U.S. patent application number 17/470572 was filed with the patent office on 2022-04-21 for fused ring derivative used as fgfr4 inhibitor.
The applicant listed for this patent is JACOBIO PHARMACEUTICALS CO., LTD. Invention is credited to Xin SUN, Hongwei YANG, Liang ZHOU, Rui ZHOU.
Application Number | 20220119386 17/470572 |
Document ID | / |
Family ID | |
Filed Date | 2022-04-21 |
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United States Patent
Application |
20220119386 |
Kind Code |
A1 |
YANG; Hongwei ; et
al. |
April 21, 2022 |
FUSED RING DERIVATIVE USED AS FGFR4 INHIBITOR
Abstract
A compound represented by formula I or a pharmaceutically
acceptable salt thereof and a use thereof in preparing a drug for
treating, stopping or preventing a disease or disorder mediated by
FGFR4 activity. ##STR00001##
Inventors: |
YANG; Hongwei; (Beijing,
CN) ; ZHOU; Rui; (Beijing, CN) ; ZHOU;
Liang; (Beijing, CN) ; SUN; Xin; (Beijing,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JACOBIO PHARMACEUTICALS CO., LTD |
Beijing |
|
CN |
|
|
Appl. No.: |
17/470572 |
Filed: |
September 9, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17263571 |
Jan 27, 2021 |
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PCT/CN2019/098076 |
Jul 29, 2019 |
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17470572 |
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International
Class: |
C07D 471/04 20060101
C07D471/04; A61P 35/00 20060101 A61P035/00; C07D 519/00 20060101
C07D519/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 27, 2018 |
CN |
PCT/CN2018/097450 |
Claims
1-50. (canceled)
51. A compound of formula (I), or a pharmaceutically acceptable
salt thereof: ##STR00118## wherein: R.sub.1 is selected from:
##STR00119## R.sub.2 and R.sub.3 are H; ##STR00120## is selected
from: ##STR00121##
52. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 51, wherein R.sub.1 is selected from:
##STR00122##
53. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 52, wherein R.sub.1 is selected from:
##STR00123##
54. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 51, wherein ##STR00124## is selected
from: ##STR00125##
55. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 54, wherein ##STR00126## is selected
from: ##STR00127##
56. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 51, which is selected from:
TABLE-US-00022 Com- pound No. Chemical Name Structure Formula 1
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00128## 4
(R)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00129## 6
N-(5-cyano-4-((2-methyl-2-(methylthio)propyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00130## 7
(R)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-
formyl-6-((2-oxopyrrolidine-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00131## 8
(R)-N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-
((3-methoxy-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00132## 9
N-(5-cyano-4-(((R)-1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-
formyl-6-(((R)-3-methoxy-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00133## 13
(S)-N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-
((3-methoxy-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00134## 14
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((5-
oxo-6-oxa-4-azaspiro[2.4]heptan-4-yl)methyl)-3,4-dihydro-1,8-naphthyridin-
e- 1(2H)-carboxamide ##STR00135## 15
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-6-((4-cyclopropy-
l-
2-oxopiperazin-1-yl)methyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00136## 16
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((2-
oxo-1,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-
carboxamide ##STR00137## 19
N-(5-cyano-4-((2-((methyl-d3)thio)ethyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00138## 23
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((2-
oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carbox-
amide ##STR00139## 27
N-(5-cyano-4-((2-(methylsulfinyl)ethyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00140## 31
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl-d2)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00141## 62
N-(5-cyano-4-((2-((trifluoromethyl)thio)ethyl)amino)pyridin-2-yl)-7-for-
myl-
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridin-
e- 1(2H)-carboxamide ##STR00142## 64
N-(5-cyano-4-((3-(methylthio)propyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00143## 69
N-(5-cyano-4-(((2R)-1-(methylsulfinyl)propan-2-yl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00144## 70
(R)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-
formyl-6-((2-oxo-1,3-oxozepan-3-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00145## 71
N-(5-cyano-4-((2-(ethylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-
carboxamide hydrochloride ##STR00146## 72
N-(5-cyano-4-((2-(methylsulfonyl)ethyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide hydrochloride ##STR00147## 82
N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-formyl-
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00148## 83
N-(5-cyano-4-(((2R)-1-(methylsulfonyl)propan-2-yl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00149##
57. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 56, which is: TABLE-US-00023 6
N-(5-cyano-4-((2-methyl-2-(methylthio)propyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00150##
58. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 56, which is: TABLE-US-00024 9
N-(5-cyano-4-(((R)-1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-
formyl-6-(((R)-3-methoxy-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00151##
59. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 56, which is: TABLE-US-00025 62
N-(5-cyano-4-((2-((trifluoromethyl)thio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00152##
60. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 56, which is: TABLE-US-00026 64
N-(5-cyano-4-((3-(methylthio)propyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00153##
61. The compound of formula (I) or pharmaceutically acceptable salt
thereof according to claim 56, which is: TABLE-US-00027 71
N-(5-cyano-4-((2-(ethylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-
carboxamide hydrochloride ##STR00154##
62. A pharmaceutical composition comprising the compound of formula
(I) or pharmaceutically acceptable salt thereof according to claim
51, and at least one pharmaceutically acceptable excipient.
63. The pharmaceutical composition according to claim 62, wherein
the compound of formula (I) is: TABLE-US-00028 6
N-(5-cyano-4-((2-methyl-2-(methylthio)propyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00155##
64. The pharmaceutical composition according to claim 62, wherein
the compound of formula (I) is: TABLE-US-00029 9
N-(5-cyano-4-(((R)-1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-
formyl-6-(((R)-3-methoxy-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00156##
65. The pharmaceutical composition according to claim 62, wherein
the compound of formula (I) is: TABLE-US-00030 62
N-(5-cyano-4-((2-((trifluoromethyl)thio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00157##
66. The pharmaceutical composition according to claim 62, wherein
the compound of formula (I) is: TABLE-US-00031 64
N-(5-cyano-4-((3-(methylthio)propyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide ##STR00158##
67. The pharmaceutical composition according to claim 62, wherein
the compound of formula (I) is: TABLE-US-00032 71
N-(5-cyano-4-((2-(ethylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-
carboxamide hydrochloride ##STR00159##
68. A method for the treatment or prevention of a disease or
condition mediated by FGFR4 activity, comprising administering to a
subject a therapeutically effective amount of the compound of
formula (I) or pharmaceutically acceptable salt thereof according
to claim 51.
69. The method according to claim 68, wherein the disease or
condition mediated by FGFR4 activity is selected from one or more
of liver cancer, head and neck cancer, esophageal cancer, stomach
cancer, prostate cancer, ovarian cancer, lung cancer, breast
cancer, colorectal cancer, rhabdomyoma, and a combination
thereof.
70. The method according to claim 68, wherein the compound of
formula (I) is: TABLE-US-00033 4
(R)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00160##
Description
TECHNICAL FIELD
[0001] The present invention provides fused ring derivative
compound, uses for inhibiting FGFR4 and methods of treating
diseases using said compound thereof.
BACKGROUND ART
[0002] Fibroblast Growth Factor Receptor (FGFR) belongs to the
family of receptor protein tyrosine kinases. Many signaling
pathways, including Ras-MAPK, AKT-PI3K, and phospholipase C, can be
activated through the binding of FGFR and its corresponding
ligands, and these pathways play an important role in cell growth,
proliferation and survival.
[0003] Alterations in FGFRs are associated with many human cancers,
and these alterations, including overexpression of FGF ligand, FGFR
or activated FGFR mutations, can lead to tumor occurrence,
development and resistance to traditional cancer treatments by
activating the pathway. Large-scale DNA sequencing of thousands of
tumor samples revealed that components of the FGFR pathway are the
most common mutations in human cancers. FGFR4 is a tyrosine kinase
receptor in the human body encoded by the gene FGFR4 and is highly
conserved in evolution, and it works by combining with its specific
ligand FGF19. The signaling pathway of FGFR is roughly shown as
follows: activated FGFR4 causes phosphorylation of FRS2 and
recruits GRB2, thus the signaling pathways of Ras-Raf-ERK1/2MAPK
and PI3KAkt are finally activated, which makes the cells
proliferate and resist apoptosis. More and more researches have
indicated that FGFR activation and the overexpression of FGF19 play
an important role in the occurrence and development of liver
cancer, and the inhibition of FGFR4 can effectively reduce the
occurrence of liver cancer. FGFR4, ligand FGF19 and coreceptor KLB
were highly expressed in about 1/3 of liver cancer patients. In
addition, the changes of FGFR4-FGF19 signal axis are also related
to the occurrence of colorectal cancer, breast cancer, pancreatic
cancer, prostate cancer, lung cancer, and thyroid cancer.
[0004] According to preliminary studies, fibroblast growth factor
receptor 4 (FGFR4) inhibitors have great potential for the
treatment of liver cancer, and have better pertinence and
effectiveness than the similar drugs. Liver cancer, the second only
to lung cancer, is the most common malignant tumor and fatal
disease, and china has the most liver cancer patients in the world.
Sorafenib, as the only approved first-line drug for the treatment
of patients with advanced liver cancer, only extends average three
months survival time of the patient, and it has strong side effects
because it is a multi-targeted tyrosine kinase inhibitor.
Therefore, the development of more effective liver cancer drugs has
become an urgent need in the world, and FGFR4 inhibitors provide a
possibility for breakthroughs in this area.
[0005] At present, the inhibitor of FGFR4 is a hot research
direction in the field of worldwide liver cancer therapeutic
research, and the world biopharmaceutical companies are competing
for a market direction of FGFR4 inhibitors. However, no one drug of
FGFR4 inhibitor has been marketed currently due to the limitation
of experimental methods and the period of the research and so on.
China has the highest incidence of liver cancer and the most
patients with liver cancer in the world, thus the breakthrough in
this direction of FGFR inhibitors will have strong significance to
clinical application. At present, no similar drugs of FGFR
inhibitors are in clinical studies in China, and the worldwide FGFR
inhibitors are all in the early clinical research stage. Therefore,
the breakthrough in this direction of FGFR inhibitors will greatly
enhance the international competitiveness of the new drug research
and development of China.
SUMMARY OF INVENTION
[0006] The present invention relates to fused ring compound, which
as an FGFR4 inhibitors use for treating diseases mediated by FGFR4.
The invention first provides the compound shown in structural
formula I or a pharmaceutically acceptable salt thereof:
##STR00002##
[0007] Wherein:
[0008] R.sub.1 at each occurrence is independently
##STR00003##
[0009] X at each occurrence is independently selected from absent,
O, --NR.sub.X1-- or --CR.sub.X1R.sub.X2--; and p is 0, 1, 2 or
3;
[0010] R.sub.X1 and R.sub.X2 at each occurrence are independently
selected from H; D; --F; --Cl; --Br; --I; --C.sub.1-6 alkyl;
--C.sub.1-6alkyl substituted with 1, 2, or 3 substituents;
--C.sub.1-6 alkoxy or --C.sub.1-6 alkoxy substituted with 1, 2, or
3 substituents; each said substituent at each occurrence is
independently optionally selected from D, halogen, --OH, --CN,
--NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3alkyl or
--C.sub.1-3alkoxy;
[0011] Y at each occurrence is independently selected from O or
S;
[0012] R.sub.7 at each occurrence is independently selected from H,
D, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --C.sub.3-8 cycloalkyl or
3-8 membered heterocyclic, and R.sub.7 at each occurrence is
independently optionally substituted or unsubstituted with one or
more substituents selected from D, --F, --Cl, --Br, --I, --OH, oxo,
.dbd.O, --SH, --CN, --NO.sub.2, --N.sub.3, --C.sub.1-3 alkyl,
--C.sub.1-3 alkoxy, --C.sub.2-4alkenyl, --C.sub.2-4 akynyl,
--C.sub.1-3 haloalkyl, --C.sub.3-6 cycloalkyl, 3-6 membered
heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered
heterocyclylthio, C.sub.5-8 aryl, C.sub.5-8aryloxy,
C.sub.5-8arylthio, 5-8 membered heteroaryl ring, 5-8 membered
heteroaryloxy, 5-8 membered heteroarylthio, --S(O).sub.tR.sub.9,
--C.sub.1-3 alkyl-S(O).sub.tR.sub.9, --O--R.sub.10, --C.sub.1-3
alkyl-O--R.sub.10, --C(O)OR.sub.10, --C.sub.1-3
alkyl-C(O)OR.sub.10, --C(O)R.sub.11, --C.sub.1-3alkyl-C(O)R.sub.11,
--O--C(O)R.sub.11, --C.sub.1-3alkyl-O--C(O)R.sub.11,
--NR.sub.12R.sub.13, --C.sub.1-3alkyl-NR.sub.12R.sub.13,
--C(O)NR.sub.12R.sub.13, --C.sub.1-3alkyl-C(O)NR.sub.12R.sub.13,
--N(R.sub.12)--C(O)R.sub.11 or --N(R.sub.12)--C(O)OR.sub.10;
[0013] R.sub.8 at each occurrence is independently selected from H,
D, --C.sub.1-6 alkyl, --C.sub.1-6 alkoxy, --C.sub.2-6 alkenyl,
--C.sub.2-6akynyl, --C(O)R.sub.11, --C.sub.1-6 alkyl-C(O)R.sub.11,
--C.sub.3-6 cycloalkyl, 3-8 membered heterocyclic, and R.sub.8 at
each occurrence is independently optionally substituted or
unsubstituted with one or more substituents selected from D, --F,
--Cl, --Br, --I, --OH, oxo, .dbd.O, --SH, --CN, --NO.sub.2,
--N.sub.3, --C.sub.1-3 alkyl, --C.sub.2-4 alkenyl, --C.sub.2-4
akynyl, --C.sub.1-3 haloalkyl, --C.sub.3-6 cycloalkyl, 3-6 membered
heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered
heterocyclylthio, C.sub.5-8 aryl, C.sub.5-8 aryloxy, C.sub.5-8
arylthio, 5-8 membered heteroaryl ring, 5-8 membered heteroaryloxy,
5-8 membered heteroarylthio, --S(O).sub.tR.sub.9, --C.sub.1-3
alkyl-S(O).sub.tR.sub.9, --O--R.sub.10, --C.sub.1-3
alkyl-O--R.sub.10, --C(O)OR.sub.10, --C.sub.1-3alkyl-C(O)OR.sub.10,
--C(O)R.sub.11, --C.sub.1-3alkyl-C(O)R.sub.11, --O--C(O)R.sub.11,
--C.sub.1-3alkyl-O--C(O)R.sub.11, --NR.sub.12R.sub.13,
--C.sub.1-3alkyl-NR.sub.12R.sub.13, --C(O)NR.sub.12R.sub.13,
--C.sub.1-3alkyl-C(O)NR.sub.12R.sub.13, --N(R.sub.12)--C(O)R.sub.11
or --N(R.sub.12)--C(O)OR.sub.10; or
[0014] R.sub.7 and R.sub.8 together with the carbon and nitrogen to
which they are respectively attached form 5-10 membered monocyclic
heterocyclic, 5-12 membered spirocyclic heterocyclic, 5-12 membered
fused heterocyclic, or 5-12 membered bridged heterocyclic, and each
said ring system at each occurrence is independently optionally
substituted or unsubstituted with one or more substituents selected
from D, --F, --Cl, --Br, --I, --OH, oxo, .dbd.O, --SH, --CN,
--NO.sub.2, --N.sub.3, --C.sub.1-3 alkyl, --C.sub.1-3 alkoxy,
--C.sub.2-4 alkenyl, --C.sub.2-4 alkynyl, --C.sub.1-3haloalkyl,
--C.sub.3-6 cycloalkyl, substituted or unsubstituted 3-6 membered
heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered
heterocyclylthio, C.sub.5-8 aryl, C.sub.5-8 aryloxy, C.sub.5-8
arylthio, 5-8 membered heteroaryl ring, 5-8 membered heteroaryloxy,
5-8 membered heteroarylthio, --S(O).sub.tR.sub.9, --C.sub.1-3
alkyl-S(O).sub.tR.sub.9, --O--R.sub.10,
--C.sub.1-3alkyl-O--R.sub.10, --C(O)OR.sub.10, --C.sub.1-3
alkyl-C(O)OR.sub.10, --C(O)R.sub.11, --C.sub.1-3
alkyl-C(O)R.sub.11, --O--C(O)R.sub.11, --C.sub.1-3
alkyl-O--C(O)R.sub.11, --NR.sub.12R.sub.13,
--C.sub.1-3alkyl-NR.sub.12R.sub.13, --C(O)NR.sub.12R.sub.13,
--C.sub.1-3alkyl-C(O)NR.sub.12R.sub.13, --N(R.sub.12)--C(O)R.sub.11
or --N(R.sub.12)--C(O)OR.sub.10;
[0015] R.sub.2 and R.sub.3 at each occurrence are independently
selected from H; D; --F; --Cl; --Br; --I; --OH; --SH; --CN;
--NH.sub.2; --NO.sub.2; --N.sub.3; --C.sub.1-6alkyl; --C.sub.1-6
alkyl; --C.sub.1-6 alkyl substituted with 1, 2 or 3 substituents
selected from -D, --F, --Cl, --Br, --I, --OH, --CN, --NH.sub.2,
--NO.sub.2, --COOH, --C.sub.1-3alkyl or C.sub.1-3alkoxy;
C.sub.1-6alkoxy; --C.sub.1-6alkoxy substituted with 1, 2 or 3
substituents selected from -D, --F, --Cl, --Br, --I, --OH, --CN,
--NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3alkyl or --C.sub.1-3
alkoxy; substituted or unsubstituted C.sub.3-8 cycloalkyl;
substituted or unsubstituted 3-8 membered heterocyclic; substituted
or unsubstituted 3-8 membered heterocyclyloxy; substituted or
unsubstituted 3-8 membered heterocyclylthio; --S(O).sub.tR.sub.9;
C.sub.1-6 alkyl-S(O).sub.tR.sub.9; --O--R.sub.10; --C.sub.1-6
alkyl-O--R.sub.10; --C(O)OR.sub.10; --C.sub.1-6
alkyl-C(O)OR.sub.10; --C(O)R.sub.11; --C.sub.1-6
alkyl-C(O)R.sub.11; --O--C(O)R.sub.11;
--C.sub.1-6alkyl-O--C(O)R.sub.11; --NR.sub.12R.sub.13;
--C.sub.1-6alkyl-NR.sub.12R.sub.13; --C(O)NR.sub.12R.sub.13;
--C.sub.1-6 alkyl-C(O)NR.sub.12R.sub.13;
--N(R.sub.12)--C(O)R.sub.11 or --N(R.sub.12)--C(O)OR.sub.10;
[0016] G at each occurrence is independently selected from
--CR.sub.G1R.sub.G2--, --NR.sub.G1--, --S--, --SO--, --SO.sub.2--
or O; m is 0, 1, 2, 3 or 4;
[0017] Each R.sub.G1 and R.sub.G2 at each occurrence is
independently selected from H; D; --C.sub.1-6 alkyl; --C.sub.1-6
alkyl substituted with 1, 2 or 3 substituents; --C.sub.1-6 alkoxy;
--C.sub.1-6 alkoxy substituted with 1, 2 or 3 substituents; each
said substituent is independently optionally selected from D,
halogen, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3
alkyl or C.sub.1-3 alkoxy;
[0018] Q at each occurrence is independently selected from
--CR.sub.4R.sub.4'--(CR.sub.4R.sub.4').sub.q-- or
--NR.sub.4--(CR.sub.4R.sub.4').sub.q--, and q is selected from 0,
1, 2, 3 or 4;
[0019] R.sub.4 and R.sub.4' at each occurrence are independently
selected from H; D; --F; --Cl; --Br; --I; --OH; --C.sub.1-6alkyl;
--C.sub.1-6 alkyl substituted with 1, 2 or 3 substituents;
--C.sub.1-6 alkoxy; --C.sub.1-6 alkoxy substituted with 1, 2 or 3
substituents; --C.sub.3-8 cycloalkyl; C.sub.3-8 cycloalkyl
substituted with 1, 2 or 3 substituents; C.sub.3-8 heterocyclic;
3-8 membered heterocyclic substituted with 1, 2 or 3 substituents;
each said substituent at each occurrence is independently
optionally selected from D, halogen, --OH, --CN, --NH.sub.2,
--NO.sub.2, --COOH, --C.sub.1-3 alkyl or C.sub.1-3alkoxy; or
[0020] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form C.sub.3-8 carbocyclic ring, 3-8 membered
heterocyclic ring or 5-10 membered heteroaryl ring, and each ring
system at each occurrence is independently optionally substituted
or unsubstituted with one or more substituents;
[0021] R.sub.5 and R.sub.5' at each occurrence are independently
selected from H; D; --F; --Cl; --Br; --I; --OH; --C.sub.1-6 alkyl;
--C.sub.1-6 alkyl substituted with 1, 2 or 3 substituents;
--C.sub.1-6 alkoxy; --C.sub.1-6 alkoxy substituted with 1, 2 or 3
substituents; --C.sub.3-8 cycloalkyl; C.sub.3-8 cycloalkyl
substituted with 1, 2 or 3 substituents; 3-8 membered heterocyclic;
3-8 membered heterocyclic substituted with 1, 2 or 3 substituents;
each said substituent is independently optionally selected from D,
halogen, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3
alkyl or C.sub.1-3 alkoxy; or
[0022] R.sub.5 and R.sub.5' together with the carbon to which they
are both attached form --C.sub.3-8 carbocyclic ring, 3-8 membered
heterocyclic ring, 5-10 membered heteroaryl ring, and each said
heterocyclic and each said heteroaryl at each occurrence
independently optionally contains one or two heteroatoms selected
from N, O or S, and each said ring system at each occurrence is
independently optionally substituted or unsubstituted with one or
more substituents; or
[0023] R.sub.4 and R.sub.5 together with the atom to which they are
respectively attached form 5-10 membered aromatic ring,
--C.sub.3-10 carbocyclic, 4-10 membered heterocyclic ring, each
said heterocyclic at each occurrence independently optionally
contains one or two heteroatoms selected from N, O or S, and each
said ring system at each occurrence is independently optionally
substituted or unsubstituted with one or more substituents;
[0024] W at each occurrence is independently selected from
--(CR.sub.w1R.sub.w2).sub.n--S--, --(CR.sub.w1R.sub.w2).sub.n--SO--
or --(CR.sub.w1R.sub.w2).sub.n--SO.sub.2--, n is selected from 0,
1, 2, 3 or 4;
[0025] R.sub.w1 and R.sub.w2 at each occurrence are independently
selected from H; D; --F; --Cl; --Br; --OH; methyl; ethyl; propyl;
isopropyl; --C.sub.1-3 alkyl substituted with 1, 2 or 3
substituents; methoxy; ethoxy; propoxy; isopropoxy; --C.sub.1-3
alkoxy substituted with 1, 2 or 3 substituents; cyclopropyl;
cyclobutyl; cyclopentyl; cyclohexyl; --C.sub.3-6 cycloalkyl
substituted with 1, 2 or 3 substituents; 3 membered heterocyclic; 4
membered heterocyclic; 5 membered heterocyclic; 6 membered
heterocyclic or 3-6 membered heterocyclic substituted with 1, 2 or
3 substituents; and each said substituent at each occurrence is
independently optionally selected from D, --F, --Cl, --Br, --I,
--OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, methyl, ethyl, propyl,
isopropyl, methoxy, ethoxy, propoxy, or isopropoxy;
[0026] R.sub.6 at each occurrence is independently selected from H;
D; --F; --Cl; --Br; --I; --C.sub.1-3alkyl; --C.sub.1-3alkyl
substituted with 1, 2 or 3 substituents; --C.sub.1-3 alkoxy;
--C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents;
--C.sub.1-3alkyl-COO--C.sub.1-3 alkyl; --C.sub.3-6 cycloalkyl or
--C.sub.3-6 cycloalkyl substituted with 1, 2 or 3 substituents; and
each said substituent is independently optionally selected from D,
halogen, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3
alkyl or C.sub.1-3 alkoxy; or
[0027] Q and R.sub.6 together with the carbon and W to which they
are respectively attached form 4-6 membered heterocyclic ring, the
heterocyclic ring is independently optionally substituted or
unsubstituted with one or more substituents, and the heterocyclic
ring independently optionally contains 1, 2, or 3 heteroatoms
selected from N, O or S, and each said substituent is independently
optionally selected from D, halogen, --OH, --CN, --NH.sub.2,
--NO.sub.2, --COOH, --C.sub.1-3 alkyl or C.sub.1-3 alkoxy; or
[0028] R.sub.4 and R.sub.6 together with the atom to which they are
respectively attached form 5-8 membered monocyclic heterocyclic,
5-10 membered spirocyclic heterocyclic, 5-10 membered fused
heterocyclic, 5-10 membered bridged heterocyclic or 5-10 membered
heteroaryl ring, and each said ring system independently optionally
contains 1, 2 or 3 heteroatoms selected from N, O or S, and each
said ring system is independently optionally substituted or
unsubstituted with 1, 2, or 3 substituents selected from D, --F,
--Cl, --Br, --I, --OH, --NH.sub.2, --CN, --COOH, oxo, .dbd.O,
--C.sub.1-3 alkyl or C.sub.1-3 alkoxy; or
[0029] R.sub.5 and R.sub.6 together with the carbon and W to which
they are respectively attached form 4-6 membered heterocyclic ring
or 5-8 membered heteroaryl ring, each said ring system
independently optionally contains 1, 2 or 3 heteroatoms selected
from N, O or S, and each said ring system is independently
optionally substituted or unsubstituted with 1, 2, or 3
substituents selected from D, --F, --Cl, --Br, --I, --OH,
--NH.sub.2, --CN, --COOH, oxo, .dbd.O, --C.sub.1-3alkyl or
C.sub.1-3alkoxy;
[0030] Each R.sub.9 at each occurrence is independently selected
from H, D, --C.sub.1-3 alkyl, --C.sub.1-3 alkyl C.sub.1-3 alkoxy,
--C.sub.2-4 alkenyl, --C.sub.3-6 cycloalkyl, substituted or
unsubstituted 3-6 membered heterocyclic, C.sub.1-3 haloalkyl,
phenyl, p-methyl phenyl, amino, --NH--C.sub.1-3 alkyl,
--N(C.sub.1-3 alkyl).sub.2 or C.sub.1-3 alkylamide;
[0031] Each R.sub.10 at each occurrence is independently selected
from H, D, --C.sub.1-3 alkyl, --C.sub.1-3 alkyl C.sub.1-3 alkoxy,
--C.sub.3-6 cycloalkyl, --C.sub.5-10 aryl, C.sub.1-3 haloalkyl, or
C.sub.1-3 alkyl substituted with hydroxyl;
[0032] Each R.sub.11 at each occurrence is independently selected
from H, D, --C.sub.1-3 alkyl, --C.sub.1-3 alkoxy,
--C.sub.3-6cycloalkyl, --C.sub.3-6 cycloalkoxy, C.sub.1-3
haloalkyl, C.sub.1-3 haloalkoxy, C.sub.1-3 alkyl substituted with
hydroxyl, or C.sub.1-3alkoxy substituted with hydroxyl;
[0033] R.sub.12 and R.sub.13 at each occurrence are independently
selected from H, D, --C.sub.1-3 alkyl, --C.sub.1-3 alkyl
C.sub.1-3alkoxy, --C.sub.1-3 alkoxy C.sub.1-3 alkyl, --C.sub.3-6
cycloalkyl C.sub.1-3 alkyl, --C.sub.2-4 alkenyl,
--C.sub.2-4alkynyl, --C.sub.3-6 cycloalkyl, substituted or
unsubstituted C.sub.5-10 aryl, substituted or unsubstituted 5-10
membered heteroaryl, or C.sub.1-3 alkanoyl;
[0034] t at each occurrence is independently selected from 0, 1 or
2.
[0035] In some embodiments, R.sub.1 at each occurrence is
independently
##STR00004##
[0036] X at each occurrence is independently selected from absent,
O, --NR.sub.X1-- or --CR.sub.X1R.sub.X2--; and p is 0, 1 or 2;
[0037] R.sub.X1 and R.sub.X2 at each occurrence are independently
selected from H; D; --F; --Cl; --Br; --I; --C.sub.1-3alkyl;
C.sub.1-3alkyl substituted with 1, 2 or 3 substituents; C.sub.1-3
alkoxy or C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents;
each said substituent is independently optionally selected from D,
--F, --Cl, --Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH,
--C.sub.1-3 alkyl or C.sub.1-3 alkoxy;
[0038] Y at each occurrence is independently selected from O or
S;
[0039] R.sub.7 at each occurrence is independently selected from H,
D, --C.sub.1-3alkyl, --C.sub.1-3alkoxy, --C.sub.3-5cycloalkyl or
3-8 membered heterocyclic, and the heterocyclic independently
optionally contains 1, 2 or 3 heteroatoms selected from N, O or S,
and R.sub.7 at each occurrence is independently optionally
substituted or unsubstituted with one or more substituents selected
from D, --F, --Cl, --Br, --I, --OH, oxo, .dbd.O, --SH, --CN,
--NO.sub.2, --N.sub.3, --C.sub.1-3 alkyl, --C.sub.1-3 alkoxy,
--C.sub.2-4alkenyl, --C.sub.2-4alkynyl, C.sub.1-3 haloalkyl,
C.sub.3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered
heterocyclyloxy, 3-6 membered heterocyclylthio, C.sub.5-8 aryl,
C.sub.5-8aryloxy, C.sub.5-8arylthio, 5-8 membered heteroaryl ring,
5-8 membered heteroaryloxy, 5-8 membered heterocyclylthio,
--S(O).sub.tR.sub.9, --C.sub.1-3alkyl-S(O).sub.tR.sub.9,
--C.sub.1-3 alkyl-O--R.sub.10, --C(O)OR.sub.10, --C.sub.1-3
alkyl-C(O)OR.sub.10, --C(O)R.sub.11, --C.sub.1-3
alkyl-C(O)R.sub.11, --O--C(O)R.sub.11, --C.sub.1-3
alkyl-O--C(O)R.sub.11, --NR.sub.12R.sub.13,
--C.sub.1-3alkyl-NR.sub.12R.sub.13, --C(O)NR.sub.12R.sub.13,
--C.sub.1-3alkyl-C(O)NR.sub.12R.sub.13, --N(R.sub.12)--C(O)R.sub.11
or --N(R.sub.12)--C(O)OR.sub.10;
[0040] R.sub.8 at each occurrence is independently selected from H,
D, --C.sub.1-3 alkoxy, --C.sub.2-4alkenyl, --C.sub.2-4alkynyl,
--C(O)R.sub.11, --C.sub.1-3 alkyl-C(O)R.sub.11, --C.sub.3-6
cycloalkyl, or 3-8 membered heterocyclic, R.sub.8 is independently
optionally substituted or unsubstituted with one or more
substituents selected from D, --F, --Cl, --Br, --I, --OH, oxo,
.dbd.O, --SH, --CN, --NO.sub.2, --N.sub.3, --C.sub.1-3 alkyl,
--C.sub.2-4alkenyl, --C.sub.2-4alkynyl, C.sub.1-3haloalkyl,
--C.sub.3-6cycloalkyl, 3-6 membered heterocyclic, 3-6 membered
heterocyclyloxy, 3-6 membered heterocyclylthio, C.sub.5-8 aryl,
C.sub.5-8aryloxy, C.sub.5-8arylthio, 5-8 membered heteroaryl ring,
5-8 membered heteroaryloxy, 5-8 membered heterocyclylthio,
--S(O).sub.tR.sub.9, --C.sub.1-3 alkyl-S(O).sub.tR.sub.9,
--O--R.sub.10, --C.sub.1-3 alkyl-O--R.sub.10, --C(O)OR.sub.10,
--C.sub.1-3 alkyl-C(O)OR.sub.10, --C(O)R.sub.11, --C.sub.1-3
alkyl-C(O)R.sub.11, --O--C(O)R.sub.11,
--C.sub.1-3alkyl-O--C(O)R.sub.11, --NR.sub.12R.sub.13,
--C.sub.1-3alkyl-NR.sub.12R.sub.13, --C(O)NR.sub.12R.sub.13,
--C.sub.1-3alkyl-C(O)NR.sub.12R.sub.13, --N(R.sub.12)--C(O)R.sub.11
or --N(R.sub.12)--C(O)OR.sub.10; or
[0041] R.sub.7 and R.sub.8 together with the carbon and nitrogen to
which they are respectively attached form 5-7 membered monocyclic
heterocyclic, 5-10 membered spirocyclic heterocyclic, 5-10 membered
fused heterocyclic or 5-10 membered bridged heterocyclic, each said
ring system is independently optionally contains 1, 2 or 3
heteroatoms selected from N, O or S, and each said ring system is
independently optionally substituted or unsubstituted with one or
more substituents selected from D, --F, --Cl, --Br, --I, --OH, oxo,
.dbd.O, --SH, --CN, --NO.sub.2, --N.sub.3, --C.sub.1-3alkyl,
--C.sub.1-3 alkoxy, --C.sub.2-4 alkenyl, --C.sub.2-4 alkynyl,
C.sub.1-3 haloalkyl, --C.sub.3-6 cycloalkyl, substituted or
unsubstituted 3-6 membered heterocyclic, 3-6 membered
heterocyclyloxy, 3-6 membered heterocyclylthio, C.sub.5-8 aryl,
C.sub.5-8aryloxy, C.sub.5-8arylthio, 5-8 membered heteroaryl ring,
5-8 membered heteroaryloxy, 5-8 membered heterocyclylthio,
--S(O).sub.tR.sub.9, --C.sub.1-3 alkyl-S(O).sub.tR.sub.9,
--O--R.sub.10, --C(O)OR.sub.10, --C.sub.1-3 alkyl-C(O)OR.sub.10,
--C(O)R.sub.11, --C.sub.1-3 alkyl-C(O)R.sub.11, --O--C(O)R.sub.11,
--C.sub.1-3 alkyl-O--C(O)R.sub.11, --NR.sub.12R.sub.13,
--C.sub.1-3alkyl-NR.sub.12R.sub.13, --C(O)NR.sub.12R.sub.13,
--C.sub.1-3alkyl-C(O)NR.sub.12R.sub.13, --N(R.sub.12)--C(O)R.sub.11
or --N(R.sub.12)--C(O)OR.sub.10;
[0042] In R.sub.7 and R.sub.8, each R.sub.9 is independently
optionally selected from H, D, --C.sub.1-3 alkyl C.sub.1-3alkoxy,
--C.sub.2-4alkenyl, --C.sub.3-6 cycloalkyl, substituted or
unsubstituted 3-6 membered heterocyclic, C.sub.1-3haloalkyl,
phenyl, p-methyl phenyl, amino, --NH--C.sub.1-3 alkyl,
--N(C.sub.1-3 alkyl).sub.2 or C.sub.1-3alkylamide;
[0043] In R.sub.7 and R.sub.8, each R.sub.10 is independently
optionally selected from H, D, --C.sub.1-3 alkyl C.sub.1-3alkoxy,
--C.sub.3-6 cycloalkyl, C.sub.1-3 haloalkyl or C.sub.1-3 alkyl
substituted with hydroxyl;
[0044] In R.sub.7 and R.sub.8, each R.sub.11 is independently
optionally selected from H, D, --C.sub.1-3 alkoxy,
--C.sub.3-6cycloalkyl, --C.sub.3-6 cycloalkoxy, C.sub.1-3
haloalkyl, C.sub.1-3 haloalkoxy, C.sub.1-3 alkyl substituted with
hydroxyl, or C.sub.1-3alkoxy substituted with hydroxyl;
[0045] In R.sub.7 and R.sub.8, R.sub.12 and R.sub.13 are
respectively independently selected from H, D, --C.sub.1-3 alkyl
C.sub.1-3 alkoxy, --C.sub.1-3 alkoxy C.sub.1-3 alkyl, --C.sub.3-6
cycloalkyl C.sub.1-3alkyl, --C.sub.2-4alkenyl, --C.sub.2-4alkynyl,
--C.sub.3-6cycloalkyl, substituted or unsubstituted
--C.sub.5-10aryl, substituted or unsubstituted 5-10 membered
heteroaryl or --C.sub.1-3alkanoyl; [0046] t is 0, 1 or 2.
[0047] In some embodiments, R.sub.1 at each occurrence is
independently
##STR00005##
[0048] X at each occurrence is independently selected from absent,
O, --NR.sub.X1-- or --CR.sub.X1R.sub.X2--; and p is 0 or 1;
[0049] R.sub.X1 and R.sub.X2 at each occurrence are independently
selected from H; D; --F; --Cl; --Br; --I; methyl; ethyl; propyl;
isopropyl; C.sub.1-3 alkyl substituted with 1, 2 or 3 substituents;
methoxy; ethoxy; propoxy; isopropoxy or C.sub.1-3 alkoxy
substituted with 1, 2 or 3 substituents; each said substituent is
independently optionally selected from D, --F, --Cl, --Br, --I,
--OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, methyl, ethyl, propyl,
isopropyl, methoxy, ethoxy, propoxy, or isopropoxy;
[0050] Y at each occurrence is independently O;
[0051] R.sub.7 at each occurrence is independently selected from H,
D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy,
isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3
membered heterocyclic, 4 membered heterocyclic, 5 membered
heterocyclic, 6 membered heterocyclic, 7 membered heterocyclic, 8
membered heterocyclic, and each said heterocyclic independently
optionally contains one or two heteroatoms selected from N, O or S,
and R.sub.7 at each occurrence is independently optionally
substituted or unsubstituted with substituents selected from D,
--F, --Cl, --Br, --I, --OH, oxo, .dbd.O, --SH, --CN, --NO.sub.2,
--N.sub.3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,
propoxy, isopropoxy, --C.sub.2-4 alkenyl, --C.sub.2-4alkynyl,
C.sub.1-3 alkyl substituted with halogen, C.sub.3-6 cycloalkyl, 3-6
membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered
heterocyclylthio, C.sub.5-8 aryl, C.sub.5-8 aryloxy, C.sub.5-8
arylthio, 5-8 membered heteroaryl ring, 5-8 membered heteroaryloxy,
5-8 membered heterocyclylthio, --S(O).sub.tR.sub.9,
-methyl-S(O).sub.tR.sub.9, -ethyl-S(O).sub.tR.sub.9,
-propyl-S(O).sub.tR.sub.9, isopropyl-S(O).sub.tR.sub.9,
--O--R.sub.10, -methyl-O--R.sub.10, -ethyl-O--R.sub.10,
-propyl-O--R.sub.10, -isopropyl-O--R.sub.10, --C(O)OR.sub.10,
-methyl-C(O)OR.sub.10, -ethyl-C(O)OR.sub.10, -propyl-C(O)OR.sub.10,
-isopropyl-C(O)OR.sub.10, --C(O)R.sub.11, -methyl-C(O)R.sub.11,
-ethyl-C(O)R.sub.11, -propyl-C(O)R.sub.11, -isopropyl-C(O)R.sub.11,
--O--C(O)R.sub.11, -methyl-O--C(O)R.sub.11, -ethyl-O--C(O)R.sub.11,
-propyl-O--C(O)R.sub.11, -isopropyl-O--C(O)R.sub.11,
--NR.sub.12R.sub.13, -methyl-NR.sub.12R.sub.13,
-ethyl-NR.sub.12R.sub.13, -propyl-NR.sub.12R.sub.13,
-isopropyl-NR.sub.12R.sub.13, --C(O)NR.sub.12R.sub.13,
-methyl-C(O)NR.sub.12R.sub.13, -ethyl-C(O)NR.sub.12R.sub.13,
-propyl-C(O)NR.sub.12R.sub.13, -isopropyl-C(O)NR.sub.12R.sub.13,
--N(R.sub.12)--C(O)R.sub.11 or --N(R.sub.12)--C(O)OR.sub.10;
[0052] R.sub.8 at each occurrence is independently selected from H,
D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy,
isopropoxy, --C.sub.2-4alkenyl, --C.sub.2-4 alkynyl,
--C(O)R.sub.11, -methyl-C(O)R.sub.11, -ethyl-C(O)R.sub.11,
-propyl-C(O)R.sub.11, -isopropyl --C(O)R.sub.11, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, 3 membered heterocyclic, 4
membered heterocyclic, 5 membered heterocyclic, 6 membered
heterocyclic, 7 membered heterocyclic, 8 membered heterocyclic, and
said heterocyclic independently optionally contains one or two
heteroatoms selected from N, O or S, and R.sub.8 is independently
optionally substituted or unsubstituted with one or more
substituents selected from D, --F, --Cl, --Br, --I, --OH, oxo,
.dbd.O, --SH, --CN, --NO.sub.2, --N.sub.3, methyl, ethyl, propyl,
isopropyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3
haloalkyl, C.sub.3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6
membered heterocyclyloxy, 3-6 membered heterocyclylthio, C.sub.5-8
aryl, C.sub.5-8 aryloxy, C.sub.5-8arylthio, 5-8 membered heteroaryl
ring, 5-8 membered heteroaryloxy, 5-8 membered heterocyclylthio,
--S(O).sub.tR.sub.9, -methyl-S(O).sub.tR.sub.9,
-ethyl-S(O).sub.tR.sub.9, -propyl-S(O).sub.tR.sub.9,
isopropyl-S(O).sub.tR.sub.9, --O--R.sub.10, -methyl-O--R.sub.10,
-ethyl-O--R.sub.10, -propyl-O--R.sub.10, -isopropyl-O--R.sub.10,
--C(O)OR.sub.10, -methyl-C(O)OR.sub.10, -ethyl-C(O)OR.sub.10,
-propyl-C(O)OR.sub.10, -isopropyl-C(O)OR.sub.10, --C(O)R.sub.11,
-methyl-C(O)R.sub.11, -ethyl-C(O)R.sub.11, -propyl-C(O)R.sub.11,
-isopropyl-C(O)R.sub.11, --O--C(O)R.sub.11,
-methyl-O--C(O)R.sub.11, -ethyl-O--C(O)R.sub.11,
-propyl-O--C(O)R.sub.11, -isopropyl-O--C(O)R.sub.11,
--NR.sub.12R.sub.13, -methyl-NR.sub.12R.sub.13, -ethyl
--NR.sub.12R.sub.13, -propyl-NR.sub.12R.sub.13,
-isopropyl-NR.sub.12R.sub.13, --C(O)NR.sub.12R.sub.13,
-methyl-C(O)NR.sub.12R.sub.13, -ethyl-C(O)NR.sub.12R.sub.13,
-propyl-C(O)NR.sub.12R.sub.13, -isopropyl-C(O)NR.sub.12R.sub.13,
--N(R.sub.12)--C(O)R.sub.11 or --N(R.sub.12)--C(O)OR.sub.10; or
[0053] R.sub.7 and R.sub.8 together with the carbon and nitrogen to
which they are respectively attached form 5 membered monocyclic
heterocyclic, 6 membered monocyclic heterocyclic, 7 membered
monocyclic heterocyclic, 5 membered spirocyclic heterocyclic, 6
membered spirocyclic heterocyclic, 7 membered spirocyclic
heterocyclic, 8 membered spirocyclic heterocyclic, 9 membered
spirocyclic heterocyclic, 10 membered spirocyclic heterocyclic, 5
membered fused heterocyclic, 6 membered fused heterocyclic, 7
membered fused heterocyclic, 8 membered fused heterocyclic, 9
membered fused heterocyclic, 10 membered fused heterocyclic, 5
membered bridged heterocyclic, 6 membered bridged heterocyclic, 7
membered bridged heterocyclic, 8 membered bridged heterocyclic, 9
membered bridged heterocyclic, or 10 membered bridged heterocyclic,
each said ring system independently optionally contains 1, 2 or 3
heteroatoms selected from N, O or S, and each said ring system is
independently optionally substituted or unsubstituted with one or
more substituents selected from D, --F, --Cl, --Br, --I, --OH, oxo,
.dbd.O, --SH, --CN, --NO.sub.2, --N.sub.3, methyl, ethyl, propyl,
isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-3haloalkyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, substituted or unsubstituted 3-6 membered
heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered
heterocyclylthio, C.sub.5-8 aryl, C.sub.5-8 aryloxy,
C.sub.5-8arylthio, 5-8 membered heteroaryl ring, 5-8 membered
heteroaryloxy, 5-8 membered heterocyclylthio, --S(O).sub.tR.sub.9,
-methyl-S(O).sub.tR.sub.9, -ethyl-S(O).sub.tR.sub.9,
-propyl-S(O).sub.tR.sub.9, -isopropyl-S(O).sub.tR.sub.9,
--O--R.sub.10, -methyl-O--R.sub.10, -ethyl-O--R.sub.10,
-propyl-O--R.sub.10, -isopropyl-O--R.sub.10, --C(O)OR.sub.10,
-methyl-C(O)OR.sub.10, -ethyl-C(O)OR.sub.10, -propyl-C(O)OR.sub.10,
-isopropyl-C(O)OR.sub.10, --C(O)R.sub.11, -methyl-C(O)R.sub.11,
-ethyl-C(O)R.sub.11, -propyl-C(O)R.sub.11, -isopropyl-C(O)R.sub.11,
--O--C(O)R.sub.11, -methyl-O--C(O)R.sub.11, -ethyl-O--C(O)R.sub.11,
-propyl-O--C(O)R.sub.11, -isopropyl-O--C(O)R.sub.11,
--NR.sub.12R.sub.13, -methyl-NR.sub.12R.sub.13,
-ethyl-NR.sub.12R.sub.13, -propyl-NR.sub.12R.sub.13,
-isopropyl-NR.sub.12R.sub.13, --C(O)NR.sub.12R.sub.13,
-methyl-C(O)NR.sub.12R.sub.13, -ethyl-C(O)NR.sub.12R.sub.13,
-propyl-C(O)NR.sub.12R.sub.13, -isopropyl-C(O)NR.sub.12R.sub.13,
--N(R.sub.12)--C(O)R.sub.11 or --N(R.sub.12)--C(O)OR.sub.10;
[0054] In R.sub.7 and R.sub.8, each R.sub.9 is independently
optionally selected from H, D, methyl, ethyl, propyl, isopropyl,
--C.sub.1-3 alkylC.sub.1-3 alkoxy, --C.sub.2-4 alkenyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or
unsubstituted 3-6 membered heterocyclic, C.sub.1-3 haloalkyl,
phenyl, p-methyl phenyl, amino, --NH--C.sub.1-3alkyl, --N(C.sub.1-3
alkyl).sub.2 or C.sub.1-3alkylamide;
[0055] In R.sub.7 and R.sub.8, each R.sub.10 is independently
optionally selected from H, D, methyl, ethyl, propyl, isopropyl,
--C.sub.1-3 alkylC.sub.1-3 alkoxy, --C.sub.3-6 cycloalkyl,
--C.sub.5-10 aryl, C.sub.1-3 haloalkyl or C.sub.1-3 alkyl
substituted with hydroxyl;
[0056] In R.sub.7 and R.sub.8, each R.sub.11 is independently
optionally selected from H, D, methyl, ethyl, propyl, isopropyl,
methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, C.sub.3-6 membered cycloalkoxy, C.sub.1-3
haloalkyl, C.sub.1-3 haloalkoxy, C.sub.1-3 alkyl substituted with
hydroxyl, or C.sub.1-3 alkoxy substituted with hydroxyl;
[0057] In R.sub.7 and R.sub.8, R.sub.12 and R.sub.13 are
respectively independently selected from H, D, methyl, ethyl,
propyl, isopropyl, --C.sub.1-3 alkylC.sub.1-3 alkoxy, --C.sub.1-3
alkoxy C.sub.1-3 alkyl, --C.sub.3-6 cycloalkyl C.sub.1-3 alkyl,
--C.sub.2-4alkenyl, --C.sub.2-4alkynyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, substituted or unsubstituted C.sub.5-10
aryl, substituted or unsubstituted 5-10 membered heteroaryl or
--C.sub.1-3 alkylamide;
[0058] t is 0, 1 or 2.
[0059] In some embodiments, R.sub.1 at each occurrence is
independently
##STR00006##
[0060] X at each occurrence is independently selected from
--CH.sub.2--, --CHD-, --CD.sub.2-, --CH(CH.sub.3)--,
--C(CH.sub.3).sub.2--, --CHF--, --CHBr-- or --CH(OH)--; and p is 0
or 1;
[0061] Y at each occurrence is independently O;
[0062] R.sub.7 at each occurrence is independently selected from H,
D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy,
isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
dioxolane, azacyclobutyl, piperidyl, piperazinyl, oxopiperazinyl,
oxypiperidyl, tetrahydrofuranyl, tetrahydroimidazolyl,
tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl,
morpholinyl, thiomorpholinyl or oxadiazole, R.sub.7 at each
occurrence is independently optionally substituted or unsubstituted
with one or more substituents selected from D, --F, --Cl, --Br,
--I, --OH, oxo, .dbd.O, --SH, --CN, --NO.sub.2, --N.sub.3, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy,
--C.sub.2-4alkenyl, --C.sub.2-4alkynyl, C.sub.1-3 haloalkyl,
C.sub.3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered
heterocyclyloxy, 3-6 membered heterocyclylthio, C.sub.5-8 aryl,
C.sub.5-8aryloxy, C.sub.5-8arylthio, 5-8 membered heteroaryl ring,
5-8 membered heteroaryloxy, 5-8 membered heterocyclylthio, --S(O)H,
--S(O)CH.sub.3, -methyl-S(O)H, -methyl-S(O)CH.sub.3, -ethyl-S(O)H,
-ethyl-S(O)CH.sub.3, -propyl-S(O)H, -propyl-S(O)CH.sub.3,
-isopropyl-S(O)H, -isopropyl-S(O)CH.sub.3, -methyl-OH,
-methyl-OCH.sub.3, -ethyl-OH, -ethyl-OCH.sub.3, -propyl-OH,
-propyl-OCH.sub.3, -isopropyl-OH, -isopropyl-OCH3, --C(O)OH,
--C(O)OCH3, -methyl-C(O)OH, -methyl-C(O)OCH.sub.3, -ethyl-C(O)OH,
-ethyl-C(O)OCH.sub.3, -propyl-C(O)OH, -propyl-C(O)OCH.sub.3,
-isopropyl-C(O)OH, -isopropyl-C(O)OCH.sub.3, --C(O)H,
--C(O)CH.sub.3, -methyl-C(O)H, -methyl-C(O)CH.sub.3, -ethyl-C(O)H,
-ethyl-C(O)CH.sub.3, -propyl-C(O)H, -propyl-C(O)CH.sub.3,
-isopropyl-C(O)H, -isopropyl-C(O)CH.sub.3, --O--C(O)H,
--O--C(O)CH.sub.3, -methyl-O--C(O)H, -methyl-O--C(O)CH.sub.3,
-ethyl-O--C(O)H, -ethyl-O--C(O)CH.sub.3, -propyl-O--C(O)H,
-propyl-O--C(O)CH.sub.3, -isopropyl-O--C(O)H,
-isopropyl-O--C(O)CH.sub.3, --NH.sub.2, --N(CH.sub.3).sub.2,
-methyl-NH.sub.2, -methyl-N(CH.sub.3).sub.2, -ethyl-NH.sub.2,
-ethyl-N(CH.sub.3).sub.2, -propyl-NH.sub.2,
-propyl-N(CH.sub.3).sub.2, -isopropyl-NH.sub.2,
-isopropyl-N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--C(O)N(CH.sub.3).sub.2, -methyl-C(O)NH.sub.2,
-methyl-C(O)N(CH.sub.3).sub.2, -ethyl-C(O)NH.sub.2,
-ethyl-C(O)N(CH.sub.3).sub.2, -propyl-C(O)NH.sub.2,
-propyl-C(O)N(CH.sub.3).sub.2, -isopropyl-C(O)NH.sub.2,
-isopropyl-C(O)N(CH.sub.3).sub.2, --NH--C(O)H or --NH--C(O)OH;
[0063] R.sub.8 at each occurrence is independently selected from H,
D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy,
isopropoxy, --C.sub.2-4alkenyl, --C.sub.2-4alkynyl, --C(O)H,
-methyl-C(O)H, -ethyl-C(O)H, -propyl-C(O)H, -isopropyl-C(O)H,
--C(O)-methyl, -methyl-C(O)-methyl, -ethyl-C(O)-methyl,
-propoxy-C(O)-methyl, -isopropoxy-C(O)-methyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, 3 membered heterocyclic, 4
membered heterocyclic, 5 membered heterocyclic, 6 membered
heterocyclic, 7 membered heterocyclic, 8 membered heterocyclic, and
said heterocyclic independently optionally contains 1 or 2
heteroatoms selected from N, O or S, and R.sub.8 is independently
optionally substituted or unsubstituted with one or more
substituents selected from D, --F, --Cl, --Br, --I, --OH, oxo,
.dbd.O, --SH, --CN, --NO.sub.2, --N.sub.3, methyl, ethyl, propyl,
isopropyl, C.sub.2-4alkenyl, C.sub.2-4 alkynyl, C.sub.1-3
haloalkyl, C.sub.3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6
membered heterocyclyloxy, 3-6 membered heterocyclylthio, C.sub.5-8
aryl, C.sub.5-8 aryloxy, C.sub.5-8 arylthio, 5-8 membered
heteroaryl ring, 5-8 membered heteroaryloxy, 5-8 membered
heterocyclylthio, --S(O)H, --S(O)CH.sub.3, -methyl-S(O)H,
-methyl-S(O)CH.sub.3, -ethyl-S(O)H, -ethyl-S(O)CH.sub.3,
-propyl-S(O)H, -propyl-S(O)CH.sub.3, -isopropyl-S(O)H,
-isopropyl-S(O)CH.sub.3, -methyl-OH, -methyl-OCH.sub.3, -ethyl-OH,
-ethyl-OCH.sub.3, -propyl-OH, -propyl-OCH.sub.3, -isopropyl-OH,
-isopropyl-OCH.sub.3, --C(O)OH, --C(O)OCH.sub.3, -methyl-C(O)OH,
-methyl-C(O)OCH.sub.3, -ethyl-C(O)OH, -ethyl-C(O)OCH.sub.3,
-propyl-C(O)OH, -propyl-C(O)OCH.sub.3, -isopropyl-C(O)OH,
-isopropyl-C(O)OCH.sub.3, --C(O)H, --C(O)CH.sub.3, -methyl-C(O)H,
-methyl-C(O)CH.sub.3, -ethyl-C(O)H, -ethyl-C(O)CH.sub.3,
-propyl-C(O)H, -propyl-C(O)CH.sub.3, -isopropyl-C(O)H,
-isopropyl-C(O)CH.sub.3, --O--C(O)H, --O--C(O)CH.sub.3,
-methyl-O--C(O)H, -methyl-O--C(O)CH.sub.3, -ethyl-O--C(O)H,
-ethyl-O--C(O)CH.sub.3, -propyl-O--C(O)H, -propyl-O--C(O)CH.sub.3,
-isopropyl-O--C(O)H, -isopropyl-O--C(O)CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, -methyl-NH.sub.2, -methyl-N(CH.sub.3).sub.2,
-ethyl-NH.sub.2, -ethyl-N(CH.sub.3).sub.2, -propyl-NH.sub.2,
-propyl-N(CH.sub.3).sub.2, -isopropyl-NH.sub.2,
-isopropyl-N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--C(O)N(CH.sub.3).sub.2, -methyl-C(O)NH.sub.2,
-methyl-C(O)N(CH.sub.3).sub.2, -ethyl-C(O)NH.sub.2,
-ethyl-C(O)N(CH.sub.3).sub.2, -propyl-C(O)NH.sub.2,
-propyl-C(O)N(CH.sub.3).sub.2, -isopropyl-C(O)NH.sub.2,
-isopropyl-C(O)N(CH.sub.3).sub.2, --NH--C(O)H or --NH--C(O)OH;
[0064] R.sub.7 and R.sub.8 together with the carbon and nitrogen to
which they are respectively attached form dioxolane, azetidine,
piperidine, piperazine, oxopiperazine, oxopiperidine,
tetrahydrofuran, tetrahydroimidazole, tetrahydrothiazole,
tetrahydrooxazole, tetrahydropyran, tetrahydropyrrole, azapentyl
ring, morpholinyl, thiomorpholinyl, 7-membered oxazacyclo or
7-membered oxazacyclospiro, each said ring system is independently
optionally substituted or unsubstituted with one or more
substituents selected from D, --F; --Cl; --Br; --I; --OH; oxo;
.dbd.O; --SH; --CN; --NO.sub.2; --N.sub.3; methyl; ethyl; propyl;
isopropyl; methoxy; ethoxy; propoxy; isopropoxy; C.sub.2-4alkenyl;
C.sub.2-4 alkynyl; C.sub.1-3 alkyl substituted with halogen;
cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; piperazinyl;
piperazinyl substituted with 1, 2 or 3 substituents selected from
F, Cl, Br, I, --OH, --CH.sub.3, or 3-6 membered heterocyclyloxy;
3-6 membered heterocyclylthio; C.sub.5-8 aryl, C.sub.5-8 aryloxy;
C.sub.5-8 arylthio; 5-8 membered heteroaryl ring; 5-8 membered
heteroaryloxy; 5-8 membered heterocyclylthio; --S(O)H;
--S(O)CH.sub.3; -methyl-S(O)H; -methyl-S(O)CH.sub.3; -ethyl-S(O)H;
-ethyl-S(O)CH.sub.3; -propyl-S(O)H; -propyl-S(O)CH.sub.3;
-isopropyl-S(O)H; -isopropyl-S(O)CH.sub.3; -methyl-OH;
-methyl-OCH.sub.3; -ethyl-OH; -ethyl-OCH.sub.3; -propyl-OH;
-propyl-OCH.sub.3; -isopropyl-OH; -isopropyl-OCH.sub.3; --C(O)OH;
--C(O)OCH.sub.3; -methyl-C(O)OH; -methyl-C(O)OCH.sub.3;
-ethyl-C(O)OH; -ethyl-C(O)OCH.sub.3; -propyl-C(O)OH;
-propyl-C(O)OCH.sub.3; -isopropyl-C(O)OH; -isopropyl-C(O)OCH.sub.3;
--C(O)H; --C(O)CH.sub.3; -methyl-C(O)H; -methyl-C(O)CH.sub.3;
-ethyl-C(O)H; -ethyl-C(O)CH.sub.3; -propyl-C(O)H;
-propyl-C(O)CH.sub.3; -isopropyl-C(O)H; -isopropyl-C(O)CH.sub.3;
--O--C(O)H; --O--C(O)CH.sub.3; -methyl-O--C(O)H;
-methyl-O--C(O)CH.sub.3; -ethyl-O--C(O)H; -ethyl-O--C(O)CH.sub.3;
-propyl-O--C(O)H; -propyl-O--C(O)CH.sub.3; -isopropyl-O--C(O)H;
-isopropyl-O--C(O)CH.sub.3; --NH.sub.2; --N(CH.sub.3).sub.2;
-methyl-NH.sub.2; -methyl-N(CH.sub.3).sub.2; -ethyl-NH.sub.2;
-ethyl-N(CH.sub.3).sub.2; -propyl-NH.sub.2;
-propyl-N(CH.sub.3).sub.2; -isopropyl-NH.sub.2;
-isopropyl-N(CH.sub.3).sub.2; --C(O)NH.sub.2;
--C(O)N(CH.sub.3).sub.2; -methyl-C(O)NH.sub.2;
-methyl-C(O)N(CH.sub.3).sub.2; -ethyl-C(O)NH.sub.2;
-ethyl-C(O)N(CH.sub.3).sub.2; -propyl-C(O)NH.sub.2;
-propyl-C(O)N(CH.sub.3).sub.2; -isopropyl-C(O)NH.sub.2;
-isopropyl-C(O)N(CH.sub.3).sub.2; --NH--C(O)H or --NH--C(O)OH.
[0065] In some embodiments, R.sub.t is selected from:
##STR00007##
[0066] In some embodiments, R.sub.t is selected from:
##STR00008##
[0067] In some embodiments, R.sub.2 and R.sub.3 are respectively
independently selected from H; D; --F; --Cl; --Br; --I; --OH; --SH;
--CN; --NH.sub.2; --NO.sub.2; --N.sub.3; --C.sub.1-3 alkyl;
--C.sub.1-3 alkyl substituted with 1, 2 or 3 substituents selected
from -D, --F, --Cl, --Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2,
--COOH, --C.sub.1-3 alkyl or C.sub.1-3 alkoxy; --C.sub.1-3 alkoxy;
C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents selected
from -D, --F, --Cl, --Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2,
--COOH, --C.sub.1-3 alkyl or C.sub.1-3 alkoxy; substituted or
unsubstituted C.sub.3-6 cycloalkyl; substituted or unsubstituted
C.sub.3-6 heterocyclic; substituted or unsubstituted 3-6 membered
heterocyclyloxy; substituted or unsubstituted 3-6 membered
heterocyclylthio; --S(O).sub.tR.sub.9; --C.sub.1-3
alkyl-S(O).sub.tR.sub.9; --O--R.sub.10; --C.sub.1-3
alkyl-O--R.sub.10; --C(O)OR.sub.10; --C.sub.1-3alkyl-C(O)OR.sub.10;
--C(O)R.sub.11; --C.sub.1-3alkyl-C(O)R.sub.11; --O--C(O)R.sub.11;
--C.sub.1-3alkyl-O--C(O)R.sub.11; --NR.sub.12R.sub.13;
--C.sub.1-3alkyl-NR.sub.12R.sub.13; --C(O)NR.sub.12R.sub.13;
--C.sub.1-3alkyl-C(O)NR.sub.12R.sub.13; --N(R.sub.12)--C(O)R.sub.11
or --N(R.sub.12)--C(O)OR.sub.10;
[0068] In R.sub.2 and R.sub.3, each R.sub.9 is independently
optionally selected from H, D, --C.sub.1-3 alkyl C.sub.1-3alkoxy,
--C.sub.2-4 alkenyl, --C.sub.3-6 cycloalkyl, substituted or
unsubstituted 3-6 membered heterocyclic, C.sub.1-3haloalkyl,
phenyl, p-methyl phenyl, amino, --NH--C.sub.1-3 alkyl,
--N(C.sub.1-3 alkyl).sub.2 or C.sub.1-3alkylamide;
[0069] In R.sub.2 and R.sub.3, each R.sub.10 is independently
optionally selected from H, D, --C.sub.1-3 alkyl C.sub.1-3alkoxy,
--C.sub.3-6 cycloalkyl, --C.sub.5-8 aryl, C.sub.1-3 haloalkyl or
C.sub.1-3 alkyl substituted with hydroxyl;
[0070] In R.sub.2 and R.sub.3, each Rut is independently optionally
selected from H, D, --C.sub.1-3 alkoxy, --C.sub.3-6cycloalkyl,
--C.sub.3-6 cycloalkoxy, C.sub.1-3 haloalkyl, C.sub.1-3 haloalkoxy,
C.sub.1-3 alkyl substituted with hydroxyl, or C.sub.1-3alkoxy
substituted with hydroxyl;
[0071] In R.sub.2 and R.sub.3, each R.sub.12 and R.sub.13 is
respectively independently optionally selected from H, D,
--C.sub.1-3 alkyl C.sub.1-3 alkoxy, --C.sub.1-3 alkoxy
C.sub.1-3alkyl, --C.sub.3-6 cycloalkyl C.sub.1-3 alkyl, --C.sub.2-4
alkenyl, --C.sub.2-4 alkynyl, --C.sub.3-6cycloalkyl, substituted or
unsubstituted C.sub.5-8 aryl, substituted or unsubstituted 5-8
membered heteroaryl or C.sub.1-3alkanoyl;
[0072] t is 0, 1 or 2.
[0073] In some embodiments, R.sub.2 and R.sub.3 are respectively
independently selected from H; D; --F; --Cl; --Br; --I; --OH; --SH;
--CN; --NO.sub.2; --N.sub.3; methyl; ethyl; propyl; isopropyl;
--C.sub.1-3 alkyl substituted with 1, 2 or 3 substituents selected
from -D, --F, --Cl, --Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2,
--COOH, --C.sub.1-3 alkyl or C.sub.1-3 alkoxy; methoxy; ethoxy;
propoxy; isopropoxy; C.sub.1-3alkoxy substituted with 1, 2 or 3
substituents selected from -D, --F, --Cl, --Br, --I, --OH, --CN,
--NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3 alkyl or C.sub.1-3
alkoxy; substituted or unsubstituted C.sub.3-6cycloalkyl;
substituted or unsubstituted C.sub.3-6 heterocyclic; substituted or
unsubstituted 3-6 membered heterocyclyloxy; substituted or
unsubstituted 3-6 membered heterocyclylthio; --S(O).sub.tR.sub.9;
--C.sub.1-3 alkyl-S(O).sub.tR.sub.9; --O--R.sub.10; --C.sub.1-3
alkyl-O--R.sub.10; --C(O)OR.sub.10; --C.sub.1-3
alkyl-C(O)OR.sub.10; --C(O)R.sub.11; --C.sub.1-3
alkyl-C(O)R.sub.11; --O--C(O)R.sub.11;
--C.sub.1-3alkyl-O--C(O)R.sub.11; --NR.sub.12R.sub.13;
--C.sub.1-3alkyl-NR.sub.12R.sub.13; --C(O)NR.sub.12R.sub.13;
--C.sub.1-3alkyl-C(O)NR.sub.12R.sub.13; --N(R.sub.12)--C(O)R.sub.11
or --N(R.sub.12)--C(O)OR.sub.10;
[0074] In R.sub.2 and R.sub.3, each R.sub.9 is independently
optionally selected from H, D, methyl, ethyl, propyl, isopropyl,
--C.sub.1-3 allkyl C.sub.1-3 alkoxy, --C.sub.2-4 alkenyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or
unsubstituted 3-6 membered heterocyclic, C.sub.1-3 haloalkyl,
phenyl, p-methyl phenyl, amino, --NH--C.sub.1-3 alkyl,
--N(C.sub.1-3 alkyl).sub.2 or C.sub.1-3 alkylamide;
[0075] In R.sub.2 and R.sub.3, each R.sub.10 is independently
optionally selected from H, D, methyl, ethyl, propyl, isopropyl,
--C.sub.1-3 allkyl C.sub.1-3 alkoxy, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, --C.sub.5-8 aryl, C.sub.1-3 haloalkyl or
C.sub.1-3 alkyl substituted with hydroxyl;
[0076] In R.sub.2 and R.sub.3, each R.sub.11 is independently
optionally selected from H, D, methyl, ethyl, propyl, isopropyl,
methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, --C.sub.3-6cycloalkoxy, C.sub.1-3
haloalkyl, C.sub.1-3 haloalkoxy, C.sub.1-3 alkyl substituted with
hydroxyl, or C.sub.1-3 alkoxy substituted with hydroxyl;
[0077] In R.sub.2 and R.sub.3, each R.sub.12 and R.sub.13 is
respectively independently optionally selected from H, D, methyl,
ethyl, propyl, isopropyl, --C.sub.1-3 alkyl C.sub.1-3 alkoxy,
--C.sub.1-3 alkoxy C.sub.1-3 alkyl, --C.sub.3-6 cycloalkyl
C.sub.1-3 alkyl, --C.sub.2-4alkenyl, --C.sub.2-4 alkynyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or
unsubstituted C.sub.5-8 aryl, substituted or unsubstituted 5-8
membered heteroaryl or C.sub.1-3 alkanoyl;
[0078] t is 0 or 1.
[0079] In some embodiments, R.sub.2 and R.sub.3 are respectively
independently selected from H; D; --F; --Cl; --Br; --I; --OH; --SH;
--CN; --NO.sub.2; --N.sub.3; methyl; ethyl; propyl; isopropyl;
--C.sub.1-3 alkyl substituted with 1, 2 or 3 substituents selected
from -D, --F, --Cl, --Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2,
--COOH, --C.sub.1-3 alkyl or C.sub.1-3 alkoxy; methoxy, ethoxy,
propoxy, isopropoxy; C.sub.1-3alkoxy substituted with 1, 2 or 3
substituents selected from -D, --F, --Cl, --Br, --I, --OH, --CN,
--NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3 alkyl or C.sub.1-3
alkoxy; substituted or unsubstituted C.sub.3-6cycloalkyl;
substituted or unsubstituted 3-6 membered heterocyclic; substituted
or unsubstituted 3-6 membered heterocyclyloxy; substituted or
unsubstituted 3-6 membered heterocyclylthio; --S(O)H;
--S(O)CH.sub.3; -methyl-S(O)H; -methyl-S(O)CH.sub.3; -ethyl-S(O)H;
-ethyl-S(O)CH.sub.3; -propyl-S(O)H; -propyl-S(O)CH.sub.3;
-isopropyl-S(O)H; -isopropyl-S(O)CH.sub.3; -methyl-OH;
-methyl-OCH.sub.3; -ethyl-OH; -ethyl-OCH.sub.3; -propyl-OH;
-propyl-OCH.sub.3; -isopropyl-OH; -isopropyl-OCH.sub.3; --C(O)OH;
--C(O)OCH.sub.3; -methyl-C(O)OH; -methyl-C(O)OCH.sub.3;
-ethyl-C(O)OH; -ethyl-C(O)OCH.sub.3; -propyl-C(O)OH;
-propyl-C(O)OCH.sub.3; -isopropyl-C(O)OH; -isopropyl-C(O)OCH.sub.3;
--C(O)H; --C(O)CH.sub.3; -methyl-C(O)H; -methyl-C(O)CH.sub.3;
-ethyl-C(O)H; -ethyl-C(O)CH.sub.3; -propyl-C(O)H;
-propyl-C(O)CH.sub.3; -isopropyl-C(O)H; -isopropyl-C(O)CH.sub.3;
--O--C(O)H; --O--C(O)CH.sub.3; -methyl-O--C(O)H;
-methyl-O--C(O)CH.sub.3; -ethyl-O--C(O)H; -ethyl-O--C(O)CH.sub.3;
-propyl-O--C(O)H; -propyl-O--C(O)CH.sub.3; -isopropyl-O--C(O)H;
-isopropyl-O--C(O)CH.sub.3; --NH.sub.2; --N(CH.sub.3).sub.2;
-methyl-NH.sub.2; -methyl-N(CH.sub.3).sub.2; -ethyl-NH.sub.2;
-ethyl-N(CH.sub.3).sub.2; -propyl-NH.sub.2;
-propyl-N(CH.sub.3).sub.2; -isopropyl-NH.sub.2;
-isopropyl-N(CH.sub.3).sub.2; --C(O)NH.sub.2;
--C(O)N(CH.sub.3).sub.2; -methyl-C(O)NH.sub.2;
-methyl-C(O)N(CH.sub.3).sub.2; -ethyl-C(O)NH.sub.2;
-ethyl-C(O)N(CH.sub.3).sub.2; -propyl-C(O)NH.sub.2;
-propyl-C(O)N(CH.sub.3).sub.2; -isopropyl-C(O)NH.sub.2;
-isopropyl-C(O)N(CH.sub.3).sub.2; --NH--C(O)H or --NH--C(O)OH.
[0080] In some embodiments, R.sub.2 and R.sub.3 are respectively
independently selected from H, D, --F, --Cl, --Br, --I, --OH, --SH,
--CN, --NO.sub.2, --N.sub.3, methyl, ethyl, propyl, isopropyl,
methoxy, ethoxy, propoxy or isopropoxy. In some embodiments,
R.sub.2 and R.sub.3 are respectively independently selected from H,
D, --F or methyl.
[0081] In some embodiments, G at each occurrence is independently
selected from --CR.sub.G1R.sub.G2--, --NR.sub.G1--, --S--, --SO--,
--SO.sub.2-- or O; m is 0, 1, 2, 3 or 4;
[0082] each R.sub.G1 and R.sub.G2 is independently selected from H,
D, --C.sub.1-3 alkyl, --C.sub.1-3 alkyl substituted with 1, 2 or 3
substituents; --C.sub.1-3 alkoxy; --C.sub.1-3 alkoxy substituted
with 1, 2 or 3 substituents; each said substituent is independently
optionally selected from D, halogen, --OH, --CN, --NH.sub.2,
--NO.sub.2, --COOH, --C.sub.1-3 alkyl or C.sub.1-3 alkoxy.
[0083] In some embodiments, G at each occurrence is independently
selected from --CR.sub.G1R.sub.G2--, --NR.sub.G1--, --S--, --SO--,
--SO.sub.2-- or O; m is 0, 1, 2 or 3;
[0084] each R.sub.G1 and R.sub.G2 is independently selected from H;
D; --C.sub.1-3 alkyl; --C.sub.1-3 alkyl substituted with 1, 2 or 3
substituents; --C.sub.1-3 alkoxy; or --C.sub.1-3 alkoxy substituted
with 1, 2 or 3 substituents; each said substituent is independently
optionally selected from D, --F, --Cl, --Br, --I, --OH, --CN,
--NH.sub.2, --NO.sub.2, --COOH, methyl, ethyl, propyl, isopropyl,
methoxy, ethoxy, propoxy or isopropoxy.
[0085] In some embodiments, G at each occurrence is independently
selected from --CR.sub.G1R.sub.G2--, --NR.sub.G1--, --S--, --SO--,
--SO.sub.2-- or O; m is 0, 1, 2, or 3;
[0086] each R.sub.G1 and R.sub.G2 is independently selected from H;
D; methyl; ethyl; propyl; isopropyl; --C.sub.1-3 alkyl substituted
with 1, 2 or 3 substituents; methoxy, ethoxy, propoxy; isopropoxy;
--C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents; each
said substituent is independently optionally selected from D, --F,
--Cl, --Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or
isopropoxy.
[0087] In some embodiments, G at each occurrence is independently
selected from --CH.sub.2--, --CHD-, --CD.sub.2-, --NH--, --S--,
--SO--, --SO.sub.2-- or O; m is 0, for 2.
[0088] In some embodiments, G at each occurrence is independently
selected from --CH.sub.2--, --CHD-, --CD.sub.2-, --NH--, --S--,
--SO--, --SO.sub.2-- or O; m is 0 or 1.
[0089] In some embodiments, G at each occurrence is independently
selected from --NH-- or O; m is 0 or 1.
[0090] In some embodiments, G at each occurrence is independently
selected from --NH-- or O; m is 1.
[0091] In some embodiments, G at each occurrence is independently
selected from --NH--; m is 0 or 1.
[0092] In some embodiments, G at each occurrence is independently
selected from --NH--; m is 1.
[0093] In some embodiments, m is 0.
[0094] In some embodiments, Q at each occurrence is independently
selected from --CR.sub.4R.sub.4'--(CR.sub.4R.sub.4')q-;
[0095] Both R.sub.4 and R.sub.4' are independently selected from H;
D; --F; --Cl; --Br; --I; --OH; --C.sub.1-6 alkyl; C.sub.1-6 alkyl
substituted with 1, 2 or 3 substituents; --C.sub.1-6 alkoxy;
C.sub.1-6 alkoxy substituted with 1, 2 or 3 substituents;
--C.sub.3-8cycloalkyl; C.sub.3-8 cycloalkyl substituted with 1, 2
or 3 substituents; 3-8 membered heterocyclic; 3-8 membered
heterocyclic substituted with 1, 2 or 3 substituents; each said
substituent is independently optionally selected from D, halogen,
--OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3 alkyl or
C.sub.1-3 alkoxy; or
[0096] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form --C.sub.3-8 carbocyclic ring, -3-8 membered
heterocyclic ring or -5-10 membered heteroaryl ring, each ring
system is independently optionally substituted or unsubstituted
with one or more substituents.
[0097] In some embodiments, Q is
--NR.sub.4--(CR.sub.4R.sub.4').sub.q--;
[0098] Both R.sub.4 and R.sub.4' are independently selected from H;
D; --F; --Cl; --Br; --I; --OH; --C.sub.1-6 alkyl; C.sub.1-6 alkyl
substituted with 1, 2 or 3 substituents; --C.sub.1-6 alkoxy;
C.sub.1-6 alkoxy substituted with 1, 2 or 3 substituents;
--C.sub.3-8cycloalkyl; C.sub.3-8 cycloalkyl substituted with 1, 2
or 3 substituents; 3-8 membered heterocyclic; 3-8 membered
heterocyclic substituted with 1, 2 or 3 substituents; each said
substituent is independently optionally selected from D, halogen,
--OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3alkyl or
C.sub.1-3alkoxy; or
[0099] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form --C.sub.3-8 carbocyclic ring, -3-8 membered
heterocyclic ring or -5-10 membered heteroaryl ring, each ring
system is independently optionally substituted or unsubstituted
with one or more substituents.
[0100] In some embodiments, Q is
--CR.sub.4R.sub.4'--(CR.sub.4R.sub.4').sub.q-- or
--NR.sub.4--(CR.sub.4R.sub.4').sub.q--, and q is selected from 0,
1, 2, 3 or 4; Both R.sub.4 and R.sub.4' are independently selected
from H; D; --F; --Cl; --Br; --I; --OH; --C.sub.1-3 alkyl; C.sub.1-3
alkyl substituted with 1, 2 or 3 substituents; --C.sub.1-3 alkoxy;
C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents;
--C.sub.3-6cycloalkyl; C.sub.3-6cycloalkyl substituted with 1, 2 or
3 substituents; 3-6 membered heterocyclic; 3-6 membered
heterocyclic substituted with 1, 2 or 3 substituents; each said
substituent is independently optionally selected from D, halogen,
--OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3 alkyl or
C.sub.1-3 alkoxy; or R.sub.4 and R.sub.4' together with the carbon
to which they are both attached form --C.sub.3-6 carbocyclic ring,
-3-6 membered heterocyclic ring or 5-8 membered heteroaryl ring,
and each ring system is independently optionally substituted or
unsubstituted with one or more substituents.
[0101] In some embodiments, Q is
--CR.sub.4R.sub.4'--(CR.sub.4R.sub.4').sub.q--;
[0102] Both R.sub.4 and R.sub.4' are independently selected from H;
D; --F; --Cl; --Br; --I; --OH; --C.sub.1-3 alkyl; C.sub.1-3 alkyl
substituted with 1, 2 or 3 substituents; --C.sub.1-3 alkoxy;
C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents;
--C.sub.3-6cycloalkyl; C.sub.3-6cycloalkyl substituted with 1, 2 or
3 substituents; 3-6 membered heterocyclic; 3-6 membered
heterocyclic substituted with 1, 2 or 3 substituents; each said
substituent is independently optionally selected from D, halogen,
--OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3 alkyl or
C.sub.1-3 alkoxy; or
[0103] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form --C.sub.3-6 carbocyclic ring, -3-6 membered
heterocyclic ring or 5-8 membered heteroaryl ring, and each ring
system is independently optionally substituted or unsubstituted
with one or more substituents.
[0104] In some embodiments, Q is
--NR.sub.4--(CR.sub.4R.sub.4').sub.q--;
[0105] Both R.sub.4 and R.sub.4' are independently selected from H;
D; --F; --Cl; --Br; --I; --OH; --C.sub.1-3 alkyl; C.sub.1-3 alkyl
substituted with 1, 2 or 3 substituents; --C.sub.1-3 alkoxy;
C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents;
--C.sub.3-6cycloalkyl; C.sub.3-6cycloalkyl substituted with 1, 2 or
3 substituents; 3-6 membered heterocyclic; 3-6 membered
heterocyclic substituted with 1, 2 or 3 substituents; each said
substituent is independently optionally selected from D, halogen,
--OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3 alkyl or
C.sub.1-3 alkoxy; or
[0106] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form --C.sub.3-6 carbocyclic ring, -3-6 membered
heterocyclic ring or 5-8 membered heteroaryl ring, each ring system
is independently optionally substituted or unsubstituted with one
or more substituents.
[0107] In some embodiments, Q is
--CR.sub.4R.sub.4'--(CR.sub.4R.sub.4').sub.q-- or
--NR.sub.4--(CR.sub.4R.sub.4').sub.q--, and q is selected from 0,
1, 2, 3 or 4;
[0108] Both R.sub.4 and are independently selected from H; D; --F;
--Cl; --Br; --I; --OH; --C.sub.1-3 alkyl; C.sub.1-3 alkyl
substituted with 1, 2 or 3 substituents; --C.sub.1-3 alkoxy;
C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents;
--C.sub.3-6cycloalkyl; C.sub.3-6cycloalkyl substituted with 1, 2 or
3 substituents; 3-6 membered heterocyclic; 3-6 membered
heterocyclic substituted with 1, 2 or 3 substituents; each said
substituent is independently optionally selected from D, --F, --Cl,
--Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;
or
[0109] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form --C.sub.3-6 carbocyclic ring, -3-6 membered
heterocyclic ring or 5-8 membered heteroaryl ring, said each
heterocyclic ring and each heteroaryl ring independently optionally
contains 1 or 2 heteroatoms selected from N, O or S, and each ring
system is independently optionally substituted or unsubstituted
with one or more substituents.
[0110] In some embodiments, Q is
--CR.sub.4R.sub.4'--(CR.sub.4R.sub.4').sub.q--;
[0111] Both R.sub.4 and are independently selected from H; D; --F;
--Cl; --Br; --I; --OH; --C.sub.1-3 alkyl; C.sub.1-3 alkyl
substituted with 1, 2 or 3 substituents; --C.sub.1-3 alkoxy;
C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents;
--C.sub.3-6cycloalkyl; C.sub.3-6cycloalkyl substituted with 1, 2 or
3 substituents; 3-6 membered heterocyclic; 3-6 membered
heterocyclic substituted with 1, 2 or 3 substituents; each said
substituent is independently optionally selected from D, --F, --Cl,
--Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;
or
[0112] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form --C.sub.3-6 carbocyclic ring, -3-6 membered
heterocyclic ring or -5-8 membered heteroaryl ring, said each
heterocyclic ring and each heteroaryl ring independently optionally
contains 1 or 2 heteroatoms selected from N, O or S, and each ring
system is independently optionally substituted or unsubstituted
with one or more substituents.
[0113] In some embodiments, Q is
--NR.sub.4--(CR.sub.4R.sub.4').sub.q--;
[0114] Both R.sub.4 and are independently selected from H; D; --F;
--Cl; --Br; --I; --OH; --C.sub.1-3 alkyl; C.sub.1-3 alkyl
substituted with 1, 2 or 3 substituents; --C.sub.1-3 alkoxy;
C.sub.1-3 alkoxy substituted with 1, 2 or 3 substituents;
--C.sub.3-6cycloalkyl; C.sub.3-6cycloalkyl substituted with 1, 2 or
3 substituents; 3-6 membered heterocyclic; 3-6 membered
heterocyclic substituted with 1, 2 or 3 substituents; each said
substituent is independently optionally selected from D, --F, --Cl,
--Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;
or
[0115] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form --C.sub.3-6carbocyclic ring, -3-6 membered
heterocyclic ring or -5-8 membered heteroaryl ring, said each
heterocyclic ring and each heteroaryl ring independently optionally
contains 1 or 2 heteroatoms selected from N, O or S, and each ring
system is independently optionally substituted or unsubstituted
with one or more substituents.
[0116] In some embodiments, Q is
--CR.sub.4R.sub.4'--(CR.sub.4R.sub.4').sub.q-- or
--NR.sub.4--(CR.sub.4R.sub.4').sub.q--, and q is selected from 0,
1, 2, 3 or 4;
[0117] Both R.sub.4 and R.sub.4' are independently selected from H;
D; --F; --Cl; --Br; --I; --OH; methyl; ethyl; propyl; isopropyl;
--C.sub.1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy;
ethoxy; propoxy; isopropoxy; or --C.sub.1-3 alkoxy substituted with
1, 2 or 3 substituents; cyclopropyl; cyclobutyl; cyclopentyl;
cyclohexyl; C.sub.3-6 cycloalkyl substituted with 1, 2 or 3
substituents; 3-6 membered heterocyclic; or 3-6 membered
heterocyclic substituted with 1, 2 or 3 substituents; each said
substituent is independently optionally selected from D, --F, --Cl,
--Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;
or
[0118] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form 3 membered carbocyclic ring; 4 membered
carbocyclic ring; 5 membered carbocyclic ring; 6 membered
carbocyclic ring; 3 membered heterocyclic ring; 4 membered
heterocyclic ring; 5 membered heterocyclic ring; 6 membered
heterocyclic ring; 5 membered heteroaryl ring; 6 membered
heteroaryl ring; 7 membered heteroaryl ring; 8 membered heteroaryl
ring; said each heterocyclic ring and each heteroaryl ring
independently optionally contains 1 or 2 heteroatoms selected from
N, O or S, and said each carbocyclic ring, each heterocyclic ring,
and heteroaryl ring is independently optionally substituted or
unsubstituted with 1, 2 or 3 substituents.
[0119] In some embodiments, Q is
--CR.sub.4R.sub.4'--(CR.sub.4R.sub.4').sub.q--; Both R.sub.4 and
R.sub.4' are independently selected from H; D; --F; --Cl; --Br;
--I; --OH; methyl; ethyl; propyl; isopropyl; --C.sub.1-3 alkyl
substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy;
isopropoxy; --C.sub.1-3alkoxy substituted with 1, 2 or 3
substituents; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl;
C.sub.3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6
membered heterocyclic; 3-6 membered heterocyclic substituted with
1, 2 or 3 substituents; each said substituent is independently
optionally selected from D, --F, --Cl, --Br, --I, --OH, --CN,
--NH.sub.2, --NO.sub.2, --COOH, methyl, ethyl, propyl, isopropyl,
methoxy, ethoxy, propoxy or isopropoxy; or
[0120] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form 3 membered carbocyclic ring; 4 membered
carbocyclic ring; 5 membered carbocyclic ring; 6 membered
carbocyclic ring; 3 membered heterocyclic ring; 4 membered
heterocyclic ring; 5 membered heterocyclic ring; 6 membered
heterocyclic ring; 5 membered heteroaryl ring; 6 membered
heteroaryl ring; 7 membered heteroaryl ring; 8 membered heteroaryl
ring; said each heterocyclic ring and each heteroaryl ring
independently optionally contains 1 or 2 heteroatoms selected from
N, O or S, and said each carbocyclic ring, each heterocyclic ring,
each heteroaryl ring is independently optionally substituted or
unsubstituted with 1, 2 or 3 substituents.
[0121] In some embodiments, Q is
--NR.sub.4--(CR.sub.4R.sub.4').sub.q--;
[0122] Both R.sub.4 and R.sub.4' are independently selected from H;
D; --F; --Cl; --Br; --I; --OH; methyl; ethyl; propyl; isopropyl;
--C.sub.1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy;
ethoxy; propoxy; isopropoxy; --C.sub.1-3alkoxy substituted with 1,
2 or 3 substituents; cyclopropyl; cyclobutyl; cyclopentyl;
cyclohexyl; C.sub.3-6 cycloalkyl substituted with 1, 2 or 3
substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic
substituted with 1, 2 or 3 substituents; each said substituent is
independently optionally selected from D, --F, --Cl, --Br, --I,
--OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, methyl, ethyl, propyl,
isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or
[0123] R.sub.4 and R.sub.4' together with the carbon to which they
are both attached form 3 membered carbocyclic ring; 4 membered
carbocyclic ring; 5 membered carbocyclic ring; 6 membered
carbocyclic ring; 3 membered heterocyclic ring; 4 membered
heterocyclic ring; 5 membered heterocyclic ring; 6 membered
heterocyclic ring; 5 membered heteroaryl ring; 6 membered
heteroaryl ring; 7 membered heteroaryl ring; 8 membered heteroaryl
ring; said each heterocyclic ring and heteroaryl ring independently
optionally contains 1 or 2 heteroatoms selected from N, O or S, and
said each carbocyclic ring, each heterocyclic ring, and each
heteroaryl ring is independently optionally substituted or
unsubstituted with 1, 2 or 3 substituents.
[0124] In some embodiments, Both R.sub.5 and R.sub.5' are
independently selected from H; D; --F; --Cl; --Br; --I; --OH;
--C.sub.1-3 alkyl; --C.sub.1-3 alkyl substituted with 1, 2 or 3
substituents; --C.sub.1-3 alkoxy; --C.sub.1-3 alkoxy substituted
with 1, 2 or 3 substituents; --C.sub.3-6 cycloalkyl; --C.sub.3-6
cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered
heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3
substituents; each said substituent is independently optionally
selected from D, halogen, --OH, --CN, --NH.sub.2, --NO.sub.2,
--COOH, --C.sub.1-3 alkyl or C.sub.1-3alkoxy; or
[0125] R.sub.5 and R.sub.5' together with the carbon to which they
are both attached to form --C.sub.3-6 carbocyclic ring, 3-6
membered heterocyclic ring, 5-8 membered heteroaryl ring, said each
heterocyclic ring and each heteroaryl ring independently optionally
contains 1 or 2 heteroatoms selected from N, O or S, and said ring
system is independently optionally substituted or unsubstituted
with one or more substituents; or
[0126] R.sub.4 and R.sub.5 together with the atom to which they are
respectively attached form 5-10 membered aromatic ring, --C.sub.3-8
carbocyclic ring, 4-8 membered heterocyclic ring, each said
heterocyclic independently optionally contains 1 or 2 substituents
selected from N, O or S, and each said ring system is dependently
optionally substituted or unsubstituted with one or more
substituents.
[0127] In some embodiments, Both R.sub.5 and R.sub.5' are
independently selected from H; D; --F; --Cl; --Br; --I; --OH;
methyl; ethyl; propyl; isopropyl; --C.sub.1-3 alkyl substituted
with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy;
--C.sub.1-3alkoxy substituted with 1, 2 or 3 substituents;
cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; --C.sub.3-6
cycloalkyl substituted with 1, 2 or 3 substituents; 3 membered
heterocyclic; 4 membered heterocyclic; 5 membered heterocyclic; 6
membered heterocyclic; 3-6 membered heterocyclic substituted with
1, 2 or 3 substituents; each said heterocyclic dependently
optionally contains 1 or 2 substituents selected from N, O or S;
each said substituent is independently optionally selected from D,
--F, --Cl, --Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or
isopropoxy; or
[0128] R.sub.5 and R.sub.5' together with the carbon to which they
are both attached to form 3 membered carbocyclic ring, 4 membered
carbocyclic ring, 5 membered carbocyclic ring, 6 membered
carbocyclic ring, 3 membered heterocyclic ring, 4 membered
heterocyclic ring, 5 membered heterocyclic ring, 6 membered
heterocyclic ring, 5 membered heteroaryl ring, 6 membered
heteroaryl ring, 7 membered heteroaryl ring or 8 membered
heteroaryl ring, said each heterocyclic ring and each heteroaryl
ring independently optionally contains 1 or 2 heteroatoms selected
from N, O or S, and said each ring system is independently
optionally substituted or unsubstituted with 1, 2 or 3
substituents; or
[0129] R.sub.4 and R.sub.5 together with the atom to which they are
respectively attached form 5 membered aromatic ring, 6 membered
aromatic ring, 7 membered aromatic ring, 8 membered aromatic ring,
9 membered aromatic ring, 10 membered aromatic ring, 4 membered
carbocyclic ring, 5 membered carbocyclic ring, 6 membered
carbocyclic ring, 7 membered carbocyclic ring, 8 membered
carbocyclic ring, 4 membered heterocyclic ring, 5 membered
heterocyclic ring, 6 membered heterocyclic ring, 7 membered
heterocyclic ring, 8 membered heterocyclic ring, the each
heterocyclic independently optionally contains 1 or 2 heteroatoms
selected from N, O or S, and said each ring system is independently
optionally substituted or unsubstituted with 1, 2 or 3
substituents.
[0130] In some embodiments, Both R.sub.5 and R.sub.5' are
independently selected from H; D; --F; --Cl; --Br; --I; --OH;
methyl; ethyl; propyl; isopropyl; --C.sub.1-3 alkyl substituted
with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy;
--C.sub.1-3alkoxy substituted with 1, 2 or 3 substituents;
cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; --C.sub.3-6
cycloalkyl substituted with 1, 2 or 3 substituents; 3 membered
heterocyclic; 4 membered heterocyclic; 5 membered heterocyclic; 6
membered heterocyclic; 3-6 membered heterocyclic substituted with
1, 2 or 3 substituents; each said heterocyclic independently
optionally contains 1 or 2 heteroatoms selected from N, O or S;
each said substituent is independently optionally selected from D,
--F, --Cl, --Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or
isopropoxy; or
[0131] R.sub.5 and R.sub.5' together with the carbon to which they
are both attached form 3 membered carbocyclic ring, 4 membered
carbocyclic ring, 5 membered carbocyclic ring, 6 membered
carbocyclic ring, 3 membered heterocyclic ring, 4 membered
heterocyclic ring, 5 membered heterocyclic ring, 6 membered
heterocyclic ring, 5 membered heteroaryl ring, 6 membered
heteroaryl ring, 7 membered heteroaryl ring, 8 membered heteroaryl
ring; said each heterocyclic ring and each heteroaryl ring
independently optionally contains 1 or 2 heteroatoms selected from
N, O or S, and said each ring system is independently optionally
substituted or unsubstituted with 1, 2 or 3 substituents selected
from D, --F, --Cl, --Br, --I, --OH, oxo, .dbd.O, --NH.sub.2, --CN,
--COOH, --NO.sub.2, methyl, ethyl, propyl, isopropyl, methoxy,
ethoxy, propoxy or isopropoxy; or
[0132] R.sub.4 and R.sub.5 together with the atom to which they are
respectively attached form benzene, naphthalene, 3 membered
carbocyclic ring, 4 membered carbocyclic ring, 5 membered
carbocyclic ring, 6 membered carbocyclic ring, piperidine,
piperazine, oxopiperazine, oxopiperidine, tetrahydrofuran,
tetrahydroimidazole, tetrahydrothiazole, tetrahydrooxazole,
tetrahydropyran, tetrahydropyrrole or azapentyl ring, and said each
ring system is independently optionally substituted or
unsubstituted with 1, 2 or 3 substituents selected from D, --F,
--Cl, --Br, --I, --OH, NH.sub.2, --CN, --COOH, --NO.sub.2, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or
isopropoxy.
[0133] In some embodiments, R.sub.6 at each occurrence is
independently selected from H; D; --F; --Cl; --Br; --I; methyl;
ethyl; propyl; isopropyl; --C.sub.1-3 alkyl substituted with 1, 2
or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy;
--C.sub.1-3alkoxy substituted with 1, 2 or 3 substituents;
-methyl-COO-methyl; -ethyl-COO-ethyl; -propyl-COO-propyl;
-isopropyl-COO-isopropyl; cyclopropyl; cyclobutyl; cyclopentyl;
cyclohexyl; --C.sub.3-6 carbocyclic substituted with 1, 2 or 3
substituents; each said substituent is independently optionally
selected from D, --F, --Cl, --Br, --I, --OH, --NH.sub.2, --CN,
--COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy
or isopropoxy; or
[0134] Q and R.sub.6 together with the carbon and W to which they
are respectively attached form 4 membered heterocyclic ring, 5
membered heterocyclic ring, 6 membered heterocyclic ring or 7
membered heterocyclic ring, said heterocyclic ring is independently
optionally substituted or unsubstituted with one or more
substituents, said heterocyclic ring is independently optionally
contains 1, 2 or 3 heteroatoms selected from N, O or S, said each
substituent is independently optionally selected from D, --F, --Cl,
--Br, --I, --OH, --CN, --NH.sub.2, --NO.sub.2, --COOH, --C.sub.1-3
alkyl or C.sub.1-3 alkoxy; or R.sub.4 and R.sub.6 together with the
atom to which they are respectively attached form 5 membered
monocyclic heterocyclic, 6 membered monocyclic heterocyclic, 7
membered monocyclic heterocyclic, 8 membered monocyclic
heterocyclic, 5 membered spirocyclic heterocyclic, 6 membered
spirocyclic heterocyclic, 7 membered spirocyclic heterocyclic, 8
membered spirocyclic heterocyclic, 9 membered spirocyclic
heterocyclic, 10 membered spirocyclic heterocyclic, 5 membered
fused heterocyclic, 6 membered fused heterocyclic, 7 membered fused
heterocyclic, 8 membered fused heterocyclic, 9 membered fused
heterocyclic, 10 membered fused heterocyclic, 5 membered bridged
heterocyclic, 6 membered bridged heterocyclic, 7 membered bridged
heterocyclic, 8 membered bridged heterocyclic, 9 membered bridged
heterocyclic, 10 membered bridged heterocyclic, 5 membered
heteroaryl ring, 6 membered heteroaryl ring, 7 membered heteroaryl
ring, 8 membered heteroaryl ring, 9 membered heteroaryl ring or 10
membered heteroaryl ring, the each ring system is independently
optionally contains 1, 2 or 3 heteroatoms which are selected from
N, O or S, and each said ring system is independently optionally
substituted or unsubstituted with 1, 2 or 3 substituents selected
from D, --F, --Cl, --Br, --I, --OH, --NH.sub.2, --CN, --COOH, oxo,
.dbd.O, --C.sub.1-3 alkyl or --C.sub.1-3 alkoxy; or
[0135] R.sub.5 and R.sub.6 together with the carbon and W to which
they are respectively attached form 4 membered heterocyclic ring, 5
membered heterocyclic ring, 6 membered heterocyclic ring, 5
membered heteroaryl ring, 6 membered heteroaryl ring, 7 membered
heteroaryl ring, 8 membered heteroaryl ring, the each ring system
independently optionally contains 1, 2 or 3 heteroatoms selected
from N, O or S, and each said ring system is independently
optionally substituted or unsubstituted with 1, 2 or 3 substituents
selected from D, --F, --Cl, --Br, --I, --OH, --NH.sub.2, --CN,
--COOH, oxo, .dbd.O, Methyl, ethyl, propyl, isopropyl, methoxy,
ethoxy, propoxy or isopropoxy.
[0136] In some embodiments,
##STR00009##
is selected from:
##STR00010## ##STR00011## ##STR00012## ##STR00013##
[0137] In some embodiments,
##STR00014##
is selected from:
##STR00015##
[0138] In some embodiments, the compound is selected from:
TABLE-US-00001 1.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 2.
N-(5-cyano-4-(2-(methylthio)ethoxy)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide; 3.
N-(5-cyano-4-thiomorpholinopyridin-2-yl)-7-formyl-6-((4-methyl-
2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-
carboxamide; 4.
(R)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 5.
N-(5-cyano-4-((tetrahydrothiophen-3-yl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 6.
(R)-N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((3-methoxy-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 7.
N-(5-Cyano-4-(((R)-1-(methylthio)propan-2-yl)amino)pyridin-2-
yl)-7-formyl-6-(((R)-3-methoxy-2-oxopyrrolidin-1-yl)methyl)-
3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 8.
(R)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-
yl)-7-formyl-6-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 9.
N-(5-cyano-4-((2-methyl-2-(methylthio)propyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 10.
N-(5-cyano-4-((2-(methylthio)phenyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 11.
(S)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-
3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 12.
N-(5-cyano-4-((2-(cyclohexylthio)ethyl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 13.
(S)-N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-
7-formyl-6-((3-methoxy-2-oxopyrrolidin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 14.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((5-oxo-6-oxa-4-azaspiro[2.4]heptan-4-
yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 15.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-6-((4-
cyclopropyl-2-oxopiperazin-1-yl)methyl)-7-formyl-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 16.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((2-oxo-1,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 17.
N-(5-cyano-4-((2-(ethylthio)-2-methylpropyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 18.
N-(5-Cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-4,4-
difluoro-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-
3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 19.
N-(5-Cyano-4-((2-((methyl-d3)thio)ethyl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 20.
N-(5-cyano-4-((tetrahydro-2H-thiopyran-4-yl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 21.
N-(5-Cyano-4-(thiazolidin-3-yl)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 22.
N-(5-cyano-4-((2-(methylthio)-propyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 23.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 24.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-6-((1-
(dimethylamino)-N-methylcyclopropane-1-carboxamido)methyl)-7-
formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 25.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-4,4-d2-1(2H)-carboxamide; 26.
N-(5-cyano-4-((2-(cyclopropylthio)ethyl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 27.
N-(5-cyano-4-((2-(methylsulfinyl)ethyl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 28.
N-(5-cyano-4-((2-(cyclopentylthio)ethyl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 29.
Methyl-2-((2-((5-cyano-2-(7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-
1-carboxamido)pyridin-4-yl)amino)ethyl)thio)acetate; 30.
N-(5-Cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-4,4-dimethyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-
3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 31.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl-d2)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 32.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-(1-(4-methyl-2-oxopiperazin-1-yl)ethyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 33.
N-(5-cyano-4-(((tetrahydrothiophen-2-yl)methyl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 34.
N-(5-cyano-4-((thietan-2-yl-methyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 35.
N-(5-cyano-4-(((tetrahydro-2H-thiopyran-2-yl)methyl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 36.
N-(5-cyano-4-(1-thia-8-azaspiro[4.5]decan-8-yl)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 37.
N-(5-cyano-4-(((tetrahydro-2H-thiopyran-4-yl)methyl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 38.
N-(5-cyano-4-(((4-methylthiomorpholin-2-yl)methyl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 39.
N-(4-(((1,4-oxathian-2-yl)methyl)amino)-5-cyanopyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 40.
N-(5-cyano-4-((2-(methylthio)cyclopentyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 41.
N-(5-cyano-4-((4-(methylthio)tetrahydrofuran-3-yl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 42.
N-(5-cyano-4-(3-(methylthio)pyrrolidin-1-yl)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 43.
N-(5-cyano-4-(((1-(methylthio)cyclopropyl)methyl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 44.
N-(5-cyano-4-((1-((methylthio)methyl)cyclopropyl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 45.
N-(5-cyano-4-((4-(methylthio)tetrahydro-2H-pyran-3-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-
1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 46.
N-(5-cyano-4-((3-(methylthio)tetrahydro-2H-pyran-4-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-
1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 47.
N-(5-cyano-4-(thietan-3-yl-amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide; 48.
N-(5-cyano-4-(((1-(ethylthio)cyclopropyl)methyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 49.
N-(5-cyano-4-((1-((ethylthio)methyl)cyclopropyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 50.
N-(5-Cyano-4-((4-methoxytetrahydrothiophen-3-yl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 51.
N-(5-Cyano-4-((4-methoxytetrahydro-2H-thiopyran-3-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 52.
N-(5-Cyano-4-((3-methoxytetrahydro-2H-thiopyran-4-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-
1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 53.
N-(5-cyano-4-(2-(ethylthio)ethoxy)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide; 54.
N-(5-cyano-4-((1-(methylthio)propan-2-yl)oxy)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 55.
N-(5-Cyano-4-((thiazol-5-yl-methyl)amino)pyridin-2-yl)-7-formyl-
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 56.
N-(5-Cyano-4-((thiazol-2-yl-methyl)amino)pyridin-2-yl)-7-formyl-
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 57.
N-(5-Cyano-4-((isothiazol-5-yl-methyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 58.
N-(5-Cyano-4-(((5-methylthiophen-2-yl)methyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 59.
N-(5-Cyano-4-((thiazol-4-ylmethyl)amino)pyridin-2-yl)-7-formyl-
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 60.
N-(5-cyano-4-((1-(thiazol-2-yl)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 61.
N-(5-cyano-4-((1-(5-methylthiophen-2-yl)ethyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 62.
N-(5-cyano-4-((2-(ethylthio)ethyl)amino)pyridin-2-yl)-7-formyl-
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 63.
N-(5-cyano-4-((2-(methylsulfonyl)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 64.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-
6-((N-methyltetrahydro-2H-pyran-4-carboxamido)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 65.
(R)-N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((N-methyltetrahydrofuran-2-carboxamido)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 66.
(S)-N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((N-methyltetrahydrofuran-2-carboxamido)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 67.
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-
6-((N-methyltetrahydrofuran-3-carboxamido)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 68.
N-(5-cyano-4-((1-mercapto-2-methylpropan-2-yl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 69.
N-(5-cyano-4-(4-mercapto-4-methylpiperidin-1-yl)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; 70.
N-(5-cyano-4-((2-mercapto-2-methylpropyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide; or 71.
N-(5-cyano-4-(3,6-dihydro-2H-thiopyran-4-yl)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide.
[0139] In some embodiments, the compound is selected from:
TABLE-US-00002 72.
N-(5-cyano-4-((2-((trifluoromethyl)thio)ethyl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 73.
2-((2-((5-cyano-2-(7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-1-
carboxamido)pyridin-4-yl)amino)ethyl)thio)acetic acid; 74.
N-(5-cyano-4-((3-(methylthio)propyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide; 75.
N-(5-cyano-4-((1,1-dioxidotetrahydrothiophen-3-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide; 76.
N-(5-cyano-4-((2-(phenylthio)ethyl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 77.
N-(5-cyano-4-((2-(pyridin-3-yl-thio)ethyl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-
3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 78.
N-(5-cyano-4-((isothiazol-3-yl-methyl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 79.
N-(5-cyano-4-(((2R)-1-(methylsulfinyl)propan-2-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide; 80.
(R)-N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-
2-yl)-7-formyl-6-((2-oxo-1,3-oxazepan-3-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide; 81.
Ethyl-2-((2-((5-cyano-2-(7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-1,2,3,4-tetrahydro-1,8-
naphthyridine-1-carboxamido)pyridin-4- yl)amino)ethyl)thio)acetate;
82. N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-
3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; or 83.
N-(5-cyano-4-(((2R)-1-(methylsulfonyl)propan-2-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-
1(2H)-carboxamide.
[0140] In another aspect, the present invention provided a
pharmaceutical composition comprising at least one compound of
formula I or a pharmaceutically acceptable salt thereof, and at
least one pharmaceutically acceptable excipient.
[0141] In another aspect, the present invention provided a
pharmaceutical composition comprising at least one compound of
formula I of the invention or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable
excipient.
[0142] In another aspect, the present invention provided the use of
the compound of formula I or a pharmaceutically acceptable salt
thereof, or pharmaceutical composition for the manufacture of a
medicament.
[0143] In some embodiments, the said medicament is used for the
treatment, prevention or precaution of diseases or conditions
mediated by FGFR4 activity.
[0144] In some embodiments, the diseases or conditions mediated by
FGFR4 activity are cancer and/or cancermetastasis.
[0145] In some embodiments, the diseases mediated by FGFR4 activity
are selected from one or more of the following diseases: liver
cancer, head and neck cancer, esophageal cancer, stomach cancer,
prostate cancer, ovarian cancer, lung cancer, breast cancer,
colorectal cancer, rhabdomyoma and combinations thereof.
[0146] In another aspect, the present invention provides a method
for the treatment, prevention or precaution of the diseases or
conditions mediated by FGFR4 activity, said method comprises
administering to the subject a therapeutically effective amount of
compound of formula I or the pharmaceutically acceptable salt
thereof, or the pharmaceutical composition thereof.
[0147] In some embodiments, the diseases or conditions mediated by
FGFR4 activity are cancer and/or cancerometastasis.
[0148] In some embodiments, the diseases mediated by FGFR4 activity
are selected from one or more following diseases: liver cancer,
head and neck cancer, esophageal cancer, stomach cancer, prostate
cancer, ovarian cancer, lung cancer, breast cancer, colorectal
cancer, rhabdomyoma and combinations thereof.
[0149] In another aspect, the present invention provides the
compound of formula I or the pharmaceutically acceptable salt
thereof, or the pharmaceutical composition thereof for use in the
treatment, prevention or precaution of the diseases or conditions
mediated by FGFR4 activity.
[0150] In some embodiments, the diseases or conditions mediated by
FGFR4 activity are cancer and/or cancerometastasis.
[0151] In some embodiments, the diseases mediated by FGFR4 activity
are selected from one or more following diseases: liver cancer,
head and neck cancer, esophageal cancer, stomach cancer, prostate
cancer, ovarian cancer, lung cancer, breast cancer, colorectal
cancer, rhabdomyoma and combinations thereof.
[0152] In the present invention, unless otherwise indicated, the
term "halogen" refers to fluorine, chlorine, bromine and iodine.
The preferred halogen group refers to fluorine, chlorine and
bromine. The term "C.sub.1-6alkyl substituted with halogen",
"C.sub.2-6 alkenyl substituted with halogen", "C.sub.2-6 alkynyl
substituted with halogen" and "C.sub.1-6 alkoxy substituted with
halogen" refer to one or more (especially 1, 2 or 3) hydrogen atoms
of them substituted by halogen atoms, especially fluorine or
chlorine atoms. In some embodiments, C.sub.1-6 alkyl substituted
with fluorine, C.sub.2-6 alkenyl substituted with fluorine,
C.sub.2-6 alkynyl substituted with fluorine and C.sub.1-6 alkoxy
substituted with fluorine are preferred, especially C.sub.1-6 alkyl
substituted with fluorine, for example --CF.sub.3, --CHF.sub.2,
--CH.sub.2F, --CH.sub.2CH.sub.2F, --CH.sub.2CHF.sub.2,
--CH.sub.2CF.sub.3; C.sub.1-6 alkyl substituted with fluorine, for
example --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F,
--OCH.sub.2CH.sub.2F, --OCH.sub.2CHF.sub.2 or --OCH.sub.2CF.sub.3;
especially --CF.sub.3, --OCF.sub.3 and --OCHF.sub.2.
[0153] In the present invention, unless otherwise indicated, the
term "alkyl" includes saturated monovalent hydrocarbon radicals
having straight, branched or cyclic moieties. For example, alkyl
radicals include methyl, ethyl, propyl, isopropyl, cyclopropyl,
n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl,
3-(2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl,
cyclopentyl, n-hexyl, 2-hexyl and 2-methylpentyl and cyclohexyl.
Similarly, the C.sub.1-8 alkyl in the present invention is defined
as a group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in
straight chain or branched chain.
[0154] The term "alkylene" means a difunctional group obtained by
removal of hydrogen atom from an alkyl that is defined above. For
example, methylene (i.e., --CH.sub.2--), ethylene (i.e.,
--CH.sub.2--CH.sub.2-- or --CH(CH.sub.3)--) and propylene (i.e.,
--CH.sub.2--CH.sub.2-- CH.sub.2--, --CH(--CH.sub.2--CH.sub.3)-- or
--CH.sub.2--CH(CH.sub.3)--).
[0155] In the present invention, unless otherwise indicated, the
term "alkoxy" refers to straight or branched chain alkoxy group
containing specific number of carbon atoms. For example, "C.sub.1-6
alkoxy" refers to straight or branched chain alkoxy group
containing at least one, at most six carbon atoms, including but
not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,
but-2-oxy, 2-methyl prop-1-oxy, 2-methyl prop-2-oxy, pentyloxy,
hexyloxy, cyclopentyloxy or methylcyclopropoxy and so on.
[0156] Unless otherwise indicated, the term "alkenyl" refers to an
alkyl as defined above consisting of at least two carbons and at
least one carbon-carbon double bonds, "C.sub.2-8 alkenyl" refers to
a straight or branched alkenyl containing 2-8 carbons. For example,
ethyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.
[0157] Unless otherwise indicated, the term "alkynyl" refers to
alkyl as defined above consisting of at least two carbons and at
least one carbon-carbon triple bonds, "C.sub.2-8alkynyl" refers to
a straight or branched alkenyl containing 2-8 carbons. For example,
ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.
[0158] Unless otherwise indicated, the term "aryl" as used in the
present invention by itself or as part of another substituent
refers to a monocyclic or polycyclic aromatic hydrocarbon. Phenyl
and naphthyl are preferred aryl. The most preferred aryl is
phenyl.
[0159] Unless otherwise indicated, the term "heterocyclic" as used
in the present invention by itself or as part of another
substituent refers to a monocyclic or polycyclic non-aromatic
family containing one or more heteroatoms, partially unsaturated or
completely saturated ring system. Preferred heteroatoms include N,
O and S, including N-oxides, sulfur oxides and dioxides. Preferably
the ring is three to eight membered and is either fully saturated
or has one or more degrees of unsaturation. Multiple degrees of
substitution, preferably 1, 2 or 3, are included within the present
definition.
[0160] Examples of such heterocyclic include but are not limited to
azacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl,
oxopiperazinyl, oxopiperidinyl, azacycloheptyl, tetrahydrofuranyl,
dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl,
tetrahydrooxazolyl, tetrahydropyranyl, morpholino, thiomorpholino,
thiomorpholino sulfoxide, oxadiazole, nitroxanyl, pyridazinyl,
indolyl, pyrimidinyl, pyrazinyl, isothiazolyl, diazanonaphthyl or
indolazinyl.
[0161] "Heterocyclic" includes but is not limited to monocyclic
heterocyclic and/or polycyclic heterocyclic.
[0162] Monocyclic heterocyclic includes but is not limited to
pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyranyl, piperazinyl,
morpholinyl, thiomorpholinyl or homopiperazinyl, etc., preferably
pyrrolidinyl, tetrahydrofuranyl or pyranyl.
[0163] Polycyclic heterocyclic includes but is not limited to
spirocyclic, fused ring and bridged-ring heterocyclic. "Spirocyclic
heterocyclic" refers to polycyclic heterocyclic atom sharing a
single atom (abbreviated spiroatom) between single rings, wherein
one or more ring atom selected from heteroatoms of nitrogen,
oxygen, S(O)r (wherein r is an integer of 0, 1, 2), and the
remaining ring atoms are carbon. These can contain one or more
double bonds, but none of the rings has a fully conjugated
.pi.-electron system. Spirocycloalkyl is classified as
monospiroheterocyclyl, dispiroheterocyclyl or polyspiroheterocyclyl
according to the number of spiroatoms shared between the rings.
Spirocycloalkyl includes but is not limited to:
##STR00016##
[0164] "Fused ring heterocyclic" refers to a polycyclic
heterocyclic in which each ring in the system shares an adjacent
pair of atoms with other rings in the system. One or more rings may
contain one or more double bonds, but none of the ring has a fully
conjugated .pi.-electron system, wherein one or more ring atoms are
selected from heteroatoms of nitrogen, oxygen, and S(O)r (wherein r
is an integer of 0, 1, 2), and the remaining ring atoms are carbon.
According to the number of constituent rings, it can be classified
as bicyclic, tricyclic, tetracyclic or polycyclic fused
heterocycloalkyl. The fused heterocyclic includes but is not
limited to:
##STR00017##
[0165] "Bridged heterocyclic group" refers to a polycyclic
heterocyclic group in which any two rings share two atoms that are
not directly connected. These may contain one or more double bonds,
but none of the rings has a fully conjugated n-electron system. One
or more ring atoms are selected from nitrogen, oxygen, and S(O)r
(wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining
ring atoms are carbon. According to the number of constituent
rings, it can be divided into bicyclic, tricyclic, tetracyclic or
polycyclic bridged cycloalkyls. Bridged cycloalkyl includes but are
not limited to:
##STR00018##
[0166] Unless otherwise indicated, otherwise the term "heteroaryl"
used in the present invention by itself or as part of another
substituent refers to an aromatic ring system containing carbon and
at least one heteroatom. The heteroaryl can be monocyclic or
polycyclic, substituted or unsubstituted. Monocyclic heteroaryl can
have one to four heteroatoms in the ring, while polycyclic
heteroaryl can have one to ten heteroatoms. The polycyclic
heteroaryl ring may contain a fused spiroring or bridged ring,
e.g., the cyclic heteroaryl is a polycyclic heteroaryl. The
bicyclic heteroaryl ring may contain 8 to 12 member atoms.
Monocyclic heteroaryl rings can contain 5 to 8 member atoms (number
of carbon and heteroatoms). Examples of heteroaryl include but are
not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl,
pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl,
pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,
benzofuranyl, benzothienyl, benzothiazolyl, benzothiadiazolyl,
benzotriazolyl adenine, quinolinyl or isoquinolinyl.
[0167] Unless otherwise indicated, otherwise the term "cycloalkyl"
used in the present invention by itself or as part of another
substituent refers to monocyclic, bicyclic or polycyclic of
non-aromatic family saturated or partially unsubstituted
hydrocarbyl, and optionally includes alkylene linker through which
cycloalkyl can be connected. Exemplary "cycloalkyl" group includes
but is not limited to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and so on.
[0168] The term "oxo" refers to the group
##STR00019##
which is formed by oxygen together with the attached carbon
atom.
[0169] Whenever the term "alkyl" or "aryl" or any prefix roots
thereof appears in the name of a substituent (for example, aralkyl
or dialkylamino), unless otherwise specified, either by itself or
as a part of another substituent should be construed as inclusion
of the limitations of "alkyl" and "aryl" above mentioned. The
designated number of carbon atoms (for example, C.sub.1-6) shall
independently refer to the number of carbon atoms in the alkyl
moiety or the number of carbon atoms in the alkyl moiety of a
larger substituent with an alkyl group as its prefix.
[0170] The compounds described herein, when specifically designated
as R- or S-isomers by chemical names, should be understood as the
main configuration as R-isomer or S-isomer, respectively. For
example, in any of the embodiments described herein, such R- or
S-designated isomers may be substantially free (as determined by
chiral HPLC, less than 5%, less than 1%, or undetectable) of the
other isomer of the chiral center. The R- or S-isomer can be
prepared by the methods exemplified in this application, for
example, by using a chiral auxiliary such as R- or
S-tert-butylsulfinamide in the synthesis process. Other methods for
preparing R- or S-isomers of the dominant configuration herein
include, but are not limited to, chiral HPLC purification of
mixtures of stereoisomers (such as racemic mixtures). General
methods for separating stereoisomers (e.g., enantiomers and/or
diastereomers) using HPLC are known in the art.
[0171] The compounds described herein may exist in an
isotope-labeled or enriched form, which contains one or more atoms
with atomic mass or mass number different from the most abundant
atomic mass or mass number in nature. Isotopes can be radioactive
or non-radioactive isotopes. Isotopes of atoms such as hydrogen,
carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include
but are not limited to .sup.2H, .sup.3H, .sup.13C, .sup.14C,
.sup.15N, .sup.18O, .sup.32P, .sup.35S, .sup.18F, .sup.36Cl, and
.sup.125I. Compounds containing other isotopes of these and/or
other atoms are within the scope of the present invention. In some
embodiments, one or more hydrogen atoms of any compound described
herein can be replaced with deuterium to provide a corresponding
labeled or enriched compound.
[0172] As used herein, the term "subject" (optionally referred to
as "patient" in the present invention) refers to an animal that has
become a subject of treatment, observation or experiment,
preferably a mammal, and most preferably a human.
[0173] Unless otherwise specified, the term "ring system" (which
may also be referred to as a "ring system") as used herein
includes, but is not limited to, carbon rings, heterocycles,
heteroaryl rings, etc., and may include only heterocycles and/or
heteroaryl rings, and includes determining which rings are needed
based on the context.
[0174] The term "composition", as used herein, is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts. Accordingly, pharmaceutical compositions
containing the compounds of the present invention as the active
ingredient as well as methods of preparing the instant compounds
are also part of the present invention. Furthermore, some of the
crystalline forms for the compounds may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents and such solvates are also
intended to be encompassed within the scope of this invention.
[0175] The compounds of the present invention may also be present
in the form of pharmaceutically acceptable salts. For use in
medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts". The pharmaceutically
acceptable salt forms include pharmaceutically acceptable
acidic/anionic or basic/cationic salts. The pharmaceutically
acceptable acidic/anionic salt generally takes a form in which the
basic nitrogen is protonated with an inorganic or organic acid.
Representative organic or inorganic acids include hydrochloric,
hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric,
acetic, propionic, glycolic, lactic, succinic, maleic, fumaric,
malic, tartaric, citric, benzoic, mandelic, methanesulfonic,
hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,
2-naphthalene sulfonic, p-toluenesulfonic, cyclohexanesulfamic,
salicylic, saccharinic or trifluoroacetic. Pharmaceutically
acceptable basic/cationic salts include, and are not limited to
aluminum, calcium, chloroprocaine, choline, diethanolamine,
ethylenediamine, lithium, magnesium, potassium, sodium and
zinc.
[0176] The present invention includes within its scope the prodrugs
of the compounds of this invention. In general, such prodrugs will
be functional derivatives of the compounds that are readily
converted in vivo into the required compound. Thus, in the methods
of treatment of the present invention, the term "administering"
encompass the treatment of the various disorders described with the
compound specifically disclosed or with a compound which may not be
specifically disclosed, but which converts to the specified
compound in vivo after administration to the subject. Conventional
procedures for the selection and preparation of suitable prodrug
derivatives are described, for example, in "Design of Prodrugs",
ed. H. Bundgaard, Elsevier, 1985.
[0177] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definitions elsewhere in that molecule. It is understood that
substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques know in the art as well as those
methods set forth herein.
[0178] The present invention includes compounds described can
contain one or more asymmetric centers and may thus give rise to
diastereomers and optical isomers. The present invention includes
all such possible diastereomers as well as their racemic mixtures,
their substantially pure resolved enantiomers, all possible
geometric isomers, and pharmaceutically acceptable salts
thereof.
[0179] The above Formula is shown without a definitive
stereochemistry at certain positions. The present invention
includes all stereoisomers of the compound of Formula (I) and
pharmaceutically acceptable salts thereof. Further, mixtures of
stereoisomers as well as isolated specific stereoisomers are also
included. During the course of the synthetic procedures used to
prepare such compounds or in using racemization or epimerization
procedures known to those skilled in the art, the products of such
procedures can be a mixture of stereoisomers.
[0180] When a tautomer of the compound of Formula (I) exists,
unless otherwise stated, the present invention includes any
possible tautomers and pharmaceutically acceptable salts thereof,
and mixtures thereof.
[0181] When the compound of Formula (I) and pharmaceutically
acceptable salts thereof exist in the form of solvates or
polymorphic forms, the present invention includes any possible
solvates and polymorphic forms. A type of a solvent that forms the
solvate is not particularly limited so long as the solvent is
pharmacologically acceptable. For example, water, ethanol,
propanol, acetone or the like can be used.
[0182] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compound of the present invention is acidic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic bases, including inorganic
bases and organic bases. Salts derived from inorganic bases include
aluminum, ammonium, calcium, copper (high and low value), trivalent
iron, ferrous iron, lithium, magnesium, manganese (high and low
value), potassium, sodium, zinc and the like. Salts of ammonium,
calcium, magnesium, potassium, and sodium are particularly
preferred. Non-toxic organic bases that can be derived into
pharmaceutically acceptable salts include primary, secondary, and
tertiary amines, as well as cyclic amines and
substituent-containing amines, such as naturally occurring and
synthetic substituent-containing amines Other pharmaceutically
acceptable non-toxic organic bases capable of forming salts,
Including ion exchange resins and arginine, betaine, caffeine,
choline, N',N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorphanol, N-ethylpiperidine, reduced
glucosamine, glucosamine, histidine, haemamine, isopropylamine,
lysine, methylglucosamine, morpholine, piperazine, piperidine,
polyamine resins, procaine, purine, theobromine, triethylamine,
trimethylamine, tripropylamine, aminobutriol etc.
[0183] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include, e.g., acetic acid,
benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric
acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic
acid, glutamic acid, hydrobromic acid, hydrochloric acid,
hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,
mandelic acid, methanesulfonic acid, mucic acid, nitric acid,
pteric acid, pantothenic acid, phosphoric acid, succinic acid,
sulfuric acid, tartaric acid, and p-toluenesulfonic acid.
Preferably, citric acid, hydrobromic acid, formic acid,
hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and
tartaric acid. Most preferably, formic acid and hydrochloric acid.
Since the compounds are intended for pharmaceutical use they are
preferably provided in substantially pure form, for example at
least 60% pure, more suitably at least 75% pure, especially at
least 98% pure (% are on a weight for weight basis).
[0184] The pharmaceutical compositions of the present invention
comprise a compound of formula I (or a pharmaceutically acceptable
salt thereof) as an active ingredient, a pharmaceutically
acceptable excipient and optionally other therapeutic ingredients
or adjuvants. The compositions include compositions suitable for
oral, rectal, topical, and parenteral (including subcutaneous,
intramuscular, and intravenous) administration, although the most
suitable route in any given case will depend on the particular
host, and nature and severity of the conditions for which the
active ingredient is being administered. The pharmaceutical
compositions may be conveniently presented in unit dosage form and
prepared by any of the methods well known in the art of
pharmacy.
[0185] In practice, the compounds or prodrugs or metabolites or
pharmaceutically acceptable salts thereof of this invention as the
active ingredient can be admixed with a pharmaceutical carrier to
form a pharmaceutical composition according to conventional
pharmaceutical compounding techniques. The carrier may take a wide
variety of forms depending on the form of preparation desired for
administration, e.g. oral or parenteral (including intravenous).
Thus, the pharmaceutical compositions of the present invention can
be presented as discrete units suitable for oral administration
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient. Further, the
compositions can be presented as a powder, as granules, as a
solution, as a suspension in an aqueous liquid, as a non-aqueous
liquid, as an oil-in-water emulsion or as a water-in-oil liquid
emulsion. In addition to the common dosage forms set out above, the
compound or a pharmaceutically acceptable salt thereof, may also be
administered by controlled release means and/or delivery devices.
The compositions may be prepared by any of the methods of pharmacy.
In general, such methods include a step of bringing into
association the active ingredient with the carrier that constitutes
one or more necessary ingredients. In general, the compositions are
prepared by uniformly and intimately admixing the active ingredient
with liquid carriers or finely divided solid carriers or both. The
product can then be conveniently shaped into the desired
presentation.
[0186] Thus, the pharmaceutical compositions of this invention may
include a pharmaceutically acceptable carrier and a compound of
formula I or a pharmaceutically acceptable salt. The compounds of
formula I or pharmaceutically acceptable salts thereof, can also be
included in pharmaceutical compositions in combination with one or
more other therapeutically active compounds.
[0187] The pharmaceutical carrier used in the present invention can
be, for example, solid carrier, liquid carrier or gas carrier.
Solid carrier includes lactose, terra alba, sucrose, talc, gelatin,
agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid
carriers include sugar syrup, peanut oil, olive oil, and water. Gas
carrier includes carbon dioxide and nitrogen. In preparing the
compositions for oral dosage form, any convenient pharmaceutical
media may be used. For example, water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents, and the like may
be used to form oral liquid formulations such as suspensions,
elixirs and solutions; while carriers such as starches, sugars,
microcrystalline cellulose, diluents, granulating agents,
lubricants, binders, disintegrating agents, and the like may be
used to form oral solid formulations such as powders, capsules and
tablets. Consider the ease of administration, tablets and capsules
are preferred for oral formulations. Optionally, tablets may be
coated by standard aqueous or nonaqueous techniques.
[0188] A tablet containing the compound or pharmaceutical
composition of this invention may be prepared by compression or
molding, optionally with one or more accessory ingredients or
adjuvants. Compressed tablets may be prepared by compressing, in a
suitable machine, the active ingredient in a free-flowing form such
as powder or granules, mixed with a lubricant, inert diluent,
surface active or dispersing agent. The powdered compound or
pharmaceutical composition is wetted with an inert liquid diluent
and then the molded tablets may be made by molding in a suitable
machine. Each tablet preferably contains from about 0.05 mg to
about 5 g of the active ingredient, each cachet or capsule
preferably containing from about 0.05 mg to about 5 g of the active
ingredient. For example, a formulation intended for the oral
administration to humans may contain from about 0.5 mg to about 5 g
of active agent, compounded with an appropriate and convenient
amount of supplementary materials which may vary from about 0.05 to
about 95 percent of the total composition. Unit dosage forms
generally contain from about 1 mg to about 2 g of the active
ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg,
500 mg, 600 mg, 800 mg, or 1000 mg.
[0189] Pharmaceutical compositions of the present invention
suitable for parenteral administration may be prepared as solutions
or suspensions of the active compounds in water. A suitable
surfactant can be included, such as, hydroxypropylcellulose.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols, and mixtures thereof in oils. Further, a preservative can
be included in the pharmaceutical composition of the present
invention to prevent the detrimental growth of microorganisms.
[0190] The present invention provides the pharmaceutical
compositions suitable for injection, including sterile aqueous
solutions or dispersions. Furthermore, the pharmaceutical
compositions can be prepared in the form of sterile powders for the
extemporaneous preparation of sterile injectable solutions or
dispersions. In any cases, the final injectable form must be
sterile and must be easily flowable for ease of injection. The
pharmaceutical compositions must be stable under the conditions of
manufacture and storage. Thus, preferably should be preserved
against the contaminating action of microorganisms such as bacteria
and fungi. The carrier can be a solvent or dispersion medium, for
example, water, ethanol, polyol (e.g., glycerol, propylene glycol
and liquid polyethylene glycol), vegetable oils, and suitable
mixtures thereof.
[0191] The pharmaceutical compositions provided by the present
invention can be in a form suitable for topical use, such as, an
aerosol, cream, ointment, lotion, dusting powder or other similar
formulations. Further, the pharmaceutical compositions provided by
the present invention can be in a form suitable for use in
transdermal devices. These formulations may be prepared, via
conventional processing methods, utilizing the compound of formula
(I) of this invention or a pharmaceutically acceptable salt
thereof. As an example, a cream or ointment is prepared by admixing
hydrophilic material and water, together with about 5 wt % to about
10 wt % of the compound, to produce a cream or ointment having a
desired consistency.
[0192] The pharmaceutical compositions provided by the present
invention can be in a form suitable for rectal administration
wherein the carrier is a solid. The preferred dosage form is a
mixture forming a unit dose of suppository. Suitable ingredients
include cocoa butter and other materials commonly used in the art.
The suppositories may be conveniently formed by first admixing the
pharmaceutical composition with the softened or melted excipients
followed by chilling and shaping in molds.
[0193] In addition to the aforementioned carrier components, the
above-mentioned pharmaceutical formulations may also include, as
appropriate, one or more additional excipients components, such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, preservatives (including
antioxidants) and the like. Furthermore, other adjuvants can also
include penetration enhancers that regulate the isotonic pressure
of the drug and blood. A compound of formula (I) or a
pharmaceutical composition including a pharmaceutically acceptable
salts thereof, may also be prepared in the form of powder or
concentrated solution.
[0194] Generally, in order to treat the conditions or discomforts
shown above, the dosage level of the drug is approximately 0.01
mg/kg to about 150 mg/kg of body weight per day, or 0.5 mg to 7 g
per patient per day. The effective dosage level of the drug for
disease and discomforts, such as inflammation, cancer, psoriasis,
allergy/asthma, disease and discomforts of the immune system,
disease and discomforts of the central nervous system (CNS), is
0.01 mg/kg to 50 mg/kg of body weight per day, or 0.5 mg to 3.5 g
per patient per day.
[0195] It is understood, however, that the specific dose level for
any particular patient will depend upon a variety of factors
including the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0196] These and other aspects will become apparent from the
following written description of the invention.
EXAMPLES
[0197] The following intermediates and examples are provided to
illustrate the present invention. Unless expressly stated
otherwise, all parts and percentages are by weight, and all
temperatures are in degrees Celsius. The following abbreviations
are used in the examples:
TABLE-US-00003 DCM Dichloromethane EtOAc Ethyl acetate EtOH Ethanol
THF Tetrahydrofuran DMF N,N-dimethylformamide CH.sub.3CN
Acetonitrile TFA Trifluoroacetic acid MnO.sub.2 Manganese dioxide
DPPF 1,1'-bis(diphenylphosphine)ferrocene DIEA/DIPEA
N,N-diisopropyl ethylamine Pd.sub.2(dba).sub.3 Tri-dibenzyl acetone
dipalladium Zn (CN).sub.2 zinc cyanide NIS Iodosuccinimide Na
sodium Na.sub.2SO.sub.4 Sodium sulfate NaCl Sodium chloride HATU
2-(7-azobenzotriazole)-N,N,N',N'- tetramethylurea
hexafluorophosphate Boc.sub.2O Di-tert butyl dicarbonate
Preparation of Intermediate A1
##STR00020##
[0199] Ethyl dimethoxyacetate (147.59 g, 1.00 mol) was dissolved in
EtOAc (150.23 g, 1.71 mol), and Na (33.42 g, 1.45 mol) was added at
60.degree. C. The reaction mixture was refluxed and stirred
overnight, cooled to room temperature, diluted with EtOAc (500 mL),
and concentrated under reduced pressure. The residue was purified
by a silica gel column to afford the compound A1-1 (135.47 g, 0.71
mol).
[0200] The compound A1-1 (83.64 g, 0.44 mol), 2-Amino-3-pyridine
carboxaldehyde (45.11 g, 0.37 mol) and L-Proline (42.92 g, 0.37
mol) were mixed with anhydrous EtOH (400 mL). The reaction mixture
was stirred overnight at 90.degree. C., cooled to room temperature,
and concentrated under reduced pressure. The concentrate was
diluted with EtOAc (1 L), filtered and washed with EtOAc (200 mL),
and the filtrate was concentrated under reduced pressure. The
residue was purified by a silica gel column to afford compound A1-2
(102.05 g, 0.37 mol).
[0201] The compound A1-2 (102.05 g, 0.37 mol) was dissolved in
EtOAc (800 mL), and palladium on carbon (6.49 g) was added. The
reaction mixture was purged with hydrogen three times, and stirred
overnight at room temperature. The resulting mixture was filtered,
and the filtrate was concentrated under reduced pressure to afford
the compound A1-3 (99.83 g, 0.36 mol).
[0202] The compound A1-3 (21.97 g, 78.37 mmol) was dissolved in THF
(50 mL), and lithium borohydride (1 mol/L in THF, 200 mL, 0.20 mol)
was added dropwise. The reaction mixture was stirred overnight at
65.degree. C., cooled to 0.degree. C., quenched with H.sub.2O (150
mL), and the THF was evaporated. EtOAc (500 mL) and H.sub.2O (100
mL) was added into the concentrate, and the liquids was separated.
The organic phase was dried over anhydrous Na.sub.2SO.sub.4,
filtered, and the filtrate was concentrated under reduced pressure
to afford the compound A1-4 (19.58 g, 82.17 mmol). MS m/z (ESI):
239 (M+H).sup.+.
[0203] The compound A1-4 (9.88 g, 41.46 mmol) was dissolved in DCM
(300 mL), and MnO.sub.2 (73.38 g, 844.03 mmol) was added. The
reaction mixture was stirred overnight at 40.degree. C., then
filtered and washed with DCM. The filtrate was concentrated under
reduced pressure to afford compound A1 (8.91 g, 37.71 mmol). MS m/z
(ESI): 237 (M+H).sup.+.
[0204] The following intermediates A2-A5 were synthesized with
appropriate raw materials:
##STR00021##
Preparation of Intermediate B1
##STR00022##
[0206] 2-amino-4-fluoropyridine (6.44 g, 57.44 mmol), NIS (15.58 g,
69.25 mmol) and TFA (3.55 g, 31.13 mmol) were dissolved in
acetonitrile (250 mL). The reaction mixture was stirred for 2 hrs
at room temperature, and then the acetonitrile was evaporated. The
concentrate was diluted with EtOAc (500 mL), washed with saturated
sodium carbonate solution (300 mL.times.1), and washed with
saturated NaCl aqueous solution (500 mL.times.1). The organic phase
was dried with anhydrous Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated under reduced pressure to obtain compound
B1-1 (12.31 g, 51.72 mmol). MS m/z (ESI): 239 (M+H).sup.+.
[0207] The Compound B1-1 (12.31 g, 51.72 mmol), Zn(CN).sub.2 (6.35
g, 54.08 mmol), Zn(1.01 g, 15.45 mmol), Pd.sub.2(dba).sub.3 (5.04
g, 5.50 mmol) and DPPF (5.97 g, 10.77 mmol) were mixed with
N,N-dimethylformamide (200 mL) under the protection of nitrogen.
The reaction mixture was stirred for 2.5 hrs at 110.degree. C.,
cooled to room temperature, diluted with EtOAc (500 mL), and washed
with saturated NaCl aqueous solution (500 mL.times.3). The organic
phase was dried over anhydrous Na.sub.2SO.sub.4, and concentrated
under reduced pressure. The residue was purified by a silica gel
column to afford the compound B1-2 (5.22 g, 38.07 mmol). MS m/z
(ESI): 138 (M+H).sup.+.
[0208] The B1-2 (5.22 g, 38.07 mmol) and pyridine (15.52 g, 196.21
mmol) were dissolved in DCM (160 mL), and phenyl chloroformate
(9.32 g, 59.53 mmol) was added. The reaction mixture was stirred
for 1.5 hrs at room temperature, and then filtered to obtain the
compound B1 as a solid. The filtrate was concentrated under reduced
pressure, and the residue was purified by a silica gel column to
afford the purified product. The purified product was combined with
the filter cake to obtain the compound B1 (8.52 g, 33.12 mmol). MS
m/z (ESI): 258 (M+H).sup.+.
Preparation of Intermediate C1
##STR00023##
[0210] 2-(methylamino)ethylcarbamic acid tert-butyl ester (69.54 g,
0.40 mol) and DIPEA (156.21 g, 1.21 mol) was dissolved in DCM (500
mL), and ethyl 2-bromoacetate (69.23 g, 0.41 mol) was added at
0.about.5.degree. C. The reaction mixture was stirred for 6.5 hrs
at room temperature, and concentrated under reduced pressure. The
concentrate was diluted with EtOAc (1000 mL), stirred for 10 mins
at room temperature, filtrated and washed with EtOAc (1000 mL). The
filtrate was concentrated under reduced pressure.
[0211] The residue was purified by a silica gel column to afford
the compound C1-1 (106.41 g, 0.41 mol). MS m/z (ESI): 261
(M+H).sup.+.
[0212] The compound C1-1 (3.35 g, 12.87 mmol) was dissolved in DCM
(10 mL), and 1,4-dioxane solution of hydrochloric acid (4 mol/L, 20
mL, 80 mmol) was added dropwise. The reaction mixture was stirred
for 2 hrs at room temperature, and concentrated under reduced
pressure to afford the compound C1 (2.93 g, 12.57 mmol). MS m/z
(ESI): 161 (M+H).sup.+.
[0213] The following intermediates C2-C3 were synthesized with
appropriate raw materials:
##STR00024##
Preparation of Intermediate D1
##STR00025##
[0215] The intermediate C1 (11.49 g, 48.63 mmol) was dissolved in
DCM (1000 mL), and triethylamine (16.22 g, 160.29 mmol) was added
dropwise. The resulting solution was stirred for 15 mins at room
temperature, then Intermediate A1 (8.91 g, 38.22 mmol) and sodium
triacetoxyborohydride (23.76 g, 112.11 mmol) were added
successively. The reaction mixture was stirred at room temperature
overnight, quenched with H.sub.2O (200 mL), and the liquids was
separated. The organic phase was washed with saturated NaCl aqueous
solution (200 mL.times.1). The organic phase was collected and
concentrated under reduced pressure. The residue was purified by a
silica gel column to afford the compound D1-1 (6.24 g, 18.66 mmol).
MS m/z (ESI): 335 (M+H).sup.+.
[0216] The compound D1-1 (2.48 g, 7.42 mmol), intermediate B1 (2.98
g, 11.59 mmol) and DIEA (5.21 g, 40.31 mmol) were mixed with
acetonitrile (50 mL). The reaction mixture was stirred for 2.5 hrs
at 65.degree. C., cooled to room temperature, and concentrated
under reduced pressure. The residue was purified by a silica gel
column to afford a light yellow solid compound D1 (1.38 g, 2.77
mmol). Ms m/z (ESI): 498 (M+H).sup.+.
[0217] The following intermediates D2-D9 were synthesized according
to the synthesis method of intermediate D1:
##STR00026## ##STR00027## ##STR00028##
Preparation of Intermediate E1
##STR00029## ##STR00030##
[0219] The preparation method of compound E1-1 was according to the
synthetic procedure of preparing D1-1 in intermediate D1.
[0220] The compound E1-1 (1.02 g, 4.06 mmol), DIEA (0.93 g, 7.20
mmol) and BOC.sub.2O (0.89 g, 4.08 mmol) were dissolved in DCM (30
mL). The reaction mixture was stirred for 2.5 hrs at room
temperature, and concentrated under reduced pressure, and the
residue was purified by a silica gel column to afford the compound
E1-2 (1.31 g, 3.73 mmol). MS m/z (ESI): 352 (M+H).sup.+.
[0221] The compound E1-2 (1.31 g, 3.73 mmol), the intermediate B1
(1.27 g, 4.94 mmol) and TEA (1.5 mL) were mixed with acetonitrile
(30 mL). The reaction mixture was stirred for 4 hours at 70.degree.
C., cooled to room temperature, and concentrated under reduced
pressure. The residue was purified by a silica gel column to afford
the compound E1-3 (0.84 g, 1.63 mmol). MS m/z (ESI): 515
(M+H).sup.+.
[0222] The compound E1-3 (0.80 g, 1.55 mmol) and TFA (4 mL) were
dissolved in DCM (10 mL) to obtain a solution. The solution was
stirred for 5 mins at room temperature, cooled in ice-water bath,
then added dropwise into TEA/DCM (8 mL/15 mL) cooled in ice-water
bath. The liquids were separated. The organic phase was washed with
saturated NaCl aqueous solution (100 mL.times.1). The organic phase
was collected, and concentrated under reduced pressure. The residue
was purified by a silica gel column to afford the compound E1-4
(0.57 g, 1.38 mmol). MS m/z (ESI): 415 (M+H).sup.+.
[0223] The compound E1-4 (115 mg, 0.28 mmol),
tetrahydropyrane-4-formic acid (46 mg, 0.35 mmol), HA-TU (129 mg,
0.34 mmol), and K.sub.2CO.sub.3 (82 mg, 0.59 mmol) were mixed with
DMF (3 mL). The reaction mixture was stirred for 0.5 h at room
temperature, diluted with DCM (20 mL), and washed with saturated
NaCl aqueous solution (30 mL.times.1). The organic phase was
collected, and concentrated under reduced pressure. The residue was
purified by TLC plate to obtain the compound E1 (62 mg, 0.12 mmol).
MS m/z (ESI): 527 (M+H).sup.+.
[0224] The following intermediates E2-E4 were synthesized according
to the synthesis method of intermediate E1:
##STR00031##
Preparation of Intermediate F1
##STR00032##
[0226] The preparation method of compound F1-1 was according to the
synthetic procedure of preparing D1-1 in intermediate D1.
[0227] The compound F1-1 (0.30 g, 0.98 mmol) and carbonyl
diimidazole (0.24 g, 1.48 mmol) were mixed with DCM (10 mL). The
reaction mixture was stirred for 2 hrs at 45.degree. C., and
purified by a silica gel column to obtain the compound F1-2 (87 mg,
0.26 mmol).
[0228] The preparation method of compound F1 was according to the
synthetic procedure of preparing E1-3 in intermediate E1. MS m/z
(ESI): 497 (M+H).sup.+.
[0229] The following intermediates F2 were synthesized according to
the synthesis method of intermediate F1:
##STR00033##
Example 1
N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-meth-
yl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxa-
mide ("Compound 1")
##STR00034##
[0231] The compound D1 (2.04 g, 4.10 mmol), 2-(methioyl) ethylamine
hydrochloride (0.83 g, 6.50 mmol) and K.sub.2CO.sub.3 (2.09 g,
15.12 mmol) were mixed with DMF (30 mL). The reaction mixture was
stirred at room temperature overnight, diluted with EtOAc (200 mL),
and washed with saturated NaCl aqueous solution (150 mL.times.3).
The organic phase was dried with anhydrous Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The residue was purified by a
silica gel column to afford compound 1-2 (2.08 g, 3.66 mmol). MS
m/z (ESI): 569 (M+H).sup.+.
[0232] The compound 1-2 (1.04 g, 1.83 mmol) was dissolved in
H.sub.2O/THF (V/V=1:3, 8 mL), and concentrated hydrochloric acid (2
mL) was added dropwise. The reaction mixture was stirred for 0.5 h
at room temperature, and saturated sodium bicarbonate aqueous
solution was added to adjust the pH of the reaction mixture to 8.
The solid was precipitated, filtered and washed with H.sub.2O (3
mL.times.2). The filter cake was dispersed in CH.sub.3CN (30 mL)
and DCM (2 mL), filtered, and washed with acetonitrile (3
mL.times.1) to obtain the compound 1 (695 mg, 1.33 mmol). MS m/z
(ESI): 523 (M+H).sup.+.
[0233] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.49 (s, 1H),
10.07 (s, 1H), 8.27 (s, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 7.15 (s,
1H), 4.89 (s, 2H), 3.96 (m, 2H), 3.43-3.41 (m, 2H), 3.28-3.27 (m,
2H), 3.05 (s, 2H), 2.93 (m, 2H), 2.72-2.70 (m, 2H), 2.63-2.62 (m,
2H), 2.24 (s, 3H), 2.15 (s, 3H), 1.93 (m, 2H).
Example 2
N-(5-cyano-4-(2-(methylthio)ethoxy)pyridin-2-yl)-7-formyl-6-((4-methyl-2-o-
xopiperazin-1-yl)
methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide ("Compound
2")
##STR00035##
[0235] The compound D-1 (48 mg, 0.10 mmol), 2-(ethylthio) ethanol
(162 mg, 1.76 mmol) and K.sub.2CO.sub.3 (51 mg, 0.37 mmol) were
mixed with DMF (3 mL). The reaction mixture was stirred at
60.degree. C. overnight, diluted with EtOAc (20 mL), and washed
with saturated NaCl aqueous solution (20 mL.times.3). The organic
phase was evaporated, and the residue was purified by TLC plate
eluted with DCM/MeOH=10/1 (v/v) to obtain the compound 2-1 (46 mg,
0.08 mmol). MS m/z (ESI): 570 (M+H).sup.+.
[0236] The compound 2-1 (46 mg, 0.08 mmol) was dissolved in
H.sub.2O/THF (V/V=1:4, 2.5 mL), and concentrated hydrochloric acid
was dropwise added (0.5 mL). The reaction mixture was stirred for
0.5 h at room temperature. Saturated sodium bicarbonate aqueous
solution was added to adjust the pH of the reaction mixture to 8.
The resulting mixture was extracted with DCM (15 mL.times.2). The
organic phase was dried with anhydrous Na.sub.2SO.sub.4, and
concentrated under reduced pressure to obtain the purified compound
2 (12 mg, 0.02 mmol). MS m/z (ESI): 524 (M+H).sup.+.
[0237] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.90 (m, 1H),
10.11 (s, 1H), 8.62-8.60 (m, 1H), 7.92 (s, 1H), 7.56 (s, 1H), 4.90
(s, 2H), 4.41-4.33 (m, 2H), 3.98-3.97 (m, 2H), 3.21 (s, 2H), 3.05
(s, 2H), 2.92-2.88 (m, 4H), 2.62 (m, 2H), 2.24-2.20 (m, 6H),
1.94-1.93 (m, 2H).
Example 3
[0238]
N-(5-Cyano-4-thiomorpholinopyridin-2-yl)-7-formyl-6-((4-methyl-2-ox-
opiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide
("Compound 3")
##STR00036##
[0239] Compound D-1 (99 mg, 0.20 mmol), thiomorpholine (94 mg, 0.91
mmol) and K.sub.2CO.sub.3 (105 mg, 0.76 mmol) were mixed with DMF
(4 mL). The reaction mixture was stirred for 3 hrs at room
temperature, diluted with EtOAc (20 mL), and washed with saturated
NaCl aqueous solution (20 mL.times.3). The organic phase was
evaporated, and the residue was purified by TLC plate eluted with
DCM/MeOH=10/1 (v/v) to obtain the compound 3-1 (100 mg, 0.17 mmol).
MS m/z (ESI): 581 (M+H).sup.+.
[0240] The compound 3-1 (100 mg, 0.17 mmol) was dissolved in
H.sub.2O/THF (V/V=1:4, 2.5 mL), and concentrated hydrochloric acid
(0.5 mL) was added dropwise. The reaction mixture was stirred for
1.5 h at room temperature. Saturated sodium bicarbonate aqueous
solution was added to adjust the pH of the reaction mixture to 8.
The resulting mixture extracted with DCM (20 mL.times.4). The
organic phase was dried with anhydrous Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The residue was purified by
HPLC to obtain the compound 3 (37 mg, 0.07 mmol). MS m/z (ESI): 535
(M+H).sup.+.
[0241] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.63 (s, 1H),
10.10 (s, 1H), 8.46 (s, 1H), 7.77 (s, 1H), 7.54 (s, 1H), 4.89 (s,
2H), 3.97-3.96 (m, 2H), 3.75-3.73 (m, 4H), 3.27-3.26 (m, 2H), 3.05
(s, 2H), 2.95-2.92 (m, 2H), 2.80-2.77 (m, 4H), 2.62-2.60 (m, 2H),
2.24 (s, 3H), 1.94 (m, 2H).
Example 4
(R)--N-(5-Cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-formyl-
-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(-
2H)-carboxamide ("Compound 4")
##STR00037##
[0243] The compound D-1 (994 mg, 2.00 mmol),
(R)-1-Methylthio-2-propylamine (432 mg, 4.11 mmol) and
K.sub.2CO.sub.3 (893 mg, 6.46 mmol) were mixed with DMF (15 mL).
The reaction mixture was stirred overnight at room temperature,
diluted with EtOAc (100 mL), and washed with saturated NaCl aqueous
solution (100 mL.times.3). The organic phase was evaporated, and
the residue was purified by a silica gel column eluted with
DCM/MeOH=98/2 (v/v) to obtain the compound 4-1 (783 mg, 1.34 mmol).
MS m/z (ESI): 583 (M+H).sup.+.
[0244] The compound 4-1 (783 mg, 1.34 mmol) was dissolved in
H.sub.2O/THF (V/V=1:4, 7.5 mL), and concentrated hydrochloric acid
(1.5 mL) was added dropwise. The reaction mixture was stirred for
0.5 h at room temperature. Saturated sodium bicarbonate aqueous
solution was added to adjust the pH of the reaction mixture to 8.
The resulting mixture was extracted with DCM (50 mL.times.3). The
organic phase was dried with anhydrous Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The residue was purified by
reverse preparation and purification to obtain the compound 4 (542
mg, 1.01 mmol). MS m/z (ESI): 537 (M+H).sup.+.
[0245] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.47 (s, 1H),
10.07 (s, 1H), 8.26 (s, 1H), 7.55 (s, 1H), 7.52 (s, 1H), 6.76 (d,
J=8.3 Hz, 1H), 4.89 (s, 2H), 3.96 (m, 2H), 3.87-3.74 (m, 1H), 3.28
(m, 2H), 3.06 (s, 2H), 2.93 (t, J=5.8 Hz, 2H), 2.82 (m, 1H), 2.64
(m, 3H), 2.24 (s, 3H), 2.13 (s, 3H), 1.93 (m, 2H), 1.29 (d, J=6.3
Hz, 3H).
Example 5
N-(5-cyano-4-((tetrahydrothiophene-3-yl)amino)pyridin-2-yl)-7-formyl-6-((4-
-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-ca-
rboxamide ("Compound 5")
##STR00038##
[0247] The compound D-1 (218 mg, 0.44 mmol),
3-Aminotetrahydrothiophene (168 mg, 1.63 mmol) and K.sub.2CO.sub.3
(192 mg, 1.39 mmol) were mixed with DMF (5 mL). The reaction
mixture was stirred overnight at room temperature, diluted with
EtOAc (30 mL), and washed with saturated NaCl aqueous solution (30
mL.times.3). The organic phase was evaporated. The residue was
purified by TLC plate eluted with DCM/MeOH=20/1 (v/v) to obtain the
compound 5-1 (254 mg, 0.44 mmol). MS m/z (ESI): 581
(M+H).sup.+.
[0248] The compound 5-1 (254 mg, 0.44 mmol) was dissolve in
H.sub.2O/CH.sub.3CN (V/V=1:3, 4 mL), and concentrated hydrochloric
acid (1 mL) was added dropwise. The reaction mixture was stirred
for 0.5 h at room temperature. Saturated sodium bicarbonate aqueous
solution was added to the pH of the reaction mixture to 8. The
resulting mixture was extracted with DCM (20 mL.times.3). The
organic phase was dried over anhydrous Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The residue was purified by
HPLC to obtain the compound 5 (100 mg, 0.19 mmol). MS m/z (ESI):
535 (M+H).sup.+.
[0249] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.50 (s, 1H),
10.08 (s, 1H), 8.30 (s, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 6.90-6.89
(d, 1H), 4.89 (s, 2H), 4.25-4.23 (m, 1H), 3.99-3.96 (m, 2H),
3.27-3.26 (m, 2H), 3.12-3.08 (m, 1H), 3.05 (s, 2H), 2.95-2.92 (m,
4H), 2.86-2.80 (m, 1H), 2.63-2.61 (m, 2H), 2.23 (s, 3H), 2.19-2.12
(m, 2H), 1.95-1.92 (m, 2H).
Example 6
N-(5-cyano-4-((2-methyl-2-(methylthio)propyl)amino)pyridin-2-yl)-7-formyl--
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2-
H)-carboxamide ("Compound 6")
##STR00039##
[0251] 1-Amino-2-methylpropane-2-thiol hydrochloride (1.14 g, 8.05
mmol) was dissolved in EtOH (20 mL). The mixture was cooled on an
ice-water bath, NaOH (1.38 g, 34.50 mmol) was added, and
iodomethane was added dropwise. The reaction mixture was stirred
for 3.5 hrs under ice-water bath condition, then filtered, and
concentrated under reduced pressure. The residue was purified by a
silica gel column to obtain the compound 6-1 (243 mg, 2.04 mmol).
MS m/z (ESI): 120 (M+H).sup.+.
[0252] The compound D-1 (137 mg, 0.28 mmol), the compound 6-1 (67
mg, 0.56 mmol) and K.sub.2CO.sub.3 (134 mg, 0.97 mmol) were mixed
with DMF (3 mL). The reaction mixture was stirred overnight at room
temperature, then diluted with EtOAc (20 mL), and washed with
saturated NaCl aqueous solution (20 mL.times.3). The organic phase
was evaporated, and the residue was purified by TLC plate eluted
with DCM/MeOH=10/1 (v/v) to obtain the compound 6-2 (127 mg, 0.21
mmol). MS: 597 (M+H).sup.+.
[0253] The compound 6-2 (127 mg, 0.21 mmol) was dissolved into
H.sub.2O/CH.sub.3CN (V/V=1:2, 3 mL), and concentrated hydrochloric
acid (1 mL) was added dropwise. The reaction mixture was stirred
for 0.5 h at room temperature, and evaporated rotarily. The residue
was purified by reverse preparation and purification to obtain the
compound 6 (57 mg, 0.10 mmol). MS m/z (ESI): 551 (M+H).sup.+.
[0254] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.49 (s, 1H),
10.07 (s, 1H), 8.29 (s, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 6.55 (s,
1H), 4.89 (s, 2H), 3.97 (m, 2H), 3.27 (m, 2H), 3.05 (s, 2H), 2.93
(m, 2H), 2.62 (m, 2H), 2.50 (m, 2H), 2.23 (s, 3H), 2.04 (s, 3H),
1.93 (d, J=5.6 Hz, 2H), 1.27 (s, 6H).
Example 7
[0255]
(R)--N-(5-cyano-4-((1-(methylthio)propan-2-yl)amino)pyridin-2-yl)-7-
-formyl-6-((2-oxopyrrolidine-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(-
2H)-carboxamide ("Compound 7")
##STR00040##
[0256] The compound D-4 (120 mg, 0.26 mmol),
(R)-1-Methylthio-2-propylamine (68 mg, 0.65 mmol) and
K.sub.2CO.sub.3 (129 mg, 0.93 mmol) were mixed with DMF (3 mL). The
reaction mixture was stirred overnight at room temperature, then
diluted with EtOAc (20 mL), washed with saturated NaCl aqueous
solution (20 mL.times.3), and concentrated under reduced pressure.
The residue was purified by TLC plate, to obtain the compound 7-1
(154 mg, 0.28 mmol). MS m/z (ESI): 554 (M+H).sup.+.
[0257] The compound 7-1 (154 mg, 0.28 mmol) was dissolved in
H.sub.2O/CH.sub.3CN (V/V=1:2, 3 mL), and concentrated hydrochloric
acid (0.5 mL) was added dropwise. The reaction mixture was stirred
for 0.5 h at room temperature. Saturated sodium bicarbonate aqueous
solution was added to adjust the pH of the reaction mixture to 8.
The resulting mixture was extracted with DCM (20 mL.times.3). The
organic phase was dried over anhydrous Na.sub.2SO.sub.4, and
concentrated under reduced pressure to obtain the compound 7 (108
mg, 0.21 mmol). MS m/z (ESI): 508 (M+H).sup.+.
[0258] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.50 (s, 1H),
10.08 (s, 1H), 8.29 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.16 (t,
J=5.6 Hz, 1H), 4.75 (s, 2H), 4.01-3.91 (m, 2H), 3.41 (m, 2H), 2.94
(t, J=6.3 Hz, 2H), 2.71 (m, 2H), 2.56-2.46 (m, 2H), 2.32 (t, J=8.0
Hz, 2H), 2.16 (s, 3H), 2.02-1.88 (m, 4H).
[0259] The following compounds were synthesized according to the
synthesis method of example 1:
TABLE-US-00004 com- pound Chemical structure Formula MS and
H.sup.1NMR 8 (R)-N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((3-methoxy-2-oxopyrrolidin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00041## MS m/z(ESI): 524 (M + H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.48 (s, 1H), 10.06 (s, 1H), 8.27 (s, 1H),
7.56 (s, 1H), 7.51 (s, 1H), 7.15 (s, 1H), 4.76 (s, 2H), 4.04 (s,
1H), 3.96 (m, 2H), 3.40 (s, 5H), 2.93 (m, 2H), 2.70 (m, 2H), 2.33
(m, 2H), 2.16 (s, 3H), 1.93-1.76 (m, 4H). 9
N-(5-cyano-4-(((R)-1-(methylthio)propan-2-
yl)amino)pyridin-2-yl)-7-formyl-6-(((R)-3-
methoxy-2-oxopyrrolidin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00042## MS
m/z(ESI): 538 (M + H).sup.+. 10 N-(5-cyano-4-((2-
(methylthio)phenyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00043## MS m/z(ESI): 571 (M + H).sup.+. 11
(S)-N-(5-cyano-4-((1-(methylthio)propan-2-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00044## MS
m/z(ESI): 537 (M + H).sup.+. 12 N-(5-cyano-4-((2-
(cyclohexylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00045## MS m/z(ESI): 591 (M + H).sup.+. 13
(S)-N-(5-cyano-4-((2- (methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((3-methoxy-2-oxopyrrolidin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00046## MS m/z(ESI): 524 (M + H).sup.+. 14 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-7- formyl-6-((5-oxo-6-oxa-4-
azaspiro[2.4]heptan-4-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00047## MS
m/z(ESI): 522 (M + H).sup.+. 15 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-6-((4-
cyclopropyl-2-oxopiperazin-1-yl)methyl)-7-
formyl-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxamide
##STR00048## MS m/z(ESI): 549 (M + H).sup.+. 16 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((2-oxo-1,3-oxazepan-3-yl)methyl)-
3,4-dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00049## MS
m/z(ESI): 524 (M + H).sup.+. 17 N-(5-cyano-4-((2-(ethylthio)-2-
methylpropyl)amino)pyridin-2-yl)-7-formyl-
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-
3,4-dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00050## MS
m/z(ESI): 565 (M + H).sup.+. 18 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-4,4-
difluoro-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00051## MS m/z(ESI): 559 (M +
H).sup.+. 19 N-(5-cyano-4-((2-((methyl-
d3)thio)ethyl)amino)pyridin-2-yl)-7-formyl-
6-((4-methyl-2-oxopiperazin-1-yl)methyl)-
3,4-dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00052## MS
m/z(ESI): 526 (M + H).sup.+. 20
N-(5-cyano-4-((tetrahydro-2H-thiopyran-4-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00053## MS
m/z(ESI): 549 (M + H).sup.+. 21
N-(5-cyano-4-(thiazolidin-3-yl)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00054## MS m/z(ESI): 521(M + H).sup.+. 22
N-(5-cyano-4-((2-(methylthio)-
propyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00055## MS
m/z(ESI): 537(M + H).sup.+. 23 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((2-oxopyrrolidin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00056## MS
m/z(ESI): 494 (M + H).sup.+. 24 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-6-((1-
(dimethylamino)-N-methylcyclopropane-1-
carboxamido)methyl)-7-formyl-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide ##STR00057## MS m/z(ESI): 551
(M + H).sup.+. 25 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 4,4-d2-1(2H)-carboxamide
##STR00058## MS m/z(ESI): 525 (M + H).sup.+. 26 N-(5-cyano-4-((2-
(cycloproylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00059## MS m/z(ESI): 549 (M + H).sup.+. 27 N-(5-cyano-4-((2-
(methylsulfinyl)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00060## MS m/z(ESI): 539 (M + H).sup.+. 28 N-(5-cyano-4-((2-
(cyclopentylthio)ethyl)amino)pyridin-2-yl)-
7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00061## MS m/z(ESI): 577 (M + H).sup.+. 29
Methyl-2-((2-((5-cyano-2-(7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-1,2,3,4-
tetrahydro-1,8-naphthyridine-1- carboxamido)pyridin-4-
yl)amino)ethyl)thio)acetate ##STR00062## MS m/z(ESI): 581 (M +
H).sup.+. 30 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-4,4-dimethyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00063## MS m/z(ESI): 551 (M +
H).sup.+. 31 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl-d2)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxamide
##STR00064## MS m/z(ESI): 525(M + H).sup.+. 32 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-(1-(4-methyl-2-oxopiperazin-1-
yl)ethyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00065## MS m/z(ESI): 537 (M + H).sup.+. 33
N-(5-cyano-4-(((tetrahydrothiophen-2-
yl)methyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00066## MS
m/z(ESI): 549 (M + H).sup.+. 34 N-(5-cyano-4-((thietan-2-
ylmethyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00067## MS
m/z(ESI): 535 (M + H).sup.+. 35
N-(5-cyano-4-(((tetrahydro-2H-thiopyran-2-
yl)methyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00068## MS
m/z(ESI): 563 (M + H).sup.+. 36
N-(5-cyano-4-(1-thia-8-azaspiro[4.5]decan-
8-yl)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00069## MS m/z(ESI): 589 (M +
H).sup.+. 37 N-(5-cyano-4-(((tetrahydro-2H-thiopyran-4-
yl)methyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00070## MS
m/z(ESI): 563 (M + H).sup.+. 38
N-(5-cyano-4-(((4-methylthiomorpholin-2-
yl)methyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00071## MS
m/z(ESI): 578 (M + H).sup.+. 39
N-(4-(((1,4-oxathian-2-yl)methyl)amino)-5-
cyanopyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00072## MS m/z(ESI): 565 (M +
H).sup.+. 40 N-(5-cyano-4-((2-
(methylthio)cyclopentyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00073## MS m/z(ESI): 563 (M + H).sup.+. 41 N-(5-cyano-4-((4-
(methylthio)tetrahydrofuran-3-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00074## MS
m/z(ESI): 565 (M + H).sup.+. 42
N-(5-cyano-4-(3-(methylthio)pyrrolidin-1-
yl)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00075## MS m/z(ESI): 549 (M +
H).sup.+. 43 N-(5-cyano-4-(((1- (methyl-
thio)cyclopropyl)methyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00076## MS m/z(ESI): 549 (M + H).sup.+. 44 N-(5-cyano-4-((1-
((methyl- thio)methyl)cyclopropyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00077## MS m/z(ESI): 549 (M + H).sup.+. 45
N-(5-cyano-4-((4-(methylthio)tetrahydro-2H-
pyran-3-yl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00078## MS
m/z(ESI): 579 (M + H).sup.+. 46
N-(5-cyano-4-((3-(methylthio)tetrahydro-2H-
pyran-4-yl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00079## MS
m/z(ESI): 579 (M + H).sup.+. 47
N-(5-cyano-4-(thietan-3-yl-amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00080## MS m/z(ESI): 521 (M + H).sup.+. 48 N-(5-cyano-4-(((1-
(ethyl- thio)cyclopropyl)methyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00081## MS m/z(ESI): 563 (M + H).sup.+. 49 N-(5-cyano-4-((1-
((ethyl- thio)methyl)cyclopropyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00082## MS m/z(ESI): 563 (M + H).sup.+. 50 N-(5-cyano-4-((4-
methoxytetrahydrothiophene-3-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00083## MS
m/z(ESI): 565 (M + H).sup.+. 51
N-(5-cyano-4-((4-methoxytetrahydro-2H-
thiopyran-3-yl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00084## MS m/z(ESI): 579 (M + H).sup.+. 52
N-(5-cyano-4-((3-methoxytetrahydro-2H-
thiopyran-4-yl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00085## MS m/z(ESI): 579 (M + H).sup.+.
53 N-(5-cyano-4-(2-(ethylthio)ethoxy)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00086## MS m/z(ESI): 538 (M + H).sup.+. 54
N-(5-cyano-4-((1-(methylthio)propan-2-
yl)oxy)pyridin-2-yl)-7-formyl-6-((4-methyl-
2-oxopiperazin-1-yl)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)-carboxamide ##STR00087## MS m/z(ESI): 538
(M + H).sup.+. 55 N-(5-cyano-4-((thiazol-5-yl-
methyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00088## MS
m/z(ESI): 546 (M + H).sup.+. 56 N-(5-cyano-4-((thiazol-2-yl-
methyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00089## MS
m/z(ESI): 546 (M + H).sup.+. 57 N-(5-cyano-4-((isothiazol-5-yl-
methyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00090## MS
m/z(ESI): 546 (M + H).sup.+. 58 N-(5-cyano-4-(((5-methylthiophen-2-
yl)methyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00091## MS
m/z(ESI): 559 (M + H).sup.+. 59 N-(5-Cyano-4-((thiazol-4-yl-
methyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00092## MS
m/z(ESI): 546 (M + H).sup.+. 60 N-(5-cyano-4-((1-(thiazol-2-
yl)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00093## MS
m/z(ESI): 560 (M + H).sup.+. 61
N-(5-cyano-4-((1-(5-methylthiophen-2-
yl)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00094## MS
m/z(ESI): 573 (M + H).sup.+. 62 N-(5-cyano-4-((2-
((trifluoromethyl)thio)ethyl)amino)pyridin-2-
yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00095## MS m/z(ESI): 577 (M + H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.51 (s, 1H), 10.08 (s, 1H), 8.31 (s, 1H),
7.53 (s, 1H), 7.51 (s, 1H), 7.28 (t, J = 5.6 Hz, 1H), 4.89 (s, 2H),
3.98 (dd, J = 16.4, 11.0 Hz, 2H), 3.54 (dd, J = 13.1, 6.4 Hz, 2H),
3.37-3.21 (m, 2H), 3.06 (s, 2H), 2.93 (t, J = 6.1 Hz, 2H), 2.64 (t,
J = 5.3 Hz, 2H), 2.57-2.42 (m, 2H), 2.24 (s, 3H), 1.99-1.82 (m,
2H). 63 2-((2-((5-cyano-2-(7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-1,2,3,4- tetrahydro-1,8-naphthyridine-1-
carboxamido)pyridin-4- yl)amino)ethyl)thio)acetic acid ##STR00096##
MS m/z(ESI): 567 (M + H).sup.+. 64 N-(5-cyano-4-((3-
(methylthio)propyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00097## MS m/z(ESI): 537 (M + H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.47 (s, 1H), 10.07 (s, 1H), 8.26 (s, 1H),
7.52 (s, 1H), 7.49 (s, 1H), 7.13 (t, J = 5.4 Hz, 1H), 4.89 (s, 2H),
4.05-3.84 (m, 2H), 3.32 (m, 2H), 3.30-3.23 (m, 2H), 3.06 (s, 2H),
2.93 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 5.3 Hz, 2H), 2.57-2.52 (m,
2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.97-1.82 (m, 4H). 65
N-(5-cyano-4-((1,1- dioxidotetrahydrothiophen-3-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00098## MS
m/z(ESI): 567 (M + H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 13.53 (s, 1H), 10.07 (s, 1H), 8.32 (s, 1H), 7.54 (d, J =
4.8 Hz, 2H), 7.27 (d, J = 7.4 Hz, 1H), 4.89 (s, 2H), 3.97 (m, 2H),
3.53 (m, 1H), 3.42-3.33 (m, 2H), 3.27 (m, 2H), 3.25-3.13 (m, 2H),
3.06 (m, 2H), 2.93 (m, 2H), 2.62 (m, 2H), 2.50 (m, 2H), 2.24 (s,
3H), 1.94 (m, 2H). 66 N-(5-Cyano-4-((2-
(phenylthio)ethyl)amino)pyridin-2-yl)-7-
formyl-6-((4-methyl-2-oxopiperazin-1-
yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00099## MS m/z(ESI): 585 (M + H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.49 (s, 1H), 10.08 (s, 1H), 8.28 (s, 1H),
7.51 (d, J = 15.3 Hz, 2H), 7.41 (d, J = 7.3 Hz, 2H), 7.35 (t, J =
7.7 Hz, 2H), 7.27- 7.18 (m, 2H), 4.89 (s, 2H), 4.04-3.92 (m, 2H),
3.43 (m, 2H), 3.27 (m, 2H), 3.24-3.17 (m, 2H), 3.06 (s, 2H), 2.94
(t, J = 5.9 Hz, 2H), 2.63 (t, J = 5.4 Hz, 2H), 2.24 (s, 3H), 1.98
(m, 2H). 67 N-(5-cyano-4-((2-(pyridin-3-yl-
thio)ethyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-diazanonaphthalene-1(2H)- carboxamide ##STR00100## MS
m/z(ESI): 586 (M + H).sup.+. 68 N-(5-Cyano-4-((isothiazol-3-yl-
methyl)amino)pyridin-2-yl)-7-formyl-6-((4-
methyl-2-oxopiperazin-1-yl)methyl)-3-1,4-
dihydro-1,8-naphthyridine-1(2H)- carboxamide ##STR00101## MS
m/z(ESI): 546 (M + H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 13.45 (s, 1H), 10.05 (s, 1H), 9.03 (d, J = 4.6 Hz, 1H),
8.30 (s, 1H), 7.68 (t, J = 6.0 Hz, 1H), 7.51 (s, 1H), 7.44 (s, 1H),
7.32 (d, J = 4.7 Hz, 1H), 4.88 (s, 2H), 4.59 (d, J = 6.0 Hz, 2H),
3.95-3.88 (m, 2H), 3.26 (t, J = 5.4 Hz, 2H), 3.05 (s, 2H), 2.91 (t,
J = 6.1 Hz, 2H), 2.61 (t, J = 5.4 Hz, 2H), 2.53-2.48 (m, 2H), 2.23
(s, 3H). 69 N-(5-cyano-4-(((2R)-1-
(methylsulfinyl)propan-2-yl)amino)pyridin-
2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-
1-yl)methyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide
##STR00102## MS m/z(ESI): 553 (M + H).sup.+. 70
(R)-N-(5-cyano-4-((1-(methylthio)propan-2-
yl)amino)pyridin-2-yl)-7-formyl-6-((2-oxo-
1,3-oxozepan-3-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00103## MS m/z(ESI): 538 (M +
H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.50 (s,
1H), 10.05 (s, 1H), 8.27 (s, 1H), 7.70 (s, 1H), 7.61-7.42 (s, 1H),
6.73 (t, J = 25.0 Hz, 1H), 4.78 (s, 2H), 4.08 (m, 2H), 3.97 (m,
2H), 3.88-3.75 (m, 1H), 3.27 (m, 2H), 2.96 (t, J = 5.7 Hz, 2H),
2.50 (m, 2H), 2.13 (s, 3H), 1.94 (m, 2H), 1.77 (m, 2H), 1.60 (m,
2H), 1.30 (d, J = 6.3 Hz, 3H).
Example 71
N-(5-cyano-4-((2-(ethylthio)ethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methy-
l-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxam-
ide hydrochloride ("Compound 71")
##STR00104##
[0261] The compound 71-1 was synthesized according to the synthesis
method of compound 1-2 of example 1.
[0262] Compound 71-1 (25 mg, 0.043 mmol) was dissolved in
H.sub.2O/CH.sub.3CN (V/V=1:2, 3 mL), and concentrated hydrochloric
acid (1 mL) was added dropwise. The reaction mixture was stirred
for 0.5 h at room temperature, and concentrated under reduced
pressure to obtain the compound 71 (30 mg, 0.052 mmol). MS m/z
(ESI): 537 (M+H).sup.+.
[0263] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.64 (s, 1H),
11.76 (m, 1H), 10.08 (s, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.46 (s,
1H), 7.34 (s, 1H), 5.17-5.12 (m, 1H), 4.82 (m, 1H), 3.99 (m, 4H),
3.67-3.42 (m, 6H), 2.86 (s, 3H), 2.76-2.73 (m, 2H), 2.63-2.58 (m,
2H), 1.93 (m, 2H), 1.21 (m, 3H).
[0264] The following compounds were synthesized according to the
synthesis method of example 71:
TABLE-US-00005 Com- pound Chemical structure Formula MS and
H.sup.1NMR 72 N-(5-cyano-4-((2- (methyl-
sulfonyl)ethyl)amino)pyridin-2-yl)- 7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-
carboxamide hydrochloride ##STR00105## MS m/z(ESI): 555 (M +
H).sup.+; .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 13.76 (s, 1H),
12.23 (m, 1H), 10.10 (s, 1H), 8.39 (s, 1H), 7.98 (s, 1H), 7.46 (s,
1H), 7.43 (s, 1H), 5.23-5.18 (m, 1H), 4.78-4.71 (m, 1H), 3.73-3.68
(m, 4H), 3.50-3.47 (m, 4H), 3.08 (s, 2H), 3.08-2.95 (m, 7H), 2.84
(s, 3H), 1.94 (m, 2H). 73 N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2- yl)-7-formyl-6-((N-
methyltetrahydro-2H-pyran-4- carboxamido)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)- carboxamide hydrochloride ##STR00106## MS
m/z(ESI): 552 (M + H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 14.06- 13.81 (m, 1H), 10.14-10.11 (m, 1H), 8.39- 8.37 (m,
1H), 7.72 (s, 1H), 7.51-7.49 (m, 1H), 7.41-7.36 (m, 1H), 5.05-4.88
(d, 2H), 3.97 (m, 2H), 3.89-3.86 (m, 2H), 3.50- 3.48 (m, 2H),
3.41-3.40 (m, 2H), 3.38- 3.37 (s, 2H), 3.07 (s, 3H), 2.99-2.91 (m,
4H), 2.83 (s, 1H), 2.76-2.72 (m, 2H), 2.15 (s, 3H), 1.94 (m, 2H),
1.62-1.56 (m, 2H). 74 (R)-N-(5-cyano-4-((2-
(methylthio)ethyl)amino)pyridin-2- yl)-7-formyl-6-((N-
methyltetrahydrofuran-2- carboxamido)methyl)-3,4-dihydro-
1,8-naphthyridine-1(2H)- carboxamide hydrochloride ##STR00107## MS
m/z(ESI): 538 (M + H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 14.02- 13.77 (m, 1H), 10.18-10.09 (m, 1H), 8.38- 8.36 (m,
1H), 7.66 (s, 1H), 7.57-7.55 (m, 1H), 7.42-7.37 (m, 1H), 5.14-5.03
(m, 1H), 4.94-4.79 (m, 2H), 3.97 (m, 3H), 3.83-3.78 (m, 2H),
3.50-3.48 (m, 2H), 3.05 (s, 2H), 2.94-2.91 (m, 2H), 2.75-2.72 (m,
2H), 2.15 (s, 3H), 2.13-2.09 (m, 2H), 1.94 (m, 2H), 1.88-1.85(m,
2H). 75 (S)-N-(5-cyano-4-((2- (methylthio)ethyl)amino)pyridin-2-
yl)-7-formyl-6-((N- methyltetrahydrofuran-2-
carboxamido)methyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-
carboxamide hydrochloride ##STR00108## MS m/z(ESI): 538 (M +
H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 14.07- 13.80
(m, 1H), 10.15-10.09 (m, 1H), 8.39- 8.38 (m, 1H), 7.74 (s, 1H),
7.57-7.56 (m, 1H), 7.41-7.36 (m, 1H), 5.14-5.03 (m, 1H), 4.99-4.79
(m, 2H), 3.97 (m, 3H), 3.81-3.77 (m, 2H), 3.50-3.47 (m, 2H),
3.74-3.66 (m, 2H) 3.06 (s, 2H), 2.97-2.91 (m, 2H), 2.76-2.70 (m,
2H), 2.15 (s, 3H), 2.09-2.03 (m, 2H), 1.96-1.83 (m, 4H). 76
N-(5-cyano-4-((2- (methylthio)ethyl)amino)pyridin-2-
yl)-7-formyl-6-((N- methyltetrahydrofuran-3-
carboxamido)methyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-
carboxamide hydrochloride ##STR00109## MS m/z(ESI): 538 (M +
H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 14.06- 13.80
(m, 1H), 10.14-10.09 (m, 1H), 8.38- 8.37 (m, 1H), 7.71 (s, 1H),
7.54 (m, 2H), 7.41-7.34 (m, 1H), 4.89 (s, 2H), 3.97-3.91 (m, 2H),
3.76-3.68 (m, 2H), 3.48-3.47 (m, 3H), 3.05 (s, 3H), 2.97-2.93 (m,
2H), 1.87 (m, 1H), 2.75-2.74 (m, 2H), 2.15 (s, 3H), 2.02-1.94 (m,
2H), 1.22 (m, 2H).
[0265] The following compounds were synthesized by selecting
appropriate raw materials:
TABLE-US-00006 Com- pound Chemical structure Formula MS and
H.sup.1NMR 77 N-(5-cyano-4-((1-mercapto-2-methylpropan-2-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00110## MS m/z(ESI): 537 (M +
H).sup.+. 78 N-(5-cyano-4-(4-mercapto-4-methylpiperidin-1-
yl)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00111## MS m/z(ESI): 563 (M +
H).sup.+. 79 N-(5-cyano-4-((2-mercapto-2-
methylpropyl)amino)pyridin-2-yl)-7-formyl-6-
((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-
dihydro-1,8-naphthyridine-1(2H)-carboxamide ##STR00112## MS
m/z(ESI): 537 (M + H).sup.+. 80
N-(5-cyano-4-(3,6-dihydro-2H-thiopyran-4-
yl)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00113## MS m/z(ESI): 532 (M +
H).sup.+. 81 Ethyl-2-((2-((5-cyano-2-(7-formyl-6-((4-methyl-
2-oxopiperazin-1-yl)methyl)-1,2,3,4-tetrahydro-
1,8-naphthyridine-1-carboxamide)pyridin-4-
yl)amino)ethyl)thio)acetate ##STR00114## MS m/z(ESI): 595 (M +
H).sup.+. 82 N-(5-cyano-4-((1-(methylthio)propan-2-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00115## MS m/z(ESI): 537 (M +
H).sup.+. 83 N-(5-cyano-4-(((2R)-1-(methylsulfonyl)propan-2-
yl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-
oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-
naphthyridine-1(2H)-carboxamide ##STR00116## MS m/z(ESI): 569(M +
H).sup.+.
Analysis of Pharmacological and Pharmacodynamic Experiment
Example A: FGFR4 Enzymatic Experiments
[0266] The FGFR4 kinase inhibition of compounds was tested by using
mobility shift assay in this experiment, and the rate of FGFR4
kinase inhibition of compounds or half inhibitory concentration
IC.sub.50 thereof was obtained.
[0267] (1) The compounds to be tested were prepared to gradient
concentration in 100% DMSO, and diluted with buffer solution (the
pH of the buffer solution was 7.5, and the buffer solution
contained 50 mM HEPES(N-(2-Hydroxyethyl)piperazine-N'-2-sulfonic
acid), 0.00015% (ml/ml)Brij-35 (Dodecyl poly ethylene glycol ether)
and the water) to the reacting solution with 10% DMSO. The reacting
solution was added into the 384-well plate. For example, when the
initial concentration of the compounds was 10 .mu.M, 500 .mu.M
would be prepared with 100% DMSO, and diluted in gradient of 10
concentrations, and then diluted 10 times in gradient with buffer
solution to prepare an intermediate dilution of the compound
containing 10% DMSO. 5 .mu.l of the intermediate dilution was
transferred to 384-well plate;
[0268] (2) FGFR4 enzyme (Invitrogen, Cat. No PR4380A, Lot. No
1856505A) was diluted with the buffer solution (the pH of the
buffer solution was 7.5, and the buffer solution contained 50 mM
HEPES, 0.00015% (ml/ml) Brij-35, 2 mM DTT (Dithiothreitol) and the
water) to obtain a FGFR enzyme solution with the optimum
concentration (the final concentration of the FGFR enzyme solution
was 12.5 nM). 10 .mu.l FGFR enzyme solution was transferred to
384-well plate above mentioned in step (1), and incubated with the
compounds to be tested for 10-15 minutes.
[0269] (3) The substrate (Peptide FAM-P22, GL Biochem, Cat. No.
112393, Lot. No. P180116-MJ112393) was diluted with buffer solution
(the pH of the buffer solution was 7.5, and the buffer solution
contained 50 mM HEPES, 0.00015% (ml/ml) Brij-35, 10 mM MgCl.sub.2,
adenosine triphosphate 66 .mu.M under Km and the water) to obtain a
substrate solution with the optimum concentration of 10 nM. 10
.mu.l the substrate solution was added into the 384-well plate
above mentioned in step (2) to start the reaction, and the reaction
was undergoing at 28.degree. C. for 1 hour;
[0270] (4) the conversion rate was read with Caliper Reader, and
the inhibition rate was the average of the two testing values.
[0271] (5) The IC.sub.50 value was obtained by XL-fit software
fitting, and the measured results are shown in Table 1 below:
TABLE-US-00007 TABLE 1 FGFR4 Compound (IC.sub.50 nM) Compound 1 1.5
Compound 4 1.4 Compound 5 2.0 Compound 6 2.1 Compound 7 1.5
Compound 8 0.42 Compound 9 2.0 Compound 16 2.2 Compound 20 4.4
Compound 27 2.4 Compound 55 3.0 Compound 56 1.6 Compound 58 2.1
Compound 59 2.1 Compound 60 3.0 Compound 62 1.7 Compound 64 1.6
Compound 69 2.1 Compound 71 2.4 Compound 72 2.0 Compound 73 2.3
Compound 75 1.8 Compound 76 2.1 Compound 83 2.1 Reference compound
2.9 (roblitinib)
[0272] The reference compound in the present invention has the
following structure
##STR00117##
[0273] From Table 1, it can be seen that most compounds in the
table have better inhibitory effect on FGFR4 than the reference
compound, such as, compound 1, compound 4, compound 5, compound 6,
compound 7, compound 9, compound 16, compound 27, compound 56,
compound 58, compound 59, compound 62, compound 64, compound 69,
compound 71, compound 72, compound 73, compound 75, compound 76 and
compound 83.
Example B: Hepatoma Cell Proliferation Inhibition Experiment
[0274] In this experiment, the MTS method was used to test the
inhibitory effect of the compounds on the proliferation of Hepatoma
cell Hep3B (high expression of FGFR4 and FGF19), and the half
inhibitory concentration IC.sub.50 of the compounds to Hep3B was
obtained. The Hep3B cell line was purchased from ATCC, and the
complete culture medium of the Hep3B cell line was MEM+10% FBS+1%
PS. MEM cell culture medium, fetal bovine serum, and trypsin were
purchased from Gibco, cell culture flasks were purchased from
Greiner, and disposable Cell Counting Plate and Taittinger Blue
Solution were purchased from Bio-Rad.
[0275] (1) 100 .mu.l Hepatoma cell Hep3B suspension was seeded in a
96-well cell culture plate, and the density of each well was
2.0.times.10.sup.4 cells/ml. The culture plate was incubated in
incubator for 16-24 h (37.degree. C., 5% CO.sub.2);
[0276] (2) The compound solution to be tested with different
concentration obtained by gradient dilution (15 mM or 7.5 mM of
stock solution was prepared by dissolving the compounds in DMSO,
then the stock solution was diluted to solution in eight different
concentrations with DMSO in a 5-fold gradient. 1.6 .mu.l
compound+400 .mu.l MEM (containing 1% PS), 100 .mu.l/well, 3 wells
per concentration.) was added into the culture plate, and the
culture plate was incubated for 120 h in incubator (37.degree. C.,
5% CO.sub.2).
[0277] (3) A mixture of MTS
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl-
)-2H-tetrazolium)/PMS (phenazine methosulfate) was added into each
well for coloration, and MTS/PMS in the mixture was at a ratio of
20:1 (ml:ml). 30 .mu.l of the mixture was added into each well of
the culture plate above mentioned in step (2), then the culture
plate was incubated for 3 h in the incubator.
[0278] (4) The chemiluminescence signal value of each plate was
measured at a wavelength of 492 nm using the enzyme-labeled
instrument;
[0279] (5) The inhibition rate was calculated by the
chemiluminescence signal value;
[0280] (6) According to the inhibition rate of the different
concentrations, the IC.sub.50 values of the compounds were obtained
by curve fitting.
[0281] The measured results were as shown in the following table
2:
TABLE-US-00008 TABLE 2 Compound Hep3B(IC.sub.50 .mu.M) compound 1
0.023 compound 2 0.028 compound 4 0.014 compound 6 0.049 compound 7
0.011 compound 8 0.008 compound 9 0.009 compound 11 0.035 compound
16 0.029 compound 20 0.021 compound 27 0.282 compound 56 0.013
compound 62 0.054 compound 64 0.018 compound 68 0.026 compound 69
0.067 compound 71 0.049 compound 72 0.282 compound 73 0.039
compound 74 0.060 compound 75 0.028 compound 76 0.006 compound 82
0.020 compound 83 0.068 Reference Compound 0.024
[0282] From the Table 2, it can be seen that most compounds in the
table have better inhibitory effect on Hepatoma cell Hep3B highly
expressed FGFR4 and FGF19 than the reference compound, such as
compound 1, compound 20, compound 4, compound 7, compound 8,
compound 9, compound 20, compound 56, compound 64, compound 76 and
compound 82.
Example C: PK Analysis of Rats
[0283] In the present invention, the pharmacokinetics experiment of
the compounds in rats was performed using the SD rats
(Vitolihua).
[0284] (1) Mode of administration: single gavage administration and
intravenous injection administration.
[0285] (2) Dosage: 10 mg/kg in the gavage administration, 3 mg/kg
in the intravenous injection administration.
[0286] (3) Sampling time point:
[0287] Gavage administration: before administration, 15 min, 30
min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h; Intravenous injection
administration: before administration, 5 min, 15 min, 30 min, 1 h,
2 h, 4 h, 6 h, 8 h, 24 h;
[0288] (4) Sample processing: 200 .mu.L of orbital blood was
collected at each sampling time point. After anticoagulation with
heparin, the blood was centrifuged at 5500 rpm for 10 min, and 60
.mu.L of the supernatant was taken and put into the refrigerator at
-80.degree. C. for waiting for testing.
[0289] Samples obtained after administration of Compound 1 were
tested using 4000 LC-MS/MS analyzer, wherein, the chromatographic
separation conditions for testing were:
[0290] Chromatographic column: Xselect HSS T3 2.5 .mu.m
(2.1.times.50 mm) (Compound 1);
[0291] The mobile phase A: 5% acetonitrile and 95% water (0.1% FA
(formic acid));
[0292] The mobile phase B: 95% acetonitrile and 5% water (0.1%
FA);
[0293] Flow rate: 0.6 ml/min;
[0294] Eluted time: 4.00 min;
[0295] Injection volume: 5 .mu.L;
[0296] The elution gradient was shown in the Table 3:
TABLE-US-00009 TABLE 3 The mobile The mobile Time phase A (%) phase
B (%) 0.00 95.0 5.00 0.20 95.0 5.00 1.00 0.00 100 2.20 0.00 100
2.21 95.0 5.00 4.00 95.0 5.00
[0297] Samples obtained after administration of Compound 7 were
tested using 4000 LC-MS/MS analyzer, wherein, the chromatographic
separation conditions for testing were:
[0298] Chromatographic column: Agilent ZORBAX 3.5 .mu.m SB C.sub.18
(2.1.times.50 mm) (Compound 7);
[0299] The mobile phase A: 5% acetonitrile and 95% water (0.1%
FA);
[0300] The mobile phase B: 95% acetonitrile and 5% water (0.1%
FA);
[0301] Flow rate: 0.6 ml/min;
[0302] Eluted time: 3.80 mins;
[0303] Injection volume: 3 .mu.L;
[0304] The elution gradient was shown in the Table 4:
TABLE-US-00010 TABLE 4 The mobile The mobile Time phase A (%) phase
B (%) 0.00 95.0 5.00 0.15 95.0 5.00 1.50 0.00 100 2.50 0.00 100
2.60 95.0 5.00 3.80 95.0 5.00
[0305] Samples obtained after administration of Compound 16 were
tested using 4000 LC-MS/MS analyzer, wherein, the chromatographic
separation conditions for testing were:
[0306] Chromatographic column: Agilent ZORBAX 3.5 .mu.m SB C.sub.18
(2.1.times.50 mm) (Compound 16);
[0307] The mobile phase A: 5% acetonitrile and 95% water (0.1%
FA);
[0308] The mobile phase B: 95% acetonitrile and 5% water (0.1%
FA);
[0309] Flow rate: 0.6 ml/min;
[0310] Eluted time: 3.80 mins;
[0311] Injection volume: 10 .mu.L;
[0312] The elution gradient was shown in the Table 5:
TABLE-US-00011 TABLE 5 The mobile The mobile Time phase A (%) phase
B (%) 0.00 95.0 5.00 0.15 95.0 5.00 1.50 0.00 100 2.50 0.00 100
2.60 95.0 5.00 3.80 95.0 5.00
[0313] Samples obtained after administration of compound 4,
compound 5, compound 20, compound 56, compound 71 or reference
compound were tested using 5500 LC-MS/MS analyzer, wherein, the
chromatographic separation conditions for the test were:
[0314] Chromatographic column: Xselect HSS T3 2.5 .mu.m
(2.1.times.50 mm)(the chromatographic column using for compound 4,
compound 5, compound 20, compound 56, compound 71); Phenomenex
Kinetex 5 .mu.m C.sub.18 100A (2.1.times.50 mm)(the chromatographic
column using for reference compound);
[0315] The mobile phase A: 5% acetonitrile and 95% water (0.1%
FA);
[0316] The mobile phase B: 95% acetonitrile and 5% water (0.1%
FA);
[0317] Flow rate: 0.6 ml/min;
[0318] Eluted time: 3.00 mins;
[0319] Injection volume: 2 .mu.L;
[0320] The elution gradient was shown in the Table 6:
TABLE-US-00012 TABLE 6 The mobile The mobile Time phase A (%) phase
B (%) 0.00 95.0 5.00 0.30 95.0 5.00 1.80 5.00 95.0 2.50 5.00 95.0
2.51 95.0 5.00 3.00 95.0 5.00
[0321] Mass spectrometry analysis conditions of compound:
[0322] The setting conditions of 4000 LC-MS/MS mass spectrometer in
mass analysis were shown in Table 7 below:
TABLE-US-00013 TABLE 7 Compound Q1 Q3 DP EP CE CXP Compound 1
523.252 175.100 96 10 35 16 Compound 7 508.287 175.100 96 10 35 16
Compound 16 538.278 175.000 111 10 37 12 Verapamil 455.216 165.100
91 10 37 12
[0323] The setting conditions of 5500 LC-MS/MS mass spectrometer in
mass analysis were shown in Table 8 and Table 9 below:
TABLE-US-00014 TABLE 8 Compound Q1 Q3 DP EP CE CXP Compound 4
537.083 175.100 76 10 37 14 Compound 5 535.095 174.900 71 10 39 12
Compound 20 549.071 175.100 71 10 37 12 Compound 56 546.026 175.100
36 10 35 12 Compound 71 537.078 175.000 146 10 37 14 Verapamil
455.216 165.100 91 10 37 12
TABLE-US-00015 TABLE 9 Compound Q1 Q3 DP EP CE CXP Reference
507.252 175.100 56 10 25 14 compound Dexamethasone 393.171 373.000
96 10 13 10
[0324] Note: Q1, Q3, DP, EP, CE and CXP in the table respectively
refer that Q1: parent ion; Q3: product ion; DP: declustering
voltage; EP: inlet voltage; CE: collision energy; CXP: collision
cell outlet voltage.
[0325] The results measured according to the above experimental
steps were shown in Table 10 below:
TABLE-US-00016 TABLE 10 p.o.(10 mg/kg) Drug concentration Curve
area in blood AUC.sub.0-24 h Compound C.sub.max (ng/mL) (h .times.
ng/mL) Compound 1 833 2369 Compound 4 1450 4671 Compound 5 1400
6727 Compound 7 736 2846 Compound 16 936 3666 Compound 20 514 1996
Compound 56 548 2014 Compound 71 657 1947 Reference Compound 350
1590
[0326] In Table 10, p.o. refers to oral administration.
[0327] From Table 10, it can be seen that, all of the compounds in
the table showed better metabolic properties compared with the
reference compound. The exposure amount AUC.sub.0-24 h and the
maximum drug concentration in blood C.sub.max were significantly
higher than the reference compound, such as compound 1, compound 4,
compound 5, compound 7, compound 16, compound 20, compound 56, and
compound 71.
Example D: PK/PD of NOD-SCID Mouse
[0328] This experiment conducted when the pharmacological
experiment in vivo was performed by gavage administration, wherein,
the blood samples and tumor samples were taken at different time
points to detect drug concentration in blood and drug
concentrations in tumors.
[0329] (1) Mode of administration: gavage administration;
[0330] (2) Dosage: 50 mg/kg in the gavage administration;
[0331] (3) Sampling time point:
[0332] Sampling time point of blood samples: the sampling point of
compound 4 and reference compound were before administration, at 1
h, 2 h, 4 h, 6 h. Three mice were sampled at each sampling
point;
[0333] Sampling time point of tumor samples: the sampling point of
compound 4 and reference compound were at 4 h, 6 h. Three mice were
sampled at each sampling point;
[0334] (4) Blood sample collection: 200 .mu.L of orbital blood was
collected at sampling time point for each blood sample. After
anticoagulation with heparin, the blood was centrifuged at 5500 rpm
for 10 mins. 60 .mu.L of the supernatant was taken and put it into
the refrigerator at -80.degree. C. for waiting for testing.
[0335] Tumour sample collection: 200-300 mg of each tumor tissue
was taken. The tumor weight was marked, quickly freezed in liquid
nitrogen and placed into a refrigerator at -80.degree. C. for
waiting for testing.
[0336] PK Detection:
[0337] Tumour sample processing: pure water was added into the
tumor sample according to a ratio of 1 mg: 3 mL between the weight
of the tumor sample and the volume of pure water and then it was
homogenized. The homogenate was stored at -90.degree. C. to
-60.degree. C. until the sample was analyzed. After 5 .mu.L of
acetonitrile/water (v/v=1:1) was added into 50 .mu.L of tumor
sample homogenate, 200 .mu.L of acetonitrile (containing
Dexamethasone 100 ng/ml as internal standard, or containing
Verapamil 2 ng/ml as internal standard) was added. After protein
precipitation, the resulting mixture was vortexed for 2 mins at
4.degree. C. with 4600 g, and then centrifuged for 15 mins to
obtain the supernatant. 100 .mu.L of the supernatant was taken and
added into 200 .mu.L of deionized water. 5500 LC/MS/MS analyser was
used for sample injection and analysis, after vortexing for
homogeneity. The conditions for chromatographic separation and mass
spectrometric analysis were as follows:
[0338] Chromatographic column: Xselect HSS T3 2.5 .mu.m
(2.1.times.50 mm) (compound 4); Phenomenex Kinetex 5 .mu.m C.sub.18
100A (2.1.times.50 mm) (reference compound);
[0339] The mobile phase A: 5% acetonitrile and 95% water (0.1%
FA);
[0340] The mobile phase B: 95% acetonitrile and 5% water (0.1%
FA);
[0341] Flow rate: 0.6 ml/min;
[0342] Eluted time: 3.00 mins;
[0343] Injection volume: 2 .mu.L;
[0344] The elution gradient was shown in the Table 11:
TABLE-US-00017 TABLE 11 The mobile The mobile Time phase A (%)
phase B (%) 0.00 95.0 5.00 0.30 95.0 5.00 1.80 5.00 95.0 2.50 5.00
95.0 2.51 95.0 5.00 3.00 95.0 5.00
[0345] The setting conditions of the mass spectrometer in the mass
spectrometry analysis were shown in Table 12 and Table 13
below:
TABLE-US-00018 TABLE 12 Compound Q1 Q3 DP EP CE CXP Reference
507.252 175.100 56 10 25 14 compound Dexamethasone 393.171 373.000
96 10 13 10
TABLE-US-00019 TABLE 13 Compound Q1 Q3 DP EP CE CXP Compound 4
537.083 175.100 76 10 37 14 Verapamil 455.216 165.100 91 10 37
12
[0346] Note: Q1, Q3, DP, EP, CE and CXP in the table respectively
refer that Q1: parent ion; Q3: product ion; DP: declustering
voltage; EP: inlet voltage; CE: collision energy; CXP: collision
cell outlet voltage.
[0347] The results measured according to the above experimental
steps were shown in Table 14 below:
TABLE-US-00020 TABLE 14 Drug p.o. (50 mg/kg) concentration
T.sub.1/2 T.sub.max C.sub.max AUC.sub.0-6 h AUC.sub.Inf in
tumor(ng/g) Compound Model (h) (h) (ng/ml) (h .times. ng/ml) (h
.times. ng/ml) 4 h 6 h Reference Hep3B 3.13 1 6203 20193 29081 64.4
44.1 compound SNU878 NA 4 5430 20356 NA 3560 1030 Compound 4 Hep3B
1.48 2 1021 3025 3358 1212 673 SNU878 2.3 1 1233 3531 4265 2336
1951
[0348] In Table 14, p.o. refers to oral administration.
[0349] From Table 14, it can be seen: the content of compound 4 at
6 h in tumor tissue was about twice than the reference compound in
the SNU878 model in vivo, and the content of compound 4 at 4 h or 6
h in tumor tissue was more than 15 times than the reference
compound in the Hep3B model in vivo. The above result indicated
that compound 4 has better tumor-targeting property.
Example E: Pharmacodynamic In Vivo
[0350] 5.1 Reagents and Materials
[0351] The Hep3B cell line was purchased from ATCC; MEM cell
culture medium, fetal bovine serum, and trypsin were purchased from
Gibco; cell culture flasks were purchased from Greiner; and
disposable Cell Counting Plate and taittinger Blue Solution
Purchased from Bio-Rad. The disposable sterile syringe was
purchased from Changzhou Jinlong Medical Plastic Instrument Co.,
Ltd, eye surgical scissors and eye surgical forceps were purchased
from Shanghai Medical Instrument (Group) Co., Ltd. Surgical
Instrument Factory, and 6-8 week old female NOD-SCID mice were
purchased from Vitalivar.
[0352] 5.2 Cell Culture and Preparation of Cell Suspension
[0353] a. One strain of Hep3B cells was taken out from the cell
bank and MEM medium (MEM+10% FBS+1% PS) was used to recover the
cells. The resuscitated cells were placed in a cell culture flask
(the wall the flask was marked with the cell type, date,
cultivator's name), and the cell culture flask was placed in a
CO.sub.2 incubator (the temperature of the incubator was 37.degree.
C. and the CO.sub.2 concentration of the incubator was 5%);
[0354] b. When the cells covered about 90% of the bottom of the
culture flask, passage was conducted. the cells were continued to
cultivate in a CO.sub.2 incubator after passage. The above process
was repeated until the number of the cell satisfied the
requirements of pharmacodynamic in vivo;
[0355] c. The cultured cells were collected and counted using a
BIO-Rad TC20 cell counter. According to the counting results, the
cultured cells were resuspended with PBS and matrix gel (1:1) to
obtain a cell suspension (density 5.times.10.sup.7/ml), and the
cell suspension was placed in an ice box for later use.
[0356] 5.3 Cell Inoculation and Tumor Measurement
[0357] a. The cells were mixed well before seeding, and 0.5 ml of
cell suspension was taken with a 1 ml syringe and bubbles in the
cell suspension were removed. The syringe with the cell suspension
was place on an ice pack for later use.
[0358] b. The NOD-SCID mice were set with the left hand, and the
skin on the right back of the mice was disinfected with 75%
alcohol. The inoculation was beginning after 30 seconds.
[0359] c. During inoculation, 1 mL syringe was on the right hand,
and the cell suspension of Hep3B was inoculated subcutaneously into
the right shoulder of the right back of the mouse at 0.1 mL/mouse.
At inoculation interval, the syringe was placed on an ice pack and
the mice were inoculated sequentially.
[0360] d. According to the tumor growth, the tumor was measured and
the tumor size was calculated on the 12-15 days after
inoculation.
tumor volume (mm.sup.3)=length (mm).times.width (mm).times.width
(mm)/2 Tumor volume calculation:
[0361] e. When the tumors grew to an average volume of 100-150
mm.sup.3, the mice were randomly divided into two groups according
to tumor size and the weight of the mouse. There were 9 mice in
either group, and one was the control group and the other was the
treatment group.
[0362] f. The method of administration was gavage, and the control
group was administered with 10% DMSO+90% ddH.sub.2O and the
treatment group was respectively administered with the compound 4
at a dosage of 15/30/60 mg/kg once a day, the compound 4 at a
dosage of 15 mg/kg twice a day, and the reference compound at a
dosage of 60 mg/kg once a day. The solvent of the compound 4 was
10% DMSO+90% ddH.sub.2O, and the solvent of the reference compound
was 100% ddH.sub.2O. Tumors were measured and the mice were weighed
twice a week after administration.
[0363] g. The experiment was finished until the tumor volume of the
control group was about 1500 mm.sup.3.
[0364] The results of the compound's inhibition of tumors were
shown in Table 15 below:
TABLE-US-00021 TABLE 15 Groups TGI % Compound 4 15 mg/kg BID 96.7
Reference Compound 60 mg/kg QD 97.7 Note: TGI(Tumor growth
inhibition) % = (1 - Tumor weight of treatment group/Tumor weight
of control group) .times. 100%. QD: once a day, BID: Twice a
day.
[0365] From Table 15, it can be seen that the compound 4 of the
present invention has an excellent antitumor effect, and the effect
of 15 mg/kg BID of the compound 4 is equivalent to the effect of 60
mg/kg QD of the reference compound in the Hep3B model. The compound
4 achieved the same efficacy compared with the reference compound
although the dose of the compound 4 was reduced by half, Therefore,
the toxic side effects is fewer and the safety is higher.
* * * * *