C-linked heterocycloaklyl substituted pyrimidines and their uses

Patent metadata

Field	Value
Publication number	US-9868720-B2
Application number	US-201514928034-A
Country	US
Kind code	B2
Filing date	Oct 30, 2015
Priority date	May 1, 2013
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

In Formula I-I in which R1, R2, R3, R4, R5, R6, m, n and the “het” ring are as described herein. Also provided are pharmaceutical compositions comprising compounds of Formula I and methods of using such compounds and compositions.

First claim

We claim:

1. Compounds of formula (I)

wherein
R 1 is selected from the group consisting of C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, —OR 1a , —SR 1a , —N(H)(R 1a ), and —N(R 1a )(R 1b ) wherein R 1a and R 1b are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, and wherein the aliphatic and aromatic portions of R 1 are independently further substituted with 0 to 5 R A1 substituents selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —CF 3 , ═O, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 heteroalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 dialkylamino, R 1c —C(═O)—, R 1c —C(═O)N(H)—, R 1c —C(═O)N(R 1d )—, R 1c —C(═O)O—, R 1c —S(O) 1-2 —, R 1c —S(O) 1-2 N(R 1d )—, R 1c —S(O) 1-2 N(H)—, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl, wherein R 1c is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 5-6 heteroaryl, 3-7 membered heterocycloalkyl, phenyl and 3-6 membered cycloalkyl, R 1d is selected from the group consisting of hydrogen, C 1-3 alkyl and C 1-3 haloalkyl, and wherein said 5-6 membered heteroaryl, phenyl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl of a R A1 substituent are substituted with from 0-4 substituents selected from —F, —Cl, —Br, I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —CF 3 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino and C 1-4 dialkylamino;
R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
R 3 is selected from the group consisting of —F, —Cl, —Br, —I, —(X 3 ) 0-1 —CN, —(X 3 ) 0-1 —NO 2 , —(X 3 ) 0-1 —SF 5 , —(X 3 ) 0-1 -OH, —(X 3 ) 0-1 —NH 2 , —(X 3 ) 0-1 —N(H)(R 3a ), —(X 3 ) 0-1 —N(R 3b )(R 3a ), —(X 3 ) 0-1 —CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylthio, —(X 3 ) 0-1 -3-7 membered cycloalkyl, —(X 3 ) 0-1 -3-7 membered heterocycloalkyl, —(X 3 ) 0-1 -5-6 membered heteroaryl, —(X 3 ) 0-1 —C 6 aryl, —(X 3 ) 0-1 —C(═Y 3 )N(H)(R 3a ), —(X 3 ) 0-1 —C(═Y 3 )NH 2 , —(X 3 ) 0-1 —C(═Y 3 )N(R 3a )(R 3b ), —(X 3 ) 0-1 —C(═Y 3 )OR 3a , —(X 3 ) 0-1 —C(═Y 3 )OH, —(X 3 ) 0-1 —N(H)C(═Y 3 )(R 3a ), —(X 3 ) 0-1 —N(R 3b )C(═Y 3 )(R 3a ), —(X 3 ) 0-1 —N(H)C(═Y 3 )OR 3a , —(X 3 ) 0-1 —N(R 3b )C(═Y 3 )OR 3a , —(X 3 ) 0-1 —S(O) 1-2 R 3a , —(X 3 ) 0-1 —N(H)S(O) 1-2 R 3a , —(X 3 ) 0-1 —N(R 3b )S(O) 1-2 R 3a , —(X 3 ) 0-1 —S(O) 0-1 N(H)(R 3a ), —(X 3 ) 0-1 —S(O) 0-1 N(R 3b )(R 3a ), —(X 3 ) 0-1 —S(O) 0-1 —NH 2 , —(X 4 ) 0-1 —S(═O)(═NR 3b )R 3a , —(X 3 ) 0-1 —C(═Y 3 )R 3a , —(X 3 ) 0-1 —C(═Y 3 )H, —(X 3 ) 0-1 —C(═NOH)R 3a , —(X 3 ) 0-1 —C(═NOR 3b )R 3a , —(X 3 ) 0-1 —NHC(═Y 3 )N(H)(R 3a ), —(X 3 ) 0-1 —NHC(═Y 3 )NH 2 , —(X 3 ) 0-1 —NHC(═Y 3 )N(R 3b )(R 3a ), —(X 3 ) 0-1 —N(R 3a )C(═Y 3 )N(H)(R 3a ), —(X 3 ) 0-1 —N(R 3a )C(═Y 3 )NH 2 , —(X 3 ) 0-1 —OC(═Y 3 )R 3a , —(X 3 ) 0-1 —OC(═Y 3 )H, —(X 3 ) 0-1 —OC(═Y 3 )OR 3a , —(X 3 ) 0-1 —OP(═Y 3 )(OR 3a )(OR 3b ), —(X 3 )—SC(═Y 3 )OR 3a and —(X 3 )—SC(═Y 3 )N(R 3a )(R 3b ) wherein X 3 is selected from the group consisting of C 1-4 alkylene, C 1-4 haloalkylene, C 1-4 heteroalkylene, C 2-4 alkenylene, and C 2-4 alkynylene, R 3a and R 3b are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkyl-C 1-4 alkyl, 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl-C 1-4 alkyl, C 6 aryl, C 6 aryl-C 1-4 alkyl and benzyl; Y 3 is O, NR 3d or S wherein R 3d is hydrogen or C 1-6 alkyl; wherein aliphatic or aromatic portion of R 3 is independently further substituted with from 0 to 4 R A3 substituents selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO 2 , —SF 5 , —OH, —NH 2 , —CF 3 , ═O, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, —C(═O)N(H)(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —C(═O)NH 2 , —C(═O)OC 1-6 alkyl, —C(═O)OH, —N(H)C(═O)(C 1-6 alkyl), —N(C 1-6 alkyl)C(═O)(C 1-6 alkyl), —N(H)C(═O)OC 1-6 alkyl, —N(C 1-6 alkyl)C(═O)OC 1-6 alkyl, —S(O) 1-2 C 1-6 alkyl, —N(H)S(O) 1-2 C 1-6 alkyl, —N(C 1-6 alkyl)S(O) 1-2 C 1-6 alkyl, —S(O) 0-1 N(H)(C 1-6 alkyl), —S(O) 0-1 N(C 1-6 alkyl) 2 , —S(O) 0-1 NH 2 , —C(═O)C 1-6 alkyl, —C(═NOH)C 1-6 alkyl, —C(═NOC 1-6 alkyl)C 1-6 alkyl, —NHC(═O)N(H)(C 1-6 alkyl), —NHC(═O)N(C 1-6 alkyl) 2 , —NHC(═O)NH 2 , —N(C 1-6 alkyl)C(═O)N(H)(C 1-6 alkyl), —N(C 1-6 alkyl)C(═O)NH 2 , —OC(═O)C 1-6 alkyl, —OC(═O)OC 1-6 alkyl, —OP(═O)(OC 1-6 alkyl) 2 , —SC(═O)OC 1-6 alkyl and —SC(═O)N(C 1-6 alkyl) 2 ; alternatively any two R 3 substituents located on adjacent atoms are optionally combined to form a 5-6 membered heteroaryl ring comprising 1-2 heteroatoms selected from N, O and S and further comprising 0 to 4 R 3a substituents;
m is an integer from 0 to 4;
the ring represented by the structure

is a 4 to 10 membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S, wherein said 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3 R 4 groups;
R 4 is selected from the group consisting of —F, —Cl, —Br, —I, —(X 4 ) 0-1 —CN, —(X 4 ) 0-1 —NO 2 , —(X 4 ) 0-1 —SF 5 , —(X 4 ) 0-1 —OH, —(X 4 ) 0-1 —NH 2 , —(X 4 ) 0-1 —N(H)(R 4a ), (X 4 ) 0-1 N(R 4b )(R 4a ), —(X 4 ) 0-1 —CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylthio, —(X 4 ) 0-1 -(3-10 membered heterocycloalkyl), —(X 4 ) 0-1 -(5-10 membered heteroaryl), —(X 4 ) 0-1 -(3-7 membered cycloalkyl), —(X 4 ) 0-1 —C(═Y 4 )N(H)(R 4a ), —(X 4 ) 0-1 —C(═Y 4 )NH 2 , —(X 4 ) 0-1 —C(═Y 4 )N(R 4a )(R 4b ), —(X 4 ) 0-1 —C(═Y 4 )OR 4a , —(X 4 ) 0-1 —C(═Y 4 )OH, —(X 4 ) 0-1 —N(H)C(═Y 4 )(R 4a ), —(X 4 ) 0-1 —N(R 4b )C(═Y 4 )(R 4a ), —(X 4 ) 0-1 —N(H)C(═Y 4 )OR 4a , —(X 4 ) 0-1 —N(R 4b )C(═Y 4 )OR 4 , —(X 4 ) 0-1 —S(O) 1-2 R 4a , —(X 4 ) 0-1 —N(H)S(O) 1-2 R 4a , —(X 4 ) 0-1 —N(R 4b )S(O) 1-2 R 4a , —(X 4 ) 0-1 —S(O) 0-1 N(H)(R 4a ), —(X 4 ) 0-1 —S(O) 0-1 N(R 4b )(R 4a ), —(X 4 ) 0-1 —S(O) 0-1 NH 2 , —(X 4 ) 0-1 —S(═O)(═NR 4b )R 4a , —(X 4 ) 0-1 —C(═Y 4 )R 4a , —(X 4 ) 0-1 —C(═Y 4 )H, —(X 4 ) 0-1 —C(═NOH)R 4a , —(X 4 ) 0-1 —C(═NOR 4b )R 4a , —(X 4 ) 0-1 —NHC(═Y 4 )N(H)(R 4a ), —(X 4 ) 0-1 —NHC(═Y 4 )NH 2 , —(X 4 ) 0-1 —NHC(═Y 4 )N(R 4b )(R 4a ), —(X 4 ) 0-1 —NR 4a C(═Y 4 )N(H)(R 4a ), —(X 4 ) 0-1 —N(R 4a )C(═Y 4 )NH 2 , —(X 4 ) 0-1 —OC(═Y 4 )R 4a , —(X 4 ) 0-1 —OC(═Y 4 )H, —(X 4 ) 0-1 —OC(═Y 4 )OR 4a , —(X 4 ) 0-1 —OP(═Y 4 )(OR 4a )(OR 4b ), —SC(═Y 4 )OR 4a and —SC(═Y 4 )N(R 4a )(R 4b ) wherein R 4a and R 4b at each occurrence are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, 6-10 membered aryl, 3-7 membered cycloalkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, 6-10 membered aryl-C 1-4 alkyl, 3-7 membered cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl and 3-7 membered heterocycloalkyl-C 1-4 alkyl, and X 4 is selected from the group consisting of C 1-4 alkylene, C 1-4 haloalkylene, C 1-4 heteroalkylene, C 2-4 alkenylene and C 2-4 alkynylene; Y 4 is O, NR 4c or S wherein R 4c is hydrogen or C 1-6 alkyl; wherein the aromatic and aliphatic portions of R 4 is independently further substituted with 0 to 4 R A4 substituents selected from the group consisting of —F, —Cl, —Br, I, —CN, —NO 2 , —SF 5

Assignees

• Genentech Inc

Inventors

• Cohen Frederick
• Patel Snahel

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title