg),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)
(78 mg), 1-hydroxybenzotriazole (HOBt) (62 mg), and triethylamine
(114 mL) are added to a solution of the compound prepared in Step 7
(100 mg) in dimethyl formamide (3 mL), the mixture is stirred at
room temperature for 3 hours. Water is added to the reaction
mixture and extraction with ethyl acetate is performed. The organic
layer is washed with saturated sodium carbonate solution and
saturated aqueous sodium chloride solution, then dried over
anhydrous sodium sulfate, and the solvent is distilled off. The
residue is purified by thin layer chromatography
(dichloromethane:methanol:28% ammonia water=90:10:1) to obtain
6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-di-
hydro-8H-purin-8-one (Formula (XXVIII-R)) (75 mg).
[0831] The hydrochloride salt of the compound of Formula (XXVIII-R)
can be prepared as follows:
6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-di-
hydro-8H-purin-8-one (3.0 g) (which may be prepared as described
above) is placed in a 300 mL 3-neck pear-shaped flask, ethyl
acetate (30 mL) and 1-propanol (4.5 mL) are added, and the external
temperature is set at 70.degree. C. (internal temperature
61.degree. C.). After it is confirmed that the compound prepared in
Step 8 has dissolved completely, 10% HCl/methanol (3.5 mL) is
added, and after precipitation of crystals is confirmed, the
crystals are ripened by the following sequence: external
temperature 70.degree. C. for 30 min, external temperature
60.degree. C. for 30 min, external temperature 50.degree. C. for 60
min, external temperature 40.degree. C. for 30 min, room
temperature for 30 min, and an ice bath for 30 min. The resulting
crystals are filtered, washed with ethyl acetate (6 mL), and dried
under vacuum at 50.degree. C. to obtain white crystals of
6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-di-
hydro-8H-purin-8-one hydrochloride (2.76 g).
[0832] In an embodiment, the BTK inhibitor is a compound selected
from the structures disclosed in U.S. Patent Application
Publication No. US 2014/0330015 A1, the disclosure of which is
incorporated by reference herein.
[0833] In an embodiment, the BTK inhibitor is a compound of Formula
(B):
##STR00057## [0834] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0835] X--Y--Z is
N--C--C and R.sup.2 is present, or C--N--N and R.sup.2 is absent;
[0836] R.sup.1 is a 3-8 membered, N-containing ring, wherein the N
is unsubstituted or substituted with R.sup.4; [0837] R.sup.2 is H
or lower alkyl, particularly methyl, ethyl, propyl or butyl; or
[0838] R.sup.1 and R.sup.2 together with the atoms to which they
are attached, form a 4-8 membered ring, preferably a 5-6 membered
ring, selected from cycloalkyl, saturated or unsaturated
heterocycle, aryl, and heteroaryl rings unsubstituted or
substituted with at least one substituent L-R.sup.4; [0839] R.sup.3
is in each instance, independently halogen, alkyl, S-alkyl, CN, or
OR.sup.5; [0840] n is 1, 2, 3, or 4, preferably 1 or 2; [0841] L is
a bond, NH, heteroalkyl, or heterocyclyl; [0842] R.sup.4 is COR',
CO.sub.2R', or SO.sub.2R', wherein R' is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl; [0843] R.sup.5 is H or
unsubstituted or substituted heteroalkyl, alkyl, cycloalkyl,
saturated or unsaturated heterocyclyl, aryl, or heteroaryl.
[0844] In some embodiments, the BTK inhibitor is one of the
following particular embodiments of Formula B: [0845] X--Y--Z is
C--N--N and R.sup.2 is absent; and R.sup.1 is 3-8 membered,
N-containing ring, N-substituted with R.sup.4; [0846] X--Y--Z is
N--C--C and R.sup.2 is present, R.sup.1 is 3-8 membered,
N-containing ring, N-substituted with R.sup.4; and R.sup.2 is H or
lower alkyl; [0847] X--Y--Z is N--C--C and R.sup.2 is present; and
R.sup.1 and R.sup.2 together with the atoms to which they are
attached, form a 4-8 membered ring selected from cycloalkyl,
saturated or unsaturated heterocycle, aryl, and heteroaryl rings
unsubstituted or substituted with at least one substituent
L-R.sup.4, wherein preferred rings of R.sup.1 and R.sup.2 are
5-6-membered, particularly dihydropyrrole, tetrahydropyridine,
tetrahydroazepine, phenyl, or pyridine; [0848] X--Y--Z is N--C--C
and R.sup.2 is present; and R.sup.1 and R.sup.2 together with the
atoms to which they are attached, form a 5-6 membered ring,
preferably (a) phenyl substituted with a single -L-R.sup.4, or (b)
dihydropyrrole or tetrahydropyridine, N-substituted with a single
-L-R.sup.4 wherein L is bond; [0849] R.sup.1 is piperidine or
azaspiro[3.3]heptane, preferably N-substituted with R.sup.4; [0850]
R.sup.4 is COR' or SO.sub.2R', particularly wherein R' is
substituted or unsubstituted alkenyl, particularly substituted or
unsubstituted ethenyl; or [0851] R.sup.5 is unsubstituted or
substituted alkyl or aryl, particularly substituted or
unsubstituted phenyl or methyl, such as cyclopropyl-substituted
methyl with or tetrabutyl-substituted phenyl.
[0852] In some embodiments, the BTK inhibitor is one of the
following particular embodiments of Formula B: [0853] R.sup.1 is
piperidine or azaspiro[3.3]heptane, N-substituted with R.sup.4,
wherein R.sup.4 is H, COR' or SO.sub.2R', and R' is substituted or
unsubstituted alkenyl, particularly substituted or unsubstituted
ethenyl; [0854] R.sup.3 is --OR.sup.5, R.sup.5 is phenyl, and n is
1; [0855] R.sup.1 and R.sup.2, together with the atoms to which
they are attached, form a 5-6 membered ring, preferably (a) phenyl
substituted with a single -L-R.sup.4, or (b) dihydropyrrole or
tetrahydropyridine, N-substituted with a single -L-R.sup.4 wherein
L is bond; R.sup.3 is --OR.sup.5; n is 1; R.sup.4 is COR', and R'
is ethenyl; and R.sup.5 is phenyl; and [0856] X--Y--Z is C--N--N
and R.sup.2 is absent; R.sup.1 is piperidine, N-substituted with
R.sup.4; R.sup.3 is --OR.sup.5; n is 1; R.sup.4 is COR', and R' is
unsubstituted or substituted alkenyl, particularly ethenyl; and
R.sup.5 is substituted or unsubstituted aryl, particularly
phenyl.
[0857] In an exemplary embodiment, the BTK inhibitor is a compound
of Formula (B1), Formula (B1-2), or Formula (B1-3):
##STR00058## [0858] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. Formula (B1-2) is also
known as BGB-3111. The preparation of these compounds is described
in International Patent Application Publication No. WO 2014/173289
A1 and U.S. Patent Application Publication No. US 2015/0005277 A1,
the disclosure of which is incorporated by reference herein.
[0859] In brief, the BTK inhibitor of Formula (B1) can be prepared
by the following procedure.
Step 1. Preparation of
2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile
##STR00059##
[0861] A solution of 4-phenoxybenzoic acid (300 g, 1.4 mol) in
SOCl.sub.2 (1.2 L) is stirred at 80.degree. C. under N.sub.2 for 3
hours. The mixture is concentrated in vacuum to give the
intermediate (315 g) which is used for next step without further
purification.
[0862] To a solution of propanedinitrile (89.5 g, 1355 mmol) and
DIEA (350 g, 2710 mmol) in THF (800 mL) is dropwise a solution of
the intermediate (315 g) in toluene (800 mL) at 0-5.degree. C. over
2 hours. The resultant mixture is allowed to warm to RT and stirred
for 16 hours. The reaction is quenched with water (2.0 L) and
extracted with of EA (2.0 L.times.3). The combined organic layers
are washed with 1000 mL of 3 N HCl aqueous solution, brine (2.0
L.times.3), dried over Na.sub.2SO.sub.4 and concentrated to give
the crude product (330 g, 93%).
Step 2. Preparation of
2-(Methoxy(4-phenoxyphenyl)methylene)malononitrile
##STR00060##
[0864] A solution of
2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8
mmol) in CH(OMe.sub.3) (500 mL) is heated to 75.degree. C. for 16
hours. Then the mixture is concentrated to a residue and washed
with MeOH (50 mL) to give 25 g (47.5%) of
2-(methoxy(4-phenoxyphenyl)methylene)malononitrile as a yellow
solid.
Step 3. Preparation of
5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile
##STR00061##
[0866] To a solution of
2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (80 g, 290 mmol)
in ethanol (200 mL) is added hydrazine hydrate (20 mL). The mixture
is stirred at RT for 16 hours then is concentrated to give the
crude product and washed with MeOH (30 mL) to afford 55 g (68.8%)
of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a
off-white solid.
Step 4. Preparation of tert-butyl
3-(tosyloxy)piperidine-1-carboxylate
[0867] ##STR00062## [0868] wherein "Boc" represents a
tert-butyloxycarbonyl protecting group.
[0869] To a solution of tert-butyl
3-hydroxypiperidine-1-carboxylate (1.05 g, 5.0 mmol) in pyridine (8
mL) is added TsCl (1.425 g, 7.5 mmol). The mixture is stirred at RT
under N.sub.2 for two days. The mixture is concentrated and
partitioned between 100 mL of EA and 100 mL of HCl (1 N) aqueous
solution. The organic layer is separated from aqueous layer, washed
with saturated NaHCO.sub.3 aqueous solution (100 mL.times.2), brine
(100 mL.times.3) and dried over Na.sub.2SO.sub.4. The organic layer
is concentrated to afford 1.1 g (60%) of tert-butyl
3-(tosyloxy)piperidine-1-carboxylate as a colorless oil.
Step 5. Preparation of tert-butyl
3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carbo-
xylate
##STR00063##
[0871] To a solution of tert-butyl
3-(tosyloxy)piperidine-1-carboxylate (355 mg, 1.0 mmol) and
5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (276 mg, 1.0
mmol) in 5 mL of DMF is added Cs.sub.2CO.sub.3 (650 mg, 2.0 mmol).
A tosyloxy leaving group is employed in this reaction. The mixture
is stirred at RT for 16 hours, 75.degree. C. for 3 hours and
60.degree. C. for 16 hours. The mixture is concentrated washed with
brine (100 mL.times.3) and dried over Na.sub.2SO.sub.4. The
material is concentrated and purified by chromatography column on
silica gel (eluted with petroleum ether/ethyl actate=3/1) to afford
60 mg (13%) of tert-butyl
3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carbo-
xylate as a yellow oil.
Step 6. Preparation of tert-butyl
3-(5-amino-4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-c-
arboxylate
##STR00064##
[0873] To a solution of tert-butyl
3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carbo-
xylate (100 mg, 0.22 mmol) in DMSO (2 mL) and ethanol (2 mL) was
added the solution of NaOH (200 mg, 5 mmol) in water (1 mL) and
H.sub.2O.sub.2 (1 mL). The mixture is stirred at 60.degree. C. for
15 min and concentrated to remove EtOH, after which 10 mL of water
and 50 mL of ethyl acetate are added. The organic layer is
separated from aqueous layer, washed with brine (30 mL.times.3) and
dried over Na.sub.2SO.sub.4. After concentration, 50 mg of residue
is used directly in the next step, wherein 50 mg of residue is
purified by pre-TLC (eluted with petroleum ether/ethyl actate=1/1)
to afford 12 mg (30%) of tert-butyl
3-(5-amino-4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-c-
arboxylate as a white solid.
Step 7. Preparation of
5-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide
##STR00065##
[0875] To a solution of tert-butyl
3-(5-amino-4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-c-
arboxylate (50 mg, 0.11 mmol) in ethyl acetate (1 mL) is added
concentrated HCl (0.75 mL). The mixture is stirred at RT for 1
hour. Then saturated NaHCO.sub.3 is added until pH>7, followed
by ethyl acetate (50 mL). The organic layer is separated from
aqueous layer, washed with brine (50 mL.times.3) and dried over
Na.sub.2SO.sub.4. The resulting product is concentrated and
purified by Pre-TLC (eluted with
dichloromethane/MeOH/NH.sub.3--H.sub.2O=5/1/0.01) to afford 10 mg
(25%) of
5-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxami-
de as a white solid.
Step 8. Preparation of
1-(1-acryloylpiperidine-3-yl)-5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-c-
arboxamide
##STR00066##
[0877] To a solution of
5-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide
(63 mg, 0.17 mmol) in dichloromethane (4 mL) is added pyridine (27
mg, 0.34 mmol). Then a solution of acryloyl chloride (12 mg, 0.17
mmol) in dichloromethane (1 mL) is added dropwise. After stirring
at RT for 4 hours, the mixture is partitioned between 100 mL of
dichloromethane and 100 mL of brine. The organic layer is separated
from aqueous layer, washed with brine (100 mL.times.2) and dried
over Na.sub.2SO.sub.4. The material is concentrated and purified by
Pre-TLC (eluted with dichloromethane/MeOH=10/1) to afford 4 mg
(5.5%) of
1-(1-acryloylpiperidine-3-yl)-5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-c-
arboxamide as a white solid.
[0878] The enantiomers of Formula (B1) provided by the procedure
above may be prepared from
5-amino-3-(phenoxyphenyl)-1H-pyrazole-4-carbonitrile and
(S)-tert-butyl 3-hydroxypiperidine-1-carboxylate using a similar
procedure (step 4 to 8) for Formula (B1-2), or from (R)-tert-butyl
3-hydroxypiperidine-1-carboxylate using a similar procedure (step 4
to 8) for Formula (B1-3). Under appropriate conditions recognized
by one of ordinary skill in the art, a racemic mixture of Formula
(B1) may be separated by chiral HPLC, the crystallization of chiral
salts, or other means described above to yield Formula (B1-2) and
Formula (B1-3) of high enantiomeric purity.
[0879] In an embodiment, the BTK inhibitor is a compound selected
from the structures disclosed in U.S. Patent Application
Publication No. US 2015/0005277A1, the disclosure of which is
incorporated by reference herein.
[0880] Other BTK inhibitors suitable for use in the described
combination with a JAK-2 inhibitor or a PI3K inhibitor, the PI3K
inhibitor being preferably selected from the group consisting of a
PI3K-.gamma. inhibitor, a PI3K-.delta. inhibitor, and a
PI3K-.gamma.,.delta. inhibitor, also include, but are not limited
to, those described in, for example, International Patent
Application Publication Nos. WO 2013/010868, WO 2012/158843, WO
2012/135944, WO 2012/135937, U.S. Patent Application Publication
No. 2011/0177011, and U.S. Pat. Nos. 8,501,751, 8,476,284,
8,008,309, 7,960,396, 7,825,118, 7,732,454, 7,514,444, 7,459,554,
7,405,295, and 7,393,848, the disclosures of each of which are
incorporated herein by reference.
JAK-2 Inhibitors
[0881] The JAK-2 inhibitor may be any JAK-2 inhibitor known in the
art. In particular, it is one of the JAK-2 inhibitors described in
more detail in the following paragraphs. In preferred embodiments,
the compositions described herein provide a combination of a JAK-2
inhibitor with a BTK inhibitor, or methods of using a combination
of a JAK-2 inhibitor with a BTK inhibitor. In some embodiments, the
JAK-2 inhibitors provided herein are selective for JAK-2, in that
the compounds bind or interact with JAK-2 at substantially lower
concentrations than they bind or interact with other JAK receptors,
including the JAK-3 receptor. In certain embodiments, the compounds
bind to the JAK-3 receptor at a binding constant that is at least
about a 2-fold higher concentration, about a 3-fold higher
concentration, about a 5-fold higher concentration, about a 10-fold
higher concentration, about a 20-fold higher concentration, about a
30-fold higher concentration, about a 50-fold higher concentration,
about a 100-fold higher concentration, about a 200-fold higher
concentration, about a 300-fold higher concentration, or about a
500-fold higher concentration than to the JAK-2 receptor.
[0882] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XXIX):
##STR00067## [0883] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [0884] A.sup.1 and
A.sup.2 are independently selected from C and N; [0885] T, U, and V
are independently selected from O, S, N, CR.sup.5, and NR.sup.6;
[0886] wherein the 5-membered ring formed by A.sup.1, A.sup.2, U,
T, and V is aromatic; [0887] X is N or CR.sup.4; [0888] Y is
C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8 alkynylene,
(CR.sup.11R.sup.12).sub.p--(C.sub.3-10
cycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(arylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p--(C.sub.1-10
heterocycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(heteroarylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pO(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)O(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pOC(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pOC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pNR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pNR.sup.cC(O)NR.sup.d(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O).sub.2(CR.sup.11R.sup.12).sub.q, or
(CR.sup.11R.sup.12).sub.pS(O).sub.2NR.sup.c(CR.sup.11R.sup.12).sub.q,
wherein said C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8
alkynylene, cycloalkylene, arylene, heterocycloalkylene, or
heteroarylene, is optionally substituted with 1, 2, or 3
substituents independently selected from
-D.sup.1-D.sup.2-D.sup.3-D.sup.4; [0889] Z is H, halo, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
.dbd.C--R.sup.i, .dbd.N--R.sup.i, Cy.sup.1, CN, NO.sub.2, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl)R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d, wherein said C.sub.1-8 alkyl, C.sub.2-8
alkenyl, or C.sub.2-8 alkynyl, is optionally substituted with 1, 2,
3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl)R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; [0890] wherein when Z is H, n is 1;
[0891] or the --(Y).sub.n--Z moiety is taken together with i)
A.sup.2 to which the moiety is attached, ii) R.sup.5 or R.sup.6 of
either T or V, and iii) the C or N atom to which the R.sup.5 or
R.sup.6 Of either T or V is attached to form a 4- to 20-membered
aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the
5-membered ring formed by A.sup.1, A.sup.2, U, T, and V, wherein
said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from --(W).sub.m-Q; [0892] W is
C.sub.1-8 alkylenyl, C.sub.2-8 alkenylenyl, C.sub.2-8 alkynylenyl,
O, S, C(O), C(O)NR.sup.c', C(O)O, OC(O), OC(O)NR.sup.c', NR.sup.c',
NR.sup.c'C(O)NR.sup.d', S(O), S(O)NR.sup.c', S(O).sub.2, or
S(O).sub.2NR.sup.c'; [0893] Q is H, halo, CN, NO.sub.2, C.sub.1-8
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8 haloalkyl,
halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl,
wherein said C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-8haloalkyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl is optionally substituted with 1, 2, 3 or 4
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.2, CN, NO.sub.2, OR.sup.a', SR.sup.a', C(O)R.sup.b',
C(O)NR.sup.c'R.sup.d', C(O)OR.sup.a', OC(O)R.sup.b',
OC(O)NR.sup.c'R.sup.d', NR.sup.c'R.sup.d', NR C(O)R.sup.b',
NR.sup.c'C(O)NR.sup.c'R.sup.d', NR.sup.c'C(O)OR.sup.a',
S(O)R.sup.b', S(O)NR.sup.c'R.sup.d', S(O).sub.2R.sup.b',
NR'S(O).sub.2R.sup.b', and S(O).sub.2NR.sup.c'R.sup.d'; [0894]
Cy.sup.1 and Cy.sup.2 are independently selected from aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4 or 5 substituents independently selected
from halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl,
C.sub.1-4 cyanoalkyl, CN, NO.sub.2, OR.sup.a'', SR.sup.a'',
C(O)R.sup.b'', C(O)NR.sup.c''R.sup.d'', C(O)OR.sup.a'',
OC(O)R.sup.b''OC(O)NR.sup.c''R.sup.d'', NR.sup.c''R.sup.d'',
NR.sup.c''C(O)R.sup.b'', NR.sup.c''C(O)OR.sup.a'',
NR.sup.c''S(O)R.sup.b'', NR.sup.c''S(O).sub.2R.sup.b'',
S(O)R.sup.b'', S(O)NR.sup.c''R.sup.d'', S(O).sub.2R.sup.b'', and
S(O).sub.2NR.sup.c''R.sup.d''; [0895] R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 are independently selected from H, halo, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN,
NO.sub.2, OR.sup.7, SR.sup.7, C(O)R.sup.8, C(O)NR.sup.9R.sup.10,
C(O)OR.sup.7OC(O)R.sup.8, OC(O)NR.sup.9R.sup.10, NR.sup.9R.sup.10,
NR.sup.9C(O)R.sup.8, NR.sup.cC(O)OR.sup.7, S(O)R.sup.8,
S(O)NR.sup.9R.sup.10, S(O).sub.2R.sup.8, NR.sup.9S(O).sub.2R.sup.8,
and S(O).sub.2NR.sup.9R.sup.10; [0896] R.sup.5 is H, halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, CN, NO.sub.2, OR.sup.7, SR.sup.7,
C(O)R.sup.8, C(O)NR.sup.9R.sup.10, C(O)OR.sup.7, OC(O)R.sup.8,
OC(O)NR.sup.9R.sup.10, NR.sup.9R.sup.10, NR.sup.9C(O)R.sup.8,
NR.sup.9C(O)OR.sup.7, S(O)R.sup.8, S(O)NR.sup.9R.sup.10,
S(O).sub.2R.sup.8, NR.sup.9S(O).sub.2R.sup.8, or
S(O).sub.2NR.sup.9R.sup.10; [0897] R.sup.6 is H, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
OR.sup.7, C(O)R.sup.8, C(O)NR.sup.9R.sup.10, C(O)OR.sup.7,
S(O)R.sup.8, S(O)NR.sup.9R.sup.10, S(O).sub.2R.sup.8, or
S(O).sub.2NR.sup.9R.sup.10; [0898] R.sup.7 is H, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; [0899]
R.sup.8 is H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl; [0900] R.sup.9 and R.sup.10 are
independently selected from H, C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkylcarbonyl, arylcarbonyl, C.sub.1-6 alkylsulfonyl, arylsulfonyl,
aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; [0901]
or R.sup.9 and R.sup.10 together with the N atom to which they are
attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
[0902] R.sup.11 and R.sup.12 are independently selected from H and
-E.sup.1-E.sup.2-E.sup.3-E.sup.4; [0903] D.sup.1 and E.sup.1 are
independently absent or independently selected from C.sub.1-6
alkylene, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, arylene,
cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each
of the C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.2-6
alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1, 2 or 3
substituents independently selected from halo, CN, NO.sub.2,
N.sub.3, SCN, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, amino,
C.sub.1-6 alkylamino, and C.sub.2-8 dialkylamino; [0904] D.sup.2
and E.sup.2 are independently absent or independently selected from
C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
(C.sub.1-6 alkylene).sub.r-O--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-S--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.s, --NR.sup.e--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-CO--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-COO--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-CONR.sup.e (C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-SO--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-SO.sub.2--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-SONR.sup.e--(C.sub.1-6 alkylene).sub.s,
and (C.sub.1-6 alkylene).sub.r-NR.sup.eCONR.sup.f--(C.sub.1-6
alkylene).sub.s, wherein each of the C.sub.1-6 alkylene, C.sub.2-6
alkenylene, and C.sub.2-6 alkynylene is optionally substituted by
1, 2 or 3 substituents independently selected from halo, CN,
NO.sub.2, N.sub.3, SCN, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
amino, C.sub.1-6 alkylamino, and C.sub.2-8 dialkylamino; [0905]
D.sup.3 and E.sup.3 are independently absent or independently
selected from C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.2-6
alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene, wherein each of the C.sub.1-6 alkylene,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, arylene, cycloalkylene,
heteroarylene, and heterocycloalkylene is optionally substituted by
1, 2 or 3 substituents independently selected from halo, CN,
NO.sub.2, N.sub.3, SCN, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
amino, C.sub.1-6 alkylamino, and C.sub.2-8 dialkylamino; [0906]
D.sup.4 and E.sup.4 are independently selected from H, halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl)R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d, wherein said C.sub.1-8 alkyl, C.sub.2-8
alkenyl, or C.sub.2-8 alkynyl, is optionally substituted with 1, 2,
3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl))R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; [0907] R.sup.a is H, Cy.sup.1,
--(C.sub.1-6 alkyl)-Cy.sup.1, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, wherein said C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl; [0908] R.sup.b is
H, Cy.sup.1, --(C.sub.1-6 alkyl)-Cy.sup.1, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, wherein
said C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl,
halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkyl and heterocycloalkyl; [0909] R.sup.a' and R.sup.a'' are
independently selected from H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl, wherein said C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl; R.sup.b' and
R.sup.b'' are independently selected from H, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein
said C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl,
halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkyl and heterocycloalkyl; R.sup.e and R.sup.d are
independently selected from H, Cy.sup.1, --(C.sub.1-6
alkyl)-Cy.sup.1, C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, wherein said C.sub.1-10 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, is
optionally substituted with 1, 2, or 3 substituents independently
selected from Cy.sup.1, --(C.sub.1-6 alkyl)-Cy.sup.1, OH, CN,
amino, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkyl, and halosulfanyl; [0910] or R.sup.c and R.sup.d together
with the N atom to which they are attached form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2,
or 3 substituents independently selected from Cy.sup.1,
--(C.sub.1-6 alkyl)-Cy.sup.1, OH, CN, amino, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl, and halosulfanyl; [0911]
R.sup.c' and R.sup.d' are independently selected from H, C.sub.1-10
alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein
said C
.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkyl, halosulfanyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
[0912] or R.sup.e' and R.sup.d' together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group optionally substituted with 1, 2, or 3 substituents
independently selected from OH, CN, amino, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and
heterocycloalkyl; [0913] R.sup.c'' and R.sup.d'' are independently
selected from H, C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted
with 1, 2, or 3 substituents independently selected from OH, CN,
amino, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, halosulfanyl,
C.sub.1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkyl and heterocycloalkyl; [0914] or R.sup.c'' and R.sup.d''
together with the N atom to which they are attached form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, or 3 substituents independently selected from OH, CN, amino,
halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl,
halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkyl and heterocycloalkyl; [0915] R.sup.i is H, CN, NO.sub.2,
or C.sub.1-6 alkyl; [0916] R.sup.e and R.sup.f are independently
selected from H and C.sub.1-6 alkyl; [0917] R.sup.i is H, CN, or
NO.sub.2; [0918] m is 0 or 1; [0919] n is 0 or 1; [0920] p is 0, 1,
2, 3, 4, 5, or 6; [0921] q is 0, 1, 2, 3, 4, 5 or 6; [0922] r is 0
or 1; and [0923] s is 0 or 1.
[0924] In some embodiments, when X is N, n is 1, and the moiety
formed by A.sup.1, A.sup.2, U, T, V, and --(Y).sub.n-- Z has the
formula:
##STR00068## [0925] then Y is other than
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q.
[0926] In some embodiments, when X is N, the 5-membered ring formed
by A.sup.1, A.sup.2, U, T, and V is other than pyrrolyl.
[0927] In some embodiments, when X is CH, n is 1, and the moiety
formed by A.sup.1, A.sup.2, U, T, V, and --(Y).sub.n-- Z has the
formula:
##STR00069## [0928] then --(Y).sub.n--Z is other than COOH.
[0929] In some embodiments, when X is CH or C-halo, R.sup.1,
R.sup.2, and R.sup.3 are each H, n is 1, and the moiety formed by
A.sup.1, A.sup.2, U, T, V, and --(Y).sub.n--Z has the formula:
##STR00070## [0930] then Y is other than
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q or
(CR.sup.11R.sup.12).sub.pC(O)(CR.sup.11R.sup.12).sub.q.
[0931] In some embodiments, when X is CH or C-halo, R.sup.1,
R.sup.2, and R.sup.3 are each H, n is 0, and the moiety formed by
A.sup.1, A.sup.2, U, T, V, and --(Y).sub.n-- Z has the formula:
##STR00071## [0932] then Z is other than CN, halo, or C.sub.1-4
alkyl.
[0933] In some embodiments, when X is CH or C-halo, R.sup.1,
R.sup.2, and R.sup.3 are each H, n is 1, and the moiety formed by
A.sup.1, A.sup.2, U, T, V, and --(Y).sub.n-- Z has the formula:
##STR00072## [0934] then Y is other than
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q or
(CR.sup.11R.sup.12).sub.pC(O)(CR.sup.11R.sup.12).sub.q.
[0935] In some embodiments, when X is CH or C-halo, R.sup.1,
R.sup.2, and R.sup.3 are each H, n is 1, and the moiety formed by
A.sup.1, A.sup.2, U, T, V, and --(Y).sub.n-- Z has the formula:
##STR00073## [0936] then Y is other than
(CR.sup.11R.sup.12).sub.pNR.sup.c(CR.sup.11R.sup.12).sub.q.
[0937] In some embodiments, when X is CH or C-halo and R.sup.1,
R.sup.2, and R.sup.3 are each H, then the moiety formed by A.sup.1,
A.sup.2, U, T, V, and --(Y).sub.n--Z has a formula other than:
##STR00074##
[0938] In some embodiments: [0939] Z is H, halo, CN, NO.sub.2,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8
haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl,
wherein said C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d; [0940] Q is H, halo, CN, NO.sub.2,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8
haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl,
wherein said C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl is optionally substituted with 1, 2, 3 or 4
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.2, CN,
NO.sub.2, OR.sup.a', SR.sup.a', C(O)R.sup.b',
C(O)NR.sup.c'R.sup.d', C(O)OR.sup.a', OC(O)R.sup.b',
OC(O)NR.sup.c'R.sup.d', NR.sup.c'R.sup.d', NR.sup.c'C(O)R.sup.b',
NR.sup.c'C(O)NR.sup.c'R.sup.d', NR.sup.c'C(O)OR.sup.a',
S(O)R.sup.b', S(O)NR.sup.c'R.sup.d', S(O).sub.2R.sup.b',
NR.sup.c'S(O).sub.2R.sup.b', and S(O).sub.2NR.sup.c'R.sup.d';
[0941] Cy.sup.1 and Cy.sup.1 are independently selected from aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4 or 5 substituents independently selected
from halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
CN, NO.sub.2, OR.sup.a'', SR.sup.a'', C(O)R.sup.b'',
C(O)NR.sup.c''R.sup.d'', C(O)OR.sup.a'', OC(O)R.sup.b'',
OC(O)NR.sup.c''R.sup.d'', NR.sup.c''R.sup.d'',
NR.sup.c''C(O)R.sup.b'', NR.sup.c''C(O)OR.sup.a'',
NR.sup.a''S(O)R.sup.b'', NR.sup.c''S(O).sub.2R.sup.b'',
S(O)R.sup.b'', S(O)NR.sup.c''R.sup.d'', S(O).sub.2R.sup.b'', and
S(O).sub.2NR.sup.c''R.sup.d'', [0942] R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 are independently selected from H, halo, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2,
OR.sup.7, SR.sup.7, C(O)R.sup.8, C(O)NR.sup.9R.sup.10,
C(O)OR.sup.7OC(O)R.sup.8, OC(O)NR.sup.9R.sup.10, NR.sup.9R.sup.10,
NR.sup.9C(O)R.sup.8, NR.sup.cC(O)OR.sup.7, S(O)R.sup.8,
S(O)NR.sup.9R.sup.10, S(O).sub.2R.sup.8, NR.sup.9S(O).sub.2R.sup.8,
and S(O).sub.2NR.sup.9R.sup.10; [0943] R.sup.5 is H, halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, CN, NO.sub.2, OR.sup.7, SR.sup.7, C(O)R.sup.8,
C(O)NR.sup.9R.sup.10, C(O)OR.sup.7, OC(O)R.sup.8,
OC(O)NR.sup.9R.sup.10, NR.sup.9R.sup.10, NR.sup.9C(O)R.sup.8,
NR.sup.9C(O)OR.sup.7, S(O)R.sup.8, S(O)NR.sup.9R.sup.10,
S(O).sub.2R.sup.8, NR.sup.9S(O).sub.2R.sup.8, or
S(O).sub.2NR.sup.9R.sup.10; [0944] R.sup.6 is H, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
OR.sup.7, C(O)R.sup.8, C(O)NR.sup.9R.sup.10, C(O)OR.sup.7,
S(O)R.sup.8, S(O)NR.sup.9R.sup.10, S(O).sub.2R.sup.8, or
S(O).sub.2NR.sup.9R.sup.10; [0945] R.sup.7 is H, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; [0946]
R.sup.8 is H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl; [0947] R.sup.9 and R.sup.10 are
independently selected from H, C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkylcarbonyl, arylcarbonyl, C.sub.1-6 alkylsulfonyl, arylsulfonyl,
aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; [0948]
or R.sup.9 and R.sup.10 together with the N atom to which they are
attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
[0949] R.sup.11 and R.sup.12 are independently selected from H,
halo, OH, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
[0950] R.sup.a, R.sup.a', and R.sup.a'' are independently selected
from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted
with 1, 2, or 3 substituents independently selected from OH, CN,
amino, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
[0951] R.sup.b, R.sup.b' and R.sup.b'' are independently selected
from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted
with 1, 2, or 3 substituents independently selected from OH, CN,
amino, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl
and heterocycloalkyl; [0952] R.sup.c and R.sup.d are independently
selected from H, C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted
with 1, 2, or 3 substituents independently selected from OH, CN,
amino, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl
or heterocycloalkyl; [0953] or R.sup.e and R.sup.d together with
the N atom to which they are attached form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2,
or 3 substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and
heterocycloalkyl; [0954] R.sup.c' and R.sup.d' are independently
selected from H, C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted
with 1, 2, or 3 substituents independently selected from OH, CN,
amino, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl
and heterocycloalkyl; or R.sup.c' and R.sup.d' together with the N
atom to which they are attached form a 4-, 5-, 6- or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and
heterocycloalkyl; R.sup.c'' and R.sup.d'' are independently
selected from H, C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein said C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted
with 1, 2, or 3 substituents independently selected from OH, CN,
amino, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl
and heterocycloalkyl; [0955] or R.sup.c'' and R.sup.d'' together
with the N atom to which they are attached form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2,
or 3 substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and
heterocycloalkyl.
[0956] In some embodiments, X is N.
[0957] In some embodiments, X is CR.sup.4.
[0958] In some embodiments, A.sup.1 is C.
[0959] In some embodiments, A.sup.1 is N.
[0960] In some embodiments, A.sup.2 is C.
[0961] In some embodiments, A.sup.2 is N.
[0962] In some embodiments, at least one of A.sup.1, A.sup.2, U, T,
and V is N.
[0963] In some embodiments, the 5-membered ring formed by A.sup.1,
A.sup.2, U, T, and V is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,
thiazolyl, or oxadiazolyl.
[0964] In some embodiments, the 5-membered ring formed by A.sup.1,
A.sup.2, U, T, and V is selected from:
##STR00075## [0965] wherein: [0966] a designates the site of
attachment of moiety --(Y).sub.n--Z; [0967] b designates the site
of attachment to the core moiety:
[0967] ##STR00076## [0968] and [0969] c and c' designate the two
sites of attachment of the fused 4- to 20-membered aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl ring.
[0970] In some embodiments, the 5-membered ring formed by A.sup.1,
A.sup.2, U, T, and V is:
##STR00077## [0971] wherein: [0972] a designates the site of
attachment of moiety --(Y).sub.n-- Z; [0973] b designates the site
of attachment to the core moiety.
[0973] ##STR00078## [0974] and [0975] c and c' designate the two
sites of attachment of the fused 4- to 20-membered aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl ring.
[0976] In some embodiments, the 5-membered ring formed by A.sup.1,
A.sup.2, U, T, and V is selected from:
##STR00079## [0977] wherein: [0978] a designates the site of
attachment of moiety --(Y).sub.n--Z; [0979] b designates the site
of attachment to the core moiety:
[0979] ##STR00080## [0980] and [0981] c and c' designate the two
sites of attachment of the fused 4- to 20-membered aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl ring.
[0982] In some embodiments, the 5-membered ring formed by A.sup.1,
A.sup.2, U, T, and V is selected from:
##STR00081## [0983] wherein: [0984] a designates the site of
attachment of moiety --(Y).sub.n--Z; [0985] b designates the site
of attachment to the core moiety:
##STR00082##
[0986] In some embodiments, the 5-membered ring formed by A.sup.1,
A.sup.2, U, T, and V is selected from:
##STR00083## [0987] wherein: [0988] a designates the site of
attachment of moiety --(Y).sub.n--Z; [0989] b designates the site
of attachment to the core moiety:
##STR00084##
[0990] In some embodiments, the 5-membered ring formed by A.sup.1,
A.sup.2, U, T, and V is selected from:
##STR00085## [0991] wherein: [0992] a designates the site of
attachment of moiety --(Y).sub.n-- Z; [0993] b designates the site
of attachment to the core moiety:
##STR00086##
[0994] In some embodiments, n is 0.
[0995] In some embodiments, n is 1.
[0996] In some embodiments, n is 1 and Y is C.sub.1-8 alkylene,
C.sub.2-8 alkenylene,
(CR.sup.11R.sup.12).sub.pC(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)O(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pOC(O)(CR.sup.11R.sup.12).sub.q, wherein
said C.sub.1-8 alkylene or C.sub.2-8 alkenylene, is optionally
substituted with 1, 2, or 3 halo, OH, CN, amino, C.sub.1-4
alkylamino, or C.sub.2-8 dialkylamino.
[0997] In some embodiments, n is 1 and Y is C.sub.1-8 alkylene,
(CR.sup.11R.sup.12).sub.pC(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)O(CR.sup.11R.sup.12).sub.q, wherein
said C.sub.1-8 alkylene is optionally substituted with 1, 2, or 3
halo, OH, CN, amino, C.sub.1-4 alkylamino, or C.sub.2-8
dialkylamino.
[0998] In some embodiments, n is 1 and Y is C.sub.1-8 alkylene
optionally substituted with 1, 2, or 3 halo, OH, CN, amino,
C.sub.1-4 alkylamino, or C.sub.2-8 dialkylamino.
[0999] In some embodiments, n is 1 and Y is ethylene optionally
substituted with 1, 2, or 3 halo, OH, CN, amino, C.sub.1-4
alkylamino, or C.sub.2-8 dialkylamino.
[1000] In some embodiments, n is 1 and Y is
(CR.sup.11R.sup.12).sub.pC(O)(CR.sup.11R.sup.12).sub.q
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q, or
(CR.sup.11R.sup.12).sub.p C(O)O(CR.sup.11R.sup.12).sub.q.
[1001] In some embodiments, Y is C.sub.1-8 alkylene, C.sub.2-8
alkenylene, C.sub.2-8 alkynylene,
(CR.sup.11R.sup.12).sub.p(C.sub.3-10
cycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(arylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12) (C.sub.1-10
heterocycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(heteroarylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pO(CR.sup.11R.sup.12).sub.q, or
(CR.sup.11R.sup.12).sub.pS(CR.sup.11R.sup.12).sub.q, wherein said
C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8 alkynylene,
cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is
optionally substituted with 1, 2, or 3 substituents independently
selected from -D -D2-D.sup.3-D.sup.4.
[1002] In some embodiments, Y is C.sub.1-8 alkylene, C.sub.2-8
alkenylene, C.sub.2-8 alkynylene,
(CR.sup.11R.sup.12).sub.p--(C.sub.3-10
cycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(arylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12) (C.sub.1-10
heterocycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(heteroarylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pO(CR.sup.11R.sup.12).sub.q, or
(CR.sup.11R.sup.12).sub.pS(CR.sup.11R.sup.12).sub.q, wherein said
C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8 alkynylene,
cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is
optionally substituted with 1, 2, or 3 substituents independently
selected from D.sup.4.
[1003] In some embodiments, Y is C.sub.1-8 alkylene, C.sub.2-8
alkenylene, C.sub.2-8 alkynylene, or (CR.sup.11R.sup.12).sub.p
(C.sub.3-10 cycloalkylene)-(CR.sup.11R.sup.12).sub.q, wherein said
C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8 alkynylene, or
cycloalkylene, is optionally substituted with 1, 2, or 3
substituents independently selected from
-D.sup.1-D.sup.2-D.sup.3-D.sup.4.
[1004] In some embodiments, Y is C.sub.1-8 alkylene, C.sub.2-8
alkenylene, C.sub.2-8 alkynylene, or (CR.sup.11R.sup.12).sub.p
(C.sub.3-10 cycloalkylene)-(CR.sup.11R.sup.12).sub.q, wherein said
C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8 alkynylene, or
cycloalkylene, is optionally substituted with 1, 2, or 3
substituents independently selected from D.sup.4.
[1005] In some embodiments, Y is C.sub.1-8 alkylene, C.sub.2-8
alkenylene, or C.sub.2-8 alkynylene, each optionally substituted
with 1, 2, or 3 substituents independently selected from -D
-D2-D.sup.3-D.sup.4
[1006] In some embodiments, Y is C.sub.1-8 alkylene optionally
substituted with 1, 2, or 3 substituents independently selected
from -D.sup.1-D.sup.2-D.sup.3-D.sup.4.
[1007] In some embodiments, Y is C.sub.1-8 alkylene optionally
substituted with 1, 2, or 3 substituents independently selected
from D.sup.4.
[1008] In some embodiments, Y is C.sub.1-8 alkylene, C.sub.2-8
alkenylene, C.sub.2-8 alkynylene,
(CR.sup.11R.sup.12).sub.pO--(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12)C(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)O(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pOC(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pOC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pNR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pNR.sup.cC(O)NR.sup.d(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O).sub.2(CR.sup.11R.sup.12).sub.q, or
(CR.sup.11R.sup.12).sub.pS(O).sub.2NR.sup.c(CR.sup.11R.sup.12).sub.q,
wherein said C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8
alkynylene is optionally substituted with 1, 2, or 3 substituents
independently selected from halo, OH, CN, amino, C.sub.1-4
alkylamino, and C.sub.2-8 dialkylamino.
[1009] In some embodiments, Y is C.sub.1-8 alkylene, C.sub.2-8
alkenylene, C.sub.2-8 alkynylene,
(CR.sup.11R.sup.12).sub.p--(C.sub.3-10
cycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(arylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12) (C.sub.1-10
heterocycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(heteroarylene)-(CR.sup.11R.sup.12).sub.q
(CR.sup.11R.sup.12).sub.pO(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.a(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)O(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pOC(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pOC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sub.11R.sup.12).sub.pNR.sup.c(CR.sup.11R.sup.12).sub.q
(CR.sup.11R.sup.12).sub.pNR.sup.cC(O)NR.sup.d(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12)S(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O).sub.2(CR.sup.11R.sup.12).sub.q, or
(CR.sup.11R.sup.12).sub.pS(O).sub.2NR.sup.c(CR.sup.11R.sup.12).sub.q,
wherein said C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8
alkynylene, cycloalkylene, arylene, heterocycloalkylene, or
heteroarylene, is optionally substituted with 1, 2, or 3
substituents independently selected from halo, OH, CN, amino,
C.sub.1-4 alkylamino, and C.sub.2-8 dialkylamino.
[1010] In some embodiments, p is 0.
[1011] In some embodiments, p is 1.
[1012] In some embodiments, p is 2.
[1013] In some embodiments, q is 0.
[1014] In some embodiments, q is 1.
[1015] In some embodiments, q is 2.
[1016] In some embodiments, one of p and q is 0 and the other of p
and q is 1, 2, or 3.
[1017] In some embodiments, Z is H, halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl)R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d, wherein said C.sub.1-8 alkyl, C.sub.2-8
alkenyl, or C.sub.2-8 alkynyl, is optionally substituted with 1, 2,
3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl))R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1018] In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5,
or 6 substituents selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, halosulfanyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.dS(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1019] In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5,
or 6 substituents selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4
hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1020] In some embodiments, Z is aryl or heteroaryl, each
optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
selected from halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-4 haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl,
C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1021] In some embodiments, Z is aryl or heteroaryl, each
optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
selected from halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1022] In some embodiments, Z is phenyl or 5- or 6-membered
heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6
substituents selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, halosulfanyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1023] In some embodiments, Z is phenyl or 5- or 6-membered
heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6
substituents selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4
hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1024] In some embodiments, Z is phenyl optionally substituted with
1, 2, 3, 4, 5, or 6 substituents selected from halo, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1025] In some embodiments, Z is phenyl optionally substituted with
1, 2, 3, 4, 5, or 6 substituents selected from halo, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1026] In some embodiments, Z is cycloalkyl or heterocycloalkyl,
each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
selected from halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-4 haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl,
C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1027] In some embodiments, Z is cycloalkyl or heterocycloalkyl,
each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
selected from halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.dC(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d, NR.sup.C(.dbd.NR)NR.sup.cR.sup.d,
S(O)R.sup.b, S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, and S(O).sub.2NR.sup.cR.sup.d.
[1028] In some embodiments, Z is cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl, each optionally
substituted with 1, 2, 3, 4, 5, or 6 substituents selected from
halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl,
C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1029] In some embodiments, Z is C.sub.1-8 alkyl, C.sub.2-8
alkenyl, or C.sub.2-8 alkynyl, each optionally substituted with 1,
2, 3, 4, 5, or 6 substituents selected from halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d. In some embodiments, Z is C.sub.1-8
alkyl, C.sub.2-8 alkenyl, or C.sub.2-8 alkynyl, each optionally
substituted with 1, 2, 3, 4, 5, or 6 substituents selected from
halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.dS(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1030] In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5,
or 6 substituents independently selected from halo, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1031] In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5,
or 6 substituents independently selected from halo, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1032] In some embodiments, Z is aryl or heteroaryl, each
optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, halosulfanyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1033] In some embodiments, Z is aryl or heteroaryl, each
optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4
hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.dC(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1034] In some embodiments, Z is phenyl or 5- or 6-membered
heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1035] In some embodiments, Z is phenyl or 5- or 6-membered
heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1036] In some embodiments, Z is phenyl optionally substituted with
1, 2, 3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1037] In some embodiments, Z is phenyl optionally substituted with
1, 2, 3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1,
CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.dC(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1038] In some embodiments, Z is cycloalkyl or heterocycloalkyl,
each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, halosulfanyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1039] In some embodiments, Z is cycloalkyl or heterocycloalkyl,
each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4
hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1040] In some embodiments, Z is C.sub.1-8 alkyl, C.sub.2-8
alkenyl, or C.sub.2-8 alkynyl, each optionally substituted with 1,
2, 3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1041] In some embodiments, Z is C.sub.1-8 alkyl, C.sub.2-8
alkenyl, or C.sub.2-8 alkynyl, each optionally substituted with 1,
2, 3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, C.sub.1-4, hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1,
CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1042] In some embodiments, Z is C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5,
or 6 substituents independently selected from halo, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl,
C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, and S(O).sub.2R.sup.b.
[1043] In some embodiments, Z is C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5,
or 6 substituents independently selected from halo, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b, and
S(O).sub.2R.sup.b.
[1044] In some embodiments, Z is C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each optionally substituted with 1, 2, or 3
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl,
C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, and S(O).sub.2R.sup.b.
[1045] In some embodiments, Z is C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each optionally substituted with 1, 2, or 3
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.1, CN, NO.sub.2, OR.sup.a, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b, and
S(O).sub.2R.sup.b.
[1046] In some embodiments, Z is substituted with at least one
substituent comprising at least one CN group.
[1047] In some embodiments, Z is C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each substituted with at least one CN or
C.sub.1-4 cyanoalkyl and optionally substituted with 1, 2, 3, 4, or
5 further substituents selected from halo, C.sub.1-4 alkyl,
C.sub.2-8 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d.
[1048] In some embodiments, Z is C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl, each substituted with at least one CN or
C.sub.1-4 cyanoalkyl and optionally substituted with 1, 2, 3, 4, or
5 further substituents selected from halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1049] In some embodiments, wherein the --(Y).sub.n-- Z moiety is
taken together with i) A.sup.2 to which said moiety is attached,
ii) R.sup.5 or R.sup.6 of either T or V, and iii) the C or N atom
to which said R.sup.5 or R.sup.6 of either T or V is attached to
form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl ring fused to the 5-membered ring formed by
A.sup.1, A.sup.2, U, T, and V, wherein said 4- to 20-membered aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from --(W).sub.m-Q.
[1050] In some embodiments, wherein the --(Y).sub.n-- Z moiety is
taken together with i) A.sup.2 to which said moiety is attached,
ii) R.sup.5 or R.sup.6 of either T or V, and iii) the C or N atom
to which said R.sup.5 or R.sup.6 of either T or V is attached to
form a 4- to 8-membered aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl ring fused to the 5-membered ring formed by
A.sup.1, A.sup.2, U, T, and V, wherein said 4- to 8-membered aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from --(W).sub.m-Q.
[1051] In some embodiments, the --(Y).sub.n--Z moiety is taken
together with i) A.sup.2 to which said moiety is attached, ii)
R.sup.5 or R.sup.6 of either T or V, and iii) the C or N atom to
which said R.sup.5 or R.sup.6 of either T or V is attached to form
a 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring
fused to the 5-membered ring formed by A.sup.1, A.sup.2, U, T, and
V, wherein said 6-membered aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl ring is optionally substituted by 1, 2, or 3
substituents independently selected from halo, CN, NO.sub.2,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8
haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl
wherein said C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-8haloalkyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl is optionally substituted by 1, 2 or 3 CN.
[1052] In some embodiments, Cy.sup.1 and Cy.sup.2 are independently
selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,
each optionally substituted by 1, 2, 3, 4 or 5 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4
hydroxyalkyl, C.sub.1-4 cyanoalkyl, CN, NO.sub.2, OR.sup.a'',
SR.sup.a'', C(O)R.sup.b'', C(O)NR.sup.c''R.sup.d, C(O)OR.sup.a'',
OC(O)R.sup.b'', OC(O)NR.sup.c''R.sup.d'', NR.sup.c''R.sup.d'',
NR.sup.c''C(O)R.sup.b'', NR.sup.c''C(O)OR.sup.a'', S(O)R.sup.b'',
S(O)NR.sup.c''R.sup.d'', S(O).sub.2R.sup.b'', and
S(O).sub.2NR.sup.c''R.sup.d''.
[1053] In some embodiments, Cy.sup.1 and Cy.sup.2 are independently
selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,
each optionally substituted by 1, 2, 3, 4 or 5 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, CN, NO.sub.2,
OR.sup.a'', SR.sup.a'', C(O)R.sup.b'', C(O)NR.sup.c''R.sup.d'',
C(O)OR.sup.a'', OC(O)R.sup.b'', OC(O)NR.sup.c''R.sup.d'',
NR.sup.c''R.sup.d'', NR.sup.c''C(O)R.sup.b'',
NR.sup.c''C(O)OR.sup.a''S(O)R.sup.b'', S(O)NR.sup.c''R.sup.d'',
S(O).sub.2R.sup.b'', and S(O).sub.2NR.sup.c''R.sup.d''.
[1054] In some embodiments, Cy.sup.1 and Cy.sup.2 are independently
selected from cycloalkyl and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4 or 5 substituents independently selected
from halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, CN, NO.sub.2, OR.sup.a'', SR.sup.a'',
C(O)R.sup.b'', C(O)NR.sup.c''R.sup.d'', C(O)OR.sup.a'',
OC(O)R.sup.b''OC(O)NR.sup.c''R.sup.d'', NR.sup.c''R.sup.d'',
NR.sup.c''C(O)R.sup.b'', NR.sup.c''C(O)OR.sup.a'', S(O)R.sup.b'',
S(O)NR.sup.c''R.sup.d'', S(O).sub.2R.sup.b'', and
S(O).sub.2NR.sup.c''R.sup.d''.
[1055] In some embodiments, Cy.sup.1 and Cy.sup.2 are independently
selected from cycloalkyl optionally substituted by 1, 2, 3, 4 or 5
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, CN,
NO.sub.2, OR.sup.a'', SR.sup.a'', C(O)R.sup.b'',
C(O)NR.sup.c''R.sup.d'', C(O)OR.sup.a'', OC(O)R.sup.b'',
OC(O)NR.sup.c''R.sup.d'', NR.sup.c''R.sup.d'',
NR.sup.c''C(O)R.sup.b'', NR.sup.c''C(O)OR.sup.a''S(O)R.sup.b'',
S(O)NR.sup.c''R.sup.d'', S(O).sub.2R.sup.b'', and
S(O).sub.2NR.sup.c''R.sup.d''.
[1056] In some embodiments, R.sup.1, R.sup.2, R.sup.3, and R.sup.4
are independently selected from H, halo, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, CN, NO.sub.2, OR.sup.7, SR.sup.7,
C(O)R.sup.8, C(O)NR.sup.9R.sup.10, C(O)OR.sup.7OC(O)R.sup.8,
OC(O)NR.sup.9R.sup.10, NR.sup.9R.sup.10, NR.sup.9C(O)R.sup.8,
NR.sup.cC(O)OR.sup.7, S(O)R.sup.8, S(O)NR.sup.9R.sup.10,
S(O).sub.2R.sup.8, NR.sup.9S(O).sub.2R.sup.8, and
S(O).sub.2NR.sup.9R.sup.10.
[1057] In some embodiments, R.sup.1, R.sup.2, R.sup.3, and R.sup.4
are independently selected from H, halo, and C.sub.1-4 alkyl.
[1058] In some embodiments, R.sup.1, R.sup.2, R.sup.3, and R.sup.4
are each H.
[1059] In some embodiments, R.sup.1 is H, halo, or C.sub.1-4
alkyl.
[1060] In some embodiments, R.sup.5 is H, halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, CN,
NO.sub.2, OR.sup.7, SR.sup.7, C(O)R.sup.8, C(O)NR.sup.9R.sup.10,
C(O)OR.sup.7, OC(O)R.sup.8, OC(O)NR.sup.9R.sup.10,
NR.sup.9R.sup.10, NR.sup.9C(O)R.sup.8, NR.sup.9C(O)OR.sup.7,
S(O)R.sup.8, S(O)NR.sup.9R.sup.10, S(O).sub.2R.sup.8,
NR.sup.9S(O).sub.2R.sup.8, or S(O).sub.2NR.sup.9R.sup.10.
[1061] In some embodiments, R.sup.5 is H, halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, halosulfanyl, CN, or NR.sup.9R.sup.10.
[1062] In some embodiments, R.sup.5 is H, halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, CN, or NR.sup.9R.sup.10.
[1063] In some embodiments, R.sup.5 is H.
[1064] In some embodiments, R.sup.6 is H or C.sub.1-4 alkyl.
[1065] In some embodiments, R.sup.6 is H.
[1066] In some embodiments, R.sup.11 and R.sup.12 are independently
selected from H, halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, halosulfanyl, C.sub.1-4
hydroxyalkyl, C.sub.1-4 cyanoalkyl, Cy.sup.1, CN, NO.sub.2,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl)R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d, wherein said C.sub.1-g alkyl, C.sub.2-8
alkenyl, or C.sub.2-8 alkynyl, is optionally substituted with 1, 2,
3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl))R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[1067] In some embodiments, R.sup.11 and R.sup.12 are independently
selected from H, halo, OH, CN, (C.sub.1-4)alkyl,
(C.sub.1-4)haloalkyl, halosulfanyl, SCN, (C.sub.2-4)alkenyl,
(C.sub.2-4)alkynyl, (C.sub.1-4)hydroxyalkyl, (C.sub.1-4)cyanoalkyl,
aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.
[1068] In some embodiments, R.sup.11 and R.sup.12 are independently
selected from H, halo, OH, CN, (C.sub.1-4)alkyl,
(C.sub.1-4)haloalkyl, (C.sub.2-4)alkenyl, (C.sub.2-4)alkynyl,
(C.sub.1-4)hydroxyalkyl, (C.sub.1-4)cyanoalkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl.
[1069] In a preferred embodiment, the JAK-2 inhibitor is
ruxolitinib (available from Incyte Corp. and Novartis AG). In a
preferred embodiment, the JAK-2 inhibitor is ruxolitinib phosphate
(available from Incyte Corp. and Novartis AG). In a preferred
embodiment, the JAK-2 inhibitor is
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile. In a preferred embodiment, the JAK-2 inhibitor is
the phosphate salt of
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile. In a preferred embodiment, the JAK-2 inhibitor is
(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl-
]propanenitrile. In a preferred embodiment, the JAK-2 inhibitor is
a compound of Formula (XXX):
##STR00087## [1070] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. Nos. 8,604,043, 7,834,022,
8,486,902, 8,530,485, 7,598,257, 8,541,425, and 8,410,265 and U.S.
Patent Application Publication Nos. 2010/0298355 A1, 2008/0312258
A1, 2011/0082159 A1, 2011/0086810 A1, 2013/0345157 A1, 2014/0018374
A1, 2014/0005210 A1, 2011/0223210 A1, 2011/0224157 A1, 2007/0135461
A1, 2010/0022522 A1, 2013/0253193 A1, 2013/0253191 A1, 2013/0253190
A1, 2010/0190981 A1, 2013/0338134 A1, 2008/0312259 A1, 2014/0094477
A1, and 2014/0094476 A1, the disclosures of which are incorporated
by reference herein. In an embodiment, the JAK-2 inhibitor is a
compound selected from the structures disclosed in U.S. Pat. Nos.
8,604,043, 7,834,022, 8,486,902, 8,530,485, 7,598,257, 8,541,425,
and 8,410,265 and U.S. Patent Application Publication Nos.
2010/0298355 A1, 2008/0312258 A1, 2011/0082159 A1, 2011/0086810 A1,
2013/0345157 A1, 2014/0018374 A1, 2014/0005210 A1, 2011/0223210 A1,
2011/0224157 A1, 2007/0135461 A1, 2010/0022522 A1, 2013/0253193 A1,
2013/0253191 A1, 2013/0253190 A1, 2010/0190981 A1, 2013/0338134 A1,
2008/0312259 A1, 2014/0094477 A1, and 2014/0094476 A1, the
disclosures of which are incorporated by reference herein.
[1071] Ruxolitinib may be prepared according to the procedures
given in the references above, or by the procedure of Example 67 of
U.S. Pat. No. 7,598,257, the disclosure of which is specifically
incorporated by reference herein. Briefly, the preparation is as
follows:
Step 1
[1072] (2E)- and (2Z)-3-Cyclopentylacrylonitrile. To a solution of
1.0 M potassium tert-butoxide in THF (235 mL) at 0.degree. C. was
added dropwise a solution of diethyl cyanomethylphosphonate (39.9
mL, 0.246 mol) in TBF (300 mL). The cold bath was removed and the
reaction was warmed to room temperature followed by recooling to
0.degree. C., at which time a solution of cyclopentanecarbaldehyde
(22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. The bath was
removed and the reaction warmed to ambient temperature and stirred
for 64 hours. The mixture was partitioned between diethyl ether and
water, the aqueous was extracted with three portions of ether,
followed by two portions of ethyl acetate. The combined extracts
were washed with brine, then dried over sodium sulfate, filtered
and concentrated in vacuo to afford a mixture containing 24.4 g of
olefin isomers which was used without further purification (89%).
.sup.1H NMR (400 MHz, CDCl3): .delta. 6.69 (dd, 1H, trans olefin),
6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 (d, 1H,
cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H,
trans product), 1.98-1.26 (m, 16H).
Step 2
[1073] (3R)- and
(3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,-
3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile. To a solution
of
4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]--
pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added
3-cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis
and trans isomers), followed by DBU (15 mL, 0.10 mol). The
resulting mixture was stirred at room temperature overnight. The
ACN was evaporated. The mixture was diluted with ethyl acetate, and
the solution was washed with 1.0 N HCl. The aqueous layer was
back-extracted with three portions of ethyl acetate. The combined
organic extracts were washed with brine, dried over sodium sulfate,
filtered and concentrated. The crude product was purified by silica
gel chromatography (gradient of ethyl acetate/hexanes) to yield a
viscous clear syrup, which was dissolved in ethanol and evaporated
several times to remove ethyl acetate, to afford 19.4 g of racemic
adduct (93%). The enantiomers were separated by preparative-HPLC,
(OD-H column, 15% ethanol/hexanes) and used separately in the next
step to generate their corresponding final product. The final
products (see Step 3) stemming from each of the separated
enantiomers were found to be active JAK inhibitors; however, the
final product stemming from the second peak to elute from the
preparative-HPLC was more active than its enantiomer. The products
may be isolated by preparative HPLC or other means known to those
of skill in the art for use in Step 3 below. 1H NMR (300 MHz,
CDCl3): .delta. 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d,
1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95
(dd, 1H), 2.67-2.50 (m, 1H), 2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H),
0.92 (t, 2H), -0.06 (s, 9H); MS(ES): 437 (M+1).
Step 3
[1074] To a solution of
3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]--
pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (6.5 g, 0.015 mol, R
or S enantiomer as isolated above) in DCM (40 mL) was added TFA (16
mL) and this was stirred for 6 hours. The solvent and TFA were
removed in vacuo. The residue was dissolved in DCM and concentrated
using a rotary evaporator two further times to remove as much as
possible of the TFA. Following this, the residue was stirred with
ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. The
solvent was removed in vacuo, water was added and the product was
extracted into three portions of ethyl acetate. The combined
extracts were washed with brine, dried over sodium sulfate,
decanted and concentrated to afford the crude product which was
purified by flash column chromatography (eluting with a gradient of
methanol/DCM). The resulting mixture was further purified by
preparative-HPLC/MS (C18 eluting with a gradient of ACN/H2O
containing 0.15% NH4OH) to afford product (2.68 g, 58%). .sup.1H
NMR (400 MHz, D6-dmso): .delta. 12.11 (br s, 1H), 8.80 (s, 1H),
8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d, 1H), 4.53 (dt,
1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48-2.36 (m, 1H), 1.86-1.76 (m,
1H), 1.68-1.13 (m, 7H); MS(ES): 307 (M+1).
[1075] Ruxolitinib prepared according to the steps above, or any
other procedure, may be used as its free base for the compositions
and methods described herein. Ruxolitinib may also be used in a
salt form. For example, a crystalline phosphoric acid salt of
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile may be prepared from the free base as follows
according to the procedure given in Example 2 of U.S. Pat. No.
8,722,693, the disclosure of which is specifically incorporated
herein by reference. To a test tube was added
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile (153.5 mg) and phosphoric acid (56.6 mg) followed by
isopropyl alcohol (IPA) (5.75 mL). The resulting mixture was heated
to clear, cooled to room temperature, and then stirred for another
2 hours. The precipitate was collected by filtration and the cake
was washed with 0.6 mL of cold IPA. The cake was dried under vacuum
to constant weight to provide the final salt product (171.7 mg).
The phosphroic acid salt is a 1:1 salt by .sup.1H NMR and
crystallinity is confirmed by X-ray powder diffraction (XRPD).
Differential scanning calorimetry (DSC) of the produce yields a
sharp melting peak at about 198.7.degree. C.
[1076] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XXXI):
##STR00088## [1077] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [1078] L is
SO.sub.2 or CO; [1079] R.sup.1 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl,
NR.sup.2R.sup.3, or OR.sup.4, wherein said alkyl, cycloalkyl,
phenyl, or heteroaryl is optionally substituted with 1, 2, or 3
substituents independently selected from F, CN, and C.sub.1-4
alkyl; [1080] R.sup.2 and R.sup.3 are independently selected from
H, C.sub.1-4 alkyl, and phenyl; and [1081] R.sup.4 is C.sub.1-6
alkyl, phenyl, or benzyl.
[1082] In some embodiments, when L is SO.sub.2, then R.sup.1 is
other than OR.sup.4.
[1083] In some embodiments, when L is SO.sub.2, then R.sup.1 is
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, 5- or 6-membered
heteroaryl, or NR.sup.2R.sup.3, wherein said alkyl, cycloalkyl,
phenyl, or heteroaryl is optionally substituted with 1, 2, or 3
substituents independently selected from F and C.sub.1-4 alkyl.
[1084] In some embodiments, when L is CO, then R.sup.1 is C.sub.3-7
cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl,
NR.sup.2R.sup.3, or OR.sup.4, wherein said cycloalkyl, phenyl, or
heteroaryl is optionally substituted with 1, 2, or 3 substituents
independently selected from CN and C.sub.1-4 alkyl.
[1085] In some embodiments, L is SO.sub.2.
[1086] In some embodiments, L is CO.
[1087] In some embodiments, R.sup.1 is methyl, ethyl, n-propyl,
isopropyl, n-butyl, t-butyl, 2-methylprop-1-yl, 1-methylprop-1-yl,
each optionally substituted with 1, 2, or 3 F.
[1088] In some embodiments, R.sup.1 is C.sub.1-4 alkyl.
[1089] In some embodiments, R.sup.1 is ethyl.
[1090] In some embodiments, R.sup.1 is C.sub.3-7 cycloalkyl
optionally substituted by C.sub.1-4 alkyl.
[1091] In some embodiments, R.sup.1 is phenyl optionally
substituted with F, methyl, or CN.
[1092] In some embodiments, R.sup.1 is 5-membered heteroaryl
selected from thienyl, pyrazolyl, pyrrolyl, 1,2,4-oxadiazolyl, and
isoxazolyl, each optionally substituted with C.sub.1-4 alkyl.
[1093] In some embodiments, R.sup.1 is pyridinyl.
[1094] In some embodiments, R.sup.1 is NR.sup.2R.sup.3 or
OR.sup.4.
[1095] In some embodiments, L is SO.sub.2 and R.sup.1 is C.sub.1-6
alkyl.
[1096] In an embodiment, the JAK-2 inhibitor is baricitinib
(available from Incyte Corp. and Eli Lilly & Co.). In an
embodiment, the JAK-2 inhibitor is
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfon-
yl)azetidin-3-yl)acetonitrile. In an embodiment, the JAK-2
inhibitor is a compound of Formula (XXXII):
##STR00089## [1097] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. Nos. 8,158,616 and 8,420,629,
U.S. Patent Application Publication Nos. 2009/0233903 A1;
2013/0225556 A1; and, 2012/0077798 A1, and International Patent
Application Publication No. WO 2014/0028756, the disclosures of
which are incorporated by reference herein. In an embodiment, the
JAK-2 inhibitor is a compound described in U.S. Pat. Nos. 8,158,616
and 8,420,629, U.S. Patent Application Publication Nos.
2009/0233903 A1; 2013/0225556 A1; and, 2012/0077798 A1, and
International Patent Application Publication No. WO 2014/0028756,
the disclosures of which are incorporated by reference herein.
[1098] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XXXIII):
##STR00090## [1099] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [1100] Q and Z are
independently selected from N and CR.sup.1; n is 1, 2 or 3; [1101]
R.sup.1 is independently selected from hydrogen, halogen, R.sup.2,
OR.sup.2, OH, R.sup.4, OR.sup.4, CN, CF.sub.3,
(CH.sub.2).sub.nN(R.sup.2).sub.2, NO.sub.2, R.sup.2R.sup.4,
SO.sub.2R.sup.4, NR.sup.2SO.sub.2R.sup.3, COR.sup.4,
NR.sup.2COR.sup.3, CO.sub.2H, CO.sub.2R.sup.2, NR.sup.2COR.sup.4,
R.sup.2CN, R.sup.2CN, R.sup.2OH, R.sup.2OR.sup.3 and
OR.sup.5R.sup.4; or two R.sup.1 substituents together with the
carbons which they are attached to form an unsaturated 5 or 6
membered heterocyclyl; [1102] R.sup.2 is substituted or
unsubstituted C.sub.1-4alkyl or substituted or unsubstituted
C.sub.1-4 alkylene where up to 2 carbon atoms can be optionally
replaced with CO, NR.sup.Y, CONR.sup.Y, S, SO.sub.2 or O; [1103]
R.sup.3 is R.sup.2, C.sub.2-4 alkenyl or substituted or
unsubstituted aryl; [1104] R.sup.4 is NH.sub.2, NHR.sup.2,
N(R').sub.2, substituted or unsubstituted morpholino, substituted
or unsubstituted thiomorpholino, substituted or unsubstituted
thiomorpholino-1-oxide, substituted or unsubstituted
thiomorpholino-1, 1-dioxide, substituted or unsubstituted
piperazinyl, substituted or unsubstituted piperidinyl, substituted
or unsubstituted pyridinyl, substituted or unsubstituted
pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or
unsubstituted oxazolyl, substituted or unsubstituted imidazolyl,
substituted or unsubstituted tetrahydrofuranyl and substituted or
unsubstituted tetrahydropyranyl; [1105] R.sup.5 is substituted or
unsubstituted C.sub.1-4alkylene; [1106] R.sup.6-R.sup.10 are
independently selected from H, R.sup.XCN, halogen, substituted or
unsubstituted C.sub.Malkyl, OR.sup.1, CO.sub.2R.sup.1, N(R').sub.2,
NO.sub.2, CON(R').sub.2J SO.sub.2N(R.sup.Y).sub.2, N(SO.sub.2R
.sub.2, substituted or unsubstituted piperazinyl,
N(R.sup.Y)SO.sub.2R.sup.2 and CF.sub.3; R.sup.x is absent or
substituted or unsubstituted C.sub.1-6alkylene wherein up to 2
carbon atoms can be optionally replaced with CO, NSO.sub.2R.sup.1,
NR.sup.Y, CONR.sup.Y, S, SO.sub.2 or O; R.sup..gamma. is H or
substituted or unsubstituted C.sub.1-4 alkyl; and [1107] R.sup.11
is selected from H, halogen, substituted or unsubstituted C.sub.1-4
alkyl, OR.sup.2, CO.sub.2R.sup.2, CN, CON(R').sub.2 and CF.sub.3,
or an enantiomer thereof.
[1108] In a preferred embodiment, the JAK-2 inhibitor is
momelotinib (Gilead Sciences). Momelotinib is also known as
CYT-387. In a preferred embodiment, the JAK-2 inhibitor is
N-(cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide.
In a preferred embodiment, the JAK-2 inhibitor is a compound of
Formula (XXXIV):
##STR00091## [1109] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. No. 8,486,941 and U.S. Patent
Application Publication Nos. 2010/0197671 A1; 2014/0005180 A1;
2014/0011803 A1; and, 2014/0073643 A1, the disclosures of which are
incorporated by reference herein. In an embodiment, the JAK-2
inhibitor is a compound described in U.S. Pat. No. 8,486,941 and
U.S. Patent Application Publication Nos. 2010/0197671 A1;
2014/0005180 A1; 2014/0011803 A1; and, 2014/0073643 A1, the
disclosures of which are incorporated by reference herein.
[1110] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XXXV):
##STR00092## [1111] or a tautomer thereof, or a clathrate thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug thereof, wherein: [1112] X.sub.41 is O, S, or NR.sub.42;
[1113] X.sub.42 is CR.sub.44 or N; [1114] Y.sub.40 is N or
CR.sub.43; [1115] Y.sub.41 is N or CR.sub.45; [1116] Y.sub.42, for
each occurrence, is independently N, C or CR.sub.46; [1117] Z is OH
SH, or NHR.sub.7; [1118] R.sub.41 is --H, --OH, --SH, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, halo, cyano, nitro, guanadino,
a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,
--NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7,
--C(S)R.sub.7, --C(O)SR.sub.7, --C(S)SR.sub.7, --C(S)OR.sub.7,
--C(S)NR.sub.10R.sub.11, --C(NR.sub.8)OR.sub.7,
--C(NR.sub.8)R.sub.7, --C(NR.sub.8)NR.sub.10R.sub.11,
--C(NR.sub.8)SR.sub.7, --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(S)OR.sub.7, --OC(s)OR.sub.7, --SC(O)R.sub.7, --SC(O)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --OC(S)R.sub.7, --SC(S)R.sub.7,
--SC(S)OR.sub.7, --OC(O)NR.sub.10R.sub.11,
--OC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --NR.sub.7C(S)R.sub.7,
--NR.sub.7C(S)OR.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--NR.sub.7C(O)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7,
--S(O).sub.pR.sup.7, --OS(O).sub.pR.sup.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sup.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sup.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [1119] R.sub.42 is --H, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a
haloalkyl, a heteroalkyl, --C(O)R.sub.7,
--(CH.sub.2).sub.mC(O)OR.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7,
--C(O)NR.sub.10R.sub.11, --S(O).sub.pR.sup.7, --S(O).sub.pOR.sub.7,
or --S(O).sub.pNR.sub.10R.sub.11; [1120] R.sub.43 and R.sub.44 are,
independently, --H, --OH, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro,
guanadino, a haloalkyl, a heteroalkyl, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sup.7,
--OS(O).sub.pR.sup.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sup.7, --S(O).sub.pNR.sub.10R.sub.11, or
R.sub.43 and R.sub.44 taken together with the carbon atoms to which
they are attached form an optionally substituted cycloalkenyl, an
optionally substituted aryl, an optionally substituted
heterocyclyl, or an optionally substituted heteroaryl; [1121]
R.sub.45 is --H, --OH, --SH, --NR.sub.7H, --OR.sub.26, --SR.sub.26,
--NHR.sub.26, --O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH,
--O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.mOH,
--S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H,
--OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11,
--NR.sub.7C(O)NR.sub.10R.sub.11, --OC(O)R.sub.7, --SC(O)R.sub.7,
--NR.sub.7C(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7,
--NR.sub.7C(O)OR.sub.7, --OCH.sub.2C(O)R.sub.7,
--SCH.sub.2C(O)R.sub.7, --NR.sub.7CH.sub.2C(O)R.sub.T,
--OCH.sub.2C(O)OR.sub.7, --SCR.sub.2C(O)OR.sub.7,
--NR.sub.7CH.sub.2C(O)OR.sub.7, --OCH.sub.2C(O)NR.sub.10R.sub.11,
--SCH.sub.2C(O)NR.sub.10R.sub.11,
--NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sup.7,
--SS(O).sub.pR.sup.7, --NR.sub.7S(O).sub.pR.sup.7,
--OS(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7,
--OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7,
--OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(N.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(NR.sub.8)NR.sub.10R.sub.11, or
--NR.sub.7C(N.sub.8)NR.sub.10R.sub.11; [1122] R.sub.46, for each
occurrence, is independently, selected from the group consisting of
H, an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, an optionally substituted heteraralkyl, halo,
cyano, nitro, guanadino, a haloalkyl, a heteroalkyl,
--NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7,
--OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11, --NR.sub.8C(O)R.sub.7,
--SR.sub.7, --S(O)R.sub.7, --OS(O).sub.pR.sup.7,
--S(O).sub.pOR.sub.7, --NR.sub.8S(O).sub.pR.sup.7, or
--S(O).sub.pNR.sub.10R.sub.11; [1123] R.sub.7 and R.sub.8, for each
occurrence, are, independently, --H, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; [1124] R.sub.10 and R.sub.11, for each
occurrence, are independently --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted heteroaryl;
[1125] R.sub.26, for each occurrence is, is independently, a lower
alkyl; [1126] p, for each occurrence, is, independently, 1 or 2;
and [1127] m, for each occurrence, is independently, 1, 2, 3, or
4.
[1128] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XXXVI):
##STR00093## [1129] or a tautomer thereof, or a clathrate thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug thereof, wherein: [1130] X.sub.45 is CR.sub.54 or N;
[1131] Z1 is --OH or --SH; [1132] R.sub.56 is selected from the
group consisting of --H, methyl, ethyl, isopropyl, and cyclopropyl;
[1133] R.sub.52 is selected from the group consisting of --H,
methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl,
--(CH.sub.2).sub.2OCH.sub.3, --CH.sub.2C(O)OH, and
--C(O)N(CH.sub.3).sub.2; [1134] R.sub.53 and R.sub.54 are each,
independently, --H, methyl, ethyl, or isopropyl; or R.sub.53 and
R.sub.54 taken together with the carbon atoms to which they are
attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
[1135] R.sub.55 is selected from the group consisting of --H, --OH,
--OCH.sub.3, and --OCH.sub.2CH.sub.3.
[1136] In a preferred embodiment, the JAK-2 inhibitor is
ganetespib. In a preferred embodiment, the JAK-2 inhibitor is
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-2,4-dihydr-
o-3H-1,2,4-triazol-3-one. In a preferred embodiment, the JAK-2
inhibitor is a compound of Formula (XXXVII):
##STR00094## [1137] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. Nos. 7,825,148 and 8,628,752,
U.S. Patent Application Publication Nos. 2006/0167070 A1;
2014/0024030 A1; 2014/0051665 A1; 2014/0045908 A1; 2012/0128665 A1;
2013/0109045 A1, and 2014/0079636 A1, and, International Patent
Application Publication No. WO 2013/170182; WO 2013/028505; WO
2013/067162; WO 2013/173436; WO 2013/006864; WO 2012/162584; WO
2013/170159; WO 2013/067165; WO 2013/074594; WO 2012/162372; WO
2012/162293; and WO 2012/155063, the disclosures of which are
incorporated by reference herein. In an embodiment, the JAK-2
inhibitor is a compound described in U.S. Pat. Nos. 7,825,148 and
8,628,752, U.S. Patent Application Publication Nos. 2006/0167070
A1; 2014/0024030 A1; 2014/0051665 A1; 2014/0045908 A1; 2012/0128665
A1; 2013/0109045 A1, and 2014/0079636 A1, and, International Patent
Application Publication No. WO 2013/170182; WO 2013/028505; WO
2013/067162; WO 2013/173436; WO 2013/006864; WO 2012/162584; WO
2013/170159; WO 2013/067165; WO 2013/074594; WO 2012/162372; WO
2012/162293; and WO 2012/155063, the disclosures of which are
incorporated by reference herein.
[1138] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XXXVIII):
##STR00095## [1139] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein the compound is
defined by the following (I) or (II). [1140] (I): X represents CH
or N; R.sub.1 represents a halogen; [1141] R.sub.2 represents: (1)
H, (2) a halogen, (3) cyano, (4) a group represented by the
following general formula [2]:
[1141] ##STR00096## [1142] (wherein * indicates the binding
position; and R.sup.c, R.sup.D and R.sup.E are the same or
different and each represents (a) H, or (b) alkyl optionally
substituted by hydroxy or alkoxy, or alternatively two of R.sup.c,
R.sup.D and R.sup.E are taken together with the adjacent C to
represent a N-containing saturated heterocyclic group and the other
one is H, the saturated heterocyclic group optionally substituted
by alkylsulfonyl), [1143] (5) a group represented by the following
general formula [3]:
[1143] ##STR00097## [1144] (wherein * has the same meaning as
described above; and R.sup.F and R.sup.G are the same or different
and each represents (a) H, (b) alkyl optionally substituted by one
or two groups selected from the group consisting of hydroxy, amino,
dialkylamino, a saturated cyclic amino group, alkylcarbonylamino,
alkylsulfonylamino, aryl, heteroaryl optionally substituted by
alkyl, tetrahydrofuranyl, and carbamoyl, (c) alkylcarbonyl, (d)
alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally
substituted by alkyl, or alternatively R.sup.F and R.sup.G are
taken together with the adjacent N to represent a saturated cyclic
amino group, which may optionally be substituted by one or two
groups selected from the group consisting of (a) halogen, (b)
cyano, (c) hydroxy, (d) alkyl optionally substituted by one or two
groups selected from the group consisting of hydroxy, alkoxy,
amino, alkoxycarbonylamino, alkylsulfonylamino, and
alkylcarbonylamino, (e) cycloalkyl, (f) haloalkyl, (g) alkoxy, (h)
oxo, (i) a group represented by the following general formula
[4]:
[1144] ##STR00098## [1145] (wherein * has the same meaning as
described above; and R.sup.H represents alkyl or aryl), (j) a group
represented by the following general formula [5]:
[1145] ##STR00099## [1146] (wherein * has the same meaning as
described above; and R.sup.I and R.sup.J are the same or different
and each represents H, alkyl, carbamoyl, alkylcarbonyl, or
alkylsulfonyl), (k) a group represented by the following general
formula [6]:
[1146] ##STR00100## [1147] (wherein * has the same meaning as
described above; and R.sup.K represents alkyl, hydroxy, amino,
alkylamino, dialkylamino, cycloalkylamino, (cycloalkyl)alkylamino,
(hydroxyalkyl)amino, (alkoxyalkyl)amino, alkoxy,
alkylsulfonylamino, or a saturated cyclic amino group), and (1) a
saturated cyclic amino group optionally substituted by hydroxy; and
the saturated cyclic amino group, which is formed by combining
R.sup.F, R.sup.G and the adjacent N, may form a spiro-linkage with
a group represented by the following general formula [7A] or
[7B]:
[1147] ##STR00101## [1148] (wherein has the same meaning as
described above)), [1149] (6) a group represented by the following
general formula [8]:
[1149] ##STR00102## [1150] (wherein * has the same meaning as
described above; and R.sup.L represents (a) alkyl, (b) hydroxy, (c)
alkoxy, (d) saturated cyclic amino group optionally substituted by
alkyl or alkylsulfonyl, or (e) an amino optionally substituted by
one or two groups selected from the group consisting of alkyl,
cycloalkyl, (cycloalkyl)alkyl, aralkyl; haloalkyl,
dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl), [1151] (7) a
group represented by the following general formula [9]:
[1151] ##STR00103## [1152] (wherein * has the same meaning as
described above; and R.sup.M, R.sup.N and R.sup.O are the same or
different and each represents H, halogen, cyano, alkoxy, carbamoyl,
sulfamoyl, monoalkylaminosulfonyl, or alkylsulfonyl, or
alternatively two of R.sup.M, R.sup.N and R.sup.O are taken
together to represent methylenedioxy), [1153] (8) --OR.sup.P
(R.sup.P represents an alkyl optionally substituted by a group
selected from the group consisting of hydroxy, dialkylamino,
alkoxy, tetrahydrofuranyl, and cycloalkyl, or an optionally
O-containing saturated cyclic group optionally substituted by
hydroxy), or [1154] (9) a heteroaryl optionally substituted by one
or two groups selected from the group consisting of cyano, halogen,
hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl,
(cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl; [1155]
R.sub.3 represents H or hydroxy; [1156] R.sub.2 represents H or
alkyl; and [1157] R.sub.5 represents H or alkyl; [1158] (II): X
represents --CR.sup.A; [1159] R.sup.A represents a group
represented by the following general formula [10]:
[1159] ##STR00104## [1160] (wherein * has the same meaning as
described above; and R.sup.B represents (a) amino optionally
substituted by one or two groups selected from the group consisting
of alkyl, cycloalkyl, (cycloalkyl)alkyl, and alkoxyalkyl, (b)
alkoxy, (c) hydroxy, or (d) a saturated cyclic amino group); [1161]
R.sub.1 represents a halogen; [1162] R.sub.2 represents H; [1163]
R.sub.3 represents E or hydroxy; [1164] R.sub.4 represents H or
alkyl; and [1165] R.sub.5 represents H or alkyl.
[1166] In a preferred embodiment, the JAK-2 inhibitor is NS-018. In
an embodiment, the JAK-2 inhibitor is
(S)--N.sup.2-(1-(4-fluorophenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-N.sup-
.4-(pyrazin-2-yl)pyrimidine-2,4-diamine. NS-018 has been described
in Nakaya, et al., Blood Cancer J. 2014, 4, e174. In an embodiment,
the JAK-2 inhibitor has the chemical structure shown in Formula
(XXXIX):
##STR00105## [1167] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. Nos. 8,673,891 and 8,586,591,
U.S. Patent Application Publication Nos. 2011/0288065 A1 and
2013/0131082 A1, and International Patent Application Publication
No. WO 2012/020787 and WO 2012/020786, the disclosures of which are
incorporated by reference herein. In an embodiment, the JAK-2
inhibitor is a compound described in U.S. Pat. Nos. 8,673,891 and
8,586,591, U.S. Patent Application Publication Nos. 2011/0288065 A1
and 2013/0131082 A1, and International Patent Application
Publication No. WO 2012/020787 and WO 2012/020786, the disclosures
of which are incorporated by reference herein.
[1168] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XL):
##STR00106## [1169] or a stereoisomer, tautomer, or
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, wherein: [1170] Y is C.sub.1-4 alkyl; [1171] X is
C.sub.1-4 alkyl; [1172] R is
[1172] ##STR00107## [1173] any of which are optionally fused with a
5 or 6 membered carbocycle or heterocycle having one heteroatom
selected from NR.sup.3 or S, said fused carbocycle or heterocycle
being optionally substituted with 0-3 R.sup.1. [1174] R.sup.1 is H,
halo, CN, C.sub.1-6 alkyl substituted with 0-3 R.sup.c, CF.sub.3,
CONR.sup.aR.sup.a, NR.sup.aR.sup.a, COOR.sup.b,
SO.sub.2--(C.sub.1-4)alkyl, C(O)R.sup.d, cycloalkyl substituted
with 0-3 R.sup.e, furanyl, tetrahydropyranyl, or pyridinyl; [1175]
R.sup.2 is absent, H, C.sub.1-6 alkyl substituted with 0-3 R.sup.c,
C(O)O--(C.sub.1-4)alkyl, SO.sub.2--(C.sub.1-4)alkyl, cycloalkyl
substituted with 0-3 R.sup.e, or tetrahydropyranyl; [1176] R.sup.3
is absent, H, or C(O)O--(C.sub.1-4)alkyl; [1177] R.sup.a is H,
C.sub.1-6 alkyl substituted with 0-3 R.sup.e, C.sub.3-6 cycloalkyl
substituted with 0-3 R.sup.e, tetrahydropyranyl, or
dioxotetrahydrothiophenyl; [1178] R.sup.b is H or C.sub.1-6 alkyl;
[1179] R.sup.e is H, halo, CN, OH, O--(C.sub.1-4)alkyl,
O--(C.sub.1-4)alkyl-O--(C.sub.1-4)alkyl, NH.sub.2, N(C.sub.1-4
alkyl).sub.2, C(O)N(C.sub.1-4 alkyl).sub.2,
SO.sub.2--(C.sub.1-4)alkyl, or morpholinyl or piperazinyl, either
of which are optionally substituted with 0-1 C.sub.1-4 alkyl;
[1180] R.sup.d is C.sub.1-6 alkyl, or azeridinyl, azetidinyl,
pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,
dioxidothiomorpholinyl or tetrahydropyranyl, any of which are
substituted with 0-2 R.sup.e; and [1181] R.sup.e is H, halo, CN,
C.sub.1-4 alkyl, OH, O--(C.sub.1-4)alkyl,
SO.sub.2--(C.sub.1-4)alkyl, NHC(O)--(C.sub.1-4)alkyl, morpholinyl,
OC(O)--(C.sub.1-4)alkyl, C(O)N(C.sub.1-4 alkyl).sub.2, or
O--(C.sub.1-4)alkyl-O--(C.sub.1-4)alkyl.
[1182] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XL), wherein: [1183] R is:
[1183] ##STR00108## ##STR00109## [1184] any of which are optionally
substituted with 0-3 R.sup.1.
[1185] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XL), wherein Y is methyl and X is ethyl.
[1186] In another embodiment, the JAK-2 inhibitor is a compound of
Formula (XL), wherein: [1187] R is:
##STR00110##
[1188] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XL), wherein: [1189] R is:
[1189] ##STR00111## [1190] any of which are optionally substituted
with 0-2 R.sup.1.
[1191] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XL), wherein [1192] R is:
[1192] ##STR00112## [1193] R.sup.1 is H, halo, CN, C.sub.1-6 alkyl
substituted with 0-3 R.sup.c, CF.sub.3, CONR.sup.aR.sup.a,
COOR.sup.b, SO.sub.2--(C.sub.1-4)alkyl, C(O)R.sup.d, cycloalkyl
substituted with 0-3 R.sup.e, or pyridinyl; [1194] R.sup.a is H,
C.sub.1-6 alkyl substituted with 0-3 R.sup.e, C.sub.3-6 cycloalkyl
substituted with 0-3 R.sup.e, tetrahydropyranyl or
dioxotetrahydrothiophenyl; [1195] R.sup.b is H or C.sub.1-6 alkyl;
[1196] R.sup.c is H, halo, OH, O--(C.sub.1-4)alkyl,
SO.sub.2--(C.sub.1-4)alkyl or morpholinyl; [1197] R.sup.d is
C.sub.1-6 alkyl, or azetidinyl, pyrrolidinyl, morpholinyl,
piperazinyl or dioxidothiomorpholinyl, any of which are substituted
with 0-2 R.sup.e; [1198] R.sup.e is H, halo, CN, OH,
O--(C.sub.1-4)alkyl, SO.sub.2--(C.sub.1-4)alkyl,
NHC(O)--(C.sub.1-4)alkyl or morpholinyl.
[1199] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XL), wherein: [1200] R is:
[1200] ##STR00113## [1201] R.sup.1 is H, halo, C.sub.1-6 alkyl
substituted with 0-3 R.sup.c, CF.sub.3, CONR.sup.aR.sup.a,
COOR.sup.b, C(O)R.sup.d, cycloalkyl substituted with 0-3 R.sup.e or
furanyl; [1202] R.sup.2 is H, C.sub.1-6 alkyl substituted with 0-3
R.sup.e, SO.sub.2--(C.sub.1-4)alkyl, cycloalkyl substituted with
0-3 R.sup.e, or tetrahydropyranyl; [1203] R.sup.a is H, or
C.sub.1-6 alkyl substituted with 0-3 R.sup.e; [1204] R.sup.b is H
or C.sub.1-6 alkyl; [1205] R.sup.e is H, halo, CN, OH,
O--(C.sub.1-4)alkyl, O--(C.sub.1-4)alkyl-O--(C.sub.1-4)alkyl,
NH.sub.2, N(C.sub.1-4 alkyl).sub.2, C(O)N(C.sub.1-4 alkyl).sub.2,
SO.sub.2--(C.sub.1-4)alkyl, or morpholinyl or piperazinyl, either
of which are optionally substituted with 0-1 C.sub.1-4 alkyl;
[1206] R.sup.d is C.sub.1-6 alkyl, or morpholinyl, piperazinyl or
dioxidothiomorpholinyl, any of which are substituted with 0-2
R.sup.e; and [1207] R.sup.e is H, C.sub.1-4 alkyl, CN, OH,
NHC(O)--(C.sub.1-4)alkyl or morpholinyl.
[1208] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XL), wherein: [1209] R is:
[1209] ##STR00114## [1210] R.sup.1 is C.sub.1-6 alkyl substituted
with 0-3 R.sup.c; and [1211] R.sup.2 is C.sub.1-6 alkyl.
[1212] In a preferred embodiment, the JAK-2 inhibitor is
BMS-911543. In a preferred embodiment, the JAK-2 inhibitor is
N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methy-
l-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide. In
a preferred embodiment, the JAK-2 inhibitor is a compound of
Formula (XLI):
##STR00115## [1213] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. Nos. 8,673,933 and 8,202,881 and
U.S. Patent Application Publication Nos. 2013/0225551 A1 and
2011/0059943 A1, the disclosures of which are incorporated by
reference herein. In an embodiment, the JAK-2 inhibitor is a
compound described in U.S. Pat. Nos. 8,673,933 and 8,202,881 and
U.S. Patent Application Publication Nos. 2013/0225551 A1 and
2011/0059943 A1, the disclosures of which are incorporated by
reference herein.
[1214] In a preferred embodiment, the JAK-2 inhibitor is
gandotinib. In a preferred embodiment, the JAK-2 inhibitor is
3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(morp-
holinomethyl)imidazo[1,2-b]pyridazin-6-amine. In a preferred
embodiment, the JAK-2 inhibitor is a compound of Formula
(XLII):
##STR00116## [1215] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. No. 7,897,600 and U.S. Patent
Application Publication Nos. 2010/0152181 A1 and 2010/0286139 A1,
the disclosures of which are incorporated by reference herein. In
an embodiment, the JAK-2 inhibitor is a compound described in U.S.
Pat. No. 7,897,600 and U.S. Patent Application Publication Nos.
2010/0152181 A1 and 2010/0286139 A1, the disclosures of which are
incorporated by reference herein.
[1216] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XLIII):
##STR00117## [1217] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [1218] R.sup.x and
R.sup.y are independently selected from the group consisting of
-T-R.sup.3 and -L-Z--R.sup.3; [1219] Q' is selected from the group
consisting of --CR.sup.6''.dbd.CR.sup.6''-- and wherein said
--CR.sup.6''.dbd.CR.sup.6'' may be a cis or trans double bond or a
mixture thereof, [1220] R.sup.1 is -T-(Ring D); [1221] Ring D is a
5-7 membered monocyclic ring or 8-10 membered bicyclic ring
selected from the group consisting of aryl, heteroaryl,
heterocyclyl, and carbocyclyl, said heteroaryl or heterocyclyl ring
having 1-4 ring heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, wherein each substitutable ring
carbon of Ring D is independently substituted by oxo, -T-R.sup.5 or
--V--Z--R.sup.5, and each substitutable ring nitrogen of Ring D is
independently substituted by --R.sup.4; [1222] T is a valence bond
or --(C(R.sup.6').sub.2)-A-; [1223] A is a valence bond or a
C.sub.1-C.sub.3 alkylidene chain wherein a methylene unit of said
C.sub.1-3 alkylidene chain is optionally replaced by --O--, --S--,
--N(R.sup.4)--, --CO--, --CONH--, --NHCO--, --SO.sub.2--,
--SO.sub.2NH--, --NHSO.sub.2--, --CO.sub.2--, --OC(O)--,
--OC(O)NH--, or --NHCO.sub.2--; [1224] Z is a C.sub.1-4 alkylidene
chain; [1225] L is selected from the group consisting of --O--,
--S--, --SO--, --SO.sub.2--,
--N(R.sup.6)SO.sub.2---SO.sub.2N(R.sup.6)--, --N(R.sup.6)--,
--CO--, --CO.sub.2--, --N(R.sup.6)CO--, --N(R.sup.6)C(O)O--,
--N(R.sup.6)CON(R.sup.6)--, --N(R.sup.6)SO.sub.2N(R.sup.6)--,
--N(R.sup.6)N(R.sup.6)--, --C(O)N(R.sup.6)--, --OC(O)N(R.sup.6)--,
--C(R.sup.6).sub.2--O--, --C(R.sup.6).sub.2--,
--C(R.sup.6).sub.2SO--, --C(R.sup.6).sub.2SO.sub.2--,
--C(R.sup.6).sub.2SO.sub.2N(R.sup.6)--,
--C(R.sup.6).sub.2N(R.sup.6)--, --C(R.sup.6).sub.2N(R.sup.6)C(O)--,
--C(R.sup.6).sub.2N(R.sup.6)C(O)O--,
--C(R.sup.6).dbd.NN(R.sup.6)--, --C(R.sup.6).dbd.N--O--,
--C(R.sup.6).sub.2N(R.sup.6)N(R.sup.6)--,
--C(R.sup.6).sub.2N(R.sup.6)SO.sub.2N(R.sup.6)--, and
--C(R.sup.6).sub.2N(R.sup.6)CON(R.sup.6)--; [1226] R.sup.2 and
R.sup.2' are independently selected from the group consisting of
--R and -T-W--R.sup.6, or R.sup.2 and R.sup.2' taken together with
their intervening atoms form a fused, 5-8 membered, unsaturated or
partially unsaturated ring having 0-3 ring heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, wherein
each substitutable ring carbon of said fused ring formed by R.sup.2
and R.sup.2' is independently substituted by halo, oxo, --CN,
--NO.sub.2, R.sup.7, or --V--R.sup.6, and each substitutable ring
nitrogen of said ring formed by R.sup.2 and R.sup.2' is
independently substituted by --R.sup.4; [1227] R.sup.3 is selected
from the group consisting of --R, -halo, --OR, --C(.dbd.O)R,
--CO.sub.2R, --COCOR, --COCH.sub.2COR, --NO.sub.2, --CN, --S(O)R,
--S(O).sub.2R, --SR, --N(R.sup.4).sub.2, --CON(R.sup.7).sub.2,
--SO.sub.2N(R.sup.7).sub.2, --OC(.dbd.O)R, --N(R.sup.7)COR,
--N(R.sup.7)CO.sub.2(C.sub.1-6 aliphatic),
--N(R.sup.4)N(R.sup.4).sub.2, --C.dbd.NN(R.sup.4).sub.2,
--C.dbd.N--OR, --N(R.sup.7)CON(R.sup.7).sub.2,
--N(R.sup.7)SO.sub.2N(R.sup.7).sub.2, --N(R.sup.4)SO.sub.2R, and
--OC(.dbd.O)N(R).sub.2; [1228] each R is independently hydrogen or
an optionally substituted group selected from the group consisting
of C.sub.1-6 aliphatic, C.sub.6-10 aryl, a heteroaryl ring having
5-10 ring atoms, and a heterocyclyl ring having 5-10 ring atoms;
[1229] each R.sup.4 is independently selected from the group
consisting of --R.sup.7, --COR.sup.7, --CO.sub.2 (optionally
substituted C.sub.1-6 aliphatic), --CON(R.sup.7).sub.2, and
--SO.sub.2R.sup.7; [1230] each R.sup.5 is independently selected
from the group consisting of --R, halo, --OR, --C(.dbd.O)R,
--CO.sub.2R, --COCOR, --NO.sub.2, --CN, --S(O)R, --SO.sub.2R, --SR,
--N(R.sup.4).sub.2, --CON(R.sup.4).sub.2,
--SO.sub.2N(R.sup.4).sub.2, --OC(.dbd.O)R, --N(R.sup.4)COR,
--N(R.sup.4)CO.sub.2 (optionally substituted C.sub.1-6 aliphatic),
--N(R.sup.4)N(R.sup.4).sub.2, --C.dbd.NN(R.sup.4).sub.2,
--C.dbd.N--OR, --N(R.sup.4)CON(R.sup.4).sub.2,
--N(R.sup.4)SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4)SO.sub.2R, and
--OC(.dbd.O)N(R.sup.4).sub.2; [1231] V is selected from the group
consisting of --O--, --S--, --SO--, --SO.sub.2--,
--N(R.sup.6)SO.sub.2--, SO.sub.2N(R.sup.6)--, --N(R.sup.6)--,
--CO--, --CO.sub.2--, --N(R.sup.6)CO--, --N(R.sup.6)C(O)O--,
--N(R.sup.6)CON(R.sup.6)--, --N(R.sup.6)SO.sub.2N(R.sup.6)--,
--N(R.sup.6)N(R.sup.6)--, --C(O)N(R.sup.6), --OC(O)N(R.sup.6)--,
--C(R.sup.6).sub.2O--, --C(R.sup.6).sub.2S--,
--C(R.sup.6).sub.2SO--, --C(R.sup.6).sub.2SO.sub.2--,
--C(R.sup.6).sub.2SO.sub.2N(R.sup.6)--,
--C(R.sup.6).sub.2N(R.sup.6)--, --C(R.sup.6).sub.2N(R.sup.6)C(O)--,
--C(R.sup.6).sub.2N(R.sup.6)C(O)O--,
--C(R.sup.6).dbd.NN(R.sup.6)--, --C(R.sup.6).dbd.N--O--,
--C(R.sup.6).sub.2N(R.sup.6)N(R.sup.6)--,
--C(R.sup.6).sub.2N(R.sup.6)SO.sub.2N(R.sup.6)--, and
--C(R.sup.6).sub.2N(R.sup.6)CON(R.sup.6)--; [1232] W is selected
from the group consisting of --C(R.sup.6).sub.2O--,
--C(R.sup.6).sub.2S--, --C(R.sup.6).sub.2SO--,
--C(R.sup.6).sub.2SO.sub.2--,
--C(R.sup.6).sub.2SO.sub.2N(R.sup.6)--,
--C(R.sup.6).sub.2N(R.sup.6)--, --CO--, --CO.sub.2--,
--C(R.sup.6)OC(O).sup.-, --C(R.sup.6)OC(O)N(R.sup.6)--,
--C(R.sup.6).sub.2N(R.sup.6)CO--,
--C(R.sup.6).sub.2N(R.sup.6)C(O)O--,
--C(R.sup.6).dbd.NN(R.sup.6)--, --C(R.sup.6).dbd.N--O--,
--C(R.sup.6).sub.2N(R.sup.6)N(R.sup.6)--,
--C(R.sup.6).sub.2N(R.sup.6)SO.sub.2N(R.sup.6)--,
--C(R.sup.6).sub.2N(R.sup.6)CON(R.sup.6)--, and --CON(R.sup.6)--;
[1233] each R.sup.6 is independently selected from the group
consisting of hydrogen and an optionally substituted C.sub.1-4
aliphatic group, or two R.sup.6 groups on the same nitrogen atom
may be taken together with the nitrogen atom to form a 3-6 membered
heterocyclyl or heteroaryl ring; [1234] each R.sup.6' is
independently selected from the group consisting of hydrogen and a
C.sub.1-4 aliphatic group, or two R.sup.6' on the same carbon atom
are taken together to form a 3-8 membered carbocyclic ring; [1235]
each R.sup.6''is independently selected from the group consisting
of hydrogen, a C.sub.1-4 aliphatic group, halogen, optionally
substituted aryl, and optionally substituted heteroaryl, or two
R.sup.6 on adjacent carbon atoms are taken together to form a 5-7
membered carbocyclic ring; and [1236] each R.sup.7 is independently
selected from the group consisting of hydrogen and an optionally
substituted C.sub.1-6 aliphatic group, or two R.sup.7 on the same
nitrogen are taken together with the nitrogen to form a 5-8
membered heterocyclyl or heteroaryl ring.
[1237] In a preferred embodiment, the JAK-2 inhibitor is ENMD-2076.
In a preferred embodiment, the JAK-2 inhibitor is
(E)-N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrim-
idine-4-amine. In a preferred embodiment, the JAK-2 inhibitor is a
compound of Formula (XLIV):
##STR00118## [1238] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. Nos. 8,153,630; 7,563,787; and,
8,114,870 and U.S. Patent Application Publication Nos. 2008/0200485
A1; 2007/0142368 A1; 2009/0264422 A1; 2011/0318393 A1; and,
2009/0029992 A1, the disclosures of which are incorporated by
reference herein. In an embodiment, the JAK-2 inhibitor is a
compound described in U.S. Pat. Nos. 8,153,630; 7,563,787; and,
8,114,870 and U.S. Patent Application Publication Nos. 2008/0200485
A1; 2007/0142368 A1; 2009/0264422 A1; 2011/0318393 A1; and,
2009/0029992 A1, the disclosures of which are incorporated by
reference herein.
[1239] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XLV):
##STR00119## [1240] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, prodrug, tautomer or N-oxide thereof, [1241]
wherein M is selected from a group D1 and a group D2:
[1241] ##STR00120## [1242] and wherein: [1243] (A) when M is a
group D1: [1244] X is selected from O, NH and NCH.sub.3; [1245] A
is selected from a bond and a group NR.sub.2 where R.sub.2 is
hydrogen or methyl; [1246] E is selected from a bond, CH.sub.2,
CH(CN) and C(CH.sub.3).sub.2; [1247] R.sub.1 is selected from:
[1248] (i) a cycloalkyl group of 3 to 5 ring members optionally
substituted by hydroxy, fluorine, amino, methylamino, methyl or
ethyl; [1249] (ii) a saturated heterocyclic group of 4 to 6 ring
members containing 1 or 2 heteroatom ring members selected from O,
N, S and SO.sub.2, the heterocyclic group being optionally
substituted by (C.sub.1-4)alkyl, amino or hydroxy; but excluding
unsubstituted 4-morpholinyl, unsubstituted tetrahydropyran-4-yl,
unsubstituted 2-pyrrolidinyl, and unsubstituted and 1-substituted
piperidine-4-yl; [1250] (iii) a 2,5-substituted phenyl group of the
formula:
[1250] ##STR00121## [1251] wherein (a) when X is NH or N--CH.sub.3,
R.sub.3 is selected from chlorine and cyano; [1252] and (b) when X
is O, R.sub.3 is CN; [1253] (iv) a group CR.sub.6R.sub.7R.sub.8
wherein R.sub.6 and R.sub.7 are each selected from hydrogen and
methyl, and R.sub.8 is selected from hydrogen, methyl,
(C.sub.1-4)alkylsulphonylmethyl, hydroxymethyl and cyano; [1254]
(v) a pyridazin-4-yl group optionally substituted by one or two
substituents selected from methyl, ethyl, methoxy and ethoxy;
[1255] (vi) a substituted imidazothiazole group wherein the
substituents are selected from methyl, ethyl, amino, fluorine,
chlorine, amino and methylamino; and [1256] (vii) an optionally
substituted 1,3-dihydro-isoindol-2-yl or optionally substituted
2,3-dihydro-indol-1-yl group wherein the optional substituents in
each case are selected from halogen, cyano, amino, C.sub.1-4 mono-
and dialkylamino, CONH.sub.2 or CONH--(C.sub.1-4)alkyl, C.sub.1-4
alkyl and C.sub.1-4 alkoxy wherein the C.sub.1-4 alkyl and
C.sub.1-4 alkoxy groups are optionally substituted by hydroxy,
methoxy, or amino; [1257] (viii) 3-pyridyl optionally substituted
by one or two substituents selected from hydroxy, halogen, cyano,
amino, C.sub.1-4 mono- and dialkylamino, CONH.sub.2 or
CONH--C.sub.1-4 alkyl, C.sub.1-4 alkyl and C.sub.1-4 alkoxy wherein
the C.sub.1-4 alkyl and C.sub.1-4 alkoxy groups are optionally
substituted by hydroxy, methoxy, or amino, but excluding the
compounds 2-oxo-1,2-dihydro-pyridine-3-carboxylic acid
[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide
and
2,6-dimethoxy-N-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H--
pyrazol-4-yl]-nicotinamide; [1258] (ix) thiomorpholine or an
S-oxide or S,S-dioxide thereof optionally substituted by one or two
substituents selected from halogen, cyano, amino, C.sub.1-4 mono-
and dialkylamino, CONH.sub.2 or CONH--C.sub.1-4 alkyl, C.sub.1-4
alkyl and C.sub.1-4 alkoxy wherein the C.sub.1-4 alkyl and
C.sub.1-4 alkoxy groups are optionally substituted by hydroxy,
methoxy, or amino; and when E-A is NR.sub.2, R.sub.1 is
additionally selected from: [1259] (x) 2-fluorophenyl,
3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,
3,4-difluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl,
2,4,6-trifluorophenyl, 2-methoxyphenyl, 5-chloro-2-methoxyphenyl,
cyclohexyl, unsubstituted 4-tetrahydropyranyl and tert-butyl;
[1260] (xi) a group NR.sub.10R.sub.11 where R.sub.10 and R.sub.11
are each C.sub.1-4 alkyl or R.sub.10 and R.sub.11 are linked so
that NR.sup.10R.sub.11 forms a saturated heterocyclic group of 4 to
6 ring members optionally containing a second heteroatom ring
member selected from O, N, S and SO.sub.2, the heterocyclic group
being optionally substituted by C1-4 alkyl, amino or hydroxy;
[1261] (xii) pyridone optionally substituted by one or two
substituents selected from hydroxy, halogen, cyano, amino,
C.sub.1-4 mono- and dialkylamino, CONH2, CONH--C.sub.1-4 alkyl,
C.sub.1-4 alkyl and C.sub.1-4 alkoxy wherein the C.sub.1-4 alkyl
and C.sub.1-4 alkoxy groups are optionally substituted by hydroxy,
methoxy, or amino; [1262] when E-A is C(CH.sub.3).sub.2NR.sub.2 or
CH.sub.2--NR.sub.2, R.sub.1 is additionally selected from: [1263]
(xiii) unsubstituted 2-furyl and 2,6-difluorophenyl; and [1264]
when E-A is C(CH3).sub.2NR.sub.2, R.sub.1 is additionally selected
from: [1265] (xiv) unsubstituted phenyl; and [1266] when E is
CH.sub.2, R.sub.1 is additionally selected from: [1267] (xv)
unsubstituted tetrahydropyran-4-yl; and [1268] (B) when M is a
group D2: [1269] A is selected from a bond and a group NR.sub.2
where R.sub.2 is hydrogen or methyl; [1270] E is selected from a
bond, CH.sub.2, CH(CN) and C(CH.sub.3).sub.2; [1271] R.sub.1 is
selected from: [1272] (xvi) a 2-substituted 3-furyl group of the
formula:
[1272] ##STR00122## [1273] wherein R.sub.4 and R.sub.5 are the same
or different and are selected from hydrogen and C.sub.1-4 alkyl, or
R.sub.4 and R.sub.5 are linked so that NR.sub.4R.sub.5 forms a 5-
or 6-membered saturated heterocyclic group optionally containing a
second heteroatom or group selected from O, NH, NMe, S or SO.sub.2,
the 5- or 6-membered saturated ring being optionally substituted by
hydroxy, fluorine, amino, methylamino, methyl or ethyl; (xvii) a
5-substituted 2-furyl group of the formula:
[1273] ##STR00123## [1274] wherein R.sub.4 and R.sub.5 are the same
or different and are selected from hydrogen and C.sub.1-4 alkyl, or
R.sub.4 and R.sub.5 are linked so that NR.sub.4R.sub.5 forms a 5-
or 6-membered saturated heterocyclic group optionally containing a
second heteroatom or group selected from O, NH, NMe, S or SO.sub.2,
the 5- or 6-membered saturated heterocyclic group being optionally
substituted by hydroxy, fluorine, amino, methylamino, methyl or
ethyl; [1275] with the proviso that the compound is not
5-piperidin-1-ylmethyl-furan-2-carboxylic acid
[3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;
[1276] (xviii) a group of the formula:
[1276] ##STR00124## [1277] wherein R.sub.9 is hydrogen, methyl,
ethyl or isopropyl; G is CH, O, S, SO, SO.sub.2 or NH and the group
is optionally substituted by one, two or three substituents
selected from C.sub.1-4 hydrocarbyl, hydroxy, C.sub.1-4
hydrocarbyloxy, fluorine, amino, mono- and di-C.sub.1-4 alkylamino
and wherein the C.sub.1-4 hydrocarbyl and C.sub.1-4 hydrocarbyloxy
groups are each optionally substituted by hydroxy, fluorine, amino,
mono- or di-C.sub.1-4 alkylamino; and [1278] (xix) a
3,5-disubstituted phenyl group of the formula:
[1278] ##STR00125## [1279] wherein X is selected from O, NH and
NCH.sub.3; and [1280] (C) when M is a group D1: [1281] and X is O;
A is a group NR.sub.2 where R.sub.2 is hydrogen; E is a bond; and
R.sub.1 is 2,6-difluorophenyl; then the compound of the Formula
(XLV) is an acid addition salt selected from salts formed with an
acid selected from the group consisting of acetic, adipic, alginic,
ascorbic (e.g. L-ascorbic), aspartic (e.g. L-aspartic),
benzenesulphonic, benzoic, camphoric (e.g. (+) camphoric), capric,
caprylic, carbonic, citric, cyclamic, dodecanoate,
dodecylsulphuric, ethane-1,2-disulphonic, ethanesulphonic, fumaric,
galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g.
D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic,
hippuric, hydrochloric, isethionic, isobutyric, lactic (e.g.
(+)-L-lactic and (+)-DL-lactic), lactobionic, laurylsulphonic,
maleic, malic, (-)-L-malic, malonic, methanesulphonic, mucic,
naphthalenesulphonic (e.g. naphthalene-2-sulphonic),
naphthalene-1,5-disulphonic, nicotinic, oleic, orotic, oxalic,
palmitic, pamoic, phosphoric, propionic, sebacic, stearic,
succinic, sulphuric, tartaric (e.g. (+)-L-tartaric), thiocyanic,
toluenesulphonic (e.g. p-toluenesulphonic), valeric and xinafoic
acids.
[1282] In a preferred embodiment, the JAK-2 inhibitor is AT-9283.
In a preferred embodiment, the JAK-2 inhibitor is
1-cyclopropyl-3-(3-(5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1H-pyr-
azol-4-yl)urea. In a preferred embodiment, the JAK-2 inhibitor is a
compound of Formula (XLVI):
##STR00126## [1283] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. Nos. 8,399,442 and 7,977,477 and
U.S. Patent Application Publication Nos. 2010/0004232 A1;
2014/0010892 A1; 2011/0224203 A1; and, 2007/0135477, the
disclosures of which are incorporated by reference herein. In an
embodiment, the JAK-2 inhibitor is a compound described in U.S.
Pat. Nos. 8,399,442 and 7,977,477 and U.S. Patent Application
Publication Nos. 2010/0004232 A1; 2014/0010892 A1; 2011/0224203 A1;
and, 2007/0135477, the disclosures of which are incorporated by
reference herein.
[1284] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XLVII):
##STR00127## [1285] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [1286] R.sup.1 and
R.sup.2 are each independently selected from the group consisting
of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,
cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,
alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,
cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,
phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,
acylamino, arylamino, sulfonylamino, sulfinylamino, --COOH,
--COR.sup.3, --COOR.sup.3, --CONHR.sup.3, --NHCOR.sup.3,
--NHCOOR.sup.3, --NHCONHR.sup.3, alkoxycarbonyl,
alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,
arylsulfonyl, arylsulfinyl, aminosulfonyl, --SR.sup.3,
R.sup.4S(O)R.sup.6--, R.sup.4S(O).sub.2R.sup.6--,
R.sup.4C(O)N(R.sup.5)R.sup.6--, R.sup.4SO.sub.2N(R.sup.5)R.sup.6--,
R.sup.4N(R.sup.5)C(O)R.sup.6--, R.sup.4N(R.sup.5)SO.sub.2R.sup.6--,
R.sup.4N(R)C(O)N(R)R.sup.6-- and acyl, each of which may be
optionally substituted; [1287] each R.sup.3, R.sup.4, and R.sup.5
is independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of
which may be optionally substituted; [1288] each R.sup.6 is
independently selected from the group consisting of a bond, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of
which may be optionally substituted; [1289] Z.sup.2 is
independently selected from the group consisting of a bond, O, S,
--N(R.sup.7)--, --N(R.sup.7)C.sub.1-2alkyl-, and
--C.sub.1-2alkylN(R.sup.7)--; [1290] each R.sup.7 is independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,
heteroarylalkyl and acyl, each of which may be optionally
substituted; [1291] Ar.sup.1 and Ar.sup.2 are each independently
selected from the group consisting of aryl and heteroaryl, each of
which may be optionally substituted; [1292] L is a group of
formula:
[1292] --X.sup.1--Y--X.sup.2-- [1293] wherein X.sup.1 is attached
to Ar.sup.1 and X.sup.2 is attached to Ar.sup.2, and wherein
X.sup.1, X.sup.2 and Y are selected such that the group L has
between 5 and 15 atoms in the normal chain, [1294] X.sup.1 and
X.sup.2 are each independently a heteroalkyl group containing at
least one oxygen atom in the normal chain, [1295] Y is a group of
formula --CR.sup.a.dbd.CR.sup.b-- or an optionally substituted
cycloalkyl group, wherein R.sup.a and R.sup.b are each
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of
which may be optionally substituted, or [1296] R.sup.a and R.sup.b
may be joined such that when taken together with the carbon atoms
to which they are attached they form a cycloalkenyl or
cycloheteroalkenyl group; [1297] or a pharmaceutically acceptable
salt, solvate, hydrate, cocrystal, or prodrug thereof, or an
N-oxide thereof.
[1298] In certain embodiments Z.sup.2 is selected from the group
consisting of a bond, --N(R.sup.7)--, and --S--. In one specific
embodiment Z.sup.2 is --N(R.sup.7)--. In an even more specific
embodiment Z.sup.2 is --N(H)--. [1299] Ar.sup.1 and Ar.sup.2 are
each independently selected from the group consisting of aryl and
heteroaryl and may be monocyclic, bicyclic or polycyclic moieties.
In certain embodiments each of Ar.sup.1 and Ar.sup.2 is a
monocyclic or bicyclic moiety. In certain embodiments each of
Ar.sup.1 and Ar.sup.2 are a monocyclic moiety.
[1300] In certain embodiments Ar.sup.1 is selected from the group
consisting of:
##STR00128## [1301] wherein V.sup.1, V.sup.2, V.sup.3 and V.sup.4
are each independently selected from the group consisting of N, and
C(R.sup.10); [1302] W is selected from the group consisting of O, S
and NR.sup.10; [1303] W.sup.1 and W.sup.2 are each independently
selected from the group consisting of N and CR.sup.10; [1304]
wherein each R.sup.10 is independently selected from the group
consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,
arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,
alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,
cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,
phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,
acylamino, arylamino, sulfonylamino, sulfinylamino, --COOH,
--COR.sup.3, --COOR.sup.3, --CONHR.sup.3, --NHCOR.sup.3,
--NHCOOR.sup.3, --NHCONHR.sup.3, alkoxycarbonyl,
alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,
arylsulfonyl, arylsulfinyl, aminosulfonyl, --SR.sup.3,
R.sup.4S(O)R.sup.6--, R.sup.4S(O).sub.2R.sup.6--,
R.sup.4C(O)N(R.sup.5)R.sup.6--, R.sup.4SO.sub.2N(R.sup.5)R.sup.6--,
R.sup.4N(R.sup.5)C(O)R.sup.6--, R.sup.4N(R.sup.5)SO.sub.2R.sup.6--,
R.sup.4N(R)C(O)N(R.sup.5)R.sup.6-- and acyl, each of which may be
optionally substituted, [1305] wherein R.sup.3, R.sup.4, R.sup.5
and R.sup.6 are as defined above.
[1306] In certain embodiments Ar.sup.1 is selected from the group
consisting of:
##STR00129## [1307] wherein V.sup.1, V.sup.2, V.sup.3, V.sup.4, W,
W.sup.1, W.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as
defined above.
[1308] In certain embodiments Ar.sup.1 is selected from the group
consisting of:
##STR00130## [1309] wherein each R.sup.10 is independently as
defined above, [1310] k is an integer selected from the group
consisting of 0, 1, 2, 3, and 4; and [1311] n is an integer
selected from the group consisting of 0, 1, and 2.
[1312] In yet an even further embodiment Ar.sup.1 is selected from
the group consisting of:
##STR00131## [1313] wherein R.sup.10 is as defined above.
[1314] In certain embodiments Ar.sup.1 is selected from the group
consisting of:
##STR00132## [1315] wherein each R.sup.10 is independently as
defined above, and [1316] q is an integer selected from the group
consisting of 0, 1 and 2.
[1317] In certain embodiments Ar.sup.1 is selected from the group
consisting of:
##STR00133##
[1318] In certain embodiments Ar.sup.1 is selected from the group
consisting of:
##STR00134##
[1319] In certain embodiments Ar.sup.2 is selected from the group
consisting of:
##STR00135## [1320] wherein V.sup.5, V.sup.6, V.sup.7 and V.sup.8
are independently selected from the group consisting of N, and
C(R.sup.11); [1321] wherein each R.sup.11 is independently selected
from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl,
haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,
arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,
alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,
cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,
phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,
acylamino, arylamino, sulfonylamino, sulfinylamino, --COOH,
--COR.sup.3, --COOR.sup.3, --CONHR.sup.3, --NHCOR.sup.3,
--NHCOOR.sup.3, --NHCONHR.sup.3, alkoxycarbonyl,
alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,
arylsulfonyl, arylsulfinyl, aminosulfonyl, --SR.sup.3,
R.sup.4S(O)R.sup.6--, R.sup.4S(O).sub.2R.sup.6--,
R.sup.4C(O)N(R.sup.5)R.sup.6--, R.sup.4SO.sub.2N(R)R.sup.6--,
R.sup.4N(R.sup.5)C(O)R.sup.6--, R.sup.4N(R.sup.5)SO.sub.2R.sup.6--,
R.sup.4N(R)C(O)N(R)R.sup.6-- and acyl, each of which may be
optionally substituted.
[1322] In certain embodiments Ar.sup.2 is selected from the group
consisting of:
##STR00136## [1323] wherein each R.sup.11 is independently as
defined above [1324] o is an integer selected from the group
consisting of 0, 1, 2, 3, and 4; and [1325] p is an integer
selected from the group consisting of 0, 1, 2, and 3.
[1326] In certain embodiments Ar.sup.2 is selected from the group
consisting of:
##STR00137## [1327] wherein each R.sup.11 is as defined above.
[1328] In a further embodiment Ar.sup.2 is selected from the group
consisting of:
##STR00138##
[1329] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XLVIII):
##STR00139## [1330] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof [1331] wherein R.sup.1,
R.sup.2, R.sup.10, R.sup.11, X.sup.1, X.sup.2, Y, k and o are as
defined above.
[1332] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (XLIX):
##STR00140## [1333] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof [1334] wherein R.sup.1,
R.sup.2, R.sup.10, R.sup.11, X.sup.1, X.sup.2, Y, q and o are as
defined above.
[1335] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (L):
##STR00141## [1336] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof [1337] wherein R.sup.1,
R.sup.2, R.sup.10, R.sup.11, X.sup.1, X.sup.2, Y, q and o are as
defined above.
[1338] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (L):
##STR00142## [1339] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof [1340] wherein R.sup.1,
R.sup.2, R.sup.10, R.sup.11, X.sup.1, X.sup.2, Y, q and o are as
defined above.
[1341] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (LII):
##STR00143## [1342] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof [1343] wherein R.sup.1,
R.sup.2, R.sup.10, R.sup.11, X.sup.1, X.sup.2, Y, q and o are as
defined above.
[1344] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (LIII):
##STR00144## [1345] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof [1346] wherein R.sup.1,
R.sup.2, R.sup.10, R.sup.11, X.sup.1, X.sup.2, Y, q and o are as
defined above.
[1347] In embodiments where the JAK-2 inhibitor is a compound of
Formulas (XLVII)-(LIII), X.sup.1, X.sup.2 and Y are chosen such
that there are between 5 and 15 atoms in the normal chain. In one
embodiment, X.sup.1, X.sup.2 and Y are chosen such that there are
between 6 and 15 atoms in the normal chain. In one specific
embodiment, X.sup.1, X.sup.2 and Y are chosen such that there are 7
atoms in the normal chain. In another specific embodiment, X.sup.1,
X.sup.2 and Y are chosen such that there are 8 atoms in the normal
chain.
[1348] In embodiments where the JAK-2 inhibitor is a compound of
Formulas (XLVII)-(LIII), X.sup.1 and X.sup.2 are each independently
a heteroalkyl group containing at least one oxygen atom in the
normal chain. In certain embodiments X.sup.1 is selected from the
group consisting of: (a) --O(C.sub.1-5)alkyl-, (b)
--(C.sub.1-5)alkylO-, and (c) --(C.sub.1-5)alkylO(C.sub.1-5)alkyl.
In certain embodiments X.sup.1 is selected from the group
consisting of: (a) --OCH.sub.2-- (b) --CH.sub.2O--, (c)
--OCH.sub.2C.sub.2--, (d) --CH.sub.2CH.sub.2--, (e)
--CH.sub.2OCH.sub.2--, and (f)
--CH.sub.2CH.sub.2CH.sub.2OCH.sub.2--. In one specific embodiment
X.sup.1 is --OCH.sub.2--. In another specific embodiment X.sup.1 is
--CH.sub.2O--. In another specific embodiment X.sup.1 is
--OCH.sub.2CH.sub.2--. In another specific embodiment X.sup.1 is
--CH.sub.2CH.sub.2O--. In another specific embodiment X.sup.1 is
--CH.sub.2OCH.sub.2--. In another specific embodiment X.sup.1 is
--CH.sub.2CH.sub.2OCH.sub.2--. In certain embodiments X.sup.1 is
selected from the group consisting of: (a) --O(C.sub.1-5)alkyl-,
(b) --(C.sub.1-5)alkylO-, and (c)
--(C.sub.1-5)alkylO(C.sub.1-5)alkyl. In certain embodiments X.sup.2
is selected from the group consisting of: (a) --OCH.sub.2-- (b)
--CH.sub.2O--, (c) --OCH.sub.2CH.sub.2--, (d)
--CH.sub.2CH.sub.2O--, (e) --CH.sub.2OCH.sub.2--, and (f)
--CH.sub.2CH.sub.2OCH.sub.2--. In one specific embodiment X is
--OCH.sub.2--. In another specific embodiment X.sup.1 is
--CH.sub.2O--. In another specific embodiment X.sup.2 is
--OCH.sub.2--C--. In another specific embodiment X.sup.2 is
--CH.sub.2CH.sub.2O--. In another specific embodiment X.sup.2 is
--CH.sub.2OCH.sub.2--. In another specific embodiment X is
--CH.sub.2C.sub.2OCH.sub.2--.
[1349] In a preferred embodiment, the JAK-2 inhibitor is
pacritinib. Pacritinib is also known as SB1518. In a preferred
embodiment, the JAK-2 inhibitor is
(E)-4.sup.4-(2-(pyrrolidin-1-yl)ethoxy)-6,11-dioxa-3-aza-2(4,2)-pyrimidin-
a-1,4(1,3)-dibenzenacyclododecaphan-8-ene. In a preferred
embodiment, the JAK-2 inhibitor is
14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-
-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene,
11-[2-(1-pyrrolidinyl)ethoxy]-, (16E)-. In a preferred embodiment,
the JAK-2 inhibitor is
(16E)-11-[2-(pyrrolidin-1-yl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[-
19.3.1.1.sup.2,6.1.sup.8,12]heptacosa-1(24),2,4,6,8,10,12(26),16,21(25),22-
-decaene. In an embodiment, the JAK-2 inhibitor is a compound of
Formula (LIV):
##STR00145## [1350] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. In an embodiment, the
structure of Formula (LIV) may be a tautomeric form. The
preparation of Formula (LIV) is described in U.S. Pat. Nos.
8,143,255; 8,153,632; and, 8,415,338 and U.S. Patent Application
Publication Nos. 2009/0258886 A1; 2012/0142680 A1; 2012/0196855 A1;
and 2013/0172338 A1, the disclosures of which are incorporated by
reference herein. The preparation and properties of this JAK-2
inhibitor are known to those of ordinary skill in the art, and for
example are described in: Hart, et al., SB1518, a novel macrocyclic
pyrimidine-based JAK2 inhibitor for the treatment of myeloid and
lymphoid malignancies, Leukemia 2011, 25, 1751-1759; Hart, et al.,
Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of
acute myeloid leukemia, Blood Cancer J., 2011, 1(11), e44; William,
et al., Discovery of the macrocycle
11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1-
.1(2,6). 1(8,12)]heptacosa-1 (25),2(26),3,5,8,10,12(27),
16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like
tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of
myelofibrosis and lymphoma. J. Med. Chem. 2011, 54, 4638-4658;
Poulsen, et al. Structure-based design of oxygen-linked macrocyclic
kinase inhibitors: discovery of SB1518 and SB1578, potent
inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3
(FLT3). J. Comput. Aided Mol. Des. 2012, 26, 437-450.
[1351] In an embodiment, the JAK-2 inhibitor is selected from the
structures disclosed in U.S. Pat. Nos. 8,143,255; 8,153,632; and
8,415,338 and U.S. Patent Application Publication Nos. 2009/0258886
A1; 2012/0142680 A1; 2012/0196855 A1; and 2013/0172338 A1, the
disclosures of which are incorporated by reference herein.
[1352] In a preferred embodiment, the JAK-2 inhibitor is
(E)-4.sup.4-(2-(pyrrolidin-1-yl)ethoxy)-6,11-dioxa-3-aza-2(4,2)-pyrimidin-
a-1(2,5)-furana-4(1,3)-benzenacyclododecaphan-8-ene. In a preferred
embodiment, the JAK-2 inhibitor is
(9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetrac-
yclo[18.3.1.1(2,5).
1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene. In a
preferred embodiment, the JAK-2 inhibitor is a compound of Formula
(LIV-A):
##STR00146## [1353] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation and
properties of this JAK-2 inhibitor are known to those of ordinary
skill in the art, and for example are described in: Madan et al.,
SB1578, a novel inhibitor of JAK2, FLT3, and c-Fms for the
treatment of rheumatoid arthritis, J. Immunol. 2012, 189, 4123-4134
and William et al., Discovery of the macrocycle
(9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetrac-
yclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),
15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase
2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of
rheumatoid arthritis. J. Med. Chem. 2012, 55, 2623-2640.
[1354] In an embodiment, the JAK-2 inhibitor is a compound selected
from the structures disclosed in U.S. Pat. No. 8,349,851 and U.S.
Patent Application Publication Nos. 2010/0317659 A1, 2013/0245014,
2013/0296363 A1, the disclosures of which are incorporated by
reference herein. In an embodiment, the JAK-2 inhibitor is a
compound of Formula (LV):
##STR00147## [1355] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein [1356] R.sup.1 and
R.sup.2 are selected from (i), (ii), (iii), (iv), and (v) as
follows: [1357] (i) R.sup.1 and R.sup.2 together form .dbd.O,
.dbd.S, .dbd.NR.sup.9 or .dbd.CR.sup.10R.sup.11; [1358] (ii)
R.sup.1 and R.sup.2 are both --OR.sup.8, or R.sup.1 and R.sup.2,
together with the carbon atom to which they are attached, form
dioxacycloalkyl; [1359] (iii) R.sup.1 is hydrogen or halo; and
R.sup.2 is halo; and [1360] (iv) R.sup.1 is alkyl, alkenyl,
alkynyl, cycloalkyl or aryl, wherein the alkyl, alkenyl, alkynyl,
cycloalkyl and aryl is optionally substituted with one or more
substitutents selected from halo, cyano, alkyl, --R.sup.xOR.sup.w,
--R.sup.xS(O).sub.qR.sup.v, --R.sup.xNR.sup.yR.sup.z and
--C(O)OR.sup.w; and R.sup.2 is halo or --OR.sup.8; and [1361] (v)
R.sup.1 is halo, deutero, --OR.sup.12, --NR.sup.13R.sup.14, or
S(O).sub.qR.sup.15; and R.sup.2 is hydrogen, deutero, alkyl,
alkenyl, alkynyl, cycloalkyl or aryl, wherein the alkyl, alkenyl,
alkynyl, cycloalkyl and aryl, is optionally substituted with one or
more substitutents selected from halo, cyano, alkyl,
--R.sup.xOR.sup.w, --R.sup.xS(O).sub.qR.sup.v and
--R.sup.xNR.sup.yR.sup.z; [1362] R.sup.3 is hydrogen, halo, alkyl,
cyano, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxy or alkoxy;
[1363] R.sup.4 and R.sup.5 are each independently hydrogen or
alkyl; [1364] each R.sup.6 is independently selected from halo,
alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, --R.sup.xOR.sup.18,
--R.sup.xNR.sup.19R.sup.20, and --R.sup.xS(O).sub.qR.sup.v; [1365]
each R.sup.7 is independently halo, alkyl, haloalkyl or
--R.sup.xOR.sup.W; [1366] R.sup.8 is alkyl, alkenyl or alkynyl;
[1367] R.sup.9 is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy or
amino; [1368] R.sup.10 is hydrogen or alkyl; [1369] R.sup.11 is
hydrogen, alkyl, haloalkyl or --C(O)OR.sup.8; [1370] R.sup.12 is
selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, --C(O)R.sup.v, --C(O)OR.sup.w and
--C(O)NR.sup.yR.sup.z, wherein the alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
aralkyl, heteroaryl and heteroaralkyl are each optionally
substituted with one or more substituents independently selected
from halo, oxo, alkyl, hydroxy, alkoxy, amino and alkylthio; [1371]
R.sup.13 and R.sup.14 are selected as follows: [1372] (i) R.sup.13
is hydrogen or alkyl; and R.sup.14 is selected from hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,
alkoxy, --C(O)R.sup.v, --C(O)OR.sup.w, --C(O)NR.sup.yR.sup.z and
--S(O).sub.qR.sup.v, wherein the alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
aralkyl, heteroaryl and heteroaralkyl are each optionally
substituted with one or more substituents independently selected
from halo, oxo, alkyl, hydroxy, alkoxy, amino and alkylthio; or
[1373] (ii) R.sup.13 and R.sup.14, together with the nitrogen atom
to which they are attached, form heterocyclyl or heteroaryl wherein
the heterocyclyl or heteroaryl is optionally substituted with one
or more substituents independently selected from halo, alkyl,
hydroxy, alkoxy, amino and alkylthio and wherein the heterocyclyl
is also optionally substituted with oxo; [1374] R.sup.15 is alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,
--C(O)NR.sup.yR.sup.z or --NR.sup.yR.sup.z, wherein the alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl are
each optionally substituted with one or more substituents
independently selected from halo, oxo, alkyl, hydroxy, alkoxy,
amino and alkylthio; [1375] R.sup.18 is hydrogen, alkyl, haloalkyl,
hydroxy(C.sub.2-6)alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,
heteroaryl or heteroarylalkyl; wherein R.sup.18 is optionally
substituted with 1 to 3 groups Q.sup.1, each Q.sup.1 independently
selected from alkyl, hydroxyl, halo, haloalkyl, alkoxy, aryloxy,
alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, hydroxycarbonyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, haloaryl and amino;
[1376] R.sup.19 and R.sup.20 are selected as follows: [1377] (i)
R.sup.19 and R.sup.20 are each independently hydrogen or alkyl; or
[1378] (ii) R.sup.19 and R.sup.20, together with the nitrogen atom
to which they are attached, form a heterocyclyl or heteroaryl which
is optionally substituted with 1 to 2 groups each independently
selected from halo, alkyl, haloalkyl, hydroxyl and alkoxy; [1379]
each R.sup.x is independently alkylene or a direct bond; [1380]
R.sup.v is hydrogen, alkyl, alkenyl or alkynyl; [1381] R.sup.w is
independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl;
[1382] R.sup.y and R.sup.z are selected as follows: [1383] (i)
R.sup.y and R.sup.z are each independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl or haloalkyl; [1384] (ii) R.sup.y and
R.sup.z, together with the nitrogen atom to which they are
attached, form a heterocyclyl or heteroaryl which is optionally
substituted with 1 to 2 groups each independently selected from
halo, alkyl, haloalkyl, hydroxyl and alkoxy; [1385] n is 0-4;
[1386] p is 0-5; and [1387] each q is independently 0, 1 or 2.
[1388] In a preferred embodiment, the JAK-2 inhibitor is AC-410
(available from Ambit Biosciences). In a preferred embodiment, the
JAK-2 inhibitor is
(S)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-y-
l)methanol. In a preferred embodiment, the JAK-2 inhibitor is a
compound of Formula (LVI):
##STR00148## [1389] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of racemic
(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)metha-
nol hydrochloride is described in Examples 3 and 12 of U.S. Pat.
No. 8,349,851, the disclosure of which is incorporated by reference
herein. Other preparation methods known to one of skill in the art
also may be used. The preparation of the compound of Formula (LVI)
is also described in the following paragraphs.
[1390] The preparation of
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne is accomplished by the following two steps (A and B). Step A: To
a solution of ethyl 4-chloroquinazoline-2-carboxylate (0.6 g, 2.53
mmol) in THF (6 mL) at -40.degree. C., was added dropwise a 1 M
solution of 4-fluorophenylmagnesium bromide in THF (3 mL, 3.0 mmol,
1.2 eq). The mixture was stirred at -40.degree. C. for 4 h. The
reaction was quenched by adding 0.5 N HCl solution (5 mL) and the
mixture was extracted with EtOAc (2.times.10 mL). The combined
organic layers were washed with brine and dried over MgSO.sub.4.
The crude product was purified on a silica gel column using a
mixture of EtOAc-hexanes as eluent.
(4-chloroquinazoline-2-yl)(4-fluorophenyl)methanone was obtained as
a light yellow solid (440 mg, 60%). .sup.1H NMR (300 MHz, DMSO-d6)
.delta. 7.45-740 (m, 2H), 8.07-8.03 (m, 1H), 8.17-8.13 (m, 2H),
8.23 (m, 2H), 8.42 (d, 1H); LC-MS (ESI) m/z 287 (M+H).sup.+. Step
B: To a solution of
(4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone (84 mg, 0.30
mmol) in DMF (3 mL) were added DIEA (0.103 mL, 0.6 mmol) and
5-methyl-1H-pyrazol-3-amine (88 mg, 0.9 mmol at rt. The reaction
mixture was heated at 40.degree. C. overnight. The reaction was
quenched by adding water and the yellow precipitate was collected
by filtration and washed with water. The crude product was purified
by silica gel chromatography eluting with DCM/MeOH to give
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne (30 mg, 29%). .sup.1H NMR (300 MHz, DMSO-d6) .delta. 2.19 (s,
3H), 6.54 (s, 1H), 7.40 (m, 2H), 7.68 (t, 1H), 7.9-7.7 (m, 2H),
8.08 (m, 2H), 8.74 (d, 1H), 10.66 (s, 1H), 12.20 (s, 1H); LC-MS
(ESI) m/z 348 (M+H).sup.+.
[1391] To a solution of
4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanon-
e (60 mg, 0.172 mmol) in 1:1 MeOH/THF (10 mL) at 0.degree. C., was
added NaBH.sub.4 (64 mg, 1.69 mmol). The reaction mixture was
stirred at 0.degree. C. for 1.5 h. The reaction mixture was
quenched by adding a few drops of acetone and concentrated to
dryness. The crude solid was purified on HPLC to afford
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
l (18 mg, 30%); .sup.1H NMR (300 MHz, DMSO-d6) .delta. 2.25 (s,
3H), 5.67 (s, 1H), 5.83 (bs, 1H), 6.40 (bs, 1H), 7.13 (m, 2H),
7.55-7.53 (m, 3H), 7.79 (s, 2H), 8.57 (bs, 1H), 10.43 (s, 1H),
12.12 (bs, 1H); LC-MS (ESI) m/z 350 (M+H).
[1392] To a suspension of
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne (2.3 g) in 30% MeOH/DCM (60 mL) at 0.degree. C. was added
dropwise 4M HCl/1,4-dioxane (10 mL). After all solid material had
dissolved, the mixture was concentrated under reduced pressure, and
to the residue was added 30% CH.sub.3CN/H.sub.2O (80 mL) and the
mixture was sonicated until all solid material had dissolved. The
mixture was frozen and lyophilized overnight to afford
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
l hydrochloride (100%). .sup.1H NMR (300 MHz, DMSO-d6) .delta. 2.25
(s, 3H), 6.02 (s, 1H), 6.20 (s, 1H), 7.27 (t, 2H), 7.60 (qt, 2H),
7.80 (t, 1H), 8.08 (t, 1H), 8.23 (d, 1H), 8.83 (d, 1H), 12.16 (s,
1H), 14.51 (b, 1H); LC-MS (ESI) m/z 350 (M+H).sup.+. The compound
of Formula (LVI),
(S)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)m-
ethanol, may be obtained from this preparation by chiral liquid
chromatographic separation of the enantiomers, or by other well
known techniques for resolution of enantiomers, such as those
described in: Eliel et al., Stereochemistry of Organic Compounds,
Wiley-Interscience, New York, 1994.
[1393] In a preferred embodiment, the JAK-2 inhibitor is
(R)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)m-
ethanol, which is also known in the art to be active as a JAK-2
inhibitor. In a preferred embodiment, the JAK-2 inhibitor is
racemic
(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)metha-
nol, which is also known in the art to be active as a JAK-2
inhibitor.
[1394] In some preferred embodiments, JAK-2 inhibitors having
Formula (LV) or Formula (LVI) can be prepared, isolated, or
obtained by any method known to one of skill in the art, including,
but not limited to, synthesis from a suitable optically pure
precursor, asymmetric synthesis from an achiral starting material,
or resolution of a racemic or enantiomeric mixture, for example,
chiral chromatography, recrystallization, resolution,
diastereomeric salt formation, or derivatization into
diastereomeric adducts followed by separation.
[1395] A method for preparation of the compound of Formula
(LVI)comprises resolving racemic
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
l with chiral chromatography. In certain embodiments, the two
individual enantiomers are separated using a chiral column, wherein
the stationary phase is silica gel coated with a chiral selector
such as tris-(3,5-dimethylphenyl)carbamoyl cellulose.
[1396] A method for preparation of the compound of Formula (LVI)
comprises the step of reducing the achiral ketone
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne, prepared as described above or by other methods known to one of
skill in the art, with hydrogen in the present of a chiral
catalyst. The achiral ketone
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne may be reduced to predominantly a single enantiomeric product
with a chiral reducing system of "type A" or "type B," wherein type
A and type B differ from each other solely by having chiral
auxiliaries of opposite chiralities. In certain embodiments, the
chiral catalyst is [(S)--P-Phos RuCl.sub.2 (S)-DAIPEN].
[1397] The reduction of the achiral ketone
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne in presence of a chiral catalyst may be carried out in isopropyl
alcohol as a solvent. The reduction of achiral ketone
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne in the presence of a chiral catalyst is carried out in isopropyl
alcohol and water mixture as a solvent. Isopropyl alcohol and water
are used in a ratio of 1:1, 8:1 or 9:1. DMSO is used as a cosolvent
in the reaction. Alternatively, DMSO is used in amounts of 10, 20
or 30% based on the total amount of isopropyl alcohol and water
mixture. Alternatively, isopropyl alcohol, DMSO and water are used
in a ratio of 1:1:1, 4:4:0.5, 8:1:1, 47:47:6, 41:58:1, 44:50:6, or
18:79:3. Alternatively, isopropyl alcohol, DMSO and water are used
in a ratio of 41:58:1. Alternatively, isopropyl alcohol, and DMSO
are used in a ratio of 1:1. Alternatively, the reduction is carried
out in presence of a base, such as potassium hydroxide, potassium
tert butoxide and others. Alternatively, the base is used in 2-15
mol %, in one embodiment, 2 mol %, 5 mol %, 10 mol %, 12.5 mol % or
15 mol %. Alternatively, the reduction is carried out at a
temperature of 40-80.degree. C., in one embodiment, 40.degree. C.,
50.degree. C., 60.degree. C., 70.degree. C. or 80.degree. C.
Alternatively, the reduction is carried out at a temperature of
70.degree. C. Alternatively, the reduction is carried out at a
pressure of 4 bar to 30 bar, in one embodiment, 4, 5, 10, 15, 20,
25 or 30 bar. Alternatively, the reduction is carried out at a
pressure of 4 bar. Alternatively, the catalyst loading in the
reaction is 100/1, 250/1, 500/1, 1000/1, 2000/1, 3000/1, 4000/1,
5000/1, 7000/1, 10,0000/1 or 20,000/1. In certain embodiments, the
catalyst loading in the reaction is 2000/1 or 4000/1.
[1398] A method for preparation of the compound of Formula
(LVI)comprises the step of reducing the achiral ketone
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne with a ketoreductase (e.g., alcohol dehydrogenase). See Moore,
et al., Acc. Chem. Res. 2007, 40, 1412-1419; Daussmann, et al.,
Engineering in Life Sciences 2006, 6, 125-129; Schlummer, et al.,
Specialty Chemicals Magazine 2008, 28, 48-49; Osswald, et al.,
Chimica Oggi 2007, 25(Suppl.), 16-18; and Kambourakis, et al.,
PharmaChem 2006, 5(9), 2-5.
[1399] An alternative method for preparation of the compound of
Formula (LVI) comprises the step of reducing the achiral ketone
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne with a reducing reagent (e.g., borane or borohydride reagents)
in the presence of a chiral catalyst. In certain embodiments, the
reducing agent is borane or a borohydride reagent. In certain
embodiments, the chiral catalyst is a chiral oxazaborolidine. Cory,
et al., Tetrahedron Letters 1996, 37, 5675; Cho, Chem. Soc. Rev.
2009, 38, 443.
[1400] Another method for preparation of the compound of Formula
(LVI) comprises the step of reducing the achiral ketone
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne via asymmetric hydrosilylation, as described in U.S. Patent
Application Publication No. 2008/0269490, the disclosure of which
is specifically incorporated herein by reference.
[1401] Another method for preparation of the compound of Formula
(LVI) comprises the step of reducing the achiral ketone
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne via transfer hydrogenation catalyzed by an iridium complex, as
described in Malacea, et al., Coord. Chem. Rev. 2010, 254,
729-752.
[1402] The starting materials used in the synthesis of the compound
of Formula (LVI) provided herein are either commercially available
or can be prepared by a method known to one of skill in the art.
For example, the achiral ketone
(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methano-
ne can be prepared according to the methods described in U.S. Pat.
No. 8,349,851, issued Jan. 8, 2013, and U.S. Pat. No. 8,703,943,
issued Apr. 22, 2014, the disclosures of which are incorporated
herein by reference in their entireties.
[1403] In an embodiment, the JAK-2 inhibitor is a JAK-2 inhibitor
described in U.S. Patent Application Publication No. US
2013/0225614 A1, the disclosure of which are specifically
incorporated herein by reference. In an embodiment, the the JAK-2
inhibitor is a compound of Formula (LV-A):
##STR00149## [1404] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein [1405] A is azolyl
other than pyrazolyl; [1406] R.sup.1 and R.sup.2 are selected from
(i), (ii), (iii), (iv) and (v) as follows: [1407] (i) R.sup.1 and
R.sup.2 together form .dbd.O, .dbd.S, .dbd.NR.sup.9 or
.dbd.CR.sup.10R.sup.n; [1408] (ii) R.sup.1 and R.sup.2 are both
--OR.sup.8, or R.sup.1 and R.sup.2, together with the carbon atom
to which they are attached, form cycloalkyl or heterocyclyl wherein
the cycloalkyl is substituted with one to four substituents
selected from halo, deutero, alkyl, haloalkyl, --OR, --N(R).sub.2,
and --S(O).sub.qR and wherein the heterocyclyl contains one to two
heteroatoms wherein each heteroatom is independently selected from
O, NR.sup.24, S, S(O) and S(O).sub.2; [1409] (iii) R.sup.1 is
hydrogen or halo; and R.sup.2 is halo; [1410] (iv) R.sup.1 is
alkyl, alkenyl, alkynyl, cycloalkyl or aryl, wherein the alkyl,
alkenyl, alkynyl, cycloalkyl and aryl are each optionally
substituted with one to four substitutents selected from halo,
deutero, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyano,
=0, .dbd.N--OR.sup.21, --R.sup.xOR.sup.21,
--R.sup.XN(R.sup.22).sub.2, --R.sup.XS(O).sub.qR.sup.23,
--C(O)R.sup.21, --C(O)OR.sup.21 and --C(O)N(R.sup.22).sub.2; and
[1411] (v) R.sup.1 is halo, deutero, --OR.sup.12,
--NR.sup.13R.sup.14, or --S(O).sub.qR.sup.15; and R.sup.2 is
hydrogen, deutero, alkyl, alkenyl, alkynyl, cycloalkyl or aryl,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl are each
optionally substituted with one to four substitutents selected from
halo, cyano, alkyl, --R.sup.xOR.sup.w, --R.sup.xS(O).sub.qR.sup.v
and --R.sup.xNR.sup.yR.sup.z; [1412] R.sup.3 is hydrogen, deutero,
halo, alkyl, cyano, haloalkyl, deuteroalkyl, cycloalkyl,
cycloalkylalkyl, hydroxy or alkoxy; [1413] R.sup.5 is hydrogen or
alkyl; each R.sup.6 is independently selected from halo, alkyl,
alkenyl, alkynyl, haloalkyl, cycloalkyl, --R.sup.xOR.sup.18,
--R.sup.XNR.sup.19R.sup.20, and --R.sup.xS(O).sub.qR.sup.v; [1414]
each R.sup.7 is independently halo, alkyl, haloalkyl or
--R.sup.xOR.sup.w; [1415] R is alkyl, alkenyl or alkynyl; [1416]
R.sup.9 is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy or amino;
[1417] R.sup.10 is hydrogen or alkyl; [1418] R.sup.11 is hydrogen,
alkyl, haloalkyl or --C(O)OR.sup.8; [1419] R.sup.12 is selected
from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, --C(O)R.sup.v, --C(O)OR.sup.w and
--C(O)NR.sup.yR.sup.z, wherein the alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
aralkyl, heteroaryl and heteroaralkyl are each optionally
substituted with one or more, in one embodiment, one to four, in
one embodiment, one to three, in one embodiment, one, two or three,
substituents independently selected from halo, oxo, alkyl, hydroxy,
alkoxy, amino and alkylthio; [1420] R.sup.13 and R.sup.14 are
selected as follows: [1421] (i) R.sup.13 is hydrogen or alkyl; and
R.sup.14 is selected from hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
aralkyl, heteroaryl, heteroaralkyl, alkoxy, --C(O)R.sup.v,
--C(O)OR.sup.w, --C(O)NR.sup.yR.sup.z and --S(O).sub.qR.sup.v,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and
heteroaralkyl are each optionally substituted with one or more, in
one embodiment, one to four, in one embodiment, one to three, in
one embodiment, one, two or three, substituents independently
selected from halo, oxo, alkyl, hydroxy, alkoxy, amino and
alkylthio; or [1422] (ii) R.sup.13 and R.sup.14, together with the
nitrogen atom to which they are attached, form heterocyclyl or
heteroaryl wherein the heterocyclyl or heteroaryl are substituted
with one or more, in one embodiment, one to four, in one
embodiment, one to three, in one embodiment, one, two or three,
substituents independently selected from halo, alkyl, hydroxy,
alkoxy, amino and alkylthio and wherein the heterocyclyl is
optionally substituted with oxo; R.sup.15 is alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,
--C(O)NR.sup.yR.sup.z or --NR.sup.yR.sup.z, wherein the alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl are
each optionally substituted with one or more, in one embodiment,
one to four, in one embodiment, one to three, in one embodiment,
one, two or three, substituents independently selected from halo,
oxo, alkyl, hydroxy, alkoxy, amino and alkylthio; [1423] R.sup.18
is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
aralkyl, heteroaryl or heteroarylalkyl; wherein R.sup.18 is
optionally substituted with 1 to 3 groups Q.sup.1, each Q.sup.1
independently selected from alkyl, hydroxyl, halo, oxo, haloalkyl,
alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl,
carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, haloaryl and
amino; [1424] R.sup.19 and R.sup.20 are selected as follows: [1425]
(i) R.sup.19 and R.sup.20 are each independently hydrogen or alkyl;
or [1426] (ii) R.sup.19 and R.sup.20, together with the nitrogen
atom to which they are attached, form a heterocyclyl or heteroaryl
which are each optionally substituted with 1 to 2 groups each
independently selected from halo, oxo, alkyl, haloalkyl, hydroxyl
and alkoxy; [1427] R.sup.21 is hydrogen, alkyl, alkenyl, alkynyl,
haloalkyl or cycloalkyl; [1428] each R.sup.22 is independently
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; or both
R.sup.22, together with the nitrogen atom to which they are
attached, form a heterocyclyl optionally substituted with oxo;
[1429] R.sup.23 is alkyl, alkenyl, alkynyl or haloalkyl; [1430]
R.sup.24 is hydrogen or alkyl; [1431] each R.sup.x is independently
alkylene or a direct bond; [1432] R.sup.v is hydrogen, alkyl,
alkenyl or alkynyl; [1433] R.sup.w is independently hydrogen,
alkyl, alkenyl, alkynyl or haloalkyl; [1434] R.sup.y and R.sup.z
are selected as follows: [1435] (i) R.sup.y and R.sup.z are each
independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or
haloalkyl; or [1436] (ii) R.sup.y and R.sup.z, together with the
nitrogen atom to which they are attached, form a heterocyclyl or
heteroaryl which are optionally substituted with 1 to 2 groups each
independently selected from halo, alkyl, haloalkyl, hydroxyl and
alkoxy; [1437] n is 0-4; [1438] p is 0-5; [1439] each q is
independently 0, 1 or 2; and [1440] r is 1-3.
[1441] In an embodiment, the JAK-2 inhibitor of Formula (LV-A) is a
compound of Formula (LV-B):
##STR00150## [1442] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein [1443] A is
imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, or triazolyl; [1444]
R.sup.3 is hydrogen, alkyl, haloalkyl or cycloalkyl; [1445] each
R.sup.6 is independently selected from halo, alkyl, alkenyl,
alkynyl, haloalkyl, cycloalkyl, --R.sup.xOR.sup.18,
--R.sup.XNR.sup.19R.sup.20, and --R.sup.xS(O).sub.qR.sup.v; [1446]
R.sup.7 is halo; [1447] R.sup.18 is hydrogen, alkyl, haloalkyl,
hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or
heteroarylalkyl; wherein R.sup.18 is optionally substituted with 1
to 3 groups Q.sup.1, each Q.sup.1 independently selected from
alkyl, hydroxyl, halo, oxo, haloalkyl, alkoxy, aryloxy,
alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, carboxyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, haloaryl and amino; [1448] R.sup.19
and R.sup.20 are selected as follows: [1449] (i) R.sup.19 and
R.sup.20 are each independently hydrogen or alkyl; or [1450] (ii)
R.sup.19 and R.sup.20, together with the nitrogen atom to which
they are attached, form a heterocyclyl or heteroaryl which are each
optionally substituted with 1 to 2 groups each independently
selected from halo, oxo, alkyl, haloalkyl, hydroxyl and alkoxy;
[1451] each R.sup.x is independently alkylene or a direct bond;
[1452] R.sup.v is hydrogen, alkyl, alkenyl or alkynyl; [1453]
R.sup.y and R.sup.z are selected as follows: [1454] (i) R.sup.y and
R.sup.z are each independently hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl or haloalkyl; or [1455] (ii) R.sup.y and R.sup.z,
together with the nitrogen atom to which they are attached, form a
heterocyclyl or heteroaryl which are optionally substituted with 1
to 2 groups each independently selected from halo, alkyl,
haloalkyl, hydroxyl and alkoxy; [1456] n is 0-3; [1457] each q is
independently 0, 1 or 2; and [1458] r is 1-3.
[1459] In a preferred embodiment of the JAK-2 inhibitor of Formula
(LV-A) or (LV-B), R.sup.3 is hydrogen or alkyl.
[1460] In a preferred embodiment of the JAK-2 inhibitor of Formula
(LV-A) or (LV-B), A is imidazolyl, oxazolyl, thiazolyl,
thiadiazolyl, or triazolyl.
[1461] In a preferred embodiment of the JAK-2 inhibitor of Formula
(LV-A) or (LV-B), R.sup.7 is fluro.
[1462] In a preferred embodiment, the JAK-2 inhibitor of Formula
(LV-A) is a compound of Formula (LV-C):
##STR00151## [1463] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, where [1464] R.sup.1 and
R.sup.2 are selected as follows: [1465] (i) R.sup.1 and R.sup.2
together form =0; [1466] (ii) R.sup.1 and R.sup.2, together with
the carbon atom to which they are attached, form dioxacycloalkyl or
cycloalkyl wherein the cycloalkyl is substituted with one to four
substituents selected from halo, deutero, alkyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, cyano, =0, and hydroxy; [1467]
(iii) R.sup.1 is hydrogen or halo; and R.sup.2 is halo; [1468] (iv)
R.sup.1 is alkyl, and R.sup.2 is hydrogen, alkyl, halo, hydroxy or
alkoxy; or [1469] (v) R.sup.1 is halo, hydroxy or alkoxy; and
R.sup.2 is hydrogen or alkyl; [1470] R.sup.3 is hydrogen, alkyl or
cycloalkyl, [1471] R.sup.4 is hydrogen or alkyl; [1472] R.sup.5 is
hydrogen or alkyl; [1473] R.sup.7 is halo; and [1474] n is 0-3.
[1475] In a preferred embodiment of the JAK-2 inhibitor of Formula
(LV-C), n is 0.
[1476] In an embodiment, JAK-2 inhibitor of Formula (LV-A) has the
structure of Formula (LV-D):
##STR00152## [1477] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, where [1478] R.sup.1 and
R.sup.2 are selected as follows: [1479] (i) R.sup.1 and R.sup.2
together form =0; [1480] (ii) R.sup.1 and R.sup.2, together with
the carbon atom to which they are attached, form dioxacycloalkyl or
cycloalkyl wherein the cycloalkyl is substituted with one to four
substituents selected from halo, deutero, alkyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, cyano, =0, and hydroxy; [1481]
(iii) R.sup.1 is hydrogen or halo; and R.sup.2 is halo; [1482] (iv)
R.sup.1 is alkyl, and R.sup.2 is hydrogen, alkyl, halo, hydroxy or
alkoxy; or [1483] (v) R.sup.1 is halo, hydroxy or alkoxy; and
R.sup.2 is hydrogen or alkyl; R.sup.3 is hydrogen, alkyl or
cycloalkyl, [1484] R.sup.5 is hydrogen or alkyl; [1485] R.sup.7 is
halo; and [1486] n is 0-3.
[1487] In a preferred embodiment of the JAK-2 inhibitor of Formula
(LV-D), n is 0.
[1488] In a preferred embodiment, JAK-2 inhibitor of Formula (LV-D)
is selected from the group consisting of: [1489]
(4-fluorophenyl)(4-((1-methyl-1H-imidazol-4-yl)amino)quinazolin-2-yl)meth-
anol;
(4-((1H-imidazol-4-yl)amino)quinazolin-2-yl)(4-fluorophenyl)methanol-
; [1490]
(4-fluorophenyl)(4-(thiazol-4-ylamino)quinazolin-2-yl)methanol;
[1491]
(4-fluorophenyl)(4-((5-methylthiazol-2-yl)amino)quinazolin-2-yl)me-
thanol; and
2-(difluoro(4-fluorophenyl)methyl)-N-(1-methyl-1H-imidazol-4-yl)quinazoli-
n-4-amine,
[1492] or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[1493] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (LVII):
##STR00153## [1494] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [1495] R.sup.1 is
selected from hydrogen, hydroxy, amino, mercapto, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
C.sub.1-6alkylsulphonylamino, 3-5-membered carbocyclyl or
3-5-membered heterocyclyl; wherein R.sup.1 may be optionally
substituted on carbon by one or more R.sup.6; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.7; [1496]
R.sup.2 and R.sup.3 are independently selected from hydrogen, halo,
nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2-amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--NH--,
(C.sub.1-6alkyl)NH--S(O).sub.2--NH--, NH.sub.2--S(O).sub.2--NH--,
(C.sub.1-6alkyl).sub.2N--S(O).sub.2--N(C.sub.1-6alkyl)-,
(C.sub.1-6alkyl)NH--S(O).sub.2--N(C.sub.1-6alkyl)-,
NH.sub.2--S(O).sub.2--N(C.sub.1-6alkyl)-,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21; wherein R.sup.2 and R.sup.3 independently of
each other may be optionally substituted on carbon by one or more
R.sup.8; and wherein if said heterocyclyl contains an --NH-- moiety
that nitrogen may be optionally substituted by a group selected
from R.sup.9; [1497] R.sup.4 is selected from cyano, carboxy,
carbamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkanoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkoxycarbonyl,
carbocyclyl or heterocyclyl; wherein R.sup.4 may be optionally
substituted on carbon by one or more R.sup.10; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.11; [1498]
R.sup.5 is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.5 may be optionally substituted on carbon by one or more
R.sup.12; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.13; [1499] n=0, 1, 2 or 3; wherein the values
of R.sup.5 may be the same or different; [1500] R.sup.6, R.sup.8,
R.sup.10 and R.sup.12 are independently selected from halo, nitro,
cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.6, R.sup.8, R.sup.10 and R.sup.12 independently of each other
may be optionally substituted on carbon by one or more R.sup.14;
and wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.15; [1501] R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15
are independently selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein
R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 independently of
each other may be optionally substituted on carbon by on or more
R.sup.16; [1502] R.sup.14 and R.sup.16 are independently selected
from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.14 and R.sup.16 independently of each other may be optionally
substituted on carbon by one or more R.sup.17; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.18; [1503]
R.sup.17 is selected from halo, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl,
acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl; and [1504] R.sup.19 and R.sup.21 are
independently selected from a direct bond, --O--, --N(R.sup.22)--,
--C(O)--, --N(R.sup.23)C(O)--, --C(O)N(R.sup.24)--, --S(O).sub.s--,
--SO.sub.2N(R.sup.25)-- or --N(R.sup.26)SO.sub.2--; wherein
R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are
independently selected from hydrogen or C.sub.1-6alkyl and s is
0-2; R.sup.18 is selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; [1505] or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[1506] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (LVII), wherein: [1507] R.sup.1 is selected from hydrogen,
hydroxy, amino, mercapto, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, C.sub.1-6alkylsulphonylamino, 3-5-membered
carbocyclyl or 3-5-membered heterocyclyl; wherein R.sup.1 may be
optionally substituted on carbon by one or more R.sup.6; and
wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.7; [1508] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21--; wherein R.sup.2 and R.sup.3 independently
of each other may be optionally substituted on carbon by one or
more R.sup.8; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.9; [1509] R.sup.4 is selected from cyano,
carboxy, carbamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkanoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkoxycarbonyl,
carbocyclyl or heterocyclyl; wherein R.sup.4 may be optionally
substituted on carbon by one or more R.sup.10; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.11; [1510]
R.sup.5 is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.5 may be optionally substituted on carbon by one or more
R.sup.2; and wherein if said heterocyclyl contains an --NH-- moiety
that nitrogen may be optionally substituted by a group selected
from R.sup.13; [1511] n=0, 1, 2 or 3; wherein the values of R.sup.5
may be the same or different; [1512] R.sup.6, R.sup.8, R.sup.10 and
R.sup.12 are independently selected from halo, nitro, cyano,
hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.6, R.sup.8, R.sup.10 and R.sup.12 independently of each other
may be optionally substituted on carbon by one or more R.sup.14;
and wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.15; [1513] R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15
are independently selected from C.sub.1-6alkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6alkoxycarbonyl, carbamoyl,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein
R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 independently of
each other may be optionally substituted on carbon by on or more
R.sup.16; [1514] R.sup.14 and R.sup.16 are independently selected
from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.14 and R.sup.16 independently of each other may be optionally
substituted on carbon by one or more R.sup.17; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.18; [1515]
R.sup.17 is selected from halo, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl,
acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl; and [1516] R.sup.19 and R.sup.21 are
independently selected from --O--, --N(R.sup.22)--, --C(O)--,
--N(R.sup.23)C(O)--, --C(O)N(R.sup.24)--, --S(O).sub.s--,
--SO.sub.2N(R.sup.25)-- or --N(R.sup.26)SO.sub.2--; wherein
R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are
independently selected from hydrogen or C.sub.1-6alkyl and s is
0-2; [1517] R.sup.18 is selected from C.sub.1-6alkyl,
C.sub.1-6alkanoyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6alkoxycarbonyl, carbamoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl
and phenylsulphonyl; [1518] or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof.
[1519] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (LVII), wherein: [1520] R.sup.1 is selected from hydrogen,
hydroxy, amino, mercapto, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, C.sub.1-6alkylsulphonylamino, 3-5-membered
carbocyclyl or 3-5-membered heterocyclyl; wherein R.sup.1 may be
optionally substituted on carbon by one or more R.sup.6; and
wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.7; [1521] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
N--(C.sub.1-6alkyl)-N--(C.sub.1-6alkylsulphonyl)amino,
C.sub.1-6alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21--; wherein R.sup.2 and R.sup.3 independently
of each other may be optionally substituted on carbon by one or
more R.sup.8; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.9; [1522] R.sup.4 is selected from cyano,
carboxy, carbamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkanoyl, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkoxycarbonyl,
carbocyclyl or heterocyclyl; wherein R.sup.4 may be optionally
substituted on carbon by one or more R.sup.10; and wherein if said
heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.11; [1523]
R.sup.5 is selected from halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl, N,N--(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R.sup.5 may be optionally substituted on carbon by one or more
R.sup.12; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.13; [1524] n=0, 1, 2 or 3; wherein the values
of R.sup.5 may be the same or different; [1525] R.sup.6, R.sup.8,
R.sup.10 and R.sup.12 are independently selected from halo, nitro,
cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N-(C.sub.1-6alkyl).sub.2sulphamoyl, C.sub.1-6alkylsulphonylamino,
carbocyclyl or heterocyclyl; wherein R.sup.6, R.sup.8, R.sup.10 and
R.sup.12 independently of each other may be optionally substituted
on carbon by one or more R.sup.14; and wherein if said heterocyclyl
contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from R.sup.15; [1526] R.sup.7,
R.sup.9, R.sup.11, R.sup.13 and R.sup.15 are independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkanoyl,
(C.sub.1-6)alkylsulphonyl, (C.sub.1-6)alkoxycarbonyl, carbamoyl,
N--((C.sub.1-6)alkyl)carbamoyl, N,N--((C.sub.1-6)alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein
R.sup.7, R.sup.9, R.sup.11, R.sup.13 and R.sup.15 independently of
each other may be optionally substituted on carbon by on or more
R.sup.16; [1527] R.sup.14 and R.sup.16 are independently selected
from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.2-6)alkynyl, (C.sub.1-6)alkoxy, (C.sub.1-6)alkanoyl,
(C.sub.1-6)alkanoyloxy, N--((C.sub.1-6)alkyl)amino,
N,N--((C.sub.1-6)alkyl).sub.2amino, (C.sub.1-6)alkanoylamino,
N--((C.sub.1-6)alkyl)carbamoyl,
N,N--((C.sub.1-6)alkyl).sub.2carbamoyl, (C.sub.1-6)alkylS(O).sub.a
wherein a is 0 to 2, (C.sub.1-6)alkoxycarbonyl,
N--((C.sub.1-6)alkyl)sulphamoyl,
N,N--((C.sub.1-6)alkyl).sub.2sulphamoyl,
(C.sub.1-6)alkylsulphonylamino, carbocyclyl or heterocyclyl;
wherein R.sup.14 and R.sup.16 independently of each other may be
optionally substituted on carbon by one or more R.sup.17; and
wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.18; [1528] R.sup.17 is selected from halo, nitro, cyano,
hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl,
N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl; and [1529] R.sup.19 and R.sup.21 are
independently selected from a direct bond, --O--, --N(R.sup.22)--,
--C(O)--, --N(R.sup.23)C(O)--, --C(O)N(R.sup.24)--, --S(O).sub.s--,
--SO.sub.2N(R.sup.25)-- or --N(R.sup.26)SO.sub.2--; wherein
R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are
independently selected from hydrogen or (C.sub.1-6)alkyl and s is
0-2; [1530] R.sup.18 is selected from (C.sub.1-6)alkyl,
(C.sub.1-6)alkanoyl, (C.sub.1-6)alkylsulphonyl,
(C.sub.1-6)alkoxycarbonyl, carbamoyl,
N--((C.sub.1-6)alkyl)carbamoyl, N,N--((C.sub.1-6)alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; [1531] or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[1532] Particular values of the variable groups contained in
Formula (LVII) are as follows. Such values may be used, where
appropriate, with any of the definitions, claims or embodiments
defined hereinbefore or hereinafter in relation to compounds of
Formula (LVII). [1533] R.sup.1 is selected from (C.sub.1-6)alkyl,
(C.sub.1-6)alkoxy, 3-5-membered carbocyclyl, and
N,N--((C.sub.1-6)alkyl).sub.2amino, wherein R.sup.1 may be
optionally substituted on carbon by one or more R.sup.6; and
wherein R.sup.6 is halo, [1534] R.sup.1 is (C.sub.1-6)alkoxy or
3-5-membered carbocyclyl. [1535] R.sup.1 is selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkoxy or 3-5-membered carbocyclyl.
[1536] R.sup.1 is (C.sub.1-6)alkyl or (C.sub.1-6)alkoxy. [1537]
R.sup.1 is 3-5 membered carbocyclyl. [1538] R.sup.1 is
N,N((C.sub.1-6)alkyl).sub.2amino. [1539] R.sup.1 is
(C.sub.1-6)alkyl. [1540] R.sup.1 is (C.sub.1-4)alkyl. [1541]
R.sup.1 is (C.sub.1-6)alkoxy. [1542] R.sup.1 is selected from
methyl, methoxy, trifluoroethoxy, isopropoxy, cyclopropyl, and
N,N-dimethylamino; [1543] R.sup.1 is isopropoxy or cyclopropyl.
[1544] R.sup.1 is methyl, methoxy, isopropoxy or cyclopropyl.
[1545] R.sup.1 is selected from methyl, methoxy, isopropoxy,
N,N-dimethylamino, and cyclopropyl. [1546] R.sup.1 is isopropoxy.
[1547] R.sup.1 is methyl. [1548] R.sup.1 is ethyl. [1549] R.sup.1
is selected from methyl, ethyl, propyl, and butyl. [1550] R.sup.1
is selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, and
cyclopropyl. [1551] R.sup.1 is methoxy. [1552] R.sup.1 is
cyclopropyl. R.sup.1 is N,N-dimethylamino. [1553] R.sup.2 is
selected from hydrogen, halo, nitro, and (C.sub.1-6)alkyl, wherein
R.sup.2 may be optionally substituted on carbon by one or more
R.sup.8; and wherein R.sup.8 is halo. [1554] R.sup.2 is selected
from hydrogen, chloro, fluoro, bromo, nitro, and trifluoromethyl.
[1555] R.sup.2 is halo. [1556] R.sup.2 is (C.sub.1-6)alkyl, wherein
R.sup.2 may be optionally substituted on carbon by one or more
R.sup.8; and wherein R.sup.8 is halo.
[1557] R.sup.2 and R.sup.3 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.2-6)alkynyl, (C.sub.1-6)alkoxy, (C.sub.1-6)alkanoyl,
(C.sub.1-6)alkanoyloxy, N--((C.sub.1-6)alkyl)amino,
N,N--((C.sub.1-6)alkyl).sub.2amino, (C.sub.1-6)alkanoylamino,
N--((C.sub.1-6)alkyl)carbamoyl,
N,N--((C.sub.1-6)alkyl).sub.2carbamoyl, (C.sub.1-6)alkylS(O).sub.a
wherein a is 0 to 2, (C.sub.1-6)alkoxycarbonyl,
N--((C.sub.1-6)alkyl)sulphamoyl,
N,N--((C.sub.1-6)alkyl).sub.2sulphamoyl,
(C.sub.1-6)alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21--; wherein R.sup.2 and R.sup.3 independently
of each other may be optionally substituted on carbon by one or
more R.sub.8; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.9. [1558] R.sup.2 and R.sup.3 are independently
selected from hydrogen, halo, nitro, cyano, hydroxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, (C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl, (C.sub.2-6)alkynyl, (C.sub.1-6)alkoxy,
(C.sub.1-6)alkanoyl, (C.sub.1-6)alkanoyloxy,
N--((C.sub.1-6)alkyl)amino, N,N--((C.sub.1-6)alkyl).sub.2amino,
(C.sub.1-6)alkanoylamino, N--((C.sub.1-6)alkyl)carbamoyl,
N,N--((C.sub.1-6)alkyl).sub.2carbamoyl, (C.sub.1-6)alkylS(O).sub.a
wherein a is 0 to 2, (C.sub.1-6)alkoxycarbonyl, N--(
)C.sub.1-6)alkyl)sulphamoyl,
N,N--((C.sub.1-6)alkyl).sub.2sulphamoyl,
N--((C.sub.1-6)alkyl)-N--((C.sub.1-6)alkylsulphonyl)amino,
(C.sub.1-6)alkylsulphonylamino, carbocyclyl-R.sup.19-- or
heterocyclyl-R.sup.21; wherein R.sup.2 and R.sup.3 independently of
each other may be optionally substituted on carbon by one or more
R.sup.8; and wherein if said heterocyclyl contains an --NH-- moiety
that nitrogen may be optionally substituted by a group selected
from R.sup.9. [1559] R.sup.2 and R.sup.3 are independently selected
from hydrogen, halo,
N--((C.sub.1-6)alkyl)-N--((C.sub.1-6)alkylsulphonyl)amino, or
heterocyclyl-R.sup.21--; wherein R.sup.21 is a direct bond. [1560]
R.sup.2 and R.sup.3 are independently selected from hydrogen and
halo. [1561] R.sup.2 and R.sup.3 are independently selected from
hydrogen and chloro. [1562] R.sup.2 and R.sup.3 are independently
selected from hydrogen, fluoro, chloro, bromo,
N-methyl-N-mesylamino and morpholino. [1563] R.sup.2 is halo and
R.sup.3 is hydrogen. [1564] R.sup.2 is chloro and R.sup.3 is
hydrogen. [1565] R.sup.2 is chloro or fluoro and R.sup.3 is
hydrogen. R.sup.3 is selected from hydrogen, halo, cyano,
N--((C.sub.1-6)alkyl)-N--((C.sub.1-6)alkylsulphonyl)amino,
(C.sub.1-6)alkyl,
((C.sub.1-6)alkyl).sub.2N--S(O).sub.2--N((C.sub.1-6)alkyl)-, and
heterocyclyl-R.sup.21--, wherein R.sup.3 may be optionally
substituted on carbon by one or more R.sup.8; wherein R.sup.8 is
halo; and wherein R.sup.21 is a bond. [1566] R.sup.3 is hydrogen.
[1567] R.sup.3 is halo. [1568] R.sup.3 is selected from
N--((C.sub.1-6)alkyl)-N--((C.sub.1-6)alkylsulphonyl)amino and
((C.sub.1-6)alkyl).sub.2N--S(O).sub.2--N((C.sub.1-6)alkyl)-. [1569]
R.sup.3 is selected from heterocyclyl-R.sup.21--, wherein R.sup.3
may be optionally substituted on carbon by one or more R.sup.5;
wherein R.sup.5 is halo; and wherein R.sup.21 is a bond. [1570]
R.sup.3 is selected from hydrogen, chloro, cyano, trifluoromethyl,
(CH.sub.3).sub.2N--S(O).sub.2--N(CH.sub.3)--,
N-methyl-N-mesylamino, and morpholino. [1571] R.sup.3 is
(CH.sub.3).sub.2N--S(O).sub.2--N(CH.sub.3)--. [1572] R.sup.3 is
N-methyl-N-mesylamino, [1573] R.sup.3 is morpholino. [1574] R.sup.4
is (C.sub.1-6)alkyl. [1575] R.sup.4 is methyl. [1576] R.sup.5 is
halo. [1577] R.sup.5 is fluoro. [1578] n=1. [1579] R.sup.19 and
R.sup.21 are independently selected from --O--, --N(R.sup.22)--,
--C(O)--, --N(l.sup.23)C(O), C(O)N(R.sup.24).sup.-, --S(O).sub.s--,
--SO.sub.2N(R.sup.25)-- or --N(R.sup.26)SO.sub.2--; wherein
R.sup.22, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are
independently selected from hydrogen or (C.sub.1-6)alkyl and s is
0-2.
[1580] Therefore in a further aspect of the invention there is
provided a compound of Formula (LVII) (as depicted herein above)
wherein: [1581] R.sup.1 is selected from (C.sub.1-6)alkyl,
(C.sub.1-6)alkoxy or 3-5-membered carbocyclyl; [1582] R.sup.1 and
R.sup.3 are independently selected from hydrogen, halo,
N--((C.sub.1-6)alkyl)-N--((C.sub.1-6)alkylsulphonyl)amino, or
heterocyclyl-R.sup.21--; [1583] R.sup.4 is (C.sub.1-6)alkyl; [1584]
R.sup.5 is halo; [1585] n=1; [1586] R.sup.21 is a direct bond;
[1587] or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[1588] Therefore, in an embodiment of the invention, the JAK-2
inhibitor is a compound of Formula (LVII) wherein: [1589] R.sup.1
is (C.sub.1-6)alkoxy; [1590] R.sup.2 and R.sup.3 are independently
selected from hydrogen and halo; [1591] R.sup.4 is
(C.sub.1-6)alkyl; [1592] R.sup.5 is halo; [1593] n=1; [1594] or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[1595] Therefore, in an embodiment of the invention, the JAK-2
inhibitor is a compound of Formula (LVII) wherein: [1596] R.sup.1
is methyl, methoxy, isopropoxy or cyclopropyl; [1597] R.sup.2 and
R.sup.3 are independently selected from hydrogen, fluoro, chloro,
bromo, N-methyl-N-mesylamino and morpholino; [1598] R.sup.4 is
methyl; [1599] R.sup.5 is fluoro; and [1600] n=1; [1601] or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[1602] Therefore, in an embodiment of the invention, the JAK-2
inhibitor is a compound of Formula (LVII) wherein: [1603] R.sup.1
is selected from (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, 3-5-membered
carbocyclyl, and N,N--((C.sub.1-6)alkyl).sub.2amino, wherein
R.sup.1 may be optionally substituted on carbon by one or more
R.sup.6; [1604] R.sup.2 is selected from hydrogen, halo, nitro, and
(C.sub.1-6)alkyl, wherein R.sup.2 may be optionally substituted on
carbon by one or more R.sup.8; [1605] R.sup.3 is selected from
hydrogen, halo, cyano,
N--((C.sub.1-6)alkyl)-N--((C.sub.1-6)alkylsulphonyl)amino,
(C.sub.1-6)alkyl,
((C.sub.1-6)alkyl).sub.2N--S(O).sub.2--N((C.sub.1-6)alkyl)-, and
heterocyclyl-R.sup.21--, wherein R.sup.3 may be optionally
substituted on carbon by one or more R.sup.8; [1606] R.sup.4 is
(C.sub.1-6)alkyl; [1607] R.sup.5 is halo; [1608] R.sup.6 is halo;
[1609] R.sup.8 is halo; [1610] R.sup.21 is a bond; and [1611] n=1;
[1612] or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[1613] Therefore, in an embodiment of the invention, the JAK-2
inhibitor is a compound of Formula (LVII) wherein: [1614] R.sup.1
is selected from methyl, methoxy, trifluoroethoxy, isopropoxy,
cyclopropyl, and N,N-dimethylamino; [1615] R.sup.2 is selected from
hydrogen, chloro, fluoro, bromo, nitro, and trifluoromethyl; [1616]
R.sup.3 is selected from hydrogen, chloro, cyano, trifluoromethyl,
(CH.sub.3).sub.2N--S(O).sub.2--N(CH.sub.3)--,
N-methyl-N-mesylamino, and morpholino; [1617] R.sup.4 is methyl;
[1618] R.sup.5 is fluoro; and [1619] n is 1; [1620] or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[1621] Therefore, in an embodiment of the invention, the JAK-2
inhibitor is a compound of Formula (LVII) wherein: [1622] R.sup.1
is selected from (C.sub.1-6)alkoxy, wherein R.sup.1 may be
optionally substituted on carbon by one or more R.sup.6; [1623]
R.sup.2 is selected from hydrogen and halo; [1624] R.sup.3 is
selected from hydrogen, halo, and heterocyclyl-R.sup.21--; [1625]
R.sup.4 is (C.sub.1-6)alkyl; [1626] R.sup.5 is halo; [1627] R.sup.6
is halo; [1628] R.sup.21 is a bond; [1629] n is 1; [1630] or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[1631] Therefore, in an embodiment of the invention, the JAK-2
inhibitor is a compound of Formula (LVII) wherein: [1632] R.sup.1
is selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, and
cyclopropyl; [1633] R.sup.2 is selected from hydrogen, halo, nitro,
and (C.sub.1-6)alkyl, wherein R.sup.2 may be optionally substituted
on carbon by one or more R.sup.8; [1634] R.sup.3 is selected from
hydrogen, halo, cyano,
N--((C.sub.1-6)alkyl)-N--((C.sub.1-6)alkylsulphonyl)amino,
(C.sub.1-6)alkyl,
((C.sub.1-6)alkyl).sub.2N--S(O).sub.2--N((C.sub.1-6)alkyl)-, and
heterocyclyl-R.sup.21--, wherein R.sup.3 may be optionally
substituted on carbon by one or more R.sup.8; [1635] R.sup.4 is
(C.sub.1-6)alkyl; [1636] R.sup.5 is halo; [1637] R.sup.6 is halo;
[1638] R.sup.8 is halo; [1639] R.sup.21 is a bond; and [1640] n=1;
[1641] or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof.
[1642] In a preferred embodiment, the JAK-2 inhibitor is AZD-1480.
In a preferred embodiment, the JAK-2 inhibitor is
(S)-5-chloro-N.sup.2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N.sup.4-(5-methyl--
1H-pyrazol-3-yl)pyrimidine-2,4-diamine. In a preferred embodiment,
the JAK-2 inhibitor has the chemical structure shown in Formula
(LVIII):
##STR00154## [1643] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. No. 8,088,784 and U.S. Patent
Application Publication Nos. 2008/0287475 A1; 2010/0160325 A1; and,
2012/0071480 A1, the disclosures of which are incorporated by
reference herein. In an embodiment, the JAK-2 inhibitor is selected
from the compounds described in U.S. Pat. No. 8,088,784 and U.S.
Patent Application Publication Nos. 2008/0287475 A1; 2010/0160325
A1; and, 2012/0071480 A1, the disclosures of which are incorporated
by reference herein.
[1644] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (LIX):
##STR00155## [1645] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [1646] R.sup.1 and
R.sup.2 are independently selected from hydrogen, halo, nitro,
cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, C.sub.1-6
alkanoyloxy, N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6
alkyl).sub.2-amino, C.sub.1-6 alkanoylamino, N--(C.sub.1-6
alkyl)carbamoyl, N,N--(C.sub.1-6 alkyl).sub.2-carbamoyl, C.sub.1-6
alkylS(O).sub.a wherein a is 0 to 2, C.sub.1-6 alkoxycarbonyl,
N--(C.sub.1-6 alkyl)sulphamoyl, N,N--(C.sub.1-6
alkyl).sub.2sulphamoyl, C.sub.1-6 alkylsulphonylamino, carbocyclyl
or heterocyclyl; wherein R.sup.1 and R.sup.2 independently of each
other may be optionally substituted on carbon by one or more
R.sup.6; and wherein if said heterocyclyl contains an --NH-- moiety
that nitrogen may be optionally substituted by a group selected
from R.sup.7; [1647] one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4
is .dbd.N--, the other three are independently selected from
.dbd.CR.sup.8--, .dbd.CR.sup.9-- and .dbd.CR.sup.10--; [1648]
R.sup.3 is hydrogen or optionally substituted C.sub.1-6 alkyl;
wherein said optional substituents are selected from one or more
R.sup.11; [1649] R.sup.4 and R.sup.34 are independently selected
from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6
alkanoyl, C.sub.1-6 alkanoyloxy, N--(C.sub.1-6 alkyl)amino,
N,N--(C.sub.1-6 alkyl).sub.2amino, C.sub.1-6 alkanoylamino,
N--(C.sub.1-6 alkyl)carbamoyl, N,N--(C.sub.1-6
alkyl).sub.2carbamoyl, C.sub.1-6 alkylS(O).sub.a wherein a is 0 to
2, C.sub.1-6 alkoxycarbonyl, N--(C.sub.1-6 alkyl)sulphamoyl,
N,N--(C.sub.1-6 alkyl).sub.2sulphamoyl, C.sub.1-6
alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R.sup.4
and R.sup.34 may be independently optionally substituted on carbon
by one or more R.sup.12; and wherein if said heterocyclyl contains
an --NH-- moiety that nitrogen may be optionally substituted by a
group selected from R.sup.13; [1650] A is a direct bond or
C.sub.1-2alkylene; wherein said C.sub.1-2alkylene may be optionally
substituted by one or more R.sup.14; [1651] Ring C is carbocyclyl
or heterocyclyl; wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.15; [1652] R.sup.5 is selected from halo,
nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, C.sub.1-6
alkanoyloxy, N--(C.sub.1-6 alkyl)amino, N,N--(C.sub.1-6
alkyl).sub.2amino, C.sub.1-6 alkanoylamino, N--(C.sub.1-6
alkyl)carbamoyl, N,N--(C.sub.1-6 alkyl).sub.2carbamoyl, C.sub.1-6
alkylS(O).sub.a wherein a is 0 to 2, C.sub.1-6 alkoxycarbonyl,
N--(C.sub.1-6 alkyl)sulphamoyl, N,N--(C.sub.1-6
alkyl).sub.2sulphamoyl, C.sub.1-6 alkylsulphonylamino,
carbocyclyl-R.sup.37-- or heterocyclyl-R.sup.38--; wherein R.sup.5
may be optionally substituted on carbon by one or more R.sup.16;
and wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.17; [1653] n is 0, 1, 2 or 3; wherein the values of R.sup.5
may be the same or different; [1654] R.sup.8, R.sup.9 and R.sup.10
are independently selected from hydrogen, halo, nitro, cyano,
hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, C.sub.1-6 alkanoyloxy,
N--(C.sub.1-6 alkyl)amino, N,N--(C.sub.1-6 alkyl).sub.2amino,
C.sub.1-6 alkanoylamino, N--(C.sub.1-6 alkyl)carbamoyl,
N,N--(C.sub.1-6 alkyl).sub.2carbamoyl, C.sub.1-6 alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6 alkoxycarbonyl, N--(C.sub.1-6
alkyl)sulphamoyl, N,N--(C.sub.1-6 alkyl).sub.2sulphamoyl, C.sub.1-6
alkylsulphonylamino, carbocyclyl-R.sup.25-- or
heterocyclyl-R.sup.26--; wherein R.sup.8, R.sup.9 and R.sup.10
independently of each other may be optionally substituted on carbon
by one or more R.sup.8; and wherein if said heterocyclyl contains
an --NH-- moiety that nitrogen may be optionally substituted by a
group selected from R.sup.19; [1655] R.sup.6, R.sup.11, R.sup.12,
R.sup.14, R.sup.16 and R.sup.18 are independently selected from
halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl,
C.sub.1-6 alkanoyloxy, N--(C.sub.1-6 alkyl)amino, N,N--(C.sub.1-6
alkyl).sub.2amino, C.sub.1-6 alkanoylamino, N--(C.sub.1-6
alkyl)carbamoyl, N,N--(C.sub.1-6 alkyl).sub.2carbamoyl, C.sub.1-6
alkylS(O).sub.a wherein a is 0 to 2, C.sub.1-6 alkoxycarbonyl,
N--(C.sub.1-6 alkyl)sulphamoyl, N,N--(C.sub.1-6
alkyl).sub.2sulphamoyl, C.sub.1-6 alkylsulphonylamino,
carbocyclyl-R.sup.27-- or heterocyclyl-R.sup.28--; wherein R.sup.6,
R.sup.11, R.sup.12, R.sup.14, R.sup.16 and R.sup.18 independently
of each other may be optionally substituted on carbon by one or
more R.sup.20; and wherein if said heterocyclyl contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.21; [1656] R.sup.7, R.sup.13, R.sup.15,
R.sup.17, R.sup.19 and R.sup.21 are independently selected from
C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-6 alkylsulphonyl,
C.sub.1-6 alkoxycarbonyl, carbamoyl, N--(C.sub.1-6 alkyl)carbamoyl,
N,N--(C.sub.1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl
and phenylsulphonyl; wherein R.sup.7, R.sup.13, R.sup.15, R.sup.17,
R.sup.19 and R.sup.21 independently of each other may be optionally
substituted on carbon by on or more R.sup.22; [1657] R.sup.20 and
R.sup.22 are independently selected from halo, nitro, cyano,
hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, C.sub.1-6 alkanoyloxy,
N--(C.sub.1-6 alkyl)amino, N,N--(C.sub.1-6 alkyl).sub.2amino,
C.sub.1-6 alkanoylamino, N--(C.sub.1-6 alkyl)carbamoyl,
N,N--(C.sub.1-6 alkyl).sub.2carbamoyl, C.sub.1-6 alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6 alkoxycarbonyl, N--(C.sub.1-6
alkyl)sulphamoyl, N,N--(C.sub.1-6 alkyl).sub.2sulphamoyl, C.sub.1-6
alkylsulphonylamino, C.sub.1-6 alkylsulphonyl-N--(C.sub.1-6
alkyl)amino, carbocyclyl-R.sup.35-- or heterocyclyl-R.sup.36--;
wherein R.sup.20 and R.sup.22 independently of each other may be
optionally substituted on carbon by one or more R.sup.23; and
wherein if said heterocyclyl contains an --NH-- moiety that
nitrogen may be optionally substituted by a group selected from
R.sup.24; [1658] R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.35,
R.sup.36, R.sup.37 and R.sup.38 are independently selected from a
direct bond, --O--, --N(R.sup.29)--, --C(O)--, --N(R.sup.30)C(O)--,
--C(O)N(R.sup.31)--, --S(O).sub.s--, --NH.dbd.CH--,
--SO.sub.2N(R.sup.32)-- or --N(R.sup.33)SO.sub.2--; wherein
R.sup.29, R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are
independently selected from hydrogen or C.sub.1-6 alkyl and s is
0-2; [1659] R.sup.23 is selected from halo, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl,
acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl,
N-methyl-N-ethylsulphamoyl or phenyl; and [1660] R.sup.24 is
selected from C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-6
alkylsulphonyl, C.sub.1-6 alkoxycarbonyl, carbamoyl, N--(C.sub.1-6
alkyl)carbamoyl, N,N--(C.sub.1-6 alkyl)carbamoyl, benzyl,
benzyloxycarbonyl, benzoyl and phenylsulphonyl; [1661] or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[1662] In a preferred embodiment, the JAK-2 inhibitor is
(S)-5-fluoro-2-((l-(4-fluorophenyl)ethyl)amino)-6-((5-methyl-1H-pyrazol-3-
-yl)amino)nicotinonitrile. In a preferred embodiment, the JAK-2
inhibitor is a compound of Formula (LX):
##STR00156## [1663] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is described in U.S. Pat. No. 8,324,252 and U.S. Patent
Application Publication Nos. 2008/0139561 A1 and 2013/0090358 A1,
the disclosures of which are incorporated by reference herein. In
an embodiment, the JAK-2 inhibitor is selected from the compounds
described in U.S. Pat. No. 8,324,252 and U.S. Patent Application
Publication Nos. 2008/0139561 A1 and 2013/0090358 A1, the
disclosures of which are incorporated by reference herein.
[1664] In an embodiment, the JAK-2 inhibitor is a compound of
Formula (LXII):
##STR00157## [1665] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, or a stereoisomer thereof,
wherein: [1666] D is CH or N; [1667] E is CH or N; [1668] X is
CH.sub.2, NR.sub.4, O or S; [1669] U is CH or N; [1670] V is CH or
N; [1671] Y is CH or N; [1672] Z is CH or N; [1673] R1 is
NR.sub.5R.sub.6, CR.sub.5R.sub.6R.sub.7, SR.sub.5 or OR.sub.5;
[1674] R.sub.2 is (C.dbd.O)OH, (C.dbd.O)NH.sub.2,
(C.dbd.O)NHR.sub.4 or heterocyclyl; [1675] R.sub.3 is [1676] (a)
hydrogen; [1677] (b) C.sub.1-6 alkyl, which is optionally
substituted with halo, hydroxyl, amino, phenyl, heterocyclyl,
C.sub.1-6 alkyl or R.sub.10; [1678] (c) C.sub.2-6 alkenyl, which is
optionally substituted with halo, hydroxyl, amino, phenyl,
heterocyclyl, C.sub.1-6 alkyl or R.sub.4; [1679] (d) C.sub.3-10
cycloalkyl, which is optionally substituted with C.sub.1-6 alkyl,
OR.sub.4, NR.sub.8R.sub.4, phenyl (which is optionally substituted
with C.sub.1-6 alkyl, OR.sub.4 or NR.sub.8R.sub.4), halo, R.sub.10
or heterocyclyl; [1680] (e) --(CO)R.sub.8; [1681] (f)
--(CO)--NR.sub.8R.sub.9; [1682] (g) C.sub.4-10 heterocyclyl, which
is optionally substituted on either the carbon or the heteroatom
with C.sub.1-6 alkyl, halo, R.sub.10, OR.sub.4, NR.sub.8R.sub.4,
phenyl (which is optionally substituted with C.sub.1-6 alkyl,
OR.sub.4 or NR.sub.8R.sub.4), --(CO)R.sub.8 or
--(CO)--NR.sub.8R.sub.9; [1683] (h) OR.sub.4; [1684] (i)
NR.sub.8R.sub.4; [1685] (j) halo; [1686] (k) Aryl, which is
optionally substituted with one or more groups selected from
C.sub.1-6 alkyl (which is optionally substituted with one to three
halo), halo or R.sub.10; [1687] (l) Heteroaryl, which is optionally
substituted with one or more groups selected from C.sub.1-6 alkyl
(which is optionally substituted with one to three halo), halo or
R.sub.10; [1688] (m) O-aryl, which is optionally substituted with
one or more groups selected from C.sub.1-6 alkyl, halo or R.sub.10;
[1689] (n) O--C.sub.1-6 alkyl, which is optionally substituted with
C.sub.1-6 alky, halo or R.sub.10; or [1690] (o) L-A-R.sub.10;
[1691] R.sub.4 is [1692] (a) hydrogen; [1693] (b) C.sub.1-6 alkyl,
which is optionally substituted with halo, hydroxyl, amino, aryl or
heterocyclyl; [1694] (c) C.sub.3-10 cycloalkyl, which is optionally
substituted with C.sub.1-6 alkyl, OR.sub.11, NR.sub.8R.sub.11,
phenyl (which is optionally substituted with C.sub.1-6 alkyl,
OR.sub.11 or NR.sub.8R.sub.11), heterocyclyl, aryl or heteroaryl;
[1695] (d) --(CO)R.sub.8; [1696] (e) --(CO)--NR.sub.8R.sub.9;
[1697] (f) C.sub.4-10 heterocyclyl, which is optionally substituted
on either the carbon or the heteroatom with C.sub.1-6 alkyl,
OR.sub.11, NR.sub.8R.sub.11, phenyl (which is optionally
substituted with C.sub.1-6 alkyl, OR.sub.11 or NR.sub.8R.sub.11),
heterocyclyl, --(CO)R.sub.8 or --(CO)--NR.sub.8R.sub.9; [1698] (g)
OR.sub.11; [1699] (h) NR.sub.8R.sub.11; [1700] (i) Aryl, which is
optionally substituted with one to five halo or R.sub.10; [1701]
(j) Heteroaryl (wherein the heteroaryl has 5 or 6 members in which
1, 2, 3, or 4 of the atoms is a heteroatom selected from N, S and
O), which is optionally substituted with one to five halo or
R.sub.10; [1702] R.sub.5 is [1703] (a) hydrogen; [1704] (b)
C.sub.1-8 alkyl, which is optionally substituted with halo,
hydroxyl, amino, aryl, cycloalkyl or heterocyclyl; [1705] (c)
C.sub.3-10 cycloalkyl, which is optionally substituted with
C.sub.1-6 alkyl, (C.sub.1-6 alkyl)aryl, (C.sub.1-6 alkyl)OR.sub.9,
OR.sub.4, NR.sub.8R.sub.4, phenyl (which is optionally substituted
with C.sub.1-6 alkyl, OR.sub.4, NR.sub.8R.sub.4, heterocyclyl,
--(CO)R.sub.8 or --(CO)--NR.sub.8R.sub.9); [1706] (d)
--(CO)R.sub.8; [1707] (e) --(CO)--NR.sub.8R.sub.9; [1708] (f)
C.sub.1-6 alkyl(C.dbd.O)NR.sub.8CR.sub.9(C.dbd.O)NR.sub.8R.sub.9;
[1709] (g) C.sub.4-10 heterocyclyl which is optionally substituted
on either the carbon or the heteroatom with one to three
substituents selected from C.sub.1-6 alkyl, halo, OR.sub.4,
NR.sub.8R.sub.4, --(CO)R.sub.8, (CO)--NR.sub.8R.sub.9 or phenyl
(which is optionally substituted with C.sub.1-6 alkyl, OR.sub.4,
NR.sub.8R.sub.4, heterocyclyl, --(CO)R.sub.8 or
--(CO)--NR.sub.8R.sub.9); [1710] R.sub.6 is [1711] (a) hydrogen;
[1712] (b) C.sub.1-8 alkyl, which is optionally substituted with
halo, hydroxyl, amino, aryl, cycloalkyl or heterocyclyl; [1713] (c)
C.sub.3-10 cycloalkyl, which is optionally substituted with
C.sub.1-6 alkyl, (C.sub.1-6 alkyl)aryl, (C.sub.1-6 alkyl)OR.sub.9,
OR.sub.4, NR.sub.8R.sub.4, phenyl (which is optionally substituted
with C.sub.1-6 alkyl, OR.sub.4, NR.sub.8R.sub.4, heterocyclyl,
--(CO)R.sub.8 or --(CO)--NR.sub.8R.sub.9; [1714] (d) --(CO)R.sub.8;
[1715] (e) --(CO)--NR.sub.8R.sub.9; [1716] (f) C.sub.1-6
alkyl(C.dbd.O)NR.sub.8CR.sub.9(C.dbd.O)NR.sub.8R.sub.9; [1717] (g)
C.sub.4-10 heterocyclyl which is optionally substituted on either
the carbon or the heteroatom with one to three substituents
selected from C.sub.1-6 alkyl, halo, OR.sub.4, NR.sub.8R.sub.4,
--(CO)R.sub.8, (CO)--NR.sub.8R.sub.9 or phenyl (which is optionally
substituted with C.sub.1-6 alkyl, OR.sub.4, NR.sub.8R.sub.4,
heterocyclyl, --(CO)R.sub.8 or --(CO)--NR.sub.8R.sub.9); [1718]
R.sub.7 is [1719] (a) hydrogen; [1720] (b) C.sub.1-6 alkyl, which
is optionally substituted with halo, hydroxyl, amino, phenyl or
heterocyclyl; [1721] (c) C.sub.3-10 cycloalkyl, which is optionally
substituted with C.sub.1-6 alkyl, OR.sub.4, NR.sub.8R.sub.4, phenyl
(which is optionally substituted with C.sub.1-6 alkyl, OR.sub.4,
NR.sub.8R.sub.4, heterocyclyl, --(CO)R.sub.8 or
--(CO)--NR.sub.8R.sub.9); [1722] (d) C.sub.4-10 heterocyclyl which
is optionally substituted on either the carbon or the heteroatom
with C.sub.1-6 alkyl, OR.sub.4, NR.sub.8R.sub.4, phenyl (which is
optionally substituted with C.sub.1-6 alkyl, OR.sub.4,
NR.sub.8R.sub.4, heterocyclyl, --(CO)R.sub.8 or
--(CO)--NR.sub.8R.sub.9); [1723] Or R.sub.5 and R.sub.6, together
with the atoms between them, can form a three to ten membered
heterocyclic or heteroaryl ring which is optionally substituted
with C.sub.1-6 alkyl, (C.sub.1-6 alkyl)aryl, (C.sub.1-6
alkenyl)aryl, (C.sub.1-6 alkyl)OR.sub.9, OR.sub.4, NR.sub.8R.sub.4,
phenyl (which is optionally substituted with C.sub.1-6 alkyl,
OR.sub.4, NR.sub.8R.sub.4, heterocyclyl, --(CO)R.sub.8 or
--(CO)--NR.sub.8R.sub.9), --(CO)R.sub.8; --(CO)--NR8R9, or
heterocyclyl; [1724] R.sub.8 is hydrogen or C.sub.1-6 alkyl,
--(CO)R.sub.11, --(CO)N(R.sub.11).sub.2; [1725] R.sub.9 is hydrogen
or C.sub.1-6 alkyl; [1726] R.sub.10 is: [1727] (a) hydrogen; [1728]
(b) CO.sub.2R.sub.11; [1729] (c) C(O)R.sub.11; [1730] (d)
NHR.sub.11; [1731] (e) NR.sub.11R.sub.12; [1732] (f)
NHS(O).sub.2R.sub.11; [1733] (g) NHC(O)R.sub.11; [1734] (h)
NHC(O)OR.sub.11; [1735] (i) NH--C.dbd.(NH)NH.sub.2; [1736] (j)
NHC(O)NH.sub.2; [1737] (k) NHC(O)NHR.sub.11; [1738] (l)
NHC(O)NR.sub.11R.sub.12; [1739] (m) NC3-6cycloalkyl; [1740] (n)
C(O)NHR.sub.11; [1741] (o) C(O)NR.sub.11R.sub.12; [1742] (p)
SO.sub.2NHR.sub.11; [1743] (q) SO.sub.2NHC(O)R.sub.12; or [1744]
(r) SO.sub.2R.sub.11; [1745] R.sub.11 is selected from the group
consisting of: [1746] (a) hydrogen, [1747] (b) C.sub.3-6cycloalkyl,
which is optionally substituted with aryl, heteroaryl or one to
five halo; [1748] (c) C.sub.1-6 alkyl, which is optionally
substituted with aryl, heteroaryl, or one to five halo; [1749] (d)
Aryl, which is optionally substituted with one to five halo; [1750]
(e) Heteroaryl (wherein the heteroaryl has 5 or 6 members in which
1, 2, 3, or 4 of the atoms is a heteroatom selected from N, S and
O), which is optionally substituted with one to five halo; [1751]
R.sub.12 is selected from the group consisting of: [1752] (a)
hydrogen, [1753] (b) C.sub.1-6alkyl, which is optionally
substituted with aryl, heteroaryl or one to five halo; [1754] (c)
C.sub.3-6cycloalkyl, which is optionally substituted with aryl,
heteroaryl or one to five halo; [1755] (d) Aryl, which is
optionally substituted with one to five halo; [1756] (e) Heteroaryl
(wherein the heteroaryl has 5 or 6 members in which 1, 2, 3, or 4
of the atoms is a heteroatom selected from N, S and O), which is
optionally substituted with one to five halo; [1757] A is absent or
is selected from the group consisting of: aryl or heteroaryl
(wherein the heteroaryl is a monocyclic ring of 5 or 6 atoms or a
bicyclic ring of 9 or 10 atoms in which 1, 2, 3, or 4 of the atoms
is a heteroatom selected from N, S and O), wherein said aryl or
heteroaryl is optionally substituted with one or more substituents
selected from halo, (C.sub.1-3)alkyl, --C(O)OH, CF.sub.3,
SO.sub.2(C.sub.1-3)alkyl, SO.sub.2N(C.sub.1-3)alkyl,
SO.sub.2NHC(O)--(C.sub.1-3)alkyl or N(CH.sub.3).sub.2; [1758] L is
absent or is selected from the group consisting of:
--(CH.sub.2)k-W--, --Z--(CH.sub.2)k-, C.ident.C--,
--C.sub.1-6alkyl-, --C.sub.3-6cycloalkyl- and --C.sub.2-5alkene-,
wherein the alkene is optionally substituted with one or more
groups selected from C.sub.1-6alkyl or C.sub.1-6cycloalkyl; [1759]
W is selected from the group consisting of: O, NH, NC.sub.1-6alkyl
and S(O)m, with the proviso that when W is O, S(O)m, NH or
NC.sub.1-6alkyl and simultaneously A is absent then R.sub.10 is
CO.sub.2R.sub.11, COR.sub.11, CONHR.sub.11 or CONR.sub.11R.sub.12;
[1760] k=0, 1, 2, 3, 4, or 5; [1761] m=0, 1, or 2; and [1762] n=0,
1, 2, or 3.
[1763] In a preferred embodiment, the JAK-2 inhibitor is
((R)-7-(2-aminopyrimidin-5-yl)-1-((1-cyclopropyl-2,2,2-trifluoroethyl)ami-
no)-5H-pyrido[4,3-b]indole-4-carboxamide, which is also named
7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]ami-
no}-5H-pyrido[4,3-b]indole-4-carboxamide. In a preferred
embodiment, the JAK-2 inhibitor is a compound of Formula
(LXII):
##STR00158## [1764] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. The preparation of this
compound is known to those of ordinary skill in the art, and is
described in Lim, et al., Discovery of
1-amino-5H-pyrido[4,3-b]indol-4-carboxamide inhibitors of Janus
kinase-2 (JAK2) for the treatment of myeloproliferative disorders,
J. Med. Chem. 2011, 54, 7334-7349, the disclosure of which is
incorporated by reference herein.
[1765] In an embodiment, the JAK-2 inhibitor is is a compound
selected from the JAK-2 inhibitors disclosed in U.S. Pat. No.
8,518,964 or U.S. Patent Application Publication Nos. 2010/0048551
A1, the disclosures of which are incorporated by reference
herein.
Pharmaceutical Compositions
[1766] In one embodiment, the invention provides a pharmaceutical
composition for use in the treatment of the diseases and conditions
described herein. In a preferred embodiment, the invention provides
pharmaceutical compositions, including those described below, for
use in the treatment of a hyperproliferative disease. In a
preferred embodiment, the invention provides pharmaceutical
compositions, including those described below, for use in the
treatment of cancer.
[1767] In some embodiments, the invention provides pharmaceutical
compositions for treating solid tumor cancers, lymphomas and
leukemia.
[1768] In preferred embodiments, the invention provides a
composition comprising therapeutically effective amounts of (1) a
JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; and (2) a BTK inhibitor or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, for use in the treatment of cancer. This
composition is typically a pharmaceutical composition.
[1769] In preferred embodiments, the invention provides a
composition comprising therapeutically effective amounts of (1) a
JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
This composition is typically a pharmaceutical composition.
[1770] In preferred embodiments, the invention provides a
composition comprising therapeutically effective amounts of (1) a
JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K-.delta. inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. This composition is typically a pharmaceutical
composition.
[1771] In preferred embodiments, the invention provides a
composition comprising therapeutically effective amounts of (1) a
JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) an anti-CD20 antibody selected from the
group consisting of rituximab, obinutuzumab, ofatumumab,
veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,
conjugates, variants, radioisotope-labeled complexes, and
biosimilars thereof. This composition is typically a pharmaceutical
composition.
[1772] In preferred embodiments, the invention provides a
composition comprising therapeutically effective amounts of (1) a
JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a PI3K inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
and (4) an anti-CD20 antibody selected from the group consisting of
rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,
ibritumomab, and fragments, derivatives, conjugates, variants,
radioisotope-labeled complexes, and biosimilars thereof. This
composition is typically a pharmaceutical composition.
[1773] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a PI3K-.delta. inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
and (4) an anti-CD20 antibody selected from the group consisting of
rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,
ibritumomab, and fragments, derivatives, conjugates, variants,
radioisotope-labeled complexes, and biosimilars thereof. This
composition is typically a pharmaceutical composition.
[1774] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a compound selected from the group
consisting of gemcitabine, albumin-bound paclitaxel, bendamustine,
fludarabine, cyclophosphamide, chlorambucil, an anticoagulant or
antiplatelet active pharmaceutical ingredient, or combinations
thereof. This composition is typically a pharmaceutical
composition.
[1775] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a PI3K inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
and (4) a compound selected from the group consisting of
gemcitabine, albumin-bound paclitaxel, bendamustine, fludarabine,
cyclophosphamide, chlorambucil, an anticoagulant or antiplatelet
active pharmaceutical ingredient, and combinations thereof. This
composition is typically a pharmaceutical composition.
[1776] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a PI3K-.delta. inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
and (4) a compound selected from the group consisting of
gemcitabine, albumin-bound paclitaxel, bendamustine, fludarabine,
cyclophosphamide, chlorambucil, an anticoagulant or antiplatelet
active pharmaceutical ingredient, and combinations thereof. This
composition is typically a pharmaceutical composition.
[1777] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, for use in the treatment of cancer; (3) an
anti-CD20 antibody selected from the group consisting of rituximab,
obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and
fragments, derivatives, conjugates, variants, radioisotope-labeled
complexes, biosimilars thereof, and combinations thereof; and (4) a
compound selected from the group consisting of gemcitabine,
albumin-bound paclitaxel, bendamustine, fludarabine,
cyclophosphamide, chlorambucil, an anticoagulant or antiplatelet
active pharmaceutical ingredient, and combinations thereof. This
composition is typically a pharmaceutical composition.
[1778] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a PI3K inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
(4) an anti-CD20 antibody selected from the group consisting of
rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,
ibritumomab, and fragments, derivatives, conjugates, variants,
radioisotope-labeled complexes, biosimilars thereof, and
combinations thereof; and (5) a compound selected from the group
consisting of gemcitabine, albumin-bound paclitaxel, bendamustine,
fludarabine, cyclophosphamide, chlorambucil, an anticoagulant or
antiplatelet active pharmaceutical ingredient, and combinations
thereof. This composition is typically a pharmaceutical
composition.
[1779] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a PI3K-.delta. inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
(4) an anti-CD20 antibody selected from the group consisting of
rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,
ibritumomab, and fragments, derivatives, conjugates, variants,
radioisotope-labeled complexes, and biosimilars thereof; and (5) a
compound selected from the group consisting of gemcitabine,
albumin-bound paclitaxel, bendamustine, fludarabine,
cyclophosphamide, chlorambucil, an anticoagulant or antiplatelet
active pharmaceutical ingredient, and combinations thereof. This
composition is typically a pharmaceutical composition.
[1780] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; and (2) a BTK inhibitor having the
structure:
##STR00159## [1781] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. This composition is
typically a pharmaceutical composition.
[1782] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor having the
structure:
##STR00160## [1783] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof and (3) a PI3K inhibitor or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. This composition is typically a pharmaceutical
composition.
[1784] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor having the
structure:
##STR00161## [1785] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; and (3) a PI3K-.delta.
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof. This composition is typically a
pharmaceutical composition.
[1786] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor having the
structure:
##STR00162## [1787] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; and (3) an anti-CD20
antibody selected from the group consisting of rituximab,
obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and
fragments, derivatives, conjugates, variants, radioisotope-labeled
complexes, and biosimilars thereof. This composition is typically a
pharmaceutical composition.
[1788] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor having the
structure:
##STR00163## [1789] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (3) a PI3K inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (4) an anti-CD20 antibody selected from the
group consisting of rituximab, obinutuzumab, ofatumumab,
veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,
conjugates, variants, radioisotope-labeled complexes, and
biosimilars thereof. This composition is typically a pharmaceutical
composition.
[1790] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor having the
structure:
##STR00164## [1791] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (3) a PI3K-.delta.
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; and (4) an anti-CD20 antibody
selected from the group consisting of rituximab, obinutuzumab,
ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,
derivatives, conjugates, variants, radioisotope-labeled complexes,
and biosimilars thereof. This composition is typically a
pharmaceutical composition.
[1792] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; and (2) a BTK inhibitor selected
from the group consisting of:
##STR00165## [1793] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof. This
composition is typically a pharmaceutical composition.
[1794] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor selected from
the group consisting of:
##STR00166## [1795] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof; and (3) a
PI3K inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof. This composition is
typically a pharmaceutical composition.
[1796] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor selected from
the group consisting of:
##STR00167## [1797] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof; and (3) a
PI3K-.delta. inhibitor or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof. This composition
is typically a pharmaceutical composition.
[1798] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor selected from
the group consisting of:
##STR00168## [1799] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof; and (3) an
anti-CD20 antibody selected from the group consisting of rituximab,
obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and
fragments, derivatives, conjugates, variants, radioisotope-labeled
complexes, and biosimilars thereof. This composition is typically a
pharmaceutical composition.
[1800] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor selected from
the group consisting of:
##STR00169## [1801] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof; (3) a PI3K
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; and (4) an anti-CD20 antibody
selected from the group consisting of rituximab, obinutuzumab,
ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,
derivatives, conjugates, variants, radioisotope-labeled complexes,
and biosimilars thereof. This composition is typically a
pharmaceutical composition.
[1802] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor selected from
the group consisting of:
##STR00170## [1803] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof; (3) a
PI3K-.delta. inhibitor or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof; and (4) an
anti-CD20 antibody selected from the group consisting of rituximab,
obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and
fragments, derivatives, conjugates, variants, radioisotope-labeled
complexes, and biosimilars thereof. This composition is typically a
pharmaceutical composition.
[1804] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor selected from the group consisting of ruxolitinib,
pacritinib, and pharmaceutically-acceptable salts, cocrystals,
hydrates, solvates, and prodrugs thereof; and (2) a BTK inhibitor
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug thereof. This composition is typically a pharmaceutical
composition.
[1805] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor selected from the group consisting of:
##STR00171## [1806] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof; and (2) a BTK
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof. This composition is typically a
pharmaceutical composition.
[1807] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor selected from the group consisting of ruxolitinib,
pacritinib, and pharmaceutically-acceptable salts, cocrystals,
hydrates, solvates, and prodrugs thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K-.delta. inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. This composition is typically a pharmaceutical
composition.
[1808] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor selected from the group consisting of:
##STR00172## [1809] and pharmaceutically-acceptable salts,
cocrystals, hydrates, solvates, and prodrugs thereof; (2) a BTK
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; and (3) a PI3K-.delta. inhibitor or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. This composition is typically a pharmaceutical
composition.
[1810] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor selected from the group consisting of ruxolitinib,
pacritinib, and pharmaceutically-acceptable salts, cocrystals,
hydrates, solvates, and prodrugs thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, for use in the treatment of cancer; and (3) an
anti-CD20 antibody selected from the group consisting of rituximab,
obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and
fragments, derivatives, conjugates, variants, radioisotope-labeled
complexes, and biosimilars thereof. This composition is typically a
pharmaceutical composition.
[1811] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor selected from the group consisting of ruxolitinib,
pacritinib, and pharmaceutically-acceptable salts, cocrystals,
hydrates, solvates, and prodrugs thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a PI3K inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
and (4) an anti-CD20 antibody selected from the group consisting of
rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,
ibritumomab, and fragments, derivatives, conjugates, variants,
radioisotope-labeled complexes, and biosimilars thereof. This
composition is typically a pharmaceutical composition.
[1812] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor selected from the group consisting of ruxolitinib,
pacritinib, and pharmaceutically-acceptable salts, cocrystals,
hydrates, solvates, or prodrugs thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a PI3K-.delta. inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
and (4) a therapeutically effective amount of an anti-CD20 antibody
selected from the group consisting of rituximab, obinutuzumab,
ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,
derivatives, conjugates, variants, radioisotope-labeled complexes,
and biosimilars thereof. This composition is typically a
pharmaceutical composition.
[1813] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K inhibitor selected from the group
consisting of:
##STR00173## ##STR00174## [1814] and pharmaceutically acceptable
salts, solvates, hydrates, cocrystals, and prodrugs thereof. This
composition is typically a pharmaceutical composition.
[1815] In some embodiments, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K-.delta. inhibitor selected from the
group consisting of:
##STR00175## ##STR00176## [1816] and pharmaceutically acceptable
salts, solvates, hydrates, cocrystals, and prodrugs thereof. This
composition is typically a pharmaceutical composition.
[1817] In one embodiment, the invention provides a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a PI3K-.delta. inhibitor selected from the
group consisting of:
##STR00177## ##STR00178## [1818] and pharmaceutically acceptable
salts, solvates, hydrates, cocrystals, and prodrugs thereof; and
(4) a therapeutically effective amount of an anti-CD20 antibody
selected from the group consisting of rituximab, obinutuzumab,
ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,
derivatives, conjugates, variants, radioisotope-labeled complexes,
and biosimilars thereof. This composition is typically a
pharmaceutical composition.
[1819] The pharmaceutical compositions are typically formulated to
provide a therapeutically effective amount of a combination as
described herein, i.e., a combination of a PI3K inhibitor,
including a PI3K-.gamma. or PI3K-.delta. inhibitor, a JAK-2
inhibitor, and/or a BTK inhibitor as the active ingredients, or
pharmaceutically acceptable salts, prodrugs, solvates, or hydrates
thereof. Where desired, the pharmaceutical compositions contain a
pharmaceutically acceptable salt and/or coordination complex of one
or more of the active ingredients. Typically, the pharmaceutical
compositions also comprise one or more pharmaceutically acceptable
excipients, carriers, including inert solid diluents and fillers,
diluents, including sterile aqueous solution and various organic
solvents, permeation enhancers, solubilizers and adjuvants.
[1820] The pharmaceutical compositions described above are
preferably for use in the treatment of the diseases and conditions
described below. In a preferred embodiment, the pharmaceutical
compositions are for use in the treatment of cancer. In preferred
embodiments, the pharmaceutical compositions are for use in
treating solid tumor cancers, lymphomas, and leukemias.
[1821] In a preferred embodiment, the pharmaceutical compositions
of the present invention are for use in the treatment of cancer. In
one embodiment, the pharmaceutical compositions of the present
invention are for use in the treatment of a cancer selected from
the group consisting of bladder cancer, squamous cell carcinoma
including head and neck cancer, pancreatic ductal adenocarcinoma
(PDA), pancreatic cancer, colon carcinoma, mammary carcinoma,
breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma,
lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian
cancer, acute myeloid leukemia, thymus cancer, brain cancer,
squamous cell cancer, skin cancer, eye cancer, retinoblastoma,
melanoma, intraocular melanoma, oral cavity and oropharyngeal
cancers, gastric cancer, stomach cancer, cervical cancer, renal
cancer, kidney cancer, liver cancer, ovarian cancer, esophageal
cancer, testicular cancer, gynecological cancer, thyroid cancer,
acquired immune deficiency syndrome (AIDS)-related cancers (e.g.,
lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma,
esophageal tumors, hematological neoplasms, non-small-cell lung
cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma,
esophagus tumor, follicle center lymphoma, head and neck tumor,
hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's
disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's
lymphoma, indolent non-Hodgkin's lymphoma, ovary tumor, pancreas
tumor, renal cell carcinoma, small-cell lung cancer, stage IV
melanoma, chronic lymphocytic leukemia, B-cell acute lymphoblastic
leukemia (ALL), mature B-cell ALL, follicular lymphoma, mantle cell
lymphoma, and Burkitt's lymphoma.
[1822] The pharmaceutical compositions are administered as a
combination of a JAK-2 inhibitor with a PI3K inhibitor, which may
be a PI3K-.gamma. or PI3K-.delta. inhibitor, and/or a BTK
inhibitor. Where desired, other active pharmaceutical ingredient(s)
may be mixed into a preparation or two or more components of the
combination may be formulated into separate preparations for use in
combination separately or at the same time. A kit containing the
components of the combination, formulated into separate
preparations for said use, in also provided by the invention.
[1823] In an embodiment, the molar ratio of the JAK-2 inhibitor to
the BTK inhibitor in the pharmaceutical compositions is in the
range from 10:1 to 1:10, preferably from 2.5:1 to 1:2.5, and more
preferably about 1:1. In an embodiment, the molar ratio of the
JAK-2 inhibitor to the PI3K inhibitor in the pharmaceutical
compositions is in the range from 10:1 to 1:10, preferably from
2.5:1 to 1:2.5, and more preferably about 1:1. In an embodiment,
the weight ratio of the JAK-2 inhibitor to the BTK inhibitor in the
pharmaceutical compositions is selected from the group consisting
of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1,
10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4,
1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16,
1:17, 1:18, 1:19, and 1:20. In an embodiment, the weight ratio of
the JAK-2 inhibitor to the PI3K inhibitor in the pharmaceutical
compositions is selected from the group consisting of 20:1, 19:1,
18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1,
7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7,
1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18,
1:19, and 1:20.
[1824] In some embodiments, the concentration of each of the PI3K,
JAK-2, and BTK inhibitors provided in the pharmaceutical
compositions of the invention is less than, for example, 100%, 90%,
80%, 70%, 60%,50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%,
13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%,
0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,
0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%,
0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,
0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v of
the pharmaceutical composition.
[1825] In some embodiments, the concentration of each of the PI3K,
JAK-2, and BTK inhibitors provided in the pharmaceutical
compositions of the invention is greater than 90%, 80%, 70%, 60%,
50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%,
18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%,
15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%,
13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%,
11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%,
8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25%
6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%,
3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%,
0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%,
0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,
0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,
0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v of
the pharmaceutical composition.
[1826] In some embodiments, the concentration of each of the PI3K,
JAK-2 and BTK inhibitors provided in the pharmaceutical
compositions is in the range from about 0.0001% to about 50%, about
0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about
29%, about 0.03% to about 28%, about 0.04% to about 27%, about
0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about
24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1%
to about 21%, about 0.2% to about 20%, about 0.3% to about 19%,
about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to
about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about
0.9% to about 12% or about 1% to about 10% w/w, w/v or v/v of the
pharmaceutical composition.
[1827] In some embodiments, the concentration of each of the PI3K,
JAK-2, and BTK inhibitors provided in the pharmaceutical
compositions is in the range from about 0.001% to about 10%, about
0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about
4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06%
to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%,
about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v or v/v
of the pharmaceutical composition.
[1828] In some embodiments, the amount of each of the PI3K, JAK-2,
and BTK inhibitors provided in the pharmaceutical compositions is
equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0
g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g,
2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g,
0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g,
0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04
g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g,
0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g,
0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or
0.0001 g.
[1829] In some embodiments, the amount of each of the PI3K, JAK-2,
and BTK inhibitors provided in the pharmaceutical compositions is
more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006
g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025
g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006
g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095
g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045
g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085
g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g,
0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g,
0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g,
5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10
g.
[1830] Each of the PI3K, JAK-2, and BTK inhibitors according to the
invention is effective over a wide dosage range. For example, in
the treatment of adult humans, dosages independently range from
0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and
from 5 to 40 mg per day are examples of dosages that may be used.
The exact dosage will depend upon the route of administration, the
form in which the compound is administered, the gender and age of
the subject to be treated, the body weight of the subject to be
treated, and the preference and experience of the attending
physician.
[1831] In a preferred embodiment, the pharmaceutical compositions
of the present invention are for use in the treatment of cancer. In
a preferred embodiment, the pharmaceutical compositions of the
present invention are for use in the treatment of a cancer selected
from the group consisting of bladder cancer, squamous cell
carcinoma including head and neck cancer, pancreatic ductal
adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary
carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell
carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal
cancer, ovarian cancer, acute myeloid leukemia, thymus cancer,
brain cancer, squamous cell cancer, skin cancer, eye cancer,
retinoblastoma, melanoma, intraocular melanoma, oral cavity and
oropharyngeal cancers, gastric cancer, stomach cancer, cervical
cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer,
esophageal cancer, testicular cancer, gynecological cancer, thyroid
cancer, acquired immune deficiency syndrome (AIDS)-related cancers
(e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer,
glioblastoma, esophageal tumors, hematological neoplasms,
non-small-cell lung cancer, chronic myelocytic leukemia, diffuse
large B-cell lymphoma, esophagus tumor, follicle center lymphoma,
head and neck tumor, hepatitis C virus infection, hepatocellular
carcinoma, Hodgkin's disease, metastatic colon cancer, multiple
myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma,
ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung
cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell
acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular
lymphoma, mantle cell lymphoma, and Burkitt's lymphoma.
[1832] Described below are non-limiting pharmaceutical compositions
and methods for preparing the same.
Pharmaceutical Compositions for Oral Administration
[1833] In preferred embodiments, the invention provides a
pharmaceutical composition for oral administration containing the
combination of a PI3K, JAK-2, and BTK inhibitor, and a
pharmaceutical excipient suitable for oral administration.
[1834] In preferred embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing: (i)
an effective amount of each of a PI3K, JAK-2, and BTK inhibitor in
combination and (ii) a pharmaceutical excipient suitable for oral
administration. In some embodiments, the composition further
contains (iii) an effective amount of a fourth active
pharmaceutical ingredient.
[1835] In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing: (i)
an effective amount of a JAK-2 inhibitor in combination with a PI3K
inhibitor and (ii) a pharmaceutical excipient suitable for oral
administration. In selected embodiments, the composition further
contains (iii) an effective amount of a third active pharmaceutical
ingredient.
[1836] In preferred embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing: (i)
an effective amount of a JAK-2 inhibitor in combination with a BTK
inhibitor and (ii) a pharmaceutical excipient suitable for oral
administration. In selected embodiments, the composition further
contains (iii) an effective amount of a third active pharmaceutical
ingredient.
[1837] In some embodiments, the pharmaceutical composition may be a
liquid pharmaceutical composition suitable for oral consumption.
Pharmaceutical compositions of the invention suitable for oral
administration can be presented as discrete dosage forms, such as
capsules, cachets, or tablets, or liquids or aerosol sprays each
containing a predetermined amount of an active ingredient as a
powder or in granules, a solution, or a suspension in an aqueous or
non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil
liquid emulsion. Such dosage forms can be prepared by any of the
methods of pharmacy, but all methods include the step of bringing
the active ingredient(s) into association with the carrier, which
constitutes one or more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredient(s) with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation. For example, a tablet can be prepared by
compression or molding, optionally with one or more accessory
ingredients. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as powder or granules, optionally mixed with an excipient such as,
but not limited to, a binder, a lubricant, an inert diluent, and/or
a surface active or dispersing agent. Molded tablets can be made by
molding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent.
[1838] The invention further encompasses anhydrous pharmaceutical
compositions and dosage forms since water can facilitate the
degradation of some compounds. For example, water may be added
(e.g., 5%) in the pharmaceutical arts as a means of simulating
long-term storage in order to determine characteristics such as
shelf-life or the stability of formulations over time. Anhydrous
pharmaceutical compositions and dosage forms of the invention can
be prepared using anhydrous or low moisture containing ingredients
and low moisture or low humidity conditions. Pharmaceutical
compositions and dosage forms of the invention which contain
lactose can be made anhydrous if substantial contact with moisture
and/or humidity during manufacturing, packaging, and/or storage is
expected. An anhydrous pharmaceutical composition may be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions may be packaged using materials
known to prevent exposure to water such that they can be included
in suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastic or the
like, unit dose containers, blister packs, and strip packs.
[1839] Each of the PI3K, JAK-2, and BTK inhibitors as active
ingredients can be combined in an intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier can take a wide variety of
forms depending on the form of preparation desired for
administration. In preparing the compositions for an oral dosage
form, any of the usual pharmaceutical media can be employed as
carriers, such as, for example, water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents, and the like in
the case of oral liquid preparations (such as suspensions,
solutions, and elixirs) or aerosols; or carriers such as starches,
sugars, micro-crystalline cellulose, diluents, granulating agents,
lubricants, binders, and disintegrating agents can be used in the
case of oral solid preparations, in some embodiments without
employing the use of lactose. For example, suitable carriers
include powders, capsules, and tablets, with the solid oral
preparations. If desired, tablets can be coated by standard aqueous
or nonaqueous techniques.
[1840] Binders suitable for use in pharmaceutical compositions and
dosage forms include, but are not limited to, corn starch, potato
starch, or other starches, gelatin, natural and synthetic gums such
as acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl
cellulose, cellulose acetate, carboxymethyl cellulose calcium,
sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl
cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,
microcrystalline cellulose, and mixtures thereof.
[1841] Examples of suitable fillers for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof.
[1842] Disintegrants may be used in the compositions of the
invention to provide tablets that disintegrate when exposed to an
aqueous environment. Too much of a disintegrant may produce tablets
which disintegrate in the bottle. Too little may be insufficient
for disintegration to occur, thus altering the rate and extent of
release of the active ingredients from the dosage form. Thus, a
sufficient amount of disintegrant that is neither too little nor
too much to detrimentally alter the release of the active
ingredient(s) may be used to form the dosage forms of the compounds
disclosed herein. The amount of disintegrant used may vary based
upon the type of formulation and mode of administration, and may be
readily discernible to those of ordinary skill in the art. About
0.5 to about 15 weight percent of disintegrant, or about 1 to about
5 weight percent of disintegrant, may be used in the pharmaceutical
composition. Disintegrants that can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums or mixtures
thereof.
[1843] Lubricants which can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, calcium stearate, magnesium stearate, mineral oil,
light mineral oil, glycerin, sorbitol, mannitol, polyethylene
glycol, other glycols, stearic acid, sodium lauryl sulfate, talc,
hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil, and soybean oil),
zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures
thereof. Additional lubricants include, for example, a syloid
silica gel, a coagulated aerosol of synthetic silica, or mixtures
thereof. A lubricant can optionally be added, in an amount of less
than about 1 weight percent of the pharmaceutical composition.
[1844] When aqueous suspensions and/or elixirs are desired for oral
administration, the essential active ingredient therein may be
combined with various sweetening or flavoring agents, coloring
matter or dyes and, if so desired, emulsifying and/or suspending
agents, together with such diluents as water, ethanol, propylene
glycol, glycerin and various combinations thereof.
[1845] The tablets can be uncoated or coated by known techniques to
delay disintegration and absorption in the gastrointestinal tract
and thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate can be employed. Formulations for oral use can
also be presented as hard gelatin capsules wherein the active
ingredient is mixed with an inert solid diluent, for example,
calcium carbonate, calcium phosphate or kaolin, or as soft gelatin
capsules wherein the active ingredient is mixed with water or an
oil medium, for example, peanut oil, liquid paraffin or olive
oil.
[1846] Surfactants which can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, hydrophilic surfactants, lipophilic surfactants, and
mixtures thereof. That is, a mixture of hydrophilic surfactants may
be employed, a mixture of lipophilic surfactants may be employed,
or a mixture of at least one hydrophilic surfactant and at least
one lipophilic surfactant may be employed.
[1847] A suitable hydrophilic surfactant may generally have an HLB
value of at least 10, while suitable lipophilic surfactants may
generally have an HLB value of or less than about 10. An empirical
parameter used to characterize the relative hydrophilicity and
hydrophobicity of non-ionic amphiphilic compounds is the
hydrophilic-lipophilic balance ("HLB" value). Surfactants with
lower HLB values are more lipophilic or hydrophobic, and have
greater solubility in oils, while surfactants with higher HLB
values are more hydrophilic, and have greater solubility in aqueous
solutions. Hydrophilic surfactants are generally considered to be
those compounds having an HLB value greater than about 10, as well
as anionic, cationic, or zwitterionic compounds for which the HLB
scale is not generally applicable. Similarly, lipophilic (i.e.,
hydrophobic) surfactants are compounds having an HLB value equal to
or less than about 10. However, HLB value of a surfactant is merely
a rough guide generally used to enable formulation of industrial,
pharmaceutical and cosmetic emulsions.
[1848] Hydrophilic surfactants may be either ionic or non-ionic.
Suitable ionic surfactants include, but are not limited to,
alkylammonium salts; fusidic acid salts; fatty acid derivatives of
amino acids, oligopeptides, and polypeptides; glyceride derivatives
of amino acids, oligopeptides, and polypeptides; lecithins and
hydrogenated lecithins; lysolecithins and hydrogenated
lysolecithins; phospholipids and derivatives thereof;
lysophospholipids and derivatives thereof; carnitine fatty acid
ester salts; salts of alkylsulfates; fatty acid salts; sodium
docusate; acylactylates; mono- and di-acetylated tartaric acid
esters of mono- and di-glycerides; succinylated mono- and
di-glycerides; citric acid esters of mono- and di-glycerides; and
mixtures thereof.
[1849] Within the aforementioned group, ionic surfactants include,
by way of example: lecithins, lysolecithin, phospholipids,
lysophospholipids and derivatives thereof; carnitine fatty acid
ester salts; salts of alkylsulfates; fatty acid salts; sodium
docusate; acylactylates; mono- and di-acetylated tartaric acid
esters of mono- and di-glycerides; succinylated mono- and
di-glycerides; citric acid esters of mono- and di-glycerides; and
mixtures thereof.
[1850] Ionic surfactants may be the ionized forms of lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylglycerol, phosphatidic acid, phosphatidylserine,
lysophosphatidylcholine, lysophosphatidylethanolamine,
lysophosphatidylglycerol, lysophosphatidic acid,
lysophosphatidylserine, PEG-phosphatidylethanolamine,
PVP-phosphatidylethanolamine, lactylic esters of fatty acids,
stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
cholylsarcosine, caproate, caprylate, caprate, laurate, myristate,
palmitate, oleate, ricinoleate, linoleate, linolenate, stearate,
lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines,
palmitoyl carnitines, myristoyl carnitines, and salts and mixtures
thereof.
[1851] Hydrophilic non-ionic surfactants may include, but not
limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides;
lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as
polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such
as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol
fatty acid esters such as polyethylene glycol fatty acids
monoesters and polyethylene glycol fatty acids diesters;
polyethylene glycol glycerol fatty acid esters; polyglycerol fatty
acid esters; polyoxyalkylene sorbitan fatty acid esters such as
polyethylene glycol sorbitan fatty acid esters; hydrophilic
transesterification products of a polyol with at least one member
of the group consisting of glycerides, vegetable oils, hydrogenated
vegetable oils, fatty acids, and sterols; polyoxyethylene sterols,
derivatives, and analogues thereof; polyoxyethylated vitamins and
derivatives thereof; polyoxyethylene-polyoxypropylene block
copolymers; and mixtures thereof; polyethylene glycol sorbitan
fatty acid esters and hydrophilic transesterification products of a
polyol with at least one member of the group consisting of
triglycerides, vegetable oils, and hydrogenated vegetable oils. The
polyol may be glycerol, ethylene glycol, polyethylene glycol,
sorbitol, propylene glycol, pentaerythritol, or a saccharide.
[1852] Other hydrophilic-non-ionic surfactants include, without
limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32
laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20
oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400
oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate,
PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate,
PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,
PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl
oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40
palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil,
PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor
oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6
caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,
polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol,
PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate,
PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9
lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl
ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24
cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose
monostearate, sucrose monolaurate, sucrose monopalmitate, PEG
10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and
poloxamers.
[1853] Suitable lipophilic surfactants include, by way of example
only: fatty alcohols; glycerol fatty acid esters; acetylated
glycerol fatty acid esters; lower alcohol fatty acids esters;
propylene glycol fatty acid esters; sorbitan fatty acid esters;
polyethylene glycol sorbitan fatty acid esters; sterols and sterol
derivatives; polyoxyethylated sterols and sterol derivatives;
polyethylene glycol alkyl ethers; sugar esters; sugar ethers;
lactic acid derivatives of mono- and di-glycerides; hydrophobic
transesterification products of a polyol with at least one member
of the group consisting of glycerides, vegetable oils, hydrogenated
vegetable oils, fatty acids and sterols; oil-soluble
vitamins/vitamin derivatives; and mixtures thereof. Within this
group, preferred lipophilic surfactants include glycerol fatty acid
esters, propylene glycol fatty acid esters, and mixtures thereof,
or are hydrophobic transesterification products of a polyol with at
least one member of the group consisting of vegetable oils,
hydrogenated vegetable oils, and triglycerides.
[1854] In an embodiment, the composition may include a solubilizer
to ensure good solubilization and/or dissolution of the compound of
the present invention and to minimize precipitation of the compound
of the present invention. This can be especially important for
compositions for non-oral use--e.g., compositions for injection. A
solubilizer may also be added to increase the solubility of the
hydrophilic drug and/or other components, such as surfactants, or
to maintain the composition as a stable or homogeneous solution or
dispersion.
[1855] Examples of suitable solubilizers include, but are not
limited to, the following: alcohols and polyols, such as ethanol,
isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene
glycol, butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl
methylcellulose and other cellulose derivatives, cyclodextrins and
cyclodextrin derivatives; ethers of polyethylene glycols having an
average molecular weight of about 200 to about 6000, such as
tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG;
amides and other nitrogen-containing compounds such as
2-pyrrolidone, 2-piperidone, .epsilon.-caprolactam,
N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,
N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone;
esters such as ethyl propionate, tributylcitrate, acetyl
triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl
oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene
glycol monoacetate, propylene glycol diacetate,
.epsilon.-caprolactone and isomers thereof, .delta.-valerolactone
and isomers thereof, .beta.-butyrolactone and isomers thereof; and
other solubilizers known in the art, such as dimethyl acetamide,
dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin,
diethylene glycol monoethyl ether, and water.
[1856] Mixtures of solubilizers may also be used. Examples include,
but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl
caprylate, dimethylacetamide, N-methylpyrrolidone,
N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl
methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene
glycol 200-100, glycofurol, transcutol, propylene glycol, and
dimethyl isosorbide. Particularly preferred solubilizers include
sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol
and propylene glycol.
[1857] The amount of solubilizer that can be included is not
particularly limited. The amount of a given solubilizer may be
limited to a bioacceptable amount, which may be readily determined
by one of skill in the art. In some circumstances, it may be
advantageous to include amounts of solubilizers far in excess of
bioacceptable amounts, for example to maximize the concentration of
the drug, with excess solubilizer removed prior to providing the
composition to a patient using conventional techniques, such as
distillation or evaporation. Thus, if present, the solubilizer can
be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by
weight, based on the combined weight of the drug, and other
excipients. If desired, very small amounts of solubilizer may also
be used, such as 5%, 2%, 1% or even less. Typically, the
solubilizer may be present in an amount of about 1% to about 100%,
more typically about 5% to about 25% by weight.
[1858] The composition can further include one or more
pharmaceutically acceptable additives and excipients. Such
additives and excipients include, without limitation, detackifiers,
anti-foaming agents, buffering agents, polymers, antioxidants,
preservatives, chelating agents, viscomodulators, tonicifiers,
flavorants, colorants, odorants, opacifiers, suspending agents,
binders, fillers, plasticizers, lubricants, and mixtures
thereof.
[1859] In addition, an acid or a base may be incorporated into the
composition to facilitate processing, to enhance stability, or for
other reasons. Examples of pharmaceutically acceptable bases
include amino acids, amino acid esters, ammonium hydroxide,
potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,
aluminum hydroxide, calcium carbonate, magnesium hydroxide,
magnesium aluminum silicate, synthetic aluminum silicate, synthetic
hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine,
ethanolamine, ethylenediamine, triethanolamine, triethylamine,
triisopropanolamine, trimethylamine,
tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable
are bases that are salts of a pharmaceutically acceptable acid,
such as acetic acid, acrylic acid, adipic acid, alginic acid,
alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid,
boric acid, butyric acid, carbonic acid, citric acid, fatty acids,
formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid,
isoascorbic acid, lactic acid, maleic acid, oxalic acid,
para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic
acid, salicylic acid, stearic acid, succinic acid, tannic acid,
tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid,
and the like. Salts of polyprotic acids, such as sodium phosphate,
disodium hydrogen phosphate, and sodium dihydrogen phosphate can
also be used. When the base is a salt, the cation can be any
convenient and pharmaceutically acceptable cation, such as
ammonium, alkali metals and alkaline earth metals. Example may
include, but not limited to, sodium, potassium, lithium, magnesium,
calcium and ammonium.
[1860] Suitable acids are pharmaceutically acceptable organic or
inorganic acids. Examples of suitable inorganic acids include
hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,
nitric acid, boric acid, phosphoric acid, and the like. Examples of
suitable organic acids include acetic acid, acrylic acid, adipic
acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic
acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric
acid, fatty acids, formic acid, fumaric acid, gluconic acid,
hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic
acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic
acid, propionic acid, p-toluenesulfonic acid, salicylic acid,
stearic acid, succinic acid, tannic acid, tartaric acid,
thioglycolic acid, toluenesulfonic acid and uric acid.
Pharmaceutical Compositions for Injection
[1861] In preferred embodiments, the invention provides a
pharmaceutical composition for injection containing the combination
of the PI3K, JAK-2, and BTK inhibitors, most preferably a
combination of the JAK-2 and BTK inhibitors, and a pharmaceutical
excipient suitable for injection. Components and amounts of agents
in the compositions are as described herein.
[1862] The forms in which the compositions of the present invention
may be incorporated for administration by injection include aqueous
or oil suspensions, or emulsions, with sesame oil, corn oil,
cottonseed oil, or peanut oil, as well as elixirs, mannitol,
dextrose, or a sterile aqueous solution, and similar pharmaceutical
vehicles.
[1863] Aqueous solutions in saline are also conventionally used for
injection. Ethanol, glycerol, propylene glycol and liquid
polyethylene glycol (and suitable mixtures thereof), cyclodextrin
derivatives, and vegetable oils may also be employed. The proper
fluidity can be maintained, for example, by the use of a coating,
such as lecithin, for the maintenance of the required particle size
in the case of dispersion and by the use of surfactants. The
prevention of the action of microorganisms can be brought about by
various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid and thimerosal.
[1864] Sterile injectable solutions are prepared by incorporating
the combination of the PI3K, JAK-2, and BTK inhibitors in the
required amounts in the appropriate solvent with various other
ingredients as enumerated above, as required, followed by filtered
sterilization. Generally, dispersions are prepared by incorporating
the various sterilized active ingredients into a sterile vehicle
which contains the basic dispersion medium and the required other
ingredients from those enumerated above. In the case of sterile
powders for the preparation of sterile injectable solutions,
certain desirable methods of preparation are vacuum-drying and
freeze-drying techniques which yield a powder of the active
ingredient plus any additional desired ingredient from a previously
sterile-filtered solution thereof.
Pharmaceutical Compositions for Topical Delivery
[1865] In preferred embodiments, the invention provides a
pharmaceutical composition for transdermal delivery containing the
combination of the PI3K, JAK-2, and BTK inhibitors, most preferably
a combination of the JAK-2 and BTK inhibitors, and a pharmaceutical
excipient suitable for transdermal delivery.
[1866] Compositions of the present invention can be formulated into
preparations in solid, semi-solid, or liquid forms suitable for
local or topical administration, such as gels, water soluble
jellies, creams, lotions, suspensions, foams, powders, slurries,
ointments, solutions, oils, pastes, suppositories, sprays,
emulsions, saline solutions, dimethylsulfoxide (DMSO)-based
solutions. In general, carriers with higher densities are capable
of providing an area with a prolonged exposure to the active
ingredients. In contrast, a solution formulation may provide more
immediate exposure of the active ingredient to the chosen area.
[1867] The pharmaceutical compositions also may comprise suitable
solid or gel phase carriers or excipients, which are compounds that
allow increased penetration of, or assist in the delivery of,
therapeutic molecules across the stratum corneum permeability
barrier of the skin. There are many of these penetration-enhancing
molecules known to those trained in the art of topical formulation.
Examples of such carriers and excipients include, but are not
limited to, humectants (e.g., urea), glycols (e.g., propylene
glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid),
surfactants (e.g., isopropyl myristate and sodium lauryl sulfate),
pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g.,
menthol), amines, amides, alkanes, alkanols, water, calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[1868] Another exemplary formulation for use in the methods of the
present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or
discontinuous infusion of the combination of the PI3K, JAK-2, and
BTK inhibitors in controlled amounts, either with or without
another active pharmaceutical ingredient.
[1869] The construction and use of transdermal patches for the
delivery of pharmaceutical agents is well known in the art. See,
e.g., U.S. Pat. Nos. 5,023,252; 4,992,445 and 5,001,139. Such
patches may be constructed for continuous, pulsatile, or on demand
delivery of pharmaceutical agents.
Pharmaceutical Compositions for Inhalation
[1870] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. Preferably the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions in preferably
pharmaceutically acceptable solvents may be nebulized by use of
inert gases. Nebulized solutions may be inhaled directly from the
nebulizing device or the nebulizing device may be attached to a
face mask tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions may be
administered, preferably orally or nasally, from devices that
deliver the formulation in an appropriate manner. Dry powder
inhalers may also be used to provide inhaled delivery of the
compositions.
Other Pharmaceutical Compositions
[1871] Pharmaceutical compositions may also be prepared from
compositions described herein and one or more pharmaceutically
acceptable excipients suitable for sublingual, buccal, rectal,
intraosseous, intraocular, intranasal, epidural, or intraspinal
administration. Preparations for such pharmaceutical compositions
are well-known in the art. See, e.g., Anderson, Philip O.; Knoben,
James E.; Troutman, William G, eds., Handbook of Clinical Drug
Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds.,
Principles of Drug Action, Third Edition, Churchill Livingston,
N.Y., 1990, each of which is incorporated by reference herein in
its entirety.
[1872] Administration of the combination of the PI3K, JAK-2, and
BTK inhibitors or pharmaceutical composition of these compounds can
be effected by any method that enables delivery of the compounds to
the site of action. These methods include oral routes,
intraduodenal routes, parenteral injection (including intravenous,
intraarterial, subcutaneous, intramuscular, intravascular,
intraperitoneal or infusion), topical (e.g., transdermal
application), rectal administration, via local delivery by catheter
or stent or through inhalation. The combination of compounds can
also be administered intraadiposally or intrathecally.
[1873] The compositions of the invention may also be delivered via
an impregnated or coated device such as a stent, for example, or an
artery-inserted cylindrical polymer. Such a method of
administration may, for example, aid in the prevention or
amelioration of restenosis following procedures such as balloon
angioplasty. Without being bound by theory, compounds of the
invention may slow or inhibit the migration and proliferation of
smooth muscle cells in the arterial wall which contribute to
restenosis. A compound of the invention may be administered, for
example, by local delivery from the struts of a stent, from a stent
graft, from grafts, or from the cover or sheath of a stent. In some
embodiments, a compound of the invention is admixed with a matrix.
Such a matrix may be a polymeric matrix, and may serve to bond the
compound to the stent. Polymeric matrices suitable for such use,
include, for example, lactone-based polyesters or copolyesters such
as polylactide, polycaprolactonglycolide, polyorthoesters,
polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes,
poly(ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane,
poly(ethylene-vinylacetate), acrylate-based polymers or copolymers
(e.g., polyhydroxyethyl methylmethacrylate, polyvinyl
pyrrolidinone), fluorinated polymers such as
polytetrafluoroethylene and cellulose esters. Suitable matrices may
be nondegrading or may degrade with time, releasing the compound or
compounds. The combination of the JAK-2, PI3K, and/or BTK
inhibitors may be applied to the surface of the stent by various
methods such as dip/spin coating, spray coating, dip-coating,
and/or brush-coating. The compounds may be applied in a solvent and
the solvent may be allowed to evaporate, thus forming a layer of
compound onto the stent. Alternatively, the compound may be located
in the body of the stent or graft, for example in microchannels or
micropores. When implanted, the compound diffuses out of the body
of the stent to contact the arterial wall. Such stents may be
prepared by dipping a stent manufactured to contain such micropores
or microchannels into a solution of the compound of the invention
in a suitable solvent, followed by evaporation of the solvent.
Excess drug on the surface of the stent may be removed via an
additional brief solvent wash. In yet other embodiments, compounds
of the invention may be covalently linked to a stent or graft. A
covalent linker may be used which degrades in vivo, leading to the
release of the compound of the invention. Any bio-labile linkage
may be used for such a purpose, such as ester, amide or anhydride
linkages. The combination of the PI3K, JAK-2, and BTK inhibitors
may additionally be administered intravascularly from a balloon
used during angioplasty. Extravascular administration of the
combination of the PI3K, JAK-2, and BTK inhibitors via the pericard
or via advential application of formulations of the invention may
also be performed to decrease restenosis.
[1874] Exemplary parenteral administration forms include solutions
or suspensions of active compound in sterile aqueous solutions, for
example, aqueous propylene glycol or dextrose solutions. Such
dosage forms can be suitably buffered, if desired.
[1875] The invention also provides kits. The kits include each of
the PI3K, JAK-2, and BTK inhibitors, either alone or in combination
in suitable packaging, and written material that can include
instructions for use, discussion of clinical studies and listing of
side effects. Such kits may also include information, such as
scientific literature references, package insert materials,
clinical trial results, and/or summaries of these and the like,
which indicate or establish the activities and/or advantages of the
composition, and/or which describe dosing, administration, side
effects, drug interactions, or other information useful to the
health care provider. Such information may be based on the results
of various studies, for example, studies using experimental animals
involving in vivo models and studies based on human clinical
trials. The kit may further contain another active pharmaceutical
ingredient. In selected embodiments, the PI3K, JAK-2, and BTK
inhibitors and another active pharmaceutical ingredient are
provided as separate compositions in separate containers within the
kit. In selected embodiments, the PI3K, JAK-2, and BTK inhibitors
and the agent are provided as a single composition within a
container in the kit. Suitable packaging and additional articles
for use (e.g., measuring cup for liquid preparations, foil wrapping
to minimize exposure to air, and the like) are known in the art and
may be included in the kit. Kits described herein can be provided,
marketed and/or promoted to health providers, including physicians,
nurses, pharmacists, formulary officials, and the like. Kits may
also, in selected embodiments, be marketed directly to the
consumer.
[1876] In some embodiments, the invention provides a kit comprising
(1) a composition comprising a therapeutically effective amount of
a JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; and (2) a composition
comprising a therapeutically effective amount of a BTK inhibitor or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof. These compositions are typically pharmaceutical
compositions. The kit is for co-administration of the JAK-2 and the
BTK inhibitors, either simultaneously or separately.
[1877] In some embodiments, the invention provides a kit comprising
(1) a composition comprising a therapeutically effective amount of
a JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (2) a composition
comprising a therapeutically effective amount of a BTK inhibitor or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a composition comprising a therapeutically
effective amount of a PI3K inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
These compositions are typically pharmaceutical compositions. The
kit is for co-administration of the JAK-2, the BTK, and the PI3K
inhibitors, either simultaneously or separately.
[1878] In some embodiments, the invention provides a kit comprising
(1) a composition comprising a therapeutically effective amount of
a JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (2) a composition
comprising a therapeutically effective amount of a BTK inhibitor or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a composition comprising a therapeutically
effective amount of a PI3K-.delta. inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
These compositions are typically pharmaceutical compositions. The
kit is for co-administration of the JAK-2, the BTK, and the
PI3K-.delta. inhibitors, either simultaneously or separately.
[1879] In some embodiments, the invention provides a kit comprising
(1) a composition comprising a therapeutically effective amount of
JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (2) a composition
comprising a therapeutically effective amount of a BTK inhibitor or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a composition comprising a therapeutically
effective amount of an anti-CD20 antibody selected from the group
consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,
tositumomab, ibritumomab, and fragments, derivatives, conjugates,
variants, radioisotope-labeled complexes, and biosimilars thereof.
These compositions are typically pharmaceutical compositions. The
kit is for co-administration of the JAK-2 inhibitor, the BTK
inhibitor, and the anti-CD20 antibody, either simultaneously or
separately.
[1880] In some embodiments, the invention provides a kit
comprising, (1) a composition comprising a therapeutically
effective amount of a JAK-2 inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
(2) a composition comprising a therapeutically effective amount of
a BTK inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (3) a composition
comprising a therapeutically effective amount of a PI3K inhibitor
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug thereof; and (4) a composition comprising a
therapeutically effective amount of an anti-CD20 antibody selected
from the group consisting of rituximab, obinutuzumab, ofatumumab,
veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,
conjugates, variants, radioisotope-labeled complexes, and
biosimilars thereof. These compositions are typically
pharmaceutical compositions. The kit is for co-administration of
the JAK-2 inhibitor, the BTK inhibitor, and the anti-CD20 antibody,
either simultaneously or separately.
[1881] In some embodiments, the invention provides a kit
comprising, (1) a composition comprising a therapeutically
effective amount of a JAK-2 inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
(2) a composition comprising a therapeutically effective amount of
a BTK inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (3) a composition
comprising a therapeutically effective amount of a PI3K-.delta.
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; and (4) a composition comprising a
therapeutically effective amount of an anti-CD20 antibody selected
from the group consisting of rituximab, obinutuzumab, ofatumumab,
veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,
conjugates, variants, radioisotope-labeled complexes, and
biosimilars thereof. These compositions are typically
pharmaceutical compositions. The kit is for co-administration of
the JAK-2 inhibitor, the BTK inhibitor, the PI3K-.delta. inhibitor
and the anti-CD20 antibody, either simultaneously or
separately.
[1882] In some embodiments, the invention provides a kit comprising
(1) a composition comprising a therapeutically effective amount of
a JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (2) a composition
comprising a therapeutically effective amount of a BTK inhibitor or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; and (3) a composition comprising a therapeutically
effective amount of gemcitabine, albumin-bound paclitaxel,
bendamustine, fludarabine, cyclophosphamide, chlorambucil, an
anticoagulant or antiplatelet active pharmaceutical ingredient, or
combinations thereof. These compositions are typically
pharmaceutical compositions. The kit is for co-administration of
the JAK-2 inhibitor, BTK inhibitor, gemcitabine, albumin-bound
paclitaxel, bendamustine, fludarabine, cyclophosphamide,
chlorambucil, and/or the anticoagulant or the antiplatelet active
pharmaceutical ingredient, either simultaneously or separately.
[1883] In some embodiments, the invention provides a kit
comprising, (1) a composition comprising a therapeutically
effective amount of a JAK-2 inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
(2) a composition comprising a therapeutically effective amount of
a BTK inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (3) a composition
comprising a therapeutically effective amount of a PI3K inhibitor
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug thereof; and (4) a composition comprising a
therapeutically effective amount of gemcitabine, albumin-bound
paclitaxel, bendamustine, an anticoagulant or antiplatelet active
pharmaceutical ingredient, or combinations thereof. These
compositions are typically pharmaceutical compositions. The kit is
for co-administration of the JAK-2 inhibitor, BTK inhibitor, PI3K
inhibitor, gemcitabine, albumin-bound paclitaxel, bendamustine,
fludarabine, cyclophosphamide, chlorambucil, and/or the
anticoagulant or the antiplatelet active pharmaceutical ingredient,
either simultaneously or separately.
[1884] In some embodiments, the invention provides a kit
comprising, (1) a composition comprising a therapeutically
effective amount of a JAK-2 inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
(2) a composition comprising a therapeutically effective amount of
a BTK inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (3) a composition
comprising a therapeutically effective amount of a PI3K-.delta.
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; and (4) a composition comprising a
therapeutically effective amount of gemcitabine, albumin-bound
paclitaxel, bendamustine, fludarabine, cyclophosphamide,
chlorambucil, and/or an anticoagulant or antiplatelet active
pharmaceutical ingredient. These compositions are typically
pharmaceutical compositions. The kit is for co-administration of
the JAK-2 inhibitor, BTK inhibitor, PI3K-.delta. inhibitor,
gemcitabine, albumin-bound paclitaxel, bendamustine, fludarabine,
cyclophosphamide, chlorambucil, and/or the anticoagulant or the
antiplatelet active pharmaceutical ingredient, either
simultaneously or separately.
[1885] In some embodiments, the invention provides a kit comprising
(1) a composition comprising a therapeutically effective amount of
a JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (2) a composition
comprising a therapeutically effective amount of a BTK inhibitor or
a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof; (3) a composition comprising a therapeutically
effective amount of an anti-CD20 antibody selected from the group
consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,
tositumomab, ibritumomab, and fragments, derivatives, conjugates,
variants, radioisotope-labeled complexes, biosimilars thereof, and
combinations thereof; and (4) a composition comprising a
therapeutically effective amount of gemcitabine, albumin-bound
paclitaxel, bendamustine, fludarabine, cyclophosphamide,
chlorambucil, an anticoagulant or antiplatelet active
pharmaceutical ingredient, or combinations thereof. These
compositions are typically pharmaceutical compositions. The kit is
for co-administration of the JAK-2 inhibitor, BTK inhibitor,
anti-CD20 antibody, gemcitabine, albumin-bound paclitaxel,
bendamustine, fludarabine, cyclophosphamide, chlorambucil, and/or
the anticoagulant or the antiplatelet active pharmaceutical
ingredient, either simultaneously or separately.
[1886] In some embodiments, the invention provides a kit
comprising, (1) a composition comprising a therapeutically
effective amount of a JAK-2 inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
(2) a composition comprising a therapeutically effective amount of
a BTK inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (3) a composition
comprising a therapeutically effective amount of a PI3K inhibitor
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug thereof; (4) a composition comprising a therapeutically
effective amount of an anti-CD20 antibody selected from the group
consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,
tositumomab, ibritumomab, and fragments, derivatives, conjugates,
variants, radioisotope-labeled complexes, biosimilars thereof, and
combinations thereof; and (5) a composition comprising a
therapeutically effective amount of gemcitabine, albumin-bound
paclitaxel, bendamustine, fludarabine, cyclophosphamide,
chlorambucil, and/or an anticoagulant or antiplatelet active
pharmaceutical ingredient. These compositions are typically
pharmaceutical compositions. The kit is for co-administration of
the JAK-2 inhibitor, BTK inhibitor, PI3K inhibitor, anti-CD20
antibody, gemcitabine, albumin-bound paclitaxel, bendamustine,
fludarabine, cyclophosphamide, chlorambucil, and/or the
anticoagulant or the antiplatelet active pharmaceutical ingredient,
either simultaneously or separately.
[1887] In some embodiments, the invention provides a kit
comprising, (1) a composition comprising a therapeutically
effective amount of a JAK-2 inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof;
(2) a composition comprising a therapeutically effective amount of
a BTK inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof; (3) a composition
comprising a therapeutically effective amount of a PI3K-.delta.
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof; (4) a composition comprising a
therapeutically effective amount of an anti-CD20 antibody selected
from the group consisting of rituximab, obinutuzumab, ofatumumab,
veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,
conjugates, variants, radioisotope-labeled complexes, biosimilars
thereof, and combinations thereof; and (5) a composition comprising
a therapeutically effective amount of gemcitabine, albumin-bound
paclitaxel, bendamustine, fludarabine, cyclophosphamide,
chlorambucil, and/or an anticoagulant or antiplatelet active
pharmaceutical ingredient. These compositions are typically
pharmaceutical compositions. The kit is for co-administration of
the JAK-2 inhibitor, BTK inhibitor, PI3K-.delta. inhibitor,
anti-CD20 antibody, gemcitabine, albumin-bound paclitaxel,
bendamustine, fludarabine, cyclophosphamide, chlorambucil, and/or
the anticoagulant or the antiplatelet active pharmaceutical
ingredient, either simultaneously or separately.
[1888] The kits described above are preferably for use in the
treatment of the diseases and conditions described herein. In a
preferred embodiment, the kits are for use in the treatment of
cancer. In preferred embodiments, the kits are for use in treating
solid tumor cancers, lymphomas and leukemias.
[1889] In a preferred embodiment, the kits of the present invention
are for use in the treatment of cancer. In a preferred embodiment,
the kits of the present invention are for use in the treatment of a
cancer selected from the group consisting of bladder cancer,
squamous cell carcinoma including head and neck cancer, pancreatic
ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma,
mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal
cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal
cancer, ovarian cancer, acute myeloid leukemia, thymus cancer,
brain cancer, squamous cell cancer, skin cancer, eye cancer,
retinoblastoma, melanoma, intraocular melanoma, oral cavity and
oropharyngeal cancers, gastric cancer, stomach cancer, cervical
cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer,
esophageal cancer, testicular cancer, gynecological cancer, thyroid
cancer, acquired immune deficiency syndrome (AIDS)-related cancers
(e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer,
glioblastoma, esophageal tumors, hematological neoplasms,
non-small-cell lung cancer, chronic myelocytic leukemia, diffuse
large B-cell lymphoma, esophagus tumor, follicle center lymphoma,
head and neck tumor, hepatitis C virus infection, hepatocellular
carcinoma, Hodgkin's disease, metastatic colon cancer, multiple
myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma,
ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung
cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell
acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular
lymphoma, mantle cell lymphoma, and Burkitt's lymphoma.
Dosages and Dosing Regimens
[1890] The amounts of BTK inhibitors, PI3K inhibitors, and JAK-2
inhibitors administered will be dependent on the human or mammal
being treated, the severity of the disorder or condition, the rate
of administration, the disposition of the compounds and the
discretion of the prescribing physician. However, an effective
dosage is in the range of about 0.001 to about 100 mg per kg body
weight per day, such as about 1 to about 35 mg/kg/day, in single or
divided doses. For a 70 kg human, this would amount to about 0.05
to 7 g/day, such as about 0.05 to about 2.5 g/day. In some
instances, dosage levels below the lower limit of the aforesaid
range may be more than adequate, while in other cases still larger
doses may be employed without causing any harmful side
effect--e.g., by dividing such larger doses into several small
doses for administration throughout the day. The dosage of BTK
inhibitors, PI3K inhibitors, and JAK-2 inhibitors may be provided
in units of mg/kg of body mass or in mg/m.sup.2 of body surface
area. In an embodiment, the ratio of the dose of the JAK-2
inhibitor to the dose of the BTK inhibitor in mg/kg or in
mg/m.sup.2 is in the range from 10:1 to 1:10, preferably from 2.5:1
to 1:2.5, and more preferably about 1:1. In an embodiment, the
ratio of the dose of the JAK-2 inhibitor to the dose of the PI3K
inhibitor in mg/kg or in mg/m.sup.2 is in the range from 10:1 to
1:10, preferably from 2.5:1 to 1:2.5, and more preferably about
1:1. In an embodiment, the ratio of the JAK-2 inhibitor to the BTK
inhibitor in mg/kg or in mg/m.sup.2 is selected from the group
consisting of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1,
11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1,2:1, 1:1, 1:2, 1:3,
1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15,
1:16, 1:17, 1:18, 1:19, and 1:20. In an embodiment, the weight
ratio of the JAK-2 inhibitor to the PI3K inhibitor in mg/kg or in
mg/m.sup.2 is selected from the group consisting of 20:1, 19:1,
18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1,
7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7,
1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18,
1:19, and 1:20.
[1891] In some embodiments, the combination of the PI3K, JAK-2,
and/or BTK inhibitors is administered in a single dose. Such
administration may be by injection, e.g., intravenous injection, in
order to introduce the PI3K, JAK-2, and/or BTK inhibitors quickly.
However, other routes, including the preferred oral route, may be
used as appropriate. A single dose of the combination of the PI3K,
JAK-2, and/or BTK inhibitors may also be used for treatment of an
acute condition.
[1892] In some embodiments, the combination of the PI3K, JAK-2,
and/or BTK inhibitors is administered in multiple doses. In a
preferred embodiment, the combination of the JAK-2 and BTK
inhibitors is administered in multiple doses. Dosing may be once,
twice, three times, four times, five times, six times, or more than
six times per day. Dosing may be once a month, once every two
weeks, once a week, or once every other day. In other embodiments,
the combination of the PI3K, JAK-2, and/or BTK inhibitors is
administered about once per day to about 6 times per day. In some
embodiments, the combination of the PI3K, JAK-2, and/or BTK
inhibitors is administered once daily, while in other embodiments,
the combination of the PI3K, JAK-2, and/or BTK inhibitors is
administered twice daily, and in other embodiments the combination
of the PI3K, JAK-2, and/or BTK inhibitors is administered three
times daily. In some embodiments, a BTK inhibitor disclosed herein
is administered in combination with a PI3K-.delta. inhibitor and/or
a JAK-2 inhibitor once daily, while in other embodiments a BTK
inhibitor disclosed herein is administered in combination with a
PI3K-.delta. inhibitor and/or a JAK-2 inhibitor twice daily, and in
other embodiments a BTK inhibitor disclosed herein is administered
in combination with a PI3K-.delta. inhibitor and/or a JAK-2
inhibitor three times daily. In some embodiments a PI3K-.delta.
inhibitor disclosed herein is administered in combination with a
BTK inhibitor and/or a JAK-2 inhibitor once daily, while in other
embodiments a PI3K-.delta. inhibitor disclosed herein is
administered in combination with a BTK inhibitor and/or a JAK-2
inhibitor twice daily, and in other embodiments a PI3K-.delta.
inhibitor disclosed herein is administered in combination with a
BTK inhibitor and/or a JAK-2 inhibitor three times daily. In some
embodiments a JAK-2 inhibitor disclosed herein is administered in
combination with a BTK inhibitor and/or a PI3K-.delta. inhibitor
once daily, while in other embodiments a JAK-2 inhibitor disclosed
herein is administered in combination with a BTK inhibitor and/or a
PI3K-.delta. inhibitor twice daily, and in other embodiments a
JAK-2 inhibitor disclosed herein is administered in combination
with a BTK inhibitor and/or a PI3K-.delta. inhibitor three times
daily.
[1893] Administration of the active pharmaceutical ingredients of
the invention may continue as long as necessary. In selected
embodiments, the combination of the PI3K, JAK-2, and/or BTK
inhibitors is administered for more than 1, 2, 3, 4, 5, 6, 7, 14,
or 28 days. In some embodiments, the combination of the PI3K,
JAK-2, and BTK inhibitors is administered for less than 28, 14, 7,
6, 5, 4, 3, 2, or 1 day. In selected embodiments, the combination
of the PI3K, JAK-2, and/or BTK inhibitors is administered
chronically on an ongoing basis--e.g., for the treatment of chronic
effects. In another embodiment the administration of the
combination of the PI3K, JAK-2, and/or BTK inhibitors continues for
less than about 7 days. In yet another embodiment the
administration continues for more than about 6, 10, 14, 28 days,
two months, six months, or one year. In some cases, continuous
dosing is achieved and maintained as long as necessary.
[1894] In some embodiments, an effective dosage of a BTK inhibitor
disclosed herein is in the range of about 1 mg to about 500 mg,
about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25
mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to
about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90
mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about
40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to
about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140
mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about
90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to
about 250 mg, about 160 mg to about 240 mg, about 170 mg to about
230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg,
about 195 mg to about 205 mg, or about 198 to about 202 mg. In some
embodiments, an effective dosage of a BTK inhibitor disclosed
herein is about 25 mg, about 50 mg, about 75 mg, about 100 mg,
about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225
mg, or about 250 mg.
[1895] In some embodiments, an effective dosage of a BTK inhibitor
disclosed herein is in the range of about 0.01 mg/kg to about 4.3
mg/kg, about 0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to
about 3.2 mg/kg, about 0.35 mg/kg to about 2.85 mg/kg, about 0.15
mg/kg to about 2.85 mg/kg, about 0.3 mg to about 2.15 mg/kg, about
0.45 mg/kg to about 1.7 mg/kg, about 0.15 mg/kg to about 1.3 mg/kg,
about 0.3 mg/kg to about 1.15 mg/kg, about 0.45 mg/kg to about 1
mg/kg, about 0.55 mg/kg to about 0.85 mg/kg, about 0.65 mg/kg to
about 0.8 mg/kg, about 0.7 mg/kg to about 0.75 mg/kg, about 0.7
mg/kg to about 2.15 mg/kg, about 0.85 mg/kg to about 2 mg/kg, about
1 mg/kg to about 1.85 mg/kg, about 1.15 mg/kg to about 1.7 mg/kg,
about 1.3 mg/kg mg to about 1.6 mg/kg, about 1.35 mg/kg to about
1.5 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kg to
about 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6
mg/kg to about 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about
2.8 mg/kg to about 3 mg/kg, or about 2.85 mg/kg to about 2.95
mg/kg. In some embodiments, an effective dosage of a BTK inhibitor
disclosed herein is about 0.35 mg/kg, about 0.7 mg/kg, about 1
mg/kg, about 1.4 mg/kg, about 1.8 mg/kg, about 2.1 mg/kg, about 2.5
mg/kg, about 2.85 mg/kg, about 3.2 mg/kg, or about 3.6 mg/kg.
[1896] In some embodiments, an effective dosage of a PI3K inhibitor
disclosed herein is in the range of about 1 mg to about 500 mg,
about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25
mg to about 200 mg, about 1 mg to about 50 mg, about 5 mg to about
45 mg, about 10 mg to about 40 mg, about 15 mg to about 35 mg,
about 20 mg to about 30 mg, about 23 mg to about 28 mg, about 50 mg
to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about
130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg,
or about 95 mg to about 105 mg, about 98 mg to about 102 mg, about
150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg
to about 230 mg, about 180 mg to about 220 mg, about 190 mg to
about 210 mg, about 195 mg to about 205 mg, or about 198 to about
207 mg. In some embodiments, an effective dosage of a PI3K
inhibitor disclosed herein is about 25 mg, about 50 mg, about 75
mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about
200 mg, about 225 mg, or about 250 mg.
[1897] In some embodiments, an effective dosage of a PI3K inhibitor
disclosed herein is in the range of about 0.01 mg/kg to about 4.3
mg/kg, about 0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to
about 3.2 mg/kg, about 0.35 mg/kg to about 2.85 mg/kg, about 0.01
mg/kg to about 0.7 mg/kg, about 0.07 mg/kg to about 0.65 mg/kg,
about 0.15 mg/kg to about 0.6 mg/kg, about 0.2 mg/kg to about 0.5
mg/kg, about 0.3 mg/kg to about 0.45 mg/kg, about 0.3 mg/kg to
about 0.4 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85
mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85 mg/kg, about
1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg to about 1.6 mg/kg,
about 1.35 mg/kg to about 1.5 mg/kg, about 1.4 mg/kg to about 1.45
mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kg to
about 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6
mg/kg to about 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about
2.8 mg/kg to about 3 mg/kg, or about 2.85 mg/kg to about 2.95
mg/kg. In some embodiments, an effective dosage of a PI3K inhibitor
disclosed herein is about 0.4 mg/kg, about 0.7 mg/kg, about 1
mg/kg, about 1.4 mg/kg, about 1.8 mg/kg, about 2.1 mg/kg, about 2.5
mg/kg, about 2.85 mg/kg, about 3.2 mg/kg, or about 3.6 mg/kg.
[1898] In some embodiments, an effective dosage of a JAK-2
inhibitor disclosed herein is in the range of about 1 mg to about
500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg,
about 25 mg to about 200 mg, about 1 mg to about 50 mg, about 5 mg
to about 45 mg, about 10 mg to about 40 mg, about 15 mg to about 35
mg, about 20 mg to about 30 mg, about 23 mg to about 28 mg, about
50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to
about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110
mg, or about 95 mg to about 105 mg, about 98 mg to about 102 mg,
about 150 mg to about 250 mg, about 160 mg to about 240 mg, about
170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg
to about 210 mg, about 195 mg to about 205 mg, or about 198 to
about 207 mg. In some embodiments, an effective dosage of a JAK-2
inhibitor disclosed herein is about 25 mg, about 50 mg, about 75
mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about
200 mg, about 225 mg, or about 250 mg.
[1899] In some embodiments, an effective dosage of a JAK-2
inhibitor disclosed herein is in the range of about 0.01 mg/kg to
about 4.3 mg/kg, about 0.15 mg/kg to about 3.6 mg/kg, about 0.3
mg/kg to about 3.2 mg/kg, about 0.35 mg/kg to about 2.85 mg/kg,
about 0.01 mg/kg to about 0.7 mg/kg, about 0.07 mg/kg to about 0.65
mg/kg, about 0.15 mg/kg to about 0.6 mg/kg, about 0.2 mg/kg to
about 0.5 mg/kg, about 0.3 mg/kg to about 0.45 mg/kg, about 0.3
mg/kg to about 0.4 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg,
about 0.85 mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85
mg/kg, about 1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg to
about 1.6 mg/kg, about 1.35 mg/kg to about 1.5 mg/kg, about 1.4
mg/kg to about 1.45 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg,
about 2.3 mg/kg to about 3.4 mg/kg, about 2.4 mg/kg to about 3.3
mg/kg, about 2.6 mg/kg to about 3.15 mg/kg, about 2.7 mg/kg to
about 3 mg/kg, about 2.8 mg/kg to about 3 mg/kg, or about 2.85
mg/kg to about 2.95 mg/kg. In some embodiments, an effective dosage
of a JAK-2 inhibitor disclosed herein is about 0.4 mg/kg, about 0.7
mg/kg, about 1 mg/kg, about 1.4 mg/kg, about 1.8 mg/kg, about 2.1
mg/kg, about 2.5 mg/kg, about 2.85 mg/kg, about 3.2 mg/kg, or about
3.6 mg/kg.
[1900] In some embodiments, a combination of a BTK inhibitor and a
PI3K inhibitor is adminstered at a dosage of 10 to 200 mg BID,
including 50, 60, 70, 80, 90, 100, 150, or 200 mg BID, for the BTK
inhibitor, and 10 to 200 mg BID, including 25, 50, 75, 100, 150, or
200 mg BID for the PI3K inhibitor.
[1901] In some embodiments, a combination of a BTK inhibitor and a
JAK-2 inhibitor is adminstered at a dosage of 10 to 200 mg BID,
including 50, 60, 70, 80, 90, 100, or 150 mg BID, for the BTK
inhibitor, and 10 to 500 mg BID, including 1, 5, 10, 15, 25, 50,
75, 100, 150, 200, 300, 400, or 500 mg BID for the JAK-2
inhibitor.
[1902] In some embodiments, a combination of a PI3K inhibitor and a
JAK-2 inhibitor is adminstered at a dosage of 10 to 200 mg BID,
including 50, 60, 70, 80, 90, 100, or 150 mg BID, for the PI3K
inhibitor, and 10 to 500 mg BID, including 1, 5, 10, 15, 25, 50,
75, 100, 150, 200, 300, 400, or 500 mg BID for the JAK-2
inhibitor.
[1903] In some embodiments, a combination of a a BTK inhibitor, a
PI3K inhibitor, and a JAK-2 inhibitor is adminstered at a dosage of
10 to 200 mg BID, including 50, 60, 70, 80, 90, 100, or 150 mg BID,
for the BTK inhibitor, 10 to 200 mg BID, including 50, 60, 70, 80,
90, 100, or 150 mg BID, for the PI3K inhibitor, and 10 to 500 mg
BID, including 1, 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400,
or 500 mg BID for the JAK-2 inhibitor.
[1904] In some instances, dosage levels below the lower limit of
the aforesaid ranges may be more than adequate, while in other
cases still larger doses may be employed without causing any
harmful side effect--e.g., by dividing such larger doses into
several small doses for administration throughout the day.
[1905] An effective amount of the combination of the PI3K, JAK-2,
and BTK inhibitors may be administered in either single or multiple
doses by any of the accepted modes of administration of agents
having similar utilities, including rectal, buccal, intranasal and
transdermal routes, by intra-arterial injection, intravenously,
intraperitoneally, parenterally, intramuscularly, subcutaneously,
orally, topically, or as an inhalant.
Methods of Treating Solid Tumor Cancers, Hematological
Malignancies, and Other Diseases
[1906] The compositions and combinations of inhibitors described
above can be used in a method for treating diseases. In a preferred
embodiment, they are for use in treating hyperproliferative
disorders. They may also be used in treating other disorders as
described herein and in the following paragraphs.
[1907] In some embodiments, the invention provides a method of
treating a hyperproliferative disorder in a mammal that comprises
administering to said mammal a therapeutically effective amount of
a PI3K inhibitor (or a PI3K-.gamma. inhibitor, PI3K-.delta.
inhibitor, or PI3K-.gamma.,.delta. inhibitor) and a BTK inhibitor,
or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
or prodrug of either or both the PI3K inhibitor (or a PI3K-.gamma.
inhibitor, PI3K-.delta. inhibitor, or PI3K-.gamma.,.delta.
inhibitor) or the BTK inhibitor. In some embodiments, the invention
provides a method of treating a hyperproliferative disorder in a
mammal that comprises administering to said mammal a
therapeutically effective amount of a JAK-2 inhibitor and a BTK
inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug of either or both the JAK-2 inhibitor or the
BTK inhibitor. In some embodiments, the invention provides a method
of treating a hyperproliferative disorder in a mammal that
comprises administering to said mammal a therapeutically effective
amount of a JAK-2 inhibitor and a PI3K inhibitor, or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug of either or both the JAK-2 inhibitor or the PI3K
inhibitor. In some embodiments, the invention provides a method of
treating a hyperproliferative disorder in a mammal that comprises
administering to said mammal a therapeutically effective amount of
a JAK-2 inhibitor, a BTK inhibitor, and a PI3K inhibitor, or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug of the JAK-2 inhibitor, the BTK inhibitor, and/or the PI3K
inhibitor.
[1908] In some embodiments, the hyperproliferative disorder is
cancer. In selected embodiments, the cancer is selected from the
group consisting of non-Hodgkin's lymphomas (such as diffuse large
B-cell lymphoma), acute myeloid leukemia, thymus, brain, lung,
squamous cell, skin, eye, retinoblastoma, intraocular melanoma,
oral cavity and oropharyngeal, bladder, gastric, stomach,
pancreatic, bladder, breast, cervical, head, neck, renal, kidney,
liver, ovarian, prostate, colorectal, bone (e.g., metastatic bone),
esophageal, testicular, gynecological, thyroid, CNS, PNS,
AIDS-related (e.g. lymphoma and Kaposi's sarcoma), viral-induced
cancers such as cervical carcinoma (human papillomavirus), B-cell
lymphoproliferative disease and nasopharyngeal carcinoma
(Epstein-Barr virus), Kaposi's sarcoma and primary effusion
lymphomas (Kaposi's sarcoma herpesvirus), hepatocellular carcinoma
(hepatitis B and hepatitis C viruses), and T-cell leukemias (Human
T-cell leukemia virus-1), B cell acute lymphoblastic leukemia,
Burkitt's leukemia, juvenile myelomonocytic leukemia, hairy cell
leukemia, Hodgkin's disease, multiple myeloma, mast cell leukemia,
and mastocytosis. In selected embodiments, the method relates to
the treatment of a non-cancerous hyperproliferative disorder such
as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or
prostate conditions (e.g., benign prostatic hypertrophy (BPH)).
[1909] In some embodiments, the hyperproliferative disorder is an
inflammatory, immune, or autoimmune disorder. In some embodiments,
the hyperproliferative disorder is selected from the group
consisting of tumor angiogenesis, chronic inflammatory disease,
rheumatoid arthritis, atherosclerosis, inflammatory bowel disease,
skin diseases such as psoriasis, eczema, and scleroderma, diabetes,
diabetic retinopathy, retinopathy of prematurity, age-related
macular degeneration, hemangioma, glioma and melanoma, ulcerative
colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis,
Behcet's disease, polymyalgia rheumatica, giant-cell arteritis,
sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis,
hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis,
juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's
disease, lupus, and lupus nephritis.
[1910] In some embodiments, the invention provides pharmaceutical
compositions of a combination of a PI3K inhibitor, including a
PI3K-.gamma., PI3K-.delta., or PI3K-.gamma.,.delta. inhibitor, a
JAK-2 inhibitor, and/or a BTK inhibitor for the treatment of
disorders such as hyperproliferative disorder including but not
limited to cancer such as acute myeloid leukemia, thymus, brain,
lung, squamous cell, skin, eye, retinoblastoma, intraocular
melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach,
pancreatic, bladder, breast, cervical, head, neck, renal, kidney,
liver, ovarian, prostate, colorectal, esophageal, testicular,
gynecological, thyroid, CNS, PNS, AIDS-related (e.g., lymphoma and
Kaposi's sarcoma) or viral-induced cancer. In some embodiments,
said pharmaceutical composition is for the treatment of a
non-cancerous hyperproliferative disorder such as benign
hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate
(e.g., benign prostatic hypertrophy (BPH)).
[1911] In some embodiments, the invention provides pharmaceutical
compositions of a combination of a PI3K inhibitor, including a
PI3K-.gamma., PI3K-.delta., or PI3K-.gamma.,.delta. inhibitor, a
JAK-2 inhibitor, and/or a BTK inhibitor for the treatment of
disorders such as myeloproliferative disorders (MPDs),
myeloproliferative neoplasms, polycythemia vera (PV), essential
thrombocythemia (ET), primary myelofibrosis (PMF), myelodysplastic
syndrome, chronic myelogenous leukemia (BCR-ABL1-positive), chronic
neutrophilic leukemia, chronic eosinophilic leukemia, or
mastocytosis.
[1912] The invention further provides a composition as described
herein for the prevention of blastocyte implantation in a
mammal.
[1913] The invention also provides a composition for treating a
disease related to vasculogenesis or angiogenesis in a mammal which
can manifest as tumor angiogenesis, chronic inflammatory disease
such as rheumatoid arthritis, inflammatory bowel disease,
atherosclerosis, skin diseases such as psoriasis, eczema, and
scleroderma, diabetes, diabetic retinopathy, retinopathy of
prematurity, age-related macular degeneration, hemangioma, glioma,
melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic,
prostate, colon and epidermoid cancer.
[1914] In one embodiment, provided herein is a method of treating,
preventing and/or managing asthma. As used herein, "asthma"
encompasses airway constriction regardless of the cause. Common
triggers of asthma include, but are not limited to, exposure to an
environmental stimulants (e.g., allergens), cold air, warm air,
perfume, moist air, exercise or exertion, and emotional stress.
Also provided herein is a method of treating, preventing and/or
managing one or more symptoms associated with asthma. Examples of
the symptoms include, but are not limited to, severe coughing,
airway constriction and mucus production.
[1915] Efficacy of the compounds and combinations of compounds
described herein in treating, preventing and/or managing the
indicated diseases or disorders can be tested using various animal
models known in the art. Efficacy in treating, preventing and/or
managing asthma can be assessed using the ova induced asthma model
described, for example, in Lee, et al., J. Allergy Clin. Immunol.
2006, 118, 403-9. Efficacy in treating, preventing and/or managing
arthritis (e.g., rheumatoid or psoriatic arthritis) can be assessed
using the autoimmune animal models described in, for example,
Williams, et al., Chem. Biol. 2010, 17, 123-34, WO 2009/088986, WO
2009/088880, and WO 2011/008302. Efficacy in treating, preventing
and/or managing psoriasis can be assessed using transgenic or
knockout mouse model with targeted mutations in epidermis,
vasculature or immune cells, mouse model resulting from spontaneous
mutations, and immuno-deficient mouse model with
xenotransplantation of human skin or immune cells, all of which are
described, for example, in Boehncke, et al., Clinics in
Dermatology, 2007, 25, 596-605. Efficacy in treating, preventing
and/or managing fibrosis or fibrotic conditions can be assessed
using the unilateral ureteral obstruction model of renal fibrosis,
which is described, for example, in Chevalier, et al., Kidney
International 2009, 75, 1145-1152; the bleomycin induced model of
pulmonary fibrosis described in, for example, Moore, et al., Am. J.
Physiol. Lung. Cell. Mol. Physiol. 2008, 294, L152-L160; a variety
of liver/biliary fibrosis models described in, for example, Chuang,
et al., Clin. Liver Dis. 2008, 12, 333-347 and Omenetti, et al.,
Laboratory Investigation, 2007, 87, 499-514 (biliary duct-ligated
model); or any of a number of myelofibrosis mouse models such as
described in Varicchio, et al., Expert Rev. Hematol. 2009, 2(3),
315-334. Efficacy in treating, preventing and/or managing
scleroderma can be assessed using a mouse model induced by repeated
local injections of bleomycin described, for example, in Yamamoto,
et al., J. Invest. Dermatol. 1999, 112, 456-462. Efficacy in
treating, preventing and/or managing dermatomyositis can be
assessed using a myositis mouse model induced by immunization with
rabbit myosin as described, for example, in Phyanagi, et al.,
Arthritis & Rheumatism, 2009, 60(10), 3118-3127. Efficacy in
treating, preventing and/or managing lupus can be assessed using
various animal models described, for example, in Ghoreishi, et al.,
Lupus, 2009, 19, 1029-1035; Ohl, et al., J. Biomed. Biotechnol.,
2011, Article ID 432595; Xia, et al., Rheumatology, 2011, 50,
2187-2196; Pau, et al., PLoS ONE, 2012, 7(5), e36761; Mustafa, et
al., Toxicology, 2011, 290, 156-168; Ichikawa, et al., Arthritis
& Rheumatism, 2012, 62(2), 493-503; Rankin, et al., J.
Immunology, 2012, 188, 1656-1667. Efficacy in treating, preventing
and/or managing Sjogren's syndrome can be assessed using various
mouse models described, for example, in Chiorini, et al., J.
Autoimmunity, 2009, 33, 190-196.
[1916] In selected embodiments, the invention provides a method of
treating a solid tumor cancer with a composition including a
combination of a PI3K inhibitor (e.g., a PI3K-.gamma. or
PI3K-.delta. inhibitor), a JAK-2 inhibitor, and/or a BTK inhibitor,
wherein the dose is effective to inhibit signaling between the
solid tumor cells and at least one microenvironment selected from
the group consisting of macrophages, monocytes, mast cells, helper
T cells, cytotoxic T cells, regulatory T cells, natural killer
cells, myeloid-derived suppressor cells, regulatory B cells,
neutrophils, dendritic cells, and fibroblasts. In selected
embodiments, the invention provides a method of treating pancreatic
cancer, breast cancer, ovarian cancer, melanoma, lung cancer,
squamous cell carcinoma including head and neck cancer, and
colorectal cancer using a combination of a BTK inhibitor, a PI3K
inhibitor, and/or a JAK-2 inhibitor, wherein the dose is effective
to inhibit signaling between the solid tumor cells and at least one
microenvironment selected from the group consisting of macrophages,
monocytes, mast cells, helper T cells, cytotoxic T cells,
regulatory T cells, natural killer cells, myeloid-derived
suppressor cells, regulatory B cells, neutrophils, dendritic cells,
and fibroblasts. In an embodiment, the invention provides a method
for treating pancreatic cancer, breast cancer, ovarian cancer,
melanoma, lung cancer, head and neck cancer, and colorectal cancer
using a combination of a BTK inhibitor, a PI3K inhibitor, and/or a
JAK-2 inhibitor and gemcitabine, or a pharmaceutically-acceptable
salt, cocrystal, hydrate, solvate, or prodrug thereof. In an
embodiment, the invention provides a method for treating pancreatic
cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head
and neck cancer, and colorectal cancer using a combination of a BTK
inhibitor, a PI3K inhibitor, and/or a JAK-2 inhibitor and
gemcitabine, or a pharmaceutically-acceptable salt, cocrystal,
hydrate, solvate, or prodrug thereof, wherein the BTK inhibitor is
a compound of Formula (XVIII). Efficacy of the compounds and
combinations of compounds described herein in treating, preventing
and/or managing the indicated diseases or disorders can be tested
using various models known in the art. For example, models for
determining efficacy of treatments for pancreatic cancer are
described in Herreros-Villanueva, et al., World J. Gastroenterol.
2012, 18, 1286-1294. Models for determining efficacy of treatments
for breast cancer are described, e.g., in Fantozzi, Breast Cancer
Res. 2006, 8, 212. Models for determining efficacy of treatments
for ovarian cancer are described, e.g., in Mullany, et al.,
Endocrinology 2012, 153, 1585-92; and Fong, et al., J. Ovarian Res.
2009, 2, 12. Models for determining efficacy of treatments for
melanoma are described, e.g., in Damsky, et al., Pigment Cell &
Melanoma Res. 2010, 23, 853-859. Models for determining efficacy of
treatments for lung cancer are described, e.g., in Meuwissen, et
al., Genes & Development, 2005, 19, 643-664. Models for
determining efficacy of treatments for lung cancer are described,
e.g., in Kim, Clin. Exp. Otorhinolaryngol. 2009, 2, 55-60; and
Sano, Head Neck Oncol. 2009, 1, 32. Models for determining efficacy
of treatments for colorectal cancer, including the CT26 model, are
described below in the examples.
Methods of Treating Patients Intolerant to Bleeding Events
[1917] In selected embodiments, the invention provides a method of
treating a cancer in a human sensitive to or intolerant to bleeding
events, comprising the step of administering a therapeutically
effective amount of a BTK inhibitor, or a
pharmaceutically-acceptable salt, cocrystal, hydrate, solvate, or
prodrug thereof, and a JAK-2 inhibitor and/or a PI3K inhibitor, or
a pharmaceutically-acceptable salt, cocrystal, hydrate, solvate, or
prodrug thereof. In a preferred embodiment, the invention provides
a method of treating a cancer in a human sensitive to or intolerant
to bleeding events, comprising the step of administering a
therapeutically effective amount of a BTK inhibitor, wherein the
BTK inhibitor is selected from the group consisting of Formula
(XVIII), Formula (XVIII-A), Formula (XVIII-B), Formula (XVIII-C),
Formula (XVIII-D), and Formula (XVIII-E), and a
pharmaceutically-acceptable salt, cocrystal, hydrate, solvate, and
prodrug thereof. In a preferred embodiment, the invention provides
a method of treating a cancer in a human sensitive to or intolerant
to bleeding events, comprising the step of administering a
therapeutically effective amount of a BTK inhibitor and a JAK-2
inhibitor, wherein the BTK inhibitor is selected from the group
consisting of Formula (XVIII), Formula (XVIII-A), Formula
(XVIII-B), Formula (XVIII-C), Formula (XVIII-D), and Formula
(XVIII-E), and a pharmaceutically-acceptable salt, cocrystal,
hydrate, solvate, and prodrug thereof, and wherein the JAK-2
inhibitor is selected from the group consisting of ruxolitinib,
pacritinib, and a pharmaceutically-acceptable salt, cocrystal,
hydrate, solvate, and prodrug thereof.
[1918] In an embodiment, the invention provides a method of
treating a cancer in a human intolerant to bleeding events,
comprising the step of administering a therapeutically effective
amount of a BTK inhibitor, wherein the BTK inhibitor is Formula
(XVIII), or a pharmaceutically-acceptable salt, cocrystal, hydrate,
solvate, or prodrug thereof, and a JAK-2 inhibitor, or a
pharmaceutically-acceptable salt, cocrystal, hydrate, solvate, or
prodrug thereof, further comprising the step of administering a
therapeutically effective amount of an anticoagulant or
antiplatelet active pharmaceutical ingredient.
[1919] In selected embodiments, the invention provides a method of
treating a cancer in a human intolerant to bleeding events,
comprising the step of administering a therapeutically effective
amount of a BTK inhibitor, wherein the BTK inhibitor is preferably
a compound of Formula (XVIII), and wherein the cancer is selected
from the group consisting of bladder cancer, squamous cell
carcinoma including head and neck cancer, pancreatic ductal
adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary
carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell
carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal
cancer, ovarian cancer, acute myeloid leukemia, thymus cancer,
brain cancer, squamous cell cancer, skin cancer, eye cancer,
retinoblastoma, melanoma, intraocular melanoma, oral cavity and
oropharyngeal cancers, gastric cancer, stomach cancer, cervical
cancer, head, neck, renal cancer, kidney cancer, liver cancer,
colorectal cancer, esophageal cancer, testicular cancer,
gynecological cancer, thyroid cancer, acquired immune deficiency
syndrome (AIDS)-related cancers (e.g., lymphoma and Kaposi's
sarcoma), viral-induced cancer, glioblastoma, esophageal tumors,
hematological neoplasms, non-small-cell lung cancer, chronic
myelocytic leukemia, diffuse large B-cell lymphoma, esophagus
tumor, follicle center lymphoma, head and neck tumor, hepatitis C
virus infection, hepatocellular carcinoma, Hodgkin's disease,
metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma,
indolent non-Hodgkin's lymphoma, ovary tumor, pancreas tumor, renal
cell carcinoma, small-cell lung cancer, stage IV melanoma, chronic
lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL),
mature B-cell ALL, follicular lymphoma, mantle cell lymphoma, and
Burkitt's lymphoma.
[1920] In some embodiments, the invention provides a method of
treating a cancer in a human intolerant to platelet-mediated
thrombosis comprising the step of administering a therapeutically
effective amount of a BTK inhibitor, wherein the BTK inhibitor is
Formula (XVIII), or a pharmaceutically-acceptable salt, cocrystal,
hydrate, solvate, or prodrug thereof, and a JAK-2 inhibitor, or a
pharmaceutically-acceptable salt, cocrystal, hydrate, solvate, or
prodrug thereof.
[1921] In some embodiments, the BTK inhibitor and the anticoagulant
or the antiplatelet active pharmaceutical ingredient are
administered sequentially. In some embodiments, the BTK inhibitor
and the anticoagulant or the antiplatelet active pharmaceutical
ingredient are administered concomitantly. In selected embodiments,
the BTK inhibitor is administered before the anticoagulant or the
antiplatelet active pharmaceutical ingredient. In selected
embodiments, the BTK inhibitor is administered after the
anticoagulant or the antiplatelet active pharmaceutical ingredient.
In selected embodiments, a JAK-2 inhibitor is co-administered with
the BTK inhibitor and the anticoagulant or the antiplatelet active
pharmaceutical ingredient at the same time or at different
times.
[1922] Selected anti-platelet and anticoagulant active
pharmaceutical ingredients for use in the methods of the present
invention include, but are not limited to, cyclooxygenase
inhibitors (e.g., aspirin), adenosine diphosphate (ADP) receptor
inhibitors (e.g., clopidogrel and ticlopidine), phosphodiesterase
inhibitors (e.g., cilostazol), glycoprotein IIb/IIIa inhibitors
(e.g., abciximab, eptifibatide, and tirofiban), and adenosine
reuptake inhibitors (e.g., dipyridamole). In other embodiments,
examples of anti-platelet active pharmaceutical ingredients for use
in the methods of the present invention include anagrelide,
aspirin/extended-release dipyridamole, cilostazol, clopidogrel,
dipyridamole, prasugrel, ticagrelor, ticlopidine, vorapaxar,
tirofiban HCl, eptifibatide, abciximab, argatroban, bivalirudin,
dalteparin, desirudin, enoxaparin, fondaparinux, heparin,
lepirudin, apixaban, dabigatran etexilate mesylate, rivaroxaban,
and warfarin.
[1923] In an embodiment, the invention provides a method of
treating a cancer, comprising the step of orally administering, to
a human in need thereof, a Bruton's tyrosine kinase (BTK)
inhibitor, wherein the BTK inhibitor is
(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1--
yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable
salt, solvate, hydrate, cocrystal, or prodrug thereof, and a JAK-2
inhibitor, or pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof, further comprising the step of
administering a therapeutically effective amount of an
anticoagulant or antiplatelet active pharmaceutical ingredient,
wherein the anticoagulant or antiplatelet active pharmaceutical
ingredient is selected from the group consisting of acenocoumarol,
anagrelide, anagrelide hydrochloride, abciximab, aloxiprin,
antithrombin, apixaban, argatroban, aspirin, aspirin with
extended-release dipyridamole, beraprost, betrixaban, bivalirudin,
carbasalate calcium, cilostazol, clopidogrel, clopidogrel
bisulfate, cloricromen, dabigatran etexilate, darexaban,
dalteparin, dalteparin sodium, defibrotide, dicumarol,
diphenadione, dipyridamole, ditazole, desirudin, edoxaban,
enoxaparin, enoxaparin sodium, eptifibatide, fondaparinux,
fondaparinux sodium, heparin, heparin sodium, heparin calcium,
idraparinux, idraparinux sodium, iloprost, indobufen, lepirudin,
low molecular weight heparin, melagatran, nadroparin, otamixaban,
parnaparin, phenindione, phenprocoumon, prasugrel, picotamide,
prostacyclin, ramatroban, reviparin, rivaroxaban, sulodexide,
terutroban, terutroban sodium, ticagrelor, ticlopidine, ticlopidine
hydrochloride, tinzaparin, tinzaparin sodium, tirofiban, tirofiban
hydrochloride, treprostinil, treprostinil sodium, triflusal,
vorapaxar, warfarin, warfarin sodium, ximelagatran, salts thereof,
solvates thereof, hydrates thereof, prodrugs thereof, and
combinations thereof.
Combinations of BTK Inhibitors, PI3K Inhibitors, and JAK-2
Inhibitors
[1924] Non-limiting, exemplary embodiments of combinations of the
PI3K inhibitors, BTK inhibitors, and JAK-2 inhibitors described
above are given in the following paragraphs. The disclosure
encompassed herein should in no way be construed as being limited
to these examples, but rather should be construed to encompass any
and all variations which become evident as a result of the
teachings provided herein.
[1925] In an embodiment, the invention provides a method of
treating leukemia, lymphoma, or a solid tumor cancer, comprising
co-administering, to a mammal in need thereof, a composition
comprising therapeutically effective amounts of (1) a PI3K
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof, (2) a JAK-2 inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, and (3) a BTK inhibitor or a pharmaceutically
acceptable salt, solvate, hydrate, cocrystal, or prodrug
thereof.
[1926] In an embodiment, the invention provides a method of
treating leukemia, lymphoma, or a solid tumor cancer, comprising
co-administering, to a mammal in need thereof, a composition
comprising therapeutically effective amounts of (1) a PI3K
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof, and (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[1927] In an embodiment, the invention provides a method of
treating leukemia, lymphoma, or a solid tumor cancer, comprising
co-administering, to a mammal in need thereof, a composition
comprising therapeutically effective amounts of (1) a JAK-2
inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal, or prodrug thereof, and (2) a BTK inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof.
[1928] In an embodiment, the invention provides the method as in
any of the preceding paragraphs, wherein the composition is
administered by oral, intravenous, intramuscular, intraperitoneal,
subcutaneous or transdermal means.
[1929] In an embodiment, the invention provides the method as in
any of the preceding paragraphs, wherein the PI3K inhibitor is a
PI3K-.gamma. inhibitor, a PI3K-.delta. inhibitor, or a
PI3K-.gamma.,.delta. inhibitor.
[1930] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the leukemia is selected from
the group consisting of chronic lymphocytic leukemia, acute myeloid
leukemia, and B cell acute lymphoblastic leukemia. In an
embodiment, the invention provides the method of any of the
preceding paragraphs, wherein the lymphoma is selected from the
group consisting of Burkitt's lymphoma, mantle cell lymphoma,
follicular lymphoma, indolent B-cell non-Hodgkin's lymphoma,
histiocytic lymphoma, activated B-cell like diffuse large B cell
lymphoma, and germinal center B-cell like diffuse large B cell
lymphoma. In an embodiment, the invention provides the method of
any of the preceding paragraphs, wherein the solid tumor cancer is
selected from the group consisting of breast, lung, colorectal,
thyroid, bone sarcoma, and stomach cancers.
[1931] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the PI3K inhibitor is
administered to the subject before administration of the BTK
inhibitor. In an embodiment, the invention provides the method of
any of the preceding paragraphs, wherein the PI3K inhibitor is
administered concurrently with the administration of the BTK
inhibitor. In an embodiment, the invention provides the method of
any of preceding paragraphs, wherein the PI3K inhibitor is
administered to the subject after administration of the BTK
inhibitor.
[1932] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the JAK-2 inhibitor is
administered to the subject before administration of the BTK
inhibitor. In an embodiment, the invention provides the method of
any of the preceding paragraphs, wherein the JAK-2 inhibitor is
administered concurrently with the administration of the BTK
inhibitor. In an embodiment, the invention provides the method of
any of the preceding paragraphs, wherein the JAK-2 inhibitor is
administered to the subject after administration of the BTK
inhibitor.
[1933] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the JAK-2 inhibitor is
administered to the subject before administration of the PI3K
inhibitor. In an embodiment, the invention provides the method of
any of the preceding paragraphs, wherein the JAK-2 inhibitor is
administered concurrently with the administration of the PI3K
inhibitor. In an embodiment, the invention provides the method of
any of the preceding paragraphs, wherein the JAK-2 inhibitor is
administered to the subject after administration of the PI3K
inhibitor.
[1934] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the PI3K inhibitor is a
compound according to:
##STR00179## [1935] or any pharmaceutically-acceptable salt,
solvate, hydrate, cocrystal, or prodrug thereof, wherein: [1936]
X.sup.1 is C(R.sup.9) or N; [1937] X.sup.2 is C(R.sub.10) or N;
[1938] Y is N(R.sup.11), O or S; [1939] Z is CR.sup.8 or N; [1940]
n is 0, 1, 2 or 3; [1941] R.sup.1 is a direct-bonded or
oxygen-linked saturated, partially saturated or unsaturated 5-, 6-
or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms
selected from N, O and S, but containing no more than one 0 or S,
wherein the available carbon atoms of the ring are substituted by
0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by
0 or 1 R.sup.2 substituents, and the ring is additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitro, cyano, (C.sub.1-4)alkyl, O(C.sub.1-4)alkyl,
O(C.sub.1-4)haloalkyl, NH(C.sub.1-4),
N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl and (C.sub.1-4)haloalkyl;
[1942] R.sup.2 is selected from halo, C.sub.1-4haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a.
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, OS(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aC.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.a(C.sub.2-6)alkylOR.sup.a; or
R.sup.2 is selected from (C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl, heterocycle, --((C.sub.1-3)alkyl)heteroaryl,
--((C.sub.1-3)alkyl)heterocycle, --O((C.sub.1-3)alkyl)heteroaryl,
--O((C.sub.1-3)alkyl)heterocycle,
--NR.sup.a((C.sub.1-3)alkyl)heteroaryl,
--NR.sup.a((C.sub.1-3)alkyl)heterocycle,
--((C.sub.1-3)alkyl)phenyl, --O((C.sub.1-3)alkyl)phenyl and
--NR.sup.a((C.sub.1-3)alkyl)phenyl all of which are substituted by
0, 1, 2 or 3 substituents selected from (C.sub.1-4)haloalkyl,
O(C.sub.1-4)alkyl, Br, Cl, F, I and (C.sub.1-4)alkyl; [1943]
R.sup.3 is selected from H, halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)R.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.2,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.a NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a, (C.sub.1-6)alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the (C.sub.1-6)alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from
(C.sub.1-6)haloalkyl, O(C.sub.1-6)alkyl, Br, Cl, F, I and
(C.sub.1-6)alkyl; [1944] R.sup.4 is, independently, in each
instance, halo, nitro, cyano, (C.sub.1-4)alkyl, O(C.sub.1-4)alkyl,
O(C.sub.1-4)haloalkyl, NH(C.sub.1-4)alkyl,
N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl or (C.sub.1-4)haloalkyl; [1945]
R.sup.5 is, independently, in each instance, H, halo,
(C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl, or (C.sub.1-6)alkyl
substituted by 1, 2 or 3 substituents selected from halo, cyano,
OH, O(C.sub.1-4)alkyl, (C.sub.1-4)alkyl, (C.sub.1-3)haloalkyl,
O(C.sub.1-4)alkyl, NH.sub.2, NH(C.sub.1-4)alkyl,
N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl; or both R.sup.5 groups
together form a (C.sub.3-6)spiroalkyl substituted by 0, 1, 2 or 3
substituents selected from halo, cyano, OH, O(C.sub.1-4)alkyl,
(C.sub.1-4)alkyl, (C.sub.1-3)haloalkyl, O(C.sub.1-4)alkyl,
NH.sub.2, NH(C.sub.1-4)alkyl, N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl;
[1946] R.sup.6 is selected from H, halo, (C.sub.1-6)alkyl,
(C.sub.1-4)haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [1947] R.sup.7
is selected from H, halo, (C.sub.1-6)alkyl, (C.sub.1-4)haloalkyl,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, S(.dbd.O).sub.2R.sup.a,
S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; [1948] R.sup.8
is selected from H, (C.sub.1-6)haloalkyl, Br, Cl, F, I, OR.sup.a,
NR.sup.aR.sup.a, (C.sub.1-6)alkyl, phenyl, benzyl, heteroaryl and
heterocycle, wherein the (C.sub.1-6)alkyl, phenyl, benzyl,
heteroaryl and heterocycle are additionally substituted by 0, 1, 2
or 3 substituents selected from (C.sub.1-6)haloalkyl,
O(C.sub.1-6)alkyl, Br, Cl, F, I and (C.sub.1-6)alkyl; [1949]
R.sup.9 is selected from H, halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(O)NR.sup.aR.sup.aN(R.sup.aC(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aC.sub.2-6
alkylNR.sup.aR.sup.a, --NR.sup.aC.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the (C.sub.1-6)alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, (C.sub.1-4)haloalkyl,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylNR.sup.aR.sup.a, --O(C.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a,
--NR.sup.a(C.sub.2-6)alkylOR.sup.a; or R.sup.9 is a saturated,
partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the available carbon
atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo
groups, wherein the ring is substituted by 0, 1, 2, 3 or 4
substituents selected from halo, (C.sub.1-4)haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--O(C.sub.2-6)alkylNR.sup.aR.sup.a, --O(C.sub.2-6)alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6)alkylNR.sup.aR.sup.a and
--NR.sup.a(C.sub.2-6)alkylOR.sup.a; [1950] R.sup.10 is H,
(C.sub.1-3)alkyl, (C.sub.1-3)haloalkyl, cyano, nitro,
CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a; [1951] R.sup.11 is H or
(C.sub.1-4)alkyl; [1952] R.sup.a is independently, at each
instance, H or R.sup.b; and R.sup.b is independently, at each
instance, phenyl, benzyl or (C.sub.1-6)alkyl, the phenyl, benzyl
and (C.sub.1-6)alkyl being substituted by 0, 1, 2 or 3 substituents
selected from halo, (C.sub.1-4)alkyl, (C.sub.1-3)haloalkyl,
--O(C.sub.1-4)alkyl, --NH.sub.2, --NH(C.sub.1-4)alkyl,
--N((C.sub.1-4)alkyl)(C.sub.1-4)alkyl.
[1953] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the PI3K inhibitor is a
compound according to:
##STR00180## [1954] or an enantiomer, a mixture of enantiomers, or
a mixture of two or more diastereomers thereof, or a
pharmaceutically acceptable salt, hydrate, solvate, cocrystal, or
prodrug thereof, wherein [1955] Cy is aryl or heteroaryl
substituted by 0 or 1 occurrence of R.sup.3 and 0, 1, 2, or 3
occurrence(s) of R.sup.5; [1956] W.sub.b.sup.5 is CR.sup.8,
CHR.sup.8, or N; [1957] R.sup.8 is hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl,
acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro; B is
hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,
aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3,
or 4 occurrence(s) of R.sup.2; [1958] each R.sup.2 is independently
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino,
acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl,
nitro, phosphate, urea, or carbonate; [1959] X is
--(CH(R.sup.9)).sub.z--; [1960] Y is --N(R.sup.9)--C(.dbd.O)--,
--C(.dbd.O)--N(R.sup.9)--, --C(.dbd.O)--N(R.sup.9)--(CHR.sup.9)--,
--N(R.sup.9)--S(.dbd.O)--, --S(.dbd.O)--N(R.sup.9)--,
--S(.dbd.O).sub.2--N(R.sup.9)--,
--N(R.sup.9)--C(.dbd.O)--N(R.sup.9) or
--N(R.sup.9)S(.dbd.O).sub.2--; [1961] z is an integer of 1, 2, 3,
or 4; [1962] R.sup.3 is alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl,
acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo,
cyano, aryl, heteroaryl, hydroxyl, or nitro; [1963] each R.sup.5 is
independently alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,
alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano,
hydroxyl, or nitro; [1964] each R.sup.9 is independently hydrogen,
alkyl, cycloalkyl, heterocyclyl, or heteroalkyl; or two adjacent
occurrences of R.sup.9 together with the atoms to which they are
attached form a 4- to 7-membered ring; [1965] W.sub.d is
heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which is
substituted with one or more R.sup.10, R.sup.11, R.sup.12 or
R.sup.13, and [1966] R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are
each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl,
acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro,
phosphate, urea, carbonate or NR'R'' wherein R' and R'' are taken
together with nitrogen to form a cyclic moiety.
[1967] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the PI3K inhibitor is a
compound according to:
##STR00181## [1968] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein B is:
[1968] ##STR00182## [1969] wherein W, is aryl, heteroaryl,
heterocycloalkyl, or cycloalkyl, and [1970] q is an integer of 0,
1, 2, 3, or 4; [1971] X is a bond or --(CH(R.sup.9)).sub.z--, and z
is an integer of 1; [1972] Y is --N(R.sup.9)--; [1973] W.sub.d
is:
[1973] ##STR00183## ##STR00184## [1974] X.sub.1, X.sub.2 and
X.sub.3 are each independently C, CR.sup.13 or N; and X.sub.4,
X.sub.5 and X.sub.6 are each independently N, NH, CR.sup.13, S or
O; [1975] R.sup.1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro; [1976]
R.sup.2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano,
hydroxy or nitro; R.sup.3 is hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl
sulfonamido, halo, cyano, hydroxy or nitro; and [1977] each
instance of R.sup.9 is independently hydrogen, alkyl, or
heterocycloalkyl.
[1978] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the BTK inhibitor is a
compound according to:
##STR00185## [1979] or a pharmaceutically acceptable salt, hydrate,
solvate, cocrystal, or prodrug thereof, wherein [1980] X is CH, N,
O or S; [1981] Y is C(R.sub.6), N, O or S; [1982] Z is CH, N or
bond; [1983] A is CH or N; [1984] B.sub.1 is N or C(R.sub.7);
[1985] B.sub.2 is N or C(R.sub.8); [1986] B.sub.3 is N or
C(R.sub.9); [1987] B.sub.4 is N or C(R.sub.10); [1988] R.sub.1 is
R.sub.11C(O), R.sub.12S(O), R.sub.13SO.sub.2 or (C.sub.1-6)alkyl
optionally substituted with R.sub.14; [1989] R.sub.2 is H,
(C.sub.1-3)alkyl or (C.sub.3-7)cycloalkyl; [1990] R.sub.3 is H,
(C.sub.1-6)alkyl or (C.sub.3-7)cycloalkyl; or [1991] R.sub.2 and
R.sub.3 form, together with the N and C atom they are attached to,
a (C.sub.3-7)heterocycloalkyl optionally substituted with one or
more fluorine, hydroxyl, (C.sub.1-3)alkyl, (C.sub.1-3)alkoxy or
oxo; [1992] R.sub.4 is H or (C.sub.1-3)alkyl; [1993] R.sub.5 is H,
halogen, cyano, (C.sub.1-4)alkyl, (C.sub.1-3)alkoxy,
(C.sub.3-6)cycloalkyl, any alkyl group of which is optionally
substituted with one or more halogen; or R.sub.5 is
(C.sub.6-10)aryl or (C.sub.2-6)heterocycloalkyl; [1994] R.sub.6 is
H or (C.sub.1-3)alkyl; or [1995] R.sub.5 and R.sub.6 together may
form a (C.sub.3-7)cycloalkenyl, or (C.sub.2-6)heterocycloalkenyl;
each optionally substituted with (C.sub.1-3)alkyl, or one or more
halogen; [1996] R.sub.7 is H, halogen, CF.sub.3, (C.sub.1-3)alkyl
or (C.sub.1-3)alkoxy; [1997] R.sub.8 is H, halogen, CF.sub.3,
(C.sub.1-3)alkyl or (C.sub.1-3)alkoxy; or [1998] R.sub.7 and
R.sub.8 together with the carbon atoms they are attached to, form
(C.sub.6-10)aryl or (C.sub.1-9)heteroaryl; [1999] R.sub.9 is H,
halogen, (C.sub.1-3)alkyl or (C.sub.1-3)alkoxy; [2000] R.sub.10 is
H, halogen, (C.sub.1-3)alkyl or (C.sub.1-3)alkoxy; [2001] R.sub.11
is independently selected from a group consisting of
(C.sub.1-6)alkyl, (C.sub.1-6)alkenyl and (C.sub.2-6)alkynyl each
alkyl, alkenyl or alkynyl optionally substituted with one or more
groups selected from hydroxyl, (C.sub.1-4)alkyl,
(C.sub.3-7)cycloalkyl, [(C.sub.1-4)alkyl]amino,
di[(C.sub.1-4)alkyl]amino, (C.sub.1-3)alkoxy,
(C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl or
(C.sub.3-7)heterocycloalkyl; or R.sub.11 is
(C.sub.1-3)alkyl-C(O)--S--(C.sub.1-3)alkyl; or [2002] R.sub.11 is
(C.sub.1-5)heteroaryl optionally substituted with one or more
groups selected from halogen or cyano; [2003] R.sub.12 and R.sub.13
are independently selected from a group consisting of
(C.sub.2-6)alkenyl or (C.sub.2-6)alkynyl both optionally
substituted with one or more groups selected from hydroxyl,
(C.sub.1-4)alkyl, (C.sub.3-7)cycloalkyl, [(C.sub.1-4)alkyl]amino,
di[(C.sub.1-4)alkyl]amino, (C.sub.1-3)alkoxy,
(C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl or
(C.sub.3-7)heterocycloalkyl; or [2004] (C.sub.1-5)heteroaryl
optionally substituted with one or more groups selected from
halogen or cyano; and [2005] R.sub.14 is independently selected
from a group consisting of halogen, cyano or (C.sub.2-6)alkenyl or
(C.sub.2-6)alkynyl both optionally substituted with one or more
groups selected from hydroxyl, (C.sub.1-4)alkyl,
(C.sub.3-7)cycloalkyl, (C.sub.1-4)alkylamino,
di[(C.sub.1-4)alkyl]amino, (C.sub.1-3)alkoxy,
(C.sub.3-7)cycloalkoxy, (C.sub.6-10)aryl, (C.sub.1-5)heteroaryl or
(C.sub.3-7)heterocycloalkyl.
[2006] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the BTK inhibitor is a
compound according to:
##STR00186## [2007] or a pharmaceutically acceptable salt, hydrate,
solvate, cocrystal, or prodrug thereof, wherein [2008] L.sub.a is
CH.sub.2, O, NH or S; [2009] Ar is a substituted or unsubstituted
aryl, or a substituted or unsubstituted heteroaryl; [2010] Y is an
optionally substituted group selected from the group consisting of
alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl; [2011] Z is C(.dbd.O), OC(.dbd.O), NRC(.dbd.O),
C(.dbd.S), S(.dbd.O).sub.x, OS(.dbd.O).sub.x, NRS(.dbd.O).sub.x,
where x is 1 or 2; [2012] R.sub.7 and R.sub.8 are each H; or
R.sub.7 and R.sub.8 taken together form a bond; [2013] R.sub.6 is
H; and [2014] R is H or (C.sub.1-C.sub.6)alkyl.
[2015] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the BTK inhibitor is a
compound according to:
##STR00187## [2016] or a pharmaceutically acceptable salt, hydrate,
solvate, cocrystal, or prodrug thereof, wherein [2017] L.sub.a is
CH.sub.2, O, NH or S; [2018] Ar is a substituted or unsubstituted
aryl, or a substituted or unsubstituted heteroaryl; [2019] Y is an
optionally substituted group selected from the group consisting of
alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl; [2020] Z is C(.dbd.O), OC(.dbd.O), NRC(.dbd.O),
C(.dbd.S), S(.dbd.O).sub.x, OS(.dbd.O).sub.x, NRS(.dbd.O).sub.x,
where x is 1 or 2; [2021] R.sub.7 and R.sub.8 are each H; or
R.sub.7 and R.sub.8 taken together form a bond; [2022] R.sub.6 is
H; and [2023] R is H or (C.sub.1-C.sub.6)alkyl.
[2024] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the BTK inhibitor is a
compound according to:
##STR00188## [2025] or a pharmaceutically acceptable salt, hydrate,
solvate, cocrystal, or prodrug thereof, wherein [2026] L.sub.a is
CH.sub.2, O, NH or S; [2027] Ar is a substituted or unsubstituted
aryl, or a substituted or unsubstituted heteroaryl; [2028] Y is an
optionally substituted group selected from the group consisting of
alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl; [2029] Z is C(.dbd.O), OC(.dbd.O), NRC(.dbd.O),
C(.dbd.S), S(.dbd.O).sub.x, OS(.dbd.O).sub.x, NRS(.dbd.O).sub.x,
where x is 1 or 2; [2030] R.sub.7 and R.sub.8 are each H; or
R.sub.7 and R.sub.8 taken together form a bond; [2031] R.sub.6 is
H; and [2032] R is H or (C.sub.1-C.sub.6)alkyl.
[2033] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the BTK inhibitor is a
compound according to:
##STR00189## [2034] or a pharmaceutically acceptable salt, hydrate,
solvate, cocrystal, or prodrug thereof, wherein [2035] L.sub.a is
CH.sub.2, O, NH or S; [2036] Ar is a substituted or unsubstituted
aryl, or a substituted or unsubstituted heteroaryl; [2037] Y is an
optionally substituted group selected from the group consisting of
alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl; [2038] Z is C(.dbd.O), OC(.dbd.O), NRC(.dbd.O),
C(.dbd.S), S(.dbd.O).sub.x, OS(.dbd.O).sub.x, NRS(.dbd.O).sub.x,
where x is 1 or 2; [2039] R.sub.7 and R.sub.8 are each H; or
R.sub.7 and R.sub.8 taken together form a bond; [2040] R.sub.6 is
H; and [2041] R is H or (C.sub.1-C.sub.6)alkyl.
[2042] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the BTK inhibitor is a
compound according to:
##STR00190## [2043] or a pharmaceutically acceptable salt, hydrate,
solvate, cocrystal, or prodrug thereof, wherein: [2044] Q.sup.1 is
aryl.sup.1, heteroaryl.sup.1, cycloalkyl, heterocyclyl,
cycloalkenyl, or heterocycloalkenyl, any of which is optionally
substituted by one to five independent G.sup.1 substituents; [2045]
R.sup.1 is alkyl, cycloalkyl, bicycloalkyl, aryl, heteroaryl,
aralkyl, heteroaralkyl, heterocyclyl, or heterobicycloalkyl, any of
which is optionally substituted by one or more independent G.sup.11
substituents; [2046] G.sup.1 and G.sup.41 are each independently
halo, oxo, --CF.sub.3, --OCF.sub.3, --OR.sup.2,
--NR.sup.2R.sup.3(R.sup.3a).sub.j1, --C(O)R.sup.2,
--CO.sub.2R.sup.2, --CONR.sup.2R.sup.3, --NO.sub.2, --CN,
--S(O).sub.j1R.sup.2, --SO.sub.2NR.sup.2R.sup.3,
NR.sup.2(C.dbd.O)R.sup.3, NR.sup.2(C.dbd.O)OR.sup.3,
--NR.sup.2(C.dbd.O)NR.sup.2R.sup.3, NR.sup.2S(O).sub.j1R.sup.3,
--(C.dbd.S)OR.sup.2, --(C.dbd.O)SR.sup.2,
--NR.sup.2(C.dbd.NR.sup.3)NR.sup.2aR.sup.3a,
--NR.sup.2(C.dbd.NR.sup.3)OR.sup.2a,
--NR.sup.2(C.dbd.NR.sup.3)SR.sup.3a, --O(C.dbd.O)OR.sup.2,
--O(C.dbd.O)NR.sup.2R.sup.3, --O(C.dbd.O)SR.sup.2,
--S(C.dbd.O)OR.sup.2, --S(C.dbd.O)NR.sup.2R.sup.3,
(C.sub.0-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted with one or more independent halo, oxo, --CF.sub.3,
--OCF.sub.3, --OR.sup.222,
--NR.sup.222R.sup.333(R.sup.333a).sub.j1a, --C(O)R.sup.222,
--CO.sub.2R.sup.222, --CONR.sup.222R.sup.333, --NO.sub.2, --CN,
--S(O).sub.j1aR.sup.222, --SO.sub.2NR.sup.222R.sup.333,
NR.sup.222(C.dbd.O)R.sup.333, NR.sup.222(C.dbd.O)OR.sup.333,
NR.sup.222(C.dbd.O)NR.sup.222R.sup.333,
--NR.sup.222S(O).sub.j1aR.sup.333, --(C.dbd.S)OR.sup.222,
--(C.dbd.O)SR.sup.222,
--NR.sup.222(C.dbd.NR.sup.333)NR.sup.222aR.sup.333a,
--NR.sup.222(C.dbd.NR.sup.333)OR.sup.222a,
--NR.sup.222(C.dbd.NR.sup.333)SR.sup.333a, --O(C.dbd.O)OR.sup.222,
--O(C.dbd.O)NR.sup.222R.sup.333, --O(C.dbd.O)SR.sup.222,
--S(C.dbd.O)OR.sup.222, or --S(C.dbd.O)NR.sup.222R.sup.333
substituents; or --(X.sup.1).sub.n--(Y.sup.1).sub.m--R.sup.4; or
aryl-(C.sub.0-10)alkyl, aryl-(C.sub.2-10)alkenyl, or
aryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, --CF.sub.3, --OCF.sub.3,
--OR.sup.222, --NR.sup.222R.sup.333(R.sup.333a).sub.j2a,
--C(O)R.sup.222, CO.sub.2R.sup.222, --CONR.sup.222R.sup.333,
--NO.sub.2, --CN, --S(O).sub.j2aR.sup.222,
--SO.sub.2NR.sup.222R.sup.333, NR.sup.222(C.dbd.O)R.sup.333,
NR.sup.222(C.dbd.O)OR.sup.333,
NR.sup.222(C.dbd.O)NR.sup.222R.sup.333,
NR.sup.222S(O).sub.j2aR.sup.333, --(C.dbd.S)OR.sup.222,
--(C.dbd.O)SR.sup.222,
--NR.sup.222(C.dbd.NR.sup.333)NR.sup.222aR.sup.333a,
--NR.sup.222(C.dbd.NR.sup.333)OR.sup.222a,
--NR.sup.222(C.dbd.NR.sup.333)SR.sup.333a, --O(C.dbd.O)OR.sup.222,
--O(C.dbd.O)NR.sup.222R.sup.333, --O(C.dbd.O)SR.sup.222,
--S(C.dbd.O)OR.sup.222, or --S(C.dbd.O)NR.sup.222R.sup.333
substituents; or hetaryl-(C.sub.0-10)alkyl,
hetaryl-(C.sub.2-10)alkenyl, or hetaryl-(C.sub.2-10)alkynyl, any of
which is optionally substituted with one or more independent halo,
--CF.sub.3, --OCF.sub.3, --OR.sup.222, --NR.sup.222,
R.sup.333(R.sup.333a).sub.j3a, --C(O)R.sup.222,
--CO.sub.2R.sup.222, --CONR.sup.222R.sup.333, --NO.sub.2, --CN,
--S(O).sub.j3aR.sup.222, --SO.sub.2NR.sup.222R.sup.333,
NR.sup.222(C.dbd.O)R.sup.333, NR.sup.222(C.dbd.O)OR.sup.333,
NR.sup.222(C.dbd.O)NR.sup.222R.sup.333,
NR.sup.222S(O).sub.j3aR.sup.333, --(C.dbd.S)OR.sup.222,
--(C.dbd.O)SR.sup.222,
--NR.sup.222(C.dbd.NR.sup.333)NR.sup.222aR.sup.333a,
--NR.sup.222(C.dbd.NR.sup.333)OR.sup.222a,
--NR.sup.222(C.dbd.NR.sup.333)SR.sup.333a, --O(C.dbd.O)OR.sup.222,
--O(C.dbd.O)NR.sup.222R.sup.333, --O(C.dbd.O)SR.sup.222,
--S(C.dbd.O)OR.sup.222, or --S(C.dbd.O)NR.sup.222R.sup.333
substituents; [2047] G.sup.11 is halo, oxo, --CF.sub.3,
--OCF.sub.3, --OR.sup.21, --NR.sup.21R.sup.31(R.sup.3a1).sub.j4,
--C(O)R.sup.21, --CO.sub.2R.sup.21, --CONR.sup.21R.sup.31,
--NO.sub.2, --CN, --S(O).sub.j4R.sup.21,
--SO.sub.2NR.sup.21R.sup.31, NR.sup.21(C.dbd.O)R.sup.31,
NR.sup.21(C.dbd.O)OR.sup.31, NR.sup.21(C.dbd.O)NR.sup.21R.sup.31,
NR.sup.21S(O).sub.j4R.sup.31, --(C.dbd.S)OR.sup.21,
--(C.dbd.O)SR.sup.21, --NR.sup.21
(C.dbd.NR.sup.31)NR.sup.2a1R.sup.3a1,
--NR.sup.21(C.dbd.NR.sup.31)OR.sup.2a1,
--NR.sup.21(C.dbd.NR.sup.31)SR.sup.3a1, --O(C.dbd.O)OR.sup.21,
--O(C.dbd.O)NR.sup.21R.sup.31, --O(C.dbd.O)SR.sup.21,
--S(C.dbd.O)OR.sup.21, --S(C.dbd.O)NR.sup.21R.sup.31,
--P(O)OR.sup.21OR.sup.31, (C.sub.0-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, (C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted with one or more independent halo, oxo, --CF.sub.3,
--OCF.sub.3, --OR.sup.2221,
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j4a, --C(O)R.sup.2221,
--CO.sub.2R.sup.2221, --CONR.sup.2221R.sup.3331, --NO.sub.2, --CN,
--S(O).sub.j4aR.sup.2221, --SO.sub.2NR.sup.2221R.sup.3331,
NR.sup.2221(C.dbd.O)R.sup.3331, NR.sup.2221(C.dbd.O)OR.sup.3331,
NR.sup.2221(C.dbd.O)NR.sup.2221R.sup.3331,
NR.sup.2221S(O).sub.j4aR.sup.3331, --(C.dbd.S)OR.sup.2221,
--(C.dbd.O)SR.sup.2221,
--NR.sup.2221(C.dbd.NR.sup.3331)NR.sup.222a1R.sup.333a1,
--NR.sup.2221(C.dbd.NR.sup.3331)OR.sup.222a,
--NR.sup.2221(C.dbd.NR.sup.3331)SR.sup.333a1,
--O(C.dbd.O)OR.sup.2221, --O(C.dbd.O)NR.sup.2221R.sup.3331,
--O(C.dbd.O)SR.sup.2221, --S(C.dbd.O)OR.sup.2221,
--P(O)OR.sup.2221R.sup.3331, or --S(C.dbd.O)NR.sup.2221R.sup.3331
substituents; or aryl-(C.sub.0-10)alkyl, aryl-(C.sub.2-10)alkenyl,
or aryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, --CF.sub.3, --OCF.sub.3,
--OR.sup.2221, --NR.sup.2221R.sup.3331(R.sup.333a1).sub.j5a,
--C(O)R.sup.2221, --CO.sub.2R.sup.2221, --CONR.sup.2221R.sup.3331,
--NO.sub.2, --CN, --S(O).sub.j5aR.sup.2221,
--SO.sub.2NR.sup.2221R.sup.3331, NR.sup.2221(C.dbd.O)R.sup.3331,
NR.sup.2221(C.dbd.O)OR.sup.3331,
NR.sup.2221(C.dbd.O)NR.sup.2221R.sup.3331,
NR.sup.2221S(O).sub.j5aR.sup.3331, --(C.dbd.S)OR.sup.2221,
--(C.dbd.O)SR.sup.2221,
--NR.sup.2221(C.dbd.NR.sup.3331)NR.sup.222a1R.sup.333a1,
--NR.sup.2221(C.dbd.NR.sup.3331)OR.sup.222a1,
--NR.sup.2221(C.dbd.NR.sup.3331)SR.sup.333a1,
--O(C.dbd.O)OR.sup.2221, --O(C.dbd.O)NR.sup.2221R.sup.3331,
--O(C.dbd.O)SR.sup.2221, --S(C.dbd.O)OR.sup.2221,
--P(O)OR.sup.2221R.sup.3331, or --S(C.dbd.O)NR.sup.2221R.sup.3331
substituents; or hetaryl-(C.sub.0-10)alkyl,
hetaryl-(C.sub.2-10)alkenyl, or hetaryl-(C.sub.2-10)alkynyl, any of
which is optionally substituted with one or more independent halo,
--CF.sub.3, --OCF.sub.3, --OR.sup.2221,
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j6a, --C(O)R.sup.2221,
--CO.sub.2R.sup.2221, --CONR.sup.2221R.sup.3331, --NO.sub.2, --CN,
--S(O).sub.j6aR.sup.2221, --SO.sub.2NR.sup.2221R.sup.3331,
NR.sup.2221(C.dbd.O)R.sup.3331, NR.sup.2221(C.dbd.O)OR.sup.3331,
NR.sup.2221(C.dbd.O)NR.sup.2221R.sup.3331,
NR.sup.2221S(O).sub.j6aR.sup.3331, --(C.dbd.S)OR.sup.2221,
--(C.dbd.O)SR.sup.2221,
--NR.sup.2221(C.dbd.NR.sup.3331)NR.sup.222a1R.sup.333a1,
--NR.sup.2221(C.dbd.NR.sup.3331)OR.sup.222a1,
--NR.sup.2221(C.dbd.NR.sup.3331)SR.sup.333a1,
--O(C.dbd.O)OR.sup.2221, --O(C.dbd.O)NR.sup.2221R.sup.3331,
--O(C.dbd.O)SR.sup.2221, --S(C.dbd.O)OR.sup.2221,
--P(O)OR.sup.2221OR.sup.3331, or --S(C.dbd.O)NR.sup.2221R.sup.3331
substituents; or G.sup.11 is taken together with the carbon to
which it is attached to form a double bond which is substituted
with R.sup.5 and G.sup.111; [2048] R.sup.2, R.sup.2a, R.sup.3,
R.sup.3a, R.sup.222, R.sup.222a, R.sup.333, R.sup.333a, R.sup.21,
R.sup.2a1, R.sup.31, R.sup.3a1, R.sup.2221, R.sup.222a1,
R.sup.3331, and R.sup.333a1 are each independently equal to
(C.sub.0-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted by one or more G.sup.111 substituents; or
aryl-(C.sub.0-10)alkyl, aryl-(C.sub.2-10)alkenyl, or
aryl-(C.sub.2-10)alkynyl, hetaryl-(C.sub.0-10)alkyl,
hetaryl-(C.sub.2-10)alkenyl, or hetaryl-(C.sub.2-10)alkynyl, any of
which is optionally substituted by one or more G.sup.111
substituents; or in the case of --NR.sup.2R.sup.3(R.sup.3a).sub.j1
or --NR.sup.222R.sup.333(R.sup.333a).sub.j1a or
--NR.sup.222R.sup.333(R.sup.333a)j2a or
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j3a or
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j4a or
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j5a or
--NR.sup.2221R.sup.3331(R.sup.333a1).sub.j6a, R.sup.2 and R.sup.3
or R.sup.222 and R.sup.3333 or R.sup.2221 and R.sup.3331 taken
together with the nitrogen atom to which they are attached form a
3-10 membered saturated ring, unsaturated ring, heterocyclic
saturated ring, or heterocyclic unsaturated ring, wherein said ring
is optionally substituted by one or more G.sup.111 substituents;
[2049] X.sup.1 and Y.sup.1 are each independently --O--,
--NR.sup.7--, --S(O).sub.7--, --CR.sup.5R.sup.6--,
--N(C(O)OR.sup.7)--, --N(C(O)R.sup.7)--, --N(SO.sub.2R.sup.7)--,
--CH.sub.2O--, --CH.sub.2S--, --CH.sub.2N(R.sup.7)--,
--CH(NR.sup.7)--, --CH.sub.2N(C(O)R.sup.7)--,
--CH.sub.2N(C(O)OR.sup.7)--, --CH.sub.2N(SO.sub.2R.sup.7)--,
--CH(NHR.sup.7)--, --CH(NHC(O)R.sup.7)--,
--CH(NHSO.sub.2R.sup.7)--, --CH(NHC(O)OR.sup.7)--,
--CHO(C(O)R.sup.7)--, --CHO(C(O)NHR.sup.7)--, --CH.dbd.CH--,
--C.ident.C--, --C(.dbd.NOR.sup.7)--, --C(O)--, --CH(OR.sup.7)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2-- --OC(O)N(R.sup.7)--,
--N(R.sup.7)C(O)N(R.sup.7)--, --NR.sup.7C(O)O--,
--S(O)N(R.sup.7)--, --S(O).sub.2N(R.sup.7)--,
--N(C(O)R.sup.7)S(O)--, --N(C(O)R.sup.7)S(O).sub.2--,
--N(R.sup.7)S(O)N(R.sup.7)--, --N(R.sup.7)S(O).sub.2N(R.sup.7)--,
--C(O)N(R.sup.7)C(O)--, --S(O)N(R.sup.7)C(O)--,
--S(O).sub.2N(R.sup.7)C(O)--, --OS(O)N(R.sup.7)--,
--OS(O).sub.2N(R.sup.7)--, --N(R.sup.7)S(O)O--,
--N(R.sup.7)S(O).sub.2O--, --N(R.sup.7)S(O)C(O)--,
--N(R.sup.7)S(O).sub.2C(O)--, --SON(C(O)R.sup.7)--,
--SO.sub.2N(C(O)R.sup.7)--, --N(R.sup.7)SON(R.sup.7)--,
--N(R.sup.7)SO.sub.2N(R.sup.7)--, --C(O)O--,
--N(R.sup.7)P(OR.sup.8)O--, --N(R.sup.7)P(OR.sup.8)--,
--N(R.sup.7)P(O)(OR.sup.8)O--, --N(R.sup.7)P(O)(OR.sup.8)--,
--N(C(O)R.sup.7)P(OR.sup.8)O--, --N(C(O)R.sup.7)P(OR.sup.8)--,
--N(C(O)R.sup.7)P(O)(OR.sup.8)O--, --N(C(O)R.sup.7)P(OR.sup.8)--,
--CH(R.sup.7)S(O)--, --CH(R.sup.7)S(O).sub.2--,
--CH(R.sup.7)N(C(O)OR.sup.7)--, --CH(R.sup.7)N(C(O)R.sup.7)--,
--CH(R.sup.7)N(SO.sub.2R.sup.7)--, --CH(R.sup.7)O--,
--CH(R.sup.7)S--, --CH(R.sup.7)N(R.sup.7)--,
--CH(R.sup.7)N(C(O)R.sup.7)--, --CH(R.sup.7)N(C(O)OR.sup.7)--,
--CH(R.sup.7)N(SO.sub.2R.sup.7)--,
--CH(R.sup.7)C(.dbd.NOR.sup.7)--, --CH(R.sup.7)C(O)--,
--CH(R.sup.7)CH(OR.sup.7)--, --CH(R.sup.7)C(O)N(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)C(O)--, --CH(R.sup.7)N(R.sup.7)S(O)--,
--CH(R.sup.7)N(R.sup.7)S(O).sub.2--,
--CH(R.sup.7)OC(O)N(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)C(O)N(R.sup.7)--,
--CH(R.sup.7)NR.sup.7C(O)O--, --CH(R.sup.7)S(O)N(R.sup.7)--,
--CH(R.sup.7)S(O).sub.2N(R.sup.7)--,
--CH(R.sup.7)N(C(O)R.sup.7)S(O)--,
--CH(R.sup.7)N(C(O)R.sup.7)S(O)--,
--CH(R.sup.7)N(R.sup.7)S(O)N(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)S(O).sub.2N(R.sup.7)--,
--CH(R.sup.7)C(O)N(R.sup.7)C(O)--,
--CH(R.sup.7)S(O)N(R.sup.7)C(O)--,
--CH(R.sup.7)S(O).sub.2N(R.sup.7)C(O)--,
--CH(R.sup.7)OS(O)N(R.sup.7)--,
--CH(R.sup.7)OS(O).sub.2N(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)S(O)O--,
--CH(R.sup.7)N(R.sup.7)S(O).sub.2O--,
--CH(R.sup.7)N(R.sup.7)S(O)C(O)--,
--CH(R.sup.7)N(R.sup.7)S(O).sub.2C(O)--,
--CH(R.sup.7)SON(C(O)R.sup.7)--,
--CH(R.sup.7)SO.sub.2N(C(O)R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)SON(R.sup.7)--,
--CH(R.sup.7)N(R.sup.7)SO.sub.2N(R.sup.7)--, --CH(R.sup.7)C(O)O--,
--CH(R.sup.7)N(R.sup.7)P(OR.sup.8)O--,
--CH(R.sup.7)N(R.sup.7)P(OR.sup.8)--,
--CH(R.sup.7)N(R.sup.7)P(O)(OR.sup.8)O--,
--CH(R.sup.7)N(R.sup.7)P(O)(OR.sup.8)--,
--CH(R.sup.7)N(C(O)R.sup.7)P(OR.sup.8)O--,
--CH(R.sup.7)N(C(O)R.sup.7)P(OR.sup.8)--,
--CH(R.sup.7)N(C(O)R.sup.7)P(O)(OR.sup.8)O--, or
--CH(R.sup.7)N(C(O)R.sup.7)P(OR.sup.8)--; or [2050] X.sup.1 and
Y.sup.1 are each independently represented by one of the following
structural formulas:
[2050] ##STR00191## [2051] R.sup.10, taken together with the
phosphinamide or phosphonamide, is a 5-, 6-, or 7-membered aryl,
heteroaryl or heterocyclyl ring system; [2052] R.sup.5, R.sup.6,
and G.sup.111 are each independently a (C.sub.0-10)alkyl,
(C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted with one or more independent halo, --CF.sub.3,
--OCF.sub.3, --OR.sup.77, --NR.sup.77R.sup.87, --C(O)R.sup.77,
--CO.sub.2R.sup.77, --CONR.sup.77R.sup.87, --NO.sub.2, --CN,
--S(O).sub.j5aR.sup.77, --SO.sub.2NR.sup.77R.sup.87,
NR.sup.77(C.dbd.O)R.sup.87, NR.sup.77(C.dbd.O)OR.sup.87,
NR.sup.77(C.dbd.O)NR.sup.78R.sup.87, NR.sup.77S(O).sub.j5aR.sup.87,
--(C.dbd.S)OR.sup.77, --(C.dbd.O)SR.sup.77,
--NR.sup.77(C.dbd.NR.sup.87)NR.sup.78R.sup.78,
--NR.sup.77(C.dbd.NR.sup.87)OR.sup.78,
--NR.sup.77(C.dbd.NR.sup.87)SR.sup.78, --O(C.dbd.O)OR.sup.77,
--O(C.dbd.O)NR.sup.77R.sup.87, --O(C.dbd.O)SR.sup.77,
--S(C.dbd.O)OR.sup.77, --P(O)OR.sup.77R.sup.87, or
--S(C.dbd.O)NR.sup.77R.sup.87 substituents; or
aryl-C.sub.0-10alkyl, aryl-C.sub.2-10alkenyl, or
aryl-C.sub.2-10alkynyl, any of which is optionally substituted with
one or more independent halo, --CF.sub.3, --OCF.sub.3, --OR.sup.77,
--NR.sup.77R.sup.87, --C(O)R.sup.77, --CO.sub.2R.sup.77,
--CONR.sup.77R.sup.87, --NO.sub.2, --CN, --S(O).sub.j5aR.sup.77,
--SO.sub.2NR.sup.77R.sup.87, NR.sup.77(C.dbd.O)R.sup.87,
NR.sup.77(C.dbd.O)OR.sup.87, NR.sup.77(C.dbd.O)NR.sup.78R.sup.87,
NR.sup.77S(O).sub.j5aR.sup.87, --(C.dbd.S)OR.sup.77,
--(C.dbd.O)SR.sup.77,
--NR.sup.77(C.dbd.NR.sup.87)NR.sup.78R.sup.88,
--NR.sup.77(C.dbd.NR.sup.87)OR.sup.78,
--NR.sup.77(C.dbd.NR.sup.87)SR.sup.78, --O(C.dbd.O)OR.sup.77,
--O(C.dbd.O)NR.sup.77R.sup.87, --O(C.dbd.O)SR.sup.77,
--S(C.dbd.O)OR.sup.77, --P(O)OR.sup.77R.sup.87, or
--S(C.dbd.O)NR.sup.77R.sup.87 substituents; or
hetaryl-(C.sub.0-10)alkyl, hetaryl-(C.sub.2-10)alkenyl, or
hetaryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, --CF.sub.3, --OCF.sub.3,
--OR.sup.77, --NR.sup.77R.sup.87, --C(O)R.sup.77,
--CO.sub.2R.sup.77, --CONR.sup.77R.sup.87, --NO.sub.2, --CN,
--S(O).sub.j5aR.sup.77, --SO.sub.2NR.sup.77R.sup.87,
NR.sup.77(C.dbd.O)R.sup.87, NR.sup.77(C.dbd.O)OR.sup.87,
NR.sup.77(C.dbd.O)NR.sup.78R.sup.87, NR.sup.77S(O).sub.j5aR.sup.87,
--(C.dbd.S)OR.sup.77, --(C.dbd.O)SR.sup.77,
--NR.sup.77(C.dbd.NR.sup.87)NR.sup.78R.sup.88,
--NR.sup.77(C.dbd.NR.sup.87)OR.sup.78,
--NR.sup.77(C.dbd.NR.sup.87)SR.sup.78, --O(C.dbd.O)OR.sup.77,
--O(C.dbd.O)NR.sup.77R.sup.87, --O(C.dbd.O)SR.sup.77,
--S(C.dbd.O)OR.sup.77, --P(O)OR.sup.77OR.sup.87, or
--S(C.dbd.O)NR.sup.77R.sup.87 substituents; or R.sup.5 with R.sup.6
taken together with the respective carbon atom to which they are
attached, form a 3-10 membered saturated or unsaturated ring,
wherein said ring is optionally substituted with R.sup.69; or
R.sup.5 with R.sup.6 taken together with the respective carbon atom
to which they are attached, form a 3-10 membered saturated or
unsaturated heterocyclic ring, wherein said ring is optionally
substituted with R.sup.69; [2053] R.sup.7 and R.sup.8 are each
independently H, acyl, alkyl, alkenyl, aryl, heteroaryl,
heterocyclyl or cycloalkyl, any of which is optionally substituted
by one or more G.sup.111 substituents; [2054] R.sup.4 is H, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,
cycloalkenyl, or heterocycloalkenyl, any of which is optionally
substituted by one or more G.sup.41 substituents; [2055] R.sup.69
is equal to halo, --OR.sup.78, --SH, --NR.sup.78R.sup.88,
--CO.sub.2R.sup.78, --CONR.sup.78R.sup.88, --NO.sub.2, --CN,
--S(O).sub.j8R.sup.78, --SO.sub.2NR.sup.78R.sup.88,
(C.sub.0-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
or heterocyclyl-(C.sub.2-10)alkynyl, any of which is optionally
substituted with one or more independent halo, cyano, nitro,
--OR.sup.778, --SO.sub.2NR.sup.778R.sup.888, or
--NR.sup.778R.sup.888 substituents; or aryl-(C.sub.0-10)alkyl,
aryl-(C.sub.2-10)alkenyl, or aryl-(C.sub.2-10)alkynyl, any of which
is optionally substituted with one or more independent halo, cyano,
nitro, --OR.sup.778, (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl, haloC.sub.2-10alkenyl,
haloC.sub.2-10alkynyl, --COOH, (C.sub.1-4)alkoxycarbonyl,
--CONR.sup.778R.sup.888, --SO.sub.2NR.sup.778R.sup.888, or
--NR.sup.778R.sup.888 substituents; or hetaryl-(C.sub.0-10)alkyl,
hetaryl-(C.sub.2-10)alkenyl, or hetaryl-(C.sub.2-10)alkynyl, any of
which is optionally substituted with one or more independent halo,
cyano, nitro, --OR.sup.778, (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl, --CONR.sup.778R.sup.888,
--SO.sub.2NR.sup.778R.sup.888, or --NR.sup.778R.sup.888
substituents; or mono((C.sub.1-6)alkyl)amino(C.sub.1-6)alkyl,
di((C.sub.1-6)alkyl)amino(C.sub.1-6)alkyl,
mono(aryl)amino(C.sub.1-6)alkyl, di(aryl)amino(C.sub.1-6)alkyl, or
--N((C.sub.1-6)alkyl)-(C.sub.1-6)alkyl-aryl, any of which is
optionally substituted with one or more independent halo, cyano,
nitro, --OR.sup.778, (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl, --CONR.sup.778R.sup.888
SO.sub.2NR.sup.778R.sup.888, or --NR.sup.778R.sup.888 substituents;
or in the case of --NR.sup.78R.sup.88, R.sup.78 and R.sup.88 taken
together with the nitrogen atom to which they are attached form a
3-10 membered saturated ring, unsaturated ring, heterocyclic
saturated ring, or heterocyclic unsaturated ring, wherein said ring
is optionally substituted with one or more independent halo, cyano,
hydroxy, nitro, (C.sub.1-10)alkoxy, --SO.sub.2NR.sup.778R.sup.888,
or --NR.sup.778R.sup.888 substituents; [2056] R.sup.77, R.sup.78,
R.sup.87, R.sup.88, R.sup.778, and R.sup.888 are each independently
(C.sub.0-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl,
(C.sub.1-10)alkoxy(C.sub.1-10)alkyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkenyl,
(C.sub.1-10)alkoxy(C.sub.2-10)alkynyl,
(C.sub.1-10)alkylthio(C.sub.1-10)alkyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkenyl,
(C.sub.1-10)alkylthio(C.sub.2-10)alkynyl, cyclo(C.sub.3-8)alkyl,
cyclo(C.sub.3-8)alkenyl, cyclo(C.sub.3-8)alkyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkenyl(C.sub.1-10)alkyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkenyl,
cyclo(C.sub.3-8)alkyl(C.sub.2-10)alkynyl,
cyclo(C.sub.3-8)alkenyl(C.sub.2-10)alkynyl,
heterocyclyl-(C.sub.0-10)alkyl, heterocyclyl-(C.sub.2-10)alkenyl,
heterocyclyl-(C.sub.2-10)alkynyl, (C.sub.1-10)alkylcarbonyl,
(C.sub.2-10)alkenylcarbonyl, (C.sub.2-10)alkynylcarbonyl,
(C.sub.1-10)alkoxycarbonyl,
(C.sub.1-10)alkoxycarbonyl(C.sub.1-10)alkyl,
mono(C.sub.1-6)alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl,
mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or
(C.sub.1-10)alkyl(aryl)aminocarbonyl, any of which is optionally
substituted with one or more independent halo, cyano, hydroxy,
nitro, (C.sub.1-10)alkoxy,
--SO.sub.2N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl), or
--N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl) substituents; or
aryl-(C.sub.0-10)alkyl, aryl-(C.sub.2-10)alkenyl, or
aryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, cyano, nitro,
--O((C.sub.0-4)alkyl), (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl,
--CON((C.sub.0-4)alkyl)((C.sub.0-10)alkyl),
--SO.sub.2N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl), or
--N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl) substituents; or
hetaryl-(C.sub.0-10)alkyl, hetaryl-(C.sub.2-10)alkenyl, or
hetaryl-(C.sub.2-10)alkynyl, any of which is optionally substituted
with one or more independent halo, cyano, nitro,
--O((C.sub.0-4)alkyl), (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl,
(C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl,
--CON((C.sub.0-4)alkyl)((C.sub.0-4)alkyl),
--SO.sub.2N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl), or
--N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl) substituents; or
mono((C.sub.1-6)alkyl)amino(C.sub.1-6)alkyl,
di((C.sub.1-6)alkyl)amino(C.sub.1-6)alkyl,
mono(aryl)amino(C.sub.1-6)alkyl, di(aryl)amino(C.sub.1-6)alkyl, or
--N((C.sub.1-6)alkyl)-(C.sub.1-6)alkyl-aryl, any of which is
optionally substituted with one or more independent halo, cyano,
nitro, --O((C.sub.0-4)alkyl), (C.sub.1-10)alkyl,
(C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl, halo(C.sub.1-10)alkyl,
halo(C.sub.2-10)alkenyl, halo(C.sub.2-10)alkynyl, --COOH,
(C.sub.1-4)alkoxycarbonyl,
--CON((C.sub.0-4)alkyl)((C.sub.0-4)alkyl),
--SO.sub.2N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl), or
--N((C.sub.0-4)alkyl)((C.sub.0-4)alkyl) substituents; and [2057] n,
m, j1, j1a, j2a, j3a, j4, j4a, j5a, j6a, j7, and j8 are each
independently equal to 0, 1, or 2.
[2058] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the BTK inhibitor is a
compound according to:
##STR00192## [2059] or a pharmaceutically acceptable salt, hydrate,
solvate, cocrystal, or prodrug thereof, wherein [2060] L represents
(1) --O--, (2) --S--, (3) --SO--, (4) --SO.sub.2-- (5) --NH--, (6)
--C(O)--, (7) --CH.sub.2O--, (8) --O--CH.sub.2--, (9) --CH.sub.2--,
or (10) --CH(OH)--; [2061] R.sup.1 represents (1) a halogen atom,
(2) a C.sub.1-4 alkyl group, (3) a C.sub.1-4 alkoxy group, (4) a
C.sub.1-4 haloalkyl group, or (5) a C.sub.1-4 haloalkoxy group;
[2062] ring1 represents a 4- to 7-membered cyclic group, which may
be substituted by from one to five substituents each independently
selected from the group consisting of (1) halogen atoms, (2)
C.sub.1-4 alkyl groups, (3) C.sub.1-4 alkoxy groups, (4) nitrile,
(5) C.sub.1-4 haloalkyl groups, and (6) C.sub.1-4 haloalkoxy
groups, wherein when two or more substituents are present on ring1,
these substituents may form a 4- to 7-membered cyclic group
together with the atoms in ring1 to which these substituents are
bound; [2063] ring2 represents a 4- to 7-membered saturated
heterocycle, which may be substituted by from one to three
--K--R.sup.2; K represents (1) a bond, (2) a C.sub.1-4 alkylene,
(3) --C(O)--, (4) --C(O)--CH.sub.2--, (5) --CH.sub.2--C(O)--, (6)
--C(O)O--, or (7) --SO.sub.2-- (wherein the bond on the left is
bound to the ring2); [2064] R.sup.2 represents (1) a C.sub.1-4
alkyl, (2) a C.sub.2-4 alkenyl, or (3) a C.sub.2-4 alkynyl group,
each of which may be substituted by from one to five substituents
each independently selected from the group consisting of (1)
NR.sup.3R.sup.4, (2) halogen atoms, (3) CONR.sup.5R.sup.6, (4)
CO.sub.2R.sup.7, and (5) OR.sup.8; [2065] R.sup.3 and R.sup.4 each
independently represent (1) a hydrogen atom, or (2) a C.sub.1-4
alkyl group which may be substituted by OR.sup.9 or
CONR.sup.10R.sup.11; R.sup.3 and R.sup.4 may, together with the
nitrogen atom to which they are bound, form a 4- to 7-membered
nitrogenous saturated heterocycle, which may be substituted by an
oxo group or a hydroxyl group; [2066] R.sup.5 and R.sup.6 each
independently represent (1) a hydrogen atom, (2) a C.sub.1-4 alkyl
group, or (3) a phenyl group; [2067] R.sup.7 represents (1) a
hydrogen atom or (2) a C.sub.1-4 alkyl group; [2068] R.sup.8
represents (1) a hydrogen atom, (2) a C.sub.1-4 alkyl group, (3) a
phenyl group, or (4) a benzotriazolyl group; R.sup.9 represents (1)
a hydrogen atom or (2) a C.sub.1-4 alkyl group; [2069] R.sup.10 and
R.sup.11 each independently represent (1) a hydrogen atom or (2) a
C.sub.1-4 alkyl group; [2070] n represents an integer from 0 to 4;
[2071] m represents an integer from 0 to 2; and [2072] when n is
two or more, the R.sup.1's may be the same as each other or may
differ from one another).
[2073] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the JAK-2 inhibitor is a
compound according to:
##STR00193## [2074] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [2075] A.sup.1 and
A.sup.2 are independently selected from C and N; [2076] T, U, and V
are independently selected from O, S, N, CR.sup.5, and NR.sup.6;
[2077] wherein the 5-membered ring formed by A.sup.1, A.sup.2, U,
T, and V is aromatic; [2078] X is N or CR.sup.4; [2079] Y is
C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8 alkynylene,
(CR.sup.11R.sup.12).sub.p--(C.sub.3-10
cycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(arylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p--(C.sub.1-10
heterocycloalkylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.p-(heteroarylene)-(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pO(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12)C(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pC(O)O(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pOC(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pOC(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pNR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pNR.sup.cC(O)NR.sup.d(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O)(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O)NR.sup.c(CR.sup.11R.sup.12).sub.q,
(CR.sup.11R.sup.12).sub.pS(O).sub.2(CR.sup.11R.sup.12).sub.q, or
(CR.sup.11R.sup.12).sub.pS(O).sub.2NR.sup.c(CR.sup.11R.sup.12).sub.q,
wherein said C.sub.1-8 alkylene, C.sub.2-8 alkenylene, C.sub.2-8
alkynylene, cycloalkylene, arylene, heterocycloalkylene, or
heteroarylene, is optionally substituted with 1, 2, or 3
substituents independently selected from
-D.sup.1-D.sup.2-D.sup.3-D.sup.4; [2080] Z is H, halo, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
.dbd.C--R.sup.i, .dbd.N--R.sup.i, Cy.sup.1, CN, NO.sub.2, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl)R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d, wherein said C.sub.1-8 alkyl, C.sub.2-8
alkenyl, or C.sub.2-8 alkynyl, is optionally substituted with 1, 2,
3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl)R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; [2081] wherein when Z is H, n is 1;
[2082] or the --(Y).sub.n-- Z moiety is taken together with i)
A.sup.2 to which the moiety is attached, ii) R.sup.5 or R.sup.6 of
either T or V, and iii) the C or N atom to which the R.sup.5 or
R.sup.6 of either T or V is attached to form a 4- to 20-membered
aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the
5-membered ring formed by A.sup.1, A.sup.2, U, T, and V, wherein
said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from --(W).sub.m-Q; [2083] W is
C.sub.1-8 alkylenyl, C.sub.2-8 alkenylenyl, C.sub.2-8 alkynylenyl,
O, S, C(O), C(O)NR.sup.c', C(O)O, OC(O), OC(O)NR.sup.c', NR.sup.c',
NR.sup.c'C(O)NR.sup.d', S(O), S(O)NR.sup.c', S(O).sub.2, or
S(O).sub.2NR.sup.c'; [2084] Q is H, halo, CN, NO.sub.2, C.sub.1-8
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8 haloalkyl,
halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl,
wherein said C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-8haloalkyl, aryl, cycloalkyl, heteroaryl, or
heterocycloalkyl is optionally substituted with 1, 2, 3 or 4
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4 cyanoalkyl,
Cy.sup.2, CN, NO.sub.2, OR.sup.a', SR.sup.a', C(O)R.sup.b',
C(O)NR.sup.c'R.sup.d', C(O)OR.sup.a', OC(O)R.sup.b',
OC(O)NR.sup.c'R.sup.d', NR.sup.c'R.sup.d', NR.sup.c'C(O)R.sup.b',
NR.sup.c'C(O)NR.sup.c'R.sup.d', NR.sup.c'C(O)OR.sup.a',
S(O)R.sup.b', S(O)NR.sup.c'R.sup.d', S(O).sub.2R.sup.b',
NR'S(O).sub.2R.sup.b', and S(O).sub.2NR.sup.c'R.sup.d'; [2085]
Cy.sup.1 and Cy.sup.2 are independently selected from aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4 or 5 substituents independently selected
from halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl,
C.sub.1-4 cyanoalkyl, CN, NO.sub.2, OR.sup.a'', SR.sup.a'',
C(O)R.sup.b'', C(O)NR.sup.c''R.sup.d'', C(O)OR.sup.a'',
OC(O)R.sup.b''OC(O)NR.sup.c''R.sup.d'', NR.sup.c''R.sup.d'',
NR.sup.c''C(O)R.sup.b'', NR.sup.c''C(O)OR.sup.a'',
NR.sup.c''S(O)R.sup.b'', NR.sup.c''S(O).sub.2R.sup.b'',
S(O)R.sup.b'', S(O)NR.sup.c''R.sup.d'', S(O).sub.2R.sup.b'', and
S(O).sub.2NR.sup.c''R.sup.d''; [2086] R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 are independently selected from H, halo, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN,
NO.sub.2, OR.sup.7, SR.sup.7, C(O)R.sup.8, C(O)NR.sup.9R.sup.10,
C(O)OR.sup.7OC(O)R.sup.8, OC(O)NR.sup.9R.sup.10, NR.sup.9R.sup.10,
NR.sup.9C(O)R.sup.8, NR.sup.cC(O)OR.sup.7, S(O)R.sup.8,
S(O)NR.sup.9R.sup.10, S(O).sub.2R.sup.8, NR.sup.9S(O).sub.2R.sup.8,
and S(O).sub.2NR.sup.9R.sup.10; [2087] R.sup.5 is H, halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, CN, NO.sub.2, OR.sup.7, SR.sup.7,
C(O)R.sup.8, C(O)NR.sup.9R.sup.10, C(O)OR.sup.7, OC(O)R.sup.8,
OC(O)NR.sup.9R.sup.10, NR.sup.9R.sup.10, NR.sup.9C(O)R.sup.8,
NR.sup.9C(O)OR.sup.7, S(O)R.sup.8, S(O)NR.sup.9R.sup.10,
S(O).sub.2R.sup.8, NR.sup.9S(O).sub.2R.sup.8, or
S(O).sub.2NR.sup.9R.sup.10; [2088] R.sup.6 is H, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
OR.sup.7, C(O)R.sup.8, C(O)NR.sup.9R.sup.10, C(O)OR.sup.7,
S(O)R.sup.8, S(O)NR.sup.9R.sup.10, S(O).sub.2R.sup.8, or
S(O).sub.2NR.sup.9R.sup.10; [2089] R.sup.7 is H, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; [2090]
R.sup.8 is H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl; [2091] R.sup.9 and R.sup.10 are
independently selected from H, C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkylcarbonyl, arylcarbonyl, C.sub.1-6 alkylsulfonyl, arylsulfonyl,
aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; [2092]
or R.sup.9 and R.sup.10 together with the N atom to which they are
attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
[2093] R.sup.11 and R.sup.12 are independently selected from H and
-E.sup.1-E.sup.2-E.sup.3-E.sup.4; [2094] D.sup.1 and E.sup.1 are
independently absent or independently selected from C.sub.1-6
alkylene, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, arylene,
cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each
of the C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.2-6
alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene is optionally substituted by 1, 2 or 3
substituents independently selected from halo, CN, NO.sub.2,
N.sub.3, SCN, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, amino,
C.sub.1-6 alkylamino, and C.sub.2-8 dialkylamino; [2095] D.sup.2
and E.sup.2 are independently absent or independently selected from
C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene,
(C.sub.1-6 alkylene).sub.r-O--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-S--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.s, --NR.sup.e--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-CO--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-COO--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-CONR.sup.e--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-SO--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-SO.sub.2--(C.sub.1-6 alkylene).sub.s,
(C.sub.1-6 alkylene).sub.r-SONR.sup.e--(C.sub.1-6 alkylene).sub.s,
and (C.sub.1-6 alkylene).sub.r-NR.sup.eCONR.sup.f--(C.sub.1-6
alkylene).sub.s, wherein each of the C.sub.1-6 alkylene, C.sub.2-6
alkenylene, and C.sub.2-6 alkynylene is optionally substituted by
1, 2 or 3 substituents independently selected from halo, CN,
NO.sub.2, N.sub.3, SCN, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
amino, C.sub.1-6 alkylamino, and C.sub.2-8 dialkylamino; [2096]
D.sup.3 and E.sup.3 are independently absent or independently
selected from C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.2-6
alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene, wherein each of the C.sub.1-6 alkylene,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, arylene, cycloalkylene,
heteroarylene, and heterocycloalkylene is optionally substituted by
1, 2 or 3 substituents independently selected from halo, CN,
NO.sub.2, N.sub.3, SCN, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
amino, C.sub.1-6 alkylamino, and C.sub.2-8 dialkylamino; [2097]
D.sup.4 and E.sup.4 are independently selected from H, halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl)R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d, wherein said C.sub.1-8 alkyl, C.sub.2-8
alkenyl, or C.sub.2-8 alkynyl, is optionally substituted with 1, 2,
3, 4, 5, or 6 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, halosulfanyl, C.sub.1-4 hydroxyalkyl, C.sub.1-4
cyanoalkyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.i)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.i)NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
C(.dbd.NOH)R.sup.b, C(.dbd.NO(C.sub.1-6 alkyl))R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; [2098] R.sup.a is H, Cy.sup.1,
--(C.sub.1-6 alkyl)-Cy.sup.1, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, wherein said C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl; [2099] R.sup.b is
H, Cy.sup.1, (C.sub.1-6 alkyl)-Cy.sup.1, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, wherein said
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl,
halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkyl and heterocycloalkyl; [2100] R.sup.a' and R.sup.a'' are
independently selected from H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl, wherein said C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl and heterocycloalkyl; [2101] R.sup.b'
and R.sup.b'' are independently selected from H, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein
said C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl,
halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkyl and heterocycloalkyl; [2102] R.sup.c and R.sup.d are
independently selected from H, Cy.sup.1, (C.sub.1-6
alkyl)-Cy.sup.1, C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, wherein said C.sub.1-10 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl, is
optionally substituted with 1, 2, or 3 substituents independently
selected from Cy.sup.1, (C.sub.1-6 alkyl)-Cy.sup.1, OH, CN, amino,
halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl,
and halosulfanyl; [2103] or R.sup.c and R.sup.d together with the N
atom to which they are attached form a 4-, 5-, 6- or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
substituents independently selected from Cy.sup.1, (C.sub.1-6
alkyl)-Cy.sup.1, OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 haloalkyl, and halosulfanyl; [2104] R.sup.c'
and R.sup.d' are independently selected from H, C.sub.1-10 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein
said C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl,
halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkyl and heterocycloalkyl; [2105] or R.sup.c' and R.sup.d'
together with the N atom to which they are attached form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, or 3 substituents independently selected from OH, CN, amino,
halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl,
halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkyl and heterocycloalkyl; [2106] R.sup.c'' and R.sup.d'' are
independently selected from H, C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl, wherein said C.sub.1-10
alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halosulfanyl, C.sub.1-6 haloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
[2107] or R.sup.c'' and R.sup.d'' together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group optionally substituted with 1, 2, or 3 substituents
independently selected from OH, CN, amino, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 haloalkyl, halosulfanyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and
heterocycloalkyl; [2108] R.sup.i is H, CN, NO.sub.2, or C.sub.1-6
alkyl; [2109] R.sup.e and R.sup.f are independently selected from H
and C.sub.1-6 alkyl; [2110] R.sup.i is H, CN, or NO.sub.2; [2111] m
is 0 or 1; [2112] n is 0 or 1; [2113] p is 0, 1, 2, 3, 4, 5, or 6;
[2114] q is 0, 1, 2, 3, 4, 5 or 6; [2115] r is 0 or 1; and [2116] s
is 0 or 1.
[2117] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the JAK-2 inhibitor is a
compound according to:
##STR00194## [2118] or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, wherein: [2119] R.sup.1 and
R.sup.2 are each independently selected from the group consisting
of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,
cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,
alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,
cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,
phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,
acylamino, arylamino, sulfonylamino, sulfinylamino, --COOH,
--COR.sup.3, --COOR.sup.3, --CONHR.sup.3, --NHCOR.sup.3,
--NHCOOR.sup.3, --NHCONHR.sup.3, alkoxycarbonyl,
alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,
arylsulfonyl, arylsulfinyl, aminosulfonyl, --SR.sup.3,
R.sup.4S(O)R.sup.6--, R.sup.4S(O).sub.2R.sup.6--,
R.sup.4C(O)N(R.sup.5)R.sup.6--, R.sup.4SO.sub.2N(R.sup.5)R.sup.6--,
R.sup.4N(R.sup.5)C(O)R.sup.6--, R.sup.4N(R.sup.5)SO.sub.2R.sup.6--,
R.sup.4N(R)C(O)N(R)R.sup.6-- and acyl, each of which may be
optionally substituted; [2120] each R.sup.3, R.sup.4, and R.sup.5
is independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of
which may be optionally substituted; [2121] each R.sup.6 is
independently selected from the group consisting of a bond, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of
which may be optionally substituted; [2122] Z.sup.2 is
independently selected from the group consisting of a bond, O, S,
--N(R.sup.7)--, --N(R.sup.7)C.sub.1-2alkyl-, and
--C.sub.1-2alkylN(R.sup.7)--; [2123] each R.sup.7 is independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,
heteroarylalkyl and acyl, each of which may be optionally
substituted; [2124] A.sup.1 and Ar.sup.2 are each independently
selected from the group consisting of aryl and heteroaryl, each of
which may be optionally substituted; [2125] L is a group of
formula:
[2125] --X.sup.1--Y--X.sup.2-- [2126] wherein X.sup.1 is attached
to A.sup.1 and X.sup.2 is attached to Ar.sup.2, and wherein
X.sup.1, X.sup.2 and Y are selected such that the group L has
between 5 and 15 atoms in the normal chain, [2127] X.sup.1 and
X.sup.2 are each independently a heteroalkyl group containing at
least one oxygen atom in the normal chain, [2128] Y is a group of
formula --CR.sup.a.dbd.CR.sup.b-- or an optionally substituted
cycloalkyl group, [2129] wherein R.sup.a and R.sup.b are each
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of
which may be optionally substituted, or [2130] R.sup.a and R.sup.b
may be joined such that when taken together with the carbon atoms
to which they are attached they form a cycloalkenyl or
cycloheteroalkenyl group; [2131] or a pharmaceutically acceptable
salt, solvate, hydrate, cocrystal, or prodrug thereof, or an
N-oxide thereof.
[2132] In certain embodiments Z.sup.2 is selected from the group
consisting of a bond, --N(R.sup.7)--, and --S--. In one specific
embodiment Z.sup.2 is --N(R.sup.7)--. In an even more specific
embodiment Z.sup.2 is --N(H)--. [2133] A.sup.1 and Ar.sup.2 are
each independently selected from the group consisting of aryl and
heteroaryl and may be monocyclic, bicyclic or polycyclic moieties.
In certain embodiments each of A.sup.1 and Ar.sup.2 is a monocyclic
or bicyclic moiety. In certain embodiments each of A.sup.1 and
Ar.sup.2 are a monocyclic moiety.
[2134] In certain embodiments A.sup.1 is selected from the group
consisting of:
##STR00195## [2135] wherein V.sup.1, V.sup.2, V.sup.3 and V.sup.4
are each independently selected from the group consisting of N, and
C(R.sup.10); [2136] W is selected from the group consisting of O, S
and NR.sup.10; [2137] W.sup.1 and W.sup.2 are each independently
selected from the group consisting of N and CR.sup.10; [2138]
wherein each R.sup.10 is independently selected from the group
consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,
arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,
alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,
cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,
phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,
acylamino, arylamino, sulfonylamino, sulfinylamino, --COOH,
--COR.sup.3, --COOR.sup.3, --CONHR.sup.3, --NHCOR.sup.3,
--NHCOOR.sup.3, --NHCONHR.sup.3, alkoxycarbonyl,
alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,
arylsulfonyl, arylsulfinyl, aminosulfonyl, --SR.sup.3,
R.sup.4S(O)R.sup.6--, R.sup.4S(O).sub.2R.sup.6--,
R.sup.4C(O)N(R.sup.5)R.sup.6--, R.sup.4SO.sub.2N(R.sup.5)R.sup.6--,
R.sup.4N(R.sup.5)C(O)R.sup.6--, R.sup.4N(R.sup.5)SO.sub.2R.sup.6--,
R.sup.4N(R)C(O)N(R)R.sup.6-- and acyl, each of which may be
optionally substituted, [2139] wherein R.sup.3, R.sup.4, R.sup.5
and R.sup.6 are as defined above.
[2140] In certain embodiments A.sup.1 is selected from the group
consisting of:
##STR00196## [2141] wherein V.sup.1, V.sup.2, V.sup.3, V.sup.4, W,
W.sup.1, W.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as
defined above.
[2142] In certain embodiments A.sup.1 is selected from the group
consisting of:
##STR00197## [2143] wherein each R.sup.10 is independently as
defined above, [2144] k is an integer selected from the group
consisting of 0, 1, 2, 3, and 4; and [2145] n is an integer
selected from the group consisting of 0, 1, and 2.
[2146] In yet an even further embodiment A.sup.1 is selected from
the group consisting of:
##STR00198## [2147] wherein R.sup.10 is as defined above.
[2148] In certain embodiments A.sup.1 is selected from the group
consisting of:
##STR00199## [2149] wherein each R.sup.10 is independently as
defined above, and [2150] q is an integer selected from the group
consisting of 0, 1 and 2.
[2151] In certain embodiments Ar.sup.1 is selected from the group
consisting of:
##STR00200##
[2152] In certain embodiments A.sup.1 is selected from the group
consisting of:
##STR00201##
[2153] In certain embodiments Ar.sup.2 is selected from the group
consisting of:
##STR00202## [2154] wherein V.sup.5, V.sup.6, V.sup.7 and V.sup.8
are independently selected from the group consisting of N, and
C(R.sup.11); [2155] wherein each R.sup.11 is independently selected
from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl,
haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,
arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,
heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,
alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,
cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy,
phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl,
acylamino, arylamino, sulfonylamino, sulfinylamino, --COOH,
--COR.sup.3, --COOR.sup.3, --CONHR.sup.3, --NHCOR.sup.3,
--NHCOOR.sup.3, --NHCONHR.sup.3, alkoxycarbonyl,
alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,
arylsulfonyl, arylsulfinyl, aminosulfonyl, --SR.sup.3,
R.sup.4S(O)R.sup.6--, R.sup.4S(O).sub.2R.sup.6--,
R.sup.4C(O)N(R.sup.5)R.sup.6--, R.sup.4SO.sub.2N(R)R.sup.6--,
R.sup.4N(R.sup.5)C(O)R.sup.6--, R.sup.4N(R.sup.5)SO.sub.2R.sup.6--,
R.sup.4N(R)C(O)N(R)R.sup.6-- and acyl, each of which may be
optionally substituted.
[2156] In certain embodiments Ar.sup.2 is selected from the group
consisting of:
##STR00203## [2157] wherein each R.sup.11 is independently as
defined above [2158] o is an integer selected from the group
consisting of 0, 1, 2, 3, and 4; and [2159] p is an integer
selected from the group consisting of 0, 1, 2, and 3.
[2160] In certain embodiments Ar.sup.2 is selected from the group
consisting of:
##STR00204## [2161] wherein each R.sup.11 is as defined above.
[2162] In an even further embodiment Ar.sup.2 is selected from the
group consisting of:
##STR00205##
[2163] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the BTK inhibitor is selected
from the group consisting of:
##STR00206## ##STR00207## ##STR00208## [2164] and pharmaceutically
acceptable salts, solvates, hydrates, cocrystals, and prodrugs
thereof; and [2165] the JAK-2 inhibitor is selected from the group
consisting of:
[2165] ##STR00209## [2166] and pharmaceutically acceptable salts,
solvates, hydrates, cocrystals, and prodrugs thereof.
[2167] In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the BTK inhibitor is selected
from the group consisting of:
##STR00210## ##STR00211## ##STR00212## [2168] and pharmaceutically
acceptable salts, solvates, hydrates, cocrystals, and prodrugs
thereof; and the JAK-2 inhibitor is selected from the group
consisting of:
[2168] ##STR00213## [2169] and pharmaceutically acceptable salts,
solvates, hydrates, cocrystals, and prodrugs thereof; and a PI3K
inhibitor selected from the group consisting of:
[2169] ##STR00214## [2170] and pharmaceutically acceptable salts,
solvates, hydrates, cocrystals, and prodrugs thereof.
[2171] In an embodiment, the invention provides a method of
treating a solid tumor cancer in a human comprising administering a
therapeutically effective amount of a BTK inhibitor, a JAK-2
inhibitor, and/or a PI3K-.delta. inhibitor, wherein the dose is
effective to inhibit signaling between the cells of the solid tumor
cancer and at least one tumor microenvironment selected from the
group consisting of macrophages, monocytes, mast cells, helper T
cells, cytotoxic T cells, regulatory T cells, natural killer cells,
myeloid-derived suppressor cells, regulatory B cells, neutrophils,
dendritic cells, and fibroblasts. In an embodiment, the solid tumor
cancer is selected from the group consisting of pancreatic cancer,
ovarian cancer, colon carcinoma, breast cancer, lung cancer,
colorectal cancer, thyroid cancer, bone sarcoma, and stomach
cancers. In an embodiment, the invention provides the method of any
of the preceding paragraphs, wherein the dose is further effective
to increase immune system recognition and rejection of the solid
tumor by the human.
Combinations of BTK Inhibitors, PI3K Inhibitors, and/or JAK-2
Inhibitors with Anti-CD20 Antibodies
[2172] The BTK inhibitors of the present invention and combinations
of the BTK inhibitors with PI3K inhibitors and/or JAK-2 inhibitors
may also be safely co-administered with immunotherapeutic
antibodies such as the anti-CD20 antibodies rituximab,
obinutuzumab, ofatumumab, veltuzumab, tositumomab, and ibritumomab,
and or antigen-binding fragments, derivatives, conjugates,
variants, and radioisotope-labeled complexes thereof, which may be
given alone or with conventional chemotherapeutic active
pharmaceutical ingredients such as those described herein. In an
embodiment, the foregoing combinations exhibit synergistic effects
that may result in greater efficacy, less side effects, the use of
less active pharmaceutical ingredient to achieve a given clinical
result, or other synergistic effects.
[2173] In an embodiment, the invention provides a method of
treating a hematological malignancy or a solid tumor cancer in a
human comprising the step of administering to said human a BTK
inhibitor of Formula (XVIII), or a pharmaceutically acceptable salt
or ester, prodrug, cocrystal, solvate or hydrate thereof, and
further comprising the step of administering an anti-CD20 antibody,
wherein the anti-CD20 antibody is a monoclonal antibody or an
antigen-binding fragment, derivative, conjugate, variant, or
radioisotope-labeled complex thereof. In an embodiment, the
invention provides a method of treating a hematological malignancy
or a solid tumor cancer in a human comprising the step of
administering to said human a BTK inhibitor of Formula (XVIII), or
a pharmaceutically acceptable salt or ester, prodrug, cocrystal,
solvate or hydrate thereof, and further comprising the step of
administering an anti-CD20 antibody, wherein the anti-CD20 antibody
is an anti-CD20 monoclonal antibody or an antigen-binding fragment,
derivative, conjugate, variant, or radioisotope-labeled complex
thereof, and wherein the anti-CD20 antibody specifically binds to
human CD20 with a K.sub.D selected from the group consisting of
1.times.10.sup.-7 M or less, 5.times.10.sup.-8 M or less,
1.times.10.sup.-8 M or less, and 5.times.10.sup.-9 M or less.
Anti-CD20 monoclonal antibodies are classified as Type I or Type
II, as described in Klein, et al., mAbs 2013, 5, 22-33. Type I
anti-CD20 monoclonal antibodies are characterized by binding to the
Class I epitope, localization of CD20 to lipid rafts, high
complement-dependent cytotoxicity, full binding capacity, weak
homotypic aggregation, and moderate cell death induction. Type II
anti-CD20 monoclonal antibodies are characterized by binding to the
Class I epitope, a lack of localization of CD20 to lipid rafts, low
complement-dependent cytotoxicity, half binding capacity, homotypic
aggregation, and strong cell death induction. Both Type I and Type
II anti-CD20 monoclonal antibodies exhibit antibody-dependent
cytotoxiticy (ADCC) and are thus useful with BTK inhibitors
described herein. Type I anti-CD20 monoclonal antibodies include
but are not limited to rituximab, ocrelizumab, and ofatumumab. Type
II anti-CD20 monoclonal antibodies include but are not limited to
obinutuzumab and tositumomab. In an embodiment, the foregoing
methods exhibit synergistic effects that may result in greater
efficacy, less side effects, the use of less active pharmaceutical
ingredient to achieve a given clinical result, or other synergistic
effects.
[2174] In an embodiment, the invention provides a method of
treating a hematological malignancy or a solid tumor cancer in a
human comprising the step of administering to said human a BTK
inhibitor of Formula (XVIII), or a pharmaceutically acceptable salt
or ester, prodrug, cocrystal, solvate or hydrate thereof, and
further comprising the step of administering an anti-CD20 antibody,
wherein the anti-CD20 antibody is a monoclonal antibody or an
antigen-binding fragment, derivative, conjugate, variant, or
radioisotope-labeled complex thereof. In an embodiment, the
invention provides a method of treating a hematological malignancy
or a solid tumor cancer in a human comprising the step of
administering to said human a BTK inhibitor of Formula (XVIII), or
a pharmaceutically acceptable salt or ester, prodrug, cocrystal,
solvate or hydrate thereof, and further comprising the step of
administering an anti-CD20 antibody, wherein the anti-CD20 antibody
is an anti-CD20 monoclonal antibody or an antigen-binding fragment,
derivative, conjugate, variant, or radioisotope-labeled complex
thereof, and wherein the anti-CD20 antibody specifically binds to
human CD20 with a K.sub.D selected from the group consisting of
1.times.10.sup.-7 M or less, 5.times.10.sup.-8 M or less,
1.times.10.sup.-8 M or less, and 5.times.10.sup.-9 M or less.
[2175] In an embodiment, the invention provides a method of
treating a hematological malignancy or a solid tumor cancer in a
human comprising the step of administering to said human a BTK
inhibitor of Formula (XVIII), or a pharmaceutically acceptable salt
or ester, prodrug, cocrystal, solvate or hydrate thereof, and
further comprising the step of administering an Type I anti-CD20
antibody, or an antigen-binding fragment, derivative, conjugate,
variant, or radioisotope-labeled complex thereof. In an embodiment,
the invention provides a method of treating a hematological
malignancy or a solid tumor cancer in a human comprising the step
of administering to said human a BTK inhibitor of Formula (XVIII),
or a pharmaceutically acceptable salt or ester, prodrug, cocrystal,
solvate or hydrate thereof, and further comprising the step of
administering an Type II anti-CD20 antibody, or an antigen-binding
fragment, derivative, conjugate, variant, or radioisotope-labeled
complex thereof. In an embodiment, the invention provides a method
of treating a hematological malignancy or a solid tumor cancer in a
human comprising the step of administering to said human a BTK
inhibitor of Formula (XVIII), or a pharmaceutically acceptable salt
or ester, prodrug, cocrystal, solvate or hydrate thereof, and a
JAK-2 inhibitor or a pharmaceutically acceptable salt, solvate,
hydrate, cocrystal, or prodrug thereof, and further comprising the
step of administering an Type I anti-CD20 antibody, or an
antigen-binding fragment, derivative, conjugate, variant, or
radioisotope-labeled complex thereof. In an embodiment, the
invention provides a method of treating a hematological malignancy
or a solid tumor cancer in a human comprising the step of
administering to said human a BTK inhibitor of Formula (XVIII), or
a pharmaceutically acceptable salt or ester, prodrug, cocrystal,
solvate or hydrate thereof, and a JAK-2 inhibitor or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or
prodrug thereof, and further comprising the step of administering
an Type II anti-CD20 antibody, or an antigen-binding fragment,
derivative, conjugate, variant, or radioisotope-labeled complex
thereof.
[2176] In selected embodiments, the BTK inhibitors of the present
invention and combinations of the BTK inhibitors with PI3K
inhibitors, and/or JAK-2 inhibitors, and the anti-CD20 monoclonal
antibody are administered sequentially. In selected embodiments,
the BTK inhibitors of the present invention and combinations of the
BTK inhibitors with PI3K inhibitors, and/or JAK-2 inhibitors, and
the anti-CD20 monoclonal antibody are administered concomitantly.
In selected embodiments, the BTK inhibitors of the present
invention and combinations of the BTK inhibitors with PI3K
inhibitors and/or JAK-2 inhibitors is administered before the
anti-CD20 monoclonal antibody. In selected embodiments, the BTK
inhibitors of the present invention and combinations of the BTK
inhibitors with PI3K inhibitors and/or JAK-2 inhibitors is
administered after the anticoagulant or the antiplatelet active
pharmaceutical ingredient. In selected embodiments, the BTK
inhibitors of the present invention and combinations of the BTK
inhibitors with PI3K inhibitors and/or JAK-2 inhibitors and the
anti-CD20 monoclonal antibody are administered over the same time
period, and the BTK inhibitor administration continues after the
anti-CD20 monoclonal antibody administration is completed.
[2177] In an embodiment, the anti-CD20 monoclonal antibody is
rituximab, or an antigen-binding fragment, derivative, conjugate,
variant, or radioisotope-labeled complex thereof. Rituximab is a
chimeric murine-human monoclonal antibody directed against CD20,
and its structure comprises an IgG1 kappa immunoglobulin containing
murine light- and heavy-chain variable region sequences and human
constant region sequences. Rituximab is composed of two heavy
chains of 451 amino acids and two light chains of 213 amino acids.
The amino acid sequence for the heavy chains of rituximab is set
forth in SEQ ID NO:1. The amino acid sequence for the light chains
of rituximab is set forth in SEQ ID NO:2. Rituximab is commercially
available, and its properties and use in cancer and other diseases
is described in more detail in Rastetter, et al., Ann. Rev. Med.
2004, 55, 477-503, and in Plosker and Figgett, Drugs, 2003, 63,
803-43. In an embodiment, the anti-CD20 monoclonal antibody is an
anti-CD20 biosimilar monoclonal antibody approved by drug
regulatory authorities with reference to rituximab. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 90% to SEQ ID NO:1. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 90% to SEQ ID NO:2. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 95% to SEQ ID NO:1. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 95% to SEQ ID NO:2. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 98% to SEQ ID NO:1. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 98% to SEQ ID NO:2. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 99% to SEQ ID NO:1. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 99% to SEQ ID NO:2.
[2178] In an embodiment, the anti-CD20 monoclonal antibody is
obinutuzumab, or an antigen-binding fragment, derivative,
conjugate, variant, or radioisotope-labeled complex thereof.
Obinutuzumab is also known as afutuzumab or GA-101. Obinutuzumab is
a humanized monoclonal antibody directed against CD20. The amino
acid sequence for the heavy chains of obinutuzumab is set forth in
SEQ ID NO:3. The amino acid sequence for the light chains of
obinutuzumab is set forth in SEQ ID NO:4. Obinutuzumab is
commercially available, and its properties and use in cancer and
other diseases is described in more detail in Robak, Curr. Opin.
Investig. Drugs 2009, 10, 588-96. In an embodiment, the anti-CD20
monoclonal antibody is an anti-CD20 biosimilar monoclonal antibody
approved by drug regulatory authorities with reference to
obinutuzumab. In an embodiment, the anti-CD20 monoclonal antibody
has a heavy chain sequence identity of greater than 90% to SEQ ID
NO:3. In an embodiment, the anti-CD20 monoclonal antibody has a
light chain sequence identity of greater than 90% to SEQ ID NO:4.
In an embodiment, the anti-CD20 monoclonal antibody has a heavy
chain sequence identity of greater than 95% to SEQ ID NO:3. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 95% to SEQ ID NO:4. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 98% to SEQ ID NO:3. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 98% to SEQ ID NO:4. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 99% to SEQ ID NO:3. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 99% to SEQ ID NO:4. In an
embodiment, the anti-CD20 monoclonal antibody obinutuzumab is an
immunoglobulin G1, anti-(human B-lymphocyte antigen CD20
(membrane-spanning 4-domains subfamily A member 1, B-lymphocyte
surface antigen B1, Leu-16 or Bp35)), humanized mouse monoclonal
obinutuzumab des-CH3107-K-.gamma.1 heavy chain (222-219')-disulfide
with humanized mouse monoclonal obinutuzumab .kappa. light chain
dimer (228-228'':231-231'')-bisdisulfide antibody.
[2179] In an embodiment, the anti-CD20 monoclonal antibody is
ofatumumab, or an antigen-binding fragment, derivative, conjugate,
variant, or radioisotope-labeled complex thereof Ofatumumab is
described in Cheson, J. Clin. Oncol. 2010, 28, 3525-30. The crystal
structure of the Fab fragment of ofatumumab has been reported in
Protein Data Bank reference 3GIZ and in Du, et al., Mol. Immunol.
2009, 46, 2419-2423. Ofatumumab is commercially available, and its
preparation, properties, and use in cancer and other diseases are
described in more detail in U.S. Pat. No. 8,529,202 B2, the
disclosure of which is incorporated herein by reference. In an
embodiment, the anti-CD20 monoclonal antibody is an anti-CD20
biosimilar monoclonal antibody approved by drug regulatory
authorities with reference to ofatumumab. In an embodiment, the
anti-CD20 monoclonal antibody has a variable heavy chain sequence
identity of greater than 90% to SEQ ID NO:5. In an embodiment, the
anti-CD20 monoclonal antibody has a variable light chain sequence
identity of greater than 90% to SEQ ID NO:6. In an embodiment, the
anti-CD20 monoclonal antibody has a variable heavy chain sequence
identity of greater than 95% to SEQ ID NO:5. In an embodiment, the
anti-CD20 monoclonal antibody has a variable light chain sequence
identity of greater than 95% to SEQ ID NO:6. In an embodiment, the
anti-CD20 monoclonal antibody has a variable heavy chain sequence
identity of greater than 98% to SEQ ID NO:5. In an embodiment, the
anti-CD20 monoclonal antibody has a variable light chain sequence
identity of greater than 98% to SEQ ID NO:6. In an embodiment, the
anti-CD20 monoclonal antibody has a variable heavy chain sequence
identity of greater than 99% to SEQ ID NO:5. In an embodiment, the
anti-CD20 monoclonal antibody has a variable light chain sequence
identity of greater than 99% to SEQ ID NO:6. In an embodiment, the
anti-CD20 monoclonal antibody has a Fab fragment heavy chain
sequence identity of greater than 90% to SEQ ID NO:7. In an
embodiment, the anti-CD20 monoclonal antibody has a Fab fragment
light chain sequence identity of greater than 90% to SEQ ID NO:8.
In an embodiment, the anti-CD20 monoclonal antibody has a Fab
fragment heavy chain sequence identity of greater than 95% to SEQ
ID NO:7. In an embodiment, the anti-CD20 monoclonal antibody has a
Fab fragment light chain sequence identity of greater than 95% to
SEQ ID NO:8. In an embodiment, the anti-CD20 monoclonal antibody
has a Fab fragment heavy chain sequence identity of greater than
98% to SEQ ID NO:7. In an embodiment, the anti-CD20 monoclonal
antibody has a Fab fragment light chain sequence identity of
greater than 98% to SEQ ID NO:8. In an embodiment, the anti-CD20
monoclonal antibody has a Fab fragment heavy chain sequence
identity of greater than 99% to SEQ ID NO:7. In an embodiment, the
anti-CD20 monoclonal antibody has a Fab fragment light chain
sequence identity of greater than 99% to SEQ ID NO:8. In an
embodiment, the anti-CD20 monoclonal antibody ofatumumab is an
immunoglobulin G1, anti-(human B-lymphocyte antigen CD20
(membrane-spanning 4-domains subfamily A member 1, B-lymphocyte
surface antigen B1, Leu-16 or Bp35)); human monoclonal
ofatumumab-CD20 .gamma.l heavy chain (225-214')-disulfide with
human monoclonal ofatumumab-CD20 .kappa. light chain, dimer
(231-231'':234-234'')-bisdisulfide antibody.
[2180] In an embodiment, the anti-CD20 monoclonal antibody is
veltuzumab, or an antigen-binding fragment, derivative, conjugate,
variant, or radioisotope-labeled complex thereof. Veltuzumab is
also known as hA20. Veltuzumab is described in Goldenberg, et al.,
Leuk. Lymphoma 2010, 51, 747-55. In an embodiment, the anti-CD20
monoclonal antibody is an anti-CD20 biosimilar monoclonal antibody
approved by drug regulatory authorities with reference to
veltuzumab. In an embodiment, the anti-CD20 monoclonal antibody has
a heavy chain sequence identity of greater than 90% to SEQ ID NO:9.
In an embodiment, the anti-CD20 monoclonal antibody has a light
chain sequence identity of greater than 90% to SEQ ID NO:10. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 95% to SEQ ID NO:9. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 95% to SEQ ID NO:10. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 98% to SEQ ID NO:9. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 98% to SEQ ID NO:10. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 99% to SEQ ID NO:9. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 99% to SEQ ID NO:10. In an
embodiment, the anti-CD20 monoclonal antibody ofatumumab is an
immunoglobulin G1, anti-(human B-lymphocyte antigen CD20
(membrane-spanning 4-domains subfamily A member 1, Leu-16, Bp35));
[218-arginine, 360-glutamic acid, 362-methionine]humanized mouse
monoclonal hA20 .gamma.1 heavy chain (224-213')-disulfide with
humanized mouse monoclonal hA20 .kappa. light chain
(230-230'':233-233'')-bisdisulfide dimer
[2181] In an embodiment, the anti-CD20 monoclonal antibody is
tositumomab, or an antigen-binding fragment, derivative, conjugate,
variant, or radioisotope-labeled complex thereof. In an embodiment,
the anti-CD20 monoclonal antibody is .sup.131I-labeled tositumomab.
In an embodiment, the anti-CD20 monoclonal antibody is an anti-CD20
biosimilar monoclonal antibody approved by drug regulatory
authorities with reference to tositumomab. In an embodiment, the
anti-CD20 monoclonal antibody has a heavy chain sequence identity
of greater than 90% to SEQ ID NO:11. In an embodiment, the
anti-CD20 monoclonal antibody has a light chain sequence identity
of greater than 90% to SEQ ID NO:12. In an embodiment, the
anti-CD20 monoclonal antibody has a heavy chain sequence identity
of greater than 95% to SEQ ID NO:11. In an embodiment, the
anti-CD20 monoclonal antibody has a light chain sequence identity
of greater than 95% to SEQ ID NO:12. In an embodiment, the
anti-CD20 monoclonal antibody has a heavy chain sequence identity
of greater than 98% to SEQ ID NO:11. In an embodiment, the
anti-CD20 monoclonal antibody has a light chain sequence identity
of greater than 98% to SEQ ID NO:12. In an embodiment, the
anti-CD20 monoclonal antibody has a heavy chain sequence identity
of greater than 99% to SEQ ID NO:11. In an embodiment, the
anti-CD20 monoclonal antibody has a light chain sequence identity
of greater than 99% to SEQ ID NO:12.
[2182] In an embodiment, the anti-CD20 monoclonal antibody is
ibritumomab, or an antigen-binding fragment, derivative, conjugate,
variant, or radioisotope-labeled complex thereof. The active form
of ibritumomab used in therapy is ibritumomab tiuxetan. When used
with ibritumomab, the chelator tiuxetan (diethylene triamine
pentaacetic acid) is complexed with a radioactive isotope such as
.sup.90Y or .sup.111In. In an embodiment, the anti-CD20 monoclonal
antibody is ibritumomab tiuxetan, or radioisotope-labeled complex
thereof. In an embodiment, the anti-CD20 monoclonal antibody is an
anti-CD20 biosimilar monoclonal antibody approved by drug
regulatory authorities with reference to tositumomab. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 90% to SEQ ID NO:13. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 90% to SEQ ID NO:14. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 95% to SEQ ID NO:13. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 95% to SEQ ID NO:14. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 98% to SEQ ID NO:13. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 98% to SEQ ID NO:14. In an
embodiment, the anti-CD20 monoclonal antibody has a heavy chain
sequence identity of greater than 99% to SEQ ID NO:13. In an
embodiment, the anti-CD20 monoclonal antibody has a light chain
sequence identity of greater than 99% to SEQ ID NO:14.
[2183] In an embodiment, an anti-CD20 antibody selected from the
group consisting of obinutuzumab, ofatumumab, veltuzumab,
tositumomab, and ibritumomab, and or antigen-binding fragments,
derivatives, conjugates, variants, and radioisotope-labeled
complexes thereof, is administered to a subject by infusing a dose
selected from the group consisting of about 10 mg, about 20 mg,
about 25 mg, about 50 mg, about 75 mg, 100 mg, about 200 mg, about
300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg,
about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about
1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600
mg, about 1700 mg, about 1800 mg, about 1900 mg, and about 2000 mg.
In an embodiment, the anti-CD20 antibody is admininstered weekly.
In an embodiment, the anti-CD20 antibody is admininstered every two
weeks. In an embodiment, the anti-CD20 antibody is admininstered
every three weeks. In an embodiment, the anti-CD20 antibody is
admininstered monthly. In an embodiment, the anti-CD20 antibody is
administered at a lower initial dose, which is escalated when
administered at subsequent intervals admininstered monthly. For
example, the first infusion can deliver 300 mg of anti-CD20
antibody, and subsequent weekly doses could deliver 2,000 mg of
anti-CD20 antibody for eight weeks, followed by monthly doses of
2,000 mg of anti-CD20 antibody. During any of the foregoing
embodiments, the BTK inhibitors of the present invention and
combinations of the BTK inhibitors with PI3K inhibitors and/or
JAK-2 inhibitors may be administered daily, twice daily, or at
different intervals as described above, at the dosages described
above.
[2184] In an embodiment, the invention provides a kit comprising a
first composition comprising a BTK inhibitor and/or combinations of
the BTK inhibitor with PI3K inhibitor and/or JAK-2 inhibitor and a
second composition comprising an anti-CD20 antibody selected from
the group consisting of rituximab, obinutuzumab, ofatumumab,
veltuzumab, tositumomab, and ibritumomab, or an antigen-binding
fragment, derivative, conjugate, variant, or radioisotope-labeled
complex thereof, for use in the treatment of CLL or SLL,
hematological malignancies, B cell malignancies or, or any of the
other diseases described herein. The compositions are typically
both pharmaceutical compositions. The kit is for use in
co-administration of the anti-CD20 antibody and the BTK inhibitor,
either simultaneously or separately, in the treatment of CLL or
SLL, hematological malignancies, B cell malignancies, or any of the
other diseases described herein.
Combinations of BTK Inhibitors with Chemotherapeutic Active
Pharmaceutical Ingredients
[2185] The combinations of the BTK inhibitors with PI3K inhibitors
and/or JAK-2 inhibitors may also be safely co-administered with
chemotherapeutic active pharmaceutical ingredients such as
gemcitabine, albumin-bound paclitaxel (nab-paclitaxel), and
bendamustine or bendamustine hydrochloride. In a preferred
embodiment, the invention provides a method of treating a
hematological malignancy or a solid tumor cancer in a human
comprising the step of administering to said human a BTK inhibitor,
a PI3K inhibitor, and/or a JAK-2 inhibitor, and further comprising
the step of administering a therapeutically-effective amount of
gemcitabine, or a pharmaceutically acceptable salt, prodrug,
cocrystal, solvate or hydrate thereof. In an embodiment, the
invention provides a method of treating a hematological malignancy
or a solid tumor cancer in a human comprising the step of
administering to said human a BTK inhibitor of Formula (XVIII), or
a pharmaceutically acceptable salt, prodrug, cocrystal, solvate or
hydrate thereof, and further comprising the step of administering a
therapeutically-effective amount of gemcitabine, or a
pharmaceutically acceptable salt, prodrug, cocrystal, solvate or
hydrate thereof. In an embodiment, the solid tumor cancer in any of
the foregoing embodiments is pancreatic cancer.
[2186] In an embodiment, the invention provides a method of
treating a hematological malignancy or a solid tumor cancer in a
human comprising the step of administering to said human a BTK
inhibitor, a PI3K inhibitor, and/or a JAK-2 inhibitor, and further
comprising the step of administering a therapeutically-effective
amount of albumin-bound paclitaxel. In an embodiment, the invention
provides a method of treating a hematological malignancy or a solid
tumor cancer in a human comprising the step of administering to
said human a BTK inhibitor of Formula (XVIII), or a
pharmaceutically acceptable salt or ester, prodrug, cocrystal,
solvate or hydrate thereof, and further comprising the step of
administering a therapeutically-effective amount of
albumin-boundpaclitaxel. In an embodiment, the solid tumor cancer
in any of the foregoing embodiments is pancreatic cancer.
[2187] In an embodiment, the invention provides a method of
treating a hematological malignancy or a solid tumor cancer in a
human comprising the step of administering to said human a BTK
inhibitor, a PI3K inhibitor, and/or a JAK-2 inhibitor, and further
comprising the step of administering a therapeutically-effective
amount of bendamustine hydrochloride. In an embodiment, the
invention provides a method of treating a hematological malignancy
or a solid tumor cancer in a human comprising the step of
administering to said human a BTK inhibitor of Formula (XVIII), or
a pharmaceutically acceptable salt or ester, prodrug, cocrystal,
solvate or hydrate thereof, and further comprising the step of
administering a therapeutically-effective amount of bendamustine
hydrochloride. In an embodiment, the hematological malignancy in
any of the foregoing embodiments is CLL or SLL. In an embodiment,
the invention provides the treatment of a hematological malignancy,
including CLL or SLL, comprising the step of administering to said
human a BTK inhibitor and/or a JAK-2 inhibitor, an anti-CD20
antibody selected from the group consisting of rituximab,
obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and
fragments, derivatives, conjugates, variants, radioisotope-labeled
complexes, and biosimilars thereof, and further comprising the step
of administering a therapeutically-effective amount of bendamustine
or bendamustine hydrochloride.
[2188] The anti-CD20 antibody sequences referenced in the foregoing
are summarized in Table 1.
TABLE-US-00001 TABLE 1 Anti-CD20 antibody sequences. Identifier
Sequence (One-Letter Amino Acid Symbols) SEQ ID NO: 1 QVQLQQPGAE
LVKPGASVKM SCKASGYTFT SYNMHWVKQT PGRGLEWIGA IYPGNGDTSY 60
NQKFKGKATL TADKSSSTAY MQLSSLTSED SAVYYCARST YYGGDWYFNV WGAGTTVTVS
120 AASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG
VHTFPAVLQS 180 SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKKVE
PKSCDKTHTC PPCPAPELLG 240 GPSVFLFPPK PKDTLMISRT PEVTCVVVDV
SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300 NSTYRVVSVL TVLHQDWLNG
KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRD 360 ELTKNQVSLT
CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR 420
WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K 451 SEQ ID NO: 2 QIVLSQSPAI
LSASPGEKVT MTCRASSSVS YIHWFQQKPG SSPKPWIYAT SNLASGVPVR 60
FSGSGSGTSY SLTISRVEAE DAATYYCQQW TSNPPTFGGG TKLEIKRTVA APSVFIFPPS
120 DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS
TYSLSSTLTL 180 SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC 213 SEQ ID NO:
3 QVQLVQSGAE VKKPGSSVKV SCKASGYAFS YSWINWVRQA PGQGLEWMGR IFPGDGDTDY
60 NGKFKGRVTI TADKSTSTAY MELSSLRSED TAVYYCARNV FDGYWLVYWG
QGTLVTVSSA 120 STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW
NSGALTSGVH TFPAVLQSSG 180 LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN
TKVDKKVEPK SCDKTHTCPP CPAPELLGGP 240 SVFLFPPKPK DTLMISRTPE
VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV
LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL 360
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ
420 QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 SEQ ID NO: 4 DIVMTQTPLS
LPVTPGEPAS ISCRSSKSLL HSNGITYLYW YLQKPGQSPQ LLIYQMSNLV 60
SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCAQNLELP YTFGGGTKVE IKRTVAAPSV
120 FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE
QDSKDSTYSL 180 SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC 219 SEQ
ID NO: 5 EVQLVESGGG LVQPGRSLRL SCAASGFTFN DYAMHWVRQA PGKGLEWVST
ISWNSGSIGY 60 ADSVKGRFTI SRDNAKKSLY LQMNSLRAED TALYYCAKDI
QYGNYYYGMD VWGQGTTVTV 120 SS 122 SEQ ID NO: 6 EIVLTQSPAT LSTSPGERAT
LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA 60 RFSGSGSGTD
FTLTISSLEP EDFAVYYCQQ RSNWPITFGQ GTRLEIK 107 SEQ ID NO: 7
EVQLVESGGG LVQPGRSLRL SCAASGFTFN DYAMHWVRQA PGKGLEWVST ISWNSGSIGY
60 ADSVKGRFTI SRDNAKKSLY LQMNSLRAED TALYYCAKDI QYGNYYYGMD
VWGQGTTVTV 120 SSASTKGPSV FPLAPGSSKS TSGTAALGCL VKDYFPEPVT
VSWNSGALTS GVHTFPAVLQ 180 SSGLYSLSSV VTVPSSSLGT QTYICNVNHK
PSNTKVDKKV EP 222 SEQ ID NO: 8 EIVLTQSPAT LSLSPGERAT LSCRASQSVS
SYLAWYQQKP GQAPRLLIYD ASNRATGIPA 60 RFSGSGSGTD FTLTISSLEP
EDFAVYYCQQ RSNWPITFGQ GTRLEIKRTV AAPSVFIFPP 120 SDEQLKSGTA
SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT 180
LSKADYEKHK VYACEVTHQG LSSPVTKSFN R 211 SEQ ID NO: 9 QVQLQQSGAE
VKKPGSSVKV SCKASGYTFT SYNMHWVKQA PGQGLEWIGA IYPGMGDTSY 60
NQKFKGKATL TADESTNTAY MELSSLRSED TAFYYCARST YYGGDWYFDV WGQGTTVTVS
120 SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG
VHTFPAVLQS 180 SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKRVE
PKSCDKTHTC PPCPAPELLG 240 GPSVFLFPPK PKDTLMISRT PEVTCVVVDV
SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300 NSTYRVVSVL TVLHQDWLNG
KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRE 360 EMTKNQVSLT
CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR 420
WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K 451 SEQ ID NO: 10 DIQLTQSPSS
LSASVGDRVT MTCRASSSVS YIHWFQQKPG KAPKPWIYAT SNLASGVPVR 60
FSGSGSGTDY TFTISSLQPE DIATYYCQQW TSNPPTFGGG TKLEIKRTVA APSVFIFPPS
120 DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS
TYSLSSTLTL 180 SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC 213 SEQ ID NO:
11 QAYLQQSGAE LVRPGASVKM SCKASGYTFT SYNMHWVKQT PRQGLEWIGA
IYPGNGDTSY 60 NQKFKGKATL TVDKSSSTAY MQLSSLTSED SAVYFCARVV
YYSNSYWYFD VWGTGTTVTV 120 SGPSVFPLAP SSKSTSGGTA ALGCLVKDYF
PEPVTVSWNS GALTSGVHTF PAVLQSSGLY 180 SLSSVVTVPS SSLGTQTYIC
NVNHKPSNTK VDKKAEPKSC DKTHTCPPCP APELLGGPSV 240 FLFPPKPKDT
LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 300
RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK
360 NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL
TVDKSRWQQG 420 NVFSCSVMHE ALHNHYTQKS LSLSPGK 447 SEQ ID NO: 12
QIVLSQSPAI LSASPGEKVT MTCRASSSVS YMHWYQQKPG SSPKPWIYAP SNLASGVPAR
60 FSGSGSGTSY SLTISRVEAE DAATYYCQQW SFNPPTFGAG TKLELKRTVA
APSVFIFPPS 120 DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE
SVTEQDSKDS TYSLSSTLTL 180 SKADYEKHKV YACEVTHQGL SSPVTKSFNR 210 SEQ
ID NO: 13 QAYLQQSGAE LVRPGASVKM SCKASGYTFT SYNMHWVKQT PRQGLEWIGA
IYPGNGDTSY 60 NQKFKGKATL TVDKSSSTAY MQLSSLTSED SAVYFCARVV
YYSNSYWYFD VWGTGTTVTV 120 SAPSVYPLAP VCGDTTGSSV TLGCLVKGYF
PEPVTLTWNS GSLSSGVHTF PAVLQSDLYT 180 LSSSVTVTSS TWPSQSITCN
VAHPASSTKV DKKIEPRGPT IKPCPPCKCP APNLLGGPSV 240 FIFPPKIKDV
LMISLSPIVT CVVVDVSEDD PDVQISWFVN NVEVHTAQTQ THREDYNSTL 300
RVVSALPIQH QDWMSGKEFK CKVNNKDLPA PIERTISKPK GSVRAPQVYV LPPPEEEMTK
360 KQVILICMVT DFMPEDIYVE WTNNGKTELN YKNTEPVLDS DGSYFMYSKL
RVEKKNWVER 420 NSYSCSVVHE GLHNHHTTKS FSR 443 SEQ ID NO: 14
QIVLSQSPAI LSASPGEKVT MTCRASSSVS YMHWYQQKPG SSPKPWIYAP SNLASGVPAR
60 FSGSGSGTSY SLTISRVEAE DAATYYCQQW SFNPPTFGAG TKLELKRADA
APTVFIFPPS 120 DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE
SVTEQDSKDS TYSLSSTLTL 180 SKADYEKHKV YACEVTHQGL SSPVTKSFN 209
[2189] While preferred embodiments of the invention are shown and
described herein, such embodiments are provided by way of example
only and are not intended to otherwise limit the scope of the
invention. Various alternatives to the described embodiments of the
invention may be employed in practicing the invention.
EXAMPLES
[2190] The embodiments encompassed herein are now described with
reference to the following examples. These examples are provided
for the purpose of illustration only and the disclosure encompassed
herein should in no way be construed as being limited to these
examples, but rather should be construed to encompass any and all
variations which become evident as a result of the teachings
provided herein.
Example 1 Synergistic Combination of a BTK Inhibitor and a
PI3K-.delta. Inhibitor
[2191] Ficoll purified mantle cell lymphoma (MCL) cells
(2.times.10.sup.5) isolated from bone marrow or peripheral blood
were treated with each drug alone and with six equimolar
concentrations of a BTK inhibitor (Formula (XVIII)) and a
PI3K-.delta. inhibitor (Formula (IX)) ranging from 0.01 nM to 10
.mu.M on 96-well plates in triplicate. Plated cells were then
cultured in HS-5 conditioned media at 37.degree. C. with 5%
CO.sub.2. After 72 hours of culture, cell viability was determined
using an
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl-
)-2H-tetrazolium) (MTS) assay (Cell Titer 96, Promega). Viability
data were used to generate cell viability curves for each drug
alone and in combination for each sample. The potential synergy of
the combination of the BTK inhibitor of Formula (XVIII) and the
PI3K-.delta. inhibitor of Formula (IX) at a given equimolar
concentration was determined using the median effect model as
described in Chou and Talalay, Adv Enzyme Regul. 1984, 22, 27-55.
The statistical modeling was run in R using a script that utilizes
the median effect model as described in Lee et al., J. Biopharm.
Stat. 2007, 17, 461-80. A value of 1, less than 1, and greater than
1 using R defines an additive interaction, a synergistic
interaction, and an antagonistic interaction, respectively. The Lee
et al. method calculates a 95% confidence interval for each data
point. For each viability curve, to be considered synergistic, a
data point must have an interaction index below 1 and the upper
confidence interval must also be below 1. In order to summarize and
demonstrate collective synergy results, an interaction dot blot was
generated for the primary patient samples.
[2192] A similar approach was utilized to study diffuse large B
cell lymphoma (DLBCL) (TMD8) and MCL (MINO) cell lines. Cells were
treated with each drug alone and with six equimolar concentrations
of the BTK inhibitor of Formula (XVIII) and the PI3K-.delta.
inhibitor of Formula (IX) ranging from 0.003 nM to 1.0 .mu.M (for
TMD8) or 0.03 nM to 10 .mu.M (for MINO) on 96-well plates in
triplicate. Plated cells were then cultured in standard conditioned
media plus FBS at 37.degree. C. with 5% CO.sub.2. After 72 hours of
culture, viability was determined using an MTS assay (Cell Titer
96, Promega). Viability data were used to generate cell viability
curves for each drug alone and in combination for each sample. The
results of the experiments described in this example are shown in
FIG. 1, FIG. 2, FIG. 3, and FIG. 4.
Example 2 Synergistic Combination of a BTK Inhibitor and a
PI3K-.delta. Inhibitor
[2193] Combination experiments were performed to determine the
synergistic, additive, or antagonistic behavior of drug
combinations using the Chou/Talalay method/algorithm by defining
combination indexes for drug combinations. Information about
experimental design for evaluation of synergy is described in e.g.
Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55 and more
generally in e.g. Greco et al., Pharmacol. Rev. 1995, 47, 331-385.
The study was performed using the BTK inhibitor of Formula (XVIII)
and the PI3K-.delta. inhibitor of Formula (IX). Single drug
activities were first determined in the various cell lines and
subsequently, the combination indexes were established using
equimolar ratios taking the single agent drug EC50s into
consideration. For individual drugs that displayed no single drug
activity, equimolar ratios were used at fixed concentrations to
establish combination indexes. The readout from 72 hour
proliferation assays using Cell TiterGlo (ATP content of remaining
cells) determined the fraction of cells that were effected as
compared to untreated cells (Fa=fraction
affected=(1-((cells+inhibitor) background signal)/((cells+DMSO)
background signal)).
[2194] The combination index obtained was ranked according to Table
2.
TABLE-US-00002 TABLE 2 Combination Index (CI) Ranking Scheme Range
of CI Description <0.1 Very strong synergism 0.1-0.3 Strong
synergism 0.3-0.7 Synergism 0.7-0.85 Moderate synergism 0.85-0.9
Slight synergism 0.9-1.1 Nearly additive 1.1-1.2 Slight antagonism
1.2-1.45 Moderate antagonism 1.45-3.3 Antagonism 3.3-10 Strong
antagonism >10 Very strong antagonism
[2195] The detailed results of the cell line studies for the BTK
inhibitor of Formula (XVIII) and the PI3K-.delta. inhibitor of
Formula (IX) are given in FIG. 5 to FIG. 37. The results of the
cell line studies are summarized in Table 3.
TABLE-US-00003 TABLE 3 Summary of results of the combination of a
BTK inhibitor with a PI3K-.delta. inhibitor Cell Line Indication
ED25 ED50 ED75 ED90 Raji Burkitt's S S S S Ramos Burkitt's X X X X
Daudi Burkitt's S S S S Mino MCL S S S S Pfeiffer iNHL S S S S DOHH
iNHL S S S S REC-1 iNHL S S A A U937 Myeloid S S S S K562 CML X X X
X SU-DHL-1 ABC S A X X SU-DHL-2 ABC S S S S HBL-1 ABC S S S S TMD8
ABC S S S S LY19 GCB X X X X LY7 GCB S S S S LY1 GCB X X X X
SU-DHL-6 GCB S S S S SupB15 B-ALL S S S S CCRF B-ALL S A/S X X (S =
synergistic, A = additive, X = no effect).
Example 3 Synergistic Combination of a BTK Inhibitor and the JAK-2
Inhibitor Ruxolitinib
[2196] Combination experiments were performed to determine the
synergistic, additive, or antagonistic behavior of drug
combinations using the methods described above in Example 2. The
study was performed using the BTK inhibitor of Formula (XVIII) and
the JAK-2 inhibitor of Formula XXX (ruxolitinib).
[2197] The detailed results of the cell line studies for the BTK
inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula XXX
(ruxolitinib) are given in FIG. 38 to FIG. 65. The results of the
cell line studies are summarized in Table 4.
TABLE-US-00004 TABLE 4 Summary of results of the combination of a
BTK inhibitor with the JAK-2 inhibitor of Formula XXX (ruxolitinib)
Cell Line Indication ED25 ED50 ED75 ED90 Raji Burkitt's S S S S
Ramos Burkitt's S S S S Daudi Burkitt's S S S S Mino MCL S S S S
Pfeiffer iNHL S S S S DOHH iNHL S S S S REC-1 iNHL S S S S JVM-2
CLL like S S S X U937 Myeloid X X X X K562 CML X X X X SU-DHL-1 ABC
S S S S SU-DHL-2 ABC S S S X HBL-1 ABC S S S S TMD8 ABC S S S S
LY19 GCB X X X X LY7 GCB X X X X LY1 GCB X X X X SU-DHL-6 GCB S S X
X SupB15 B-ALL X X X X CCRF B-ALL X X A A (S = synergistic, A =
additive, X = no effect).
Example 4 Synergistic Combination of a BTK Inhibitor and the JAK-2
Inhibitor Pacritinib
[2198] Combination experiments were performed to determine the
synergistic, additive, or antagonistic behavior of drug
combinations using the methods described above in Example 2. The
study was performed using the BTK inhibitor of Formula (XVIII) and
the JAK-2 inhibitor of Formula LIV (pacritinib).
[2199] The detailed results of the cell line studies for the BTK
inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula LIV
(pacritinib) are given in FIG. 66 to FIG. 94. The results of the
cell line studies are summarized in Table 5.
TABLE-US-00005 TABLE 5 Summary of results of the combination of a
BTK inhibitor with the JAK-2 inhibitor of Formula LIV (pacritinib)
Cell Line Indication ED25 ED50 ED75 ED90 Mino MCL S S S S JVM-2
prolymphocytic leukemia S S S S Mayer-1 B-ALL, MCL S S S S Raji
B-ALL, Burkitt's S S S S Daudi Burkitt's S S S S Rec-1 FL X S S S
CCRF B-ALL S S S S Sup-B15 B-ALL S S A A SU-DHL-4 DLBCL-ABC S S S S
EB3 B-ALL, Burkitt's S S S S CA46 B-ALL, Burkitt's S S S S Pfeiffer
FL S S S S DB B-ALL, MCL S S S S DOHH2 FL S S S S Namalwa B-ALL,
Burkitt's S S S S JVM-13 B-ALL, MCL S S S S SU-DHL-1 DLBCL-ABC S S
S S SU-DHL-2 DLBCL-ABC S S S X Ramos Burkitt's S S S S SU-DHL-6
DLBCL-GCB S S S A TMD-8 DLBCL-ABC X X S S SU-DHL-10 DLBCL-GCB S S S
S HBL-1 DLBCL-ABC S S S X OCI-Ly3 DLBCL-ABC S S S S OCI-Ly7
DLBCL-ABC S S S S Jeko B-ALL, MCL S S S S (S = synergistic, A =
additive, X = no effect).
Example 5 BTK Inhibitory Effects on Solid Tumor Microenvironment in
an Orthotopic Pancreatic Cancer Model
[2200] An orthotopic pancreatic cancer model was used to
investigate the therapeutic efficacy of the combination of the BTK
inhibitor of Formula (XVIII) and the PI3K-.delta. inhibitor of
Formula (IX) through treatment of the solid tumor microenvironment.
Mice were dosed orally with 15 mg/kg of Formula (XVIII), 15 mg/kg
of Formula (IX), or a combination of 15 mg/kg of both drugs.
[2201] Cell line derived from KrasG12D;Trp53R.sup.172H;Pdx1-Cre
(KPC) mice were orthotopically implanted into the head of the
pancreas after 35 passages. Based on the mice background from where
the cell lines were generated, 1.times.10.sup.6 cells were injected
in C57BL/6 mice. Throughout the experiment, animals were provided
with food and water ad libitum and subjected to a 12-h dark/light
cycle. Animal studies were performed in accordance with the U.S.
Public Health Service "Guidelines for the Care and Use of
Laboratory Animals" (IACUC). After euthanization, pancreatic tumors
were dissected out, weighed and single cell suspensions were
prepared for flow cytometry analysis.
[2202] Results of the experiments are shown in FIG. 95, which
illustrates tumor growth suppression in the orthotopic pancreatic
cancer model. The statistical p-value (presumption against null
hypothesis) is shown for each tested single agent and for the
combination against the vehicle. The results show that all three
treatments provide statistically significant reductions in tumor
volume in the pancreatic cancer model.
[2203] Additional results of the experiments relating to treatment
of the tumor microenvironment are shown in FIG. 96 to FIG. 98. FIG.
96 shows the effects of oral dosing with 15 mg/kg of the BTK
inhibitor of Formula (XVIII), 15 mg/kg of the PI3K inhibitor of
Formula (IX), or a combination of both drugs on myeloid
tumor-associated macrophages (TAMs) in pancreatic tumor-bearing
mice. FIG. 97 illustrates the effects of oral dosing with 15 mg/kg
of the BTK inhibitor of Formula (XVIII), 15 mg/kg of the PI3K
inhibitor of Formula (IX), or a combination of both inhibitors on
myeloid-derived suppressor cells (MDSCs) in pancreatic
tumor-bearing mice. FIG. 98 illustrates the effects of oral dosing
with 15 mg/kg of the BTK inhibitor of Formula (XVIII), 15 mg/kg of
the PI3K inhibitor of Formula (IX), or a combination of both
inhibitors on regulatory T cells (Tregs) in pancreatic
tumor-bearing mice. The results shown in FIG. 96 to FIG. 98
demonstrate that administration of the BTK inhibitor of Formula
(XVIII) and the combination of the BTK inhibitor of Formula (XVIII)
and the PI3K inhibitor of Formula (IX) reduce immunosuppressive
tumor associated myeloid cells and Tregs in pancreatic
tumor-bearing mice. Overall, BTK inhibition with Formula (XVIII) or
a combination of Formula (XVIII) and Formula (IX) significantly
reduced tumor burden in an aggressive orthotopic PDA model,
decreased immature myeloid infiltrate, reduced the number of tumor
associated macrophages, and reduced the number of immunosuppressive
Tregs, demonstrating a strong effect on the tumor
microenvironment.
Example 6 BTK Inhibitory Effects on Solid Tumor Microenvironment in
an Ovarian Cancer Model
[2204] The ID8 syngeneic orthotropic ovarian cancer murine model
was used to investigate the therapeutic efficacy of the BTK
inhibitor of Formula (XVIII) through treatment of the solid tumor
microenvironment. Human ovarian cancer models, including the ID8
syngeneic orthotropic ovarian cancer model and other animal models,
are described in Fong and Kakar, J. Ovarian Res. 2009, 2, 12;
Greenaway et al., Gynecol. Oncol. 2008, 108, 385-94; Urzua et al.,
Tumour Biol. 2005, 26, 236-44; Janat-Amsbury et al., Anticancer
Res. 2006, 26, 3223-28; Janat-Amsbury et al., Anticancer Res. 2006,
26, 2785-89. Animals were treated with vehicle or Formula (XVIII),
15 mg/kg/BID given orally. The results of the study are shown in
FIG. 99, FIG. 100, FIG. 101, FIG. 102, FIG. 103, FIG. 104, FIG.
105, and FIG. 106.
[2205] FIG. 99 and FIG. 100 demonstrate that the BTK inhibitor of
Formula (XVIII) impairs ID8 ovarian cancer growth in the ID8
syngeneic murine model. FIG. 101 shows that tumor response to
treatment with the BTK inhibitor of Formula (XVIII) correlates with
a significant reduction in immunosuppressive tumor-associated
lymphocytes in tumor-bearing mice. FIG. 102 shows treatment with
the BTK inhibitor of Formula (XVIII) impairs ID8 ovarian cancer
growth (through reduction in tumor volume) in the syngeneic murine
model. FIG. 103 and FIG. 104 show that the tumor response induced
by treatment with the BTK inhibitor of Formula (XVIII) correlates
with a significant reduction in immunosuppressive B cells in
tumor-bearing mice. FIG. 105 and FIG. 106 show that the tumor
response induced by treatment with the BTK inhibitor of Formula
(XVIII) correlates with a significant reduction in
immunosuppressive tumor associated Tregs and an increase in
CD8.sup.+ T cells.
[2206] The results shown in FIG. 99 to FIG. 106 illustrate the
surprising efficacy of the BTK inhibitor of Formula (XVIII) in
modulating tumor microenvironment in a model predictive of efficacy
as a treatment for ovarian cancer in humans.
Example 7 Synergistic Combination of a BTK Inhibitor and
Gemcitabine in an Orthotopic Pancreatic Cancer Model and Effects on
Solid Tumor Microenvironment
[2207] A study was performed to observe potential reduction in
tumor burden through modulation of tumor infiltrating MDSCs and
TAMs using the BTK inhibitor of Formula (XVIII) and/or gemcitabine
("Gem"). In this study, KPC derived mouse pancreatic cancer cells
(KrasG12D;Trp53R.sup.172H;Pdx1-Cre) were injected into the
pancreases. Animals were treated with (1) vehicle; (2) Formula
(XVIII), 15 mg/kg/BID given orally; (3) gemcitabine 15 mg/kg
intravenous (IV) administered every 4 days for 3 injections; or (4)
Formula (XVIII), 15 mg/kg/BID given orally together with
gemcitabine, 15 mg/kg IV administered every 4 days for 3
injections.
[2208] Single cell suspensions from tumor samples. Mouse tumor
tissue was collected and stored in PBS/0.1% soybean trypsin
inhibitor prior to enzymatic dissociation. Samples were finely
minced with a scissors and mouse tissue was transferred into DMEM
containing 1.0 mg/ml collagenase IV (Gibco), 0.1% soybean trypsin
inhibitor, and 50 U/ml DNase (Roche) and incubated at 37.degree. C.
for 30 min. with constant stirring while human tissue was digested
in 2.0 mg/ml collagenase IV, 1.0 mg/ml hyaluronidase, 0.1% soybean
trypsin inhibitor, and 50 U/ml DNase for 45 minutes. Suspensions
were filtered through a 100 micron filter and washed with FACS
buffer (PBS/0.5% BSA/2.0 mM EDTA) prior to staining. Two million
total cells were stained with antibodies as indicated.
Intracellular detection of FoxP3 was achieved following
permeabilization with BD Perm Buffer III (BD Biosciences) and
eBioscience Fix/Perm respectively. Following surface staining,
samples were acquired on a BD Fortessa and analyzed using FlowJo
(Treestar) software.
[2209] In FIG. 107, the reduction in tumor size upon treatment is
shown. The effects on particular cell subsets are shown in the flow
cytometry data presented in FIG. 108, FIG. 109, FIG. 110, and FIG.
111.
[2210] The results shown in FIG. 107 to FIG. 111 illustrate
reduction in tumor burden by modulating the tumor infiltrating
MDSCs and TAMs, which affects Treg and CD8.sup.+ T cell levels,
through inhibition of BTK using Formula (XVIII). A synergistic
effect using the combination of Formula (XVIII) and gemcitabine is
observed in the tumor volumes shown in FIG. 107, which are reduced
well beyond the level observed with either Formula (XVIII) or
gemcitabine alone or expected from their additive combination.
Example 8 Effects of BTK Inhibitors on Thrombosis
[2211] Clinical studies have shown that targeting the BCR signaling
pathway by inhibiting BTK produces significant clinical benefit
(Byrd, et al., N. Engl. J. Med. 2013, 369(1), 32-42, Wang, et al.,
N. Engl. J. Med. 2013, 369(6), 507-16). However, in these studies,
bleeding has been reported in up to 50% of ibrutinib-treated
patients. Most bleeding events were of grade 1-2 (spontaneous
bruising or petechiae) but, in 5% of patients, they were of grade 3
or higher after trauma. These results are reflected in the
prescribing information for ibrutinib, where bleeding events of any
grade, including bruising and petechiae, were reported in about
half of patients treated with ibrutinib (IMBRUVICA package insert
and prescribing information, revised July 2014, U.S. Food and Drug
Administration).
[2212] Constitutive or aberrant activation of the BCR signaling
cascade has been implicated in the propagation and maintenance of a
variety of B cell malignancies. Small molecule inhibitors of BTK, a
protein early in this cascade and specifically expressed in B
cells, have emerged as a new class of targeted agents. There are
several BTK inhibitors, including Formula XXVII (CC-292), and
Formula XX-A (PCI-32765, ibrutinib), in clinical development.
Importantly, early stage clinical trials have found ibrutinib to be
particularly active in chronic lymphocytic leukemia (CLL) and
mantle cell lymphoma (MCL), suggesting that this class of
inhibitors may play a significant role in various types of cancers
(Aalipour and Advani, Br. J. Haematol. 2013, 163, 436-43). However,
their effects are not limited to leukemia or lymphomas as platelets
also rely on the Tec kinases family members BTK and Tec for signal
transduction in response to various thrombogenic stimuli (Oda, et
al., Blood 2000, 95(5), 1663-70; Atkinson, et al., Blood 2003,
102(10), 3592-99). In fact, both Tec and BTK play an important role
in the regulation of phospholipase C.gamma.2 (PLC.gamma.2)
downstream of the collagen receptor glycoprotein VI (GPVI) in human
platelets. In addition, BTK is activated and undergoes tyrosine
phosphorylation upon challenge of the platelet thrombin receptor,
which requires the engagement of .alpha.IIb.beta.3 integrin and
PI3K activity (Laffargue, et al., FEBS Lett. 1999, 443(1), 66-70).
It has also been implicated in GPIb.alpha.-dependent thrombus
stability at sites of vascular injury (Liu, et al., Blood 2006,
108(8), 2596-603). Thus, BTK and Tec are involved in several
processes important in supporting the formation of a stable
hemostatic plug, which is critical for preventing significant blood
loss in response to vascular injury. Hence, the effects of the BTK
inhibitor of Formula (XVIII) and ibrutinib were evaluated on human
platelet-mediated thrombosis by utilizing the in vivo human
thrombus formation in the VWF HA1 mice model described in Chen, et
al., Nat. Biotechnol. 2008, 26(1), 114-19.
[2213] Administration of anesthesia, insertion of venous and
arterial catheters, fluorescent labeling and administration of
human platelets (5.times.10.sup.8/ml), and surgical preparation of
the cremaster muscle in mice have been previously described (Chen
et al., Nat Biotechnol. 2008, 26(1), 114-19). Injury to the vessel
wall of arterioles (.about.40-65 mm diameter) was performed using a
pulsed nitrogen dye laser (440 nm, Photonic Instruments) applied
through a 20.times. water-immersion Olympus objective (LUMPlanF1,
0.5 numerical aperature (NA)) of a Zeiss Axiotech vario microscope.
Human platelet and wall interactions were visualized by
fluorescence microscopy using a system equipped with a Yokogawa
CSU-22 spinning disk confocal scanner, iXON EM camera, and 488 nm
and 561 nm laser lines to detect BCECF-labeled and
rhodamine-labeled platelets, respectively (Revolution XD, Andor
Technology). The extent of thrombus formation was assessed for 2
minutes after injury and the area (.mu.m.sup.2) of coverage
determined (Image IQ, Andor Technology). For the Formula (XVIII),
Formula (XXVII) (CC-292), and Formula (XX-A) (ibrutinib) inhibition
studies, the BTK inhibitors were were added to purified human
platelets for 30 minutes before administration.
[2214] The in vivo throbus effects of the BTK inhibitors, Formula
(XVIII), Formula (XXVII) (CC-292), and Formula (XX-A) (ibrutinib),
were evaluated on human platelet-mediated thrombosis by utilizing
the in vivo human thrombus formation in the VWF HA1 mice model,
which has been previously described (Chen, et al., Nat Biotechnol.
2008, 26(1), 114-19). Purified human platelets were preincubated
with various concentrations of the BTK inhibitors (0.1 .mu.M, 0.5
.mu.M, or 1 .mu.M) or DMSO and then administered to VWF HA1 mice,
followed by laser-induced thrombus formation. The BTK
inhibitor-treated human platelets were fluorescently labeled and
infused continuously through a catheter inserted into the femoral
artery. Their behavior in response to laser-induced vascular injury
was monitored in real time using two-channel confocal intravital
microscopy (Furie and Furie, J. Clin. Invest. 2005, 115(12),
2255-62). Upon induction of arteriole injury untreated platelets
rapidly formed thrombi with an average thrombus size of
6,450.+-.292 mm.sup.2 (mean.+-.s.e.m.), as shown in FIG. 112 and
FIG. 113. Similarly, Formula (XVIII) (1 .mu.M) treated platelets
formed a slightly smaller but not significantly different thrombi
with an average thrombus size of 5733.+-.393 mm.sup.2
(mean.+-.s.e.m.). In contrast, a dramatic reduction in thrombus
size occurred in platelets pretreated with 1 .mu.M of Formula XX-A
(ibrutinib), 2600.+-.246 mm.sup.2 (mean.+-.s.e.m.), resulting in a
reduction in maximal thrombus size by about 61% compared with
control (P>0.001) (FIG. 112 and FIG. 114). Similar results were
obtained with platelets pretreated with 500 nM of Formula (XVIII)
or ibrutinib: thrombus size of 5946.+-.283 mm.sup.2, and
2710.+-.325 mm.sup.2 respectively. These initial results may
provide some mechanic background and explanation on the reported
44% bleeding related adverse event rates in the Phase III RESONATE
study comparing ibrutinib with ofatumumab. The results obtained for
Formula XXVII (CC-292) were similar to that for Formula XX-A
(ibrutinib), as shown in FIGS. 112, 113, and 114. The effect of the
BTK inhibitor concentration is shown in FIG. 115. These results
demonstrate the surprising advantage of the BTK inhibitor of
Formula (XVIII), which does not interfere with thrombus formation,
while the BTK inhibitors of Formula XXVII (CC-292) and Formula XX-A
(ibrutinib) interfere with thrombus formation.
[2215] The objective of this study was to evaluate in vivo thrombus
formation in the presence of BTK inhibitors. In vivo testing of
novel antiplatelet agents requires informative biomarkers. By
utilizing a genetic modified mouse von Willebrand factor
(VWFR1326H) model that supports human but not mouse
platelet-mediated thrombosis, we evaluated the effects of Formula
(XVIII), Formula XXVII (CC-292), and Formula XX-A (ibrutinib) on
thrombus formation. These results show that Formula (XVIII) had no
significant effect on human platelet-mediated thrombus formation
while Formula XX-A (ibrutinib) was able to limit this process,
resulting in a reduction in maximal thrombus size by 61% compared
with control. Formula XXVII (CC-292) showed an effect similar to
Formula XX-A (ibrutinib). These results, which show reduced
thrombus formation for ibrutinib at physiologically relevant
concentrations, may provide some mechanistic background for the
Grade .gtoreq.3 bleeding events (eg, subdural hematoma,
gastrointestinal bleeding, hematuria and postprocedural hemorrhage)
that have been reported in .ltoreq.6% of patients treated with
Formula XX-A (ibrutinib).
[2216] GPVI platelet aggregation was measured for Formula (XVIII)
and Formula XX-A (ibrutinib). Blood was obtained from untreated
humans, and platelets were purified from plasma-rich protein by
centrifugation. Cells were resuspended to a final concentration of
350,000/.mu.L in buffer containing 145 mmol/L NaCl, 10 mmol/L
HEPES, 0.5 mmol/L Na.sub.2HPO.sub.4, 5 mmol/L KCl, 2 mmol/L
MgCl.sub.2, 1 mmol/L CaCl.sub.2, and 0.1% glucose, at pH 7.4. Stock
solutions of Convulxin (CVX) GPVI were prepared on the day of
experimentation and added to platelet suspensions 5 minutes
(37.degree. C., 1200 rpm) before the induction of aggregation.
Aggregation was assessed with a Chronolog Lumi-Aggregometer (model
540 VS; Chronolog, Havertown, Pa.) and permitted to proceed for 6
minutes after the addition of agonist. The results are reported as
maximum percent change in light transmittance from baseline with
platelet buffer used as a reference. The results are shown in FIG.
116.
[2217] In FIG. 117, the results of CVX-induced (250 ng/mL) human
platelet aggregation results before and 15 minutes after
administration of the BTK inhibitors to 6 healthy individuals are
shown.
[2218] The results depicted in FIG. 116 and FIG. 117 indicate that
the BTK inhibitor of Formula XX-A (ibrutinib) significantly
inhibits GPVI platelet aggregation, while the BTK inhibitor of
Formula (XVIII) does not, further illustrating the surprising
benefits of the latter compound. Furthermore, the combination of
the BTK inhibitor of Formula (XVIII) with a JAK-2 inhibitor,
including the JAK-2 inhibitors ruxolitinib and pacritinib, is
suprisingly favorable because of the tendency of these JAK-2
inhibitors to cause thrombocytopenia and other disordered
associated with increased bleeding.
Example 9 Study of a BTK Inhibitor and a Combination of a BTK
Inhibitor and a PI3K Inhibitor in Canine Lymphoma
[2219] Canine B cell lymphoma exists as a pathological entity that
is characterized by large anaplastic, centroblastic or
immunoblastic lymphocytes with high proliferative grade,
significant peripheral lymphadenopathy and an aggressive clinical
course. While some dogs respond initially to prednisone, most
canine lymphomas progress quickly and must be treated with
combination therapies, including cyclophosphamide, vincristine,
doxorubicin, and prednisone (CHOP), or other cytotoxic agents. In
their histopathologic features, clinical course, and high relapse
rate after initial treatment, canine B cell lymphomas resemble
diffuse large B cell lymphoma (DLBCL) in humans. Thus, responses of
canine B cell lymphomas to experimental treatments are considered
to provide proof of concept for therapeutic candidates in
DLBCL.
[2220] In this example, companion dogs with newly diagnosed or
relapsed/refractory B cell lymphoma were enrolled on a veterinary
clinical trial of the BTK inhibitor of Formula (XVIII) ("Arm 1") or
the BTK inhibitor of Formula (XVIII) and the PI3K-.delta. inhibitor
of Formula (IX) ("Arm 2"). Enrollment has completed for both arms.
The results show that combined treatment with the BTK inhibitor of
Formula (XVIII) and the PI3K-.delta. inhibitor of Formula (IX) may
have greater efficacy than treatment with the BTK inhibitor of
Formula (XVIII) alone in aggressive lymphomas.
[2221] Twenty-one dogs were treated in Arm 1 with the BTK inhibitor
of Formula (XVIII) at dosages of 2.5 mg/kg once daily to 20 mg/kg
twice daily. Intra-subject dose escalation was allowed. Six of the
11 dogs that initiated at 2.5 or 5 mg/kg once daily were escalated
and completed the study with dosages of 10 mg/kg twice daily. Among
all the dose cohorts, 8 dogs had shrinkage of target lesions
>20%; the best tumor responses were between 45-49% reduction in
the sum of target lesions in two dogs. Complete responses ("CR",
disappearance of all evidence of disease per evaluator judgment;
and absence of new lesions) were not observed in Arm 1. CR were
defined as disappearance of all evidence of disease per evaluator
judgment, and absence of new lesions. Vali, et al., Vet. Comp.
Oncol. 2010, 8, 28-37.
[2222] In the combination phase of the study (Arm 2), 10 dogs were
treated with 10 mg/kg the BTK inhibitor of Formula (XVIII) and the
PI3K-.delta. inhibitor of Formula (IX) at 2.5 or 3.5 mg/kg, on a
twice daily schedule. Of these, 7 dogs had shrinkage of target
lesions >20%, providing evidence of biological activity for the
combination; four of these dogs achieved a PR. The best tumor
responses were between 58-65% reduction in the sum of target
lesions, with one sustained CR observed among the 10 dogs treated.
The initial reductions in the sum of target lesions continued to
deepen during the course of therapy in 7 of the 10 dogs. A summary
of the results is presented in Table 6.
TABLE-US-00006 TABLE 6 Summary of the results of the canine
lymphoma study. Formula Formula (XVIII) and (XVIII) Response Metric
Formula (IX) monotherapy Sum LD.sup.a decreased by .gtoreq.20% 7/10
(70%) 8/21 (38%) Sum LD.sup.a decreased by .gtoreq.30% (PR) 4/10
(40%) 6/21 (28.6%) CR by investigator evaluation 1/10 (10%) 0/21
(0%) Median time on study 23 days 24 days Median time to best
response 18 days 7 days .sup.aLD, longest diameter, sum of up to 5
target lesions.
[2223] These data suggest that in companion dogs with naturally
occurring B cell lymphomas, treatment with the combination of the
BTK inhibitor of Formula (XVIII) and the PI3K-.delta. inhibitor of
Formula (IX) may provide increased biological activity (tumor
shrinkage and stable disease) and may possibly lead to deeper
responses than treatment with the BTK inhibitor of Formula (XVIII)
alone. The higher rate of biological responses and extended
response duration (median time to best response), along with the
observation of a CR in this aggressive disease setting, provide
evidence of synergy between Formula (XVIII) and Formula (IX).
Example 10 Study of a Combination of a BTK Inhibitor and a PI3K
Inhibitor in DLBCL Cell Lines
[2224] To explore the role of PI3K signaling in diffuse large
B-cell lymphoma ("DLBCL"), several DLBCL cell lines of varying
molecular profiles may be utilized. In an exemplary embodiment, a
cellular growth inhibition assay used five cell lines, including
four GCB (SU-DHL-4, SU-DHL-6, OCI-LY-8 and WSU-DLCL-2) and one ABC
(Ri-1) subtype. In an exemplary embodiment, a cellular growth
inhibition assay used five cell lines that were OCI-LY-3, OCI-LY-7,
Pfeiffer, Toledo and U2932. In an exemplary embodiment, evidence of
PI3K pathway inhibition is measured by reduction in phospho
(p)-AKT. In an exemplary embodiment, the kinetics of pathway
modulation was characterized by examination of phosphorylation of
AKT, PRAS40 and S6 following a time-course of treatment by a
PI3K-inhibitor in selected cell lines. In one embodiment, upon
B-cell receptor stimulation via antibody-induced crosslinking, some
cell lines exhibited enhanced AKT phosphorylation.
[2225] In an exemplary embodiment, the combination effect of a PI3K
inhibitor with a BTK inhibitor was observed in a cellular growth
inhibition assay in the SU-DHL-4 cell line and in the OCI-LY-8 cell
line with BCR crosslinking
Example 11 BTK Inhibitory Effects on Solid Tumor Microenvironment
in the KPC Pancreatic Cancer Model
[2226] Given the potential for BTK inhibition to affect TAMs and
MDSCs, single-active pharmaceutical ingredient Formula (XVIII) was
evaluated in mice with advanced pancreatic cancer arising as the
result of genetic modifications of oncogenes KRAS and p53, and the
pancreatic differentiation promoter PDX-1 (KPC mice). The KPC mouse
model recapitulates many of the molecular, histopathologic, and
clinical features of human disease (Westphalen and Olive, Cancer J.
2012, 18, 502-510). Combination therapy with gemcitabine was also
evaluated in this model. Mice were enrolled after identification of
spontaneously appearing tumors in the pancreas that were >100
mm.sup.3 (as assessed by high-resolution ultrasonography). Mice
were treated with (1) vehicle (N=6); or (2) Formula (XVIII), 15
mg/kg BID given orally (N=6).
[2227] As shown in FIG. 118, treatment with single-active
pharmaceutical ingredient Formula (XVIII) substantially slowed
pancreatic cancer growth and increased animal survival. With
vehicle, tumor volumes predose averaged 152 mm.sup.3, and at day 28
averaged 525 mm.sup.3. In the cohort treated with Formula (XVIII),
tumor volumes predose averaged 165 mm.sup.3, and at day 28 averaged
272 mm.sup.3, indicating significant improvement. With vehicle,
survival at day 14 was 5/6 animals, and at day 28 was 0/6 animals.
With Formula (XVIII), survival at day 14 was 6/6 animals, and at
day 28 was 5/6 animals.
[2228] Analysis of tumor tissues showed that immunosuppressive TAMs
(CD11b.sup.+Ly6ClowF4/80.sup.+Csf1r.sup.+), MDSCs
(Gr1.sup.+Ly6CHi), and Tregs (CD4.sup.+CD25.sup.+FoxP3.sup.+) were
significantly reduced with Formula (XVIII) treatment (FIG. 119,
FIG. 120, and FIG. 121). As expected, the decrease in these
immunosuppressive cell subsets correlated with a significant
increase in CD8.sup.+ cells (FIG. 122).
Example 12 Effects of BTK Inhibitors on Antibody-Dependent NK Cell
Mediated Cytotoxicity Using Rituximab
[2229] Rituximab-combination chemotherapy is today's standard of
care in CD20.sup.+ B-cell malignancies. Previous studies
investigated and determined that ibrutinib antagonizes rituximab
antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by NK
cells. This may be due to ibrutinib's secondary irreversible
binding to interleukin-2 inducible tyrosine kinase (ITK) which is
required for FcR-stimulated NK cell function including calcium
mobilization, granule release, and overall ADCC. Kohrt, et al.,
Blood 2014, 123, 1957-60.
[2230] In this example, the effects of Formula (XVIII) and
ibrutinib on NK cell function were evaluated in cell lines and
primary NK cells from healthy volunteers and CLL patients. In
summary, the results show that the activation of NK cells
co-cultured with antibody-coated target cells was strongly
inhibited by ibrutinib. The secretion of IFN-.gamma. was reduced by
48% (p=0.018) and 72% (p=0.002) in cultures treated with ibrutinib
at 0.1 and 1.0 .mu.M respectively and NK cell degranulation was
significantly (p=0.002) reduced, compared with control cultures.
Formula (XVIII) treatment at 1 .mu.M, a clinically relevant
concentration, did not inhibit IFN-.gamma. or NK cell
degranulation. Rituximab-mediated ADCC was evaluated in NK cells
from healthy volunteers as well as assays of NK cells from CLL
patients targeting autologous CLL cells. In both cases, ADCC was
not inhibited by Formula (XVIII) treatment at 1 .mu.M. In contrast,
addition of ibrutinib to the ADCC assays strongly inhibited the
rituximab-mediated cytotoxicity of target cells, and no increase
over natural cytotoxicity was observed at any rituximab
concentration. This result indicates that the combination of
rituximab and Formula (XVIII) provides an unexpected benefit in the
treatment of B cell malignancies and other diseases where NK cell
inhibition is undesirable.
[2231] BTK is a non-receptor enzyme in the Tec kinase family that
is expressed among cells of hematopoietic origin, including B
cells, myeloid cells, mast cells and platelets, where it regulates
multiple cellular processes including proliferation,
differentiation, apoptosis, and cell migration. Khan, Immunol Res.
2001, 23, 147-56; Mohamed, et al., Immunol Rev. 2009, 228, 58-73;
Bradshaw, Cell Signal. 2010, 22, 1175-84. Functional null mutations
of BTK in humans cause the inherited disease, X linked
agammaglobulinemia, which is characterized by a lack of mature
peripheral B cells. Vihinen, et al., Front Biosci. 2000, 5,
D917-28. Conversely, BTK activation is implicated in the
pathogenesis of several B-cell malignancies. Herman, et al., Blood
2011, 117, 6287-96; Kil, et al., Am. J. Blood Res. 2013, 3, 71-83;
Tai, et al., Blood 2012, 120, 1877-87; Buggy, and Elias, Int. Rev.
Immunol. 2012, 31, 119-32 (Erratum in: Int. Rev. Immunol. 2012, 31,
428). In addition, BTK-dependent activation of mast cells and other
immunocytes in peritumoral inflammatory stroma has been shown to
sustain the complex microenvironment needed for lymphoid and solid
tumor maintenance. Soucek, et al., Neoplasia 2011, 13, 1093-100;
Ponader, et al., Blood 2012, 119, 1182-89; de Rooij, et al., Blood
2012, 119, 2590-94. Taken together, these findings have suggested
that inhibition of BTK may offer an attractive strategy for
treating B cell neoplasms, other hematologic malignancies, and
solid tumors.
[2232] Ibrutinib (PCI-32765, IMBRUVICA), is a first-in-class
therapeutic BTK inhibitor. This orally delivered, small-molecule
drug is being developed by Pharmacyclics, Inc. for the therapy of B
cell malignancies. As described above, in patients with heavily
pretreated indolent non-Hodgkin lymphoma (iNHL), mantle cell
lymphoma (MCL), and CLL, ibrutinib showed substantial antitumor
activity, inducing durable regressions of lymphadenopathy and
splenomegaly in the majority of patients. Advani, et al., J. Clin.
Oncol. 2013, 31, 88-94; Byrd, et al., N. Engl. J. Med. 2013, 369,
32-42; Wang, et al., N. Engl. J. Med. 2013, 369, 507-16; O'Brien,
et al., Blood 2012, 119, 1182-89. The pattern of changes in CLL was
notable. Inhibition of BTK with ibrutinib caused rapid and
substantial mobilization of malignant CLL cells from tissues sites
into the peripheral blood, as described in Woyach, et al., Blood
2014, 123, 1810-17; this effect was consistent with decreased
adherence of CLL to protective stromal cells. Ponader, et al.,
Blood 2012, 119, 1182-89; de Rooij, et al., Blood 2012, 119,
2590-94. Ibrutinib has been generally well tolerated. At dose
levels associated with total BTK occupancy, no dose-limiting
toxicities were identified and subjects found the drug tolerable
over periods extending to >2.5 years.
[2233] Given the homology between BTK and interleukin-2 inducible
tyrosine kinase (ITK), it has been recently confirmed that
ibrutinib irreversibly binds ITK. Dubovsky, et al., Blood 2013,
122, 2539-2549. ITK expression in Fc receptor (FcR)-stimulated NK
cells leads to increased calcium mobilization, granule release, and
cytotoxicity. Khurana, et al., J. Immunol. 2007, 178, 3575-3582. As
rituximab is a backbone of lymphoma therapy, with mechanisms of
action including ADCC, as well as direct induction of apoptosis and
complement-dependent cytotoxicity, and FcR stimulation is requisite
for ADCC, we investigated if ibrutinib or Formula (XVIII) (the
latter lacking ITK inhibition) influenced rituximab's anti-lymphoma
activity in vitro by assessing NK cell IFN-.gamma. secretion,
degranulation by CD107a mobilization, and cytotoxicity by chromium
release using CD20.sup.+ cell lines and autologous patient samples
with chronic lymphocytic leukemia (CLL).
[2234] Formula (XVIII) is a more selective inhibitor than
ibrutinib, as shown previously. Formula (XVIII) is not a potent
inhibitor of ITK in contrast to ibrutinib, as shown herein (see,
e.g., Table 7). ITK is required for FcR-stimulated NK cell function
including calcium mobilization, granule release, and overall ADCC.
Anti-CD20 antibodies like rituximab are currently the standard of
care for the treatment of many CD20.sup.+ B cell malignancies,
often as part of combination regimens with older chemotherapeutic
agents. The potential of ibrutinib or Formula (XVIII) to antagonize
ADCC was evaluated in vitro. Previous studies have determined that
ibrutinib undesirably antagonizes rituximab ADCC effects mediated
by NK cells. Kohrt, et al., Blood 2014, 123, 1957-60. We
hypothesized that the BTK inhibitor of Formula (XVIII), which does
not have activity against ITK, may preserve NK cell function and
therefore synergize rather than antagonize rituximab-mediated ADCC.
Rituximab-dependent NK-cell mediated cytotoxicity was assessed
using lymphoma cell lines as well as autologous CLL tumor
cells.
[2235] Cell culture conditions were as follows. Cell lines Raji and
DHL-4 were maintained in RPMI 1630 supplemented with fetal bovine
serum, L-glutamine, 2-mercaptoethanol and penicillin-streptomycin
at 37.degree. C. in a humidified incubator. The HER18 cells were
maintained in DEM supplemented with fetal bovine serum,
penicillin-streptomycin and. Prior to assay, HER18 cells were
harvested using trypsin-EDTA, washed with phosphate-buffered saline
(PBS) containing 5% serum and viable cells were counted. For
culture of primary target cells, peripheral blood from CLL patients
was subject to density centrifugation to obtain peripheral blood
mononuclear cells (PBMC). Cell preparations were washed and then
subject to positive selection of CD5.sup.+CD19.sup.+ CLL cells
using magnetic beads (MACS, Miltenyi Biotech). Cell preparations
were used fresh after selection. NK cells from CLL patients and
healthy volunteers were enriched from peripheral blood collected in
sodium citrate anti-coagulant tubes and then subject to density
centrifugation. Removal of non NK cells was performed using
negative selection by MACS separation. Freshly isolated NK cells
were washed three times, enumerated, and then used immediately for
ADCC assays.
[2236] Cytokine secretion was determined as follows. Rituximab and
trastuzumab-dependent NK-cell mediated degranulation and cytokine
release were assessed using lymphoma and HER2+ breast cancer cell
lines (DHL-4 and HER18, respectively). Target cells were cultured
in flat-bottom plates containing 10 .mu.g/mL of rituximab (DHL-4)
or trastuzumab (HER18) and test articles (0.1 or 1 .mu.M ibrutinib,
1 .mu.M Formula (XVIII), or DMSO vehicle control). NK cells from
healthy donors were enriched as described above and then added to
the target cells and incubated for 4 hours at 37.degree. C.
Triplicate cultures were performed on NK cells from donors. After
incubation, supernatants were harvested, centrifuged briefly, and
then analyzed for interferon-.gamma. using an enzyme-linked
immunosorbent assay (ELISA) (R&D Systems, Minneapolis, Minn.,
USA).
[2237] Lytic granule release was determined as follows. NK cells
from healthy donors were enriched and cultured in the presence of
target cells, monoclonal antibodies and test articles as described
above. After 4 hours, the cultures were harvested and cells were
pelleted, washed, and then stained for flow cytometry evaluation.
Degranulation was evaluated via by flow cytometery by
externalization of CD107a, a protein normally present on the inner
leaflet of lytic granules, and gating on NK cells (CD3-CD16.sup.+
lymphocytes). The percentage of CD107a positive NK cells was
quantified by comparison with a negative control (isotype control,
unstained cells/FMO). Control cultures (NK cells cultured without
target cells, or NK, target cell co-cultures in the absence of
appropriate monoclonal antibody) were also evaluated; all
experiments were performed in triplicate.
[2238] ADCC assays were performed as follows. Briefly, target cells
(Raji or primary CLL) were labeled by incubation at 37.degree. C.
with 100 .mu.Ci .sup.51Cr for 4 hours prior to co-culture with NK
cells. Cells were washed, enumerated, and then added in triplicate
to prepared 96-well plates containing treated NK cells at an
effector:target (E:T) ratio of 25:1. Rituximab (Genentech) was
added to ADCC wells at concentrations of 0.1, 1.0 or 10 .mu.g/mL
and the assays were briefly mixed and then centrifuged to collect
cells at the bottom of the wells. The effect of NK cell natural
cytotoxicity was assessed in wells containing no rituximab.
Cultures were incubated at 37.degree. C. for 4 hours, and then
centrifuged. Supernatants were harvested and .sup.51Cr release was
measured by liquid scintillation counting. All experiments were
performed in triplicate.
[2239] Ibrutinib inhibited rituximab-induced NK cell cytokine
secretion in a dose-dependent manner (0.1 and 1 .mu.M) (FIG. 123:
48% p=0.018; 72% p=0.002, respectively). At 1 .mu.M, Formula
(XVIII) did not significantly inhibit cytokine secretion (FIG. 123:
3.5%). Similarly, Formula (XVIII) had no inhibitory effect on
rituximab-stimulated NK cell degranulation (<2%) while ibrutinib
reduced degranulation by 50% (p=0.24, FIG. 124). Formula (XVIII)
had no inhibitory effect while ibrutinib prevented
trastuzumab-stimulated NK cell cytokine release and degranulation
by 92% and 84% at 1 .mu.M, respectively (FIG. 123 and FIG. 124:
***p=0.004, **p=0.002).
[2240] In Raji cell samples, ex vivo NK cell activity against
autologous tumor cells was not inhibited by addition of Formula
(XVIII) at 1 .mu.M, and increased cell lysis was observed with
increasing concentrations of rituximab at a constant E:T ratio
(FIG. 125). In primary CLL samples, ex vivo NK cell activity
against autologous tumor cells was not inhibited by addition of
Formula (XVIII) at 1 .mu.M, and increased cell lysis was observed
with increasing concentrations of rituximab at a constant E:T ratio
(FIG. 126). In contrast, addition of 1 .mu.M ibrutinib completely
inhibited ADCC, with less than 10% cell lysis at any rituximab
concentration and no increase in cell lysis in the presence of
rituximab, compared with cultures without rituximab. A graph
highlighting the significant differences between Formula (XVIII)
and ibrutinib is shown in FIG. 127 (where "Ab" refers to
rituximab). The difference between Formula (XVIII) and ibrutinib
was highly significant in this assay (p=0.001).
[2241] In ADCC assays using healthy donor NK cells,
antibody-dependent lysis of rituximab-coated Raji cells was not
inhibited by addition of 1 .mu.M of Formula (XVIII) (FIG. 127). In
these experiments, addition of rituximab stimulated a 5- to 8-fold
increase in cell lysis at 0.1 and 1 .mu.g/mL, compared with low
(<20%) natural cytotoxicity in the absence of rituximab. As
previously reported, addition of 1 .mu.M ibrutinib strongly
inhibited the antibody-dependent lysis of target cells, with less
than 20% cell lysis at all rituximab concentrations and no increase
in ADCC with at higher rituximab concentrations.
[2242] Ibrutinib is clinically effective as monotherapy and in
combination with rituximab, despite inhibition of ADCC in vitro and
in vivo murine models due to ibrutinib's secondary irreversible
binding to ITK. Preclinically, the efficacy of therapeutics which
do not inhibit NK cell function, including Formula (XVIII), is
superior to ibrutinib. These results provide support for the
unexpected property of Formula (XVIII) as a synergistic and
superior active pharmaceutical ingredient than ibrutinib to use in
combinations with antibodies that have ADCC as a mechanism of
action. The improved performance of Formula (XVIII) in combination
with anti-CD20 antibody therapies is expected to extend to its use
in combination with PI3K inhibitors and PD-1/PD-L1 inhibitors in
both hematological malignancies and solid tumors, as these
combinations would also benefit from reduced inhibition of NK cell
function.
Example 13 Effects of BTK Inhibition on Antibody-Dependent NK Cell
Mediated Cytotoxicity Using Obinutuzumab
[2243] It has been shown above that ibrutinib undesirably
antagonizes rituximab ADCC effects mediated by NK cells, and that
Formula (XVIII) does not antagonize rituximab ADCC effects and
instead allows for a synergistic combination. As noted previously,
this may be due to ibrutinib's secondary irreversible binding to
ITK, which is required for FcR-stimulated NK cell function
including calcium mobilization, granule release, and overall ADCC.
H. E. Kohrt, et al., Blood 2014, 123, 1957-60. The potential for
ibrutinib antagonization of obinutuzumab (GA-101) ADCC as mediated
by NK cells was also explored and compared to the effects of
Formula (XVIII).
[2244] The NK cell degranulation/ADCC assay was performed using a
whole blood assay with CLL targets added to normal donor whole
blood, in the presence or absence of different doses of Formula
(XVIII) and ibrutinib, followed by opsonization with the anti-CD20
antibody obinutuzumab. Ibrutinib was used as a control, and two
blinded samples of BTK inhibitors, Formula (XVIII) and a second
sample of ibrutinib, were provided to the investigators.
Degranulation in whole blood was performed as follows. CLL targets
(MEC-1 cells) were expanded in RPMI 1640 medium (Life Technologies,
Inc.) with 10% fetal bovine serum (FBS). Exponentially growing
cells were used. On the day of the experiment, 8 mL of blood was
drawn from a normal volunteer into a test tube containing desirudin
to obtain a final concentration of 50 .mu.g/mL. A white blood cell
(WBC) count of whole blood was performed. MEC-1 cells were
re-suspended at the concentration of WBC in whole blood (e.g., if
6.times.10.sup.6 WBC/mL was measured, MEC-1 cells were re-suspended
at 6.times.10.sup.6 cells/mL, to allow for a final WBC:MEC-1 cell
ratio of 1:1). The ibrutinib control and two blinded BTK inhibitors
were diluted in X-VIVO 15 serum-free hematopoietic cell medium
(Lonza Group, Ltd.) to concentrations of 200 .mu.M, 20 .mu.M and 2
.mu.M. 170 .mu.L aliquots of unmanipulated whole blood were
incubated with 10 .mu.L BTK inhibitors or X-VIVO 15 medium for one
hour into a plate. Cetuximab and obinutuzumab (GA-101) were diluted
in X-VIVO 15 medium to a concentration of 20 .mu.g/mL. Equal
volumes of MEC-1 cells and antibodies were incubated for 5 minutes.
After incubation, 20 .mu.L of MEC-1 cells and antibodies was added
to whole blood and the BTK inhibitors/X-VIVO 15 medium (for a final
volume of 200 .mu.L). The samples were placed in a 5% CO.sub.2
incubator for 4 hours at 37.degree. C. The experimental conditions
thus achieved a WBC:MEC-1 cell ratio of 1:1, with final
concentrations of the BTK inhibitors in the assay of 10 .mu.M, 1
.mu.M and 0.1 .mu.M and final concentrations of the antibodies of 1
.mu.g/mL.
[2245] After 4 hours, the samples were mixed gently and 50 .mu.L
aliquots were removed from each well and placed in
fluorescence-activated cell sorting (FACS) test tubes. A 20 .mu.L
aliquot of anti-CD56-APC antibody and anti-CD107a-PE antibody was
added. The samples were incubated for 20 minutes at room
temperature in the dark. An aliquot of 2 mL of FACS lysing solution
(BD Biosceinces) was added. The samples were again incubated for 5
minutes, and then centrifuged at 2000 rpm for 5 minutes.
Supernatant was discarded and the cell pellet was resuspended in
500 .mu.L of PBS. The samples were analyzed on the flow cytometer
for CD107a.sup.+ NK cells (CD56.sup.+).
[2246] The NK cell degranulation results are summarized in FIG. 128
for n=3 experiments, which shows the effects on whole blood after
pretreatment for 1 hour with the BTK inhibitors at the
concentrations shown and subsequent stimulation with MEC-1
opsonised with obinutuzumab or cetuximab at 1 .mu.g/mL for 4 hours.
A strong reduction in the percentage of CD56.sup.+/CD107a.sup.+ NK
cells is observed using ibrutinib (both as a control and blinded
BTK inhibitor), which indicates that ibrutinib undesirably
antagonizes NK cells. In contrast, Formula (XVIII) shows little
antagonism towards NK cells, and had a minimal effect on
obinutuzumab-stimulated NK cell degranulation while ibrutinib
reduced obinutuzumab-stimulated NK degranulation by greater than
40%. These results support the synergistic combination of
obinutuzumab and Formula (XVIII) in treatment of human B cell
malignancies.
Example 14 Effects of BTK Inhibition on Generalized NK Cell
Mediated Cytotoxicity
[2247] An assay was performed to assess the effects of BTK
inhibition using Formula (XVIII) on generalized NK killing
(non-ADCC killing). The targets (K562 cells) do not express MHC
class I, so they do not inactivate NK cells. Target cells were
grown to mid-log phase, and 5.times.10.sup.5 cells were labeled in
100 .mu.L of assay medium (IMDM with 10% FCS and
penicillin/streptomycin) with 100 .mu.Ci of .sup.51Cr for 1 hour at
37.degree. C. Cells were washed twice and resuspended in assay
medium. A total of 5000 target cells/well was used in the assay.
Effector cells were resuspended in assay medium, distributed on a
V-bottom 96-well plate, and mixed with labeled target cells at 40:1
E:T ratios. Maximum release was determined by incubating target
cells in 1% Triton X-100. For spontaneous release, targets were
incubated without effectors in assay medium alone. After a 1 minute
centrifugation at 1000 rpm, plates were incubated for 4 and 16
hours at 37.degree. C. Supernatant was harvested and .sup.51Cr
release was measured in a gamma counter. Percentage of specific
release was calculated as (experimental release-spontaneous
release)/(maximum release-spontaneous release).times.100. The
results are shown in FIG. 129.
Example 15 Effects of BTK Inhibition on T Cells
[2248] An assay was performed to assess the effects of BTK
inhibition using Formula (XVIII) on T cells. Enriched CD4.sup.+ T
cells are plated on 24-well culture dishes that have been precoated
2 hr with 250 .mu.L anti-TCR.beta. (0.5 .mu.g/mL) plus anti-CD28 (5
.mu.g/mL) at 37.degree. C. in PBS. The cells are then supplemented
with media containing BTK inhibitors along with the skewing
cytokines as indicated in the following. The Th17 and Treg cultures
are grown for 4 days before analysis. The cells are maintained for
an additional 3 days with skewing cytokines (Th17; 20 ng/mL IL-6,
0.5 ng/mL TGF-.beta., 5 .mu.g/mL IL-4, 5 .mu.g/mL IFN-.gamma. and
Treg; 0.5 ng/mL TGF-.beta., 5 .mu.g/mL IL-4, 5 .mu.g/mL
IFN-.gamma.) and are supplemented with IL2 as a growth factor.
[2249] The results are shown in FIG. 130 and FIG. 131, and further
illustrate the surprising properties of Formula (XVIII) in
comparison to ibrutinib. Because of the lack of activity of Formula
(XVIII) on Itk and Txk, no adverse effects on Th17 and Treg
development was observed. Since ibrutinib inhibits both Itk and
Txk, a profound inhibition of Th17 cells and an increase in Treg
development is observed, which is comparable to the murine Itk/Txk
double knock-out cells which were used as a control.
[2250] The effects of ibrutinib in comparison to Formula (XVIII) on
CD8.sup.+ T cell viability was also assessed. Total T cells were
plated on anti-TCR and anti-CD28 coated wells in the presence of
both BTK inhibitors. Neutral culture conditions were used that will
not polarize T cells to a helper lineage. The cells are grown for 4
days and are then stained with anti-CD4, anti-CD8 and LIVE/DEAD
reagent to determine if the drugs have selective effects on either
the CD4.sup.+ or CD8.sup.+ cells. Statistical significance was
calculated using the Mann Whitney T-test. The results, shown in
FIG. 132, indicate that higher concentrations of ibrutinib have a
strong, negative effect on CD8.sup.+ T cell viability that is not
observed with Formula (XVIII) at any concentration.
Example 16 Preclinical Characteristics of BTK Inhibitors
[2251] The BTK inhibitor ibrutinib
41-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyrimidin-1-yl]-
piperidin-1-yl]prop-2-en-1-one) is a first-generation BTK
inhibitor. In clinical testing as a monotherapy in subjects with
hematologic malignancies, ibrutinib was generally well tolerated at
dose levels through 840 mg (the highest dose tested). Advani, et
al., J. Clin. Oncol. 2013, 31, 88-94; Byrd, et al., N. Engl. J.
Med. 2013, 369, 32-42; Wang, et al., N. Engl. J. Med. 2013, 369,
507-16. No maximum tolerated dose (MTD) was apparent within the
tested dose range. Furthermore, subjects typically found the drug
tolerable over periods extending to >2 years. No subject had
tumor lysis syndrome. No overt pattern of myelosuppression was
associated with ibrutinib treatment. No drug-related reductions in
circulating CD4.sup.+ T cells or serum immunoglobulins were noted.
Adverse events with an apparent relationship to study drug included
diarrhea and rash.
[2252] In subjects with heavily pretreated non-Hodgkin lymphoma
(NHL), ibrutinib showed substantial antitumor activity, inducing
durable regressions of lymphadenopathy and splenomegaly in most
subjects. Improvements in disease-associated anemia and
thrombocytopenia were observed. The pattern of changes in subjects
with CLL was notable. Single-active pharmaceutical ingredient
ibrutinib caused rapid and substantial reductions in lymph node
size concomitant with a redistribution of malignant sites into the
peripheral blood. An asymptomatic absolute lymphocyte count (ALC)
increase was observed that was maximal during the first few months
of treatment and generally decreased thereafter but could be
persistent in some subjects or could be seen repeatedly in subjects
who had interruption and resumption of drug therapy.
[2253] Collectively, these data with ibrutinib support the
potential benefits of selective BTK inhibition in the treatment of
subjects with relapsed lymphoid cancers. However, while highly
potent in inhibiting BTK, ibrutinib has also shown in vitro
activity against other kinases with a cysteine in the same position
as Cys481 in BTK, to which the drug covalently binds. For example,
ibrutinib inhibits epidermal growth factor receptor (EGFR), which
may be the cause of ibrutinib-related diarrhea and rash. In
addition, it is a substrate for both cytochrome P450 (CYP) enzymes
3A4/5 and 2D6, which increases the possibility of drug-drug
interactions. These liabilities support the development of
alternative BTK inhibitors for use in the therapy of lymphoid
cancer.
[2254] The preclinical selectivity and potency characteristics of
the second-generation BTK inhibitor of Formula (XVIII) were
compared to the first-generation BTK inhibitor ibrutinib. In Table
7, a kinome screen (performed by Life Technologies or based on
literature data) is shown that compares these compounds.
TABLE-US-00007 TABLE 7 Kinome Screen for BTK Inhibitors (IC.sub.50,
nM) 3F-Cys Formula Ibrutinib (Formula Kinase (XVIII) (XX-A)) Btk
3.1 0.5 Tec 29 78 Bmx 39 0.80 Itk >1000 10.7 Txk 291 2.0 EGFR
>1000 5.6 ErbB2 912 9.4 ErbB4 13.2 2.7 Blk >1000 0.5 JAK-3
>1000 16.1
[2255] The results shown in Table 7 are obtained from a 10 point
biochemical assay generated from 10 point concentration curves. The
BTK inhibitor of Formula (XVIII) shows much greater selectivity for
BTK compared to other kinases than ibrutinib.
[2256] A comparison of the in vivo potency results for the BTK
inhibitors of Formula (XVIII) and ibrutinib is shown in FIG. 133.
CD86 and CD69 are cell surface proteins that are BCR activation
markers. To obtain the in vivo potency results, mice were gavaged
at increasing drug concentration and sacrificed at one time point
(3 hours post-dose). BCR was stimulated with IgM and the expression
of activation marker CD69 and CD86 are monitored by flow cytometry
and to determine EC.sub.50 values.
[2257] In vitro and in vivo safety pharmacology studies with
Formula (XVIII) have demonstrated a favorable nonclinical safety
profile. When screened at 10 .mu.M in binding assays evaluating
interactions with 80 known pharmacologic targets such as
G-protein-coupled receptors, nuclear receptors, proteases, and ion
channels, Formula (XVIII) shows significant activity only against
the A3 adenosine receptor; follow-up dose-response experiments
indicated a IC.sub.50 of 2.7 .mu.M, suggesting a low clinical risk
of off-target effects. Formula (XVIII) at 10 .mu.M showed no
inhibition of in vitro EGFR phosphorylation in an A431 human
epidermoid cancer cell line whereas ibrutinib had an IC.sub.50 of
66 nM. The in vitro effect of Formula (XVIII) on human
ether-a-go-go-related gene (hERG) channel activity was investigated
in vitro in human embryonic kidney cells stably transfected with
hERG. Formula (XVIII) inhibited hERG channel activity by 25% at 10
.mu.M, suggesting a low clinical risk that Formula (XVIII) would
induce clinical QT prolongation as predicted by this assay. Formula
(XVIII) was well tolerated in standard in vivo Good Laboratory
Practices (GLP) studies of pharmacologic safety. A functional
observation battery in rats at doses through 300 mg/kg (the highest
dose level) revealed no adverse effects on neurobehavioral effects
or body temperature at any dose level. A study of respiratory
function in rats also indicated no treatment-related adverse
effects at doses through 300 mg/kg (the highest dose level). In a
cardiovascular function study in awake telemeterized male beagle
dogs, single doses of Formula (XVIII) at dose levels through 30
mg/kg (the highest dose level) induced no meaningful changes in
body temperature, cardiovascular, or electrocardiographic (ECG)
(including QT interval) parameters. The results suggest that
Formula (XVIII) is unlikely to cause serious off-target effects or
adverse effects on critical organ systems.
[2258] The drug-drug interaction potential of Formula (XVIII) was
also evaluated. In vitro experiments evaluating loss of parent drug
as catalyzed by CYPs indicated that Formula (XVIII) is metabolized
by CYP3A4. In vitro metabolism studies using mouse, rat, dog,
rabbit, monkey, and human hepatocytes incubated with
.sup.14C-labeled Formula (XVIII) indicated two mono-oxidized
metabolites and a glutathione conjugate. No unique human metabolite
was identified. Preliminary evaluations of metabolism in the
plasma, bile, and urine of rats, dogs, and monkeys indicated
metabolic processes of oxidation, glutathione binding, and
hydrolysis. It was shown that Formula (XVIII) binds to glutathione
but does not deplete glutathione in vitro. Nonclinical CYP
interaction studies data indicate that Formula (XVIII) is very
unlikely to cause clinical drug-drug interactions through
alteration of the metabolism of drugs that are substrates for CYP
enzymes.
[2259] The in vitro potency in whole blood of Formula (XVIII),
ibrutinib and CC-292 in inhibiting signals through the B cell
receptor was also assessed. Blood from four healthy donors was
incubated for 2 hours with the compounds shown over a concentration
range, and then stimulated with anti-human IgD [10 .mu.g/mL] for 18
hours. The mean fluorescent intensity (MFI) of CD69 (and CD86, data
not shown) on gated CD19+ B cells was measured by flow cytometry.
MFI values were normalized so that 100% represents CD69 level in
stimulated cells without inhibitor, while 0% represents the
unstimulated/no drug condition. The results are shown in FIG. 134.
The EC.sub.50 values obtained were 8.2 nM (95% confidence interval:
6.5-10.3), 6.1 nM (95% confidence interval: 5.2-7.2), and 121 nM
(95% confidence interval: 94-155) for Formula (XVIII), ibrutinib,
and CC-292, respectively.
[2260] The EGF receptor phosphorylation in vitro was also
determined for Formula (XVIII) and ibrutinib. Epidermoid carcinoma
A431 cells were incubated for 2 h with a dose titration of Formula
(XVIII) or ibrutinib, before stimulation with EGF (100 ng/mL) for 5
min to induce EGFR phosphorylation (p-EGFR). Cells were fixed with
1.6% paraformaldehyde and permeabilized with 90% MeOH. Phosphoflow
cytometry was performed with p-EGFR (Y1069). MFI values were
normalized so that 100% represents the p-EGFR level in stimulated
cells without inhibitor, while 0% represents the unstimulated/no
drug condition. The results are shown in FIG. 135. EGF-induced
p-EGFR inhibition was determined to be 7% at 10 .mu.M for Formula
(XVIII), while ibrutinib has an EC.sub.50 of 66 nM. The much more
potent inhibition of EGF-induced p-EGFR by ibrutinib may be
associated with increased side effects including diarrhea and
rash.
Example 17 Clinical Study of a BTK Inhibitor in Leukemia/Lymphoma
and Effects on Bone Marrow and Lymphoid Microenvironments
[2261] Clinical studies have shown that targeting the BCR signaling
pathway by inhibiting BTK produces significant clinical benefit in
patients with non-Hodgkin's lymphoma (NHL). The second generation
BTK inhibitor, Formula (XVIII), achieves significant oral
bioavailability and potency, and has favorable preclinical
characteristics, as described above. The purpose of this study is
to evaluate the safety and efficacy of the second generation BTK
inhibitor of Formula (XVIII) in treating subjects with chronic
lymphocytic leukemia (CLL) and small lymphocytic lymphoma
(SLL).
[2262] The design and conduct of this study is supported by an
understanding of the history and current therapies for subjects
with lymphoid cancers; knowledge of the activity and safety of a
first-generation BTK inhibitor, ibrutinib, in subjects with
hematologic cancers; and the available nonclinical information
regarding Formula (XVIII). The collective data support the
following conclusions. BTK expression plays an important role in
the biology of lymphoid neoplasms, which represent serious and
life-threatening disorders with continuing unmet medical need.
Clinical evaluation of Formula (XVIII) as a potential treatment for
these disorders has sound scientific rationale based on
observations that the compound selectively abrogates BTK activity
and shows activity in nonclinical models of lymphoid cancers. These
data are supported by clinical documentation that ibrutinib, a
first-generation BTK inhibitor, is clinically active in these
diseases. Ibrutinib clinical data and Formula (XVIII) nonclinical
safety pharmacology and toxicology studies support the safety of
testing Formula (XVIII) in subjects with B cell malignancies.
[2263] The primary objectives of the clinical study are as follows:
(1) establish the safety and the MTD of orally administered Formula
(XVIII) in subjects with CLL/SLL; (2) determine pharmacokinetics
(PK) of orally administered Formula (XVIII) and identification of
its major metabolite(s); and (3) measure pharmacodynamic (PD)
parameters including drug occupancy of BTK, the target enzyme, and
effect on biologic markers of B cell function.
[2264] The secondary objective of the clinical study is to evaluate
tumor responses in patients treated with Formula (XVIII).
[2265] This study is a multicenter, open-label, nonrandomized,
sequential group, dose escalation study. The following dose cohorts
will be evaluated:
[2266] Cohort 1: 100 mg/day for 28 days (=1 cycle)
[2267] Cohort 2: 175 mg/day for 28 days (=1 cycle)
[2268] Cohort 3: 250 mg/day for 28 days (=1 cycle)
[2269] Cohort 4: 350 mg/day for 28 days (=1 cycle)
[2270] Cohort 5: 450 mg/day for 28 days (=1 cycle)
[2271] Cohort 6: To be determined amount in mg/day for 28 days (=1
cycle)
[2272] Each cohort will be enrolled sequentially with 6 subjects
per cohort. If .ltoreq.1 dose-limiting toxicity (DLT) is observed
in the cohort during Cycle 1, escalation to the next cohort will
proceed. Subjects may be enrolled in the next cohort if 4 of the 6
subjects enrolled in the cohort completed Cycle 1 without
experiencing a DLT, while the remaining 2 subjects are completing
evaluation. If .gtoreq.2 DLTs are observed during Cycle 1, dosing
at that dose and higher will be suspended and the MTD will be
established as the previous cohort. The MTD is defined as the
largest daily dose for which fewer than 33% of the subjects
experience a DLT during Cycle 1. Dose escalation will end when
either the MTD is achieved or at 3 dose levels above full BTK
occupancy, whichever occurs first. Full BTK occupancy is defined as
Formula (XVIII) active-site occupancy of >80% (average of all
subjects in cohort) at 24 hours postdose. Should escalation to
Cohort 6 be necessary, the dose will be determined based on the
aggregate data from Cohorts 1 to 5, which includes safety,
efficacy, and PK/PD results. The dose for Cohort 6 will not exceed
900 mg/day.
[2273] Treatment with Formula (XVIII) may be continued for >28
days until disease progression or an unacceptable drug-related
toxicity occurs. Subjects with disease progression will be removed
from the study. All subjects who discontinue study drug will have a
safety follow-up visit 30 (.+-.7) days after the last dose of study
drug unless they have started another cancer therapy within that
timeframe. Radiologic tumor assessment will be done at screening
and at the end of Cycle 2, Cycle 4, and Cycle 12 and at
investigator discretion. Confirmation of complete response (CR)
will require bone marrow analysis and radiologic tumor assessment.
For subjects who remain on study for >11 months, a mandatory
bone marrow aspirate and biopsy is required in Cycle 12 concurrent
with the radiologic tumor assessment.
[2274] All subjects will have standard hematology, chemistry, and
urinalysis safety panels done at screening. This study also
includes pancreatic function assessment (serum amylase and serum
lipase) due to the pancreatic findings in the 28-day GLP rat
toxicity study. Once dosing commences, all subjects will be
evaluated for safety once weekly for the first 4 weeks, every other
week for Cycle 2, and monthly thereafter. Blood samples will be
collected during the first week of treatment for PK/PD assessments.
ECGs will be done at screening, and on Day 1-2, 8, 15, 22, 28 of
Cycle 1, Day 15 and 28 of Cycle 2, and monthly thereafter through
Cycle 6. ECGs are done in triplicate for screening only.
Thereafter, single ECG tests are done unless a repeat ECG testing
is required.
[2275] Dose-limiting toxicity is defined as any of the following
events (if not related to disease progression): (1) any Grade
.gtoreq.3 non-hematologic toxicity (except alopecia) persisting
despite receipt of a single course of standard outpatient
symptomatic therapy (e.g., Grade 3 diarrhea that responds to a
single, therapeutic dose of Imodium.RTM. would not be considered a
DLT); (2) grade .gtoreq.3 prolongation of the corrected QT interval
(QTc), as determined by a central ECG laboratory overread; (3)
grade 4 neutropenia (absolute neutrophil count [ANC]<500/.mu.L)
lasting >7 days after discontinuation of therapy without growth
factors or lasting >5 days after discontinuation of therapy
while on growth factors (i.e., Grade 4 neutropenia not lasting as
long as specified will not be considered a DLT), (4) grade 4
thrombocytopenia (platelet count <20,000/.mu.L) lasting >7
days after discontinuation of therapy or requiring transfusion
(i.e., Grade 4 thrombocytopenia not lasting as long as specified
will not be considered a DLT), and (5) dosing delay due to toxicity
for >7 consecutive days.
[2276] The efficacy parameters for the study include overall
response rate, duration of response, and progression-free survival
(PFS). The safety parameters for the study include DLTs and MTD,
frequency, severity, and attribution of adverse events (AEs) based
on the Common Terminology Criteria for Adverse Events (CTCAE v4.03)
for non-hematologic AEs. Hallek, et al., Blood 2008, 111,
5446-5456.
[2277] The schedule of assessments is as follows, with all days
stated in the following meaning the given day or +/-2 days from the
given day. A physical examination, including vital signs and
weight, are performed at screening, during cycle 1 at 1, 8, 15, 22,
and 28 days, during cycle 2 at 15 and 28 days, during cycles 3 to
24 at 28 days, and at follow up (after the last dose). The
screening physical examination includes, at a minimum, the general
appearance of the subject, height (screening only) and weight, and
examination of the skin, eyes, ears, nose, throat, lungs, heart,
abdomen, extremities, musculoskeletal system, lymphatic system, and
nervous system. Symptom-directed physical exams are done
thereafter. Vital signs (blood pressure, pulse, respiratory rate,
and temperature) are assessed after the subject has rested in the
sitting position. Eastern Cooperative Oncology Group (ECOG) status
is assessed at screening, during cycle 1 at 1, 8, 15, 22, and 28
days, during cycle 2 at 15 and 28 days, during cycles 3 to 24 at 28
days, and at follow up, using the published ECOG performance status
indications described in Oken, et al., Am. J. Clin. Oncol. 1982, 5,
649-655. ECG testing is performed at screening, during cycle 1 at
1, 2, 8, 15, 22, and 28 days, during cycle 2 at 15 and 28 days,
during cycles 3 to 24 at 28 days, and at follow up. The 12-lead ECG
test will be done in triplicate (.gtoreq.1 minute apart) at
screening. The calculated QTc average of the 3 ECGs must be <480
ms for eligibility. On cycle 1, day 1 and cycle 1, day 8, single
ECGs are done predose and at 1, 2, 4, and 6 hours postdose. The
single ECG on Cycle 1 Day 2 is done predose. On cycle 1, day 15,
day 22, and day 28, a single ECG is done 2 hours post-dose.
Starting with cycle 2, a single ECG is done per visit. Subjects
should be in supine position and resting for at least 10 minutes
before study-related ECGs. Two consecutive machine-read QTc>500
ms or >60 ms above baseline require central ECG review.
Hematology, including complete blood count with differential and
platelet and reticulocyte counts, is assessed at screening, during
cycle 1 at 1, 8, 15, 22, and 28 days, during cycle 2 at 15 and 28
days, during cycles 3 to 24 at 28 days, and at follow up. Serum
chemistry is assessed at screening, during cycle 1 at 1, 8, 15, 22,
and 28 days, during cycle 2 at 15 and 28 days, during cycles 3 to
24 at 28 days, and at follow up. Serum chemistry includes albumin,
alkaline phosphatase, ALT, AST, bicarbonate, blood urea nitrogen
(BUN), calcium, chloride, creatinine, glucose, lactate
dehydrogenase (LDH), magnesium, phosphate, potassium, sodium, total
bilirubin, total protein, and uric acid. Cell counts and serum
immunoglobulin are performed at screening, at cycle 2, day 28, and
at every 6 months thereafter until last dose and include
T/B/NK/monocyte cell counts (CD3, CD4, CD8, CD14, CD19, CD19,
CD16/56, and others as needed) and serum immunoglobulin (IgG, IgM,
IgA, and total immunoglobulin). Bone marrow aspirates are performed
at cycle 12. Pharmacodynamics samples are drawn during cycle 1 at
1, 2, and 8 days, and at follow up. On days 1 and 8,
pharmacodynamic samples are drawn pre-dose and 4 hours (.+-.10
minutes) post-dose, and on day 2, pharmacodynamic samples are drawn
pre-dose. Pharmacokinetics samples are drawn during cycle 1 at 1,
2, 8, 15, 22, and 28 days. Pharmacokinetic samples for Cycle 1 Day
1 are drawn pre-dose and at 0.5, 1, 2, 4, 6 and 24 hours (before
dose on Day 2) post-dose. Samples for Cycle 1 Day 8 are drawn
pre-dose and at 0.5, 1, 2, 4, and 6 hours post-dose. On Cycle 1 Day
15, 22, and 28, a PK sample is drawn pre-dose and the second PK
sample must be drawn before (up to 10 minutes before) the ECG
acquisition, which is 2 hours postdose. Pretreatment radiologic
tumor assessments are performed within 30 days before the first
dose. A computed tomography (CT) scan (with contrast unless
contraindicated) is required of the chest, abdomen, and pelvis. In
addition, a positron emission tomography (PET) or PET/CT must done
for subjects with SLL. Radiologic tumor assessments are mandatory
at the end of Cycle 2 (-7 days), Cycle 4 (-7 days), and Cycle 12
(-7 days). Otherwise, radiologic tumor assessments are done at
investigator discretion. A CT (with contrast unless
contraindicated) scan of the chest, abdomen, and pelvis is required
for subjects with CLL. In addition, a PET/CT is required in
subjects with SLL. Bone marrow and radiologic assessments are both
required for confirmation of a complete response (CR). Clinical
assessments of tumor response should be done at the end of Cycle 6
and every 3 months thereafter. Molecular markers are measured at
screening, and include interphase cytogenetics, stimulated
karyotype, IgHV mutational status, Zap-70 methylation, and beta-2
microglobulin levels. Urinalysis is performed at screening, and
includes pH, ketones, specific gravity, bilirubin, protein, blood,
and glucose. Other assessments, including informed consent,
eligibility, medical history, and pregnancy test are done at the
time of screening.
[2278] The investigator rates the subject's response to treatment
based on recent guidelines for CLL, as given in Hallek, et al.,
Blood 2008, 111, 5446-56, and for SLL, as given in Cheson, et al.,
J. Clin. Oncol. 2007, 25, 579-586. The response assessment criteria
for CLL are summarized in Table 8.
TABLE-US-00008 TABLE 8 Response Assessment Criteria for CLL. Bone
Nodes, Marrow (if Liver, and Response Peripheral Blood performed)
Spleen.sup.a CR Lymphocytes <4 .times. 10.sup.9/L Normocellular
Normal ANC >1.5 .times. 10.sup.9/L.sup.b <30% lymphocytes
(e.g., no Platelets >100 .times. 10.sup.9/L.sup.b No B-lymphoid
lymph nodes Hemoglobin >11.0 g/dL nodules >1.5 cm)
(untransfused).sup.b CRi Lymphocytes <4 .times. 10.sup.9/L
Hypocellular Normal Persistent anemia, <30% lymphocytes (e.g.,
no thrombocytopenia, or lymph nodes neutropenia related to >1.5
cm) drug toxicity PR Lymphocytes .gtoreq.50% Not assessed
.gtoreq.50% decrease from baseline reduction in ANC >1.5 .times.
10.sup.9/L lymphadeno- or pathy.sup.c Platelets >100 .times.
10.sup.9/L or and/or in 50% improvement over spleen baseline or
liver or enlargement Hemoglobin >11.0 g/dL or 50% improvement
over baseline (untransfused).sup.b Abbreviations: ANC = absolute
neutrophil count; CR = complete remission; CRi = CR with incomplete
blood count recovery; PR = partial remission. .sup.aComputed
tomography (CT) scan of abdomen pelvis, and chest is required for
this evaluation .sup.bWithout need for exogenous growth factors
.sup.cIn the sum products of .ltoreq.6 lymph nodes or in the
largest diameter of the enlarged lymphnode(s) detected before
therapy and no increase in any lymph node or new enlarged lymph
nodes
[2279] The response assessment criteria for SLL are summarized in
Table 9.
TABLE-US-00009 TABLE 9 Response Assessment Criteria for SLL.
Response Definition Nodal Masses Spleen, Liver Bone Marrow CR
Disappearance (a) FDG-avid or PET Not palpable, If infiltrate
present of all evidence positive prior to nodules at screening, of
disease therapy; mass of any disappeared infiltrate cleared on size
permitted if PET repeat biopsy; if negative indeterminate by (b)
Variably FDG-avid morphology, or PET negative; immunohisto-
regression to normal chemistry should size on CT be negative PR
Regression of .gtoreq.50% decrease in SPD .gtoreq.50% decrease
Irrelevant if measurable of up to 6 largest in SPD of positive
prior to disease and no dominant masses; no nodules (for therapy;
cell type new sites increase in size of single nodule in should be
specified other nodes greatest (a) FDG-avid or PET transverse
positive prior to diameter); no therapy; .gtoreq.1 PET increase in
size positive at previously of liver or involved site spleen (b)
Variably FDG-avid or PET negative; regression on CT SD Failure to
(a) FDG-avid or PET attain CR/PR positive prior to or progressive
therapy; PET positive disease at prior sites of disease, and no new
sites on CT or PET (b) Variably FDG avid or PET negative; no change
in size of previous lesions on CT Abbreviations: CR = complete
remission, CT = computed tomography, FDG =
[.sup.18F]fluorodeoxyglucose, PET = positron-emission tomography,
PR = partial remission, SD = stable disease, SPD = sum of the
product of the diameters.
[2280] The PK parameters of the study are as follows. The plasma PK
of Formula (XVIII) and a metabolite is characterized using
noncompartmental analysis. The following PK parameters are
calculated, whenever possible, from plasma concentrations of
Formula (XVIII): [2281] AUC.sub.(0-t): Area under the plasma
concentration-time curve calculated using linear trapezoidal
summation from time 0 to time t, where t is the time of the last
measurable concentration (Ct), [2282] AUC.sub.(0-24): Area under
the plasma concentration-time curve from 0 to 24 hours, calculated
using linear trapezoidal summation, [2283] AUC.sub.(0-.infin.):
Area under the plasma concentration-time curve from 0 to infinity,
calculated using the formula:
AUC.sub.(0-.infin.)=AUC.sub.(0-t)+Ct/.lamda.z, where .lamda.z is
the apparent terminal elimination rate constant, [2284] C.sub.max:
Maximum observed plasma concentration, [2285] T.sub.max: Time of
the maximum plasma concentration (obtained without interpolation),
[2286] t.sub.1/2: Terminal elimination half-life (whenever
possible), [2287] .lamda..sub.2: Terminal elimination rate constant
(whenever possible), [2288] Cl/F: Oral clearance.
[2289] The PD parameters of the study are as follows. The occupancy
of BTK by Formula (XVIII) are measured in peripheral blood
mononuclear cells (PBMCs) with the aid of a biotin-tagged Formula
(XVIII) analogue probe. The effect of Formula (XVIII) on biologic
markers of B cell function will also be evaluated.
[2290] The statistical analysis used in the study is as follows. No
formal statistical tests of hypotheses are performed. Descriptive
statistics (including means, standard deviations, and medians for
continuous variables and proportions for discrete variables) are
used to summarize data as appropriate.
[2291] The following definitions are used for the safety and
efficacy analysis sets: Safety analysis set: All enrolled subjects
who receive .gtoreq.1 dose of study drug; Per-protocol (PP)
analysis set: All enrolled subjects who receive .gtoreq.1 dose of
study drug and with .gtoreq.1 tumor response assessment after
treatment. The safety analysis set will be used for evaluating the
safety parameters in this study. The PP analysis sets will be
analyzed for efficacy parameters in this study.
[2292] No imputation of values for missing data is performed except
for missing or partial start and end dates for adverse events and
concomitant medication will be imputed according to prespecified,
conservative imputation rules. Subjects lost to follow-up (or drop
out) will be included in statistical analyses to the point of their
last evaluation.
[2293] The safety endpoint analysis was performed as follows.
Safety summaries will include summaries in the form of tables and
listings. The frequency (number and percentage) of treatment
emergent adverse events will be reported in each treatment group by
Medical Dictionary for Regulatory Activities (MedDRA) System Organ
Class and Preferred Term. Summaries will also be presented by the
severity of the adverse event and by relationship to study drug.
Laboratory shift tables containing counts and percentages will be
prepared by treatment assignment, laboratory parameter, and time.
Summary tables will be prepared for each laboratory parameter.
Figures of changes in laboratory parameters over time will be
generated. Vital signs, ECGs, and physical exams will be tabulated
and summarized.
[2294] Additional analyses include summaries of subject
demographics, baseline characteristics, compliance, and concurrent
treatments. Concomitant medications will be coded according to the
World Health Organization (WHO) Drug Dictionary and tabulated.
[2295] The analysis of efficacy parameters was performed as
follows. The point estimate of the overall response rate will be
calculated for the PP analysis set. The corresponding 95%
confidence interval also will be derived. The duration of overall
response is measured from the time measurement criteria are met for
CR or PR (whichever is first recorded) until the first date that
recurrent or progressive disease is objectively documented (taking
as reference for progressive disease the smallest measurements
recorded since the treatment started). Kaplan-Meier methodology
will be used to estimate event-free curves and corresponding
quantiles (including the median). Progression-free survival is
measured from the time of first study drug administration until the
first date that recurrent or progressive disease is objectively
documented (taking as reference for progressive disease the
smallest measurements recorded since the treatment started).
Kaplan-Meier methodology will be used to estimate the event-free
curves and corresponding quantiles (including the median).
[2296] The study scheme is a sequential cohort escalation. Each
cohort consists of six subjects. The sample size of the study is 24
to 36 subjects, depending on dose escalation into subsequent
cohorts. Cohort 1 (N=6) consists of Formula (XVIII), 100 mg QD for
28 days. Cohort 2 (N=6) consists of Formula (XVIII), 175 mg QD for
28 days. Cohort 3 (N=6) consists of Formula (XVIII), 250 mg QD for
28 days. Cohort 4 (N=6) consists of Formula (XVIII), 350 mg QD for
28 days. Cohort 5 (N=6) consists of Formula (XVIII), 450 mg QD for
28 days. Cohort 6 (N=6) consists of Formula (XVIII), at a dose to
be determined QD for 28 days. The dose level for Cohort 6 will be
determined based on the safety and efficacy of Cohorts 1 to 5, and
will not exceed 900 mg/day. Escalation will end with either the MTD
cohort or three levels above full BTK occupancy, whichever is
observed first. An additional arm of the study will explore 100 mg
BID dosing. Treatment with oral Formula (XVIII) may be continued
for greater than 28 days until disease progression or an
unacceptable drug-related toxicity occurs.
[2297] The inclusion criteria for the study are as follows: (1) men
and women .gtoreq.18 years of age with a confirmed diagnosis of
CLL/SLL, which has relapsed after, or been refractory to, .gtoreq.2
previous treatments for CLL/SLL; however, subjects with 17p
deletion are eligible if they have relapsed after, or been
refractory to, 1 prior treatment for CLL/SLL; (2) body weight
.gtoreq.60 kg, (3) ECOG performance status of .ltoreq.2; (4)
agreement to use contraception during the study and for 30 days
after the last dose of study drug if sexually active and able to
bear children; (5) willing and able to participate in all required
evaluations and procedures in this study protocol including
swallowing capsules without difficulty; or (6) ability to
understand the purpose and risks of the study and provide signed
and dated informed consent and authorization to use protected
health information (in accordance with national and local subject
privacy regulations).
[2298] The dosage form and strength of Formula (XVIII) used in the
clinical study is a hard gelatin capsules prepared using standard
pharmaceutical grade excipients (microcrystalline cellulose) and
containing 25 mg of Formula (XVIII) each. The color of the capsules
is Swedish orange. The route of administration is oral (per os, or
PO). The dose regimen is once daily or twice daily, as defined by
the cohort, on an empty stomach (defined as no food 2 hours before
and 30 minutes after dosing).
[2299] The baseline characteristics for the patients enrolled in
the clinical study are given in Table 10.
TABLE-US-00010 TABLE 10 Relapsed/refractory CLL baseline
characteristics. Characteristic CLL (N = 44) Patient Demographics
Age (years), median (range) 62 (45-84) Sex, men (%) 33 (75) Prior
therapies, median 3 (1-10) (range), n .gtoreq.3 prior therapies, n
(%) 26 (59) Clinical Details ECOG performance status 28 (63)
.gtoreq.1(%) Rai stage III/IV 16 (36) Bulky disease .gtoreq.5 cm, n
(%) 15 (34) Cytopenia at baseline 33 (75) Cytogenic Status
Chromosome 11q22.3 deletion 18 (41) (Del 11q), n (%) Chromosome
17p13.1 (Del 19 (34) 17p), n (%) IgVH status (unmutated), n (%) 28
(64)
[2300] The results of the clinical study in relapsed/refractory CLL
patients are summarized in Table 11.
TABLE-US-00011 TABLE 11 Activity of Formula (XVIII) in
relapsed/refractory CLL. n (%) All Cohorts 100 mg QD 175 mg QD 250
mg QD 100 mg BID 400 mg QD (N = 31) (N = 8) (N = 8) (N = 7) (N = 3)
(N = 5) PR 22 (71) 7 (88) 5 (63) 5 (71) 3 (100) 2 (40) PR + L 7
(23) 0 (0) 3 (37) 2 (29) 0 (0) 2 (40) SD 2 (6) 1 (12) 0 (0) 0 (0) 0
(0) 1 (20) PD 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Median (range)
Cycles 7.3 10.0 8.6 7.0 5.2 5.0 (3.0-10.8) (9.0-10.8) (3.0-8.8)
(7.0-7.3) (4.7-5.5) (4.8-5.5) (PR = partial response; PR + L =
partial response with lymphocytosis; SD = stable disease; PD =
progressive disease.)
[2301] FIG. 134 shows the median % change in ALC and SPD from
baseline in the clinical study of Formula (XVIII), plotted in
comparison to the results reported for ibrutinib in FIG. 1A of
Byrd, et al., N. Engl. J. Med. 2013, 369, 32-42. The results show
that Formula (XVIII) leads to a more rapid patient response in CLL
than corresponding treatment with ibrutinib. This effect is
illustrated, for example, by the median % change in SPD, which
achieved the same status in the present study at 7 months of
treatment with Formula (XVIII) as compared to 18 months for
ibrutinib. The % change in SPD observed in the different cohorts
(i.e. by dose and dosing regimen) is shown in FIG. 135, and in all
cases shows significant responses.
[2302] A Kaplan-Meier curve showing PFS from the clinical CLL study
of Formula (XVIII) is shown in FIG. 136. A comparison of survival
curves was performed using the Log-Rank (Mantle-Cox) test, with a
p-value of 0.0206 indicating that the survival curves are
different. The number of patients at risk is shown in FIG. 137.
Both FIG. 136 and FIG. 137 show the results for Formula (XVIII) in
comparison to the results reported for ibrutinib in Byrd, et al.,
N. Engl. J. Med. 2013, 369, 32-42. An improvement in survival and a
reduction in risk are observed in CLL patients treated with Formula
(XVIII) in comparison to patients treated with ibrutinib.
[2303] Based on the data and comparisons shown in FIG. 134 to FIG.
137, the CLL study with Formula (XVIII) showed that the efficacy of
Formula (XVIII) was surprisingly superior to that of ibrutinib.
[2304] In the literature study of ibrutinib, increased disease
progression was associated with patients with high-risk cytogenetic
lesions (17p13.1 deletion or 11q22.3 deletion), as shown in FIG. 3A
in Byrd, et al., N. Engl. J. Med. 2013, 369, 32-42, which shows
ibrutinib PFS including PFS broken down by genetic abnormality. The
17p and 11q deletions are validated high-risk characteristics of
CLL, and the 17p deletion is the highest risk. In FIG. 138, the PFS
is shown for Formula (XVIII) in patients with the 17p deletion in
comparison to the results obtained for ibrutinib in Byrd, et al.,
N. Engl. J. Med. 2013, 369, 32-42. A p-value of 0.0696 was
obtained. In FIG. 139, the number of patients at risk with the 17p
deletion is compared. To date, no 17p patients have progressed on
Formula (XVIII).
[2305] The adverse events observed in the clinical study in
relapsed/refractory CLL are given in Table 12. No DLTs were
observed. The MTD was not reached. No treatment-related serious
adverse events (SAEs) were observed. No prophylactic antivirals or
antibiotics were needed.
TABLE-US-00012 TABLE 12 Treatment-related adverse events reported
in the clinical study of Formula (XVIII) in relapsed/ refractory
CLL. (Reported in .gtoreq.5% of patients.) Adverse Events
(Treatment- All Related), n (%) Grade (N = 44) Headache 1/2 7 (16)
Increased tendency 1 6 (14) to bruise Diarrhea 1 4 (9) Petechiae 1
3 (7)
[2306] The clinical study of Formula (XVIII) thus showed other
unexpectedly superior results compared to ibrutinib therapy. A lack
of lymphocytosis was observed in the study. Furthermore, only grade
1 AEs were observed, and these AEs were attributable to the high
BTK selectivity of Formula (XVIII).
[2307] BTK target occupancy was measured for relapsed/refractory
CLL patients with the results shown in FIG. 140. For 200 mg QD
dosing of the BTK inhibitor of Formula (XVIII), about 94%-99% BTK
occupancy was observed, with superior 24 hour coverage and less
inter-patient variability also observed. For 420 mg and 840 mg QD
of the BTK inhibitor ibrutinib, 80%-90% BTK occupancy was observed,
with more inter-patient variability and capped occupancy. These
results indicate that the BTK inhibitor of Formula (XVIII) achieves
superior BTK occupancy in CLL patients than ibrutinib.
[2308] The effects of Formula (XVIII) on cell subset percentages
were also evaluated using flow cytometry analysis of peripheral
blood, with the results shown in FIG. 141, FIG. 142, FIG. 143, FIG.
144, FIG. 145, and FIG. 146. PBMC samples from CLL patient samples
drawn prior to (predose) and after 28 days of dosing with Formula
(XVIII) were compared for potential changes in cell subsets. PBMCs
were stained with monoclonal antibodies conjugated to fluorescent
tags (flourochromes) to identify cell subsets via flow cytometry.
Non-viable cells were excluded from the analysis using the dye
7-aminoactinomycin D (7-AAD). To produce the metric of percent
change, the following steps were taken. First, each cell subset was
defined by hierarchical flow cytometry gating. Then, the change in
frequency (between day 1 and day 28) was calculated for each cell
subset. MDSC subsets were measured as a % of all myeloid cells. T
cell subsets were measured as a % of all CD3.sup.+ cells, and NK
cells were measured as a % of all live CD45.sup.+ cells. In FIG.
141 and FIG. 142, the results show the % change in MDSC (monocytic)
level over 28 days versus % ALC change at cycle 1 day 28 (C1D28)
and at cycle 2 day 28 (C2D28). A cycle is 28 days. A trend is
observed wherein patients with decreasing ALC % had increasing MDSC
(monocytic) %. This may include patients who had quickly resolving
lymphocytosis and those with no initial lymphocytosis. This
provides evidence that treatment with Formula (XVIII) mobilizes
MDSCs and thus affects the CLL tumor microenvironment in marrow and
lymph nodes, which is an unexpected indication of superior
efficacy. In FIG. 143 and FIG. 144, the results show the % change
in NK cell level over 28 days versus % ALC change, measured at
C1D28 or C2D28, and similar trends are observed wherein patients
with decreasing ALC % had increasing NK cell %. This may include
patients who had quickly resolving lymphocytosis and those having
no initial lymphocytosis. The effects in FIG. 141 to FIG. 144 are
observed in multiple cohorts, at doses including 100 mg BID, 200 mg
QD, and 400 mg QD. In FIG. 145 and FIG. 146, the effects on NK
cells and MDSC cells are compared to a number of other markers
versus % change in ALC at C1D28 and C2D28. These other markers
include CD4+ T cells, CD8+ T cells, CD4+/CD8+ T cell ratio, NK-T
cells, PD-1+ CD4+ T cells, and PD-1+ CD8+ T cells. The effects on
NK cells and MDSC cells are observed to be much more pronounced
than on any of these other markers.
[2309] These results suggest that after Formula (XVIII)
administration, the CLL microenvironment undergoes a change wherein
NK cells and monocytic MDSC subsets increase in frequency in the
peripheral blood in patients with falling ALC counts, an important
clinical parameter in CLL. The NK cell increase may reflect an
overall increase in cytolytic activity against B-CLL resulting in
the ALC % to drop. The increase in MDSC % in the blood may be due
to a movement of these cells out of the lymph nodes, spleen, and
bone marrow, which are all possible sites of CLL proliferation.
Fewer MDSCs at the CLL proliferation centers would likely result in
a reduced immunosuppressive microenvironment leading to an increase
in cell-mediated immunity against the tumor, decreased tumor
proliferation, and eventually lower ALC % in the circulation.
[2310] Updated clinical results from the CLL study are shown in
FIG. 149 to FIG. 154. FIG. 149 shows an update of the data
presented in FIG. 136. FIG. 150 shows an update of the data
presented in FIG. 142, and includes BID dosing results. Formula
(XVIII) 200 mg QD dosing resulted in 94%-99% BTK occupancy, 24 hour
coverage, and less inter-patient variability. Ibrutinib 420 mg and
840 mg QD dosing resulted in 80%-90% BTK occupancy, more
inter-patient variability, and capped occupancy. Formula (XVIII)
100 mg BID dosing resulted in 97%-99% BTK occupancy, complete BTK
coverage, and less inter-patient variability. The PFS for patients
with 11p deletions and 17q deletions are illustrated in FIG. 151,
FIG. 152, and FIG. 153. Updated SPD results are illustrated in FIG.
154.
[2311] Treatment of CLL patients with Formula (XVIII) also resulted
in increased apoptotis, as illustrated in FIG. 155. Apoptotic B-CLL
was defined by flow cytometry as having cleaved PARP.sup.+, Caspase
3.sup.+, CD19.sup.+, and CD5.sup.+ phenotypes. 82% of samples
tested had a baseline change greater than 25%. Treatment of CLL
patients also showed that Formula (XVIII) decreased plasma
chemokines associated with MDSC homing and retention. A significant
decrease in CXCL12 and CCL2 levels has been observed in patients
treated with Formula (XVIII), as shown in FIG. 156 and FIG. 157,
respectively.
[2312] Overall, Formula (XVIII) shows superior efficacy to first
generation BTK inhibitors such as ibrutinib, or to monotherapy with
PI3K-.delta. inhibitors such as idelalisib. Formula (XVIII) has
better target occupancy and better pharmacokinetic and metabolic
parameters than ibrutinib, leading to improved B cell apoptosis.
Furthermore, unlike treatment with ibrutinib and PI3K-.delta.
inhibitors, treatment with Formula (XVIII) does not affect NK cell
function. Finally, treatment with Formula (XVIII) leads to a CLL
tumor microenvironmental effect by excluding MDSC cells from the
marrow and lymph nodes and reducing their number.
Example 18 Clinical Study of a BTK Inhibitor in Leukemia/Lymphoma
in Combination with Obinutuzumab (GA-101)
[2313] The primary objectives of the study are (1) to determine the
overall response rate (ORR) at 12 months with the combination of
Formula (XVIII) and obinutuzumab in patients with relapsed or
refractory CLL, (2) to determine the ORR at 12 months with the
combination of Formula (XVIII) and obinutuzumab in patients with
treatment-naive CLL, and (3) to establish the safety and
feasibility of the combination of Formula (XVIII) and
obinutuzumab.
[2314] The secondary objectives of this study are: (1) to determine
the complete response (CR) rate and MRD-negative CR rate in
previously untreated and relapsed and refractory CLL with this
regimen; (2) to determine the progression-free survival (PFS), time
to next treatment (TTNT), and overall survival (OS) with this
regimen, (3) to perform baseline analysis of patients enrolled on
this trial including fluorescence in situ hybridization (FISH),
stimulated karyotype, Zap-70 methylation, and IgV.sub.H mutational
status and describe relationships between these biomarkers and ORR
or PFS for patients treated with this regimen; (4) to determine
pharmacokinetics (PK) of orally administered Formula (XVIII); (5)
to measure pharmacodynamic (PD) parameters including drug occupancy
of BTK, change in miR and gene expression on day 8 and 29 of
therapy of Formula (XVIII); (6) to determine the influence of
Formula (XVIII) on NK cell and T cell function in vivo; (7) to
assess for serial development of resistance by baseline and
longitudinal assessment of mutations of BTK and PLCG2 at regular
follow up intervals and by examining diagnosis to relapse samples
by whole exome sequencing; (8) to determine the influence of
Formula (XVIII) on emotional distress and quality of life in CLL
patients; and (9) to determine trajectory of psychological and
behavioral responses to Formula (XVIII) and covariation with
response to therapy.
[2315] CLL is the most prevalent form of adult leukemia and has a
variable clinical course, where many patients do not require
treatment for years and have survival equal to age matched
controls. Other patients, however, exhibit aggressive disease and
have a poor prognosis despite appropriate therapy. Byrd, et al.,
Chronic lymphocytic leukemia. Hematology Am. Soc. Hematol. Educ.
Program. 2004, 163-183. While patients with early disease have not
been shown to have a survival advantage with early treatment, most
patients will eventually require therapy for their disease with the
onset of symptoms or cytopenias, and despite the relatively long
life expectancy for early stage disease, CLL remains an incurable
disease. Patients diagnosed with or progressing to advanced disease
have a mean survival of 18 months to 3 years. Unfortunately these
patients with advanced disease are also more refractory to
conventional therapy.
[2316] The treatment of CLL has progressed significantly over the
previous decades. While alkylator therapy was used in the past,
randomized trials have demonstrated a higher response rate and
longer progression free survival (PFS) with fludarabine and
subsequently with fludarabine- and cyclophosphamide-based
combinations. O'Brien, et al., Advances in the biology and
treatment of B-cell chronic lymphocytic leukemia. Blood 1995, 85,
307-18; Rai, et al., Fludarabine compared with chlorambucil as
primary therapy for chronic lymphocytic leukemia. N. Engl. J. Med.
2000, 343, 1750-57; Johnson, et al., Multicentre prospective
randomised trial of fludarabine versus cyclophosphamide,
doxorubicin, and prednisone (CAP) for treatment of advanced-stage
chronic lymphocytic leukaemia. The French Cooperative Group on CLL.
Lancet 1996, 347, 1432-38; Leporrier, et al., Randomized comparison
of fludarabine, CAP, and ChOP in 938 previously untreated stage B
and C chronic lymphocytic leukemia patients. Blood 2001, 98,
2319-25; Catovsky, et al., Assessment of fludarabine plus
cyclophosphamide for patients with chronic lymphocytic leukaemia
(the LRF CLL4 Trial): A randomised controlled trial. Lancet 2007,
370, 230-239; Eichhorst, et al., Fludarabine plus cyclophosphamide
versus fludarabine alone in first-line therapy of younger patients
with chronic lymphocytic leukemia. Blood 2006, 107, 885-91. At the
same time, the chimeric anti-CD20 monoclonal antibody rituximab was
introduced for the treatment of CLL. At high doses or with dose
intensive treatment, single agent rituximab has shown efficacy;
however complete responses and extended remissions are very rare.
O'Brien, et al. Rituximab dose-escalation trial in chronic
lymphocytic leukemia. J. Clin. Oncol. 2001, 19, 2165-70; Byrd, et
al., Rituximab using a thrice weekly dosing schedule in B-cell
chronic lymphocytic leukemia and small lymphocytic lymphoma
demonstrates clinical activity and acceptable toxicity. Clin.
Oncol. 2001, 19, 2153-64. The efficacy of rituximab has been
improved by combining it with traditional cytotoxic agents such as
fludarabine or fludarabine and cyclophosphamide, which have
produced high CR rates and extended progression free survival (PFS)
compared to historical controls. Indeed, a large randomized
clinical trial reported by the German CLL study group has shown a
benefit of the addition of antibody therapy with rituximab to
fludarabine and cyclophosphamide in the prolongation of PFS and OS
in patients with untreated CLL. Hallek, et al., Addition of
rituximab to fludarabine and cyclophosphamide in patients with
chronic lymphocytic leukaemia: a randomised, open-label, phase 3
trial. Lancet 2010, 376, 1164-74. This encouraging progress in
therapy and our understanding of the disease has resulted in
significantly improved response rates and PFS. However, significant
improvements in overall survival (OS) and ultimately cure, remain
elusive goals.
[2317] While fludarabine based chemoimmunotherapy is standard for
younger patients, the therapy for older patients is less well
defined. In the large Phase 2 and 3 trials outlined previously,
median ages were typically in the early-60s, while the average age
of patients diagnosed with CLL is 72, which calls into question
whether these results are generalizable to the entire CLL
population. In fact, the one randomized Phase 3 trial investigating
primary CLL therapy in older patients demonstrated that in patients
>65 years old, fludarabine is not superior to chlorambucil.
Eichhorst, et al., First-line therapy with fludarabine compared
with chlorambucil does not result in a major benefit for elderly
patients with advanced chronic lymphocytic leukemia. Blood 2009,
114, 3382-91. This finding was corroborated by a large
retrospective study of front-line trials performed by the Alliance
for Clinical Trials in Oncology, which demonstrated again that
fludarabine is not superior to chlorambucil in older patients, but
also showed that the addition of rituximab to chemotherapy was
beneficial regardless of age. Woyach, et al., Impact of age on
outcomes after initial therapy with chemotherapy and different
chemoimmunotherapy regimens in patients with chronic lymphocytic
leukemia: Results of sequential cancer and leukemia group B
studies. J. Clin. Oncol. 2013, 31, 440-7. Two studies have
evaluated the combination of rituximab with chlorambucil, showing
that this combination is safe and moderately effective. Hillmen, et
al., rituximab plus chlorambucil in patients with CD20-positive
B-cell chronic lymphocytic leukemia (CLL): Final response analysis
of an open-label Phase II Study, ASH Annual Meeting Abstracts,
Blood 2010, 116, 697; Foa, et al., A Phase II study of chlorambucil
plus rituximab followed by maintenance versus observation in
elderly patients with previously untreated chronic lymphocytic
leukemia: Results of the first interim analysis, ASH Annual Meeting
Abstracts, Blood 2010, 116, 2462.
[2318] Recently, the type II glycoengineered CD20 monoclonal
antibody obinutuzumab was introduced. In a Phase 1 trial of
previously treated CLL as monotherapy, this antibody has a 62%
response rate including 1 MRD-negative complete response,
suggesting that alone this antibody may be more active in CLL than
rituximab. Morschhauser, et al., Phase I study of R.sup.05072759
(GA101) in relapsed/refractory chronic lymphocytic leukemia, ASH
Annual Meeting Abstracts. Blood, 2009, 114, 884. The German CLL
Study Group (GCLLSG) recently completed a Phase 3 trial of
rituximab and chlorambucil or obinutuzumab and chlorambucil vs
chlorambucil alone in patients with untreated CLL and significant
comorbidities. In this population, obinutuzumab and chlorambucil
(but not rituximab and chlorambucil) improved OS over chlorambucil
alone (hazard ratio 0.41, p=0.002), and obinutuzumab and
chlorambucil improved PFS over rituximab and chlorambucil (median
PFS 26.7 months vs 14.9 months, p<0.001). Goede, et al.,
Obinutuzumab plus chlorambucil in patients with CLL and coexisting
conditions, N. Engl. J. Med. 2014, 370, 1101-10. On the basis of
these favorable data, the combination of obinutuzumab and
chlorambucil is FDA approved as frontline therapy for CLL
patients.
[2319] Many older patients are also treated with the combination of
bendamustine plus rituximab (BR). Although BR has not been compared
directly with chlorambucil and rituximab, results of a recent Phase
2 trial show an ORR of 88% with a median event free survival of
33.9 months and 90.5% OS at 27 months. Fischer, et al.,
Bendamustine in combination with rituximab for previously untreated
patients with chronic lymphocytic leukemia: A multicenter phase II
trial of the German Chronic Lymphocytic Leukemia Study Group. J.
Clin. Oncol. 2012, 30, 3209-16. These results held for patients
>70 years old, and compare favorably with results published for
chlorambucil and rituximab. While results with this regimen appear
to be improved over historical controls, outcomes are not as good
as those observed in younger patients with chemoimmunotherapy.
Therefore, the optimal therapy for older patients remains an unmet
need in clinical trials.
[2320] Additionally, most patients eventually relapse with their
disease and are frequently refractory to existing agents. Patients
who relapse after combined chemoimmunotherapy have a poor outcome
with subsequent standard therapies. While options for these
patients include alemtuzumab, bendamustine, high dose
corticosteroids, ofatumumab, and combination based approaches, none
of these therapies produces durable remissions that exceed that
observed with first line chemoimmunotherapy. Keating, et al.,
Therapeutic role of alemtuzumab (Campath-1H) in patients who have
failed fludarabine: results of a large international study. Blood
2002, 99, 3554-61; Bergmann, et al., Efficacy of bendamustine in
patients with relapsed or refractory chronic lymphocytic leukemia:
results of a phase I/II study of the German CLL Study Group.
Haematologica 2005, 90, 1357-64; Thornton P D, Matutes E, Bosanquet
A G, et al. High dose methylprednisolone can induce remissions in
CLL patients with p53 abnormalities. Ann. Hematology 2003, 82,
759-65; Coiffier, et al., Safety and efficacy of ofatumumab, a
fully human monoclonal anti-CD20 antibody, in patients with
relapsed or refractory B-cell chronic lymphocytic leukemia: A phase
1-2 study. Blood 2008, 111, 1094-1100; Tsimberidou, et al., Phase
I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab
combination therapy in patients with Richter's syndrome or
fludarabine-refractory chronic lymphocytic leukemia. J. Clin.
Oncol. 2008, 26, 196-203. Several of these therapies including
alemtuzumab and high dose steroids are also associated with
significant toxicities and sustained immunosuppression. Lozanski G,
Heerema N A, Flinn 1W, et al. Alemtuzumab is an effective therapy
for chronic lymphocytic leukemia with p53 mutations and deletions.
Blood 2004, 103, 3278-81; Osuji, et al., The efficacy of
alemtuzumab for refractory chronic lymphocytic leukemia in relation
to cytogenetic abnormalities of p53. Haematologica 2005, 90,
1435-36; Thornton, et al., High dose methyl prednisolone in
refractory chronic lymphocytic leukaemia. Leuk. Lymphoma 1999, 34,
167-70; Bowen, et al. Methylprednisolone-rituximab is an effective
salvage therapy for patients with relapsed chronic lymphocytic
leukemia including those with unfavorable cytogenetic features.
Leuk Lymphoma 2007, 48, 2412-17; Castro, et al., Rituximab in
combination with high-dose methylprednisolone for the treatment of
fludarabine refractory high-risk chronic lymphocytic leukemia.
Leukemia 2008, 22, 2048-53.
[2321] In an ongoing Phase 1b/2 study, the BTK inhibitor ibrutinib
has shown activity in patients with relapsed or refractory CLL. In
patients with relapsed or refractory CLL and measurable
lymphadenopathy, the rate of lymph node shrinkage >50% is 89%.
With a median follow-up of 4 months, ORR was 48% due to
asymptomatic lymphocytosis, and with longer follow-up of 26 months
in patients receiving the 420 mg dose, has improved to 71%, with an
additional 20% of patients achieving a partial response with
lymphocytosis (PR-L). Byrd, et al., Activity and tolerability of
the Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 in patients
with chronic lymphocytic leukemia/small lymphocytic lymphoma
(CLL/SLL): Interim results of a phase Ib/II study. J. Clin. Oncol.
ASCO Annual Meeting Abstracts, 2011, 29, Abstract 6508; Byrd, et
al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic
leukemia. N. Engl. J. Med. 2013, 369, 32-42. This lymphocytosis is
likely related to B cell release from lymph node, spleen and marrow
microenvironment due to disruption of homing signals or
chemoattractants that are relevant to usual lymphocyte circulation
dynamics. Lymphocytosis with ibrutinib is seen within 1-2 weeks of
starting therapy, reaches plateau within the first 2-3 cycles, and
has resolved over time in virtually all patients. The duration of
lymphocytosis does not appear to be related to the depth of
eventual response nor to response duration. Woyach, et al.,
Prolonged lymphocytosis during ibrutinib therapy is associated with
distinct molecular characteristics and does not indicate a
suboptimal response to therapy. Blood 2014, 123, 1810-7. Response
to ibrutinib occurs independently of high-risk genomic features
including IgV.sub.H mutational status and del(17p13.1). Responses
to this drug have been durable as well, with an estimated 26 month
PFS of 76% and OS of 83% for these relapsed and refractory
patients. This study also included a cohort of 31 previously
untreated patients. With 16.6 months of follow-up, ORR is 71%, with
an additional 10% of patients having persistent lymphocytosis;
estimated 22 month PFS is 96%. This agent is currently in Phase 3
trials in treatment-nave disease and is currently FDA approved for
the treatment of relapsed CLL. These data with ibrutinib support
the potential benefits of selective BTK inhibition in CLL. However,
while highly potent in inhibiting BTK, ibrutinib has also shown in
vitro activity against other kinases (e.g., epidermal growth factor
receptor), which may be the cause of ibrutinib-related diarrhea and
rash. Honigberg, et al., The Bruton tyrosine kinase inhibitor
PCI-32765 blocks B-cell activation and is efficacious in models of
autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci.
USA 2010, 107, 13075-13080. In addition, it is a substrate for both
cytochrome P450 (CYP) enzymes 3A4/5, which increases the
possibility of drug-drug interactions. Finally, the inhibition of
ITK that is seen with ibrutinib has the potential to abrogate NK
cell ADCC, which makes combination with monoclonal antibodies less
effective. Kohrt, et al., Ibrutinib antagonizes rituximab-dependent
NK cell-mediated cytotoxicity. Blood 2014, 123, 1957-60. These
liabilities support the development of alternative BTK inhibitors
for use in the therapy of lymphoid cancers.
[2322] In this Phase 1B study, two cohorts (relapsed/refractory and
treatment-nave) will be evaluated with slightly staggered
enrollment. First, 6 subjects with R/R CLL will be enrolled into
Cohort 1. Once the safety has been evaluated, the R/R cohort will
be expanded to 26 subjects and enrollment of 6 treatment-nave
subjects can begin in Cohort 2. Once safety is established for
Cohort 2, then the cohort will be expanded to 19 subjects.
[2323] Formula (XVIII) will be administered starting cycle 1 day 1
and will be administered twice daily (100 mg BID) until disease
progression. Obinutuzumab will be given in the standard dosing
fashion starting on cycle 2 day 1. On cycle 2 day 1, patients will
receive 100 mg IV. On cycle 2 day 2, patients will receive 900 mg.
On cycle 2 days 8 and 15, patients will receive 1000 mg IV. On
cycles 3-7, patients will receive 1000 mg on day 1 of each cycle.
For patients treated at dose level -1, 100 mg will be given on Day
1 and 650 mg on Day 2 of Cycle 2. On cycle 2 day 8 and 15, patients
will receive 750 mg IV and during cycles 3-7, patients will receive
750 mg on Day 1 of each cycle. It is acceptable for cycles to begin
<a 24-hour (1 business day) window before and after the
protocol-defined date for Day 1 of a new cycle.
[2324] The inclusion criteria for patient eligibility are as
follows: (1) Patients with a diagnosis of intermediate or high risk
CLL (or variant immunophenotype), SLL, or B-PLL by IWCLL 2008
criteria" who have: (a) COHORT 1: Previously received at least one
therapy for their disease; (b) COHORT 2: Previously untreated
disease and >65 years old OR under 65 years old and refuse or
are ineligible for chemoimmunotherapy; (2) Patients on Cohort 1 may
have received previous ibrutinib (or another BTK inhibitor) as long
as discontinuation was for a reason other than "on-treatment"
disease progression; (3) All patients must satisfy one of the
following criteria for active disease requiring therapy: (a)
Evidence of marrow failure as manifested by the development or
worsening of anemia or thrombocytopenia (not attributable to
autoimmune hemolytic anemia or thrombocytopenia); (b) Massive
(>6 cm below the coastal margin), progressive or symptomatic
splenomegaly; (c) Massive nodes (>10 cm) or progressive or
symptomatic lymphadenopathy; (d) Constitutional symptoms, which
include any of the following: Unintentional weight loss of 10% or
more within 6 months, Significant fatigue limiting activity, Fevers
>100.5 degrees F. for 2 weeks or more without evidence of
infection, Night sweats >1 month without evidence of infection;
(4) Measurable nodal disease by computed tomography (CT).
Measurable nodal disease is defined as >1 lymph node >1.5 cm
in the longest diameter in a site; (5) Patients with a history of
Richter's syndrome are eligible if they now have evidence of CLL
only, with <10% large cells in the bone marrow; (6) Subjects
must have adequate organ function, defined as creatinine <2.5
times the upper limit of normal (ULN), ALT and AST
<3.0.times.ULN, and bilirubin <2.5.times.ULN; (7) Platelets
>50.times.10.sup.9/L. In subjects with CLL involvement of the
marrow, >30.times.10.sup.9/L; (8) ANC >750/mm.sup.3 In
subjects with CLL involvement of the marrow, ANC >500/mm.sup.3;
(9) Subject must have an ECOG performance status <2; (10)
Subject must not have secondary cancers that result in a life
expectancy of <2 years or that would confound assessment of
toxicity in this study; (11) Subjects must be >18 years of age;
(12) Subject must provide written informed consent. A signed copy
of the consent form will be retained in the patient's chart; (13)
Subject must be able to receive outpatient treatment and follow-up
at the treating institution; (14) Subject must have completed all
CLL therapies >4 weeks prior to first study dose. Palliative
steroids are allowed, but must be at a dose equivalent of <20 mg
prednisone daily for at least 1 week prior to treatment initiation;
(15) Subjects capable of reproduction and male subjects who have
partners capable of reproduction must agree to use an effective
contraceptive method during the course of the study and for 2
months following the completion of their last treatment. Females of
childbearing potential must have a negative .beta.-hCG pregnancy
test result within 3 days of first study dose. Female patients who
are surgically sterilized or who are >45 years old and have not
experienced menses for >2 years may have there 3-hCG pregnancy
test waived; (16) Subjects must be able to swallow whole
capsules.
[2325] The exclusion criteria for patient eligibility are as
follows: (1) For cohort 1, previous therapy for CLL. Treatment of
autoimmune complications of CLL with steroids or rituximab is
allowed, however, CD20 must have returned on 10% of the CLL cells
if rituximab was recently administered. Palliative steroids are
acceptable at doses <20 mg prednisone equivalent daily; (2) Any
life-threatening illness, medical condition, or organ dysfunction
which, in the investigator's opinion, could compromise the
patients' safety, interfere with the absorption or metabolism of
Formula (XVIII), or put the study outcomes at undue risk; (3)
Female subjects who are pregnant or breastfeeding; (4) Subjects
with active cardiovascular disease not medically controlled or
those who have had myocardial infarction in the past 6 months, or
QTc>480 ms; (5) Malabsorption syndrome, disease significantly
affecting gastrointestinal function, or resection of the stomach or
small bowel or gastric bypass, ulcerative colitis, symptomatic
inflammatory bowel disease, or partial or complete bowel
obstruction; (6) Grade 2 toxicity (other than alopecia) continuing
from prior anticancer therapy including radiation; (7) Major
surgery within 4 weeks before first dose of study drug; (8) History
of a bleeding diathesis (e.g., hemophilia, von Willebrand disease);
(9) Uncontrolled autoimmune hemolytic anemia or idiopathic
thrombocytopenia purpura; (10) History of stroke or intracranial
hemorrhage within 6 months before the first dose of study drug;
(11) Requires or receiving anticoagulation with warfarin or
equivalent vitamin K antagonists (eg, phenprocoumon) within 28 days
of first dose of study drug; (12) Requires treatment with
long-acting proton pump inhibitors (e.g., omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole); (13)
Subjects with active infections requiring IV antibiotic/antiviral
therapy are not eligible for entry onto the study until resolution
of the infection. Patients on prophylactic antibiotics or
antivirals are acceptable; (14) Subjects with history of or ongoing
drug-induced pneumonitis; (15) Subjects with human immunodeficiency
virus (HIV) or active infection with hepatitis C virus (HCV) or
hepatitis B virus (HBV) or any uncontrolled active systemic
infection; (16) Subjects who are known to have Hepatitis B
infection or who are hepatitis B core antibody or surface antigen
positive. Patients receiving prophylactic WIG may have false
positive hepatitis serologies. Patients who are on WIG who have
positive hepatitis serologies must have a negative hepatitis B DNA
to be eligible; (17) Subjects with substance abuse or other medical
or psychiatric conditions that, in the opinion of the investigator,
would confound study interpretation or affect the patient's ability
to tolerate or complete the study; (18) Subjects cannot
concurrently participate in another therapeutic clinical trial;
(19) Subjects who have received a live virus vaccination within 1
month of starting study drug.
[2326] In this study, Formula (XVIII) is administered 100 mg BID,
with the second dose 11-13 hours after the first. Obinutuzumab is
administered by IV infusion as an absolute (flat) dose.
Obinutuzumab is administered in a single day, with the exception of
the first administration when patients receive their first dose of
obinutuzumab over two consecutive days (split dose) in Cycle 2: 100
mg on Day 1 and 900 mg on Day 2. For patients treated at dose level
-1 (750 mg obinutuzumab), -100 mg will be given on Day 1 and 650 mg
on Day 2. On days when both Formula (XVIII) and obinutuzumab are
given, the order of study treatment administration will be Formula
(XVIII) followed at least 1 hour later by obinutuzumab. The full
dosing schedule is given in Table 13.
TABLE-US-00013 TABLE 13 Dosing of obinutuzumab during 6 treatment
cycles each of 28 days duration. Rate of Infusion (In the absence
of infusion reactions/ Day of Dose of hypersensitivity during
previous Treatment Cycle Obinutuzumab infusions) (loading Day 1 100
mg Administer at 25 mg/hr over 4 hours. doses) Do not increase the
infusion rate. Day 2 900 mg Administer at 50 mg/hr. The rate of the
infusion can be escalated in increments of 50 mg/hr every 30
minutes to a maximum rate of 400 mg/hr. Day 8 1000 mg Infusions can
be started at a rate of Day 15 1000 mg 100 mg/hr and increased by
100 mg/hr Cycles Day 1 1000 mg increments every 30 minutes 3-7 to a
maximum of 400 mg/hr.
[2327] Anti-CD20 antibodies have a known safety profile, which
include infusion related reactions (IRR). Anti-CD20 antibodies, and
in particular obinutuzumab, can cause severe and life threatening
infusion reactions. Sequelae of the infusion reactions include
patient discontinuations from antibody treatment leading to
suboptimal efficacy or increased medical resource utilization, such
as hospitalization for hypotension or prolonged antibody infusion
time. In the initial study of obinutuzumab in relapsed/refractory
CLL patients (Cartron, et al., Blood 2014, 124, 2196), all patients
(n=13) in the Phase 1 portion experienced IRRs (15% Grade 3, no
Grade 4, and 100% patients experienced all grade AE), with
hypotension and pyrexia the most common symptoms. In the Phase 2
portion of the study, 95% of patients developed IRR, with 60% of
cases developing symptoms of hypotension; of those, 25% were Grade
3 reactions. In the pivotal trial of obinutuzumab and chlorambucil
in previously untreated patients, 69% developed infusion related
reactions, of which 21% were grade 3-4.
[2328] The results of the Phase 1b study described in this example
for Formula (XVIII) in combination with obinutuzumab for patients
with relapsed/refractory or untreated CLL/SLL/PLL are as follows. 6
patients have been treated in the study to date with the
combination of Formula (XVIII) and obinutuzumab. Patients are first
treated with a month run-in of Formula (XVIII) alone, then on cycle
2, day 1, patients are given obinutuzumab. To date, 41 doses of
obinutuzumab have been administered to 6 patients. Lymphocyte
counts immediately prior to treatment with obinutuzumab have ranged
from 8 to 213.times.10.sup.9/L. No cases of serious or Grade 3-4
IRR's have been reported. Only 2 patients have had obinutuzumab
temporarily held for chills and arthralgias/sluured, respectively,
and were able to complete the planned infusion. An additional 3
patients had adverse events within 24 hours of the infusion, all
grade 1 (terms: flushing, palpitations in one patient, rash, and
restlessness and headache). Consequently, there has been a
substantial decrease in serious or Grade 3-4 IRR''s with the one
month lead-in of Formula (XVIII), which could potentially lead to
higher efficacy for the combination as well as better tolerability,
leading to a decrease in medical resource utilization.
Example 19 BTK Inhibitory Effects on MDSCs in the Solid Tumor
Microenvironment
[2329] A molecular probe assay was used to calculate the percent
irreversible occupancy of total BTK. MDSCs were purified from tumor
bearing PDA mice (as described previously) dosed at 15 mg/kg BID of
Formula (XVIII). Complete BTK occupancy is observed for both the
granulocytic and monocytic MDSC compartment on Day 8 at 4 hours
post dose (N=5). The results are shown in FIG. 158.
Example 20 BTK Inhibitory Effects on Solid Tumor Microenvironment
in a Non-Small Cell Lung Cancer (NSCLC) Model
[2330] A genetic tumor model of NSCLC (KrasLA2) was studied as a
model for lung cancer using the treatment schema shown in FIG. 159.
The model is designed to have sporadic expression in single cells
of G12D mutant Kras off its own promoter triggered by spontaneous
intrachromosomal recombination. Johnson, et al. Nature 2001, 410,
1111-16. While the mutant Kras protein is expressed in a few cells
in all tissues, tumor development is seen only in the lung at high
penetrance. Mice treated with Formula (XVIII) showed a significant
decrease in tumor volumes versus vehicle (FIG. 160) and fewer
overall tumors with dosing of 15 mg/kg. The effects on TAMs (FIG.
161), MDSCs (FIG. 162), Tregs (FIG. 163), and CD8+ cells (FIG. 164)
were consistent with suppression of the solid tumor microenviroment
as demonstrated previously.
Sequence CWU 1
1
141451PRTArtificial SequenceHeavy chain amino acid sequence of the
anti-CD20 monoclonal antibody rituximab. 1Gln Val Gln Leu Gln Gln
Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met
His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50
55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala
Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr
Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala
Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser
Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180
185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro
Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu
Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305
310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe
Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425
430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445 Pro Gly Lys 450 2213PRTArtificial sequenceLight chain
amino acid sequence of the anti-CD20 monoclonal antibody rituximab.
2Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1
5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr
Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro
Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val
Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr
Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys
Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr
Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135
140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210
3449PRTArtificial sequenceHeavy chain amino acid sequence of the
anti-CD20 monoclonal antibody obinutuzumab. 3Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser 20 25 30 Trp
Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu
Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala
Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170
175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro
Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro
Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val
Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295
300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr
Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr
Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420
425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly 435 440 445 Lys 4219PRTArtificial sequenceLight chain amino
acid sequence of the anti-CD20 monoclonal antibody obinutuzumab.
4Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1
5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His
Ser 20 25 30 Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro
Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu
Val Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp
Val Gly Val Tyr Tyr Cys Ala Gln Asn 85 90 95 Leu Glu Leu Pro Tyr
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135
140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val
Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn
Arg Gly Glu Cys 210 215 5122PRTArtificial sequenceVariable heavy
chain amino acid sequence of the anti-CD20 monoclonal antibody
ofatumumab. 5Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe Asn Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Trp Asn Ser
Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala
Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr Gly Met Asp Val Trp 100 105
110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120
6107PRTArtificial sequenceVariable light chain amino acid sequence
of the anti-CD20 monoclonal antibody ofatumumab. 6Glu Ile Val Leu
Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35
40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser
Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg
Ser Asn Trp Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu Glu
Ile Lys 100 105 7222PRTArtificial SequenceFab fragment of heavy
chain amino acid sequence of the anti-CD20 monoclonal antibody
ofatumumab. 7Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe Asn Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Trp Asn Ser
Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala
Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr Gly Met Asp Val Trp 100 105
110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125 Ser Val Phe Pro Leu Ala Pro Gly Ser Ser Lys Ser Thr Ser
Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr
Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly
Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220
8211PRTArtificial SequenceFab fragment of light chain amino acid
sequence of the anti-CD20 monoclonal antibody ofatumumab. 8Glu Ile
Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20
25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg
Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln
Gln Arg Ser Asn Trp Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Arg
Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150
155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg 210 9451PRTArtificial
SequenceHeavy chain amino acid sequence of the anti-CD20 monoclonal
antibody veltuzumab. 9Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val
Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln
Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro
Gly Met Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys
Ala Thr Leu Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Tyr Cys 85 90
95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asp Val Trp Gly
100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu
Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg
Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro
Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280
285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly
Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg
Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405
410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
Ser Leu Ser 435 440 445 Pro Gly Lys 450 10213PRTArtificial
SequenceLight chain amino acid sequence of the anti-CD20 monoclonal
antibody veltuzumab. 10Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Met Thr Cys Arg Ala
Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro
Gly Lys Ala Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu
Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly
Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp
Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90
95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn
Arg Gly Glu Cys 210 11447PRTArtificial SequenceHeavy chain amino
acid sequence of the anti-CD20 monoclonal antibody tositumomab.
11Gln Ala Tyr Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala 1
5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser
Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Arg Gln Gly Leu
Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser
Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp
Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr
Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Val Val Tyr
Tyr Ser Asn Ser Tyr Trp Tyr Phe Asp Val Trp 100 105 110 Gly Thr Gly
Thr Thr Val Thr Val Ser Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135
140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn
Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Ala
Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260
265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu
Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Asp
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385
390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser
Leu Ser Pro Gly Lys 435 440 445 12210PRTArtificial SequenceLight
chain amino acid sequence of the anti-CD20 monoclonal antibody
tositumomab. 12Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala
Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser
Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Ser
Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Pro Ser Asn Leu Ala Ser
Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser
Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala
Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr 85 90 95 Phe
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 100 105
110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg 210
13443PRTArtificial SequenceHeavy chain amino acid sequence of the
anti-CD20 monoclonal antibody ibritumomab. 13Gln Ala Tyr Leu Gln
Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys
Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn
Met His Trp Val Lys Gln Thr Pro Arg Gln Gly Leu Glu Trp Ile 35 40
45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr
Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala
Val Tyr Phe Cys 85 90 95 Ala Arg Val Val Tyr Tyr Ser Asn Ser Tyr
Trp Tyr Phe Asp Val Trp 100 105 110 Gly Thr Gly Thr Thr Val Thr Val
Ser Ala Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Val Cys Gly Asp
Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly
Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser 145 150 155 160 Gly
Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170
175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp
180 185 190 Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser
Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr
Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu
Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile
Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys
Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr
Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser 290 295
300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys
305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu
Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln
Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys
Gln Val Thr Leu Thr Cys Met 355 360 365 Val Thr Asp Phe Met Pro Glu
Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu
Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly
Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415
Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420
425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg 435 440
14209PRTArtificial SequenceLight chain amino acid sequence of the
anti-CD20 monoclonal antibody ibritumomab. 14Gln Ile Val Leu Ser
Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val
Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His
Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40
45 Ala Pro Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu
Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe
Asn Pro Pro Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
Arg Ala Asp Ala Ala Pro 100 105 110 Thr Val Phe Ile Phe Pro Pro Ser
Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser
Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170
175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
Ser Phe 195 200 205 Asn
* * * * *