U.S. patent application number 17/088298 was filed with the patent office on 2021-02-18 for pyrimidine-based antiproliferative agents.
This patent application is currently assigned to G1 Therapeutics, Inc.. The applicant listed for this patent is G1 Therapeutics, Inc.. Invention is credited to David Jung, Jay Copeland Strum.
Application Number | 20210047328 17/088298 |
Document ID | / |
Family ID | 1000005191176 |
Filed Date | 2021-02-18 |
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United States Patent
Application |
20210047328 |
Kind Code |
A1 |
Strum; Jay Copeland ; et
al. |
February 18, 2021 |
PYRIMIDINE-BASED ANTIPROLIFERATIVE AGENTS
Abstract
This invention is in the area of pyrimidine-based compounds for
the treatment of disorders involving abnormal cellular
proliferation, including but not limited to tumors and cancers.
Inventors: |
Strum; Jay Copeland;
(Hillsborough, NC) ; Jung; David; (Durham,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
G1 Therapeutics, Inc. |
Research Triangle Park |
NC |
US |
|
|
Assignee: |
G1 Therapeutics, Inc.
Research Triangle Park
NC
|
Family ID: |
1000005191176 |
Appl. No.: |
17/088298 |
Filed: |
November 3, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16230396 |
Dec 21, 2018 |
10829490 |
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17088298 |
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PCT/US2017/040093 |
Jun 29, 2017 |
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16230396 |
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62357630 |
Jul 1, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
Y02P 20/55 20151101;
C07D 495/14 20130101; C07D 491/147 20130101; C07D 491/22 20130101;
C07D 487/22 20130101; C07D 487/14 20130101; C07D 473/00 20130101;
C07D 471/14 20130101; C07D 498/22 20130101; C07D 401/14
20130101 |
International
Class: |
C07D 471/14 20060101
C07D471/14; C07D 487/14 20060101 C07D487/14; C07D 491/147 20060101
C07D491/147; C07D 491/22 20060101 C07D491/22; C07D 495/14 20060101
C07D495/14; C07D 498/22 20060101 C07D498/22; C07D 487/22 20060101
C07D487/22; C07D 401/14 20060101 C07D401/14; C07D 473/00 20060101
C07D473/00 |
Claims
1. A compound of Formula: ##STR00344## or a pharmaceutically
acceptable salt thereof, wherein: y is 0, 1, 2, 3 or 4; R is
hydrogen or C.sub.1-C.sub.6alkyl; each R.sup.1 is independently
alkyl, aryl, cycloalkyl or haloalkyl, wherein each of said alkyl,
cycloalkyl and haloalkyl groups optionally includes heteroatoms O,
N, or S in place of a carbon in the chain and two R.sup.1s on
adjacent ring atoms or on the same ring atom together with the ring
atom(s) to which they are attached optionally form a 3-8-membered
cycle; R.sup.2 is -(alkylene).sub.m-heterocyclo,
-(alkylene).sub.m-heteroaryl, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--NR.sup.3R.sup.4;
-(alkylene).sub.m-C(O)--O-alkyl; -(alkylene).sub.m-O--R.sup.5,
-(alkylene).sub.m-S(O).sub.n--R.sup.5, or
-(alkylene).sub.m-S(O).sub.n--NR.sup.3R.sup.4 any of which may be
optionally independently substituted with one or more R.sup.x
groups as allowed by valance, and wherein two R.sup.xgroups bound
to the same or adjacent atom may optionally combine to form a ring;
m is 0, 1, or 2; n is 0, 1, or 2; R.sup.3 and R.sup.4 at each
occurrence are independently selected from: (i) hydrogen or (ii)
alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkyl, arylalkyl, and heteroarylalkyl; or R.sup.3 and
R.sup.4 together with the nitrogen atom to which they are attached
may combine to form a heterocyclo ring; R.sup.5 is selected from:
(i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl,
arylalkyl, and heteroarylalkyl; R.sup.x at each occurrence is
independently selected from halo, cyano, nitro, oxo, alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkyl, -(alkylene).sub.m-OR.sup.5,
-(alkylene).sub.m-O-alkylene-OR.sup.5,
-(alkylene).sub.m-S(O)--R.sup.5, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-CN, -(alkylene).sub.m-C(O)--R.sup.5,
-(alkylene).sub.m-C(S)--R.sup.5, -(alkylene).sub.m-C(O)--OR.sup.5,
-(alkylene).sub.m-O--C(O)--R.sup.5,
-(alkylene).sub.m-C(S)--OR.sup.5,
-(alkylene).sub.m-C(O)-(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--R.sup.5,
-(alkylene).sub.m-N(R.sup.3)--C(S)--R.sup.5,
-(alkylene).sub.m-O--C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-O--C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-SO.sub.2--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.5,
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--OR.sup.5,
-(alkylene).sub.m-N(R.sup.3)--C(S)--OR.sup.5, or
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.5; R.sup.6 is
selected independently at each instance from: hydrogen, halogen,
alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl;
R.sup.7 is selected from: ##STR00345## or R.sup.7 is selected from
cycloalkyl, heterocycle, and alkyl, each of which cycloalkyl,
heterocycle, and alkyl groups is optionally substituted with one or
more substituents selected from amino, --NHR.sup.14,
--NR.sup.14R.sup.15, hydroxyl, OR.sup.14, R.sup.6, and R.sup.2;
R.sup.14 and R.sup.15 are independently selected from: hydrogen,
alkyl, alkenyl, alkynyl, --C(O)H, --C(O)alkyl, --C(S)alkyl, aryl,
--SO.sub.2alkyl, heteroaryl, arylalkyl, and heteroarylalkyl. Y is
NH, O, S, or NR.sup.9; X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are
independently N or CR, wherein at least one of X.sup.1, X.sup.2,
X.sup.3, X.sup.4, and X.sup.5 are CR; R.sup.8 is selected
independently at each instance from: R.sup.6 and R.sup.2, wherein
one R.sup.8 is R.sup.2; and R.sup.9 is selected from: --C(O)H,
--C(O)alkyl, --C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and
heteroarylalkyl.
2. The compound of claim 1 of Formula ##STR00346## or a
pharmaceutically acceptable salt thereof.
3. The compound of claim 1, wherein X.sup.1 and X.sup.2 are CH.
4. The compound of claim 1 of Formula ##STR00347## or a
pharmaceutically acceptable salt thereof.
5. The compound of claim 1, wherein at least one R.sup.1 is
alkyl.
6. The compound of claim 1, wherein two R.sup.1s on adjacent ring
atoms or on the same ring atom together with the ring atom(s) to
which they are attached form a 3-8-membered cycle.
7. The compound of claim 1, wherein two R.sup.1s on the same ring
atom together with the ring atom to which they are attached form
cyclohexyl.
8. The compound of claim 1, wherein y is 2.
9. The compound of claim 1, wherein y is 3.
10. The compound of claim 1 of Formula ##STR00348## or a
pharmaceutically acceptable salt thereof.
11. The compound of claim 1, wherein R is H.
12. The compound of claim 1, wherein R is methyl or ethyl.
13. The compound of claim 1 of Formula ##STR00349## or a
pharmaceutically acceptable salt thereof.
14. The compound of claim 1, wherein, R.sup.2 is
-(alkylene).sub.m-S(O)--NR.sup.3R.sup.4.
15. The compound of claim 14, wherein n is 2.
16. The compound of claim 1, wherein, R.sup.2 is
-(alkylene).sub.m-S(O)--NR.sup.3R.sup.4.
17. The compound of claim 1, wherein R.sup.2 is
-(alkylene).sub.m-heterocyclo optionally independently substituted
with one or more R.sup.x groups as allowed by valance.
18. The compound of claim 1, wherein R.sup.2 is selected from:
##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354##
##STR00355##
19. The compound of claim 1, wherein R.sup.2 is selected from:
##STR00356##
20. The compound of claim 1, wherein the compound is selected from
##STR00357## or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable excipient.
22. A method for the treatment of a disorder associated with
abnormal cellular proliferation comprising administering an
effective amount to a host in need thereof of a compound of claim
1, or a pharmaceutically acceptable salt thereof optionally in a
pharmaceutically acceptable carrier.
23. The method of claim 22, wherein the host is a human.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/230,396, filed Dec. 21, 2018, which is a
continuation of International Application No. PCT/US2017/040093,
filed with the Patent Cooperation Treaty, U.S. Receiving Office on
Jun. 29, 2017, which claims the benefit of U.S. Provisional
Application 62/357,630 which was filed on Jul. 1, 2016. The
entirety of these applications are hereby incorporated by reference
herein for all purposes.
FIELD OF THE INVENTION
[0002] This invention is in the area of pyrimidine-based compounds
for the treatment of disorders involving abnormal cellular
proliferation, including but not limited to tumors and cancers.
BACKGROUND
[0003] In normal tissue, cellular proliferation is generally
restricted to cells that are required to replenish the tissue. Once
cells have terminally differentiated, they have a specialized
function and no longer divide. Most tissues are made up of
non-dividing cells. Thus normal cell proliferation is tightly
controlled to ensure that only the necessary cells divide. There is
also a careful balance between cell division and programmed cell
death (apoptosis).
[0004] Cell division, sometimes referred to as the cell cycle, has
four phases: G.sub.1 phase (synthesis of various enzymes required
for DNA replication), S phase (DNA replication producing two
identical sets of chromosomes), G.sub.2 (significant protein
synthesis, including production of microtubules) and M phase
(nuclear division, cytoplasmic division and formation of new cell
membrane). Cell division also includes a complex system of cell
signaling networks that allow cells to interpret information from
numerous extracellular signals, including through receptor
proteins, inflammatory factors and pro-apoptotic and anti-apoptotic
signals. Dysfunctional signals include those from genetic mutation,
infection, exposure to environmental factors including toxins,
system stress, autoimmune disorders, and inflammation.
[0005] A range of disorders can occur when the process of cell
proliferation becomes dysfunctional, including benign growths,
neoplasms, tumorigenesis, cancerogenesis, autoimmune disorders,
inflammatory disorders graft-versus-host rejection, and fibrotic
disorders.
[0006] A number of broad-spectrum anti-neoplastic agents have been
developed. Cytoskeletal drugs like paclitaxel target tubulin to
arrest mitotic cell division and are used to treat a variety of
cancers including ovarian, breast, lung, pancreatic, and testicular
tumors (See e.g., Jordan, Wilson, Nature Reviews Cancer (2004) 4:
253-265). Organometallic-based drugs such as cisplatin have been
used to treat lymphomas, sarcomas, germ cell tumors, and some
carcinomas including bladder, small cell lung cancer, and ovarian
cancer. Cisplatin has the ability to bind nitrogenous bases and
cause extensive DNA cross-linking that ultimately leads to
apoptosis (See e.g., Siddick, Oncogene (2003) 22: 7265-7279).
Intercalating and alkylating agents have also been extensive use in
the clinic for the treatment of various neoplasms, however, the
global toxicity associated with these drugs presents a critical
concern for patients requiring long-term therapy.
[0007] Palbociclib (PD-033299; Ibrance) is sold by Pfizer for the
treatment of estrogen-positive, HER2-negative breast cancer in
combination with letrozole. The compound inhibits CDK4 and CDK6.
The structure of palbociclib is:
##STR00001##
[0008] Abemaciclib (LY2835219) is a CDK 4/6 inhibitor currently in
human clinical trials for the treatment of various types of
cancers. It is in a phase III trial for stage IV non-small cell
lung carcinoma; in combination with Fulvestrant for women with
breast cancer; and with either anastrozole or letrozole for first
line treatment of breast cancer. The structure of abemaciclib
is:
##STR00002##
[0009] Ribociclib (Lee011; Kisqali), is a CDK 4/6 inhibitor
approved for use in combination with an aromatase inhibitor to
treat some metastatic breast cancers, and is in clinical trials for
the treatment of certain other tumors. The structure of ribociclib
is:
##STR00003##
[0010] Various other pyrimidine-based agents have been developed
for the treatment of hyperproliferative diseases. U.S. Pat. Nos.
8,822,683; 8,598,197; 8,598,186; 8,691,830; 8,829,102; 8,822,683;
9,102,682; 9,499,564; 9,481,591; and U.S. Pat. No. 9,260,442, filed
by Tavares and Strum and assigned to G1 Therapeutics describe a
class of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine cyclin
dependent kinase inhibitors including those of the formula (with
variables as defined therein):
##STR00004##
[0011] WO 2013/148748 (U.S. Ser. No. 61/617,657) titled "Lactam
Kinase Inhibitors", WO 2013/163239 (U.S. Ser. No. 61/638,491)
titled "Synthesis of Lactams" and WO 2015/061407 filed by Tavares
and also assigned to G1 Therapeutics describes the synthesis of
N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines and their use as
lactam kinase inhibitors.
[0012] Other publications include the following. WO 2014/144326
filed by Strum et al. and assigned to G1 Therapeutics describes
compounds and methods for protection of normal cells during
chemotherapy using pyrimidine-based CDK4/6 inhibitors. WO
2014/144596 filed by Strum et al. and assigned to G1 Therapeutics
describes compounds and methods for protection of hematopoietic
stem and progenitor cells against ionizing radiation using
pyrimidine-based CDK4/6 inhibitors. WO 2014/144847 filed by Strum
et al. and assigned to G1 Therapeutics describes HSPC-sparing
treatments of abnormal cellular proliferation using
pyrimidine-based CDK4/6 inhibitors. WO 2014/144740 filed by Strum
et al. and assigned to G1 Therapeutics describes highly active
anti-neoplastic and anti-proliferative pyrimidine-based CDK 4/6
inhibitors. WO 2015/161285 filed by Strum et al. and assigned to G1
Therapeutics describes tricyclic pyrimidine-based CDK inhibitors
for use in radioprotection. WO 2015/161287 filed by Strum et al.
and assigned to G1 Therapeutics describes analogous tricyclic
pyrimidine-based CDK inhibitors for the protection of cells during
chemotherapy. WO 2015/161283 filed by Strum et al. and assigned to
G1 Therapeutics describes analogous tricyclic pyrimidine-based CDK
inhibitors for use in HSPC-sparing treatments of RB-positive
abnormal cellular proliferation. WO 2015/161288 filed by Strum et
al. and assigned to G1 Therapeutics describes analogous tricyclic
pyrimidine-based CDK inhibitors for use as anti-neoplastic and
anti-proliferative agents. WO 2016/040858 filed by Strum et al. and
assigned to G1 Therapeutics describes the use of combinations of
pyrimidine-based CDK4/6 inhibitors with other anti-neoplastic
agents. WO 2016/040848 filed by Strum et al. and assigned to G1
Therapeutics describes compounds and methods for treating certain
Rb-negative cancers with CDK4/6 inhibitors and topoisomerase
inhibitors.
[0013] WO 03/062236 identifies a series of
2-(pyridin-2-ylamino-pyrido[2,3]pyrimidin-7-ones for the treatment
of Rb positive cancers that show selectivity for CDK4/6, including
6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylammino)-8-
H-pyrido-[2,3-d]-pyrimidin-7-one (PD0332991), which was given
fast-track approval by the FDA and is currently sold as Ibrance
(Palbociclib) by Pfizer for the treatment of metastatic breast
cancer.
[0014] VanderWel et al. describe an iodine-containing
pyrido[2,3-d]pyrimidine-7-one (CKIA) as a potent and selective CDK4
inhibitor (see VanderWel et al., J. Med. Chem. 48 (2005)
2371-2387).
[0015] WO 2010/020675 filed by Novartis AG describes
pyrrolopyrimidine compounds as CDK inhibitors. WO 2011/101409 also
filed by Novartis describes pyrrolopyrimidines with CDK 4/6
inhibitory activity.
[0016] Johnson et al. reported that pharmacological inhibition of
CDK4/6 using the CDK4/6 inhibitors
6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylammino)-8-
H-pyrido-[2,3-d]-pyrimidin-7-one (PD0332991) and
2-bromo-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4]carbazole-5,6-dione
(2BrIC) exhibited IR protective characteristics in CDK4/6-dependent
cell lines. (Johnson et al. Mitigation of hematological radiation
toxicity in mice through pharmacological quiescence induced by
CDK4/6 inhibition. J Clin. Invest. 2010; 120(7): 2528-2536).
[0017] There remains a need for additional compounds to treat
disorders associated with abnormal cellular proliferation,
including a tumor or cancer.
SUMMARY
[0018] Compounds are presented that have advantageous
antiproliferative activity, including anticancer and antitumor
activity. Based on this discovery, compounds and methods are
presented for the treatment of a patient with a proliferative
disorder including a tumor or cancer that includes administering an
effective amount of one or a combination of the compounds described
herein to a patient in need thereof, optionally in a
pharmaceutically acceptable carrier. In certain embodiments the
antiproliferative disorder is selected from a benign growth,
neoplasm, tumor, cancer, autoimmune disorder, inflammatory
disorder, graft-versus-host rejection and a fibrotic disorder. In a
typical embodiment the patient is a human.
[0019] The invention includes an active compound of Formula I,
Formula II, Formula III Formula IV, Formula V, Formula VI, Formula
VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,
Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII,
Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII,
or Formula XXIII or a pharmaceutically acceptable salt or
composition thereof. In one embodiment, an active compound or its
salt, composition, or prodrug thereof is used to treat a medical
disorder involving abnormal cellular proliferation.
[0020] The invention includes an antiproliferative (including
antineoplastic) compound of Formula I, Formula II, Formula III
Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,
Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
or Formula XIX:
##STR00005## ##STR00006## ##STR00007##
or a pharmaceutically acceptable salt, N-oxide, isotopic
derivative, prodrug, and/or a pharmaceutically acceptable
composition thereof; wherein:
[0021] X is NH, NR.sup.9, S, or O;
[0022] y is 0, 1, 2, 3 or 4;
[0023] m is 0, 1, or 2;
[0024] n is 0, 1, or 2;
[0025] Z is independently CH, CR.sup.9, or N;
[0026] Q is CH.sub.2 or CO;
[0027] R is hydrogen, C.sub.1-C.sub.6alkyl,
--(C.sub.0-C.sub.2alkyl)(C.sub.3-C.sub.8carbocyclyl),
--(C.sub.0-C.sub.2alkyl)(C.sub.3-C.sub.8heterocyclyl),
--(C.sub.0-C.sub.2alkyl)(aryl),
--(C.sub.0-C.sub.2alkyl)(heteroaryl), --COOalkyl, --COOarylalkyl,
or --COOH;
[0028] each R.sup.1 is independently alkyl, aryl, cycloalkyl or
haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl
groups optionally includes heteroatoms O, N, or S in place of a
carbon in the chain and two R.sup.1's on adjacent ring atoms or on
the same ring atom together with the ring atom(s) to which they are
attached optionally form a 3-8-membered cycle or two R.sup.1's on
adjacent ring atoms together with the ring atom(s) to which they
are attached optionally form a 6-membered aryl ring;
[0029] or R.sup.1 is hydrogen;
[0030] R.sup.2 is -(alkylene).sub.m-heterocyclo,
-(alkylene).sub.m-heteroaryl, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--NR.sup.3R.sup.4;
-(alkylene).sub.m-C(O)--O-alkyl; -(alkylene).sub.m-O--R.sup.5,
-(alkylene).sub.m-S(O).sub.n--R.sup.5, or
-(alkylene).sub.m-S(O).sub.n--NR.sup.3R.sup.4 any of which may be
optionally independently substituted with one or more R.sup.x
groups as allowed by valance, and wherein two R.sup.x groups bound
to the same or adjacent atom may optionally combine to form a
ring;
[0031] R.sup.3 and R.sup.4 at each occurrence are independently
selected from:
[0032] (i) hydrogen or
[0033] (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl
any of which may be optionally independently substituted with one
or more R.sup.x groups as allowed by valance, and wherein two
R.sup.xgroups bound to the same or adjacent atom may optionally
combine to form a ring; or R.sup.3 and R.sup.4 together with the
nitrogen atom to which they are attached may combine to form a
heterocyclo ring optionally independently substituted with one or
more R.sup.x groups as allowed by valance, and wherein two R.sup.x
groups bound to the same or adjacent atom may optionally combine to
form a ring;
[0034] R.sup.5 is independently selected at each occurrence
from:
[0035] (i) hydrogen or
[0036] (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or
heteroarylalkyl any of which may be optionally independently
substituted with one or more R.sup.x groups as allowed by
valance;
[0037] R.sup.x at each occurrence is independently selected from
halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,
-(alkylene).sub.m-OR.sup.5, -(alkylene).sub.m-O-alkylene-OR.sup.5,
-(alkylene).sub.m-S(O)--R.sup.5, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-CN, -(alkylene).sub.m-C(O)--R.sup.5,
-(alkylene).sub.m-C(S)--R.sup.5, -(alkylene).sub.m-C(O)--OR.sup.5,
-(alkylene).sub.m-O--C(O)--R.sup.5,
-(alkylene).sub.m-C(S)--OR.sup.5,
-(alkylene).sub.m-C(O)-(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--R.sup.5,
-(alkylene).sub.m-N(R.sup.3)--C(S)--R.sup.5,
-(alkylene).sub.m-O--C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-O--C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-SO.sub.2--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.5,
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--OR.sup.5)
-(alkylene).sub.m-N(R.sup.3)--C(S)--OR.sup.5, or
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.5, wherein: said
alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkyl groups may be further independently substituted as
described herein;
[0038] R.sup.6 is selected independently at each instance from:
hydrogen, halogen, alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo,
aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or
heteroarylalkyl;
[0039] R.sup.7 is selected from:
##STR00008##
[0040] or R.sup.7 is selected from cycloalkyl, heterocycle, and
alkyl, each of which cycloalkyl, heterocycle, and alkyl groups is
optionally substituted with one or more substituents selected from
amino, --NHR.sup.14, --NR.sup.14R.sup.15, hydroxyl, OR.sup.14,
R.sup.6, and R.sup.2;
[0041] R.sup.14 and R.sup.15 are independently selected from:
hydrogen, alkyl, alkenyl, alkynyl, --C(O)H, --C(O)alkyl,
--C(S)alkyl, aryl, --SO.sub.2alkyl, heteroaryl, arylalkyl, and
heteroarylalkyl.
[0042] Y is NH, O, S, or NR.sup.9;
[0043] X.sup.1, X.sup.2, X.sup.3, and X.sup.4, are independently N
or CR, wherein at least one of X.sup.1, X.sup.2, X.sup.3, and
X.sup.4, is CR.sup.8;
[0044] R.sup.8 is selected independently at each instance from:
R.sup.6 and R.sup.2, wherein one R.sup.8 is R.sup.2;
[0045] R.sup.9 is selected from: --C(O)H, --C(O)alkyl, --C(S)alkyl,
alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
[0046] R.sup.10 is selected from: hydrogen, --COOalkyl,
--COOarylalkyl, --COOH, --OH, --C(O)H, --C(O)alkyl, --C(S)alkyl,
alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and
[0047] wherein for compounds of Formula VII y is 0, 1, or 2.
[0048] In an additional aspect the invention includes an active
compound of Formula XX, Formula XXI, Formula XXII, Formula XXIII,
or Formula XXIV or a pharmaceutically acceptable salt or
composition thereof. The compounds of Formula XX, Formula XXI,
Formula XXII, Formula XXIII, and XXIV have the following
structures:
##STR00009##
[0049] wherein m, R, R.sup.1, R.sup.7, Q, and y are defined
above.
[0050] In one embodiment the compound of Formula XX is:
##STR00010##
[0051] In an additional aspect the invention includes an active
compound of Formula XXV:
##STR00011##
[0052] wherein R, R.sup.1, R.sup.2, R.sup.6, and y are defined
above;
[0053] R.sup.16 is selected from cycloalkyl, heterocycle, and
alkyl, each of which cycloalkyl, heterocycle, and alkyl groups is
optionally substituted with one or more substituents selected from
amino, --NHR.sup.14, --NR.sup.14R.sup.15, hydroxyl, OR.sup.14,
R.sup.6, and R.sup.2;
[0054] R.sup.14 and R.sup.15 are independently selected from:
hydrogen, alkyl, alkenyl, alkynyl, --C(O)H, --C(O)alkyl,
--C(S)alkyl, aryl, --SO.sub.2alkyl, heteroaryl, arylalkyl, and
heteroarylalkyl.
[0055] In an alternative embodiment the compound of the present
invention is selected from
##STR00012##
[0056] In another alternative embodiment the compound of the
present invention is selected from
##STR00013##
[0057] In another alternative embodiment the compound of the
present invention is selected from
##STR00014##
[0058] In an alternative embodiment the compound of the present
invention is
##STR00015##
[0059] In another alternative embodiment the compound of the
present invention is:
##STR00016##
[0060] These compounds can be used to treat such condition in a
host in need thereof, typically a human.
[0061] In one embodiment, the active compound acts as an inhibitor
of a cyclin-dependent kinase (CDK), for example CDK4 and/or CDK6.
In an aspect, the compound is a selective inhibitor of CDK4 and/or
CDK6. In another embodiment, the selectivity is for CDK4 and/or
CDK6 over CDK2. Based on this, in one embodiment, the method for
the treatment of a disorder of abnormal cellular proliferation that
is mediated by CDK4 and or CDK6 is provided that includes the
administration of an effective amount of a compound of the present
invention or a pharmaceutically acceptable salt thereof, optionally
in a pharmaceutically acceptable carrier, as described in more
detail below.
[0062] In an alternative embodiment, a method for the treatment of
a disorder of abnormal cellular proliferation that is not mediated
by CDK4 and or CDK6 is provided that includes the administration of
an effective amount of a compound of the present invention or a
pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier, as described in more detail
below.
[0063] In another embodiment, a method for the treatment of a
fibrotic disorder in a host is provided that includes the
administration of an effective amount of a compound of the present
invention or a pharmaceutically acceptable salt thereof, optionally
in a pharmaceutically acceptable carrier.
[0064] In another embodiment, a method for the treatment of
rheumatoid arthritis or psoriasis in a host is provided that
includes the administration of an effective amount of a compound of
the present invention or a pharmaceutically acceptable salt
thereof, optionally in a pharmaceutically acceptable carrier.
[0065] In yet another embodiment, a method for the treatment of an
autoimmune disorder in a host is provided that includes the
administration of an effective amount of a compound of the present
invention or a pharmaceutically acceptable salt thereof, optionally
in a pharmaceutically acceptable carrier.
[0066] In a principal embodiment, a method for the treatment of a
tumor or cancer in a host is provided that includes the
administration of an effective amount of a compound of the present
invention or a pharmaceutically acceptable salt thereof, optionally
in a pharmaceutically acceptable carrier. In an aspect of this
embodiment, the cancer is an Rb-positive tumor or cancer.
[0067] In another aspect of this embodiment, the cancer is an
Rb-negative tumor or cancer. In certain aspects, the cancer is
selected from breast cancer, prostate cancer (including
androgen-resistant prostate cancer), another cancer of the
reproductive system such as endometrial, ovarian or testicular
cancer, small cell lung carcinoma, glioblastoma and head and/or
neck cancer.
[0068] In yet another embodiment, a method for the treatment of a
disorder of abnormal cellular proliferation in a host such as a
human is provided that includes administering an effective amount
of a combination of one or more of the active compounds described
herein in combination or alternation with another active compound.
In certain aspects of the invention, the second compound is a
chemotherapeutic agent. In another aspect of this embodiment, the
second active compound is an immune modulator, including but not
limited to a checkpoint inhibitor such as an anti-PD1, anti-CTLA,
anti-LAG-3, anti-Tim, etc antibody, small molecule, peptide,
nucleotide or other inhibitor (including but not limited to
ipilimumab (Yervoy), Pembrolizumab (Keytruda) and nivolumab
(Opdivo).
[0069] In yet another embodiment, one of the active compounds
described herein is administered in an effective amount for the
treatment of abnormal tissue of the female reproductive system such
as breast, ovarian, endometrial, or uterine cancer, in combination
or alternation with an effective amount of an estrogen inhibitor
including but not limited to a SERM (selective estrogen receptor
modulator), a SERD (selective estrogen receptor degrader), a
complete estrogen receptor degrader, or another form of partial or
complete estrogen antagonist.
[0070] In another embodiment, one of the active compounds described
herein is administered in an effective amount for the treatment of
abnormal tissue of the male reproductive system such as prostate or
testicular cancer, in combination or alternation with an effective
amount of an androgen (such as testosterone) inhibitor including
but not limited to a selective androgen receptor modulator, a
selective androgen receptor degrader, a complete androgen receptor
degrader, or another form of partial or complete androgen
antagonist. In one embodiment, the prostate or testicular cancer is
androgen-resistant.
[0071] In one embodiment, the compounds described herein inhibit
Cyclin Dependent Kinase. For example, a compound described in the
present invention provides a dose-dependent G1-arresting effect on
a subject's CDK replication dependent healthy cells, for example
HSPCs or renal epithelial cells. The methods provided for herein
are sufficient to afford chemoprotection to targeted CDK
replication dependent healthy cells during chemotherapeutic agent
exposure, for example, during the time period that a DNA-damaging
chemotherapeutic agent is capable of DNA-damaging effects on CDK
replication dependent healthy cells in the subject.
[0072] In one embodiment, the use of the compounds or methods
described herein is combined with the use of hematopoietic growth
factors including, but not limited to, granulocyte colony
stimulating factor (G-CSF), granulocyte-macrophage colony
stimulating factor (GM-CSF), thrombopoietin, interleukin (IL)-12,
steel factor, and erythropoietin (EPO), or their derivatives. In
one embodiment, the compound is administered prior to
administration of the hematopoietic growth factor. In one
embodiment, the hematopoietic growth factor administration is timed
so that the compound's effect on HSPCs has dissipated.
[0073] The present invention thus includes at least the following
features:
[0074] (a) a compound of the present invention as described herein,
and pharmaceutically acceptable salts and prodrugs thereof;
[0075] (b) a compound of the present invention as described herein,
and pharmaceutically acceptable salts and prodrugs thereof that are
useful in the treatment of a disorder of abnormal cellular
proliferation, including a tumor or cancer;
[0076] (c) use of a compound of the present invention, or
pharmaceutically acceptable salts and prodrugs thereof in the
manufacture of a medicament for the treatment of a disorder of
abnormal cellular proliferation, such as a tumor or cancer;
[0077] (d) a method for manufacturing a medicament intended for the
therapeutic use of treating a disorder of abnormal cellular
proliferation including a tumor or cancer, characterized in that a
compound of the present invention as described herein is used in
the manufacture;
[0078] (e) a compound of the present invention as described herein,
and pharmaceutically acceptable salts and prodrugs thereof that are
useful in the treatment of cancer, including any of the cancers
described herein;
[0079] (f) use of a compound of the present invention, and
pharmaceutically acceptable salts and prodrugs thereof in the
manufacture of a medicament for the treatment of cancer, including
any of the cancers described herein;
[0080] (g) a method for manufacturing a medicament intended for the
therapeutic use of treating cancer, including any of the cancers
described herein, characterized in that a compound of the present
invention as described herein is used in the manufacture;
[0081] (h) a compound of the present invention as described herein,
and pharmaceutically acceptable salts and prodrugs thereof that are
useful in the treatment of a tumor, including any of the tumors
described herein;
[0082] (i) use of a compound of the present invention, and
pharmaceutically acceptable salts and prodrugs thereof in the
manufacture of a medicament for the treatment of a tumor, including
any of the tumors described herein;
[0083] (j) a method for manufacturing a medicament intended for the
therapeutic use of treating a tumor, including any of the tumors
described herein, characterized in that a compound of the present
invention as described herein is used in the manufacture;
[0084] (k) a compound of the present invention as described herein,
and pharmaceutically acceptable salts and prodrugs thereof that are
useful in the treatment of a fibrotic disorder;
[0085] (l) use of a compound of the present invention, and
pharmaceutically acceptable salts and prodrugs thereof in the
manufacture of a medicament for the treatment of a fibrotic
disorder;
[0086] (m) a method for manufacturing a medicament intended for the
therapeutic use of treating a fibrotic disorder, characterized in
that a compound of the present invention as described herein is
used in the manufacture;
[0087] (n) a compound of the present invention as described herein,
and pharmaceutically acceptable salts and prodrugs thereof that are
useful in the treatment of an autoimmune or inflammatory
disorder;
[0088] (o) use of a compound of the present invention, and
pharmaceutically acceptable salts and prodrugs thereof in the
manufacture of a medicament for the treatment of an autoimmune or
inflammatory disorder;
[0089] (p) a method for manufacturing a medicament intended for the
therapeutic use of treating an autoimmune or inflammatory disorder,
characterized in that a compound of the present invention as
described herein is used in the manufacture;
[0090] (q) a pharmaceutical formulation comprising an effective
host-treating amount of the compound of the present invention or a
pharmaceutically acceptable salt or prodrug thereof together with a
pharmaceutically acceptable carrier or diluent;
[0091] (r) a compound of the present invention as described herein
as a mixture of enantiomers or diastereomers (as relevant),
including as a racemate;
[0092] (s) a compound of the present invention as described herein
in enantiomerically or diastereomerically (as relevant) enriched
form, including as an isolated enantiomer or disastereomer (i.e.,
greater than 85, 90, 95, 97 or 99% pure); and,
[0093] (t) a process for the preparation of therapeutic products
that contain an effective amount of a compound of the present
invention, as described herein.
[0094] (u) a compound of the present invention as described herein,
and pharmaceutically acceptable salts and prodrugs thereof that are
useful in chemoprotection;
[0095] (v) use of a compound of the present invention, and
pharmaceutically acceptable salts and prodrugs thereof in the
manufacture of a medicament for chemoprotection; and
[0096] (w) a method for manufacturing a medicament intended for the
therapeutic use of chemoprotection, characterized in that a
compound of the present invention as described herein is used in
the manufacture.
BRIEF DESCRIPTION OF FIGURES
[0097] FIG. 1 is a bar graph showing the population of cells with a
DNA content less than 2N, cells in the G0-G1 phase, cells in the S
phase, and cells in the G2-M phase as a way to measure the relative
amount of apoptotic cells following administration of control,
Compound 30, Compound 36, Compound 37, Compound 38, Compound 39,
Compound 40, and Compound 41. The Compound number and dose,
measured in .mu..mu.M and nM) are shown on the x-axis and the cell
population, measured in percent, is shown on the y-axis.
[0098] FIG. 2 is a bar graph showing the population of cells with a
DNA content less than 2N, cells in the G0-G1 phase, cells in the S
phase, and cells in the G2-M phase as a way to measure the relative
amount of apoptotic cells following administration of control,
Compound 31, Compound 33, and Compound 34. The Compound number and
dose, measured in .mu.M and nM) are shown on the x-axis and the
cell population, measured in percent, is shown on the y-axis.
[0099] FIG. 3 is Formula XX, Formula XXI, Formula XXII, Formula
XXIII, Formula XXIV, and Formula XXV.
[0100] FIG. 4 is a bar graph showing the population of cells with a
DNA content less than 2N, cells in the G0-G1 phase, cells in the S
phase, and cells in the G2-M phase as a way to measure the relative
amount of apoptotic cells following administration of control and
Compound 28. The population of apoptotic cells after exposure to
Compound 28 was greater than 70% at every dose administered. The
assay was done in a population of Hs68 cells. * is <2000 events.
The Compound number and dose, measured in .mu.M and nM, are shown
on the x-axis and the cell population, measured in percent, is
shown on the y-axis.
DETAILED DESCRIPTION
I. Compounds
[0101] In one embodiment, compounds of Formula I, Formula II,
Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula
VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
or Formula XIX are provided:
##STR00017## ##STR00018## ##STR00019##
or a pharmaceutically acceptable salt, N-oxide, isotopic
derivative, or prodrug, optionally in a pharmaceutically acceptable
carrier to form a pharmaceutically acceptable composition thereof;
wherein the variables are as defined above in the Summary
section.
[0102] In an alternative embodiment, a compound of Formula XX,
Formula XXI, Formula XXII, Formula XXIII or Formula XXIV is
provided:
##STR00020##
or a pharmaceutically acceptable salt, N-oxide, isotopic
derivative, or prodrug, optionally in a pharmaceutically acceptable
carrier to form a pharmaceutically acceptable composition thereof;
wherein the variables are as defined above in the Summary
section.
[0103] In another embodiment, a compound of Formula I-1, Formula
II-1, Formula III-1, Formula IV-1, Formula V-1, Formula VI-1,
Formula VII-1, Formula VIII-1, Formula IX-1, Formula X-1, Formula
XI-1, Formula XII-1, Formula XIII-1, Formula XIV-1, Formula XV-1,
Formula XVI-1, Formula XVII-1, Formula XVIII-1, Formula XIX-1,
Formula XX-1, Formula XXI-1, Formula XXII-1, Formula XXIII-1,
Formula XXIV-1, or Formula XXV-1 is provided:
##STR00021## ##STR00022## ##STR00023## ##STR00024##
or a pharmaceutically acceptable salt, N-oxide, isotopic
derivative, or prodrug, optionally in a pharmaceutically acceptable
carrier to form a pharmaceutically acceptable composition thereof;
wherein:
[0104] X is NH, NR.sup.9, S, or O;
[0105] y is 0, 1, 2, 3, or 4;
[0106] m is 0, 1, or 2;
[0107] n is 0, 1, or 2;
[0108] Z is independently CH, CR.sup.9, or N;
[0109] Q is CH.sub.2 or CO;
[0110] R is hydrogen, C.sub.1-C.sub.6alkyl,
--(C.sub.0-C.sub.2alkyl)(C.sub.3-C.sub.8carbocyclyl),
--(C.sub.0-C.sub.2alkyl)(C.sub.3-C.sub.8heterocyclyl),
--(C.sub.0-C.sub.2alkyl)(aryl),
--(C.sub.0-C.sub.2alkyl)(heteroaryl), --COOalkyl, --COOarylalkyl,
or --COOH;
[0111] each R.sup.1 is independently alkyl, aryl, cycloalkyl or
haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl
groups optionally includes heteroatoms O, N, or S in place of a
carbon in the chain and two R.sup.1's on adjacent ring atoms or on
the same ring atom together with the ring atom(s) to which they are
attached optionally form a 3-8-membered cycle or two R.sup.1's on
adjacent ring atoms together with the ring atom(s) to which they
are attached optionally form a 6-membered aryl ring;
[0112] or R.sup.1 is hydrogen;
[0113] R.sup.2 is -(alkylene).sub.m-heterocyclo,
-(alkylene).sub.m-heteroaryl, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--NR.sup.3R.sup.4;
-(alkylene).sub.m-C(O)--O-alkyl; -(alkylene).sub.m-O--R.sup.5,
-(alkylene).sub.m-S(O).sub.n--R.sup.5, or
-(alkylene).sub.m-S(O).sub.n--NR.sup.3R.sup.4 any of which may be
optionally independently substituted with one or more R.sup.x
groups as allowed by valance, and wherein two R.sup.xgroups bound
to the same or adjacent atom may optionally combine to form a
ring;
[0114] R.sup.3 and R.sup.4 at each occurrence are
independently:
[0115] (i) hydrogen or
[0116] (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl;
or R.sup.3 and R.sup.4 together with the nitrogen atom to which
they are attached may combine to form a heterocyclo ring;
[0117] R.sup.5 is independently:
[0118] (i) hydrogen or
[0119] (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or
heteroarylalkyl;
[0120] R.sup.x at each occurrence is independently selected from
halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,
-(alkylene).sub.m-OR.sup.5, -(alkylene).sub.m-O-alkylene-OR.sup.5,
-(alkylene).sub.m-S(O)--R.sup.5, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-CN, -(alkylene).sub.m-C(O)--R.sup.5,
-(alkylene).sub.m-C(S)--R.sup.5, -(alkylene).sub.m-C(O)--OR.sup.5,
-(alkylene).sub.m-O--C(O)--R.sup.5,
-(alkylene).sub.m-C(S)--OR.sup.5,
-(alkylene).sub.m-C(O)-(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--R.sup.5,
-(alkylene).sub.m-N(R.sup.3)--C(S)--R.sup.5,
-(alkylene).sub.m-O--C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-O--C(S)--NR.sup.3R.sup.4,
-(alkylene).sub.m-SO.sub.2--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.5,
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--NR.sup.3R.sup.4,
-(alkylene).sub.m-N(R.sup.3)--C(O)--OR.sup.5)
-(alkylene).sub.m-N(R.sup.3)--C(S)--OR.sup.5, or
-(alkylene).sub.m-N(R.sup.3)--SO.sub.2--R.sup.5;
[0121] R.sup.6 is selected independently at each instance from:
hydrogen, halogen, alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo,
aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or
heteroarylalkyl;
[0122] R.sup.7 is selected from:
##STR00025##
[0123] or R.sup.7 is selected from cycloalkyl, heterocycle, and
alkyl, each of which cycloalkyl, heterocycle, and alkyl groups is
optionally substituted with one or more substituents selected from
amino, --NHR.sup.14, --NR.sup.14R.sup.15, hydroxyl, OR.sup.14,
R.sup.6, and R.sup.2;
[0124] R.sup.14 and R.sup.15 are independently selected from:
hydrogen, alkyl, alkenyl, alkynyl, --C(O)H, --C(O)alkyl,
--C(S)alkyl, aryl, --SO.sub.2alkyl, heteroaryl, arylalkyl, and
heteroarylalkyl;
[0125] R.sup.16 is selected from cycloalkyl, heterocycle, and
alkyl, each of which cycloalkyl, heterocycle, and alkyl groups is
optionally substituted with one or more substituents selected from
amino, --NHR.sup.14, --NR.sup.14R.sup.15, hydroxyl, OR.sup.14,
R.sup.6, and R.sup.2;
[0126] Y is NH, O, S, or NR.sup.9;
[0127] X.sup.1, X.sup.2, X.sup.3 and X.sup.4, are independently N
or CR, wherein at least one of X.sup.1, X.sup.2, X.sup.3, and
X.sup.4, is CR.sup.8;
[0128] R.sup.8 is selected independently at each instance from:
R.sup.6 and R.sup.2, wherein one R.sup.8 is R.sup.2;
[0129] R.sup.9 is selected from: --C(O)H, --C(O)alkyl, --C(S)alkyl,
alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
[0130] R.sup.10 is selected from: hydrogen, --COOalkyl,
--COOarylalkyl, --COOH, --OH, --C(O)H, --C(O)alkyl, --C(S)alkyl,
alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and
[0131] wherein for compounds of Formula VII y is 0, 1, or 2.
[0132] In an additional embodiment, R.sup.7 is selected from:
##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031## ##STR00032## ##STR00033## ##STR00034##
##STR00035##
[0133] In an additional embodiment, R.sup.7 is selected from:
##STR00036##
[0134] In another embodiment, a compound of Formula I-2, Formula
II-2, Formula III-2, Formula IV-2, Formula V-2, Formula VI-2,
Formula VII-2, Formula VIII-2, Formula IX-2, Formula X-2, Formula
XI-2, Formula XII-2, Formula XIII-2, Formula XIV-2, Formula XV-2,
Formula XVI-2, Formula XVII-2, Formula XVIII-2, Formula XIX-2,
Formula XX-2 Formula XXI-2, Formula XXII-2, Formula XXIII-2, or
Formula XXIV-2 is provided:
##STR00037## ##STR00038## ##STR00039## ##STR00040##
or a pharmaceutically acceptable salt, N-oxide, isotopic
derivative, or prodrug, optionally in a pharmaceutically acceptable
carrier to form a pharmaceutically acceptable composition thereof;
wherein R.sup.16, R.sup.7, Q, Z, R.sup.1, y, and X are as defined
in Formula X-1 and Formula XIX-1 above.
[0135] In some aspects, R.sup.6 is hydrogen.
[0136] In some aspects, R.sup.x is not further substituted.
[0137] In some aspects, R.sup.2 is -(alkylene).sub.m-heterocyclo,
-(alkylene).sub.m-heteroaryl, -(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--NR.sup.3R.sup.4;
-(alkylene).sub.m-O--R.sup.5,
-(alkylene).sub.m-S(O).sub.n--R.sup.5, or
-(alkylene).sub.m-S(O).sub.n--NR.sup.3R.sup.4 any of which may be
optionally independently substituted with one or more R.sup.x
groups as allowed by valance, and wherein two R.sup.xgroups bound
to the same or adjacent atom may optionally combine to form a ring
and wherein m is 0 or 1 and n is 0, 1 or 2.
[0138] In some aspects, R.sup.2 is -(alkylene).sub.m-heterocyclo,
-(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--O-alkyl or -(alkylene).sub.m-OR.sup.5 any
of which may be optionally independently substituted with one or
more R.sup.x groups as allowed by valance, and wherein two R.sup.x
groups bound to the same or adjacent atom may optionally combine to
form a ring.
[0139] In some aspects, R.sup.2 is -(alkylene).sub.m-heterocyclo,
-(alkylene).sub.m-NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--NR.sup.3R.sup.4,
-(alkylene).sub.m-C(O)--O-alkyl or -(alkylene).sub.m-OR.sup.5
without further substitution.
[0140] In some aspects, m in R.sup.2 is 1. In a further aspect, the
alkylene in R.sup.2 is methylene.
[0141] In some aspects, R.sup.2 is
##STR00041##
[0142] wherein:
[0143] R.sup.2* is a bond, alkylene,
-(alkylene).sub.m-O-(alkylene).sub.m-,
-(alkylene).sub.m-C(O)-(alkylene).sub.m-,
-(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and
-(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is
independently 0 or 1;
[0144] P is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group;
[0145] each R.sup.x1 is independently
-(alkylene).sub.m-(C(O)).sub.m-(alkylene).sub.m-(N(R.sup.N)).sub.m-(alkyl-
).sub.m wherein each m is independently 0 or 1 provided at least
one m is 1, --(C(O))--O-alkyl, -(alkylene).sub.m-cycloalkyl wherein
m is 0 or 1, --N(R.sup.N)-cycloalkyl, --C(O)-cycloalkyl,
-(alkylene).sub.m-heterocyclyl wherein m is 0 or 1, or
--N(R.sup.N)-heterocyclyl, --C(O)-heterocyclyl,
--S(O).sub.2-(alkylene).sub.m wherein m is 1 or 2, wherein:
[0146] R.sup.N is H, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.6
heteroalkyl, and
[0147] wherein two R.sup.x1 can, together with the atoms to which
they attach on P, which may be the same atom, form a ring; and
[0148] t is 0, 1 or 2.
[0149] In some aspects, each R.sup.x1 is only optionally
substituted by unsubstituted alkyl, halogen or hydroxy.
[0150] In some aspects, R.sup.x1 is hydrogen or unsubstituted
C.sub.1-C.sub.4 alkyl.
[0151] In some aspects, at least one R.sup.x1 is
-(alkylene).sub.m-heterocyclyl wherein m is 0 or 1.
[0152] In some aspects, R.sup.2 is
##STR00042##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group.
[0153] In some aspects, R.sup.2 is
##STR00043##
[0154] In some aspects, R.sup.2 is
##STR00044##
[0155] In some aspects, R.sup.2 is
##STR00045##
wherein:
[0156] R.sup.2* is a bond, alkylene,
-(alkylene).sub.m-O-(alkylene).sub.m-,
-(alkylene).sub.m-C(O)-(alkylene).sub.m-,
-(alkylene).sub.m-S(O).sub.2-(alkylene).sub.m- and
-(alkylene).sub.m-NH-(alkylene).sub.m- wherein each m is
independently 0 or 1;
[0157] P is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group;
[0158] P1 is a 4- to 6-membered monocyclic saturated heterocyclyl
group;
[0159] each R.sup.x2 is independently hydrogen or alkyl; and
[0160] s is 0, 1 or 2.
[0161] In some aspects, R.sup.2 is
##STR00046##
[0162] In some aspects, P1 includes at least one nitrogen.
[0163] In some aspects, any alkylene in R.sup.2* in any previous
aspect is not further substituted.
[0164] In some aspects, R.sup.2 is
##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051##
##STR00052##
[0165] In some aspects, the compound has general Formula Ia:
##STR00053##
wherein R, R.sup.1, R.sup.2, X.sup.1, X.sup.2 and y are as
previously defined.
[0166] In some aspects, the compound has general Formula Ib:
##STR00054##
wherein R, R.sup.1, R.sup.2, and y are as previously defined.
[0167] In some aspects, the compound has general Formula Ic:
##STR00055##
wherein R and R.sup.2 are as previously defined.
[0168] In some aspects, the compound has general Formula Id:
##STR00056##
wherein R, R.sup.2, X.sup.1 and X.sup.2 are as previously
defined.
[0169] In some aspects, the compound has general Formula Ie:
##STR00057##
wherein R, R.sup.2, X.sup.1 and X.sup.2 are as previously
defined.
[0170] In some aspects, the compound has general Formula If:
##STR00058##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0171] In some aspects, the compound has general Formula IIa:
##STR00059##
wherein R, R.sup.1, R.sup.2, X.sup.1, X.sup.2, and y are as
previously defined.
[0172] In some aspects, the compound has general Formula IIb:
##STR00060##
wherein R, R.sup.1, R.sup.2, and y are as previously defined.
[0173] In some aspects, the compound has general Formula IIc:
##STR00061##
wherein R and R.sup.2, are as previously defined.
[0174] In some aspects, the compound has general Formula IId:
##STR00062##
wherein R, R.sup.2, X.sup.1 and X.sup.2 are as previously
defined.
[0175] In some aspects, the compound has general Formula IIe:
##STR00063##
wherein R, R.sup.2, X.sup.1 and X.sup.2 are as previously
defined.
[0176] In some aspects, the compound has general Formula IIf:
##STR00064##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0177] In some aspects, the compound has general Formula IIIa:
##STR00065##
wherein R, R.sup.1, R.sup.2, X.sup.1, X.sup.2, and y are as
previously defined.
[0178] In some aspects, the compound has general Formula IIIb:
##STR00066##
wherein R, R.sup.1, R.sup.2, X, and y are as previously
defined.
[0179] In some aspects, the compound has general Formula IIIc:
##STR00067##
wherein R, X, and R.sup.2 are as previously defined.
[0180] In some aspects, the compound has general Formula IIId:
##STR00068##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0181] In some aspects, the compound has general Formula IIIe:
##STR00069##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0182] In some aspects, the compound has general Formula IIIf:
##STR00070##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0183] In some aspects, the compound has general Formula IVa:
##STR00071##
wherein R, R.sup.1, R.sup.2, X.sup.1, X.sup.2 and y are as
previously defined.
[0184] In some aspects, the compound has general Formula IVb:
##STR00072##
wherein R, R.sup.1, R.sup.2, X, and y are as previously
defined.
[0185] In some aspects, the compound has general Formula IVc:
##STR00073##
wherein R, X, and R.sup.2 are as previously defined.
[0186] In some aspects, the compound has general Formula IVd:
##STR00074##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0187] In some aspects, the compound has general Formula IVe:
##STR00075##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0188] In some aspects, the compound has general Formula IVf:
##STR00076##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0189] In some aspects, the compound has general Formula Va:
##STR00077##
wherein R, R.sup.1, R.sup.2, X.sup.1, X.sup.2 and y are as
previously defined.
[0190] In some aspects, the compound has general Formula Vb:
##STR00078##
wherein R, R.sup.1, R.sup.2, and y are as previously defined.
[0191] In some aspects, the compound has general Formula Vc:
##STR00079##
wherein R and R.sup.2 are as previously defined.
[0192] In some aspects, the compound has general Formula Vd:
##STR00080##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0193] In some aspects, the compound has general Formula Ve:
##STR00081##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0194] In some aspects, the compound has general Formula Vf:
##STR00082##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0195] In some aspects, the compound has general Formula VIa:
##STR00083##
wherein R, R.sup.1, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0196] In some aspects, the compound has general Formula VIb:
##STR00084##
wherein R, R.sup.1, R.sup.2, and y are as previously defined.
[0197] In some aspects, the compound has general Formula VIc:
##STR00085##
wherein R and R.sup.2 are as previously defined.
[0198] In some aspects, the compound has general Formula VId:
##STR00086##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0199] In some aspects, the compound has general Formula VIe:
##STR00087##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0200] In some aspects, the compound has general Formula VIf:
##STR00088##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0201] In some aspects, the compound has general Formula VIIa:
##STR00089##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0202] In some aspects, the compound has general Formula VIIb:
##STR00090##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0203] In some aspects, the compound has general Formula VIIIa:
##STR00091##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0204] In some aspects, the compound has general Formula VIIIb:
##STR00092##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0205] In some aspects, the compound has general Formula VIIIc:
##STR00093##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0206] In some aspects, the compound has general Formula VIIId:
##STR00094##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0207] In some aspects, the compound has general Formula VIIIe:
##STR00095##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0208] In some aspects, the compound has general Formula VIIIf:
##STR00096##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0209] In some aspects, the compound has general Formula IXa:
##STR00097##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0210] In some aspects, the compound has general Formula IXb:
##STR00098##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0211] In some aspects, the compound has general Formula Xa:
##STR00099##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0212] In some aspects, the compound has general Formula Xb:
##STR00100##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0213] In some aspects, the compound has general Formula XIa:
##STR00101##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0214] In some aspects, the compound has general Formula XIb:
##STR00102##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0215] In some aspects, the compound has general Formula XIIa:
##STR00103##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0216] In some aspects, the compound has general Formula XIIb:
##STR00104##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0217] In some aspects, the compound has general Formula XIIIa:
##STR00105##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0218] In some aspects, the compound has general Formula XIIIb:
##STR00106##
wherein R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0219] In some aspects, the compound has general Formula XIVa:
##STR00107##
wherein X, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0220] In some aspects, the compound has general Formula XIVb:
##STR00108##
wherein X, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0221] In some aspects, the compound has general Formula XVa:
##STR00109##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0222] In some aspects, the compound has general Formula XVb:
##STR00110##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0223] In some aspects, the compound has general Formula XVIa:
##STR00111##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0224] In some aspects, the compound has general Formula XVIb:
##STR00112##
wherein R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0225] In some aspects, the compound has general Formula XVIIa:
##STR00113##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0226] In some aspects, the compound has general Formula XVIIb:
##STR00114##
wherein R, R.sup.2, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0227] In some aspects, the compound has general Formula
XVIIIa:
##STR00115##
wherein R.sup.1, R.sup.2, R.sup.10, X.sup.1, X.sup.2, X.sup.3, and
y are as previously defined.
[0228] In some aspects, the compound has general Formula
XVIIIb:
##STR00116##
wherein R, R.sup.1, R.sup.2, R.sup.10 and y are as previously
defined.
[0229] In some aspects, the compound has general Formula
XVIIIc:
##STR00117##
wherein R, R.sup.2 and R.sup.10 are as previously defined.
[0230] In some aspects, the compound has general Formula
XVIIId:
##STR00118##
wherein R, R.sup.2, R.sup.10, X.sup.1, and X.sup.2 are as
previously defined.
[0231] In some aspects, the compound has general Formula
XVIIIe:
##STR00119##
wherein R, R.sup.2, R.sup.10, X.sup.1, and X.sup.2 are as
previously defined.
[0232] In some aspects, the compound has general Formula XIVa:
##STR00120##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0233] In some aspects, the compound has general Formula XIXb:
##STR00121##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0234] In some aspects, the compound has general Formula XIXc:
##STR00122##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0235] In some aspects, the compound has general Formula XIXd:
##STR00123##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0236] In some aspects, the compound has general Formula XIXe:
##STR00124##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0237] In some aspects, the compound has general Formula XXa:
##STR00125##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0238] In some aspects, the compound has general Formula XXb:
##STR00126##
wherein R, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0239] In some aspects, the compound has general Formula XXc:
##STR00127##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0240] In some aspects, the compound has general Formula XXd:
##STR00128##
wherein R, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0241] In some aspects, the compound has general Formula XXIa:
##STR00129##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0242] In some aspects, the compound has general Formula XXIb:
##STR00130##
wherein X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0243] In some aspects, the compound has general Formula XXIIa:
##STR00131##
wherein R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0244] In some aspects, the compound has general Formula XXIIb:
##STR00132##
wherein X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0245] In some aspects, the compound has general Formula
XXIIIa:
##STR00133##
wherein R, R.sup.2, X.sup.1, and X.sup.2 are as previously
defined.
[0246] In some aspects, the compound has general Formula
XXIIIb:
##STR00134##
wherein R, X.sup.1, X.sup.2, and X.sup.3 are as previously
defined.
[0247] In some embodiments, the compound is selected from a Formula
presented above and X.sup.1 is N and X.sup.2 is CH. In other
embodiments, the compound is selected from a Formula presented
above and X.sup.1 is N and X.sup.2 is N. In other embodiments, the
compound is selected from a Formula presented above and X.sup.1 is
CH and X.sup.2 is CH. In other embodiments, the compound is
selected from a Formula presented above and X.sup.1 is CH and
X.sup.2 is N.
[0248] In some embodiments, the compound is selected from a Formula
presented above and X.sup.1 is N, X.sup.2 is CH, X.sup.3 is CH, and
X.sup.4 is CH. In other embodiments, the compound is selected from
a Formula presented above and X.sup.1 is CH, X.sup.2 is N, X.sup.3
is CH, and X.sup.4 is CH. In other embodiments, the compound is
selected from a Formula presented above and X.sup.1 is CH, X.sup.2
is N, X.sup.3 is N, and X.sup.4 is CH. In other embodiments, the
compound is selected from a Formula presented above and X.sup.1 is
CH, X.sup.2 is N, X.sup.3 is CH, and X.sup.4 is N. In other
embodiments, the compound is selected from a Formula presented
above and X.sup.1 is N, X.sup.2 is CH, X.sup.3 is N, and X.sup.4 is
CH. In other embodiments, the compound is selected from a Formula
presented above and X.sup.1 is N, X.sup.2 is CH, X.sup.3 is CH, and
X.sup.4 is N.
[0249] In some embodiments, the compound is selected from a Formula
presented above and R.sup.2 is
##STR00135##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group and R.sup.2*, R.sup.x1 and t are as previously
defined.
[0250] In some embodiments, the compound is selected from a Formula
presented above and R.sup.2 is
##STR00136##
wherein P* is a 4- to 8-membered mono- or bicyclic saturated
heterocyclyl group, R.sup.x1 is hydrogen or unsubstituted
C.sub.1-C.sub.4 alkyl and R.sup.2* is as previously defined.
[0251] In some embodiments, the compound is selected from a Formula
presented above and R.sup.2 is selected from
##STR00137##
[0252] In some embodiments, the compound is selected from a Formula
presented above and R.sup.2 is selected from,
##STR00138##
[0253] In some embodiments, the compound is selected from a Formula
presented above and R is alkyl.
[0254] In some embodiments, the compound is selected from a Formula
presented above and R is hydrogen.
[0255] In some embodiments R.sup.x is further substituted with a
substituent chosen from: -(alkylene).sub.m-CN,
-(alkylene).sub.m-OR.sup.5*, -(alkylene).sub.m-S(O).sub.n--R.sup.5*
-(alkylene).sub.m-NR.sup.3*R.sup.4*,
-(alkylene).sub.m-C(O)--R.sup.5*,
-(alkylene).sub.m-C(.dbd.S)R.sup.5*, -(alkylene).sub.m-C(.dbd.O)O
R.sup.5*, -(alkylene).sub.m-OC(.dbd.O)R.sup.5*,
-(alkylene).sub.m-C(S)--OR.sup.5*
-(alkylene).sub.m-C(O)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-C(S)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-N(R.sup.3*)--C(O)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-N(R.sup.3*)--C(S)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-N(R.sup.3*)--C(O)--R.sup.5*,
-(alkylene).sub.m-N(R.sup.3*)--C(S)--R.sup.5*,
-(alkylene).sub.m-O--C(O)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-O--C(S)--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-SO.sub.2--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-N(R.sup.3*)--SO.sub.2--R.sup.5*,
-(alkylene).sub.m-N(R.sup.3*)--SO.sub.2--NR.sup.3*R.sup.4*,
-(alkylene).sub.m-N(R.sup.3*)--C(O)--OR.sup.5*,
-(alkylene).sub.m-N(R.sup.3*)--C(S)--OR.sup.5*, and
-(alkylene).sub.m-N(R.sup.3*)--SO.sub.2--R.sup.5*;
[0256] R.sup.3* and R.sup.4* at each occurrence are independently
selected from:
[0257] (i) hydrogen or
[0258] (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl,
heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or
heteroarylalkyl any of which may be optionally independently
substituted with one or more R.sup.x groups as allowed by valance;
or R.sup.3* and R.sup.4* together with the nitrogen atom to which
they are attached may combine to form a heterocyclo ring optionally
independently substituted with one or more R.sup.x groups as
allowed by valance.
[0259] R.sup.5* is independently selected at each occurrence
from:
[0260] (i) hydrogen or
[0261] (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or
heteroarylalkyl any of which may be optionally independently
substituted with one or more R.sup.x groups as allowed by
valance;
[0262] In some embodiments the compound of the present invention is
selected from:
##STR00139## ##STR00140## ##STR00141## ##STR00142##
##STR00143##
wherein:
[0263] R.sup.2 is selected from,
##STR00144##
[0264] In an alternative embodiment, the compound of the present
invention is selected from:
##STR00145##
wherein:
[0265] R.sup.2 is selected from,
##STR00146##
II. Terminology
[0266] Compounds are described using standard nomenclature. 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.
[0267] The compounds in any of the Formulas described herein
include racemates, enantiomers, mixtures of enantiomers,
diastereomers, mixtures of diastereomers, tautomers, N-oxides,
isomers; such as rotamers, as if each is specifically
described.
[0268] The terms "a" and "an" do not denote a limitation of
quantity, but rather denote the presence of at least one of the
referenced item. The term "or" means "and/or". Recitation of ranges
of values are merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range, unless otherwise indicated herein, and each separate value
is incorporated into the specification as if it were individually
recited herein. The endpoints of all ranges are included within the
range and independently combinable. All methods described herein
can be performed in a suitable order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of
examples, or exemplary language (e.g., "such as"), is intended
merely to better illustrate the invention and does not pose a
limitation on the scope of the invention unless otherwise claimed.
Unless defined otherwise, 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.
[0269] The present invention includes compounds of Formula I,
Formula II, Formula III Formula IV, Formula V, Formula VI, Formula
VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,
Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII,
Formula XVIII, and Formula XIX with at least one desired isotopic
substitution of an atom, at an amount above the natural abundance
of the isotope, i.e., enriched. Isotopes are atoms having the same
atomic number but different mass numbers, i.e., the same number of
protons but a different number of neutrons.
[0270] Examples of isotopes that can be incorporated into compounds
of the invention include isotopes of hydrogen, carbon, nitrogen,
oxygen, phosphorous, fluorine, chlorine and iodine such as .sup.2H,
.sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18F .sup.31P,
.sup.32P .sup.35S, .sup.36Cl, and .sup.125I respectively. In one
non-limiting embodiment, isotopically labelled compounds can be
used in metabolic studies (with .sup.14C), reaction kinetic studies
(with, for example .sup.2H or .sup.3H), detection or imaging
techniques, such as positron emission tomography (PET) or
single-photon emission computed tomography (SPECT) including drug
or substrate tissue distribution assays, or in radioactive
treatment of patients. In particular, an .sup.18F labeled compound
may be particularly desirable for PET or SPECT studies.
Isotopically labeled compounds of this invention and prodrugs
thereof can generally be prepared by carrying out the procedures
disclosed in the schemes or in the examples and preparations
described below by substituting a readily available isotopically
labeled reagent for a non-isotopically labeled reagent.
[0271] By way of general example and without limitation, isotopes
of hydrogen, for example, deuterium (.sup.2H) and tritium (3H) may
be used anywhere in described structures that achieves the desired
result. Alternatively, or in addition, isotopes of carbon, e.g.,
.sup.13C and .sup.14C, may be used.
[0272] Isotopic substitutions, for example deuterium substitutions,
can be partial or complete. Partial deuterium substitution means
that at least one hydrogen is substituted with deuterium. In
certain embodiments, the isotope is 90, 95 or 99% or more enriched
in an isotope at any location of interest. In one non-limiting
embodiment, deuterium is 90, 95 or 99% enriched at a desired
location.
[0273] In one non-limiting embodiment, the substitution of a
hydrogen atom for a deuterium atom can be provided in any of
Formula I, Formula II, Formula III Formula IV, Formula V, Formula
VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,
Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI,
Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI,
Formula XXII, or Formula XXIII. In one non-limiting embodiment, the
substitution of a hydrogen atom for a deuterium atom occurs within
a group selected from any of R, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, and R.sup.x. For
example, when any of the groups are, or contain for example through
substitution, methyl, ethyl, or methoxy, the alkyl residue may be
deuterated (in non-limiting embodiments, CDH.sub.2, CD.sub.2H,
CD.sub.3, CH.sub.2CD.sub.3, CD.sub.2CD.sub.3, CHDCH.sub.2D,
CH.sub.2CD.sub.3, CHDCHD.sub.2, OCDH.sub.2, OCD.sub.2H, or
OCD.sub.3 etc.). In certain other embodiments, when two
substituents are combined to form a cycle the unsubstituted carbons
may be deuterated.
[0274] The compound of the present invention may form a solvate
with solvents (including water). Therefore, in one non-limiting
embodiment, the invention includes a solvated form of the compound.
The term "solvate" refers to a molecular complex of a compound of
the present invention (including a salt thereof) with one or more
solvent molecules. Non-limiting examples of solvents are water,
ethanol, dimethyl sulfoxide, acetone and other common organic
solvents. The term "hydrate" refers to a molecular complex
comprising a compound of the invention and water. Pharmaceutically
acceptable solvates in accordance with the invention include those
wherein the solvent may be isotopically substituted, e.g. D.sub.2O,
d.sub.6-acetone, d.sub.6-DMSO. A solvate can be in a liquid or
solid form.
[0275] A dash ("-") that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example, --(C.dbd.O)NH.sub.2 is attached through carbon of the keto
(C.dbd.O) group.
[0276] "Alkyl" is a branched or straight chain saturated aliphatic
hydrocarbon group. In one non-limiting embodiment, the alkyl group
contains from 1 to about 12 carbon atoms, more generally from 1 to
about 6 carbon atoms or from 1 to about 4 carbon atoms. In one
non-limiting embodiment, the alkyl contains from 1 to about 8
carbon atoms. In certain embodiments, the alkyl is C.sub.1-C.sub.2,
C.sub.1-C.sub.3, C.sub.1-C.sub.4, C.sub.1-C.sub.5, or
C.sub.1-C.sub.6. The specified ranges as used herein indicate an
alkyl group having each member of the range described as an
independent species. For example, the term C.sub.1-C.sub.6 alkyl as
used herein indicates a straight or branched alkyl group having
from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that
each of these is described as an independent species. For example,
the term C.sub.1-C.sub.4 alkyl as used herein indicates a straight
or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and
is intended to mean that each of these is described as an
independent species. Examples of alkyl include, but are not limited
to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl,
n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and
2,3-dimethylbutane. In an alternative embodiment, the alkyl group
is optionally substituted. The term "Alkyl" also encompasses
cycloalkyl or carbocyclic groups. For example, when a term is used
that includes "alk" then "cycloalkyl" or "carbocyclic" can be
considered part of the definition, unless unambiguously excluded by
the context. For example, and without limitation, the terms alkyl,
alkoxy, haloalkyl, etc. can all be considered to include the cyclic
forms of alkyl, unless unambiguously excluded by context.
[0277] "Alkenyl" is a linear or branched aliphatic hydrocarbon
groups having one or more carbon-carbon double bonds that may occur
at a stable point along the chain. The specified ranges as used
herein indicate an alkenyl group having each member of the range
described as an independent species, as described above for the
alkyl moiety. Examples of alkenyl radicals include, but are not
limited to ethenyl, propenyl, allyl, propenyl, butenyl and
4-methylbutenyl. The term "alkenyl" also embodies "cis" and "trans"
alkenyl geometry, or alternatively, "E" and "Z" alkenyl geometry.
In an alternative embodiment, the alkenyl group is optionally
substituted. The term "Alkenyl" also encompasses cycloalkyl or
carbocyclic groups possessing at least one point of
unsaturation.
[0278] "Alkynyl" is a branched or straight chain aliphatic
hydrocarbon group having one or more carbon-carbon triple bonds
that may occur at any stable point along the chain. The specified
ranges as used herein indicate an alkynyl group having each member
of the range described as an independent species, as described
above for the alkyl moiety. Examples of alkynyl include, but are
not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl,
1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,
2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In an alternative
embodiment, the alkynyl group is optionally substituted. The term
"Alkynyl" also encompasses cycloalkyl or carbocyclic groups
possessing at least one point of unsaturation.
[0279] "Halo" and "Halogen" is fluorine, chlorine, bromine or
iodine.
[0280] "Haloalkyl" is a branched or straight-chain alkyl groups
substituted with 1 or more halo atoms described above, up to the
maximum allowable number of halogen atoms. Examples of haloalkyl
groups include, but are not limited to, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl and dichloropropyl. "Perhaloalkyl"
means an alkyl group having all hydrogen atoms replaced with
halogen atoms. Examples include but are not limited to,
trifluoromethyl and pentafluoroethyl.
[0281] "Haloalkoxy" indicates a haloalkyl group as defined herein
attached through an oxygen bridge (oxygen of an alcohol
radical).
[0282] As used herein, "aryl" refers to a radical of a monocyclic
or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring
system (e.g., having 6, 10, or 14 .pi. electrons shared in a cyclic
array) having 6-14 ring carbon atoms and zero heteroatoms provided
in the aromatic ring system ("C.sub.6-14 aryl"). In some
embodiments, an aryl group has 6 ring carbon atoms ("C.sub.6 aryl";
e.g., phenyl). In some embodiments, an aryl group has 10 ring
carbon atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl
and 2-naphthyl). In some embodiments, an aryl group has 14 ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring, and in such
instances, the number of carbon atoms continue to designate the
number of carbon atoms in the aryl ring system. The one or more
fused carbocyclyl or heterocyclyl groups can be 4 to 7 or 5 to
7-membered saturated or partially unsaturated carbocyclyl or
heterocyclyl groups that optionally contain 1, 2 or 3 heteroatoms
independently selected from nitrogen, oxygen, phosphorus, sulfur,
silicon and boron, to form, for example, a 3,4-methylenedioxyphenyl
group. In one non-limiting embodiment, aryl groups are pendant. An
example of a pendant ring is a phenyl group substituted with a
phenyl group. In an alternative embodiment, the aryl group is
optionally substituted as described above. In certain embodiments,
the aryl group is an unsubstituted C.sub.6-14 aryl. In certain
embodiments, the aryl group is a substituted C.sub.6-14 aryl. An
aryl group may be optionally substituted with one or more
functional groups that include but are not limited to, halo,
hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and
heterocyclo.
[0283] The term "heterocyclyl" (or "heterocyclo") includes
saturated, and partially saturated heteroatom-containing ring
radicals, where the heteroatoms may be selected from nitrogen,
sulfur and oxygen. Heterocyclic rings comprise monocyclic 6-8
membered rings, as well as 5-16 membered bicyclic ring systems
(which can include bridged fused and spiro-fused bicyclic ring
systems). It does not include rings containing --O--O--.--O--S-- or
--S--S-- portions. Said "heterocyclyl" group may be optionally
substituted with 1 to 3 substituents that include but are not
limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl,
oxo, alkoxy, and amino. Examples of saturated heterocyclo groups
include saturated 3- to 6-membered heteromonocyclic groups
containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl,
imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3
to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms
and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to
6-membered heteromonocyclic group containing 1 to 2 sulfur atoms
and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of
partially saturated heterocyclyl radicals include but are not
limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and
dihydrothiazolyl. Examples of partially saturated and saturated
heterocyclo groups include but are not limited to, pyrrolidinyl,
imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl,
piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl,
isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl,
chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,
1,2,3,4-tetrahydro-quinolyl,
2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,
5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,
3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,
2,3-dihydro-1H-1.lamda.'-benzo[d]isothiazol-6-yl, dihydropyranyl,
dihydrofuryl and dihydrothiazolyl.
[0284] Heterocyclo groups also include radicals where heterocyclic
radicals are fused/condensed with aryl radicals: such as
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen
atoms, for example, indoline, isoindoline, unsaturated condensed
heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, unsaturated condensed heterocyclic group containing
1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated,
partially unsaturated and unsaturated condensed heterocyclic group
containing 1 to 2 oxygen or sulfur atoms.
[0285] The term "heteroaryl" denotes aryl ring systems that contain
one or more heteroatoms selected from O, N and S, wherein the ring
nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen
atom(s) are optionally quarternized. Examples include but are not
limited to, unsaturated 5 to 6 membered heteromonocyclyl groups
containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl,
pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to
6-membered heteromonocyclic groups containing an oxygen atom, for
example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to
6-membered heteromonocyclic groups containing a sulfur atom, for
example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered
heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];
unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to
2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,
thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl].
[0286] The term "sulfonyl", whether used alone or linked to other
terms such as alkylsulfonyl, denotes respectively divalent radicals
--SO.sub.2--.
[0287] The terms "carboxy" or "carboxyl", whether used alone or
with other terms, such as "carboxyalkyl", denotes --C(O)--OH.
[0288] The term "carbonyl", whether used alone or with other terms,
such as "aminocarbonyl", denotes --C(O)--.
[0289] The term "aminocarbonyl" denotes an amide group of the
formula --C(O)--NH.sub.2.
[0290] The terms "heterocycloalkyl" denotes
heterocyclic-substituted alkyl radicals. Examples include but are
not limited to, piperidylmethyl and morpholinylethyl.
[0291] "Arylalkyl" is an aryl group as defined herein attached
through an alkyl group. Non-limiting examples of arylalkyl groups
include:
##STR00147##
[0292] "Heteroarylalkyl" is a heteroaryl group as defined herein
attached through an alkyl group.
[0293] Non-limiting examples of heteroarylalkyl groups include:
##STR00148##
[0294] "Aryloxy" is an aryl group as defined herein attached
through a --O-- linker. Non-limiting examples of aryloxy groups
include:
##STR00149##
[0295] As used herein, "carbocyclyl", "carbocyclic", "carbocycle"
or "cycloalkyl" is a saturated or partially unsaturated (i.e., not
aromatic) group containing all carbon ring atoms and from 3 to 14
ring carbon atoms ("C.sub.3-14 carbocyclyl") and zero heteroatoms
in the non-aromatic ring system. In some embodiments, a carbocyclyl
group has 3 to 10 ring carbon atoms ("C.sub.3-10 carbocyclyl"). In
some embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms
("C.sub.3-9 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms
("C.sub.3-7 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms
("C.sub.4-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 carbocyclyl"). Exemplary C.sub.3-6 carbocyclyl groups
include, without limitation, cyclopropyl (C.sub.3), cyclopropenyl
(C.sub.3), cyclobutyl (C.sub.4), cyclobutenyl (C.sub.4),
cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclohexyl
(C.sub.6), cyclohexenyl (C.sub.6), cyclohexadienyl (C.sub.6), and
the like. Exemplary C.sub.3-8 carbocyclyl groups include, without
limitation, the aforementioned C.sub.3-6 carbocyclyl groups as well
as cycloheptyl (C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl
(C.sub.7), cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8),
cyclooctenyl (C.sub.8), and the like. Exemplary C.sub.3-10
carbocyclyl groups include, without limitation, the aforementioned
C.sub.3-8 carbocyclyl groups as well as cyclononyl (C.sub.9),
cyclononenyl (C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl
(C.sub.10), and the like. As the foregoing examples illustrate, in
certain embodiments, the carbocyclyl group can be saturated or can
contain one or more carbon-carbon double or triple bonds. In an
alternative embodiment, "Carbocyclyl" also includes ring systems
wherein the carbocyclyl ring, as defined above, is fused with one
or more heterocyclyl, aryl or heteroaryl groups wherein the point
of attachment is on the carbocyclyl ring, and in such instances,
the number of carbons continue to designate the number of carbons
in the carbocyclic ring system. In an alternative embodiment, each
instance of carbocycle is optionally substituted with one or more
substituents. In certain embodiments, the carbocyclyl group is an
unsubstituted C.sub.3-14 carbocyclyl. In certain embodiments, the
carbocyclyl group is a substituted C.sub.3-14 carbocyclyl.
[0296] "Cycloalkylalkyl" is an cycloalkyl group as defined herein
attached through an alkyl group. Non-limiting examples of
cycloalkylalkyl groups include:
##STR00150##
[0297] The term "oxo" as used herein contemplates an oxygen atom
attached with a double bond.
II. Methods of Treatment
[0298] In one aspect, a method of treating a proliferative disorder
in a host, including a human, is provided comprising administering
an effective amount of a compound of Formula I, Formula II, Formula
III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,
Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV.
[0299] or its pharmaceutically acceptable salt, N-oxide, deuterated
derivative, prodrug, and/or a pharmaceutically acceptable
composition thereof as described herein optionally in a
pharmaceutically acceptable carrier. Non-limiting examples of
disorders include tumors, cancers, disorders related to abnormal
cellular proliferation, inflammatory disorders, immune disorders,
and autoimmune disorders.
[0300] A compound of Formula I, Formula II, Formula III Formula IV,
Formula V, Formula VI, Formula VII, Formula VIII, Formula IX,
Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV,
Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,
Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV,
or Formula XXV is useful as therapeutic agents when administered in
an effective amount to a host, including a human, to treat a tumor,
cancer (solid, non-solid, diffuse, hematological, etc), abnormal
cellular proliferation, immune disorder, inflammatory disorder,
blood disorder, a myelo- or lymphoproliferative disorder such as B-
or T-cell lymphomas, multiple myeloma, breast cancer, prostate
cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon
cancer, skin cancer, melanoma, Waldenstrom's macroglobulinemia,
Wiskott-Aldrich syndrome, or a post-transplant lymphoproliferative
disorder; an autoimmune disorder, for example, Lupus, Crohn's
Disease, Addison disease, Celiac disease, dermatomyositis, Graves
disease, thyroiditis, multiple sclerosis, pernicious anemia,
reactive arthritis, or type I diabetes; a disease of cardiologic
malfunction, including hypercholesterolemia; an infectious disease,
including a viral and/or bacterial infection; an inflammatory
condition, including asthma, chronic peptic ulcers, tuberculosis,
rheumatoid arthritis, periodontitis, ulcerative colitis, or
hepatitis.
[0301] Exemplary proliferative disorders include, but are not
limited to, benign growths, neoplasms, tumors, cancer (Rb positive
or Rb negative), autoimmune disorders, inflammatory disorders
graft-versus-host rejection, and fibrotic disorders.
[0302] Non-limiting examples of cancers that can be treated
according to the present invention include, but are not limited to,
acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal
cancer, angiosarcoma (e.g., lymphangiosarcoma,
lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer,
benign monoclonal gammopathy, biliary cancer (e.g.,
cholangiocarcinoma), bladder cancer, breast cancer (e.g.,
adenocarcinoma of the breast, papillary carcinoma of the breast,
mammary cancer, medullary carcinoma of the breast), brain cancer
(e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma;
medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer
(e.g., cervical adenocarcinoma), choriocarcinoma, chordoma,
craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal
cancer, colorectal adenocarcinoma), epithelial carcinoma,
ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple
idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine
cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma
of the esophagus, Barrett's adenocarinoma), Ewing's sarcoma, eye
cancer (e.g., intraocular melanoma, retinoblastoma), familiar
hypereosinophilia, gall bladder cancer, gastric cancer (e.g.,
stomach adenocarcinoma), gastrointestinal stromal tumor (GIST),
head and neck cancer (e.g., head and neck squamous cell carcinoma,
oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat
cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal
cancer, oropharyngeal cancer)), hematopoietic cancers (e.g.,
leukemia such as acute lymphocytic leukemia (ALL)--also known as
acute lymphoblastic leukemia or acute lymphoid leukemia (e.g.,
B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g.,
B-cell AML, T-cell AMVL), chronic myelocytic leukemia (CML) (e.g.,
B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL)
(e.g., B-cell CLL, T-cell CLL); lymphoma such as Hodgkin lymphoma
(HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL)
(e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g.,
diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma,
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),
mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g.,
mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal
zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),
primary mediastinal B-cell lymphoma, Burkitt lymphoma,
lymphoplasmacytic lymphoma (i.e., "Waldenstrom's
macroglobulinemia"), hairy cell leukemia (HCL), immunoblastic large
cell lymphoma, precursor B-lymphoblastic lymphoma and primary
central nervous system (CNS) lymphoma; and T-cell NHL such as
precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell
lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,
mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell
lymphoma, extranodal natural killer T-cell lymphoma, enteropathy
type T-cell lymphoma, subcutaneous panniculitis-like T-cell
lymphoma, anaplastic large cell lymphoma); a mixture of one or more
leukemia/lymphoma as described above; and multiple myeloma (MM)),
heavy chain disease (e.g., alpha chain disease, gamma chain
disease, mu chain disease), hemangioblastoma, inflammatory
myofibroblastic tumors, immunocytic amyloidosis, kidney cancer
(e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma),
liver cancer (e.g., hepatocellular cancer (HCC), malignant
hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell
lung cancer (SCLC), non-small cell lung cancer (NSCLC),
adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis
(e.g., systemic mastocytosis), myelodysplastic syndrome (MDS),
mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia
Vera (PV), essential thrombocytosis (ET), agnogenic myeloid
metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic
myelofibrosis, chronic myelocytic leukemia (CML), chronic
neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)),
neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or
type 2, schwannomatosis), neuroendocrine cancer (e.g.,
gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid
tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma,
ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary
adenocarcinoma, pancreatic cancer (e.g., pancreatic
andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN),
Islet cell tumors), penile cancer (e.g., Paget's disease of the
penis and scrotum), pinealoma, primitive neuroectodermal tumor
(PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal
cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g.,
squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma,
basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix
cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma
(MFH), liposarcoma, malignant peripheral nerve sheath tumor
(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous
gland carcinoma, sweat gland carcinoma, synovioma, testicular
cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid
cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid
carcinoma (PTC), medullary thyroid cancer), urethral cancer,
vaginal cancer and vulvar cancer (e.g., Paget's disease of the
vulva).
[0303] In another embodiment, the disorder is myelodysplastic
syndrome (MDS).
[0304] In certain embodiments, the cancer is a hematopoietic
cancer. In certain embodiments, the hematopoietic cancer is a
lymphoma. In certain embodiments, the hematopoietic cancer is a
leukemia. In certain embodiments, the leukemia is acute myelocytic
leukemia (AML).
[0305] In certain embodiments, the proliferative disorder is a
myeloproliferative neoplasm. In certain embodiments, the
myeloproliferative neoplasm (MPN) is primary myelofibrosis
(PMF).
[0306] In certain embodiments, the cancer is a solid tumor. A solid
tumor, as used herein, refers to an abnormal mass of tissue that
usually does not contain cysts or liquid areas. Different types of
solid tumors are named for the type of cells that form them.
Examples of classes of solid tumors include, but are not limited
to, sarcomas, carcinomas, and lymphomas, as described above herein.
Additional examples of solid tumors include, but are not limited
to, squamous cell carcinoma, colon cancer, breast cancer, prostate
cancer, lung cancer, liver cancer, pancreatic cancer, and
melanoma.
[0307] In certain embodiments, the condition treated with a
compound of Formula I, Formula II, Formula III Formula IV, Formula
V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X,
Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV,
Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX,
Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula
XXV is a disorder related to abnormal cellular proliferation.
[0308] Abnormal cellular proliferation, notably hyperproliferation,
can occur as a result of a wide variety of factors, including
genetic mutation, infection, exposure to toxins, autoimmune
disorders, and benign or malignant tumor induction.
[0309] There are a number of skin disorders associated with
cellular hyperproliferation. Psoriasis, for example, is a benign
disease of human skin generally characterized by plaques covered by
thickened scales. The disease is caused by increased proliferation
of epidermal cells of unknown cause. Chronic eczema is also
associated with significant hyperproliferation of the epidermis.
Other diseases caused by hyperproliferation of skin cells include
atopic dermatitis, lichen planus, warts, pemphigus vulgaris,
actinic keratosis, basal cell carcinoma and squamous cell
carcinoma.
[0310] Other hyperproliferative cell disorders include blood vessel
proliferation disorders, fibrotic disorders, autoimmune disorders,
graft-versus-host rejection, tumors and cancers.
[0311] Blood vessel proliferative disorders include angiogenic and
vasculogenic disorders. Proliferation of smooth muscle cells in the
course of development of plaques in vascular tissue cause, for
example, restenosis, retinopathies and atherosclerosis. Both cell
migration and cell proliferation play a role in the formation of
atherosclerotic lesions.
[0312] Fibrotic disorders are often due to the abnormal formation
of an extracellular matrix. Examples of fibrotic disorders include
hepatic cirrhosis and mesangial proliferative cell disorders.
Hepatic cirrhosis is characterized by the increase in extracellular
matrix constituents resulting in the formation of a hepatic scar.
Hepatic cirrhosis can cause diseases such as cirrhosis of the
liver. An increased extracellular matrix resulting in a hepatic
scar can also be caused by viral infection such as hepatitis.
Lipocytes appear to play a major role in hepatic cirrhosis.
[0313] Mesangial disorders are brought about by abnormal
proliferation of mesangial cells. Mesangial hyperproliferative cell
disorders include various human renal diseases, such as
glomerulonephritis, diabetic nephropathy, malignant
nephrosclerosis, thrombotic micro-angiopathy syndromes, transplant
rejection, and glomerulopathies.
[0314] Another disease with a proliferative component is rheumatoid
arthritis. Rheumatoid arthritis is generally considered an
autoimmune disease that is thought to be associated with activity
of autoreactive T cells, and to be caused by autoantibodies
produced against collagen and IgE.
[0315] Other disorders that can include an abnormal cellular
proliferative component include Bechet's syndrome, acute
respiratory distress syndrome (ARDS), ischemic heart disease,
post-dialysis syndrome, leukemia, acquired immune deficiency
syndrome, vasculitis, lipid histiocytosis, septic shock and
inflammation in general.
[0316] In certain embodiments, a compound of the present invention
and its pharmaceutically acceptable derivatives or pharmaceutically
acceptable formulations containing these compounds are also useful
in the prevention and treatment of HBV infections and other related
conditions such as anti-HBV antibody positive and HBV-positive
conditions, chronic liver inflammation caused by HBV, cirrhosis,
acute hepatitis, fulminant hepatitis, chronic persistent hepatitis,
and fatigue. These compounds or formulations can also be used
prophylactically to prevent or retard the progression of clinical
illness in individuals who are anti-HBV antibody or HBV-antigen
positive or who have been exposed to HBV.
[0317] In certain embodiments, the condition is associated with an
immune response.
[0318] Cutaneous contact hypersensitivity and asthma are just two
examples of immune responses that can be associated with
significant morbidity. Others include atopic dermatitis, eczema,
Sjogren's Syndrome, including keratoconjunctivitis sicca secondary
to Sjogren's Syndrome, alopecia areata, allergic responses due to
arthropod bite reactions, Crohn's disease, aphthous ulcer, iritis,
conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous
lupus erythematosus, scleroderma, vaginitis, proctitis, and drug
eruptions. These conditions may result in any one or more of the
following symptoms or signs: itching, swelling, redness, blisters,
crusting, ulceration, pain, scaling, cracking, hair loss, scarring,
or oozing of fluid involving the skin, eye, or mucosal
membranes.
[0319] In atopic dermatitis, and eczema in general, immunologically
mediated leukocyte infiltration (particularly infiltration of
mononuclear cells, lymphocytes, neutrophils, and eosinophils) into
the skin importantly contributes to the pathogenesis of these
diseases. Chronic eczema also is associated with significant
hyperproliferation of the epidermis. Immunologically mediated
leukocyte infiltration also occurs at sites other than the skin,
such as in the airways in asthma and in the tear producing gland of
the eye in keratoconjunctivitis sicca.
[0320] In one non-limiting embodiment compounds of the present
invention are used as topical agents in treating contact
dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis,
Sjogren's Syndrome, including keratoconjunctivitis sicca secondary
to Sjogren's Syndrome, alopecia areata, allergic responses due to
arthropod bite reactions, Crohn's disease, aphthous ulcer, iritis,
conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma,
allergic asthma, cutaneous lupus erythematosus, scleroderma,
vaginitis, proctitis, and drug eruptions. The novel method may also
be useful in reducing the infiltration of skin by malignant
leukocytes in diseases such as mycosis fungoides. These compounds
can also be used to treat an aqueous-deficient dry eye state (such
as immune mediated keratoconjunctivitis) in a patient suffering
therefrom, by administering the compound topically to the eye.
[0321] The term "neoplasia" or "cancer" is used throughout the
specification to refer to the pathological process that results in
the formation and growth of a cancerous or malignant neoplasm,
i.e., abnormal tissue (solid) or cells (non-solid) that grow by
cellular proliferation, often more rapidly than normal and
continues to grow after the stimuli that initiated the new growth
cease. Malignant neoplasms show partial or complete lack of
structural organization and functional coordination with the normal
tissue and most invade surrounding tissues, can metastasize to
several sites, are likely to recur after attempted removal and may
cause the death of the patient unless adequately treated. As used
herein, the term neoplasia is used to describe all cancerous
disease states and embraces or encompasses the pathological process
associated with malignant hematogenous, ascitic and solid tumors.
Exemplary cancers which may be treated by the present disclosed
compounds either alone or in combination with at least one
additional anti-cancer agent include squamous-cell carcinoma, basal
cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and
renal cell carcinomas, cancer of the bladder, bowel, breast,
cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary,
pancreas, prostate, and stomach; leukemias; benign and malignant
lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's
lymphoma; benign and malignant melanomas; myeloproliferative
diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma,
Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral
neuroepithelioma, synovial sarcoma, gliomas, astrocytomas,
oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,
ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell
tumors, meningiomas, meningeal sarcomas, neurofibromas, and
Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical
cancer, uterine cancer, lung cancer, ovarian cancer, testicular
cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic
cancer, stomach cancer, liver cancer, colon cancer, melanoma;
carcinosarcoma, Hodgkin's disease, Wilms' tumor and
teratocarcinomas. Additional cancers which may be treated using the
disclosed compounds according to the present invention include, for
example, acute granulocytic leukemia, acute lymphocytic leukemia
(ALL), acute myelogenous leukemia (AML), adenocarcinoma,
adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal
cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer,
astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct
cancer, bladder cancer, bone cancer, bone marrow cancer, bowel
cancer, brain cancer, brain stem glioma, breast cancer, triple
(estrogen, progesterone and HER-2) negative breast cancer, double
negative breast cancer (two of estrogen, progesterone and HER-2 are
negative), single negative (one of estrogen, progesterone and HER-2
is negative), estrogen-receptor positive, HER2-negative breast
cancer, estrogen receptor-negative breast cancer, estrogen receptor
positive breast cancer, metastatic breast cancer, luminal A breast
cancer, luminal B breast cancer, Her2-negative breast cancer,
HER2-positive or negative breast cancer, progesterone
receptor-negative breast cancer, progesterone receptor-positive
breast cancer, recurrent breast cancer, carcinoid tumors, cervical
cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic
leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer,
colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous
melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS),
endometrial cancer, ependymoma, epithelioid sarcoma, esophageal
cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer,
fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric
cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer,
gastrointestinal stromal tumors (GIST), germ cell tumor
glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head
and neck cancer, hemangioendothelioma, Hodgkin lymphoma,
hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),
infiltrating lobular carcinoma (ILC), inflammatory breast cancer
(IBC), intestinal Cancer, intrahepatic bile duct cancer,
invasive/infiltrating breast cancer, Islet cell cancer, jaw cancer,
Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma,
leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver
cancer, lobular carcinoma in situ, low-grade astrocytoma, lung
cancer, lymph node cancer, lymphoma, male breast cancer, medullary
carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell
carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma
metastatic breast cancer, metastatic melanoma metastatic squamous
neck cancer, mixed gliomas, monodermal teratoma, mouth cancer
mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis
Fungoides, myelodysplastic syndrome, nasal cavity cancer,
nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine
tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer
(NSCLC), oat cell cancer, ocular cancer, ocular melanoma,
oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal
cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian
epithelial cancer ovarian germ cell tumor, ovarian primary
peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's
disease, pancreatic cancer, papillary carcinoma, paranasal sinus
cancer, parathyroid cancer, pelvic cancer, penile cancer,
peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,
pheochromocytoma, pilocytic astrocytoma, pineal region tumor,
pineoblastoma, pituitary gland cancer, primary central nervous
system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell
carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland
cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer,
skin cancer, small cell lung cancer (SCLC), small intestine cancer,
spinal cancer, spinal column cancer, spinal cord cancer, squamous
cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma,
testicular cancer, throat cancer, thymoma/thymic carcinoma, thyroid
cancer, tongue cancer, tonsil cancer, transitional cell cancer,
tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral
cancer, urethral cancer, uterine adenocarcinoma, uterine cancer,
uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage
acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic
lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia,
Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts
lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,
Philadelphia chromosome positive CML, juvenile myelomonocytic
leukemia (JMML), acute promyelocytic leukemia (a subtype of AML),
large granular lymphocytic leukemia, Adult T-cell chronic leukemia,
diffuse large B cell lymphoma, follicular lymphoma;
Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell
lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal
marginal zone B cell lymphoma (NMZL); splenic marginal zone
lymphoma (SMZL); intravascular large B-cell lymphoma; primary
effusion lymphoma; or lymphomatoid granulomatosis; B-cell
prolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,
splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic
lymphoma; heavy chain diseases, for example, Alpha heavy chain
disease, Gamma heavy chain disease, Mu heavy chain disease, plasma
cell myeloma, solitary plasmacytoma of bone; extraosseous
plasmacytoma; primary cutaneous follicle center lymphoma, T
cell/histocyte rich large B-cell lymphoma, DLBCL associated with
chronic inflammation; Epstein-Barr virus (EBV)+DLBCL of the
elderly; primary mediastinal (thymic) large B-cell lymphoma,
primary cutaneous DLBCL, leg type, ALK+large B-cell lymphoma,
plasmablastic lymphoma; large B-cell lymphoma arising in
HHV8-associated multicentric, Castleman disease; B-cell lymphoma,
unclassifiable, with features intermediate between diffuse large
B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features
intermediate between diffuse large B-cell lymphoma and classical
Hodgkin lymphoma.
[0322] In another aspect, a method of increasing BIM expression
(e.g., BCLC2L11 expression) is provided to induce apoptosis in a
cell comprising contacting a compound of the present invention or a
pharmaceutically acceptable composition, salt, isotopic analog, or
prodrug thereof with the cell. In certain embodiments, the method
is an in vitro method. In certain embodiments, the method is an in
vivo method. BCL2L11 expression is tightly regulated in a cell.
BCL2L11 encodes for BIM, a proapoptotic protein. BCL2L11 is
downregulated in many cancers and BIM is inhibited in many cancers,
including chronic myelocytic leukemia (CML) and non-small cell lung
cancer (NSCLC) and that suppression of BCL2L11 expression can
confer resistance to tyrosine kinase inhibitors. See, e.g., Ng et
al., Nat. Med. (2012) 18:521-528.
[0323] In yet another aspect, a method of treating a condition
associated with angiogenesis is provided, such as, for example, a
diabetic condition (e.g., diabetic retinopathy), an inflammatory
condition (e.g., rheumatoid arthritis), macular degeneration,
obesity, atherosclerosis, or a proliferative disorder, comprising
administering to a subject in need thereof a compound of the
present invention or a pharmaceutically acceptable composition,
salt, isotopic analog, or prodrug thereof.
[0324] In certain embodiments, the condition associated with
angiogenesis is macular degeneration. In certain embodiments,
provided is a method of treating macular degeneration comprising
administering to a subject in need thereof a compound of the
present invention or a pharmaceutically acceptable composition,
salt, isotopic analog, or prodrug thereof.
[0325] In certain embodiments, the condition associated with
angiogenesis is obesity. As used herein, "obesity" and "obese" as
used herein, refers to class I obesity, class II obesity, class III
obesity and pre-obesity (e.g., being "over-weight") as defined by
the World Health Organization. In certain embodiments, a method of
treating obesity is provided comprising administering to a subject
in need thereof a compound of the present invention or a
pharmaceutically acceptable composition, salt, isotopic analog, or
prodrug thereof.
[0326] In certain embodiments, the condition associated with
angiogenesis is atherosclerosis. In certain embodiments, provided
is a method of treating atherosclerosis comprising administering to
a subject in need thereof a compound of the present invention or a
pharmaceutically acceptable composition, salt, isotopic analog, or
prodrug thereof.
[0327] In certain embodiments, the condition associated with
angiogenesis is a proliferative disorder. In certain embodiments,
provided is a method of treating a proliferative disorder
comprising administering to a subject in need thereof a compound of
the present invention or a pharmaceutically acceptable composition,
salt, isotopic analog, or prodrug thereof.
IV. Methods to Reduce the Side Effects Related to Chemotherapy
[0328] In certain embodiments, compounds of the present invention
decrease the effect of chemotherapeutic agent toxicity on CDK4/6
replication dependent healthy cells, such as hematopoietic stem
cells and hematopoietic progenitor cells (together referred to as
HSPCs), and/or renal epithelial cells, in subjects, typically
humans, that will be, are being, or have been exposed to the
chemotherapeutic agent (typically a DNA-damaging agent).
[0329] In one embodiment, the subject has been exposed to a
chemotherapeutic agent, and, using a compound described herein, the
subject's CDK4/6-replication dependent healthy cells are placed in
G1 arrest following exposure in order to mitigate, for example, DNA
damage. In one embodiment, the compound is administered at least
hour, at least 1 hour, at least 2 hours, at least 3 hours, at least
4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at
least 8 hours, at least 10 hours, at least 12 hours, at least 14
hours, at least 16 hours, at least 18 hours, at least 20 hours or
more post chemotherapeutic agent exposure.
[0330] In one embodiment, the compound can allow for dose
intensification (e.g., more therapy can be given in a fixed period
of time) in medically related chemotherapies, which will translate
to better efficacy. Therefore, the presently disclosed methods can
result in chemotherapy regimens that are less toxic and more
effective.
[0331] In some embodiments, the use of a compound described herein
may result in reduced or substantially free of off-target effects,
for example, related to inhibition of kinases other than CDK4
and/or CDK6 such as CDK2. Furthermore, in certain embodiments, the
use of the compounds described herein should not induce cell cycle
arrest in CDK4/6 replication independent cells.
[0332] In some embodiments, the use of a compound described herein
reduces the risk of undesirable off-target effects including, but
not limited to, long term toxicity, anti-oxidant effects, and
estrogenic effects. Anti-oxidant effects can be determined by
standard assays known in the art. For example, a compound with no
significant anti-oxidant effects is a compound that does not
significantly scavenge free-radicals, such as oxygen radicals. The
anti-oxidant effects of a compound can be compared to a compound
with known anti-oxidant activity, such as genistein. Thus, a
compound with no significant anti-oxidant activity can be one that
has less than about 2, 3, 5, 10, 30, or 100 fold anti-oxidant
activity relative to genistein. Estrogenic activities can also be
determined via known assays. For instance, a non-estrogenic
compound is one that does not significantly bind and activate the
estrogen receptor. A compound that is substantially free of
estrogenic effects can be one that has less than about 2, 3, 5, 10,
20, or 100 fold estrogenic activity relative to a compound with
estrogenic activity, e.g., genistein.
V. Methods to Treat Abnormal Proliferation of T-Cells, B-Cells
and/or NK-Cells
[0333] In certain aspects, the invention includes the use of an
effective amount of a compound described herein, or its
pharmaceutically acceptable salt, prodrug or isotopic variant
optionally in a pharmaceutical composition, to treat a host,
typically a human, with a selected cancer, tumor,
hyperproliferative condition or an inflammatory or immune disorder.
Some of the disclosed compounds are highly active against T-cell
proliferation. Given the paucity of drugs for T-cell cancers and
abnormal proliferation, the identification of such uses represents
a substantial improvement in the medical therapy for these
diseases.
[0334] Abnormal proliferation of T-cells, B-cells, and/or NK-cells
can result in a wide range of diseases such as cancer,
proliferative disorders and inflammatory/immune diseases. A host,
for example a human, afflicted with any of these disorders can be
treated with an effective amount of a compound as described herein
to achieve a decrease in symptoms (a palliative agent) or a
decrease in the underlying disease (a disease modifying agent).
[0335] Examples include T-cell or NK-cell lymphoma, for example,
but not limited to: peripheral T-cell lymphoma; anaplastic large
cell lymphoma, for example anaplastic lymphoma kinase (ALK)
positive, ALK negative anaplastic large cell lymphoma, or primary
cutaneous anaplastic large cell lymphoma; angioimmunoblastic
lymphoma; cutaneous T-cell lymphoma, for example mycosis fungoides,
Sezary syndrome, primary cutaneous anaplastic large cell lymphoma,
primary cutaneous CD30+ T-cell lymphoproliferative disorder;
primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell
lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary
cutaneous small/medium CD4+ T-cell lymphoma, and lymphomatoid
papulosis; Adult T-cell Leukemia/Lymphoma (ATLL); Blastic NK-cell
Lymphoma; Enteropathy-type T-cell lymphoma; Hematosplenic
gamma-delta T-cell Lymphoma; Lymphoblastic Lymphoma; Nasal
NK/T-cell Lymphomas; Treatment-related T-cell lymphomas; for
example lymphomas that appear after solid organ or bone marrow
transplantation; T-cell prolymphocytic leukemia; T-cell large
granular lymphocytic leukemia; Chronic lymphoproliferative disorder
of NK-cells; Aggressive NK cell leukemia; Systemic EBV+ T-cell
lymphoproliferative disease of childhood (associated with chronic
active EBV infection); Hydroa vacciniforme-like lymphoma; Adult
T-cell leukemia/lymphoma; Enteropathy-associated T-cell lymphoma;
Hepatosplenic T-cell lymphoma; or Subcutaneous panniculitis-like
T-cell lymphoma.
[0336] In one embodiment, a compound disclosed herein, or its salt,
prodrug, or isotopic variant can be used in an effective amount to
treat a host, for example a human, with a lymphoma or lymphocytic
or myelocytic proliferation disorder or abnormality. For example,
the compounds as described herein can be administered to a host
suffering from a Hodgkin Lymphoma or a Non-Hodgkin Lymphoma. For
example, the host can be suffering from a Non-Hodgkin Lymphoma such
as, but not limited to: an AIDS-Related Lymphoma; Anaplastic
Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell
Lymphoma; Burkitt's Lymphoma; Burkitt-like Lymphoma (Small
Non-Cleaved Cell Lymphoma); Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large
B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular
Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic
Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal
T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas;
Primary Central Nervous System Lymphoma; T-Cell Leukemias;
Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; or
Waldenstrom's Macroglobulinemia.
[0337] Alternatively, a compound disclosed herein, or its salt,
prodrug, or isotopic variant can be used in an effective amount to
treat a host, for example a human, with a Hodgkin Lymphoma, such
as, but not limited to: Nodular Sclerosis Classical Hodgkin's
Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL;
Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or
Nodular Lymphocyte Predominant HL.
[0338] Alternatively, a compound disclosed herein, or its salt,
prodrug, or isotopic variant can be used in an effective amount to
treat a host, for example a human with a specific B-cell lymphoma
or proliferative disorder such as, but not limited to: multiple
myeloma; Diffuse large B cell lymphoma; Follicular lymphoma;
Mucosa-Associated Lymphatic Tissue lymphoma (MALT); Small cell
lymphocytic lymphoma;Mediastinal large B cell lymphoma; Nodal
marginal zone B cell lymphoma (NMZL); Splenic marginal zone
lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary
effusion lymphoma; or Lymphomatoid granulomatosis; B-cell
prolymphocytic leukemia; Hairy cell leukemia; Splenic
lymphoma/leukemia, unclassifiable; Splenic diffuse red pulp small
B-cell lymphoma; Hairy cell leukemia-variant; Lymphoplasmacytic
lymphoma; Heavy chain diseases, for example, Alpha heavy chain
disease, Gamma heavy chain disease, Mu heavy chain disease; Plasma
cell myeloma; Solitary plasmacytoma of bone; Extraosseous
plasmacytoma; Primary cutaneous follicle center lymphoma; T
cell/histiocyte rich large B-cell lymphoma; DLBCL associated with
chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the
elderly; Primary mediastinal (thymic) large B-cell lymphoma;
Primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma;
Plasmablastic lymphoma; Large B-cell lymphoma arising in
HHV8-associated multicentric; Castleman disease; B-cell lymphoma,
unclassifiable, with features intermediate between diffuse large
B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features
intermediate between diffuse large B-cell lymphoma and classical
Hodgkin lymphoma.
[0339] In one embodiment, a compound disclosed herein, or its salt,
prodrug, or isotopic variant can be used in an effective amount to
treat a host, for example a human with leukemia. For example, the
host may be suffering from an acute or chronic leukemia of a
lymphocytic or myelogenous origin, such as, but not limited to:
Acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia
(AML); Chronic lymphocytic leukemia (CLL); Chronic myelogenous
leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell
leukemia (HCL); acute promyelocytic leukemia (a subtype of AML);
large granular lymphocytic leukemia; or Adult T-cell chronic
leukemia. In one embodiment, the patient suffers from an acute
myelogenous leukemia, for example an undifferentiated AML (MO);
myeloblastic leukemia (M1; with/without minimal cell maturation);
myeloblastic leukemia (M2; with cell maturation); promyelocytic
leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or
M4 variant with eosinophilia [M4E]); monocytic leukemia (M5);
erythroleukemia (M6); or megakaryoblastic leukemia (M7).
VI. Pharmaceutical Compositions and Dosage Forms
[0340] An active compound described herein, or its salt, isotopic
analog, or prodrug can be administered in an effective amount to a
host to treat any of the disorders described herein using any
suitable approach which achieves the desired therapeutic result.
The amount and timing of active compound administered will, of
course, be dependent on the host being treated, the instructions of
the supervising medical specialist, on the time course of the
exposure, on the manner of administration, on the pharmacokinetic
properties of the particular active compound, and on the judgment
of the prescribing physician. Thus, because of host to host
variability, the dosages given below are a guideline and the
physician can titrate doses of the compound to achieve the
treatment that the physician considers appropriate for the host. In
considering the degree of treatment desired, the physician can
balance a variety of factors such as age and weight of the host,
presence of preexisting disease, as well as presence of other
diseases.
[0341] The pharmaceutical composition may be formulated as any
pharmaceutically useful form, e.g., as an aerosol, a cream, a gel,
a pill, an injection or infusion solution, a capsule, a tablet, a
syrup, a transdermal patch, a subcutaneous patch, a dry powder, an
inhalation formulation, in a medical device, suppository, buccal,
or sublingual formulation, parenteral formulation, or an ophthalmic
solution. Some dosage forms, such as tablets and capsules, are
subdivided into suitably sized unit doses containing appropriate
quantities of the active components, e.g., an effective amount to
achieve the desired purpose.
[0342] The therapeutically effective dosage of any active compound
described herein will be determined by the health care practitioner
depending on the condition, size and age of the patient as well as
the route of delivery. In one non-limited embodiment, a dosage from
about 0.1 to about 200 mg/kg has therapeutic efficacy, with all
weights being calculated based upon the weight of the active
compound, including the cases where a salt is employed. In one
embodiment the dosage is at about or greater than 0.1, 0.5, 1, 5,
10, 25, 50, 75, 100, 125, 150, 175, or 200 mg/kg. In some
embodiments, the dosage may be the amount of compound needed to
provide a serum concentration of the active compound of up to about
10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700
nM, 800 nM, 900 nM, 1 .mu.M, 5 .mu.M, 10 .mu.M, 20 .mu.M, 30 .mu.M,
or 40 .mu.M.
[0343] In certain embodiments, the pharmaceutical composition is in
a dosage form that contains from about 0.1 mg to about 2000 mg,
from about 10 mg to about 1000 mg, from about 100 mg to about 800
mg, or from about 200 mg to about 600 mg of the active compound and
optionally from about 0.1 mg to about 2000 mg, from about 10 mg to
about 1000 mg, from about 100 mg to about 800 mg, or from about 200
mg to about 600 mg of an additional active agent in a unit dosage
form. Examples of dosage forms with at least 5, 10, 15, 20, 25, 50,
100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active
compound, or its salt. The pharmaceutical composition may also
include a molar ratio of the active compound and an additional
active agent, in a ratio that achieves the desired results.
[0344] Compounds disclosed herein or used as described herein may
be administered orally, topically, parenterally, by inhalation or
spray, sublingually, via implant, including ocular implant,
transdermally, via buccal administration, rectally, as an
ophthalmic solution, injection, including ocular injection,
intraveneous, intramuscular, inhalation, intra-aortal,
intracranial, subdermal, intraperitioneal, subcutaneous,
transnasal, sublingual, or rectal or by other means, in dosage unit
formulations containing conventional pharmaceutically acceptable
carriers. For ocular delivery, the compound can be administered, as
desired, for example, via intravitreal, intrastromal, intracameral,
sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial,
conjunctival, subconjunctival, episcleral, periocular,
transscleral, retrobulbar, posterior juxtascleral, circumcorneal,
or tear duct injections, or through a mucus, mucin, or a mucosal
barrier, in an immediate or controlled release fashion or via an
ocular device.
[0345] In accordance with the presently disclosed methods, an oral
administration can be in any desired form such as a solid, gel or
liquid, including a solution, suspension, or emulsion. In some
embodiments, the compounds or salts are administered by inhalation,
intravenously, or intramuscularly as a liposomal suspension. When
administered through inhalation the active compound or salt may be
in the form of a plurality of solid particles or droplets having
any desired particle size, and for example, from about 0.01, 0.1 or
0.5 to about 5, 10, 20 or more microns, and optionally from about 1
to about 2 microns. Compounds as disclosed in the present invention
have demonstrated good pharmacokinetic and pharmacodynamics
properties, for instance when administered by the oral or
intravenous routes.
[0346] The pharmaceutical formulations can comprise an active
compound described herein or a pharmaceutically acceptable salt
thereof, in any pharmaceutically acceptable carrier. If a solution
is desired, water may sometimes be the carrier of choice for
water-soluble compounds or salts. With respect to the water-soluble
compounds or salts, an organic vehicle, such as glycerol, propylene
glycol, polyethylene glycol, or mixtures thereof, can be suitable.
In the latter instance, the organic vehicle can contain a
substantial amount of water. The solution in either instance can
then be sterilized in a suitable manner known to those in the art,
and for illustration by filtration through a 0.22-micron filter.
Subsequent to sterilization, the solution can be dispensed into
appropriate receptacles, such as depyrogenated glass vials. The
dispensing is optionally done by an aseptic method. Sterilized
closures can then be placed on the vials and, if desired, the vial
contents can be lyophilized.
[0347] Carriers include excipients and diluents and must be of
sufficiently high purity and sufficiently low toxicity to render
them suitable for administration to the patient being treated. The
carrier can be inert or it can possess pharmaceutical benefits of
its own. The amount of carrier employed in conjunction with the
compound is sufficient to provide a practical quantity of material
for administration per unit dose of the compound.
[0348] Classes of carriers include, but are not limited to binders,
buffering agents, coloring agents, diluents, disintegrants,
emulsifiers, flavorants, glidents, lubricants, preservatives,
stabilizers, surfactants, tableting agents, and wetting agents.
Some carriers may be listed in more than one class, for example
vegetable oil may be used as a lubricant in some formulations and a
diluent in others. Exemplary pharmaceutically acceptable carriers
include sugars, starches, celluloses, powdered tragacanth, malt,
gelatin; talc, and vegetable oils. Optional active agents may be
included in a pharmaceutical composition, which do not
substantially interfere with the activity of the compound of the
present invention.
[0349] Additionally, auxiliary substances, such as wetting or
emulsifying agents, biological buffering substances, surfactants,
and the like, can be present in such vehicles. A biological buffer
can be any solution which is pharmacologically acceptable and which
provides the formulation with the desired pH, i.e., a pH in the
physiologically acceptable range. Examples of buffer solutions
include saline, phosphate buffered saline, Tris buffered saline,
Hank's buffered saline, and the like.
[0350] Depending on the intended mode of administration, the
pharmaceutical compositions can be in the form of solid, semi-solid
or liquid dosage forms, such as, for example, tablets,
suppositories, pills, capsules, powders, liquids, suspensions,
creams, ointments, lotions or the like, preferably in unit dosage
form suitable for single administration of a precise dosage. The
compositions will include an effective amount of the selected drug
in combination with a pharmaceutically acceptable carrier and, in
addition, can include other pharmaceutical agents, adjuvants,
diluents, buffers, and the like.
[0351] Thus, the compositions of the disclosure can be administered
as pharmaceutical formulations including those suitable for oral
(including buccal and sub-lingual), rectal, nasal, topical,
pulmonary, vaginal or parenteral (including intramuscular,
intra-arterial, intrathecal, subcutaneous and intravenous)
administration or in a form suitable for administration by
inhalation or insufflation. The preferred manner of administration
is intravenous or oral using a convenient daily dosage regimen
which can be adjusted according to the degree of affliction.
[0352] For solid compositions, conventional nontoxic solid carriers
include, for example, pharmaceutical grades of mannitol, lactose,
starch, magnesium stearate, sodium saccharin, talc, cellulose,
glucose, sucrose, magnesium carbonate, and the like. Liquid
pharmaceutically administrable compositions can, for example, be
prepared by dissolving, dispersing, and the like, an active
compound as described herein and optional pharmaceutical adjuvants
in an excipient, such as, for example, water, saline, aqueous
dextrose, glycerol, ethanol, and the like, to thereby form a
solution or suspension. If desired, the pharmaceutical composition
to be administered can also contain minor amounts of nontoxic
auxiliary substances such as wetting or emulsifying agents, pH
buffering agents and the like, for example, sodium acetate,
sorbitan monolaurate, triethanolamine sodium acetate,
triethanolamine oleate, and the like. Actual methods of preparing
such dosage forms are known, or will be apparent, to those skilled
in this art; for example, see Remington's Pharmaceutical Sciences,
referenced above.
[0353] In yet another embodiment is the use of permeation enhancer
excipients including polymers such as: polycations (chitosan and
its quaternary ammonium derivatives, poly-L-arginine, aminated
gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid);
and, thiolated polymers (carboxymethyl cellulose-cysteine,
polycarbophil-cysteine, chitosan-thiobutylamidine,
chitosan-thioglycolic acid, chitosan-glutathione conjugates).
[0354] For oral administration, the composition will generally take
the form of a tablet, capsule, a softgel capsule or can be an
aqueous or nonaqueous solution, suspension or syrup. Tablets and
capsules are preferred oral administration forms. Tablets and
capsules for oral use can include one or more commonly used
carriers such as lactose and corn starch. Lubricating agents, such
as magnesium stearate, are also typically added. Typically, the
compositions of the disclosure can be combined with an oral,
non-toxic, pharmaceutically acceptable, inert carrier such as
lactose, starch, sucrose, glucose, methyl cellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol
and the like. Moreover, when desired or necessary, suitable
binders, lubricants, disintegrating agents, and coloring agents can
also be incorporated into the mixture. Suitable binders include
starch, gelatin, natural sugars such as glucose or beta-lactose,
corn sweeteners, natural and synthetic gums such as acacia,
tragacanth, or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes, and the like. Lubricants used in these
dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride, and the
like. Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum, and the like.
[0355] When liquid suspensions are used, the active agent can be
combined with any oral, non-toxic, pharmaceutically acceptable
inert carrier such as ethanol, glycerol, water, and the like and
with emulsifying and suspending agents. If desired, flavoring,
coloring and/or sweetening agents can be added as well. Other
optional components for incorporation into an oral formulation
herein include, but are not limited to, preservatives, suspending
agents, thickening agents, and the like.
[0356] Parenteral formulations can be prepared in conventional
forms, either as liquid solutions or suspensions, solid forms
suitable for solubilization or suspension in liquid prior to
injection, or as emulsions. Preferably, sterile injectable
suspensions are formulated according to techniques known in the art
using suitable carriers, dispersing or wetting agents and
suspending agents. The sterile injectable formulation can also be a
sterile injectable solution or a suspension in a nontoxic
parenterally acceptable diluent or solvent. Among the acceptable
vehicles and solvents that can be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils, fatty esters or polyols are conventionally
employed as solvents or suspending media. In addition, parenteral
administration can involve the use of a slow release or sustained
release system such that a constant level of dosage is
maintained.
[0357] Parenteral administration includes intraarticular,
intravenous, intramuscular, intradermal, intraperitoneal, and
subcutaneous routes, and include aqueous and non-aqueous, isotonic
sterile injection solutions, which can contain antioxidants,
buffers, bacteriostats, and solutes that render the formulation
isotonic with the blood of the intended recipient, and aqueous and
non-aqueous sterile suspensions that can include suspending agents,
solubilizers, thickening agents, stabilizers, and preservatives.
Administration via certain parenteral routes can involve
introducing the formulations of the disclosure into the body of a
patient through a needle or a catheter, propelled by a sterile
syringe or some other mechanical device such as an continuous
infusion system. A formulation provided by the disclosure can be
administered using a syringe, injector, pump, or any other device
recognized in the art for parenteral administration.
[0358] In addition to the active compounds or their salts, the
pharmaceutical formulations can contain other additives, such as
pH-adjusting additives. In particular, useful pH-adjusting agents
include acids, such as hydrochloric acid, bases or buffers, such as
sodium lactate, sodium acetate, sodium phosphate, sodium citrate,
sodium borate, or sodium gluconate. Further, the formulations can
contain antimicrobial preservatives. Useful antimicrobial
preservatives include methylparaben, propylparaben, and benzyl
alcohol. An antimicrobial preservative is typically employed when
the formulations is placed in a vial designed for multi-dose use.
The pharmaceutical formulations described herein can be lyophilized
using techniques well known in the art.
[0359] For oral administration a pharmaceutical composition can
take the form of a solution suspension, tablet, pill, capsule,
powder, and the like. Tablets containing various excipients such as
sodium citrate, calcium carbonate and calcium phosphate may be
employed along with various disintegrants such as starch (e.g.,
potato or tapioca starch) and certain complex silicates, together
with binding agents such as polyvinylpyrrolidone, sucrose, gelatin
and acacia. Additionally, lubricating agents such as magnesium
stearate, sodium lauryl sulfate, and talc are often very useful for
tableting purposes. Solid compositions of a similar type may be
employed as fillers in soft and hard-filled gelatin capsules.
Materials in this connection also include lactose or milk sugar as
well as high molecular weight polyethylene glycols. When aqueous
suspensions and/or elixirs are desired for oral administration, the
compounds of the presently disclosed host matter can be combined
with various sweetening agents, flavoring agents, coloring agents,
emulsifying agents and/or suspending agents, as well as such
diluents as water, ethanol, propylene glycol, glycerin and various
like combinations thereof.
[0360] In yet another embodiment of the host matter described
herein, there are provided injectable, stable, sterile formulations
comprising an active compound as described herein, or a salt
thereof, in a unit dosage form in a sealed container. The compound
or salt is provided in the form of a lyophilizate, which is capable
of being reconstituted with a suitable pharmaceutically acceptable
carrier to form liquid formulation suitable for injection thereof
into a host. When the compound or salt is substantially
water-insoluble, a sufficient amount of emulsifying agent, which is
physiologically acceptable, can be employed in sufficient quantity
to emulsify the compound or salt in an aqueous carrier.
Particularly useful emulsifying agents include phosphatidyl
cholines and lecithin.
[0361] Additional embodiments provided herein include liposomal
formulations of the active compounds disclosed herein. The
technology for forming liposomal suspensions is well known in the
art. When the compound is an aqueous-soluble salt, using
conventional liposome technology, the same can be incorporated into
lipid vesicles. In such an instance, due to the water solubility of
the active compound, the active compound can be substantially
entrained within the hydrophilic center or core of the liposomes.
The lipid layer employed can be of any conventional composition and
can either contain cholesterol or can be cholesterol-free. When the
active compound of interest is water-insoluble, again employing
conventional liposome formation technology, the salt can be
substantially entrained within the hydrophobic lipid bilayer that
forms the structure of the liposome. In either instance, the
liposomes that are produced can be reduced in size, as through the
use of standard sonication and homogenization techniques. The
liposomal formulations comprising the active compounds disclosed
herein can be lyophilized to produce a lyophilizate, which can be
reconstituted with a pharmaceutically acceptable carrier, such as
water, to regenerate a liposomal suspension.
[0362] Pharmaceutical formulations also are provided which are
suitable for administration as an aerosol by inhalation. These
formulations comprise a solution or suspension of a desired
compound described herein or a salt thereof, or a plurality of
solid particles of the compound or salt. The desired formulations
can be placed in a small chamber and nebulized. Nebulization can be
accomplished by compressed air or by ultrasonic energy to form a
plurality of liquid droplets or solid particles comprising the
compounds or salts. The liquid droplets or solid particles may for
example have a particle size in the range of about 0.5 to about 10
microns, and optionally from about 0.5 to about 5 microns. In one
embodiment, the solid particles provide for controlled release
through the use of a degradable polymer. The solid particles can be
obtained by processing the solid compound or a salt thereof, in any
appropriate manner known in the art, such as by micronization.
Optionally, the size of the solid particles or droplets can be from
about 1 to about 2 microns. In this respect, commercial nebulizers
are available to achieve this purpose. The compounds can be
administered via an aerosol suspension of respirable particles in a
manner set forth in U.S. Pat. No. 5,628,984, the disclosure of
which is incorporated herein by reference in its entirety.
[0363] Pharmaceutical formulations also are provided which provide
a controlled release of a compound described herein, including
through the use of a degradable polymer, as known in the art.
[0364] When the pharmaceutical formulations suitable for
administration as an aerosol is in the form of a liquid, the
formulations can comprise a water-soluble active compound in a
carrier that comprises water. A surfactant can be present, which
lowers the surface tension of the formulations sufficiently to
result in the formation of droplets within the desired size range
when hosted to nebulization.
[0365] The term "pharmaceutically acceptable salts" as used herein
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with hosts (e.g., human
hosts) without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the presently disclosed
host matter.
[0366] Thus, the term "salts" refers to the relatively non-toxic,
inorganic and organic acid addition salts of the presently
disclosed compounds. These salts can be prepared during the final
isolation and purification of the compounds or by separately
reacting the purified compound in its free base form with a
suitable organic or inorganic acid and isolating the salt thus
formed. Basic compounds are capable of forming a wide variety of
different salts with various inorganic and organic acids. Acid
addition salts of the basic compounds are prepared by contacting
the free base form with a sufficient amount of the desired acid to
produce the salt in the conventional manner. The free base form can
be regenerated by contacting the salt form with a base and
isolating the free base in the conventional manner. The free base
forms may differ from their respective salt forms in certain
physical properties such as solubility in polar solvents.
Pharmaceutically acceptable base addition salts may be formed with
metals or amines, such as alkali and alkaline earth metal
hydroxides, or of organic amines. Examples of metals used as
cations, include, but are not limited to, sodium, potassium,
magnesium, calcium, and the like. Examples of suitable amines
include, but are not limited to, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
N-methylglucamine, and procaine. The base addition salts of acidic
compounds are prepared by contacting the free acid form with a
sufficient amount of the desired base to produce the salt in the
conventional manner. The free acid form can be regenerated by
contacting the salt form with an acid and isolating the free acid
in a conventional manner. The free acid forms may differ from their
respective salt forms somewhat in certain physical properties such
as solubility in polar solvents.
[0367] Salts can be prepared from inorganic acids sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide such as hydrochloric,
nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus,
and the like. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
valerate, oleate, palmitate, stearate, laurate, borate, benzoate,
lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate mesylate, glucoheptonate,
lactobionate, laurylsulphonate and isethionate salts, and the like.
Salts can also be prepared from organic acids, such as aliphatic
mono- and dicarboxylic acids, phenyl-substituted alkanoic acids,
hydroxy alkanoic acids, alkanedioic acids, aromatic acids,
aliphatic and aromatic sulfonic acids, etc. and the like.
Representative salts include acetate, propionate, caprylate,
isobutyrate, oxalate, malonate, succinate, suberate, sebacate,
fumarate, maleate, mandelate, benzoate, chlorobenzoate,
methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate,
toluenesulfonate, phenylacetate, citrate, lactate, maleate,
tartrate, methanesulfonate, and the like. Pharmaceutically
acceptable salts can include cations based on the alkali and
alkaline earth metals, such as sodium, lithium, potassium, calcium,
magnesium and the like, as well as non-toxic ammonium, quaternary
ammonium, and amine cations including, but not limited to,
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, ethylamine, and the
like. Also contemplated are the salts of amino acids such as
arginate, gluconate, galacturonate, and the like. See, for example,
Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated
herein by reference.
[0368] Preferably, sterile injectable suspensions are formulated
according to techniques known in the art using suitable carriers,
dispersing or wetting agents and suspending agents. The sterile
injectable formulation can also be a sterile injectable solution or
a suspension in a nontoxic parenterally acceptable diluent or
solvent. Among the acceptable vehicles and solvents that can be
employed are water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils, fatty esters or polyols
are conventionally employed as solvents or suspending media. In
addition, parenteral administration can involve the use of a slow
release or sustained release system such that a constant level of
dosage is maintained.
[0369] Preparations according to the disclosure for parenteral
administration include sterile aqueous or non-aqueous solutions,
suspensions, or emulsions. Examples of non-aqueous solvents or
vehicles are propylene glycol, polyethylene glycol, vegetable oils,
such as olive oil and corn oil, gelatin, and injectable organic
esters such as ethyl oleate. Such dosage forms can also contain
adjuvants such as preserving, wetting, emulsifying, and dispersing
agents. They can be sterilized by, for example, filtration through
a bacteria retaining filter, by incorporating sterilizing agents
into the compositions, by irradiating the compositions, or by
heating the compositions. They can also be manufactured using
sterile water, or some other sterile injectable medium, immediately
before use.
[0370] Sterile injectable solutions are prepared by incorporating
one or more of the compounds of the disclosure in the required
amount in the appropriate solvent with various of the other
ingredients 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, the
preferred 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. Thus, for example, a parenteral
composition suitable for administration by injection is prepared by
stirring 1.5% by weight of active ingredient in 10% by volume
propylene glycol and water. The solution is made isotonic with
sodium chloride and sterilized.
[0371] Formulations suitable for rectal administration are
typically presented as unit dose suppositories. These may be
prepared by admixing the active disclosed compound with one or more
conventional solid carriers, for example, cocoa butter, and then
shaping the resulting mixture.
[0372] Formulations suitable for topical application to the skin
preferably take the form of an ointment, cream, lotion, paste, gel,
spray, aerosol, or oil. Carriers which may be used include
petroleum jelly, lanoline, polyethylene glycols, alcohols,
transdermal enhancers, and combinations of two or more thereof.
[0373] Formulations suitable for transdermal administration may be
presented as discrete patches adapted to remain in intimate contact
with the epidermis of the recipient for a prolonged period of time.
Formulations suitable for transdermal administration may also be
delivered by iontophoresis (see, for example, Pharmaceutical
Research 3 (6):318 (1986)) and typically take the form of an
optionally buffered aqueous solution of the active compound. In one
embodiment, microneedle patches or devices are provided for
delivery of drugs across or into biological tissue, particularly
the skin. The microneedle patches or devices permit drug delivery
at clinically relevant rates across or into skin or other tissue
barriers, with minimal or no damage, pain, or irritation to the
tissue.
[0374] Formulations suitable for administration to the lungs can be
delivered by a wide range of passive breath driven and active power
driven single/-multiple dose dry powder inhalers (DPI). The devices
most commonly used for respiratory delivery include nebulizers,
metered-dose inhalers, and dry powder inhalers. Several types of
nebulizers are available, including jet nebulizers, ultrasonic
nebulizers, and vibrating mesh nebulizers. Selection of a suitable
lung delivery device depends on parameters, such as nature of the
drug and its formulation, the site of action, and pathophysiology
of the lung.
[0375] Additional non-limiting examples of drug delivery devices
and methods include, for example, US20090203709 titled
"Pharmaceutical Dosage Form For Oral Administration Of Tyrosine
Kinase Inhibitor" (Abbott Laboratories); US20050009910 titled
"Delivery of an active drug to the posterior part of the eye via
subconjunctival or periocular delivery of a prodrug", US
20130071349 titled "Biodegradable polymers for lowering intraocular
pressure", U.S. Pat. No. 8,481,069 titled "Tyrosine kinase
microspheres", U.S. Pat. No. 8,465,778 titled "Method of making
tyrosine kinase microspheres", U.S. Pat. No. 8,409,607 titled
"Sustained release intraocular implants containing tyrosine kinase
inhibitors and related methods", U.S. Pat. No. 8,512,738 and US
2014/0031408 titled "Biodegradable intravitreal tyrosine kinase
implants", US 2014/0294986 titled "Microsphere Drug Delivery System
for Sustained Intraocular Release", U.S. Pat. No. 8,911,768 titled
"Methods For Treating Retinopathy With Extended Therapeutic Effect"
(Allergan, Inc.); U.S. Pat. No. 6,495,164 titled "Preparation of
injectable suspensions having improved injectability" (Alkermes
Controlled Therapeutics, Inc.); WO 2014/047439 titled
"Biodegradable Microcapsules Containing Filling Material" (Akina,
Inc.); WO 2010/132664 titled "Compositions And Methods For Drug
Delivery" (Baxter International Inc. Baxter Healthcare SA);
US20120052041 titled "Polymeric nanoparticles with enhanced drug
loading and methods of use thereof" (The Brigham and Women's
Hospital, Inc.); US20140178475, US20140248358, and US20140249158
titled "Therapeutic Nanoparticles Comprising a Therapeutic Agent
and Methods of Making and Using Same" (BIND Therapeutics, Inc.);
U.S. Pat. No. 5,869,103 titled "Polymer microparticles for drug
delivery" (Danbiosyst UK Ltd.); U.S. Pat. No. 8,628,801 titled
"Pegylated Nanoparticles" (Universidad de Navarra); US2014/0107025
titled "Ocular drug delivery system" (Jade Therapeutics, LLC); U.S.
Pat. No. 6,287,588 titled "Agent delivering system comprised of
microparticle and biodegradable gel with an improved releasing
profile and methods of use thereof", U.S. Pat. No. 6,589,549 titled
"Bioactive agent delivering system comprised of microparticles
within a biodegradable to improve release profiles" (Macromed,
Inc.); U.S. Pat. Nos. 6,007,845 and 5,578,325 titled "Nanoparticles
and microparticles of non-linear hydrophilic hydrophobic multiblock
copolymers" (Massachusetts Institute of Technology); US20040234611,
US20080305172, US20120269894, and US20130122064 titled "Ophthalmic
depot formulations for periocular or subconjunctival administration
(Novartis Ag); U.S. Pat. No. 6,413,539 titled "Block polymer"
(Poly-Med, Inc.); US 20070071756 titled "Delivery of an agent to
ameliorate inflammation" (Peyman); US 20080166411 titled
"Injectable Depot Formulations And Methods For Providing Sustained
Release Of Poorly Soluble Drugs Comprising Nanoparticles" (Pfizer,
Inc.); U.S. Pat. No. 6,706,289 titled "Methods and compositions for
enhanced delivery of bioactive molecules" (PR Pharmaceuticals,
Inc.); and U.S. Pat. No. 8,663,674 titled "Microparticle containing
matrices for drug delivery" (Surmodics).
VII. Combination Therapy
[0376] The disclosed compounds of Formula I, Formula II, Formula
III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,
Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV can be used in an effective amount
alone or in combination with another compound of the present
invention or another bioactive agent to treat a host such as a
human with a disorder as described herein.
[0377] The disclosed compounds described herein can be used in an
effective amount alone or in combination with another compound of
the present invention or another bioactive agent to treat a host
such as a human with a disorder as described herein.
[0378] The term "bioactive agent" is used to describe an agent,
other than the selected compound according to the present
invention, which can be used in combination or alternation with a
compound of the present invention to achieve a desired result of
therapy. In one embodiment, the compound of the present invention
and the bioactive agent are administered in a manner that they are
active in vivo during overlapping time periods, for example, have
time-period overlapping Cmax, Tmax, AUC or other pharmacokinetic
parameter. In another embodiment, the compound of the present
invention and the bioactive agent are administered to a host in
need thereof that do not have overlapping pharmacokinetic
parameter, however, one has a therapeutic impact on the therapeutic
efficacy of the other.
[0379] In one aspect of this embodiment, the bioactive agent is an
immune modulator, including but not limited to a checkpoint
inhibitor, including as non-limiting examples, a PD-1 inhibitor,
PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3
inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell
activation (VISTA) inhibitors, small molecule, peptide, nucleotide,
or other inhibitor. In certain aspects, the immune modulator is an
antibody, such as a monoclonal antibody.
[0380] PD-1 inhibitors that blocks the interaction of PD-1 and
PD-L1 by binding to the PD-1 receptor, and in turn inhibit immune
suppression include, for example, nivolumab (Opdivo), pembrolizumab
(Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune),
PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis),
REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company
and Incyte Corporation), TSR-042 (Tesaro), and the PD-Li/VISTA
inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the
interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and
in turn inhibits immune suppression, include for example,
atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune),
KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4
checkpoint inhibitors that bind to CTLA-4 and inhibits immune
suppression include, but are not limited to, ipilimumab,
tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041
(Agenus). LAG-3 checkpoint inhibitors, include, but are not limited
to, BMS-986016 (Bristol-Myers Squibb), GSK2831781
(GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and
the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example
of a TIM-3 inhibitor is TSR-022 (Tesaro).
[0381] In yet another embodiment, one of the active compounds
described herein can be administered in an effective amount for the
treatment of abnormal tissue of the female reproductive system such
as breast, ovarian, endometrial, or uterine cancer, in combination
or alternation with an effective amount of an estrogen inhibitor
including but not limited to a SERM (selective estrogen receptor
modulator), a SERD (selective estrogen receptor degrader), a
complete estrogen receptor degrader, or another form of partial or
complete estrogen antagonist or agonist. Partial anti-estrogens
like raloxifene and tamoxifen retain some estrogen-like effects,
including an estrogen-like stimulation of uterine growth, and also,
in some cases, an estrogen-like action during breast cancer
progression which actually stimulates tumor growth. In contrast,
fulvestrant, a complete anti-estrogen, is free of estrogen-like
action on the uterus and is effective in tamoxifen-resistant
tumors. Non-limiting examples of anti-estrogen compounds are
provided in WO 2014/19176 assigned to Astra Zeneca, WO2013/090921,
WO 2014/203129, WO 2014/203132, and US2013/0178445 assigned to
Olema Pharmaceuticals, and U.S. Pat. Nos. 9,078,871, 8,853,423, and
8,703, 810, as well as US 2015/0005286, WO 2014/205136, and WO
2014/205138. Additional non-limiting examples of anti-estrogen
compounds include: SERMS such as anordrin, bazedoxifene,
broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil,
lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and
fulvestrant; aromatase inhibitors such as aminoglutethimide,
testolactone, anastrozole, exemestane, fadrozole, formestane, and
letrozole; and antigonadotropins such as leuprorelin, cetrorelix,
allylestrenol, chloromadinone acetate, cyproterone acetate,
delmadinone acetate, dydrogesterone, medroxyprogesterone acetate,
megestrol acetate, nomegestrol acetate, norethisterone acetate,
progesterone, and spironolactone. Other estrogenic ligands that can
be used according to the present invention are described in U.S.
Pat. Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117,
WO2011/156518, U.S. Pat. Nos. 8,455,534 and 8,299,112, 9,078,871;
8,853,423; 8,703,810; US 2015/0005286; and WO 2014/205138,
US2016/0175289, US2015/0258080, WO 2014/191726, WO 2012/084711; WO
2002/013802; WO 2002/004418; WO 2002/003992; WO 2002/003991; WO
2002/003990; WO 2002/003989; WO 2002/003988; WO 2002/003986; WO
2002/003977; WO 2002/003976; WO 2002/003975; WO 2006/078834; U.S.
Pat. No. 6,821,989; US 2002/0128276; U.S. Pat. No. 6,777,424; US
2002/0016340; U.S. Pat. Nos. 6,326,392; 6,756,401; US 2002/0013327;
U.S. Pat. Nos. 6,512,002; 6,632,834; US 2001/0056099; U.S. Pat.
Nos. 6,583,170; 6,479,535; WO 1999/024027; U.S. Pat. No. 6,005,102;
EP 0802184; U.S. Pat. Nos. 5,998,402; 5,780,497, 5,880,137, WO
2012/048058 and WO 2007/087684.
[0382] In another embodiment, an active compound described herein
can be administered in an effective amount for the treatment of
abnormal tissue of the male reproductive system such as prostate or
testicular cancer, in combination or alternation with an effective
amount of an androgen (such as testosterone) inhibitor including
but not limited to a selective androgen receptor modulator, a
selective androgen receptor degrader, a complete androgen receptor
degrader, or another form of partial or complete androgen
antagonist. In one embodiment, the prostate or testicular cancer is
androgen-resistant. Non-limiting examples of anti-androgen
compounds are provided in WO 2011/156518 and U.S. Pat. Nos.
8,455,534 and 8,299,112. Additional non-limiting examples of
anti-androgen compounds include: enzalutamide, apalutamide,
cyproterone acetate, chlormadinone acetate, spironolactone,
canrenone, drospirenone, ketoconazole, topilutamide, abiraterone
acetate, and cimetidine.
[0383] In one embodiment, the bioactive agent is an ALK inhibitor.
Examples of ALK inhibitors include but are not limited to
Crizotinib, Alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A,
AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and
AP26113.
[0384] In one embodiment, the bioactive agent is an EGFR inhibitor.
Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib
(Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib
(Tagrisso), olmutinib (Olita), naquotinib (ASP8273), nazartinib
(EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib
(HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000;
PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647;
KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib
(PF-00299804; Pfizer).
[0385] In one embodiment, the bioactive agent is an HER-2
inhibitor. Examples of HER-2 inhibitors include trastuzumab,
lapatinib, ado-trastuzumab emtansine, and pertuzumab.
[0386] In one embodiment, the bioactive agent is a CD20 inhibitor.
Examples of CD20 inhibitors include obinutuzumab, rituximab,
fatumumab, ibritumomab, tositumomab, and ocrelizumab.
[0387] In one embodiment, the bioactive agent is a JAK3 inhibitor.
Examples of JAK3 inhibitors include tasocitinib.
[0388] In one embodiment, the bioactive agent is a BCL-2 inhibitor.
Examples of BCL-2 inhibitors include venetoclax, ABT-199
(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazi-
n-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulf-
onyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737
(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(di-
methylamino)-1-phenylsulfanylbutan-2-yl]
amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263
((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-y-
l)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)ami-
no)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),
GX15-070 (obatoclaxmesylate,
(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-
-2-ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3,
YC137
(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl
ester), pogosin, ethyl
2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate-
, Nilotinib-d3, TW-37
(N-[4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[-
[2-(1-methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2),
HA14-1, AT101, sabutoclax, gambogic acid, or G3139
(Oblimersen).
[0389] In one aspect, a treatment regimen is provided comprising
the administration of a compound of Formula I, Formula II, Formula
III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,
Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV in combination with at least one
additional chemotherapeutic agent. The combinations disclosed
herein can be administered for beneficial, additive, or synergistic
effect in the treatment of abnormal cellular proliferative
disorders.
[0390] In specific embodiments, the treatment regimen includes the
administration of a compound of Formula I, Formula II, Formula III
Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,
Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV in combination with at least one
kinase inhibitor. In one embodiment, the at least one kinase
inhibitor is selected from a phosphoinositide 3-kinase (PI3K)
inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen
tyrosine kinase (Syk) inhibitor, or a combination thereof.
[0391] PI3k inhibitors that may be used in the present invention
are well known. Examples of PI3 kinase inhibitors include but are
not limited to Wortmannin, demethoxyviridin, perifosine,
idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907,
and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib),
(2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-
-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide),
MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate;
or Methyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)),
BYL-719
((2S)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]--
2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458
(2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyrid-
inyl}benzenesulfonamide) (omipalisib), TGX-221
((.+-.)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]--
pyrimidin-4-one), GSK2636771
(2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]-
imidazole-4-carboxylic acid dihydrochloride), KIN-193
((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)et-
hyl)amino)benzoic acid), TGR-1202/RP5264, GS-9820
((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one),
GS-1101
(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quin-
azolin-4-one), AMG-319, GSK-2269557, SAR245409
(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-
-3-methoxy-4 methylbenzamide), BAY80-6946
(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]qu-
inaz), AS 252424
(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazo-
lidine-2,4-dione), CZ 24832
(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyri-
dine-3-sulfonamide), Buparlisib
(5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinami-
ne), GDC-0941
(2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-mo-
rpholinyl)thieno[3,2-d]pyrimidine), GDC-0980
((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]p-
yrimidin-6 yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also
known as RG7422)), SF1126
((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-
-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-iu-
m)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate), PF-05212384
(N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4--
morpholinyl-1,3,5-triazin-2-yl)phenyl]urea)(gedatolisib),
LY3023414, BEZ235
(2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-im-
idazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile) (dactolisib),
XL-765
(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-
-methoxy-4-methylbenzamide), and GSK1059615
(5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione),
PX886
([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-
-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hex-
ahydroindeno[4,5h]isochromen-10-yl] acetate (also known as
sonolisib)) LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317,
PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343),
CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93,
AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib,
IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946),
XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine),
AS-252424, AS-604850, apitolisib (GDC-0980; RG7422), and the
structure described in WO2014/071109.
[0392] In one embodiment, the compound of Formula I, Formula II,
Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula
VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV is combined in a single dosage form
with the PIk3 inhibitor.
[0393] BTK inhibitors for use in the present invention are well
known. Examples of BTK inhibitors include ibrutinib (also known as
PCI-32765)(Imbruvica.TM.)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo-
[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one),
dianilinopyrimidine-based inhibitors such as AVL-101 and
AVL-291/292
(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino-
)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication
No 2011/0117073, incorporated herein in its entirety), Dasatinib
([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-m-
ethylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13
(alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl)
propenamide), GDC-0834
([R--N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-
-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrob-
enzo[b]thiophene-2-carboxamide], CGI-560
4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)ben-
zamide, CGI-1746
(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phen-
yl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774
(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenox-
y)-N-methylpicolinamide), CTA056
(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imid-
azo[4,5-g]quinoxalin-6(5H)-one), GDC-0834
((R)--N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methy-
l-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b-
]thiophene-2-carboxamide), GDC-0837
((R)--N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methy-
l-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b-
]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono
Pharmaceuticals), PRT062607
(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl-
)amino)pyrimidine-5-carboxamide hydrochloride), QL-47
(1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naph-
thyridin-2(1H)-one), and RN486
(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-pip-
erazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-
-isoquinolin-1-one), and other molecules capable of inhibiting BTK
activity, for example those BTK inhibitors disclosed in Akinleye et
ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety
of which is incorporated herein by reference. In one embodiment,
the compound of Formula I, Formula II, Formula III Formula IV,
Formula V, Formula VI, Formula VII, Formula VIII, Formula IX,
Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV,
Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,
Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV,
or Formula XXV is combined in a single dosage form with the BTK
inhibitor.
[0394] Syk inhibitors for use in the present invention are well
known, and include, for example, Cerdulatinib
(4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino-
)pyrimidine-5-carboxamide), entospletinib
(6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine)-
, fostamatinib
([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-
-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl
dihydrogen phosphate), fostamatinib disodium salt (sodium
(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2--
dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl
phosphate), BAY 61-3606
(2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-ni-
cotinamide HCl), RO9021
(6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-p-
yridazine-3-carboxylic acid amide), imatinib (Gleevac;
4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimi-
din-2-yl]amino}phenyl)benzamide), staurosporine, GSK143
(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrim-
idine-5-carboxamide), PP2
(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine),
PRT-060318
(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carbox-
amide), PRT-062607
(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl-
)amino)pyrimidine-5-carboxamide hydrochloride), R112
(3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348
(3-Ethyl-4-methylpyridine), R406
(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2--
dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol
(3-Hydroxyresveratol), YM193306 (see Singh et al. Discovery and
Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.
Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see
Singh et al. Discovery and Development of Spleen Tyrosine Kinase
(SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in
its entirety herein), Compound D (see Singh et al. Discovery and
Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.
Chem. 2012, 55, 3614-3643 incorporated in its entirety herein),
PRT060318 (see Singh et al. Discovery and Development of Spleen
Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643
incorporated in its entirety herein), luteolin (see Singh et al.
Discovery and Development of Spleen Tyrosine Kinase (SYK)
Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its
entirety herein), apigenin (see Singh et al. Discovery and
Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.
Chem. 2012, 55, 3614-3643 incorporated in its entirety herein),
quercetin (see Singh et al. Discovery and Development of Spleen
Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643
incorporated in its entirety herein), fisetin (see Singh et al.
Discovery and Development of Spleen Tyrosine Kinase (SYK)
Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its
entirety herein), myricetin (see Singh et al. Discovery and
Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.
Chem. 2012, 55, 3614-3643 incorporated in its entirety herein),
morin (see Singh et al. Discovery and Development of Spleen
Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643
incorporated in its entirety herein). In one embodiment, the
compound of Formula I, Formula II, Formula III Formula IV, Formula
V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X,
Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV,
Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX,
Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula
XXV is combined in a single dosage form with the Syk inhibitor.
[0395] In one embodiment, the at least one additional
chemotherapeutic agent is a protein cell death-1 (PD-1) inhibitor.
PD-1 inhibitors are known in the art, and include, for example,
nivolumab (BMS), pembrolizumab (Merck), pidilizumab
(CureTech/Teva), AMP-244 (Amplimmune/GSK), BMS-936559 (BMS), and
MEDI4736 (Roche/Genentech). In one embodiment, the compound of
Formula I, Formula II, Formula III Formula IV, Formula V, Formula
VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,
Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI,
Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI,
Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV is
combined in a single dosage form with the PD-1 inhibitor.
[0396] In one embodiment, the at least one additional
chemotherapeutic agent is a B-cell lymphoma 2 (Bcl-2) protein
inhibitor. BCL-2 inhibitors are known in the art, and include, for
example, ABT-199
(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazi-
n-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulf-
onyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737
(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(di-
methylamino)-1-phenylsulfanylbutan-2-yl]
amino]-3-nitrophenyl]sulfonylbenzamide), ABT-263
((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-y-
l)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)ami-
no)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),
GX15-070 (obatoclaxmesylate,
(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-
-2-ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3,
YC137
(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl
ester), pogosin, ethyl
2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate-
, Nilotinib-d3, TW-37
(N-[4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[-
[2-(1-methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2),
or G3139 (Oblimersen). In one embodiment, the compound of Formula
I, Formula II, Formula III Formula IV, Formula V, Formula VI,
Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,
Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI,
Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI,
Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV is
combined in a single dosage form with the at least one BCL-2
inhibitor.
[0397] In one embodiment, a combination described herein can be
further combined with an additional therapeutic to treat the
cancer. The second therapy can be an immunotherapy. As discussed in
more detail below, the compound of Formula I, Formula II, Formula
III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,
Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV can be conjugated to an antibody,
radioactive agent, or other targeting agent that directs the
compound to the diseased or abnormally proliferating cell. In
another embodiment, the combination is used in combination with
another pharmaceutical or a biologic agent (for example an
antibody) to increase the efficacy of treatment with a combined or
a synergistic approach. In an embodiment, combination can be used
with T-cell vaccination, which typically involves immunization with
inactivated autoreactive T cells to eliminate a cancer cell
population as described herein. In another embodiment, the
combination is used in combination with a bispecific T-cell Engager
(BiTE), which is an antibody designed to simultaneously bind to
specific antigens on endogenous T cells and cancer cells as
described herein, linking the two types of cells.
[0398] In one embodiment, the bioactive agent is a MEK inhibitor.
MEK inhibitors are well known, and include, for example,
trametinib/GSK1120212
(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7--
trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-(2H-yl}phenyl)acetamide),
selumetinib
(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimi-
dazole-5-carboxamide), pimasertib/AS703026/MSC 1935369
((S)--N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotina-
mide), XL-518/GDC-0973
(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S-
)-piperidin-2-yl]azetidin-3-ol), refametinib/BAY869766/RDEA1 19
(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-d-
ihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901
(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)ami-
no]-benzamide), TAK733
((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-me-
thylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162
(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl--
1H-benzimidazole-6-carboxamide), R05126766
(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrim-
idin-2-yloxychromen-2-one), WX-554, R04987655/CH4987655
(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3--
oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330
(2-((2-fluoro-4-iodophenyl)amino)-N-(2
hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide),
U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib,
PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733,
PD318088.
[0399] In one embodiment, the bioactive agent is a Raf inhibitor.
Raf inhibitors are known and include, for example, Vemurafinib
(N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-di-
fluorophenyl]-1-propanesulfonamide), sorafenib tosylate
(4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-meth-
ylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628
(3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazol-
in-6-ylamino)phenyl)benzamide), NVP-BHG712
(4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylam-
ino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265
(1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[-
4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoaldisine
(2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf
Kinase Inhibitor IV
(2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol),
Sorafenib N-Oxide
(4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-
-N-Methyl-2pyridinecarboxaMide 1-Oxide), PLX-4720, dabrafenib
(GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074,
TAK-632, CEP-32496, LY3009120, and GX818 (Encorafenib).
[0400] In one embodiment, the additional therapy is a monoclonal
antibody (MAb). Some MAbs stimulate an immune response that
destroys cancer cells. Similar to the antibodies produced naturally
by B cells, these MAbs "coat" the cancer cell surface, triggering
its destruction by the immune system. For example, bevacizumab
targets vascular endothelial growth factor (VEGF), a protein
secreted by tumor cells and other cells in the tumor's
microenvironment that promotes the development of tumor blood
vessels. When bound to bevacizumab, VEGF cannot interact with its
cellular receptor, preventing the signaling that leads to the
growth of new blood vessels. Similarly, cetuximab and panitumumab
target the epidermal growth factor receptor (EGFR), and trastuzumab
targets the human epidermal growth factor receptor 2 (HER-2). MAbs
that bind to cell surface growth factor receptors prevent the
targeted receptors from sending their normal growth-promoting
signals. They may also trigger apoptosis and activate the immune
system to destroy tumor cells.
[0401] Another group of cancer therapeutic MAbs are the
immunoconjugates. These MAbs, which are sometimes called
immunotoxins or antibody-drug conjugates, consist of an antibody
attached to a cell-killing substance, such as a plant or bacterial
toxin, a chemotherapy drug, or a radioactive molecule. The antibody
latches onto its specific antigen on the surface of a cancer cell,
and the cell-killing substance is taken up by the cell.
FDA-approved conjugated MAbs that work this way include
ado-trastuzumab emtansine, which targets the HER-2 molecule to
deliver the drug DM1, which inhibits cell proliferation, to HER-2
expressing metastatic breast cancer cells.
[0402] Immunotherapies with T cells engineered to recognize cancer
cells via bispecific antibodies (bsAbs) or chimeric antigen
receptors (CARs) are approaches with potential to ablate both
dividing and non/slow-dividing subpopulations of cancer cells.
[0403] Bispecific antibodies, by simultaneously recognizing target
antigen and an activating receptor on the surface of an immune
effector cell, offer an opportunity to redirect immune effector
cells to kill cancer cells. The other approach is the generation of
chimeric antigen receptors by fusing extracellular antibodies to
intracellular signaling domains. Chimeric antigen
receptor-engineered T cells are able to specifically kill tumor
cells in a MHC-independent way.
[0404] In some embodiments, the combination can be administered to
the subject in further combination with other chemotherapeutic
agents. If convenient, the combination described herein can be
administered at the same time as another chemotherapeutic agent, in
order to simplify the treatment regimen. In some embodiments, the
combination and the other chemotherapeutic can be provided in a
single formulation. In one embodiment, the use of the compounds
described herein is combined in a therapeutic regime with other
agents. Such agents may include, but are not limited to, tamoxifen,
midazolam, letrozole, bortezomib, anastrozole, goserelin, an mTOR
inhibitor, a PI3 kinase inhibitors, dual mTOR-PI3K inhibitors, MEK
inhibitors, RAS inhibitors, ALK inhibitors, HSP inhibitors (for
example, HSP70 and HSP 90 inhibitors, or a combination thereof),
BCL-2 inhibitors, apopototic inducing compounds, AKT inhibitors,
including but not limited to, MK-2206, GSK690693, Perifosine,
(KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502,
and Miltefosine, PD-1 inhibitors including but not limited to,
Nivolumab, CT-011, MK-3475, BMS936558, and AMP-514 or FLT-3
inhibitors, including but not limited to, P406, Dovitinib,
Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518),
ENMD-2076, and KW-2449, or combinations thereof.
[0405] In one embodiment, the bioactive agent is an mTOR inhibitor.
Examples of mTOR inhibitors include but are not limited to
rapamycin and its analogs, everolimus (Afinitor), temsirolimus,
ridaforolimus, sirolimus, and deforolimus. Examples of MEK
inhibitors include but are not limited to tametinib/GSK1120212
(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7--
trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-(2H-yl}phenyl)acetamide),
selumetinob
(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimi-
dazole-5-carboxamide), pimasertib/AS703026/MSC1935369
((S)--N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotina-
mide), XL-518/GDC-0973
(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S-
)-piperidin-2-yl]azetidin-3-ol), refametinib/BAY869766/RDEA119
(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-d-
ihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901
(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)ami-
no]-benzamide), TAK733
((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-me-
thylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162
(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl--
1H-benzimidazole-6 carboxamide), R05126766
(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrim-
idin-2-yloxychromen-2-one), WX-554, R04987655/CH4987655
(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3--
oxo-1,2-oxazinan-2 yl)methyl)benzamide), or AZD8330
(2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo--
1,6-dihydropyridine-3-carboxamide).
[0406] In one embodiment, the bioactive agent is a RAS inhibitor.
Examples of RAS inhibitors include but are not limited to Reolysin
and siG12D LODER.
[0407] In one embodiment, the bioactive agent is an ALK inhibitor.
Examples of ALK inhibitors include but are not limited to
Crizotinib, AP26113, and LDK378.
[0408] In one embodiment, the bioactive agent is a HSP inhibitor.
HSP inhibitors include but are not limited to Geldanamycin or
17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol. In
a particular embodiment, a compound described herein is
administered in combination with letrozole and/or tamoxifen. Other
chemotherapeutic agents that can be used in combination with the
compounds described herein include, but are not limited to,
chemotherapeutic agents that do not require cell cycle activity for
their anti-neoplastic effect.
[0409] Additional bioactive compounds include, for example,
everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101,
pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886),
AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib,
ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, aFLT-3
inhibitor, a VEGFRinhibitor, an aurora kinase inhibitor, a PIK-1
modulator, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor,
a Cdk inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a
focal adhesion kinase inhibitor, a Map kinase (mek) inhibitor, a
VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab,
Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab,
edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen,
ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110,
BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001,
IPdR.sub.1KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta
744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin,
ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide,
gemcitabine, doxorubicin, liposomal doxorubicin,
5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,
seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-
benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled
irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane,
letrozole, DES (diethylstilbestrol), estradiol, estrogen,
conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258);
3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,
AG-013736, AVE-0005, goserelin acetate, leuprolide acetate,
triptorelin pamoate, medroxyprogesterone acetate,
hydroxyprogesterone caproate, megestrol acetate, raloxifene,
bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714;
TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF
antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib,
BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide
hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,
sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,
L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,
bleomycin, buserelin, busulfan, carboplatin, carmustine,
chlorambucil, cisplatin, cladribine, clodronate, cyproterone,
cytarabine, dacarbazine, dactinomycin, daunorubicin,
diethylstilbestrol, epirubicin, fludarabine, fludrocortisone,
fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea,
idarubicin, ifosfamide, imatinib, leuprolide, levamisole,
lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,
methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide,
octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin,
porfimer, procarbazine, raltitrexed, rituximab, streptozocin,
teniposide, testosterone, thalidomide, thioguanine, thiotepa,
tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard,
uracil mustard, estramustine, altretamine, floxuridine,
5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine,
deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine,
vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat,
BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974,
interleukin-12, IM862, angiostatin, vitaxin, droloxifene,
idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,
denileukin diftitox, gefitinib, bortezimib, paclitaxel,
cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550,
BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene,
ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene,
idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK
222584, VX-745, PD 184352, rapamycin,
40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,
ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,
wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,
erythropoietin, granulocyte colony-stimulating factor,
zolendronate, prednisone, cetuximab, granulocyte macrophage
colony-stimulating factor, histrelin, pegylated interferon alfa-2a,
interferon alfa-2a, pegylated interferon alfa-2b, interferon
alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab,
hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab,
all-transretinoic acid, ketoconazole, interleukin-2, megestrol,
immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab
tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene,
tositumomab, arsenic trioxide, cortisone, editronate, mitotane,
cyclosporine, liposomal daunorubicin, Edwina-asparaginase,
strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,
palonosetron, aprepitant, diphenhydramine, hydroxyzine,
metoclopramide, lorazepam, alprazolam, haloperidol, droperidol,
dronabinol, dexamethasone, methylprednisolone, prochlorperazine,
granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim,
erythropoietin, epoetin alfa, darbepoetin alfa and mixtures
thereof.
[0410] In one embodiment, a compound of Formula I, Formula II,
Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula
VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV described herein can be combined with
a chemotherapeutic selected from, but are not limited to, Imatinib
mesylate (Gleevac.RTM.), Dasatinib (Sprycel.RTM.), Nilotinib
(Tasigna.RTM.), Bosutinib (Bosulif.RTM.), Trastuzumab
(Herceptin.RTM.), Pertuzumab (Perjeta.TM.), Lapatinib
(Tykerb.RTM.), Gefitinib (Iressa.RTM.), Erlotinib (Tarceva.RTM.),
Cetuximab (Erbitux.RTM.), Panitumumab (Vectibix.RTM.), Vandetanib
(Caprelsa.RTM.), Vemurafenib (Zelboraf.RTM.), Vorinostat
(Zolinza.RTM.), Romidepsin (Istodax.RTM.), Bexarotene
(Tagretin.RTM.), Alitretinoin (Panretin.RTM.), Tretinoin
(Vesanoid.RTM.), Carfilizomib (Kyprolis.TM.), Pralatrexate
(Folotyn.RTM.), Bevacizumab (Avastin.RTM.), Ziv-aflibercept
(Zaltrap.RTM.), Sorafenib (Nexavar.RTM.), Sunitinib (Sutent.RTM.),
Pazopanib (Votrient.RTM.), Regorafenib (Stivarga.RTM.), and
Cabozantinib (Cometriq.TM.).
[0411] In certain aspects, the additional therapeutic agent is an
anti-inflammatory agent, a chemotherapeutic agent, a
radiotherapeutic, additional therapeutic agents, or
immunosuppressive agents.
[0412] Suitable chemotherapeutic agents include, but are not
limited to, radioactive molecules, toxins, also referred to as
cytotoxins or cytotoxic agents, which includes any agent that is
detrimental to the viability of cells, agents, and liposomes or
other vesicles containing chemotherapeutic compounds. General
anticancer pharmaceutical agents include: Vincristine
(Oncovin.RTM.) or liposomal vincristine (Marqibo.RTM.),
Daunorubicin (daunomycin or Cerubidine.RTM.) or doxorubicin
(Adriamycin.RTM.), Cytarabine (cytosine arabinoside, ara-C, or
Cytosar.RTM.), L-asparaginase (Elspar.RTM.) or PEG-L-asparaginase
(pegaspargase or Oncaspar.RTM.), Etoposide (VP-16), Teniposide
(Vumon.RTM.), 6-mercaptopurine (6-MP or Purinethol.RTM.),
Methotrexate, Cyclophosphamide (Cytoxan.RTM.), Prednisone,
Dexamethasone (Decadron), imatinib (Gleevec.RTM.), dasatinib
(Sprycel.RTM.), nilotinib (Tasigna.RTM.), bosutinib (Bosulif.RTM.),
and ponatinib (Iclusig.TM.) Examples of additional suitable
chemotherapeutic agents include but are not limited to
1-dehydrotestosterone, 5-fluorouracil decarbazine,
6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin,
aldesleukin, alkylating agents, allopurinol sodium, altretamine,
amifostine, anastrozole, anthramycin (AMC)), anti-mitotic agents,
cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino
dichloro platinum, anthracycline, an antibiotic, an antimetabolite,
asparaginase, BCG live (intravesical), betamethasone sodium
phosphate and betamethasone acetate, bicalutamide, bleomycin
sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine,
carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil,
Cisplatin, Cladribine, Colchicin, conjugated estrogens,
Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine,
cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin
(formerly actinomycin), daunirubicin HCL, daunorucbicin citrate,
denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy
anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCL,
dronabinol, E. coli L-asparaginase, emetine, epoetin-.alpha.,
Erwinia L-asparaginase, esterified estrogens, estradiol,
estramustine phosphate sodium, ethidium bromide, ethinyl estradiol,
etidronate, etoposide citrororum factor, etoposide phosphate,
filgrastim, floxuridine, fluconazole, fludarabine phosphate,
fluorouracil, flutamide, folinic acid, gemcitabine HCL,
glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL,
hydroxyurea, idarubicin HCL, ifosfamide, interferon .alpha.-2b,
irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate,
levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine
HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL,
mercaptipurine, mesna, methotrexate, methyltestosterone,
mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide,
octreotide acetate, ondansetron HCL, paclitaxel, pamidronate
disodium, pentostatin, pilocarpine HCL, plimycin, polifeprosan 20
with carmustine implant, porfimer sodium, procaine, procarbazine
HCL, propranolol, rituximab, sargramostim, streptozotocin,
tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine,
thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL,
toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine
sulfate, vincristine sulfate, and vinorelbine tartrate.
[0413] Additional therapeutic agents that can be administered in
combination with a compound disclosed herein can include
bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2,
finasunate, vatalanib, vandetanib, aflibercept, volociximab,
etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab,
panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab,
atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab,
tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab,
HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib,
marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir
mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab,
lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin,
talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib,
dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib,
bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin),
PD0332991, ribociclib (LEE011), amebaciclib (LY2835219), HDM201,
fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib
(INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab
(IMC-1121B).
[0414] In one aspect of the present invention, a compound described
herein can be combined with at least one immunosuppressive agent.
The immunosuppressive agent is preferably selected from the group
consisting of a calcineurin inhibitor, e.g. a cyclosporin or an
ascomycin, e.g. Cyclosporin A (NEORAL.RTM.), FK506 (tacrolimus),
pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative
thereof, e.g. Sirolimus (RAPAMUNE.RTM.), Everolimus
(Certican.RTM.), temsirolimus, zotarolimus, biolimus-7, biolimus-9,
a rapalog, e.g., ridaforolimus, azathioprine, campath 1H, a SiP
receptor modulator, e.g. fingolimod or an analogue thereof, an
antiIL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium
salt, or a prodrug thereof, e.g. Mycophenolate Mofetil
(CELLCEPT.RTM.), OKT3 (ORTHOCLONE OKT3@), Prednisone, ATGAM.RTM.,
THYMOGLOBULIN, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,
15-deoxyspergualin, tresperimus, Leflunomide ARAVA.RTM., CTLAI-Ig,
anti-CD25, anti-IL2R, Basiliximab (SIMULECT), Daclizumab
(ZENAPAX.RTM.), mizorbine, methotrexate, dexamethasone, ISAtx-247,
SDZ ASM 981 (pimecrolimus, Elidel.RTM.), CTLA4lg (Abatacept),
belatacept, LFA3lg, etanercept (sold as Enbrel.RTM. by Immunex),
adalimumab (Humira.RTM.), infliximab (Remicade.RTM.), an anti-LFA-1
antibody, natalizumab (Antegren.RTM.), Enlimomab, gavilimomab,
antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab,
pentasa, mesalazine, asacol, codeine phosphate, benorylate,
fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin
and ibuprofen.
[0415] In certain embodiments, a compound described herein is
administered to the subject prior to treatment with another
chemotherapeutic agent, during treatment with another
chemotherapeutic agent, after administration of another
chemotherapeutic agent, or a combination thereof.
[0416] In some embodiments, the compound of Formula I, Formula II,
Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula
VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV can be administered to the subject
such that the other chemotherapeutic agent can be administered
either at higher doses (increased chemotherapeutic dose intensity)
or more frequently (increased chemotherapeutic dose density).
Dose-dense chemotherapy is a chemotherapy treatment plan in which
drugs are given with less time between treatments than in a
standard chemotherapy treatment plan. Chemotherapy dose intensity
represents unit dose of chemotherapy administered per unit time.
Dose intensity can be increased or decreased through altering dose
administered, time interval of administration, or both.
[0417] In one embodiment of the invention, the compounds described
herein can be administered in a concerted regimen with another
agent such as a non-DNA-damaging, targeted anti-neoplastic agent or
a hematopoietic growth factor agent. It has been recently reported
that the untimely administration of hematopoietic growth factors
can have serious side effects. For example, the use of the EPO
family of growth factors has been associated with arterial
hypertension, cerebral convulsions, hypertensive encephalopathy,
thromboembolism, iron deficiency, influenza like syndromes and
venous thrombosis. The G-CSF family of growth factors has been
associated with spleen enlargement and rupture, respiratory
distress syndrome, allergic reactions and sickle cell
complications. As such, in one embodiment, the use of the compounds
or methods described herein is combined with the use of
hematopoietic growth factors including, but not limited to,
granulocyte colony stimulating factor (G-CSF, for example, sold as
Neupogen (filgrastin), Neulasta (peg-filgrastin), or lenograstin),
granulocyte-macrophage colony stimulating factor (GM-CSF, for
example sold as molgramostim and sargramostim (Leukine)), M-CSF
(macrophage colony stimulating factor), thrombopoietin
(megakaryocyte growth development factor (MGDF), for example sold
as Romiplostim and Eltrombopag) interleukin (IL)-12, interleukin-3,
interleukin-11 (adipogenesis inhibiting factor or oprelvekin), SCF
(stem cell factor, steel factor, kit-ligand, or KL) and
erythropoietin (EPO), and their derivatives (sold as for example
epoetin-.alpha. as Darbopoetin, Epocept, Nanokine, Epofit, Epogin,
Eprex and Procrit; epoetin-.beta. sold as for example NeoRecormon,
Recormon and Micera), epoetin-delta (sold as for example Dynepo),
epoetin-omega (sold as for example Epomax), epoetin zeta (sold as
for example Silapo and Reacrit) as well as for example Epocept,
EPOTrust, Erypro Safe, Repoeitin, Vintor, Epofit, Erykine, Wepox,
Espogen, Relipoeitin, Shanpoietin, Zyrop and EPIAO). In one
embodiment, the compound of Formula I, Formula II, Formula III
Formula IV, Formula V, Formula VI, Formula VII, Formula VIII,
Formula IX, Formula X, Formula XI, Formula XII, Formula XIII,
Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV is administered prior to
administration of the hematopoietic growth factor. In one
embodiment, the hematopoietic growth factor administration is timed
so that the compound's effect on HSPCs has dissipated. In one
embodiment, the growth factor is administered at least 20 hours
after the administration of a compound described herein.
[0418] If desired, multiple doses of a compound described herein
can be administered to the subject. Alternatively, the subject can
be given a single dose of a compound described herein.
[0419] In one aspect of the invention, a compound disclosed herein
can be beneficially administered in combination with any
therapeutic regimen entailing radiotherapy, chemotherapy, or other
therapeutic agents. In additional embodiments the compounds
disclosed herein can be beneficially administered in combination
with therapeutic agents targeting auto-immune disorders.
VIII. Synthesis
[0420] The compounds described herein can be prepared by methods
known by those skilled in the art. In one non-limiting example the
disclosed compounds can be made by the following schemes.
[0421] The disclosed compounds can be made by the following general
schemes:
##STR00151## ##STR00152##
[0422] As demonstrated in Scheme 1A, compounds that adhere to
Formula 1 can be prepared from readily available purines. In Step
1, an appropriately substituted purine A-1 can be reacted with an
appropriate substituted olefin at elevated temperature in the
presence of an organometallic catalyst in organic solvent to
furnish A-2. LG.sub.1 and LG.sub.2 are leaving groups known by
those skilled in the art. In one embodiment, LG.sub.1 and LG.sub.2
are chloro. PG.sub.1 is a protecting group known by those skilled
in the art. In one embodiment, PG.sub.1 is TBDMS. In one
embodiment, the solvent is toluene. In one embodiment, the catalyst
is Au(I) salt bound to appropriate ligands. In one embodiment, the
temperature is greater than 80.degree. C. The olefin shown in
Scheme 1 is a non-limiting example and other olefins may be used by
those skilled in the art to generate derivatives of structure A-2.
In Step 2, LG.sub.2 is replaced by another leaving group LG.sub.3
to yield A-3. In one embodiment, LG.sub.3 is amino, --NH.sub.2. In
Step 3, LG.sub.3 is removed by methods known to those skilled in
the art to generate structure A-4. In a limiting example, LG.sub.3
is replaced by hydrogen. In Step 4, structure A-4 is coupled with
an appropriately substituted amine at elevated temperature in the
presence of base and an organometallic catalyst in organic solvent.
In one embodiment, the amine is pyridin-2-amine. In one embodiment,
the base is potassium t-butoxide. In one embodiment, the catalyst
is Pd(OAc).sub.2 attached to a
[1,1'-biphenyl]-2-yldi-tert-butylphosphane ligand. In one
embodiment, the temperature is greater than 60.degree. C. In one
embodiment, the solvent is toluene. Structure A-5 is then protected
with a protecting group known to those in the art. In one
embodiment, PG.sub.2 is trityl. Structure A-6 is then transformed
to structure A-7 in Step 6 according to methods known in the art.
In one embodiment, LG.sub.1 is phenyl. In Step 7, PG.sub.1 is
removed by methods known in the art to afford A-8. Alcohol A-8 is
then converted to a leaving group, LG.sub.2 in Step 8 to afford
compound A-9. In one embodiment, LG.sub.2 is bromo. In Step 9,
LG.sub.2 is displaced to form A-10 which is a compound of Formula
I.
##STR00153##
[0423] As demonstrated in Scheme 1, compounds that adhere to
Formula II can be prepared from readily available starting
materials such as B-1. In Step 1, B-1 is protected with protecting
group PG.sub.1 known by those skilled in the art to furnish B-2. In
one embodiment, PG.sub.1 is TBDMS. In Step 2, B-2 is reacted with
an appropriately substituted epoxide in the presence of a Lewis
acid to generate B-3. In one embodiment, the Lewis acid is boron
trifluoride etherate. The epoxide shown in Scheme 2 is a
non-limiting example and other epoxides may be used by those
skilled in the art to access derivatives of B-3. In Step 3, alcohol
B-3 is protected with protecting group PG.sub.2 to furnish B-4. In
one embodiment, PG.sub.2 is TBDMS. B-4 is then converted to
structure B-5 by methods known in the art. LG is a leaving group
known by those in the art. In one embodiment, LG is phenyl. In Step
6, PG.sub.2 is removed according to methods known in the art to
yield B-7. In Step 7, B-7 is cyclized by methods known in the art
to generate lactam B-8. In Step 8, sulfide B-8 is oxidized to
afford B-9. Sulfone B-9 is then displaced by an appropriately
substituted amine to produce compound B-10 which is a compound of
Formula II.
##STR00154##
[0424] As demonstrated in Scheme IC, compounds that adhere to
Formula III can be prepared from readily available pyrimidines. In
Step 1, an appropriately substituted pyrimidine C-1 is protected
with a protecting group, PG.sub.1, known to those skilled in the
art to furnish C-2. In one embodiment, PG.sub.1 is trityl. LG.sub.1
is a leaving group known by those skilled in the art. In one
embodiment, LG.sub.1 is chloro. In Step 2, C-2 is coupled with an
appropriately substituted amine at elevated temperature in the
presence of base and an organometallic catalyst in organic solvent
to yield structure C-3. In one embodiment, the amine is
pyridin-2-amine. In one embodiment, the base is potassium
t-butoxide. In one embodiment, the catalyst is Pd(OAc).sub.2
attached to a [1,1'-biphenyl]-2-yldi-tert-butylphosphane ligand. In
one embodiment, the temperature is greater than 60.degree. C. In
one embodiment, the solvent is toluene. In Step 3, structure C-3 is
protected with protecting group PG.sub.2 known to those skilled in
the art to generate structure C-4. In one embodiment, PG.sub.2 is
trityl. In Step 4, C-4 can be reacted with an appropriate
substituted epoxide in the presence of a Lewis acid to produce
structure C-5. In one embodiment, the Lewis acid is trifluoroboron
etherate. The epoxide shown in Scheme 3 is a non-limiting example
and other epoxides may be used by those skilled in the art to
generate derivatives of structure C-5. In Step 6, alcohol C-5 is
protected with protecting group PG.sub.3 known to those skilled in
the art to generate C-6. In one embodiment, PG.sub.3 is TBDMS. In
Step 6, C-6 is transformed to structure C-7 according to methods
known in the art where LG.sub.2 is a leaving group. In one
embodiment, LG.sub.2 is phenyl. In Step 7, C-7 is cyclized to
afford lactam C-8 according to methods known in the art. In Step 8,
PG.sub.1 and PG.sub.2are removed to furnish compound C-9 which is a
compound of Formula III.
##STR00155##
[0425] As demonstrated in Scheme 1D, compounds that adhere to
Formula III can be prepared from readily available pyrimidines.
LG.sub.1 and LG.sub.2 are leaving groups known by those skilled in
the art. In one embodiment, LG.sub.1 and LG.sub.2 are chloro. In
Step 1, LG.sub.2 is removed according to methods known in the art
to furnish structure D-2. In Step 2, D-2 is coupled with an
appropriately substituted amine at elevated temperature in the
presence of base and an organometallic catalyst in organic solvent
to yield structure D-3. In one embodiment, the amine is
pyridin-2-amine. In one embodiment, the base is potassium
t-butoxide. In one embodiment, the catalyst is Pd(OAc).sub.2
attached to a [1,1'-biphenyl]-2-yldi-tert-butylphosphane ligand. In
one embodiment, the temperature is greater than 60.degree. C. In
one embodiment, the solvent is toluene. In Step 3, structure D-3 is
protected with protecting group PG.sub.1 known by those skilled in
the art. In one embodiment, PG.sub.1 is trityl. In Step 4,
pyrimidine D-4 is reacted with an appropriately substituted epoxide
in the presence of a Lewis acid to produce structure D-5. In one
embodiment, the Lewis acid is trifluoroboron etherate. The epoxide
shown in Scheme 3 is a non-limiting example and other epoxides may
be used by those skilled in the art to generate derivatives of
structure D-5. In Step 5, alcohol D-5 is protected with protecting
group PG.sub.2 known to those skilled in the art to generate D-6.
In one embodiment, PG.sub.2 is TBDMS. In Step 6, D-6 is transformed
to structure D-7 according to methods known in the art where
LG.sub.3 is a leaving group. In one embodiment, LG.sub.3 is phenyl.
In Step 7, ester D-7 is converted to amido species and the PG.sub.2
is subsequently removed to furnish the free alcohol which is then
converted to leaving group LG.sub.4 by methods known in the art to
produce structure D-8. In one embodiment, LG.sub.4 is bromo. In
Step 9, D-8 is cyclized by methods known in the art to afford
lactam D-9 which is a compound of Formula III.
##STR00156##
[0426] As demonstrated in Scheme 1E, compounds that adhere to
Formula III can be prepared from readily available pyrimidines. In
structure E-1, LG.sub.1 is a leaving group known by those skilled
in the art. In one embodiment, LG.sub.1 is chloro. In Step 1, E-1
is coupled with an appropriately substituted amine at elevated
temperature in the presence of base and an organometallic catalyst
in organic solvent to yield structure E-2. In one embodiment, the
amine is pyridin-2-amine. In one embodiment, the base is potassium
t-butoxide. In one embodiment, the catalyst is Pd(OAc).sub.2
attached to a [1,1'-biphenyl]-2-yldi-tert-butylphosphane ligand. In
one embodiment, the temperature is greater than 60.degree. C. In
one embodiment, the solvent is toluene. In Step 2, E-2 is protected
with a protecting group, PG.sub.1, known to those skilled in the
art to furnish E-3. In one embodiment, PG.sub.1 is trityl. In Step
3, E-3 can be reacted with an appropriately substituted epoxide in
the presence of a Lewis acid to produce structure E-4. In one
embodiment, the Lewis acid is trifluoroboron etherate. The epoxide
shown in Scheme 5 is a non-limiting example and other epoxides may
be used by those skilled in the art to generate derivatives of
structure E-4. In Step 4, alcohol E-4 is protected with protecting
group PG.sub.2 known to those skilled in the art to generate E-5.
In one embodiment, PG.sub.2 is TBDMS. In Step 5, E-5 is transformed
to structure E-6 according to methods known in the art where
LG.sub.1 is a leaving group. In one embodiment, LG.sub.1 is phenyl.
In step 6, ester E-6 is transformed to an amido species and
PG.sub.2 is removed to yield E-7. In Step 7, the alcohol is
converted to leaving group LG.sub.2 known by those skilled in the
art. In one embodiment, LG.sub.2 is bromo. In Step 8, E-8 is
cyclized to afford lactam E-9 which is a compound of Formula
III.
##STR00157##
[0427] As demonstrated in Scheme 1F, compounds of Formula IV can be
prepared from readily available starting materials such as F-1. In
Step 1, F-1 is protected by methods known by those skilled in the
art to furnish F-2. In one embodiment, LG is chlorine. In one
embodiment PG is trityl. In Step 2, F-2 undergoes SNAr nucleophilic
addition, yielding F-3. In Step 3, F-3 is protected to afford F-4.
In Step 4, an appropriately substituted F-4 can be reacted with an
appropriate substituted epoxide to furnish F-5. In Step 5, the
hydroxyl of F-5 is converted to an appropriate leaving group to
afford F-6. In Step 6, F-6 is converted to azide F-7. In Step 7,
F-7 undergoes nucleophilic attack to install a cyano group and
yield F-8. In Step 8, F-8 is cyclized by methods known by those
skilled in the art to afford F-9 which is a compound of Formula
IV.
##STR00158##
[0428] As demonstrated in Scheme 1G, compounds of Formula V can be
prepared from readily available starting materials such as G-1. In
Step 1, G-1 is protected by methods known by those skilled in the
art to furnish G-2. In one embodiment, LG is chlorine. In one
embodiment PG is trityl. In Step 2, G-2 undergoes SNAr nucleophilic
addition, yielding G-3. In Step 3, G-3 is protected to afford G-4.
In Step 4, an appropriately substituted G-4 can be reacted with an
appropriate substituted olefin at elevated temperature in the
presence of an organometallic catalyst in organic solvent to
furnish G-5. In one embodiment, the solvent is toluene. In one
embodiment, the catalyst is Au(I) salt bound to appropriate
ligands. In one embodiment, the temperature is greater than
80.degree. C. The olefin shown in Scheme 1G is a non-limiting
example and other olefins may be used by those skilled in the art
to generate derivatives of structure G-5. In Step 5 G-5 is
converted to azide G-6. In Step 6, G-6 is undergoes nucleophilic
attack to install a cyano group and yield G-7. In Step 7, G-7 is
cyclized by methods known by those skilled in the art to afford
G-8. In Step 8, G-8 is deprotected to afford G-9 which is a
compound of Formula V.
##STR00159##
[0429] As demonstrated in Scheme 1H, compounds of Formula VI can be
prepared from readily available starting materials such as H-1. In
Step 1, H-1 is converted to a ketone by methods known by those
skilled in the art to furnish H-2. In one embodiment, LG is
chlorine. In Step 2, H-2 is converted to an appropriate halide for
subsequent displacement, yielding H-3. In Step 3, halide H-3 is
displaced by glycine to afford H-4. H-4 is then protected to afford
structure H-5 by methods known in the art. In one embodiment PG is
ethyl. In Step 5 H-5 is converted to zwitterion H-6. In Step 6, H-6
is cyclized by methods known in the art to yield H-7. In one
embodiment silyl is TMS. In Step 7, H-7 is dehydrated to afford
H-8. In Step 8, H-8 is converted to an appropriate leaving group
containing compound H-9. In one embodiment LG1 is hydroxyl. In Step
9, the secondary amine is protected and then the LG1 of H-9 is
displaced by an appropriately substituted amine to produce
compounds of Formula H010. In one embodiment PG1 is a carbamate. In
Step 10, the hydroxyl group of H-10 is converted to an appropriate
leaving group to afford H-11. In Step 11, H-11 is cyclized to
afford H-12. In Step 12 SNAr nucleophilic addition of an amine
displacing the leaving group of H-12 affords a compound of Formula
VI.
##STR00160##
[0430] As exemplified in Scheme 2, An appropriately substituted
purine (1) is dissolved in toluene and treated with
tert-butyl(cyclohex-1-en-1-ylmethoxy)dimethylsilane in the presence
of catalytic Ph.sub.3PAuOTf at elevated temperature to produce 2.
Compound 2 is subsequently aminiated with ammonium hydroxide to
furnish amine 3. The amino moiety is then removed by conversion to
the corresponding diazonium salt with nitrous acid followed by
subsequent reduction with hydrophosphinic acid to yield 4. An
appropriately substituted amine is then coupled with 4 at elevated
temperature in the presence of base (NaOt-Bu) and a palladium
source such as Pd(OAc).sub.2 with an appropriate ligand to generate
5. This species is then protected with trityl chloride to produce
compound 6. The trityl-protected species is then lithiated with an
organolithium reagent and quenched with an appropriately
substituted electrophile to furnish compound 7. Amidation of 7 with
ammonia, followed by subsequent deprotection of the silyl ether
with TBAF yields an amido alcohol 8 that is converted to bromo
species 9 with triphenylphosphine and carbon tetrabromide. Finally,
cyclization of the alkyl bromide with the amide moiety, followed by
acidic deprotection of trityl affords the title compound 10 which
is a representative compound of Formula I.
##STR00161##
[0431] As exemplified in Scheme 3, Compound 11 is first protected
with TBDMSCl to yield silyl ether 12 which reacts with an
appropriately substituted epoxide in the presence of a suitable
Lewis acid to produce alcohol 13. Silylation of 13 affords 14 and
subsequent lithiation of the aromatic ring with an n-butyllithium
followed by treatment with an appropriately substituted
electrophile produces 15. Treatment of 15 with excess TBAF removes
both silyl ethers and the free amide is then converted to chloride
16 with POCl.sub.3. Chloride 16 is reduced to compound 17 in the
presence of finely dispersed palladium on carbon with molecular
hydrogen as the reductant. Treatment of 17 with ammonia in methanol
followed by a subsequent reaction with PPh.sub.3CBr.sub.4 yields an
intermediate bromide that undergoes cyclization in the presence of
base such as NaH under elevated temperature to afford lactam 18.
The amide is protected as a carbamate with Boc.sub.2O and the
sulfide is subsequently oxidized to the sulfone by the action of
oxone in aqueous media buffered to approximately pH 4.5. This
procedure furnishes compound 19 which readily undergoes aromatic
substitution with an appropriately substituted amine at elevated
temperature to generate 20. The Boc protecting group is then
removed under acidic conditions to yield title compound 21 which is
a representative compound of Formula II
##STR00162##
[0432] As exemplified in Scheme 4, Compound 22 is protected with
trityl chloride in the presence of base to furnish 23. An
appropriately substituted amine is then coupled with 23 at elevated
temperature in the presence of base (NaOt-Bu) and a palladium
source such as Pd(OAc).sub.2 with an appropriate ligand to generate
24. Subsequent protection of 24 with trityl chloride yields 25
which is then reacted with an appropriately substituted epoxide in
the presence of a suitable Lewis acid to produce alcohol 26.
Silylation of 26 readily affords 27 which is transformed into
compound 28 by n-butyllithium and an appropriately substituted
electrophile. Amidation of 28 is effected by methanolic ammonia and
the silyl ether is deprotected in the presence of TBAF. This
procedure affords an intermediate alcohol that is converted to the
corresponding bromide by CBr.sub.4 and PPh.sub.3 that undergoes
cyclization in the presence of base such as NaH to yield compound
29. The trityl groups are then deprotected with acid under elevated
temperatures to furnish 30 which is a representative compound of
Formula III.
##STR00163##
[0433] As exemplified in Scheme 5, Compound 31 is readily coupled
to an appropriately substituted amine at elevated temperature in
the presence of base (NaOt-Bu) and a palladium source such as
Pd(OAc).sub.2 with an appropriate ligand to generate 32. The amino
moiety is then protected with trityl chloride to furnish 33 which
reacts with an appropriately substituted epoxide in the presence of
a suitable Lewis acid to produce alcohol 34. Silylation of alcohol
34 produces 35 which is transformed to compound 36 by
n-butyllithium and an appropriately substituted electrophile. Ester
36 is then converted to an amide by methanolic ammonia and the
silyl ether is cleaved in the presence of TBAF to yield 37.
Bromination of alcohol 37 with CBr.sub.4 and PPh.sub.3 affords
bromide 38 which readily undergoes cyclization in the presence of
base to produce a cyclic lactam. This intermediate lactam is
treated with acid at elevated temperature to remove the trityl
protecting group which furnishes compound 39 which is a
representative compound of Formula III.
##STR00164##
[0434] As exemplified in Scheme 6, Compound 40 is reduced with
finely dispersed palladium on carbon in the presence of molecular
hydrogen to furnish monochloridate 41. An appropriately substituted
amine is then coupled with 41 at elevated temperature in the
presence of base (NaOt-Bu) and a palladium source such as
Pd(OAc).sub.2 with an appropriate ligand to generate 42. Compound
42 is then protected with trityl chloride to yield 43 which is then
reacted with an appropriately substituted epoxide in the presence
of a suitable Lewis acid to produce alcohol 44. Silylation of
alcohol 44 produces 45 which is transformed to compound 46 by
n-butyllithium and an appropriately substituted electrophile. Ester
46 is then converted to an amide by methanolic ammonia and the
silyl ether is cleaved in the presence of TBAF. Subsequent
bromination of the intermediate alcohol with CBr.sub.4 and
PPh.sub.3 affords bromide 47 which readily undergoes cyclization in
the presence of base to produce a cyclic lactam. This intermediate
lactam is treated with acid at elevated temperature to remove the
trityl protecting group which furnishes compound 48 which is a
representative compound of Formula III.
##STR00165## ##STR00166##
[0435] As exemplified in Scheme 7, Compound 49 is protected with
trityl chloride in the presence of base to yield 50. An
appropriately substituted amine is then coupled with 50 at elevated
temperature in the presence of base (NaOt-Bu) and a palladium
source such as Pd(OAc).sub.2 with an appropriate ligand to generate
51. Subsequent trityl protection of 51 furnishes 52 which reacts
with an appropriately substituted epoxide in the presence of a
suitable Lewis acid to produce alcohol 53. Silylation of 53 readily
affords 54 which is transformed into compound 55 by n-butyllithium
and phenylazide. The siyl ether is then cleaved with TBAF and the
resulting alcohol is tosylated and displaced by NaCN to yield
nitrile 56. Heating compound 8 at elevated temperature in the
presence of acid cleaves the trityl protecting groups and promotes
hydrolysis of the nitrile and azo moieties to generate lactam 57
which is a representative compound of Formula IV.
##STR00167## ##STR00168##
[0436] As exemplified in Scheme 8, Compound 58 is protected with
trityl chloride in the presence of base to yield 59. An
appropriately substituted amine is then coupled with 59 at elevated
temperature in the presence of base (NaOt-Bu) and a palladium
source such as Pd(OAc).sub.2 with an appropriate ligand to generate
60. Subsequent protection of 3 with benzyl chloride and
acid-mediated hydrolysis of the pre-existing trityl protecting
group yields 61. Compound 61 is then reacted with
tert-butyl(cyclohex-1-en-1-ylmethoxy)dimethylsilane in the presence
of catalytic Ph.sub.3PAuOTf at elevated temperature to produce 62.
Treatment of 62 with n-butyllithium followed by phenylazide
furnishes 63. The silyl ether is deprotected with TBAF and the
resulting alcohol is transformed into an alkyl halide with
PPh.sub.3 and CB.sub.4 and is displaced by NaCN to produce nitrile
64. Hydrolysis of the nitrile and azo moieties in the presence of
acid at elevated temperature promotes cyclization to lactam 65.
Reductive cleavage of the benzyl protecting group by finely
dispersed palladium with molecular hydrogen affords compound 66
which is a representative compound of Formula V.
##STR00169## ##STR00170## ##STR00171##
[0437] As exemplified in Scheme 9, Compound 67 is chilled to
reduced temperatures and treated with methyl magnesium bromide.
Acidic workup of the reaction mixture yields 68. Diazotination of
68 with nitrous acid followed by subsequent treatment with
HBF.sub.4 at elevated temperatures produces fluoride 69. This
intermediate is heated with glycine in the presence of base to
furnish 70. Carboxylic acid 70 is converted to the acid chloride
and esterified with EtOH to afford ethyl ester 71. Oxidation of the
secondary nitrogen to nitrone 72 is accomplished with SeO.sub.2 and
t-BuOOH. Cyclization of 72 with TMSCl in the presence of base
yields 73 which is reduced with Pd/C in the presence of molecular
hydrogen to generate amine 74. Ethyl ester 74 is then hydrolyzed
with aqueous base and simultaneously protected with Boc to afford
carboxylic acid 75. Acid 75 is then coupled with an appropriately
substituted amine to yield amide 76. The tertiary alcohol is
silylated with TBDMSCl and the amide is benzylated with sodium
hydride and benzyl bromide to furnish 77. Hydrolysis of Boc and the
silane protecting group in aqueous acid produces a tertiary
carbocation that undergoes cyclization at elevated temperature to
produce 78. Chloride 78 is then coupled with an appropriately
substituted amine to generate 79 which undergoes a Pd catalyzed
reduction to cleave the benzyl protecting group which yields
compound 80 which is a representative compound of Formula VI.
##STR00172## ##STR00173##
[0438] As shown in Scheme 10, bromide 81 is converted to aldehyde
82 followed by subsequent cyclization and oxidation to furnish
carboxylic acid 83. Acid 83 is then transformed to an alkyl ester
84 and transamidated to yield amide 85. Deprotection of the
protecting group P produces 86 which undergoes aminal formation in
the presence of a ketone to generate aminal 87. Sulfonation of 87
affords 88 which subsequently undergoes nucleophilic aromatic
substitution to furnish desired compound 89 which is a
representative compound of Formula VII.
##STR00174##
[0439] As shown in Scheme 11, commercially available chloride 90 is
coupled with an appropriate amine via nucleophilic aromatic
substitution to afford intermediate 91. Amine 91 is then
deprotected, subjected to cyclization in the presence of glyoxal,
and coupled with the desired amine to yield compound 92 which is a
representative compound of Formula VIII.
##STR00175##
[0440] Alternatively compounds of Formula VIII can be formed as
shown in Scheme 12. Commercially available chloride 93 is coupled
with an appropriate amine via nucleophilic aromatic substitution to
afford intermediate 94. Amine 94 is then deprotected and subjected
to cyclization in the presence of cyanogen bromide or an analogous
reagent to afford compound 95. Compound 95 is further cyclized in
the presence of a base to afford compound 96, which is reduced and
subjected to an appropriately substituted amine to afford compound
97, which is a compound of Formula VIII.
##STR00176##
[0441] As shown in Scheme 13, bischloride 98 is coupled with an
amine via nucleophilic aromatic substitution to furnish
intermediate 99 which then undergoes amidation in the presence of a
carboxylic acid to produce amide 100. Removal of Boc triggers
intramolecular cyclization to yield intermediate 101 which is then
oxidized upon exposure to air or other oxidants and coupled with a
desired amine to afford target 102 which is a compound of Formula
IX.
##STR00177##
[0442] As shown in Scheme 14, protected heterocycle 103 is reacted
with an electrophile as known in the art to furnish intermediate
104 which then undergoes deprotection to produce amide 105.
Nucleophilic attack of dibromoethane by 105 followed by
intramolecular cyclization affords 106 which is coupled with a
desired amine to afford compound 107 which is a compound of Formula
I.
##STR00178##
[0443] As shown in Scheme 15, protected heterocycle 108 is coupled
with a desired amine to furnish intermediate 109. Intermediate 109
is then converted to an anilino compound 110 as known in the art.
The anilino compound 110 is condensed into an oxalate derivative
111 which is subsequently deprotected and cyclized to form compound
112, which is a compound of Formula I.
##STR00179##
[0444] As shown in Scheme 16, known compound 113 can be reacted
with an amino ketal to form compound 114. Compound 114 is
subsequently reacted with a desired amine to form compound 115,
which is a representative compound of Formula XI.
##STR00180##
[0445] General Procedure for the Synthesis of Diazepinones 118. A
mixture of the suitable 2-aminobenzophenone derivative 116 (6.0
mmol) in pyridine (40 mL) containing 9.0 mmol of alanine derivative
117 is refluxed for 20 h under nitrogen. The reaction mixture is
concentrated under reduced pressure, poured into ice-water and
extracted with CH.sub.2Cl.sub.2. The organic layer is washed with
0.1 N HCl, dried over Na.sub.2SO.sub.4, and evaporated in vacuo.
The residue is purified by flash-chromatography eluting with the
suitable solvent to afford the expected compounds, which after
re-crystallization from the appropriate solvent gives 118.
[0446] Diazepinone 118 is then coupled with a pyrimidine to afford
119 which is subjected to an appropriate amine in a nucleophilic
attack to afford 120, which is a compound of Formula XII.
[0447] In the following schemes methyl piperazines products and
intermediates are synthesized. One skilled in the art, will
appreciate that a variety of different heterocycles could be used
in place of methylpiperazine (such as piperazine,
isopropylpiperazine, morpholine, etc) by selection of the
heteroaryl amine reactant in the following schemes.
##STR00181## ##STR00182##
[0448] Scheme 18 provides a synthetic preparation of compound 126
of Formula I. First commercially available dichloride 121 undergoes
nucleophilic addition to install a diamine moiety and afford 122.
Intermediate 122 is then reduced to an anilino compound and
subsequently reacted with either methyl
2,2-dichloro-2-methoxyacetate, methyl 2,2,2-trimethoxyacetate,
methyl 2,2,2-trichloroacetimidate, or a similar reagent to afford
cyclization precursor 124. 124 is then deprotected and subsequently
undergoes intramolecular cyclization to afford 125 which then
undergoes nucleophilic attack to afford final compound 126.
##STR00183## ##STR00184## ##STR00185##
[0449] Scheme 19 provides a synthetic preparation of compound 142
of Formula III. First aldehyde 127 and carboxylic acid 128 are
reacted as described in the Journal of Heterocyclic Chemistry to
afford compound 129. Compound 129 is oxidized to 130 and then
subsequently alpha brominated to bromide 131. Bromide 131 undergoes
nucleophilic attack to afford cyano species 132 and then subsequent
reduction and protection to afford the carbamate protected compound
133. Compound 133 is silyl protected to 134 and then dehalogenated
to afford thiol 135. Thiol 135 is converted to ester 136 by
reaction of an alpha brominated ester and then is subsequently
deprotected (137) and oxidized to ketone intermediate 138. Ketone
138 undergoes intramolecular cyclization to afford 140 which then
is oxidized as known in the art to sulfone 141. Sulfone 141
undergoes nucleophilic attack to afford compound 142.
##STR00186## ##STR00187## ##STR00188##
[0450] Scheme 20 provides a synthetic preparation of compound 150
of Formula III. First aldehyde 127 and carboxylic acid 128 are
reacted as described in the Journal of Heterocyclic Chemistry to
afford compound 129. Compound 129 is oxidized to 130 and then
subsequently alpha brominated to bromide 131. Bromide 131 undergoes
nucleophilic attack to afford cyano species 132 and then subsequent
reduction and protection to afford the carbamate protected compound
133. Compound 133 is silyl protected to 134 and then dehalogenated
to afford hydroxyl 143. Hydroxyl 144 is converted to ester 145 by
reaction of an alpha brominated ester and then is subsequently
deprotected (146) and oxidized to ketone intermediate 147. Ketone
147 undergoes intramolecular cyclization to afford 148 which then
is oxidized as known in the art to sulfone 149. Sulfone 149
undergoes nucleophilic attack to afford compound 150.
##STR00189## ##STR00190##
[0451] Scheme 21 provides a synthetic preparation of compound 160
of Formula IV. Commercially available compound 151 is brominated in
a radical reaction to afford 152 which then can be displaced by a
nucleophilic source of cyano (such as potassium cyanide) to afford
cyano 153. Cyano 153 is then deprotonated as described in BMCL to
afford alkene 154. Alkene 154 is coupled with a metal such as zinc
to afford ester 155. Ester 155 is then reduced with another metal
(such as iron) to afford aniline 156. Aniline 156 then undergoes
intramolecular cyclization to afford pyrazolopyrimindine 157 which
then undergoes a base catalyzed intramolecular cyclization to
afford the trifused cycle 158. Compound 158 is then oxidized to the
sulfone 159 which is subsequently displaced with an appropriate
amine in the presence of an appropriate base to afford the final
compound 160.
##STR00191## ##STR00192##
[0452] Scheme 22 provides a synthetic preparation of compound 170
of Formula V. Commercially available reagent 161 is subjected to
base and head as described in EP1754706 to afford 162. Compound 162
is then chlorinated as known in the art to afford 163. Compound 163
undergoes bromination in a radical reaction to afford bromide 164.
Bromide 164 undergoes nucleophilic attack with a cyano source (such
as potassium cyanide) to afford cyano 165. Cyano 165 is subjected
to an amine to afford 166 and then intramolecular cyclization
affords 167 as known in the art. Compound 167 undergoes
intramolecular cyclization again to afford 168 then subsequent
oxidation to afford 169. The selectivity of the oxidation can be
controlled by choice of reagents. Sulfone 169 is then displaced in
a nucleophilic SNAr type reaction to afford 170.
##STR00193##
[0453] Scheme 23 provides an alternative synthetic preparation of
compounds of Formula V.
##STR00194## ##STR00195## ##STR00196##
[0454] Scheme 24 provides a synthetic preparation of compound 191
of Formula XV. Compound 177 undergoes reduction of the cyano group
followed by protection of the resultant amine to afford protected
compound 178. Compound 178 is saponified (typically by sodium
hydroxide) to afford compound 179. Compound 179 is converted to the
Weinreb amide 180 by reaction of the Weinreb salt and an excess of
base, or alternatively by coupling the Weinreb salt in the presence
of HATU or a similar reagent. The Weinreb amide is then reacted
with a nucleophilic methyl source, such as methyl lithium or methyl
magnesium bromide to afford a ketone 181. Ketone 181 is
deprotonated and condensed to afford compound 182 which undergoes
subsequent cyclization with hydrazine to form pyrazole 183 which
undergoes subsequent installation of a nitro group to afford
compound 184. Compound 184 is reduced to amine 185 as performed in
WO2010/43633 which is then cyclized to afford 186. Compound 186 is
chlorinated with any suitable reagent (such as POCl.sub.3) to
afford chloride 187. Chloride 187 is then dehalogenated with a
proton source to afford 188. Compound 188 is coupled to an
appropriate acid and then undergoes intramolecular cyclization to
afford compound 189. Compound 189 is oxidized to compound 190 and
undergoes subsequent nucleophilic attack to afford compound
191.
IX. Exemplary Compounds
##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201##
##STR00202## ##STR00203## ##STR00204## ##STR00205## ##STR00206##
##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211##
##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216##
##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221##
##STR00222## ##STR00223## ##STR00224## ##STR00225##
[0455] X. Examples
General Methods:
[0456] .sup.1H NMR spectra were recorded on a 300 MHz Fourier
transform Brucker spectrometer. Spectra were obtained from samples
prepared in 5 mm diameter tubes in CDCl.sub.3, CD.sub.3OD or
DMSO-d.sub.6. The spin multiplicities are indicated by the symbols
s (singlet), d (doublet), t (triplet), m (multiplet) and, br
(broad). Coupling constants (J) are reported in Hz. MS spectra were
obtained using electrospray ionization (ESI) on an Agilent
Technologies 6120 quadrupole MS apparatus. The reactions were
generally carried out under a dry nitrogen atmosphere using
Sigma-Aldrich anhydrous solvents. All common chemicals were
purchased from commercial sources.
[0457] Compounds of the present invention with stereocenters are
drawn racemic for convenience. One skilled in the art will
recognize that pure enantiomers can be prepared by methods known in
the art. Examples of methods to obtain optically active materials
include at least the following.
[0458] i) physical separation of crystals--a technique whereby
macroscopic crystals of the individual enantiomers are manually
separated. This technique can be used if crystals of the separate
enantiomers exist, i.e., the material is a conglomerate, and the
crystals are visually distinct;
[0459] ii) simultaneous crystallization--a technique whereby the
individual enantiomers are separately crystallized from a solution
of the racemate, possible only if the latter is a conglomerate in
the solid state;
[0460] iii) enzymatic resolutions--a technique whereby partial or
complete separation of a racemate by virtue of differing rates of
reaction for the enantiomers with an enzyme;
[0461] iv) enzymatic asymmetric synthesis--a synthetic technique
whereby at least one step of the synthesis uses an enzymatic
reaction to obtain an enantiomerically pure or enriched synthetic
precursor of the desired enantiomer;
[0462] v) chemical asymmetric synthesis--a synthetic technique
whereby the desired enantiomer is synthesized from an achiral
precursor under conditions that produce asymmetry (i.e., chirality)
in the product, which may be achieved using chiral catalysts or
chiral auxiliaries;
[0463] vi) diastereomer separations--a technique whereby a racemic
compound is reacted with an enantiomerically pure reagent (the
chiral auxiliary) that converts the individual enantiomers to
diastereomers. The resulting diastereomers are then separated by
chromatography or crystallization by virtue of their now more
distinct structural differences and the chiral auxiliary later
removed to obtain the desired enantiomer;
[0464] vii) first- and second-order asymmetric transformations--a
technique whereby diastereomers from the racemate equilibrate to
yield a preponderance in solution of the diastereomer from the
desired enantiomer or where preferential crystallization of the
diastereomer from the desired enantiomer perturbs the equilibrium
such that eventually in principle all the material is converted to
the crystalline diastereomer from the desired enantiomer. The
desired enantiomer is then released from the diastereomer;
[0465] viii) kinetic resolutions--this technique refers to the
achievement of partial or complete resolution of a racemate (or of
a further resolution of a partially resolved compound) by virtue of
unequal reaction rates of the enantiomers with a chiral,
non-racemic reagent or catalyst under kinetic conditions;
[0466] ix) enantiospecific synthesis from non-racemic precursors--a
synthetic technique whereby the desired enantiomer is obtained from
non-chiral starting materials and where the stereochemical
integrity is not or is only minimally compromised over the course
of the synthesis;
[0467] x) chiral liquid chromatography--a technique whereby the
enantiomers of a racemate are separated in a liquid mobile phase by
virtue of their differing interactions with a stationary phase
(including via chiral HPLC). The stationary phase can be made of
chiral material or the mobile phase can contain an additional
chiral material to provoke the differing interactions;
[0468] xi) chiral gas chromatography--a technique whereby the
racemate is volatilized and enantiomers are separated by virtue of
their differing interactions in the gaseous mobile phase with a
column containing a fixed non-racemic chiral adsorbent phase;
[0469] xii) extraction with chiral solvents--a technique whereby
the enantiomers are separated by virtue of preferential dissolution
of one enantiomer into a particular chiral solvent;
[0470] xiii) transport across chiral membranes--a technique whereby
a racemate is placed in contact with a thin membrane barrier. The
barrier typically separates two miscible fluids, one containing the
racemate, and a driving force such as concentration or pressure
differential causes preferential transport across the membrane
barrier. Separation occurs as a result of the non-racemic chiral
nature of the membrane that allows only one enantiomer of the
racemate to pass through.
[0471] Chiral chromatography, including simulated moving bed
chromatography, is used in one embodiment. A wide variety of chiral
stationary phases are commercially available.
Example 1. Preparation of Substituted 2-aminopyridines
1-Methyl-4-(6-nitro-3-pyridyl)piperazine
##STR00226##
[0473] To 5-bromo-2-nitropyridine (4.93 g, 24.3 mmole) in DMF (20
mL) was added N-methylpiperazine (2.96 g, 1.1 eq) followed by the
addition of DIPEA (4.65 mL, 26.7 mmole). The contents were heated
at 90.degree. C. for 24 hrs. After the addition of ethyl acetate
(200 mL), water (100 mL) was added and the layers were separated.
Drying followed by concentration afforded the crude product which
was purified on a silica gel column using (0-10%) DCM/Methanol.
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.26 (s, 1H), 8.15 (1H, d, J=9.3
Hz), 7.49 (1H, d, J=9.4 Hz), 3.50 (m, 4H), 2.49 (m, 4H), 2.22 (s,
3H).
5-(4-Methylpiperazin-1-yl)pyridin-2-amine
##STR00227##
[0475] To 1-methyl-4-(6-nitro-3-pyridyl)piperazine 3.4 g in ethyl
acetate (100 mL) and ethanol (100 mL) was added 10% Pd/c (400 mg)
and then contents stirred under hydrogen (10 psi) overnight. After
filtration through Celite.RTM., the solvents were evaporated and
the crude product was purified over silica gel using DCM/7N Ammonia
in MeOH (0-5%) to afford 5-(4-methylpiperazin-1-yl)pyridin-2-amine
(2.2 g).
[0476] .sup.1HNMR (DMSO-d.sub.6) .delta. 7.56 (1H, d, J=3 Hz), 7.13
(1H, m), 6.36 (1H, d, J=8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47
(m, 4H), 2.16 (s, 3H).
Tert-Butyl 4-(6-amino-3-pyridyl)piperazine-1-carboxylate
##STR00228##
[0478] The compound was prepared as described in WO 2010/020675
A1.
##STR00229##
[0479] To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmole) in DMSO (4 mL)
was added 1-(4-piperidyl)piperidine (1.0 g, 5.9 mmole) and
triethylamine (0.99 mL, 7.1 mmole). The contents were heated to
120.degree. C. in a CEM Discovery microwave system for 3 hours. The
crude reaction was then loaded over a silica gel column and eluted
with DCM/methanol (0-20%) to afford
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457
mg).
[0480] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.26-1.36
(m, 2H) 1.43 (m, 6H) 1.76 (m, 2H) 2.37 (m, 5H) 2.94 (t, J=12.74 Hz,
2H) 4.06 (d, J=13.47 Hz, 2H) 7.41 (dd, J=9.37, 2.64 Hz, 1H) 8.08
(d, J=9.37 Hz, 1H) 8.20 (d, J=2.64 Hz, 1H).
5-[4-(1-Piperidyl)-1-piperidyl]pyridin-2-amine
##STR00230##
[0482] 5-[4-(1-Piperidyl)-1-piperidyl]pyridin-2-amine was prepared
in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine.
[0483] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.13-1.37
(m, 6H) 1.40-1.63 (m, 6H) 1.71 (m, 2H), 2.24 (m, 1H) 2.43 (m, 2H)
3.33 (d, J=12.30 Hz, 2H) 5.31 (s, 2H) 6.33 (d, J=8.78 Hz, 1H) 7.10
(dd, J=8.78, 2.93 Hz, 1H) 7.55 (d, J=2.64 Hz, 1H). LCMS (ESI) 261
(M+H).
4-[1-(6-Nitro-3-pyridyl)-4-piperidyl] Morpholine
##STR00231##
[0485] 4-[1-(6-Nitro-3-pyridyl)-4-piperidyl]morpholine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.
[0486] 1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.41 (m, 2H) 1.82
(m, 2H) 2.42 (m, 5H) 2.98 (t, J=12.44 Hz, 2H) 3.52 (s, 4H) 4.04 (d,
J=12.88 Hz, 2H) 7.42 (d, J=9.37 Hz, 1H) 8.08 (d, J=9.08 Hz, 1H)
8.21 (s, 1H).
5-(4-Morpholino-1-piperidyl)pyridin-2-amine
##STR00232##
[0488] 5-(4-Morpholino-1-piperidyl)pyridin-2-amine was prepared in
a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine.
[0489] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.34-1.52
(m, 2H) 1.78 (m, 2H) 2.14 (m, 1H) 2.43 (m, 4H) 3.32 (d, J=12.30 Hz,
4H) 3.47-3.59 (m, 4H) 5.32 (s, 2H) 6.34 (d, J=8.78 Hz, 1H) 7.11
(dd, J=8.93, 2.78 Hz, 1H) 7.47-7.62 (m, 1H). LCMS (ESI) 263
(M+H).
4-[1-(6-Nitro-3-pyridyl)-4-piperidyl]thiomorpholine
##STR00233##
[0491] 4-[1-(6-Nitro-3-pyridyl)-4-piperidyl] thiomorpholine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.
[0492] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.40-1.52
(m, 2H) 1.71 (m, 2H) 2.49-2.55 (m, 4H) 2.56-2.63 (m, 1H) 2.68-2.75
(m, 4H) 2.88-2.98 (m, 2H) 4.09 (d, J=13.18 Hz, 2H) 7.42 (dd,
J=9.22, 3.07 Hz, 1H) 8.08 (d, J=9.37 Hz, 1H) 8.20 (d, J=3.22 Hz,
1H).
5-(4-Thiomorpholino-1-piperidyl) pyridin-2-amine
##STR00234##
[0494] 5-(4-Thiomorpholino-1-piperidyl) pyridin-2-amine was
prepared in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine.
[0495] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.47-1.59
(m, 2H) 1.65 (m, 2H) 2.22-2.38 (m, 1H) 2.50-2.59 (m, 6H) 2.68-2.82
(m, 4H) 3.33 (d, J=12.00 Hz, 2H) 5.31 (s, 2H) 6.33 (d, J=9.08 Hz,
1H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.55 (d, J=2.64 Hz, 1H). LCMS
(ESI) 279 (M+H).
2-Nitro-5-(1-piperidyl)pyridine
##STR00235##
[0497] 2-Nitro-5-(1-piperidyl) pyridine was synthesized in a manner
similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.
[0498] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.56 (m, 6H)
3.49 (d, J=4.39 Hz, 4H) 7.30-7.47 (m, 1H) 8.02-8.12 (m, 1H)
8.15-8.26 (m, 1H).
5-(1-Piperidyl)pyridin-2-amine
##STR00236##
[0500] 5-(1-Piperidyl) pyridin-2-amine was prepared in a manner
similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine.
[0501] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.39-1.46
(m, 2H) 1.51-1.62 (m, 4H) 2.75-2.92 (m, 4H) 5.30 (s, 2H) 6.34 (d,
J=8.78 Hz, 1H) 7.09 (dd, J=8.78, 2.93 Hz, 1H) 7.54 (d, J=2.93 Hz,
1H). LCMS (ESI) 178 (M+H).
4-(6-Nitro-3-pyridyl) thiomorpholine
##STR00237##
[0503] 4-(6-nitro-3-pyridyl) thiomorpholine was synthesized in a
manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.
[0504] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 2.56-2.69
(m, 4H) 3.79-3.92 (m, 4H) 7.43 (dd, J=9.22, 3.07 Hz, 1H) 8.10 (d,
J=9.37 Hz, 1H) 8.20 (d, J=2.93 Hz, 1H).
5-Thiomorpholinopyridin-2-amine
##STR00238##
[0506] 5-Thiomorpholinopyridin-2-amine was prepared in a manner
similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)
pyridin-2-amine.
[0507] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 2.59-2.73
(m, 4H) 3.04-3.20 (m, 4H) 5.41 (s, 2H) 6.35 (d, J=8.78 Hz, 1H) 7.10
(dd, J=8.78, 2.93 Hz, 1H) 7.57 (d, J=2.64 Hz, 1H). LCMS (ESI) 196
(M+H).
Tert-Butyl(4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carb-
oxylate
##STR00239##
[0509] tert-Butyl
(4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
was synthesized in a manner similar to that used in the synthesis
of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.
[0510] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.33 (d,
J=32.21 Hz, 11H) 1.91 (m, 2H) 3.15 (d, J=10.25 Hz, 1H) 3.58 (m, 1H)
4.46 (m, 1H) 4.83 (s, 1H) 7.16 (s, 1H) 7.94 (s, 1H) 8.05-8.16 (m,
1H).
Tert-Butyl(4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carb-
oxylate
##STR00240##
[0512] tert-Butyl
(4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
was prepared in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine.
[0513] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.31 (d,
J=31.91 Hz, 11H) 1.83 (m, 2H) 2.71-2.82 (m, 1H) 3.44 (m, 1H) 4.30
(d, 2H) 5.08 (s, 2H) 6.35 (d, J=8.78 Hz, 1H) 6.77-6.91 (m, 1H) 7.33
(s, 1H). LCMS (ESI) 291 (M+H).
N,N-dimethyl-1-(6-nitro-3-pyridyl) piperidin-4-amine
##STR00241##
[0515] N,N-dimethyl-1-(6-nitro-3-pyridyl)piperidin-4-amine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.
[0516] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.30-1.45
(m, 2H) 1.79 (m, 2H) 2.14 (s, 6H) 2.33 (m, 1H) 2.92-3.04 (m, 2H)
4.03 (d, J=13.76 Hz, 2H) 7.42 (dd, J=9.22, 3.07 Hz, 1H) 8.04-8.11
(m, 1H) 8.21 (d, J=2.93 Hz, 1H).
5-[4-(Dimethylamino)-1-piperidyl] pyridin-2-amine
##STR00242##
[0518] 5-[4-(dimethylamino)-1-piperidyl]pyridin-2-amine was
prepared in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine.
[0519] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.35-1.50
(m, 2H) 1.69-1.81 (m, 2H) 2.00-2.10 (m, 1H) 2.11-2.22 (s, 6H)
3.17-3.36 (m, 4H) 5.19-5.38 (s, 2H) 6.34 (d, J=8.78 Hz, 1H) 7.10
(dd, J=8.78, 2.93 Hz, 1H) 7.55 (d, J=2.63 Hz, 1H). LCMS (ESI) 221
(M+H).
4-(6-Nitro-3-pyridyl) morpholine
##STR00243##
[0521] 4-(6-Nitro-3-pyridyl) morpholine/was synthesized in a manner
similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl] pyridine.
5-Morpholinopyridin-2-amine
##STR00244##
[0523] 5-Morpholinopyridin-2-amine was prepared in a manner similar
to that used in the synthesis of 5-(4-methylpiperazin-1-yl)
pyridin-2-amine.
[0524] .sup.1H NMR (600 MHz, CHCl.sub.3-d) 6 ppm 2.91-3.00 (m, 4H)
3.76-3.84 (m, 4H) 4.19 (br. s., 2H) 6.45 (d, J=8.78 Hz, 1H) 7.12
(dd, J=8.78, 2.93 Hz, 1H) 7.72 (d, J=2.93 Hz, 1H).
5-(4-Isobutylpiperazin-1-yl) pyridin-2-amine
##STR00245##
[0526] 1-Isobutyl-4-(6-nitro-3-pyridyl)piperazine was synthesized
in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then
converted 5-(4-isobutylpiperazin-1-yl)pyridin-2-amine in a manner
similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine.
[0527] .sup.1H NMR (600 MHz, CHCl.sub.3-d) 6 ppm 0.88 (d, J=6.73
Hz, 6H) 1.71-1.84 (m, 1H) 2.10 (d, J=7.32 Hz, 2H) 2.46-2.58 (m, 4H)
2.97-3.07 (m, 4H) 4.12 (s, 2H) 6.45 (d, J=8.78 Hz, 1H) 7.14 (dd,
J=8.78, 2.93 Hz, 1H) 7.75 (d, J=2.93 Hz, 1H). LCMS (ESI) 235
(M+H).
5-(4-Isopropylpiperazin-1-yl) pyridin-2-amine
##STR00246##
[0529] 1-Isopropyl-4-(6-nitro-3-pyridyl)piperazine was synthesized
in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then
converted to 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine in a
manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine.
[0530] .sup.1H NMR (600 MHz, CHCl.sub.3-d) 6 ppm 1.06 (d, J=6.44
Hz, 6H) 2.59-2.75 (m, 5H) 2.97-3.10 (m, 4H) 4.13 (s, 2H) 6.45 (d,
J=8.78 Hz, 1H) 7.15 (dd, J=9.08, 2.93 Hz, 1H) 7.76 (d, J=2.93 Hz,
1H). LCMS (ESI) 221 (M+H).
5-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]pyridin-2-amine
##STR00247##
[0532] (2S,6R)-2,6-Dimethyl-4-(6-nitro-3-pyridyl)morpholine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then
converted to 5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine
in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1H NMR (600 MHz,
CHCl.sub.3-d) 6 ppm 1.20 (d, J=6.44 Hz, 6H) 2.27-2.39 (m, 2H)
3.11-3.21 (m, 2H) 3.70-3.84 (m, 2H) 4.15 (s, 2H) 6.45 (d, J=8.78
Hz, 1H) 7.12 (dd, J=8.78, 2.93 Hz, 1H) 7.72 (d, J=2.63 Hz, 1H).
LCMS (ESI) 208 (M+H).
5-[(3R,5S)-3,5-Dimethylpiperazin-1-yl]pyridin-2-amine
##STR00248##
[0534] (3 S,5R)-3,5-Dimethyl-1-(6-nitro-3-pyridyl)piperazine was
synthesized in a manner similar to that used in the synthesis of
2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then
converted to 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine
in a manner similar to that used in the synthesis of
5-(4-methylpiperazin-1-yl)pyridin-2-amine. .sup.1H NMR (600 MHz,
CHCl.sub.3-d) 6 ppm 1.09 (d, J=6.44 Hz, 6H) 2.20 (t, J=10.83 Hz,
2H) 2.95-3.08 (m, 2H) 3.23 (dd, J=11.71, 2.05 Hz, 2H) 4.13 (s, 2H)
6.45 (d, J=8.78 Hz, 1H) 7.14 (dd, J=8.78, 2.93 Hz, 1H) 7.73 (d,
J=2.63 Hz, 1H). LCMS (ESI) 207 (M+H).
Example 2: Compounds of the Present Invention
TABLE-US-00001 [0535] Final Cmpd # Structure Name 1 ##STR00249##
10,10-dimethyl-2-((5-(4- methylpiperazin-1-yl)pyridin-2-
yl)amino)-6,6a,9,10-tetrahydro- 5H-pyrazino[1',2':1,6]pyrido[2,3-
d]pyrimidine-5,7(8H)-dione 2 ##STR00250## 10,10-dimethyl-2-((5-(4-
methylpiperazin-1-yl)pyridin-2- yl)amino)-6,6a,9,10-tetrahydro-
5H-pyrazino[1',2':1,6]pyrido[2,3- d]pyrimidin-7(8H)-one 3
##STR00251## 2'-((5-(4-methylpiperazin-1-
yl)pyridin-2-yl)amino)-6',6a',8',9'-
tetrahydrospiro[cyclohexane-1,10'- pyrazino[1',2':1,6]pyrido[2,3-
d]pyrimidine]-5',7'-dione 4 ##STR00252##
2'-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)-6',6a',8',9'-
tetrahydrospiro[cyclohexane-1,10'- pyrazino[1',2':1,6]pyrido[2,3-
d]pyrimidin]-7'(5'H)-one 5 ##STR00253##
2'-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)-6',6a',8',9'-
tetrahydrospiro[cyclopentane- 1,10'- pyrazino[1',2':1,6]pyrido[2,3-
d]pyrimidine]-5',7'-dione 6 ##STR00254##
2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)-6,6a,9,10-
tetrahydro-5H- pyrazino[1',2':1,6]pyrido[2,3-
d]pyrimidine-5,7(8H)-dione 7 ##STR00255##
2-((5-(4-methylpiperazin-1- yl)pyridin-2-yl)amino)-
6,6a,7,8,9,10-hexahydro-5H- pyrimido[5,4-c]quinolizin-5-one 8
##STR00256## ethyl 2-((5-(4-methylpiperazin-1-
yl)pyridin-2-yl)amino)-5-oxo- 6,6a,7,8,9,10-hexahydro-5H-
pyrimido[5,4-c]quinolizine-6- carboxylate 9 ##STR00257##
N-(5-(4-methylpiperazin-1- yl)pyridin-2-yl)-8',9'-
dihydrospiro[cyclohexane-1,10'- pyrido[1,6-a:2,3-d']dipyrimidin]-
2'-amine
Example 3: Biological Data for Compounds of the Present
Invention
TABLE-US-00002 [0536] BIOLOGICAL TABLE 1 CDK4/ CDK6/ CDK2/ CDK2/
CDK5/ Final CycD CycD3 CycE CycA p35 Cmpd IC.sub.50 IC.sub.50
IC.sub.50 IC.sub.50 IC.sub.50 # Compound (.mu.M) (.mu.M) (.mu.M)
(.mu.M) (.mu.M) 1 ##STR00258## 8.06 30.6 >100 >100 >100 2
##STR00259## >100 >100 >100 >100 >100 3 ##STR00260##
>100 >100 >100 >100 >100 4 ##STR00261## 47.7 75.9
>100 86.4 >100 5 ##STR00262## >100 >100 >100 >100
>100 6 ##STR00263## 14.4 50.4 >100 >100 >100 7
##STR00264## 4.7 1.8 >100 >100 >100 8 ##STR00265## 4.1 3.5
>100 >100 >100 9 ##STR00266## 2.6 1.8 >100 >100
>100
TABLE-US-00003 BIOLOGICAL TABLE 2 CDK7/ CDK5/ CycH/ CDK9/ Final p25
MAT1 CycT cmpd IC.sub.50 IC.sub.50 IC.sub.50 # Compound (.mu.M)
(.mu.M) (.mu.M) 1 ##STR00267## >100 >100 >100 2
##STR00268## >100 >100 3 ##STR00269## >100 >100 >100
4 ##STR00270## >100 >100 >100 5 ##STR00271## >100
>100 >100 6 ##STR00272## >100 >100 >100 7
##STR00273## >100 >100 >100 8 ##STR00274## >100 >100
>100 9 ##STR00275## >100 >100 >100
Example 4. Preparation of Final Compounds
Scheme 25: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spir-
o[cyclohexane-1,9'-pyrazino[1,2-e]purin]-6'-one (Compound 10)
##STR00276##
[0537] Step 1: Synthesis of Tert-Butyl
((1-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate
(193)
[0538] To a solution of 2,4-dichloro-5-nitropyrimidine (192, 3 g,
15.5 mmol), tert-butyl ((1-aminocyclohexyl)methyl)carbamate (3.5 g,
15.5 mmol) in THE (20 mL) was added followed by NaHCO.sub.3 (4.0 g,
47.6 mmol). After stirring at room temperature for 3 hours, the
reaction mixture was quenched with water (20 mL) and extracted with
EtOAc (20 mL). The organic layer was separated and washed with
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo.
The resulting residue was purified by column chromatography to
afford tert-butyl
((1-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate
(193, 3.5 g, 9.1 mmol). MS (ESI+): m/z 386 [M+H].sup.+.
Step 2: Synthesis of Tert-Butyl
((1-((5-amino-2-chloropyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate
(194)
[0539] To a solution of tert-butyl
((1-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)
methyl)carbamate (193, 3 g, 7.8 mmol) in EtOH (30 mL) was added Fe
powder (6 g, 107 mmol) and sat. aq. NH.sub.4Cl (1 mL). The reaction
mixture was refluxed overnight. After cooling to room temperature,
the reaction mixture was filtered and the filtrate was concentrated
to afford the crude product, which was purified by column
chromatography to afford tert-butyl
((1-((5-amino-2-chloropyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate
(194, 2.2 g, 6.2 mmol). MS (ESI+): m/z 356 [M+H].sup.+.
Step 3: Synthesis of Methyl
2-((4-((1-(((tert-butoxycarbonyl)amino)methyl)
Cyclohexyl)amino)-2-chloropyrimidin-5-yl)amino)-2-oxoacetate
(195)
[0540] To a solution of tert-butyl
((1-((5-amino-2-chloropyrimidin-4-yl)amino)
cyclohexyl)methyl)carbamate (194, 2 g, 5.6 mmol) in THE (10 mL) was
added methyl 2-chloro-2-oxoacetate (0.7 g, 5.7 mmol) and
NaHCO.sub.3 (3 g, 35.7 mmol). After stirring at room temperature
for 4 h, the reaction mixture was quenched with H.sub.2O (20 mL)
and extracted with EtOAc (20 mL). The organic layer was separated
and washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The resulting residue was purified by column
chromatography to afford methyl
2-((4-((1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)amino)-2-chlorop-
yrimidin-5-yl)amino)-2-oxoacetate (195, 2.5 g, 5.6 mmol). MS (ESI):
m/z 442 [M+H].sup.+.
Step 4: Synthesis of
2'-Chloro-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1,2-e]purin]--
6'-one (196)
[0541] A solution of methyl
2-((4-((1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)
amino)-2-chloropyrimidin-5-yl)amino)-2-oxoacetate (195, 1.5 g, 3.4
mmol) in NMP (50 mL) was stirred at 100.degree. C. for 5h. The
reaction mixture was cooled to room temperature and purified by
column chromatography to afford
2'-chloro-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1,2-e]-
purin]-6'-one (196, 300 mg, 1.0 mmol). MS (ESI+): m/z 292
[M+H].sup.+.
Step 5: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spir-
o[cyclohexane-1,9'-pyrazino[1,2-e]purin]-6'-one (Compound 10)
[0542] Under N.sub.2 atmosphere, to a solution of
2'-chloro-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1,2-e]purin]--
6'-one (196, 300 mg, 1.0 mmol),
5-(4-methylpiperazin-1-yl)pyridin-2-amine (193 mg, 1.0 mmol),
Pd.sub.2(dba).sub.3 (92.23 mg, 0.1 mmol) and BINAP (125.4 mg, 0.2
mmol) in toluene (25 mL) was added LHMIDS (1.5 mL, 1 M in THF). The
reaction mixture was kept at 100.degree. C. overnight. After
cooling to room temperature, the reaction mixture was quenched with
water (25 mL) and extracted with EtOAc (25 mL). The organic layer
was separated and concentrated in vacuo. The resulting residue was
purified by prep TLC to provide
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)
amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1,2-e]purin]-6'--
one (COMPOUND 10, 1.1 mg, 0.0025 mmol). MS (ESI+): m/z 448
[M+H].sup.+; .sup.1H NMR (300 MHz, MeOD): .delta. 8.05-7.95 (m,
2H), 7.86 (d, J=9.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 4.03 (s, 2H),
3.28-3.22 (m, 4H), 3.08-2.91 (m, 2H), 2.78-2.70 (m, 4H), 2.42 (s,
3H), 1.82-1.70 (m, 5H), 1.47-1.39 (m, 3H).
Scheme 26: Synthesis of
(4aR,12aR)-10-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-1,3,4,4a,5,-
12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one
(Compound 22)
##STR00277## ##STR00278##
[0543] Step 1: Synthesis of (4aR,8aR)-Octahydroquinoxalin-2(1H)-one
(198)
[0544] To a mixture of (1R,2R)-cyclohexane-1,2-diamine (197, 1 g,
8.75 mmol) and NaHCO.sub.3 (2.2 g, 26.2 mmol) in THF (40 mL) at
0.degree. C. was added a solution of methyl 2-bromoacetate (1.34 g,
8.75 mmol) in THE (20 mL) in dropwise. After stirring at 0.degree.
C. for 2 h, the reaction mixture was warmed to room temperature and
stirred for an additional 1 h. The reaction mixture was then
quenched with water (40 mL) and extracted with EtOAc (50
mL.times.2). The combined organic phases were dried over
MgSO.sub.4, filtered and concentrated in vacuo. The resulting
residue was purified by column chromatography to provide
(4aR,8aR)-octahydroquinoxalin-2(1H)-one (198, 700 mg, 4.54
mmol).
Step 2: Synthesis of Ethyl
2-(methylthio)-4-((4aR,8aR)-3-oxooctahydroquinoxalin-1(2H)-yl)pyrimidine--
5-carboxylate (199)
[0545] To a solution of (4aR,8aR)-octahydroquinoxalin-2(1H)-one
(198, 4.7 g, 30.5 mmol) in DMF (140 mL) was added ethyl
chloro-2-(methylthio)pyrimidine-5-carboxylate (7 g, 30.1 mmol) and
K.sub.2CO.sub.3 (12.6 g, 91.2 mmol). After stirring at 80.degree.
C. for 2 h, the reaction mixture was cooled to room temperature,
quenched with water (250 mL) and extracted with EtOAc (150
mL.times.2). The combined organic phases were washed with water
(100 mL.times.2) and brine (100 mL). After concentration in vacuo,
the resulting residue was purified by column chromatography to
afford ethyl
2-(methylthio)-4-((4aR,8aR)-3-oxooctahydroquinoxalin-1(2H)-yl)pyrimidine--
5-carboxylate (199, 7.6 g, 21.6 mmol) as a white solid. MS (ESI+):
m/z 351 [M+H].sup.+.
Step 3: Synthesis of
Tert-Butyl(4aR,8aR)-4-(5-(ethoxycarbonyl)-2-(methylthio)pyrimidin-4-yl)-2-
-oxooctahydroquinoxaline-1(2H)-carboxylate (200)
[0546] To a solution of ethyl
2-(methylthio)-4-((4aR,8aR)-3-oxooctahydroquinoxalin-1
(2H)-yl)pyrimidine-5-carboxylate (199, 7.6 g, 21.6 mmol) in DCM
(200 mL) was added Boc.sub.2O (7.1 g, 32.5 mmol) and DMAP (7.9 g,
64.7 mmol). After stirring at room temperature for 12 h, the
reaction mixture was quenched with water (250 mL) and extracted
with DCM (100 mL.times.2). The combined organic phases were washed
with water (50 mL), brine (50 mL), dried over MgSO.sub.4, and
concentrated in vacuo. The resulting residue was purified by column
chromatography to provide
tert-butyl(4aR,8aR)-4-(5-(ethoxycarbonyl)-2-(methylthio)pyrimidin-4-yl)-2-
-oxooctahydroquinoxaline-1(2H)-carboxylate (200, 8.0 g, 17.7 mmol)
as a colorless oil. MS (ESI+): m/z 451 [M+H].sup.+.
Step 4: Synthesis of Tert-Butyl
(4aR,12aR)-7-hydroxy-10-(methylthio)-6-oxo-1,2,3,4,4a,12a-hexahydropyrimi-
do[5',4':4,5]pyrrolo[1,2-a]quinoxaline-5(6H)-carboxylate (201)
[0547] To a solution of tert-butyl
(4aR,8aR)-4-(5-(ethoxycarbonyl)-2-(methylthio)
pyrimidin-4-yl)-2-oxooctahydroquinoxaline-1(2H)-carboxylate (200,
7.0 g, 15.5 mmol) in THE (100 mL) at 0.degree. C. was added DBU
(3.5 g, 23.0 mmol). The reaction was gradually warmed to room
temperature. After stirring for 2 h, the reaction mixture was
concentrated in vacuo. The resulting residue was purified by column
chromatography to provide tert-butyl
(4aR,12aR)-7-hydroxy-10-(methylthio)-6-oxo-1,2,3,4,4a,12a-hexahydropyrimi-
do[5',4':4,5]pyrrolo[1,2-a]quinoxaline-5(6H)-carboxylate (201, 4.8
g, 11.8 mmol) as a green solid. MS (ESI+): m/z 405 [M+H].sup.+.
Step 5: Synthesis of Tert-Butyl
(4aR,12aR)-10-(methylthio)-6-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3-
,4,4a,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxaline-5(6H)-carb-
oxylate (202)
[0548] To a solution of tert-butyl
(4aR,12aR)-7-hydroxy-10-(methylthio)-6-oxo-1,2,3,4,4a,12a-hexahydropyrimi-
do[5',4':4,5]pyrrolo[1,2-a]quinoxaline-5(6H)-carboxylate (201, 200
mg, 0.49 mmol) and Et.sub.3N (0.3 mL, 2.16 mmol) in DCM (5 mL) at
0.degree. C. was added Tf.sub.2O (209 mg, 0.74 mmol). The reaction
was gradually warmed to room temperature. After stirring for 2 h,
the reaction mixture was concentrated in vacuo. The resulting
residue was purified by column chromatography to provide tert-butyl
(4aR,12aR)-10-(methylthio)-6-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3-
,4,4a,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxaline-5(6H)-carb-
oxylate (202, 180 mg, 0.34 mmol). MS (ESI+): m/z 536
[M+H].sup.+.
Step 6: Synthesis of Tert-Butyl
(4aR,12aR)-10-(methylthio)-6-oxo-1,2,3,4,4a,12a-hexahydropyrimido[5',4':4-
,5]pyrrolo[1,2-a]quinoxaline-5(6H)-carboxylate (203)
[0549] Under N.sub.2 atmosphere, to a solution of tert-butyl
(4aR,12aR)-10-(methylthio)-6-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3-
,4,4a,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxaline-5(6H)-carb-
oxylate (202, 250 mg, 0.47 mmol) and Pd(PPh.sub.3).sub.4 (54 mg,
0.47 mmol) in DMF (5 mL) was added Et.sub.3SiH (81.4 mg, 0.70
mmol). After stirring at 50.degree. C. for 12 h, the reaction
mixture was quenched with water (20 mL) and extracted with EtOAc
(10 mL.times.3). The combined organic layers were washed with water
(5 mL.times.2) and brine (5 mL), dried over MgSO.sub.4, and
concentrated in vacuo. The resulting residue was purified by column
chromatography to provide tert-butyl
(4aR,12aR)-10-(methylthio)-6-oxo-1,2,3,4,4a,12a-hexahydropyrimido[5',4':4-
,5]pyrrolo[1,2-a]quinoxaline-5(6H)-carboxylate (203, 70 mg, 0.18
mmol).
Step 7: Synthesis of
(4aR,12aR)-10-(Methylthio)-1,3,4,4a,5,12a-hexahydropyrimido[5',4':4,5]pyr-
rolo[1,2-a]quinoxalin-6(2H)-one (204)
[0550] To a solution of tert-butyl
(4aR,12aR)-10-(methylthio)-6-oxo-1,2,3,4,4a,12a-hexahydropyrimido[5',4':4-
,5]pyrrolo[1,2-a]quinoxaline-5(6H)-carboxylate (203, 70 mg, 0.18
mmol) in DCM (1.5 mL) was added TFA (0.5 mL). After stirring at
room temperature for 2 h, the reaction mixture was neutralized with
saturated aqueous NaHCO.sub.3 (20 mL) and extracted with DCM (10
mL.times.3). The combined organic phases were dried over MgSO.sub.4
and concentrated in vacuo. The resulting residue was purified by
column chromatography to provide
(4aR,12aR)-10-(methylthio)-1,3,4,4a,5,12a-hexahydropyrimido[5',4':4,5]pyr-
rolo[1,2-a]quinoxalin-6(2H)-one (204, 70 mg, 0.24 mmol).
Step 8: Synthesis of
(4aR,12aR)-10-(Methylsulfonyl)-1,3,4,4a,5,12a-hexahydropyrimido[5',4':4,5-
]pyrrolo[1,2-a]quinoxalin-6(2H)-one (205)
[0551] To a solution of
(4aR,12aR)-10-(methylthio)-1,3,4,4a,5,12a-hexahydropyrimido[5',4':4,5]pyr-
rolo[1,2-a]quinoxalin-6(2H)-one (204, 70 mg, 0.24 mmol) in DCM (5
mL) was added m-CPBA (126 mg, 0.73 mmol). After stirring at room
temperature for 12 h, the reaction mixture was neutralized with
saturated aqueous NaHCO.sub.3 (5 mL) and extracted with DCM (10
mL.times.2). The combined organic phases were dried over
MgSO.sub.4, and concentrated in vacuo. The resulting residue was
purified by column chromatography to provide
(4aR,12aR)-10-(methylsulfonyl)-1,3,4,4a,5,12a-hexahydropyrimido[5',4':4,5-
]pyrrolo[1,2-a]quinoxalin-6(2H)-one (205, 30 mg, 0.09 mmol). MS:
m/z 321 (MH.sup.+).
Step 9: Synthesis of
(4aR,12aR)-10-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-1,3,4,4a,5,-
12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one
(Compound 22)
[0552] To a solution of 5-(4-methylpiperazin-1-yl)pyridin-2-amine
(180 mg, 0.94 mmol) in toluene (10 mL) at 0.degree. C. was added
LHMDS (1.1 mL, 1.1 mmol, 1 M in TF). After stirring at 0.degree. C.
for 1 h, a solution of
(4aR,12aR)-10-(methylsulfonyl)-1,3,4,4a,5,12a-hexahydropyrimido[5',4':-
4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one (205, 300 mg, 0.94 mmol) in
toluene (5 mL) was added. The reaction was kept at 80.degree. C.
for 12 h. After cooling to room temperature, the reaction mixture
was quenched with saturated aqueous NaHCO.sub.3 (5 mL) and
extracted with DCM (10 mL.times.3). The combined organic phases
were dried over MgSO.sub.4, and concentrated in vacuo. The
resulting residue was purified by column chromatography to provide
((4aR,12aR)-10-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-1,3,4,4a,5-
,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one
(COMPOUND 22, 3.0 mg, 0.007 mmol). MS (ESI+): m/z 433 [M+H].sup.+;
.sup.1H NMR (300 MHz, MeOD+CDCl.sub.3): .delta. 9.35 (s, 1H), 8.69
(d, J=8.1 Hz, 1H), 8.52 (d, J=3.0 Hz, 1H), 7.95 (dd, J=9.0, 3.0 Hz,
1H), 7.80 (s, 1H), 4.62-4.44 (m, 2H), 4.23-4.13 (m, 1H), 3.78 (t,
J=4.8 Hz, 4H), 3.25 (t, J=4.8 Hz, 4H), 2.97 (s, 3H), 2.75-2.60 (m,
1H), 2.52-2.40 (m, 2H), 2.26-2.04 (m, 4H).
Scheme 27: Synthesis of
(4aS,12aS)-10-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-1,3,4,4a,5,-
12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one
(Compound 23)
##STR00279## ##STR00280##
[0554] COMPOUND 23 was prepared according to the experimental
procedure described in Scheme 26 for the synthesis of COMPOUND 22.
MS (ESI+): m/z 433 [M+H].sup.+; .sup.1H NMR (300 MHz,
MeOD+CDCl.sub.3): .delta. 8.81 (s, 1H), 8.13-8.10 (m, 1H), 7.96 (d,
J=2.7 Hz, 1H), 7.48-7.44 (m, 1H), 7.24 (s, 1H), 4.01-3.94 (m, 2H),
3.66-3.63 (m, 1H), 3.29-3.25 (m, 4H), 2.81-2.78 (m, 4H), 2.48 (s,
3H), 2.19-2.08 (m, 2H), 1.99-1.86 (m, 2H), 1.71-1.46 (m, 3H).
Scheme 28: Synthesis of
(4aS,12aR)-10-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-1,3,4,4a,5,-
12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one
(Compound 24)
##STR00281## ##STR00282##
[0556] COMPOUND 24 was prepared according to the experimental
described in Scheme 26 for the synthesis of COMPOUND 22. MS (ESI+):
m/z 433 [M+H].sup.+; .sup.1H NMR (300 MHz, MeOH+CDCl.sub.3):
.delta. 8.83 (s, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.52-7.47 (m,
1H), 7.20 (s, 1H), 4.19-4.13 (m, 2H), 3.64 (s, 1H), 3.29-3.26 (m,
4H), 2.80-2.78 (m, 4H), 2.48 (s, 3H), 2.15-1.99 (m, 4H), 1.95-1.83
(m, 3H).
Scheme 29: Synthesis of
N-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-5'H-spiro[cyclohexane-1,6'-imi-
dazo[2'',1'':3',4']pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-9'-amine
(Compound 25)
##STR00283##
[0557] Step 1: Synthesis of
N.sup.6'-(2,2-Diethoxyethyl)-N.sup.2'-(5-(4-methylpiperazin-1-yl)
pyridin-2-yl)-8'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d-
]pyrimidine]-2',6'-diamine (223)
[0558] To a solution of
N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6'-(methylthio)-8'H-spiro[cycl-
ohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-amine
(222, 100 mg, 0.20 mmol) in toluene (5 mL) was added
2,2-diethoxyethan-1-amine (100 mg, 0.37 mmol). After stirring under
reflux for 48 h, the reaction mixture was cooled to room
temperature and concentrated in vacuo. The resulting residue was
purified by prep TLC to afford
N6'-(2,2-diethoxyethyl)-N2'-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8'H--
spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-2',6'--
diamine (223, 70 mg, 0.12 mmol). MS (ESI+): m/z 562
[M+H].sup.+.
Step 2: Synthesis of
N-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-5'H-spiro[cyclohexane-1,6'-imi-
dazo[2'',1'':3',4']pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-9'-amine
(Compound 25)
[0559] To a solution of
N6'-(2,2-diethoxyethyl)-N2'-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8'H--
spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-2',6'--
diamine (223, 65 mg, 0.11 mmol) in toluene (3 mL) was added TFA (3
drops). After stirring under reflux for 1 h, the reaction mixture
was cooled to room temperature and concentrated in vacuo. The
resulting residue was purified by prep TLC to afford
N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-5'H-spiro[cyclohexane-1,6'-imi-
dazo[2'',1'':3',4']pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-9'-amine
(COMPOUND 25, 6.9 mg, 0.015 mmol). MS (ESI+): m/z 470 [M+H].sup.+;
.sup.1H NMR (300 MHz, MeOD): .delta. 8.74 (s, 1H), 8.06 (d, J=12.0
Hz, 1H), 7.98 (d, J=3.3 Hz, 1H), 7.58 (dd, J=9.9, 4.2 Hz, 1H), 7.24
(d, J=1.2 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H), 7.04 (s, 1H), 4.55 (s,
2H), 3.41-3.37 (m, 4H), 3.16-3.12 (m, 6H), 2.73 (s, 3H), 1.95-1.86
(m, 5H), 1.75-1.44 (m, 3H).
Scheme 30: Synthesis of
N-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-8'H-spiro[cyclohexane-1,9'-imi-
dazo[2,1-h]pteridin]-2'-amine (Compound 26)
##STR00284##
[0560] Synthesis of
N.sup.4-(1-(Aminomethyl)cyclohexyl)-2-chloropyrimidine-4,5-diamine
(225)
[0561] To a solution of tert-butyl
((1-((5-amino-2-chloropyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate
(224, 300 mg, 0.84 mmol) in DCM (10 mL) was added TFA (3 mL). After
stirring at room temperature for 2 h, the reaction mixture was
neutralized with saturated aqueous NaHCO.sub.3 and extracted with
DCM (10 mL.times.3). The combined organic phases were dried over
MgSO.sub.4, filtered and concentrated in vacuo to provide
N.sup.4-(1-(aminomethyl)cyclohexyl)-2-chloropyrimidine-4,5-diamine
(225, 200 mg, 0.78 mmol), which was used for the next step without
further purification.
Step 2: Synthesis of
2'-Chloro-6',8'-dihydro-5'H-spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridin-
e] (226)
[0562] To a solution of
N.sup.4-(1-(aminomethyl)cyclohexyl)-2-chloropyrimidine-4,5-diamine
(225, 200 mg, 0.78 mmol) in EtOH (10 mL) was added glyoxal (113 mg,
0.78 mmol). After stirred at 80.degree. C. for 2 h, the reaction
mixture was concentrated in vacuo. The resulting residue was
purified by column chromatography to provide
2'-chloro-6',8'-dihydro-5'H-spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridin-
e] (226, 80 mg, 0.29 mmol). MS (ESI+): m/z 278 [M+H].sup.+.
Step 3: Synthesis of
2'-Chloro-8'H-spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridine]
(227)
[0563] To a solution of
2'-chloro-6',8'-dihydro-5'H-spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridin-
e] (226, 60 mg, 0.22 mmol) in toluene (5 mL) was added Pd/C (10
mg). After stirred at 110.degree. C. for 12 h, the reaction mixture
was filtered. The filtrate was concentrated in vacuo. The resulting
residue was purified by column chromatography to provide
2'-chloro-8'H-spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridine] (227,
20 mg, 0.07 mmol). MS (ESI+): m/z 276 [M+H].sup.+.
Step 4: Synthesis of
N-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-8'H-spiro
[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-2'-amine (Compound
26)
[0564] Under N.sub.2 atmosphere, to a solution of
2'-chloro-8'H-spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridine] (227,
80 mg, 0.29 mmol), 5-(4-methylpiperazin-1-yl)pyridin-2-amine (55
mg, 0.29 mmol), Pd.sub.2(dba).sub.3 (26.4 mg, 0.03 mmol) and BINAP
(35.2 mg, 0.06 mmol) in toluene (20 mL) was added LHMDS (0.4 mL,
0.4 mmol). After stirred at 100.degree. C. for 12 h, the reaction
mixture was cooled to room temperature, quenched with water (10 mL)
and extracted with EtOAc (10 mL). The organic phase was separated
and concentrated in vacuum. The resulting residue was purified by
column chromatography to provide
N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-8'H-spiro[cyclohexane-1,9'-imi-
dazo[2,1-h]pteridin]-2'-amine (COMPOUND 26, 11.1 mg, 0.02 mmol). MS
(ESI+): m/z 432 [M+H].sup.+; .sup.1H NMR (300 MHz, MeOD): .delta.
8.47 (s, 1H), 8.03-8.09 (m, 2H), 7.90 (s, 1H), 7.39-7.43 (m, 1H),
4.00 (s, 2H), 3.28-3.36 (m, 4H), 2.88 (d, J=12.6 Hz, 2H), 2.76-2.82
(m, 4H), 2.49 (s, 3H), 1.68-1.89 (m, 5H), 1.28-1.47 (m, 3H).
Scheme 31: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)
amino)-5'H-spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-6'(8'H)-one
(Compound 27)
##STR00285## ##STR00286##
[0565] Step 1: Synthesis of Tert-Butyl
((1-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-nitropyrimidin--
4-yl)amino)cyclohexyl)methyl)carbamate (230)
[0566] Under N.sub.2 atmosphere, to a mixture of tert-butyl
((1-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate
(228, 1.0 g, 2.6 mmol), 5-(4-methylpiperazin-1-yl)pyridin-2-amine
(229, 0.6 g, 3.1 mmol), Pd.sub.2(dba).sub.3 (120 mg, 0.13 mmol),
and BINAP (160 mg, 0.25 mmol) in toluene (30 mL) was added LHMDS
(0.52 mL, 1 M in THF). The reaction was kept at 100.degree. C.
overnight and was then quenched with water (50 mL) and extracted
with EtOAc (50 mL). The organic layer was separated and
concentrated in vacuo. The resulting residue was purified by column
chromatography to afford tert-butyl
((1-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-nitropyrimidin--
4-yl)amino)cyclohexyl)methyl)carbamate (230, 400 mg, 0.74 mmol). MS
(ESI+): m/z 542 [M+H].sup.+.
Step 2: Synthesis of Tert-Butyl
((1-((5-amino-2-((5-(4-methylpiperazin-1-yl)
pyridin-2-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate
(231)
[0567] To a solution of tert-butyl
((1-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-nitropyrimidin--
4-yl)amino)cyclohexyl)methyl)carbamate (230, 180 mg, 0.33 mmol) in
EtOH (10 mL) was added Fe powder (200 mg, 3.57 mmol) and aqueous
NH.sub.4Cl solution (1 mL). After stirring under reflux overnight,
the reaction mixture was cooled to room temperature, filtered and
concentrated in vacuo to afford the crude product, which was
purified by column chromatography to afford tert-butyl
((1-((5-amino-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin--
4-yl)amino)cyclohexyl)methyl)carbamate (231, 40 mg, 0.08 mmol). MS
(ESI+): m/z 512 [M+H].sup.+.
Step 3: Synthesis of
N.sup.4-(1-(Aminomethyl)cyclohexyl)-N.sup.2-(5-(4-methylpiperazin-1-yl)py-
ridin-2-yl)pyrimidine-2,4,5-triamine (232)
[0568] A solution of tert-butyl
((1-((5-amino-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin--
4-yl)amino)cyclohexyl)methyl)carbamate (231, 270 mg, 0.53 mmol) in
sat. HCl/MeOH solution (5 mL) was stirred at room temperature for 3
h. Then the mixture was concentrated in vacuo. To the resulting
residue was added MeOH (5 mL) and K.sub.2CO.sub.3 (300 mg). The
mixture was heated to reflux for 1 h. After cooling to room
temperature, the mixture was filtered and the filtrate was
concentrated to afford
N4-(1-(aminomethyl)cyclohexyl)-N2-(5-(4-methylpiperazin-1-yl)pyridin-2-yl-
)pyrimidine-2,4,5-triamine (232, 180 mg, 0.44 mmol), which was used
for the next step without further purification. MS (ESI): m/z 412
[M+H].sup.+.
Step 4: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-5'H-spir-
o[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-6'(6a'H)-one (233)
[0569] To a mixture of
N.sup.4-(1-(aminomethyl)cyclohexyl)-N.sup.2-(5-(4-methylpiperazin-1-yl)py-
ridin-2-yl)pyrimidine-2,4,5-triamine (232, 170 mg, 0.41 mmol),
K.sub.2CO.sub.3 (300 mg, 2.17 mmol) in EtOH (3 mL) was added a
solution of ethyl 2-oxoacetate (85 mg, 0.83 mmol) in toluene (0.1
mL). After stirring at 80.degree. C. for 2 h, the reaction mixture
was filtered and the filtrate was concentrated to afford the
residue, which was purified by prep TLC to afford
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-5'H-spir-
o[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-6'(6a'H)-one (233, 80
mg, 0.18 mmol). MS (ESI+): m/z 450 [M+H].sup.+.
Step 5: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-5'H-spiro[cyclohexane--
1,9'-imidazo[2,1-h]pteridin]-6'(8'H)-one (Compound 27)
[0570] A solution of
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-5'H-spir-
o[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-6'(6a'H)-one (233, 65
mg, 0.14 mmol) in DMSO (2 mL) was kept at 100.degree. C. for 6 h.
After cooled to room temperature, the reaction mixture was purified
by prep TLC to afford
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5'H-spiro[cyclohexane--
1,9'-imidazo[2,1-h]pteridin]-6'(8'H)-one (COMPOUND 27, 6.1 mg,
0.014 mmol). MS (ESI+): m/z 448 [M+H].sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6+D.sub.2O): .delta. 8.04 (s, 1H), 7.97 (s, 1H), 7.93
(d, J=9.6 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 3.91 (s, 2H), 3.10-3.05
(m, 2H), 3.05-3.03 (m, 2H), 3.00-2.96 (m, 2H), 2.84-2.76 (m, 5H),
2.02-1.96 (m, 2H), 1.72-1.61 (m, 5H), 1.40-1.30 (m, 3H).
Scheme 32: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyrimidin-2-yl)
amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrol-
o[2,3-d]pyrimidin]-6'-one (Compound 28)
##STR00287##
[0571] Step 1: Synthesis of
5-(4-Methylpiperazin-1-yl)pyrimidin-2-amine (235)
[0572] Under N.sub.2 atmosphere, to a solution of
5-bromopyrimidin-2-amine (234, 2 g, 11.5 mmol) in toluene (200 mL)
was added 1-methylpiperazine (32 g, 319.5 mmol), t-BuONa (1.8 g,
18.7.20 mmol), Pd.sub.2(dba).sub.3 (520 mg, 0.57 mmol) and
John-phos (680 mg, 2.28 mmol). After stirred at 100.degree. C. for
48 h, the reaction mixture was concentrated in vacuo. The resulting
residue was purified by column chromatography to provide
5-(4-methylpiperazin-1-yl)pyrimidin-2-amine (235, 200 mg, 1.0
mmol). MS (ESI+): m/z 194 [M+H].sup.+.
Step 2: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyrimidin-2-yl)amino)-7',8'-dihydro-6'H-sp-
iro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(Compound 28)
[0573] Under N.sub.2 atmosphere, to a solution of
5-(4-methylpiperazin-1-yl)pyrimidin-2-amine (235, 13 mg, 0.07
mmol),
2'-chloro-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyr-
rolo[2,3-d]pyrimidin]-6'-one (20 mg, 0.07 mmol) in dioxane (40 mL)
was added Pd(OAc).sub.2 (3 mg, 0.01 mmol), X-Phos (6 mg, 0.01 mmol)
and Cs.sub.2CO.sub.3 (45 mg, 0.14 mmol). After stirred at
100.degree. C. for 4 h, the reaction mixture was cooled to room
temperature, quenched with water (20 mL) and extracted with EtOAc
(10 mL.times.3). The combined organic phases were dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The resulting residue was
purified by prep TLC to provide
2'-((5-(4-methylpiperazin-1-yl)pyrimidin-2-yl)amino)-7',8'-dihydro-6'H-sp-
iro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(COMPOUND 28, 2.8 mg, 0.0063 mmol). MS (ESI+): m/z 448 [M+H].sup.+;
.sup.1H NMR (300 MHz, MeOD): .delta. 8.89 (s, 1H), 8.40 (br s, 2H),
7.26 (s, 1H), 3.77 (s, 2H), 3.29-3.20 (m, 4H), 3.07 (t, J=11.4 Hz,
2H), 2.80-2.72 (m 4H), 2.45 (s, 3H), 2.00-1.90 (m, 2H), 1.86-1.76
(m, 3H), 1.60-1.47 (m, 3H).
Scheme 33: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-6'H-spiro[cyclohexane--
1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6',8'(7'H)-dione
(Compound 30)
##STR00288## ##STR00289##
[0574] Step 1: Synthesis of
1-((2-Chloro-5-iodopyrimidin-4-yl)amino)cyclohexane-1-carboxamide
(237)
[0575] To a solution 2,4-dichloro-5-iodopyrimidine (236, 26 g, 94.6
mmol) and 1-aminocyclohexane-1-carboxamide (15 g, 105.4 mmol) in
DMAc (260 mL) was added NaHCO.sub.3 (33 g, 392.8 mmol). After
stirring at 80.degree. C. for 12 h, the reaction mixture was cooled
to room temperature, quenched with water (700 mL) and extracted
with EtOAc (300 mL.times.3). The combined organic phases were
washed with water (200 mL.times.2), brine (100 mL) and dried over
anhydrous Na.sub.2SO.sub.4. After concentration, the resulting
residue was purified by column chromatography to provide
1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexane-1-carboxamide
(237.12 g, 31.5 mmol). MS (ESI+): m/z 381 [M+H].sup.+.
Step 2: Synthesis of
1-((2-Chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexa-
ne-1-carboxamide (239)
[0576] Under N.sub.2 atmosphere, to a solution of
1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexane-1-carboxamide
(237, 4 g, 10.5 mmol) and DIPEA (2.7 g, 20.9 mmol) in THE (170 mL)
was added CuI (200 mg, 1.05 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2
(294 mg, 0.42 mmol). After stirring at room temperature for 10 min,
a solution of 3,3-diethoxyprop-1-yne (238, 1.6 g, 12.5 mmol) in THE
(5 mL) was added in dropwise and the reaction was stirred at room
temperature for 12 h. After concentration of the mixture in vacuo,
the resulting residue was purified by column chromatography to
provide
1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexa-
ne-1-carboxamide (239, 2.4 g, 6.3 mmol). MS (ESI+): m/z 381
[M+H].sup.+.
Step 3: Synthesis of
1-(2-Cloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]
pyrimidin-7-yl)cyclohexane-1-carboxamide (240)
[0577] To a solution of
1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexa-
ne-1-carboxamide (239, 2 g, 5.25 mmol) was added TBAF (20 mL, 20
mmol, 1M in TF). After stirring at 60.degree. C. for 2h, the
reaction mixture was cooled to room temperature, quenched with
water (70 mL) and extracted with EtOAc (50 mL.times.3). The
combined organic phases were dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The resulting residue was purified by
column chromatography to provide
1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-
e-1-carboxamide (240, 400 mg, 1.05 mmol). MS (ESI+): m/z 381
[M+H].sup.+.
Step 4: Synthesis of
1-(2-Chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)
cyclohexane-1-carboxamide (241)
[0578] To a solution of
1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-
e-1-carboxamide (240, 800 mg, 2.1 mmol) in THE (4 mL) was added
water (4 mL) and HOAc (4 mL). After stirring at 60.degree. C. for
2h, the reaction mixture was quenched with saturated aqueous
NaHCO.sub.3 and extracted with EtOAc (100 mL.times.3). The combined
organic phases were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The resulting residue was purified by column
chromatography to provide
1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-carbox-
amide (241, 527 mg, 1.72 mmol).
Step 5: Synthesis of
2'-Chloro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]
pyrrolo[2,3-d]pyrimidine]-6',8'(7'H)-dione (242)
[0579] To a solution of
1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)
cyclohexane-1-carboxamide (241, 100 mg, 0.33 mmol) in t-BuOH (5 mL)
and acetonitrile (1 mL) was added NaH.sub.2PO.sub.4 (405 mg, 3.38
mmol) and 2-methyl-2-butene (183 mg, 2.6 mmol). The reaction
mixture was brought to 0.degree. C. was a solution of NaClO.sub.2
(405 mg, 4.48 mmol) in water (10 mL) was added dropwise. After
stirring at room temperature for 12 h, the reaction mixture was
extracted with EtOAc (10 mL.times.2). The combined organic phases
were washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The resulting residue was purified by column
chromatography to provide
2'-chloro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyr-
imidine]-6',8'(7'H)-dione (242.95 mg, 0.31 mmol).
Step 6: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-6'H-spiro[cyclohexane--
1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6',8'(7'H)-dione
(Compound 30)
[0580] Under N.sub.2 atmosphere, to a solution of
2'-chloro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyr-
imidine]-6',8'(7'H)-dione (242, 100 mg, 0.33 mmol),
5-(4-methylpiperazin-1-yl)pyridin-2-amine (76 mg, 0.4 mmol) in
dioxane (5 mL) was added Pd(OAc).sub.2 (7.4 mg, 0.03 mmol),
Cs.sub.2CO.sub.3 (320 mg, 0.98 mmol) and X-Phos (62 mg, 0.13 mmol).
The reaction was stirred at 100.degree. C. for 12 h. After cooled
to room temperature, the reaction mixture was quenched with water
(10 mL) and extracted with EtOAc (10 mL.times.2). The combined
organic phases were concentrated in vacuo. The resulting residue
was purified by prep TLC to provide
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)
amino)-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimi-
dine]-6',8'(7'H)-dione (COMPOUND 30, 2.9 mg, 0.0063 mmol). MS
(ESI+): m/z 461 [M+H].sup.+; .sup.1HNMR (300 MHz, MeOD+CDCl.sub.3):
.delta. 8.93 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.48-7.42 (m,
2H), 3.32-3.21 (m, 6H), 2.93-2.84 (m, 4H), 2.55 (s, 3H), 2.30-2.15
(m, 2H), 2.13-2.02 (m, 2H), 2.00-1.91 (m, 1H), 1.91-1.78 (m, 2H),
1.70-1.59 (m, 1H).
Scheme 34: Synthesis of
N-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-6'H-spiro[cyclohexane-1,9'-pyr-
azino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-amine (Compound 31)
##STR00290## ##STR00291##
[0581] Step 1: Synthesis of (1-Aminocyclohexyl)methanol
Intermediate (244)
[0582] To a solution of 1-aminocyclohexane-1-carboxylic acid (243,
10 g, 69.9 mmol) in anhydrous THE (300 mL) at 5.degree. C. was
added LiAlH.sub.4 (8 g, 210.5 mmol) in portions over 30 min. The
reaction was then refluxed for 12 h. After cooling to 5.degree. C.
with an ice-bath, to the reaction mixture was added 8 mL of
H.sub.2O, 8 mL of 15% NaOH aqueous, followed by addition of 16 mL
of H.sub.2O. After the completion of addition, the mixture was
stirred for 30 min. Anhydrous magnesium sulfate (20 g) was added.
After stirring for 1h, the mixture was filtered and the filter cake
was washed with EtOAc (50 mL). The filtrate was concentrated to
provide (1-aminocyclohexyl)methanol (244, 5.2 g, 40 mmol) as a
yellow oil, which was used in the next step without further
purification. MS (ESI+): m/z 130 [M+H].sup.+.
Step 1: Synthesis of Tert-Butyl Prop-2-yn-1-ylcarbamate
Intermediate (246)
[0583] To a solution of prop-2-yn-1-amine (245, 2.1 g, 38.2 mmol)
in THE (30 mL) was added (Boc).sub.2O (15 g, 68.8 mmol). After
stirring at room temperature for 1 h, the reaction mixture was
concentrated in vacuo to afford the residue, which was purified by
column chromatography with a gradient elution of hexane (100%) to
hexane (80%) and EtOAc (20%) to provide tert-butyl
prop-2-yn-1-ylcarbamate (246, 4.1 g, 26.4 mmol); .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 4.70 (s, 1H), 3.85 (d, J=3.0 Hz, 2H),
2.15 (t, J=2.7 Hz, 1H), 1.38 (s, 9H).
Step 1: Synthesis of (1-((2-Chloro-5-iodopyrimidin-4-yl)amino)
cyclohexyl)methanol (248)
[0584] To a solution of 2,4-dichloro-5-iodopyrimidine (247, 2.7 g,
9.8 mmol) in DMA (20 mL) was added (1-aminocyclohexyl)methanol
(244, 1.4 g, 10.8 mmol) and NaHCO.sub.3 (5 g, 59.5 mol). The
reaction was stirred at 80.degree. C. for 4 h. After cooling to
room temperature, the reaction mixture was quenched with water (40
mL) and extracted with EtOAc (50 mL.times.2). The combined organic
phases were concentrated in vacuo to afford the residue, which was
purified by column chromatography to afford
(1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)methanol (248,
1.5 g, 4.1 mmol). MS (ESI): m/z 368 [M+H].sup.+.
Step 2: Synthesis of
1-((2-Chloro-5-iodopyrimidin-4-yl)amino)cyclohexane-1-carbaldehyde
(249)
[0585] To a solution of
(1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)methanol (248,
1 g, 2.7 mmol) in DCM (50 mL) at room temperature was added PCC
(1.1 g, 5.1 mmol). After stirring at room temperature overnight,
the solid was removed. The filter cake was washed with DCM (100 mL)
and the filtrate was washed with saturated sodium bicarbonate
solution (50 mL). The organic layer was separated and concentrated
in vacuo to afford the residue, which was purified by column
chromatography with a gradient elution hexane (95%) and EtOAc (5%)
to hexane (80%) and EtOAc (20%) to provide
1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexane-1-carbaldehyd-
e (249, 0.3 g, 0.8 mmol). MS (ESI+): m/z 366 [M+H].sup.+.
Step 3: Synthesis of Tert-Butyl
(3-(2-Chloro-4-((1-formylcyclohexyl)amino)
pyrimidin-5-yl)prop-2-yn-1-yl)carbamate (250)
[0586] Under N.sub.2 atmosphere, to a solution of
1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexane-1-carbaldehyde
(249, 300 mg, 0.8 mmol) and TEA (165 mg, 1.6 mmol) in anhydrous THE
(15 mL) at room temperature was added CuI (15.5 mg, 0.1 mmol) and
PdCl.sub.2(PPh.sub.3).sub.2 (28.7 mg, 0.04 mmol), followed by the
addition of tert-butyl prop-2-yn-1-ylcarbamate (246, 165 mg, 1.1
mmol) dropwise. After stirring at room temperature overnight, the
reaction mixture was quenched with water (20 mL) and extracted with
EtOAc (20 mL). The organic layer was separated and washed with
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford the crude product, which was purified by column
chromatography to provide tert-butyl
(3-(2-chloro-4-((1-formylcyclohexyl)amino)pyrimidin-5-yl)prop-2-yn-1-yl)c-
arbamate (250, 165 mg, 0.4 mmol). MS (ESI) m/z 393 [M+H].sup.+.
Step 4: Synthesis of Tert-Butyl
((2-chloro-7-(1-formylcyclohexyl)-7H-pyrrolo
[2,3-d]pyrimidin-6-yl)methyl)carbamate (251)
[0587] To a solution of tert-butyl
(3-(2-chloro-4-((1-formylcyclohexyl)amino)pyrimidin-5-yl)prop-2-yn-1-yl)c-
arbamate (250, 800 mg, 2.0 mmol) in anhydrous THE (5 mL) was added
TBAF (12 mL, 12 mmol, 1 M in THF). The reaction was stirred at
60.degree. C. for 1 h. After cooling to room temperature, the
reaction mixture was quenched with H.sub.2O (10 mL) and extracted
with EtOAc (10 mL). The organic layer was separated and washed with
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford the crude product, which was purified by column
chromatography to afford
tert-butyl((2-chloro-7-(1-formylcyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-6--
yl)methyl)carbamate (251, 370 mg, 0.94 mmol). MS (ESI+): m/z 393
[M+H].sup.+.
Step 5: Synthesis of 2'-Chloro-6'H-spiro[cyclohexane-1,9'-pyrazino
[1',2':1,5]pyrrolo[2,3-d]pyrimidine] (252)
[0588] To a solution of tert-butyl
((2-chloro-7-(1-formylcyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methyl)-
carbamate (251, 100 mg, 0.25 mmol) in DCM (1 mL) was added TFA (3
mL). After stirring at room temperature for 2 h, the reaction
mixture was neutralized with saturated sodium bicarbonate solution
(5 mL) and extracted with EtOAc (5 mL.times.2). The combined
organic phases were concentrated in vacuo and purified by prep TLC
to afford
2'-chloro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyr-
imidine] (252, 55 mg, 0.20 mmol) as a white solid. MS (ESI+): m/z
275 [M+H].sup.+.
Step 6: Synthesis of
N-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-6'H-spiro
[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-amine
(Compound 31)
[0589] Under N.sub.2 atmosphere, to a solution of
2'-chloro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyr-
imidine (252, 100 mg, 0.36 mmol) and
5-(4-methylpiperazin-1-yl)pyridin-2-amine (80 mg, 0.41 mmol) in
anhydrous 1,4-dioxane (5 mL) was added Pd(OAc).sub.2 (40 mg, 0.18
mmol), X-phos (100 mg, 0.21 mmol) and Cs.sub.2CO.sub.3 (520 mg,
1.60 mmol). The reaction mixture was stirred at 110.degree. C.
overnight. After cooling to room temperature, the reaction mixture
was quenched with water (10 mL) and extracted with EtOAc (20 mL).
The organic phase was separated and concentrated in vacuo to afford
the residue, which was purified by prep HPLC to provide
N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-6'H-spiro[cyclohexane-1,9'-pyr-
azino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-amine (COMPOUND 31,
15.2 mg, 0.03 mmol). MS (ESI+): m/z 431 [M+H].sup.+; .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 8.68 (s, 1H), 8.30 (s, 1H), 8.22 (d,
J=9.3 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 7.93 (s, 1H), 7.25 (dd,
J=9.0, 3.0 Hz, 1H), 6.55 (s, 1H), 4.00 (s, 2H), 3.17-3.14 (m, 4H),
2.83 (td, J=13.5, 4.2 Hz, 2H), 2.62-2.59 (m, 4H), 2.34 (s, 3H),
1.82-1.72 (m, 6H), 1.59-1.46 (m, 2H).
Scheme 35: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-6',7'-dihydro-8'H-spir-
o[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-8'-one
(Compound 33)
##STR00292## ##STR00293##
[0590] Step 1: Synthesis of
2,4-Dichloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidine (254)
[0591] Under N.sub.2 atmosphere, to a solution of
2,4-dichloro-5-iodopyrimidine (253, 1 g, 3.65 mmol) and DIEA (1.42
g, 10.99 mmol) in THE (20 mL) was added CuI (70 mg, 0.37 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (100 mg, 0.14 mmol). After stirring at
room temperature for 10 min, a solution of 3,3-diethoxyprop-1-yne
(470 mg, 3.67 mmol) in THE (5 mL) was added. After stirring at room
temperature for 12 h, the reaction mixture was quenched with water
(20 mL) and extracted with EtOAc (20 mL.times.2). The combined
organic phases were concentrated in vacuo. The resulting residue
was purified by column chromatography to provide
2,4-dichloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidine (254, 1.1 g,
4.0 mmol).
Step 2: Synthesis of Methyl
1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)
Pyrimidin-4-yl)amino)cyclohexane-1-carboxylate (255)
[0592] A solution of
2,4-dichloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidine (254, 600 mg,
2.18 mmol) and methyl 1-aminocyclohexane-1-carboxylate (336 mg,
2.14 mmol) and DIEA (619 mg, 4.8 mmol) in DMAc (20 mL) was stirred
at 60.degree. C. for 12 h. After cooling to room temperature, the
reaction mixture was quenched with water (50 mL) and extracted with
EtOAc (30 mL.times.3). The combined organic phases were washed with
brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The resulting residue was purified by column chromatography
to afford methyl
1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexa-
ne-1-carboxylate (255, 200 mg, 0.50 mmol).
Step 3: Synthesis of Methyl
1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo
[2,3-d]pyrimidin-7-yl)cyclohexane-1-carboxylate (256)
[0593] To a solution of methyl
1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexa-
ne-1-carboxylate (255, 50 mg, 0.13 mmol) in THE (1 mL) was added
TBAF (0.4 mL, 0.4 mmol, 1M in THF). After stirring at 60.degree. C.
for 2 h, the reaction mixture was quenched with water (15 mL) and
extracted with EtOAc (10 mL.times.3). The combined organic phases
were dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The resulting residue was purified by column chromatography
to provide methyl
1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-
e-1-carboxylate (256, 20 mg, 0.05 mmol). MS (ESI+): m/z 396
[M+H].sup.+.
Step 4: Synthesis of Methyl
1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-carbox-
ylate (257)
[0594] To a solution of methyl
1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-
e-1-carboxylate (256, 300 mg, 0.75 mmol) in THE (4 mL) was added
water (4 mL) and HOAc (4 mL). After stirring at 60.degree. C. for 2
h, the reaction mixture was quenched with saturated aqueous
NaHCO.sub.3 and extracted with EtOAc (100 mL.times.3). The combined
organic phases were dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The resulting residue was purified by column chromatography
to provide methyl
1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-carbox-
ylate (257, 250 mg, 0.78 mmol).
Step 5: Synthesis of Methyl
(E)-1-(2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
cyclohexane-1-carboxylate (258)
[0595] To a solution of methyl
1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-carbox-
ylate (257, 250 mg, 0.78 mmol) in EtOH (2 mL) at room temperature
was added hydroxylamine hydrochloride (107 mg, 1.54 mmol). After
stirring at 80.degree. C. for 30 min, the reaction mixture was
quenched with water (15 mL) and extracted with EtOAc (10
mL.times.3). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting
residue was purified by column chromatography to provide methyl
(E)-1-(2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
cyclohexane-1-carboxylate (258, 220 mg, 0.65 mmol). MS (ESI+): m/z
337 [M+H].sup.+.
Step 6: Synthesis of
2'-Chloro-6',7'-dihydro-8'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyr-
rolo[2,3-d]pyrimidin]-8'-one (259)
[0596] Under N.sub.2 atmosphere, to a solution of methyl
(E)-1-(2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
cyclohexane-1-carboxylate (258, 200 mg, 0.59 mmol) in EtOH (4 mL)
was added saturated aqueous NH.sub.4Cl (8 drops) and Zn power (193
mg, 2.95 mmol). After stirring at 80.degree. C. for 2 h, the
reaction mixture was cooled to room temperature and filtered. The
filtrate was concentrated in vacuo. The resulting residue was
purified by column chromatography to provide
2'-chloro-6',7'-dihydro-8'H-spiro[cyclohexane-1,9'-pyrazino[1',2'-
:1,5]pyrrolo[2,3-d]pyrimidin]-8'-one (259, 150 mg, 0.52 mmol). MS
(ESI-): m/z 289 [M-H].sup.-.
Step 7: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-6',7'-dihydro-8'H-spir-
o[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-8'-one
(Compound 33)
[0597] Under N.sub.2 atmosphere, to a solution of
5-(4-methylpiperazin-1-yl)pyrimidin-2-amine (40 mg, 0.21 mmol),
2'-chloro-6',7'-dihydro-8'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyr-
rolo[2,3-d]pyrimidin]-8'-one (259.50 mg, 0.17 mmol) in dioxane (4
mL) at room temperature was added Cs.sub.2CO.sub.3 (160 mg, 0.49
mmol), Pd(OAc).sub.2 (4 mg, 0.02 mmol) and X-Phos (16 mg, 0.03
mmol). After stirring at 100.degree. C. for 12 h, the reaction
mixture was cooled to room temperature and quenched with water (10
mL) and extracted with EtOAc (10 mL.times.2). The combined organic
phases were concentrated in vacuo. The resulting residue was
purified by prep TLC to provide
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6',7'-dihydro-8'H-spir-
o[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-8'-one
(COMPOUND 33, 4.6 mg, 0.01 mmol). MS (ESI+): m/z 447 [M+H].sup.+;
.sup.1H NMR (300 MHz, MeOD): .delta. 8.64 (s, 1H), 8.12 (d, J=9.4
Hz, 1H), 7.99 (s, 1H), 7.59 (d, J=9.6 Hz, 1H), 6.38 (s, 1H), 4.64
(s, 2H), 3.42-3.33 (m, 4H), 3.23-3.13 (m, 6H), 2.75 (s, 3H),
2.25-2.02 (m, 4H), 1.91-1.72 (m, 3H), 1.67-1.45 (m, 1H).
Scheme 36: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-2,3,5,6,7',8'-hexahydr-
o-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(Compound 34)
##STR00294## ##STR00295##
[0598] Synthesis of 4-Aminotetrahydro-2H-pyran-4-carbonitrile
(261)
[0599] Under N.sub.2 atmosphere, to a solution of Ti(O-iPr).sub.4
(68 g, 239 mmol) in NH.sub.3/EtOH (300 mL) at room temperature was
added tetrahydro-4H-pyran-4-one (260, 20 g, 200 mmol). After
stirring at 20.degree. C. for 2 h, the reaction was cooled to
-5.degree. C. TMSCN (20.6 g, 208 mmol) was added dropwise and the
reaction was continued to stir at -5.degree. C. for 3 h. The
reaction was then warmed to room temperature and stirred for 12 h.
The reaction mixture was quenched with water (20 mL), filtered, and
the filter cake was washed with EtOH (20 mL.times.2). The filtrate
was concentrated in vacuo. The resulting residue was purified by
column chromatography to provide
4-aminotetrahydro-2H-pyran-4-carbonitrile (261, 20.8 g, 165 mmol)
as a yellow oil.
Step 2: Synthesis of 4-(Aminomethyl)tetrahydro-2H-pyran-4-amine
(262)
[0600] To a suspension of LiAlH.sub.4 (9.1 g, 240 mmol) in MTBE
(120 mL) at room temperature was added
4-aminotetrahydro-2H-pyran-4-carbonitrile (261, 10 g, 80 mmol).
After stirring at 40.degree. C. for 2 h, the reaction mixture was
quenched with water (9.1 mL) and 15% aqueous NaOH (9.1 mL),
followed by the addition of water (27.3 mL). After stirring for 1h,
the mixture was filtered and the filter cake was washed with MTBE
(20 mL.times.2). The filtrate was concentrated in vacuo to provide
4-(aminomethyl)tetrahydro-2H-pyran-4-amine (262, 6 g, 46.1 mmol),
which was carried forward in the next step without further
purification.
Step 3: Synthesis of Tert-Butyl
((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (263)
[0601] Under N.sub.2 atmosphere, to a solution of
4-(aminomethyl)tetrahydro-2H-pyran-4-amine (262, 6 g, 46.1 mmol) in
DCM (230 mL) at -78.degree. C. was added Boc.sub.2O (8.5 g, 39
mmol) dropwise over 1 h. After stirring at -78.degree. C. for an
additional 2 h, the reaction was gradually warmed to room
temperature. 1 M HCl was added to adjust pH=5. The aqueous phase
was extracted with EtOAc (200 mL). The aqueous phase was collected
and adjusted to pH=10 with 15% aqueous NaOH and extracted with DCM
(200 mL.times.3). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated to provide tert-butyl
((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (263, 6.05 g,
26.3 mmol).
Step 4: Synthesis of Tert-Butyl
((4-((2-chloro-5-iodopyrimidin-4-yl)amino)
Tetrahydro-2H-pyran-4-yl)methyl)carbamate (265)
[0602] To a solution of 2,4-dichloro-5-iodopyrimidine (264, 8.7 g,
31.6 mmol) and tert-butyl
((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (263, 5 g, 21.7
mmol) in DMAc (200 mL) was added NaHCO.sub.3 (11.1 g, 132 mmol).
After stirring at 80.degree. C. for 12 h, the reaction mixture was
quenched with water (50 mL) and extracted with EtOAc (300
mL.times.3). The combined organic phases were washed with water
(200 mL.times.2) and brine (100 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The resulting residue was
purified by column chromatography to provide tert-butyl
((4-((2-chloro-5-iodopyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methyl-
) carbamate (265, 5.02 g, 10.7 mmol).
Step 5: Synthesis of Tert-Butyl
((4-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)
Pyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methyl)carbamate
(266)
[0603] Under N.sub.2 atmosphere, to a solution of
tert-butyl((4-((2-chloro-5-iodopyrimidin-4-yl)amino)
tetrahydro-2H-pyran-4-yl) methyl)carbamate (265, 5.70 g, 12.2 mmol)
and DIEA (3.11 g, 24.1 mmol) in THE (170 mL) was added CuI (228 mg,
1.2 mmol) and Pd(PPh3).sub.2Cl2 (342 mg, 0.49 mmol). After stirring
at room temperature for 10 min, 3,3-diethoxyprop-1-yne (1.9 g, 14.8
mmol) in THE (5 mL) was added dropwise and the reaction was stirred
at room temperature for 12 h. The reaction was quenched with water
(20 mL) and extracted with EtOAc (20 mL.times.2). The combined
organic phases were concentrated in vacuo. The resulting residue
was purified by column chromatography to provide tert-butyl
((4-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)tetrahy-
dro-2H-pyran-4-yl)methyl)carbamate (266, 5.03 g, 10.7 mmol). MS
(ESI+): m/z 469 [M+H].sup.+.
Step 6: Synthesis of Tert-Butyl
((4-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo
[2,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamate
(267)
[0604] To a solution of tert-butyl
((4-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)tetrahy-
dro-2H-pyran-4-yl)methyl)carbamate (266, 4.90 g, 10.4 mmol) in THE
(50 mL) was added TBAF (50 mL, 50 mmol, 1 M in THF). After stirring
at 65.degree. C. for 2 h, the reaction was cooled to room
temperature and quenched with water (150 mL). The aqueous solution
was extracted with EtOAc (100 mL.times.3). The combined organic
phases were dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The resulting residue was purified by column
chromatography to provide tert-butyl
((4-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahyd-
ro-2H-pyran-4-yl)methyl)carbamate (267, 1.8 g, 3.84 mmol). MS
(ESI+): m/z 491 [M+Na].sup.+.
Step 7: Synthesis of Tert-Butyl
((4-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]
pyrimidin-7-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamate (268)
[0605] To a solution of tert-butyl
((4-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahyd-
ro-2H-pyran-4-yl)methyl)carbamate (267, 800 mg, 1.71 mmol) in THE
(4 mL) was added water (4 mL) and AcOH (4 mL). After stirring at
60.degree. C. for 2 h, the reaction mixture was neutralized with
saturated aqueous NaHCO.sub.3 and extracted with EtOAc (100
mL.times.3). The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting residue
was purified by column chromatography to provide tert-butyl
((4-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-2H-pyra-
n-4-yl)methyl)carbamate (268, 527 mg, 1.33 mmol).
Step 8: Synthesis of Tert-Butyl
2'-chloro-6'-oxo-2,3,5,6-tetrahydro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1-
,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (269)
[0606] To a solution of tert-butyl
((4-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-2H-pyra-
n-4-yl)methyl)carbamate (268, 200 mg, 0.51 mmol) in t-BuOH (5 mL)
and acetonitrile (1 mL) at 0.degree. C. was added NaH.sub.2PO.sub.4
(610 mg, 5.08 mmol) and 2-methyl-2-butene (280 mg, 3.99 mmol). Then
a solution of NaClO.sub.2 (360 mg, 3.98 mmol) in H.sub.2O (3 mL) at
0.degree. C. was added dropwise. After completion of the addition,
the reaction was warmed to room temperature and stirred for 2 h.
The reaction mixture was quenched with water (10 mL) and extracted
with EtOAc (30 mL.times.3). The combined organic phases were dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
resulting residue was purified by column chromatography to provide
tert-butyl
2'-chloro-6'-oxo-2,3,5,6-tetrahydro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1-
,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (269, 130 mg, 0.33
mmol).
Step 9: Synthesis of Tert-Butyl
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)
amino)-6'-oxo-2,3,5,6-tetrahydro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]-
pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (270)
[0607] Under N.sub.2 atmosphere, to a mixture of tert-butyl
2'-chloro-6'-oxo-2,3,5,6-tetrahydro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1-
,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (269, 20 mg, 0.05
mmol), 5-(4-methylpiperazin-1-yl)pyridin-2-amine (11 mg, 0.06 mmol)
and Cs.sub.2CO.sub.3 (33 mg, 0.10 mmol) in dioxane (2 mL) was added
Pd(OAc).sub.2 (1.1 mg, 0.005 mmol) and X-Phos (9.6 mg, 0.02 mmol).
The reaction was stirred at 100.degree. C. for 12 h. After cooling
to room temperature, the reaction was concentrated in vacuo. The
resulting residue was purified by prep TLC to provide tert-butyl
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6'-oxo-2,3,5,6-tetrahy-
dro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8-
'H)-carboxylate (270, 10 mg, 0.02 mmol). MS (ESI+): m/z 549
[M+H].sup.+.
Step 10: Synthesis of
2'-((5-(4-Methylpiperazin-1-yl)pyridin-2-yl)amino)-2,3,5,6,7',8'-hexahydr-
o-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(Compound 34)
[0608] To a solution of tert-butyl
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6'-oxo-2,3,5,6-tetrahy-
dro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8-
'H)-carboxylate (270, 10 mg, 0.02 mmol) in DCM (3 mL) at 0.degree.
C. was added TFA (1 mL) dropwise over 5 min. After stirring for 2
h, the reaction mixture was neutralized with saturated aqueous
NaHCO.sub.3 and extracted with i-PrOH/DCM=1/3 (20 mL.times.2). The
combined organic phases were dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The resulting residue was purified by prep
TLC to provide
2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-2,3,5,6,7',8'-hexahydr-
o-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(COMPOUND 34, 5.9 mg, 0.01 mmol). MS (ESI+): m/z 449 [M+H].sup.+;
.sup.1H NMR (300 MHz, MeOD+CDCl.sub.3): .delta. 8.83 (s, 1H), 8.26
(d, J=9.1 Hz, 1H), 7.99 (d, J=2.8 Hz, 1H), 7.63 (s, 1H), 7.53 (dd,
J=9.2, 2.8 Hz, 1H), 4.09 (dd, J=12.0, 4.8 Hz, 2H), 3.90 (s, 2H),
3.70 (t, J=12.0 Hz, 2H), 3.47 (td, J=13.4, 5.1 Hz, 2H), 3.33-3.29
(m, 4H), 2.92-2.82 (m, 4H), 2.54 (s, 3H), 1.94 (d, J=13.2 Hz,
2H).
Scheme 37: Synthesis of
2'-(((1R,4R)-4-(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexyl)amino)-7',-
8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyr-
imidin]-6'-one (Compound 36) and
2'-(((1S,4S)-4-(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexyl)amino)-7',-
8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyr-
imidin]-6'-one (Compound 40)
##STR00296##
[0609] Step 1: Synthesis of
(1R,4R)-4-(Dibenzylamino)cyclohexan-1-ol (272)
[0610] To a solution of (1R,4R)-4-aminocyclohexan-1-ol (270, 30 g,
261 mmol) and K.sub.2CO.sub.3 (80 g, 575 mmol) in DMF (250 mL) was
added benzyl bromide (44 g, 257 mmol) dropwise over 30 min. After
stirring at room temperature overnight, the reaction mixture was
poured into 2 L of ice-water. The precipitated solid was collected,
washed with water (2.times.100 mL) and dried to provide
(1R,4R)-4-(dibenzylamino)cyclohexan-1-ol (272, 69.3 g, 234 mmol).
MS (ESI+): m/z 296 [M+H].sup.+.
Step 2: Synthesis of 4-(Dibenzylamino)cyclohexan-1-one (273)
[0611] To a solution of (1R,4R)-4-(dibenzylamino)cyclohexan-1-ol
(272, 40 g, 136 mmol) in DCM (250 mL) was added PCC (75 g, 348
mmol) and silica gel (75 g). After stirring at room temperature
overnight, the reaction mixture was filtered. The filter cake was
washed with DCM (50 mL.times.2) and the filtrate was washed with
100 mL of saturated sodium bicarbonate solution. The organic layer
was separated and concentrated in vacuo. The resulting residue was
purified by column chromatography with a gradient elution of hexane
(90%) and EtOAc (10%) to hexane (75%) and EtOAc (25%) to provide
4-(dibenzylamino)cyclohexan-1-one (273, 25 g, 85 mmol). MS (ESI+):
m/z 294 [M+H].sup.+.
Step 3: Synthesis of Tert-Butyl
4-(cyclopropylmethyl)piperazine-1-carboxylate
[0612] To a solution of tert-butyl piperazine-1-carboxylate (274,
32 g, 172 mmol) and (bromomethyl)cyclopropane (25 g, 185 mmol) in
DCM (100 mL) at room temperature was added TEA (20 mL, 144 mmol).
After stirring at room temperature for 48 h, the reaction mixture
was filtered and the filtrate was concentrated in vacuo. The
resulting residue was purified by column chromatography to afford
tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate (275, 30
g, 124 mmol). MS (ESI): m/z 241 [M+H].sup.+.
Step 4: Synthesis of 1-(Cyclopropylmethyl)piperazine (276)
[0613] To a solution of tert-butyl
4-(cyclopropylmethyl)piperazine-1-carboxylate (275, 30 g, 124 mmol)
in DCM (100 mL) was added TFA (50 mL). After stirring at room
temperature overnight, the reaction mixture was neutralized with
saturated sodium bicarbonate solution (500 mL) and extracted with
DCM (200 mL.times.2). The combined organic phases were dried over
MgSO.sub.4, filtered and concentrated in vacuo to provide
1-(cyclopropylmethyl)piperazine (276, 13 g, 92 mmol), which was
used carried forward in the next step without further purification.
MS (ESI+): m/z 141 [M+H].sup.+.
Step 5: Synthesis of (1R,4R)--N,N-Dibenzyl-4-(4-(cyclopropylmethyl)
piperazin-1-yl)cyclohexan-1-amine (277) and
(1S,4S)--N,N-Dibenzyl-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-
-amine (278)
[0614] To a solution of 4-(dibenzylamino)cyclohexan-1-one (273, 5
g, 17.0 mmol) and 1-(cyclopropylmethyl)piperazine (276, 2.4 g, 17.1
mmol) in DCM (30 mL) was added HOAc (1 mL). NaHB(OAc).sub.3 (20 g,
94.4 mmol) was then added in portions. After stirring at room
temperature for 48 h, the reaction mixture was neutralized with
saturated sodium bicarbonate solution and extracted with DCM (50
mL.times.3). The combined organic phases were dried over MgSO.sub.4
and concentrated in vacuo. The resulting residue was purified by
column chromatography to afford
(1r,4r)--N,N-dibenzyl-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-
-amine (277, 670 mg, 1.6 mmol) and
(1s,4s)--N,N-dibenzyl-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-
-amine (278, 1.2 g, 2.9 mmol).
[0615]
(1R,4R)--N,N-Dibenzyl-4-(4-(cyclopropylmethyl)piperazin-1-yl)cycloh-
exan-1-amine (277): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
7.29-7.26 (m, 4H), 7.24-7.18 (m, 4H), 7.15-7.10 (m, 2H), 3.53 (s,
4H), 2.81-2.60 (m, 6H), 2.44-2.36 (m, 2H), 2.29 (d, J=6.6 Hz, 2H),
1.96-1.88 (m, 4H), 1.58-1.29 (m, 4H), 1.21-1.10 (m, 2H), 0.88-0.77
(m, 1H), 0.50-0.42 (m, 2H), 0.10-0.02 (m, 2H).
[0616]
(1S,4S)--N,N-Dibenzyl-4-(4-(cyclopropylmethyl)piperazin-1-yl)cycloh-
exan-1-amine (278): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
7.29-7.27 (m, 4H), 7.23-7.18 (m, 4H), 7.14-7.09 (m, 2H), 3.57 (s,
4H), 2.96-2.49 (m, 8H), 2.40 (d, J=6.6 Hz, 2H), 2.20 (s, 1H),
1.89-1.85 (m, 2H), 1.77-1.66 (m, 2H), 1.48-1.44 (m, 2H), 1.26-1.17
(m, 3H), 1.00-0.82 (m, 1H), 0.55-0.49 (m, 2H), 0.16-0.11 (m,
2H).
Step 6: Synthesis of
(R,4R)-4-(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-amine
(279)
[0617] To a solution of
(1R,4R)--N,N-dibenzyl-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-
-amine (277, 500 mg, 1.2 mmol) in IPA (30 mL) was added Pd/C (10%,
200 mg). The reaction mixture was stirred at 40.degree. C. under
1.8 MPa of hydrogen pressure for 24 h. After completion of the
reaction, the mixture was filtered and the filtrate was
concentrated to provide
(1R,4R)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-amine
(279, 160 mg, 0.67 mmol). MS (ESI+): m/z 238 [M+H].sup.+.
Step 7: Synthesis of
(1S,4S)-4-(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-amine
(280)
[0618]
(1S,4S)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-amine
(280) was prepared from
(1S,4S)--N,N-dibenzyl-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-
-amine (278) according to the experimental procedure as described
in Step 6 for the synthesis of
(1R,4R)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-amine
(279). MS (ESI+): m/z 238 [M+H].sup.+.
Step 8: Synthesis of
2'-(((1R,4R)-4-(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexyl)amino)-7',-
8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyr-
imidin]-6'-one (Compound 36)
[0619] To a solution of
(1R,4R)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-amine
(279, 40 mg, 0.17 mmol) and
2'-chloro-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyr-
rolo[2,3-d]pyrimidin]-6'-one (280.40 mg, 0.14 mmol) in 95% EtOH (5
mL) was added TEA (0.3 mL). The reaction was stirred in a sealed
tube at 140.degree. C. overnight. After cooling to room
temperature, the reaction mixture was concentrated to the residue,
which was purified by prep TLC to provide
2'-(((1R,4R)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)amino)-7',-
8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyr-
imidin]-6'-one (COMPOUND 36, 4.3 mg, 0.008 mmol). MS (ESI+): m/z
492 [M+H].sup.+; .sup.1H NMR (300 MHz, MeOD): .delta. 8.60 (s, 1H),
7.11 (s, 1H), 3.73 (s, 2H), 3.73-3.72 (m, 1H), 3.04 (td, J=13.5,
3.9 Hz, 4H), 2.89-2.75 (m, 4H), 2.33-1.79 (m, 10H), 1.56-1.28 (m,
11H), 1.09-1.00 (m, 1H), 0.71-0.68 (m, 2H), 0.36 (s, 2H).
Step 9: Synthesis of
2'-(((1S,4S)-4-(4-(Cyclopropylmethyl)piperazin-1-yl)
cyclohexyl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2'-
:1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (Compound 40)
[0620]
2'-(((1S,4S)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)amin-
o)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-
-d]pyrimidin]-6'-one (COMPOUND 40) was prepared according to the
procedure in Step 8 for the synthesis of COMPOUND 36. MS (ESI+):
m/z 492 [M+H].sup.+; .sup.1H NMR (300 MHz, MeOD): .delta. 8.62 (s,
1H), 7.12 (s, 1H), 4.04 (s, 1H), 3.73 (s, 2H), 3.04 (td, J=13.5,
3.6 Hz, 4H), 2.86-2.80 (m, 4H), 2.18-2.10 (m, 3H), 1.95-1.78 (m,
10H), 1.60-1.46 (m, 3H), 1.39-1.29 (m, 5H), 1.13-1.02 (m, 1H),
0.71-0.68 (m, 2H), 0.36 (s, 2H).
Scheme 38: Synthesis of
2'-(((1R,4R)-4-(4-Methylpiperazin-1-yl)cyclohexyl)
amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrol-
o[2,3-d]pyrimidin]-6'-one (Compound 37) and
2'-(((1S,4S)-4-(4-Methylpiperazin-1-yl)
cyclohexyl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2'-
:1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (Compound 41)
##STR00297##
[0621] Step 1: Synthesis of Tert-Butyl
4-((1R,4R)-4-(dibenzylamino)cyclohexyl)piperazine-1-carboxylate
(284) and Tert-Butyl
4-((1S,4S)-4-(dibenzylamino)cyclohexyl)piperazine-1-carboxylate
(285)
[0622] To a solution of 4-(dibenzylamino)cyclohexan-1-one (282, 5
g, 17.0 mmol) and tert-butyl piperazine-1-carboxylate (283, 3.17 g,
22.6 mmol) in DCM (30 mL) was added HOAc (1 mL). NaHB(OAc).sub.3
(20 g, 94.4 mmol) was then added in portions. After stirring at
room temperature for 48 h, the reaction mixture was neutralized
with saturated sodium bicarbonate solution and extracted with DCM
(50 mL.times.5). The combined organic phases were dried over
anhydrous MgSO.sub.4 and concentrated in vacuo. The resulting
residue was purified by column chromatography to afford tert-butyl
4-((1R,4R)-4-(dibenzylamino)cyclohexyl)piperazine-1-carboxylate
(284, 400 mg, 0.86 mmol) and tert-butyl
4-((1S,4S)-4-(dibenzylamino)cyclohexyl)piperazine-1-carboxylate
(285, 1.4 g, 3.02 mmol).
[0623] tert-Butyl
4-((1R,4R)-4-(Dibenzylamino)cyclohexyl)piperazine-1-carboxylate:
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.29-7.20 (m, 8H),
7.15-7.10 (m, 2H), 3.54 (s, 4H), 3.41-3.29 (m, 4H), 2.47-2.33 (m,
4H), 1.95-1.81 (m, 4H), 1.38 (s, 9H), 1.31-1.06 (m, 6H).
[0624] tert-Butyl
4-((1S,4S)-4-(dibenzylamino)cyclohexyl)piperazine-1-carboxylate:
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.31-7.21 (m, 8H),
7.15-7.10 (m, 2H), 3.54 (s, 4H), 3.38-3.32 (m, 3H), 2.60-2.46 (m,
1H), 2.36-2.26 (m, 4H), 2.20-1.99 (m, 2H), 1.92-1.87 (m, 2H),
1.78-1.66 (m, 2H), 1.38 (s, 9H), 1.28-1.14 (m, 4H).
Step 2: Synthesis of
(1R,4R)--N,N-Dibenzyl-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine
(286)
[0625] To a solution of tert-butyl
4-((1R,4R)-4-(Dibenzylamino)cyclohexyl)piperazine-1-carboxylate
(284, 900 mg, 1.94 mmol) in anhydrous THE (20 mL) under ice-water
bath was added LiAlH.sub.4 (300 mg, 7.90 mmol) in portions. After
completion of the addition, the reaction mixture was refluxed for 3
h. After cooling to room temperature, the mixture was quenched with
0.3 mL of water, 0.3 mL of 15% sodium hydroxide aqueous solution,
followed by the addition of 0.6 mL of water. The mixture was
stirred for 30 min. and 1 g of anhydrous magnesium sulfate was
added and the reaction was stirred for 1h. After filtration, the
filter cake was washed with EtOAc (30 mL.times.2). The filtrate was
concentrated to afford the residue, which was purified by a column
chromatography with a gradient elution of EtOAc (100%) to EtOAc
(83%) and MeOH (16%) and NH.sub.3.H.sub.2O (1%) to provide
(1R,4R)--N,N-dibenzyl-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine
(286, 500 mg, 1.32 mmol). MS (ESI+): m/z 378 [M+H].sup.+.
Step 3: Synthesis of
(1S,4S)--N,N-Dibenzyl-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine
(287)
[0626]
(1S,4S)--N,N-dibenzyl-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine
(287) was prepared from
4-((1S,4S)-4-(dibenzylamino)cyclohexyl)piperazine-1-carboxylate
(285) according to the experimental procedure of Step 2 for the
synthesis of
(1R,4R)--N,N-dibenzyl-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine
(286) MS (ESI+): m/z 378 [M+H].sup.+.
Step 4: Synthesis of
(1R,4R)-4-(4-Methylpiperazin-1-yl)cyclohexan-1-amine (288)
[0627] (1R,4R)-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine (288)
was prepared from
(1R,4R)--N,N-dibenzyl-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine
(286) according to the experimental procedure for the synthesis of
(1R,4R)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-amine
(279, Scheme 37, Step 6). MS (ESI+): m/z 198 [M+H].sup.+.
Step 5: Synthesis of
(1S,4S)-4-(4-Methylpiperazin-1-yl)cyclohexan-1-amine (289)
[0628] (1S,4S)-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine (289)
was prepared from
(1S,4S)--N,N-dibenzyl-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine
(287) according to the experimental procedure for the synthesis of
(1R,4R)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexan-1-amine
(279, Scheme 37, Step 6). MS (ESI+): m/z 198 [M+H].sup.+.
Step 6: Synthesis of
2'-(((1R,4R)-4-(4-Methylpiperazin-1-yl)cyclohexyl)amino)-7',8'-dihydro-6'-
H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-on-
e (Compound 37)
[0629]
2'-(((1R,4R)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-7',8'-dihy-
dro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-
-6'-one (COMPOUND 37) was prepared from
(1R,4R)-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine (288)
according to the experimental procedure for the synthesis of
COMPOUND 36 as shown in Step 8, Scheme 37. MS (ESI+): m/z 452
[M+H].sup.+; .sup.1H NMR (300 MHz, MeOD): .delta. 8.60 (s, 1H),
7.11 (s, 1H), 3.73 (s, 2H), 3.73-3.68 (m, 1H), 3.03 (td, J=13.2,
3.3 Hz, 4H), 2.67 (br s, 3H), 2.33-2.28 (m, 2H), 2.19-2.13 (m, 2H),
1.96-1.92 (m, 2H), 1.83-1.79 (m, 3H), 1.57-1.36 (m, 9H), 1.31-1.25
(m, 5H).
Step 7: Synthesis of
2'-(((1S,4S)-4-(4-Methylpiperazin-1-yl)cyclohexyl)amino)-7',8'-dihydro-6'-
H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-on-
e (Compound 41)
[0630]
2'-(((1S,4S)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-7',8'-dihy-
dro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-
-6'-one (COMPOUND 41) was prepared from
(1S,4S)-4-(4-methylpiperazin-1-yl)cyclohexan-1-amine (289)
according to the experimental procedure for the synthesis of
COMPOUND 36 as shown in Step 8, Scheme 37. MS (ESI+): m/z 452
[M+H].sup.+; .sup.1H NMR (300 MHz, MeOD): .delta. 8.64 (s, 1H),
7.14 (s, 1H), 4.06 (s, 1H), 3.73 (s, 2H), 3.00 (td, J=13.2, 3.9 Hz,
4H), 2.69 (br s, 3H), 2.21-2.11 (m, 3H), 1.96-1.74 (m, 12H),
1.60-1.47 (m, 3H), 1.33-1.29 (m, 5H).
Scheme 39: Synthesis of
(1S,4S)-4-Methoxy-2'-((5-(4-methylpiperazin-1-yl)
pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',-
2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (Compound 38) and
(1R,4R)-4-Methoxy-2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8-
'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyri-
midin]-6'-one (Compound 39)
##STR00298## ##STR00299##
[0631] Step 1: Synthesis of 1,4-Dioxaspiro[4.5]decan-8-ol (291)
[0632] To a solution of 1,4-dioxaspiro[4.5]decan-8-one (290, 10 g,
64 mmol) in MeOH (100 mL) at 0.degree. C. was added NaBH.sub.4 (4.8
g, 128 mmol) in portions. The reaction was gradually warmed to room
temperature. After stirring for 12 h, aqueous NaOH (26 mL, 2 N) was
added. The mixture was filtered and the filtrate was concentrated
in vacuo. The resulting residue was purified by column
chromatography to provide 1,4-dioxaspiro[4.5]decan-8-ol (291, 9.7
g, 61.3 mmol).
Step 2: Synthesis of 8-Methoxy-1,4-dioxaspiro[4.5]decane (292)
[0633] To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (291, 9.7 g,
61.3 mmol) in THE (150 mL) at 0.degree. C. was added NaH (4.3 g,
184.0 mmol) in portions over 1 h. CH.sub.3I (43 g, 306.5 mmol) was
added. After completion of the addition, the reaction mixture was
refluxed for 12 h. The reaction mixture was then cooled to room
temperature, quenched with saturated aqueous NH.sub.4Cl and
extracted with EtOAc (200 mL.times.2), the combined organic phases
were washed with water (50 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to afford
8-methoxy-1,4-dioxaspiro[4.5]decane (292, 12 g, 69.7 mmol), which
was used in the next step without further purification.
Step 3: Synthesis of 4-Methoxycyclohexan-1-one (293)
[0634] A mixture of 8-methoxy-1,4-dioxaspiro[4.5]decane (292, 12.0
g, 69.7 mmol) and p-TsOH (1 g, 5.26 mmol) in H.sub.2O (300 mL) was
stirred at 100.degree. C. for 1 h. After cooling to room
temperature, the reaction mixture was extracted with EtOAc (100
mL.times.2). The combined organic phases were washed with brine (50
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to provide 4-methoxycyclohexan-1-one (293, 7.01 g, 54.7
mmol), which was used in the next step without further
purification.
Step 4: Synthesis of 1-Amino-4-methoxycyclohexanecarbonitrile
(294)
[0635] 1-amino-4-methoxycyclohexanecarbonitrile (294) was prepared
according to the synthesis of 4-methoxycyclohexan-1-one (261)
described in Step 1 of Scheme 36.
Step 5: Synthesis of 1-(Aminomethyl)-4-methoxycyclohexanamine
(295)
[0636] 1-(aminomethyl)-4-methoxycyclohexanamine (295) was prepared
from 1-amino-4-methoxycyclohexanecarbonitrile (294) according to
the experimental procedure for the synthesis of
4-(aminomethyl)tetrahydro-2H-pyran-4-amine (262) described in Step
2, Scheme 36.
Step 6: Synthesis of Tert-Butyl
((1-amino-4-methoxycyclohexyl)methyl)carbamate (296)
[0637] Tert-butyl ((1-amino-4-methoxycyclohexyl)methyl)carbamate
(296) was prepared from 1-(aminomethyl)-4-methoxycyclohexanamine
(295) according to the experimental procedure for the synthesis of
tert-butyl ((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (263)
shown in Step 3, Scheme 36.
Step 7: Synthesis of Tert-Butyl
(((1S,4S)-1-((2-chloro-5-iodopyrimidin-4-yl)
amino)-4-methoxycyclohexyl)methyl)carbamate (298) and tert-Butyl
(((1R,4R)-1-((2-chloro-5-iodopyrimidin-4-yl)amino)-4-methoxycyclohexyl)me-
thyl)carbamate (299)
[0638] To a solution 2,4-dichloro-5-iodopyrimidine (297, 10.3 g,
37.5 mmol) and tert-butyl
((1-amino-4-methoxycyclohexyl)methyl)carbamate (296, 9 g, 34.8
mmol) in DMAc (180 mL) was added NaHCO.sub.3 (10.8 g, 128 mmol).
After stirring at 80.degree. C. for 12 h, the reaction was quenched
with water (500 ml) and extracted with EtOAc (300 mL.times.3). The
combined organic layers were washed with water (200 mL.times.2) and
brine (100 mL). The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The resulting residue was
purified by column chromatography to provide tert-butyl
(((1S,4S)-1-((2-chloro-5-iodopyrimidin-4-yl)amino)-4-methoxycyclohexyl)me-
thyl)carbamate (298, 3.2 g, 6.44 mmol) and tert-butyl
(((1R,4R)-1-((2-chloro-5-iodopyrimidin-4-yl)amino)-4-methoxycyclohexyl)me-
thyl)carbamate (299, 5.1 g, 10.3 mmol). MS (ESI+): m/z 497
[M+H].sup.+.
[0639] tert-Butyl
(((1S,4S)-1-((2-chloro-5-iodopyrimidin-4-yl)amino)-4-methoxycyclohexyl)me-
thyl)carbamate (298): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.21 (s, 1H), 3.53 (d, J=6.6 Hz, 2H), 3.49 (d, J=6.3 Hz, 1H),
3.37-3.32 (m, 1H), 3.25 (s, 3H), 3.23-3.22 (m, 1H), 2.08-1.98 (m,
2H), 1.79-1.64 (m, 5H), 1.52-1.47 (m, 1H), 1.36 (s, 9H).
[0640] tert-Butyl
(((1R,4R)-1-((2-chloro-5-iodopyrimidin-4-yl)amino)-4-methoxycyclohexyl)me-
thyl)carbamate (299): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.22 (s, 1H), 3.56 (d, J=6.6 Hz, 2H), 3.52 (s, 1H), 3.28 (s, 3H),
3.27-3.25 (m, 1H), 3.19-3.12 (m, 1H), 2.30-2.17 (m, 2H), 1.95-1.82
(m, 2H), 1.79-1.65 (m, 2H), 1.45-1.39 (m, 2H), 1.36 (s, 9H).
Step 8: Synthesis of Tert-Butyl
(((1S,4S)-1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino-
)-4-methoxycyclohexyl)methyl)carbamate (300)
[0641] Under N.sub.2 atmosphere, to a solution of tert-butyl
(((1s,4s)-1-((2-chloro-5-iodopyrimidin-4-yl)amino)-4-methoxycyclohexyl)me-
thyl)carbamate (298, 3.2 g, 6.45 mmol) and Et.sub.3N (1.4 g, 13.8
mmol) in THE (70 mL) was added CuI (122 mg, 0.64 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (181 mg, 0.26 mmol). After the reaction
was stirred at 20.degree. C. for 10 min, 3,3-diethoxyprop-1-yne
(990 mg, 7.72 mmol) was added dropwise and the reaction was stirred
at 20.degree. C. for 12 h. The reaction mixture was then quenched
with water (100 mL) and extracted with EtOAc (100 mL.times.3). The
combined organic phases were washed with brine (100 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting
residue was purified by column chromatography to provide tert-butyl
(((1s,4s)-1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino-
)-4-methoxycyclohexyl)methyl)carbamate (300, 2.60 g, 5.23
mmol).
Step 9: Synthesis of Tert-Butyl
(((1S,4S)-1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
-4-methoxycyclohexyl)methyl)carbamate (302)
[0642] To a solution of tert-butyl
(((1s,4s)-1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino-
)-4-methoxycyclohexyl)methyl)carbamate (300, 2.60 g, 5.23 mmol) in
THE (50 mL) was added TBAF (25 mL, 25 mmol, 1 M in THF). After
stirring at 65.degree. C. for 2 h, the reaction mixture was cooled
room temperature, quenched with water (150 mL) and extracted with
EtOAc (100 mL.times.3). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting
residue was purified by column chromatography to provide tert-butyl
(((1s,4s)-1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
-4-methoxycyclohexyl)methyl)carbamate (302, 1.2 g, 2.41 mmol).
Step 10: Synthesis of Tert-Butyl
(((1S,4S)-1-(2-chloro-6-formyl-7H-pyrrolo
[2,3-d]pyrimidin-7-yl)-4-methoxycyclohexyl)methyl)carbamate
(304)
[0643] To a solution of tert-butyl
(((1s,4s)-1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-
-4-methoxycyclohexyl)methyl)carbamate (302, 1.2 g, 2.41 mmol) in
THE (4 mL) was added H.sub.2O (4 mL) and HOAc (4 mL). After
stirring at 60.degree. C. for 2 h, the reaction was quenched with
saturated aqueous NaHCO.sub.3 and extracted with EtOAc (100
mL.times.3). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting
residue was purified by column chromatography to provide tert-butyl
(((s,4s)-1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methoxyc-
yclohexyl)methyl)carbamate (304, 700 mg, 1.66 mmol).
Step 11: Synthesis of Tert-Butyl
(1S,4S)-2'-chloro-4-methoxy-6'-oxo-6'H-spiro
[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-ca-
rboxylate (306)
[0644] To a solution of tert-butyl
(((1S,4S)-1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methoxy-
cyclohexyl)methyl)carbamate (304, 240 mg, 0.57 mmol) in t-BuOH (15
mL) and acetonitrile (3 mL) was added NaH.sub.2PO.sub.4 (709 mg,
4.55 mmol) and 2-methyl-2-butene (318 mg, 4.53 mmol). After
stirring at 0.degree. C. for 5 min, a solution of NaClO.sub.2 (318
mg, 3.52 mmol) in H.sub.2O (3 mL) was added dropwise over 1 h.
After warming to room temperature and stirring for another 2 h, the
reaction mixture was quenched with water (50 mL) and extracted with
EtOAc (30 mL.times.3). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting
residue was purified by column chromatography to provide tert-butyl
(1S,4S)-2'-chloro-4-methoxy-6'-oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1'-
,2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (306, 200 mg,
0.47 mmol).
Step 12: Synthesis of Tert-Butyl
(1S,4S)-4-methoxy-2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6'-o-
xo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-
-7'(8'H)-carboxylate (308)
[0645] Under N.sub.2 atmosphere, to a solution of tert-butyl
(1S,4S)-2'-chloro-4-methoxy-6'-oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1'-
,2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (306, 100 mg,
0.24 mmol), 5-(4-methylpiperazin-1-yl)pyridin-2-amine (55.4 mg,
0.28 mmol) in dioxane (5 mL) was added Cs.sub.2CO.sub.3 (232 mg,
0.71 mmol), Pd(OAc).sub.2 (5.3 mg, 0.02 mmol) and X-Phos (59 mg,
0.12 mmol). After stirring at 100.degree. C. for 12 h, the reaction
was quenched with water (10 mL) and extracted with EtOAc (10
mL.times.2). The organic phases were concentrated in vacuo and the
resulting residue was purified by column chromatography to provide
tert-butyl
(1s,4s)-4-methoxy-2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6'-o-
xo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-
-7'(8'H)-carboxylate (308, 50 mg, 0.09 mmol). MS (ESI+): m/z 577
[M+H].sup.+.
Step 13: Synthesis of
(1S,4S)-4-Methoxy-2'-((5-(4-methylpiperazin-1-yl)
pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',-
2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (Compound 38)
[0646] To a solution of tert-butyl
(1S,4S)-4-methoxy-2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6'-o-
xo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-
-7'(8'H)-carboxylate (308, 50 mg, 0.09 mmol) in DCM (3 mL) at
0.degree. C. was added TFA (1 mL) in dropwise. After stirring for 2
h, the reaction mixture was neutralized with saturated aqueous
NaHCO.sub.3 and extracted with i-PrOH/DCM=1/3 (20 mL.times.2). The
combined organic phases were dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The resulting residue was purified by
prep TLC to provide
(1S,4S)-4-methoxy-2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)
amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrol-
o[2,3-d]pyrimidin]-6'-one (COMPOUND 38, 6.7 mg, 0.01 mmol). MS
(ESI+): m/z 477 [M+H].sup.+; .sup.1H NMR (300 MHz,
MeOD+CDCl.sub.3): .delta. 8.84 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H),
7.51-7.41 (m, 1H), 7.27 (s, 1H), 3.78 (s, 2H), 3.46 (s, 3H),
3.45-3.36 (m, 6H), 3.23-3.06 (m, 5H), 2.73 (s, 3H), 2.27-2.17 (m,
2H), 2.15-2.04 (m, 2H), 1.54-1.40 (m, 2H).
Synthesis of
(1R,4R)-4-Methoxy-2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8-
'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyri-
midin]-6'-one (Compound 39)
[0647] COMPOUND 39 was prepared according to the experimental
procedures in the synthesis of COMPOUND 38. MS (ESI+): m/z 477
[M+H].sup.+; .sup.1H NMR (300 MHz, MeOD+CDCl.sub.3): .delta. 8.82
(s, 1H), 8.39 (br s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.55 (d, J=9.7
Hz, 1H), 7.26 (s, 1H), 3.77 (s, 2H), 3.63 (s, 1H), 3.41 (s, 3H),
3.40-3.34 (m, 6H), 3.16-2.94 (m, 4H), 2.67 (s, 3H), 2.19-2.09 (m,
2H), 1.87-1.76 (m, 2H), 1.72-1.59 (m, 2H).
Example 5. Non-Limiting Examples of Compounds
TABLE-US-00004 [0648] TABLE 3 Non-limiting Examples of Final
Compounds Compd # Compound Structure 10 ##STR00300## 11
##STR00301## 12 ##STR00302## 13 ##STR00303## 14 ##STR00304## 15
##STR00305## 16 ##STR00306## 17 ##STR00307## 18 ##STR00308## 19
##STR00309## 20 ##STR00310## 21 ##STR00311## 22 ##STR00312## 23
##STR00313## 24 ##STR00314## 25 ##STR00315## 26 ##STR00316## 27
##STR00317## 28 ##STR00318## 29 ##STR00319## 30 ##STR00320## 31
##STR00321## 32 ##STR00322## 33 ##STR00323## 34 ##STR00324## 35
##STR00325## 36 ##STR00326## 37 ##STR00327## 38 ##STR00328## 39
##STR00329## 40 ##STR00330## 41 ##STR00331##
Example 6: CDK4/6 Inhibition In Vitro Assay
[0649] Selected compounds disclosed herein were tested in
CDK4/cyclinD1, CDK2/CycA and CDK2/cyclinE kinase assays by Nanosyn
(Santa Clara, Calif.) to determine their inhibitory effect on these
CDKs. The assays were performed using microfluidic kinase detection
technology (Caliper Assay Platform). The compounds were tested in
12-point dose-response format in singlicate at Km for ATP.
Phosphoacceptor substrate peptide concentration used was 1 M for
all assays and Staurosporine was used as the reference compound for
all assays. Specifics of each assay are as described below:
[0650] CDK2/CyclinA: Enzyme concentration: 0.2 nM; ATP
concentration: 50 .mu.M; Incubation time: 3 hr.
[0651] CDK2/CyclinE: Enzyme concentration: 0.28 nM; ATP
concentration: 100 .mu.M; Incubation time: 1 hr.
[0652] CDK4/CyclinD1: Enzyme concentration: 1 nM; ATP
concentration: 200 .mu.M; Incubation time: 10 hr.
TABLE-US-00005 BIOLOGICAL TABLE 3 CDK4/ CDK6/ CDK2/ CDK2/ CDK9/
Cyclin Cyclin Cyclin Cyclin Cyclin Compd D1 D3 E A T # Compound
Structure (.mu.M) (.mu.M) (.mu.M) (.mu.M) (.mu.M) 25 ##STR00332##
0.03 0.1 99 59 6.3 27 ##STR00333## 9.4 21 >100 >100 >100
28 ##STR00334## 0.02 0.06 >100 13.5 1 31 ##STR00335## 0.0006
0.001 0.04 0.1 0.04 33 ##STR00336## 0.006 0.02 4 2 3 34
##STR00337## 0.02 0.02 23 14 0.4 36 ##STR00338## 0.004 0.03 0.3 0.1
0.002 37 ##STR00339## 0.006 0.04 0.4 0.02 0.003 38 ##STR00340##
0.007 0.01 14 5 0.2 39 ##STR00341## 0.06 0.09 33 19 0.2 40
##STR00342## 0.09 0.5 5 2 0.05 41 ##STR00343## 0.14 0.8 6 2
0.07
* * * * *