US2014038935A1PendingUtilityA1
Dihydrodiazepines useful as inhibitors of protein kinases
Est. expiryFeb 14, 2026(expired)· nominal 20-yr term from priority
A61P 43/00A61P 37/06A61P 35/02A61P 35/00A61P 37/02A61P 37/00A61P 37/08A61P 25/28A61P 25/00A61P 29/00C07D 487/14A61K 31/551C07D 487/04A61P 11/00A61K 45/06A61K 31/4545C07D 401/12
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Claims
Abstract
The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of formula I:
wherein
X 1 is a bond, O, NR 8 , S, SO, or SO 2 ;
Y 1 is O or NR 9 ;
R 1 is H, C 1-10 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; wherein said R 1 is optionally substituted with 0-5 J 1 ; provided that when X 1 is a bond, R 1 is not H;
R 2 is H, C 1-10 aliphatic, —(C 1-10 aliphatic)-(C 3-10 cycloaliphatic), C 3-8 cycloaliphatic, haloC 1-4 aliphatic; wherein said R 2 is optionally substituted with 0-4 J 2 ;
each R 3 , R 4 , R 5 , and R 6 is independently H, C 1-10 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, or 5-10 membered heteroaryl; wherein each R 3 , R 4 , R 5 , and R 6 is optionally and independently substituted with 0-5 J 3 , J 4 , J 5 , and J 6 respectively; and
R 7 is H, C(O)R, C(O) OR, or C(O)NRR′, C 1-10 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, —(C 1-6 aliphatic)-(C 3-10 cycloaliphatic), —(C 1-6 aliphatic)-(C 6-10 aryl), or (C 1-6 aliphatic)-(5-10 membered heteroaryl), or (C 1-6 aliphatic)-(3-6 membered heterocyclyl; wherein said R 7 is optionally substituted with 0-5 J 7 ; or
R 3 and R 4 , together with the carbon atom to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R 3 and R 4 is optionally substituted with 0-4 J 34 ;
R 5 and R 6 , together with the carbon atom to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R 5 and R 6 is optionally substituted with 0-4 J 56 ;
R 3 and R 5 , together with the carbon atoms to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R 3 and R 5 is optionally substituted with 0-4 J 35 ;
R 3 and R 7 , together with the atoms to which they are attached, optionally form a 4-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R 3 and R 7 is optionally substituted with 0-4 J 37 ;
R 5 and R 7 , together with the atoms to which they are attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R 5 and R 7 is optionally substituted with 0-4 J 57 ;
R 3 is H, C 1-6 aliphatic, C 3-8 cycloaliphatic, C(O)R, C(O)OR, or C(O)NRR′;
R 9 is H or unsubstituted C 1-6 aliphatic; or
R 2 and R 9 , together with the atoms to which they are attached, optionally form a 5-8 membered aromatic or nonaromatic monocyclic ring containing 2-4 heteroatoms independently selected from O, N, and S; said monocyclic ring formed by R 2 and R 9 is optionally substituted with 0-4 J 29 ;
each J 1 is independently C 1-6 haloalkyl, halo, NO 2 , CN, Q, or —Z-Q; or, two J 1 taken together can optionally form ═O;
Z is C 1-6 aliphatic optionally replaced with 0-3 occurrences of —NR—, —O—, —S—, —C(O)—, —C(═NR)—, —C(═NOR)—, —SO—, or —SO 2 —; each Z is optionally substituted with 0-2 J z ;
Q is H; C 1-6 aliphatic; a 3-8-membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N, and S; or an 7-12 membered aromatic or nonaromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N, and S; each Q is optionally substituted with 0-5 J Q ;
each J 2 is halo or haloC 1-4 aliphatic;
each J 3 , J 4 , J 5 , and J 6 is independently C 1-6 aliphatic, C 3-6 cycloaliphatic, or —(C 1-4 alkyl) n -V 1 ; wherein
n is 0 or 1;
V 1 is halo(C 1-4 aliphatic), —O(haloC 1-4 aliphatic), halo, NO 2 , CN, OH, OR″, SH, SR″, NH 2 , NHR″, N(R″) 2 , COH, COR″, CO 2 H, CO 2 R″, CONH 2 , CONHR″, CONR″ 2 , OCOR″, OCONH 2 , OCONHR″, OCON(R″) 2 , NHCOR″, NR″COR″, NHCO 2 R″, NR″CO 2 R″, NHCO 2 H, NR″CO 2 H, NHCONH 2 , NHCONHR″, NHCON(R″) 2 , SO 2 NH 2 , SO 2 NHR″, SO 2 N(R″) 2 , NHSO 2 R″, NR″SO 2 R″;
or V 1 is a cyclic group selected from C 3-6 cycloaliphatic, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl; wherein said cyclic group is optionally substituted with 0-3 J V ;
R″ is unsubstituted C 1-4 aliphatic;
or two of the same J 3 , J 4 , J 5 , or J 6 , bonded to the same atom, together can optionally form ═O;
each J Z and J V is independently halo, C 1-6 aliphatic, C 3-6 cycloaliphatic, NO 2 , CN, —NH 2 , —NH(C 1-4 aliphatic), —N(C 1-4 aliphatic) 2 , —OH, —O(C 1-4 aliphatic), —CO 2 H, —CO 2 (C 1-4 aliphatic), —O(haloC 1-4 aliphatic), or halo(C 1-4 aliphatic);
each J Q , J 7 , J 29 , J 34 , J 56 , J 35 , J 37 , and J 57 is independently M or —Y-M;
each Y is independently an unsubstituted C 1-6 aliphatic optionally replaced with 0-3 occurrences of —NR—, —O—, —S—, —C(O)—, —SO—, or —SO 2 —;
each M is independently H, C 1-6 aliphatic, C 3-6 cycloaliphatic, halo(C 1-4 aliphatic), —O(haloC 1-4 aliphatic), 3-6 membered heterocyclyl, C 6-10 aryl, halo, NO 2 , CN, OH, OR′, SH, SR′, NH 2 , NHR′, N(R′) 2 , COH, COR′, CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR′ 2 , OCOR′, OCONH 2 , OCONHR′, OCON(R′) 2 , NHCOR′, NR′COR′, NHCO 2 R′, NR′CO 2 R′, NHCO 2 H, NR′ CO 2 H, NHCONH 2 , NHCONHR′, NHCON(R′) 2 , SO 2 NH 2 , SO 2 NHR′, SO 2 N(R′) 2 , NHSO 2 R′, or NR′SO 2 R′, or two M taken together can optionally form ═O;
R is H or unsubstituted C 1-6 aliphatic;
R′ is unsubstituted C 1-6 aliphatic; or two R′ groups, together with the atom to which they are bound, form an unsubstituted 3-8 membered saturated or partially unsaturated monocyclic ring having 0-1 heteroatoms independently selected from O, N, and S.
2 . The compound of claim 1 , wherein:
R 1 is H, C 1-10 aliphatic, C 6-10 aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; wherein said R 1 is optionally substituted with 0-5 J 1 ; provided that when X 1 is a bond, R 1 is not H; R 7 is H, C(O)R, C(O)OR, or C(O)NRR′, C 1-10 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, —(C 1-6 aliphatic)-(C 3-10 cycloaliphatic), —(C 1-6 aliphatic)-(C 6-10 aryl), or —(C 1-6 aliphatic)-(5-10 membered heteroaryl); wherein said R 7 is optionally substituted with 0-5 J 7 ; Q is H; C 1-6 aliphatic; a 3-8-membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms independently selected from O, N, and S; or an 8-12 membered aromatic or nonaromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N, and S; each Q is optionally substituted with 0-5 J Q ; and each M is independently H, C 1-6 aliphatic, C 3-6 cycloaliphatic, halo(C 1-4 aliphatic), —O(haloC 1-4 aliphatic), 3-6 membered heterocyclyl, halo, NO 2 , CN, OH, OR′, SH, SR′, NH 2 , NHR′, N(R′) 2 , COH, COR′, CO 2 H, CO 2 R′, CONH 2 , CONHR′, CONR′ 2 , OCOR′, OCONH 2 , OCONHR′, OCON(R′) 2 , NHCOR′, NR′COR′, NHCO 2 R′, NR′CO 2 R′, NHCO 2 H, NR′CO 2 H, NHCONH 2 , NHCONHR′, NHCON(R′) 2 , SO 2 NH 2 , SO 2 NHR′, SO 2 N(R′) 2 , NHSO 2 R′, or NR′ SO 2 R′.
3 . The compound of claim 1 or claim 2 , wherein X 1 is NR B .
4 . The compound of any one of claims 1 - 3 , wherein Y 1 is O.
5 . The compound of any one of claims 1 - 4 , wherein R 1 is C 6-10 aryl or 5-10 membered heteroaryl, wherein R 1 is substituted with 0-5 J 1 .
6 . The compound of any one of claims 1 - 5 , wherein R 2 is C 1-10 aliphatic or C 3-10 cycloaliphatic, wherein R 2 is substituted with 0-4 J 2 .
7 . The compound of any one of claims 1 - 6 , wherein R 2 —CH 3 .
8 . The compound of any one of claims 1 - 7 , wherein R 3 and R 4 , together with the carbon atom to which they are attached, form a 3-6 membered monocyclic ring substituted with 0-5 R 3 or R 4 .
9 . The compound of any one of claim 1 - 7 , wherein R 3 and R 5 , together with the carbon atoms to which they are attached, form a 3-6 membered monocyclic ring substituted with 0-5 R 3 or R 5 .
10 . The compound of any one of claim 1 - 7 , wherein each R 3 , R 4 , R 5 , and R 6 is independently a group selected from H, C 1-10 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, or 5-10 membered heteroaryl, wherein each R 3 , R 4 , R 5 , and R 6 is independently substituted with 0-5 J 3 , J 4 , J 5 , and J 6 , respectively.
11 . The compound of any one of claims 1 - 7 , wherein each R 3 and R 4 is independently H, C 1-6 aliphatic, or C 3-8 cycloaliphatic, wherein each R 3 and R 4 is independetly substituted with 0-5 J 3 and J 4 , respectively.
12 . The compound of any one of claims 1 - 7 , wherein one of R 3 and R 4 is H and the other is C 1-6 aliphatic or C 3-8 cycloaliphatic wherein the R 3 and R 4 that is not H is independently substituted with 0-5 J 3 and J 4 , respectively.
13 . The compound any one of claims 1 - 12 , wherein each J 3 and J 4 is independently halo.
14 . The compound of any one of claims 1 - 8 and 11 - 13 , wherein R 5 and R 7 , together with the atoms to which they are attached, form a 3-6 membered saturated or partially unsaturated monocyclic ring substituted with 0-5 J 5 or J 7
15 . The compound of any one of claims 1 - 13 , wherein R 7 is a group selected from C 1-10 aliphatic, C 3-10 cycloaliphatic, C 6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, wherein R 7 is substituted with 0-5 J 7 .
16 . The compound of any one of claims 1 - 13 , wherein R 7 is a group selected from C 1-10 aliphatic, C 3-8 cycloaliphatic, phenyl, a 5-membered heteroaryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,5-pyridazinyl, 3,5-pyrimidyl, and a 3-8 membered heterocyclyl, wherein R 7 is substituted with 0-5 J 7 .
17 . The compound of any one of claims 1 - 13 , wherein R 7 is not 3-amino-2,4-pyrimidine.
18 . The compound of any one of claims 1 - 13 , wherein R 7 is a group selected from C 3-6 alkyl, C 3-6 cycloalkyl, phenyl, or 5-6 membered heterocyclyl, wherein the heterocyclyl contains 1 oxygen heteroatom and wherein R 7 is substituted with 0-5 J 7 .
19 . The compound of any one of claims 1 - 13 , wherein R 7 is a C 4-5 cycloalkyl, wherein R 7 is substituted with 0-5 J 7 .
20 . The compound of any one of claims 1 - 13 , wherein R 7 is C 4-5 cycloalkyl substituted with 1 or 2-F.
21 . The compound of any one of claims 1 - 13 , wherein R 7 is an unsubstituted C 4-5 cycloalkyl.
22 . The compound of any one of claims 1 - 13 , wherein R 7 is cyclopentyl substituted with 0-5 J 7 .
23 . The compound of any one of claims 1 - 13 , wherein R 7 is cyclopentyl substituted with 1 or 2-F.
24 . The compound of any one of claims 1 - 13 , wherein R 7 is an unsubstituted cyclopentyl.
25 . The compound of any one of claims 1 - 24 , wherein R 8 is H.
26 . The compound of claim 1 or claim 2 , represented by formula II;
wherein
R 1 is optionally substituted C 6-10 aryl or optionally substituted 5-10 membered heteroaryl;
R 2 is H or an optionally substituted group selected from C 1-10 aliphatic and C 3-10 cycloaliphatic;
each R 3 , R 4 , R 5 , and R 6 is independently H, i C 1-10 aliphatic, or C 3-10 cycloaliphatic; wherein each R 3 , R 4 , R 5 , and R 6 is optionally substituted with 0-5 J 3 , J 4 , J 5 , and J 6 respectively; or
R 3 and R 4 , together with the carbon atom to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;
R 3 and R 5 , together with the carbon atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;
R 5 and R 7 , together with the atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;
R 2 and R 9 , together with the atoms to which they are attached, can form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.
27 . The compound of claim 1 or claim 2 , represented by formula III;
wherein
R 1 is optionally substituted C 6-10 aryl or optionally substituted 5-10 membered heteroaryl;
R 2 is H or an optionally substituted group selected from C 1-10 aliphatic and C 3-10 cycloaliphatic;
each R 3 , R 4 , R 5 , and R 6 is independently H, i C 1-10 aliphatic, or C 3-10 cycloaliphatic; wherein each R 3 , R 4 , R 5 , and R 6 is optionally substituted with 0-5 J 3 , J 4 , J 5 , and J 6 respectively; or
R 3 and R 4 , together with the carbon atom to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;
R 3 and R 5 , together with the carbon atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;
R 5 and R 7 , together with the atoms to which they are attached, can form an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic ring;
R 2 and R 9 , together with the atoms to which they are attached, can form an optionally substituted 5-8 membered saturated or partially unsaturated monocyclic ring.
28 . The compound according to any one of claims 1 - 27 , wherein
each J 3 , J 4 , J 5 , and J 6 is independently C 1-6 aliphatic, C 3-6 cycloaliphatic, or —(C 2-4 alkyl) n -V 1 ; wherein
n is 0 or 1;
V 1 is halo(C 2-4 aliphatic), —O(haloC 2-4 aliphatic), halo, NO 2 , CN, OH, OR″, SH, SR″, NH 2 , NHR″, N(R″) 2 , COH, COR″, CO 2 H, CO 2 R″, CONH 2 , CONHR″, CONR″ 2 , OCOR″, OCONH 2 , OCONHR″, OCON(R″) 2 , NHCOR″, NR″COR″, NHCO 2 R″, NR″CO 2 R″, NHCO 2 H, NR″CO 2 H, NHCONH 2 , NHCONHR″, NHCON(R″) 2 , SO 2 NH 2 , SO 2 NHR″, SO 2 N(R″) 2 , NHSO 2 R″, NR″SO 2 R″;
R″ is unsubstituted C 1-4 aliphatic;
or two of the same J 3 , J 4 , J 5 , or J 6 , bonded to the same atom, together can optionally form ═O.
29 . A compound selected from the following:
30 . A compound selected from the following:
31 . A composition comprising a compound of any one of claims 1 - 30 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
32 . A method of inhibiting protein kinase activity in a patient comprising administering to said patient
a) a composition of claim 31 ; or b) a compound of any one of claims 1 - 30 .
33 . A method of inhibiting protein kinase activity in a biological sample comprising contacting said biological sample with:
a) a composition of claim 31 ; or b) a compound of any one of claims 1 - 30 .
34 . The method of claim 32 or claim 33 , wherein said protein kinase is PLK.
35 . The method of claim 34 , wherein said protein kinase is PLK1.
36 . A method of treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to a patient:
a) a composition of claim 31 ; or b) a compound of any one of claims 1 - 30 .
37 . The method according to claim 36 , comprising administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:
a) said additional therapeutic agent is appropriate for the disease being treated; and b) said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
38 . A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient wherein said method comprises administering to said patient
a) a composition of claim 31 ; or b) a compound of any one of claims 1 - 30 .
39 . A method of treating cancer in a patient wherein said method comprises administering to said patient
a) a composition of claim 31 ; or b) a compound of any one of claims 1 - 30 .
40 . The method of claim 39 , wherein said method comprises the step of disrupting mitosis of the cancer cells by inhibiting PLK with:
a) a composition of claim 31 ; or b) a compound of any one of claims 1 - 30 .
41 . A process for preparing a compound of formula I:
wherein
Y 1 is O and X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined according to any one of claims 1 - 30 ;
comprising reacting a compound of formula 5;
wherein
R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined according to any one of claims 1 - 29 ; and LG 2 is a suitable leaving group;
with X 1 R 1 under suitable conditions to form the compound of formula I.
42 . The process of claim 41 , further comprising the step of reacting a compound of formula 4;
wherein R 3 , R 4 , R 5 , R 6 , and R 7 are as defined according to any one of claims 1 - 29 ; and LG 2 is a suitable leaving group;
with R 2 -LG 3 , wherein LG 3 is a leaving group capable of being displaced by an NH-amide; to form the compound of formula 5.
43 . The process of claim 42 , further comprising cyclizing a compound of formula 3-a;
wherein LG 2 is a suitable leaving group and R 3 , R 4 , R 5 , R 6 , and R 7 are as defined according to any one of claims 1 - 29 ;
under cyclo-condensation conditions to form a compound of formula 4.
44 . The process of claim 43 , further comprising the step reacting a compound of formula 3;
wherein LG 2 is a suitable leaving group and R 3 , R 4 , R 5 , R 6 , and R 7 are as defined according to any one of claims 1 - 29 ;
under suitable reduction conditions to form a compound of formula 3-a.
45 . The process of claim 43 , further comprising
a) functionalizing the amino group in the compound of formula 3-a under suitable conditions to form a compound of formula 3-b;
wherein LG 2 is a suitable leaving group and R 3 , R 4 , R 5 , R 6 , and R 7 are as defined according to any one of claims 1 - 29 ;
b) cyclizing the compound of formula 3-b under suitable cyclo-condensation conditions to form a compound of formula 4.
46 . The process of claim 44 , further comprising reacting a compound of formula 2;
wherein R 3 , R 4 , R 5 , R 6 , and R 7 are as defined according to any one of claims 1 - 29 ;
with a compound of formula 1;
wherein LG 2 and LG 2 are each independently suitable leaving groups;
under suitable displacement conditions to form the compound of formula 3.
47 . A process for preparing a compound of formula I:
wherein Y 1 is NR 9 and X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined herein;
comprising reacting the compound of formula I wherein Y 1 is O and X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , amd R 7 are defined herein;
under suitable conditions known in the art for converting amides into amidines, to form a compound of formula I wherein Y 1 is NR 9 .
48 . A process for preparing a compound of formula 5-a:
wherein LG 2 is a suitable leaving group and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 9 are as defined according to any one of claims 1 - 29 ;
comprising reacting a compound of formula 5
wherein LG 2 is a suitable leaving group and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined according to any one of claims 1 - 29 ;
under suitable conditions known in the art for converting amides into amidines, to form a compound of formula 5-a.
49 . The process of claim 48 , further comprising displacing LG 2 with X 1 R 1 to form a compound of formula I wherein Y 1 is NR 9 and X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined herein.
50 . The process of any one of claims 47 - 48 , wherein R 2 and R 9 are taken together to form Ring A, and wherein suitable conditions known in the art for converting amides into amidines comprise a multi-step cyclisation sequence to form ring A.Join the waitlist — get patent alerts
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