US2022281871A1PendingUtilityA1
Pyrazolo[1,5-A][1,3,5]Triazine and Pyrazolo[1,5-A]Pyrimidine Derivatives as CDK Inhibitors
Est. expiryMar 9, 2035(~8.7 yrs left)· nominal 20-yr term from priority
A61K 45/06C07D 487/04A61P 35/00A61P 43/00A61P 35/02A61P 31/00A61K 31/53A61P 29/00
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Claims
Abstract
The present invention provides substituted pyrazolo[1,3,5] triaziric and pyrazolo[1,5a] pyrimidine derivatives of formula (I), which are therapeutically useful, particularly as selective transcriptional CDK inhibitors including CDK7, CDK9, CDK12, CDK13 and CDK15, more particularly transcriptional CDK7 inhibitors wherein X, ring A, ring B, L1, L2, R1,R2, R3, R4, R6, m, n and p have the meanings given in the specification and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of disease or disorder associated with selective transcriptional CDKs in a mammal. The present invention also provides preparation of the compounds and pharmaccutical formulations comprising at least one of the substituted pyrazolo [1.5-a] [1-3,5] triazine and pyrazolo[1,5-a] pyrimidine derivatives of formula (I) or a pharmaceutically acceptable salt thereof or a stercoisomer liner thereof.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
or a pharmaceutically acceptable salt or a stereoisomer thereof
wherein,
X is CH or N;
Ring A is monocyclic or bicyclic aryl, heteroaryl or heterocycloalkyl;
Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl or absent;
R 1 is hydrogen, alkyl or cycloalkyl;
R 2 is:
R 3 at each occurrence independently is halo, alkyl, hydroxy, alkoxy, amino, alkylamino, cyano, nitro or haloalkyl;
R 4 at each occurrence independently is halo, alkyl, hydroxy, alkoxy, —(NH) q —S(O) 2 —CH=CH 2 , —(NH) q —CH 2 —CH=CH—C(O)—NR a R b ,
wherein R 5 and R 5 ″at each occurrence independently are hydrogen or alkyl; R 5 ′ is hydrogen, halo, alkyl, alkoxyalkyl or —CH 2 —NR a R b ;
R 6 is hydrogen or alkyl;
R a and R b are independently hydrogen or alkyl; or R a and R b along with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having 0-2 additional heteroatoms selected from O, S and N; wherein the optional substituent is one or more alkyl or halo;
L 1 is —O—, —S—, —NH— or absent;
L 2 is absent or optionally substituted C 1 -C 6 alkylene, wherein one or more methylene units of the alkylene is optionally and independently replaced with —C(O)—, —O——, —N(R 7 )— or cycloalkylene; wherein R 7 is hydrogen or alkyl;
m is 0 to 1;
n is 0, 1 or 2;
p is 1, 2 or 3; and
q is 0 to 1.
2 . The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (IA):
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof
3 . The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (TB):
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof
4 . The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (IC):
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof
5 . The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (ID):
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof
6 . The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (IE):
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof
7 . The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (IF):
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof
8 . The compound according to claim 1 , wherein ring A is phenyl, pyridyl or piperidinyl.
9 . The compound according to claim 1 , wherein ring B is cycloalkyl, aryl, heterocycloalkyl or heteroaryl.
10 . The compound according to claim 1 , wherein L 1 is NH or O.
11 . (canceled)
12 . The compound according to claim 1 , wherein R 2 is cyclohexyl, N-methyl-4-piperidinyl or tetrahydro-4-pyranyl.
13 . The compound according to claim 1 , wherein R 1 is hydrogen or alkyl.
14 . The compound according to claim 1 , wherein R 4 is
wherein R 5 , R 5 ′ and R 5 ″ are as defined in claim 1 .
15 . The compound according to claim 14 , wherein R 5 ′ is —CH 2 —NR a R b ; wherein R a and R b are independently hydrogen or alkyl.
16 . The compound according to claim 15 , wherein R a and R b along with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having 0-2 additional heteroatoms selected from O, S and N.
17 . A compound selected from the group consisting of:
Compound
No:
IUPAC name
40A.
3-acrylamido-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-4-methylbenzamide;
40B.
5-acrylamido-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][[1,3,5]triazin-4-yl)amino)methyl)phenyl)-2-methylbenzamide;
40C.
1-acryloyl-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-6-methylpiperidine-2-carboxamide;
47.
3-acrylamido-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide;
48.
2-acrylamido-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide;
48A.
3-acrylamido-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-2-methylbenzamide;
49.
(E)-4-((3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)amino)-N,N-dimethylbut-2-enamide;
50.
(E)-4-(diethylamino)-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-
yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)but-2-enamide;
51.
(E)-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-4-morpholinobut-2-enamide;
52.
(E)-4-(4-ethylpiperazin-1-yl)-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-
yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)but-2-enamide;
53.
(E)-4-(dimethylamino)-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-
yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)but-2-enamide;
54.
(E)-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide;
55.
(E)-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-4-(piperidin-1-yl)but-2-enamide;
56.
(E)-4-(3-fluoropyrrolidin-1-yl)-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-
yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)but-2-enamide;
57.
(E)-4-(3,3-difluoropyrrolidin-1-yl)-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-
4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)but-2-
enamide;
58.
(E)-4-(3-fluoropiperidin-l-yl)-N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-
yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)but-2-enamide;
59.
(E)-4-(dimethylamino)-N-(3-fluoro-5-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-
yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)but-2-enamide;
60.
(E)-4-(dimethylamino)-N-(2-fluoro-3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-
yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)but-2-enamide;
61.
(E)-N-(3-fluoro-5-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-4-morpholinobut-2-enamide;
62.
(E)-4-(dimethylamino)-N-(2-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)but-2-enamide;
63.
(E)-N-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide;
79.
N-(2-((3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)amino)-2-oxoethyl)acrylamide;
80.
N-(1-((3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)amino)-1-oxopropan-2-yl)acrylamide;
81.
N-(2-((3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)amino)-2-oxoethyl)-N-methyl
acrylamide;
82.
N-(1-((3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)phenyl)amino)-2-methyl-1-oxopropan-2-
yl)acrylamide;
125.
4-acrylamido-N-(3-((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)phenyl)benzamide;
130.
(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((8-isopropyl-2-((1-methylpiperidin-
4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)phenyl)benzamide;
137.
(E)-4-(dimethylamino)-1-(4-(2-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-
yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)piperazin-
1-yl)but-2-en-1-one;
138.
(E)-1-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-
a][1,3,5]triazin-4-yl)amino)methyl)piperidin-1-yl)-4-(pyrrolidin-1-yl)but-2-
en-1-one; and
or a pharmaceutically acceptable salt or a stereoisomer thereof.
18 . A compound [[is]] selected from the group consisting of:
Compound
No:
Structure
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
or a pharmaceutically acceptable salt or a stereoisomer thereof.
19 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
20 - 23 . (canceled)
24 . A method of treating selective transcriptional CDKs mediated disorders or diseases or condition in a subject comprising administering a therapeutically effective amount of a compound according to claim 1 .
25 . A method of inhibiting selective transcriptional CDKs in a subject, comprising administering to the subject a compound of claim 1 .
26 . (canceled)
27 . The method of claim 24 , wherein the selective transcriptional CDKs mediated disorder or disease or condition is selected from the group consisting of a cancer, an inflammatory disorder, an auto-inflammatory disorder or an infectious disease.
28 . The method of claim 27 , wherein the cancer is selected from the group consisting of a carcinoma, including that of the breast, liver, lung, colon, kidney, bladder, including small cell lung cancer, non-small cell lung cancer, head and neck, thyroid, esophagus, stomach, pancreas, ovary, gall bladder, cervix, prostate and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkins lymphoma, non-Hodgkins lymphoma, B-cell lymphoma, T- cell lymphoma, hairy cell lymphoma, myeloma, mantle cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of masenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoctanthoma, xenoderoma pigmentosum, thyroid follicular cancer and Kaposi's sarcoma.
29 . The method of claim 24 any one of the claims 24 , comprising an additional step of administering to the subject in need thereof one or more additional chemotherapeutic agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressant agents and pain-relieving agents.
30 . The method of claim 24 , wherein selective transcriptional CDKs are CDK7, CDK9, CDK12, CDK13 or CDK 18.
31 - 32 . (canceled)Cited by (0)
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