US2017320867A1PendingUtilityA1
Heteroaromatic compounds as btk inhibitors
Est. expiryAug 10, 2032(~6.1 yrs left)· nominal 20-yr term from priority
Inventors:Joerg BentzienAngela BerryTodd BosanacMichael J. BurkeDarren DisalvoJoshua Courtney HoranShuang LiangCan MaoWang MaoYue ShenFariba SoleymanzadehRenee M. Zindell
A61P 43/00A61P 35/02A61P 37/08A61P 37/06A61P 27/02A61P 29/00A61P 11/00A61P 17/00A61P 17/04A61P 11/06A61P 19/00A61P 19/02A61P 11/02A61P 1/04C07D 231/38C07D 401/14C07D 403/06C07D 417/04C07D 413/14C07D 277/56C07D 401/04C07D 417/06C07D 403/08C07D 231/14C07D 231/40C07D 417/08C07D 403/04C07D 401/06C07D 405/14C07D 417/02C07D 401/02A61K 31/4439
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Claims
Abstract
The present invention encompasses compounds of the formula (I) wherein the groups A, Cy, X1 and Y are defined herein, which are suitable for the treatment of diseases related to BTK, process of making, pharmaceutical preparations which contain compounds and their methods of use.
Claims
exact text as granted — not AI-modified1 . A compound of the formula (I)
wherein
A ring is:
R 1 is N(R 3 ) 2 or hydrogen;
Cy is aryl or heteroaryl each is substituted by R 2 and optionally substituted by halogen, halo C 1 alkyl, C 1-4 alkyl and C 1-4 alkoxy;
R 2 is chosen from:
L-Ar, C 1-6 alkyl and C 1-6 alkoxy, each Ar, C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by halogen, halo C 1-4 alkyl, C 1 alkyl, R 3 —S(O) m —, —CN, —C(O)—N(R 3 ) 2 or C 1-4 alkoxy;
L is a linker chosen from a bond, O, >C(O), —(CH 2 ) n —, —O—(CH 2 ) n —, —N(R 3 )—, —N(R 3 )—(CH 2 ) n —, —(CH 2 ) n —N(R 3 )—, —C(O)—N(R 3 )—, —C(O)—N(R 3 )—(CH 2 ) n —, —N(R 3 )—C(O)—N(R 3 )—, —N(R 3 )—C(O)—, —S(O) m —N(R 3 )— and —N(R 3 )—S(O) m —, wherein the —CH 2 — in each L can have 1-2 hydrogens replaced by C 1-3 alkyl, said C 1-3 alkyl groups can optionally cyclize to form a C 3-6 cycloalkyl ring;
Ar is carbocycle, heterocycyl or heteroaryl;
X 1 is a linker chosen from a bond, —(CH 2 ) n —;
Y is chosen from C 7 -C 10 spirocycle optionally containing 0-1 ring nitrogen atoms, a nitrogen containing mono- or bi-cyclic heterocycle, carbocycle, aryl, each substituted by one R 4 ;
R 4 is
wherein R 5 cannot be hydrogen,
each n is independently 1-4;
each m is independently 0-2;
each R 3 is independently chosen from hydrogen or C 1-4 alkyl;
each R 5 is independently chosen from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylC 1-4 alkoxy, —(CH 2 ) n -heterocycle and heterocycle each heterocycle optionally substituted by halogen, OH or R 3 —S(O) m —;
each group defined above for Cy, R 1 -R 5 , X 1 and Y can be where possible partially or fully halogenated;
or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 and wherein
A ring is:
or a pharmaceutically acceptable salt thereof.
3 . The compound according to claim 2 and wherein
Cy is phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl each is substituted by R 2 and optionally substituted by F, Cl or C 1-4 alkoxy;
R 2 is chosen from:
L-Ar and C 1-3 alkoxy, each Ar and C 1-3 alkoxy are optionally substituted by F, Cl, C 1-4 alkyl, R 3 —S(O) 2 —, —CN, —C(O)—NH(R 3 ) or C 1-3 alkoxy;
L is a linker chosen from a bond, O, >C(O), —CH 2 —, —O—CH 2 —, —NH—, —NH—CH 2 —, —CH 2 —NH—, —C(O)—NH—CH 2 —, —NH—C(O)—NH— and —N(R 3 )—S(O) m —;
Ar is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazolyl, piperidinyl, piperazinyl or pyrrolidinyl
or a pharmaceutically acceptable salt thereof.
4 . The compound according to claim 3 and wherein
Cy is phenyl or pyridinyl, each is substituted by R 2 and optionally substituted by F, Cl or C 1-2 alkoxy;
R 2 is chosen from:
L-Ar and C 1-3 alkoxy, each Ar and C 1-3 alkoxy are optionally substituted by F, Cl, C 1-4 alkyl, CH 3 —S(O) 2 —, —CN, —C(O)—NH(R 3 ) or C 1-2 alkoxy;
L is a linker chosen from a bond, O, >C(O), —CH 2 —, —O—CH 2 —, —NH—, —NH—CH 2 —, —CH 2 —NH—, —C(O)—NH—CH 2 —, —NH—C(O)—NH— and —N(R 3 )—S(O) m —;
Ar is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazolyl or piperidinyl
or a pharmaceutically acceptable salt thereof.
5 . The compound according to claim 4 and wherein
Cy is phenyl or pyridinyl, each is substituted by R 2 and optionally substituted by F, Cl or C 1-2 alkoxy;
R 2 is chosen from:
L-Ar and C 1-3 alkoxy, each Ar and C 1-3 alkoxy are optionally substituted by F, Cl, C 1-4 alkyl, CH 3 —S(O) 2 —, —CN, —C(O)—NH(CH 3 ) or C 1-2 alkoxy;
L is a linker chosen from a bond, O, >C(O), —CH 2 —, —O—CH 2 —, —NH—, —NH—CH 2 —, —CH 2 —NH—, —C(O)—NH—CH 2 —, —NH—C(O)—NH— and —N(H)—S(O) 2 —;
Ar is phenyl, pyridinyl, benzoxazolyl or piperidinyl
or a pharmaceutically acceptable salt thereof.
6 . The compound according to claim 5 and wherein
X 1 is a linker chosen from a bond and —(CH 2 ) n —;
Y is chosen from:
a spirocycle chosen from
a heterocycle chosen from piperidinyl and pyrrolidinyl;
and phenyl each heterocycle or phenyl substituted by one R 4 ;
R 4 is
wherein R 5 cannot be hydrogen,
each R 4 is optionally halogenated;
each R 5 is independently chosen from hydrogen, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkylC 1-3 alkoxy, —CH 2 -heterocycle and heterocycle each heterocycle optionally substituted by F, Cl, OH and CH 3 —S(O) 2 — and each heterocycle chosen from pyrrolidinyl, piperidinyl, morpholinyl and 1,4-oxazepane,
or a pharmaceutically acceptable salt thereof.
7 . The compound according to claim 6 and wherein
X 1 is a linker chosen from a bond and —(CH 2 ) n —;
Y is chosen from:
a spirocycle chosen from
a heterocycle chosen from piperidinyl and pyrrolidinyl;
and phenyl each heterocycle or phenyl substituted by one R 4 ;
R 4 is
each R 5 is independently chosen from hydrogen, C 1-3 alkyl, —CF 3 , C 1-3 alkylC 1-3 alkoxy, —CH 2 -heterocycle and heterocycle each heterocycle optionally substituted by F, Cl, OH and CH 3 —S(O) 2 — and each heterocycle chosen from pyrrolidinyl, piperidinyl and 1,4-oxazepane,
or a pharmaceutically acceptable salt thereof.
8 . The compound according to claim 1 and wherein
Cy is
or a pharmaceutically acceptable salt thereof.
9 . The compound according to claim 8 and wherein
X—Y=
or a pharmaceutically acceptable salt thereof.
10 . The compound according to claim 9 and wherein
A ring is:
or a pharmaceutically acceptable salt thereof.
11 . The compound according to claim 9 and wherein
A ring is:
or a pharmaceutically acceptable salt thereof.
12 . The compound according to claim 9 and wherein
A ring is:
or a pharmaceutically acceptable salt thereof.
13 . The compound according to claim 9 and wherein
A ring is:
or a pharmaceutically acceptable salt thereof.
14 . The compound according to claim 2 and wherein
R 2 is
L-Ar;
L is a linker chosen from a bond, 0, and —O—(CH 2 ) n —;
n is 1-3;
Ar is carbocycle or heterocycle.
15 . The compound according to claim 14 and wherein
Ar is C 3-5 cycloalkyl or tetrahydrofuranyl;
n=1.
16 . The compound according to claim 15 and wherein
L-Ar is
17 . The compound according to claim 2 and wherein
R 2 is:
18 . A compound chosen from:
or the pharmaceutically acceptable salts thereof.
19 . A compound chosen from:
or the pharmaceutically acceptable salts thereof.
20 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
21 . A method of treating a disease chosen from rheumatoid arthritis, systemic lupus erythromatosis, scleroderma, asthma, allergic rhinitis, allergic eczema, B cell lymphoma, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, graft versus host disease, psoriatic arthritis, ankylosing spondylitis and uveitis, comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.Cited by (0)
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