US 8,785,639 B2 · Substituted dihydropyrazolo[3,4-D]pyrrolo[2,3-B]pyridines and methods of use thereof

Abstract

The invention provides a compound of Formula (Ie), pharmaceutically acceptable salts, or stereoisomers thereof wherein the variables are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

A compound of formula (Ie)

or pharmaceutically acceptable salts, or stereoisomers thereof wherein
R1 is H, deuterium, halogen, CF3, CN, ORa, N(Ra)(Rb), OCF3, —C(O)—N(Ra)(Rb), —C(O)—ORa, —C(O)-optionally substituted (C1-C6)alkyl, —C(O)-optionally substituted (C3-C6)cycloalkyl, —C(O)-optionally substituted (C6-C10)aryl, —C(O)-optionally substituted (C1-C10)heteroaryl, —C(O)-optionally substituted (C1-C10)heterocyclyl, —S-optionally substituted (C1-C6)alkyl, —S(O)-optionally substituted (C1-C6)alkyl, —S(O)2-optionally substituted (C1-C6)alkyl, —S(O)2N(Ra)(Rb), optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted azaindolyl, optionally substituted azepinyl, optionally substituted azetidinyl, optionally substituted benzo(b)thienyl, optionally substituted benzofuranyl, optionally substituted benzimidazolyl, optionally substituted benzoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted benzoxadiazolyl, optionally substituted 6,7-dihydro-5H-cyclopentapyrimidinyl, optionally substituted furanyl, optionally substituted imidazolyl, optionally substituted imidazopyridinyl, optionally substituted 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl, optionally substituted 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazinyl, optionally substituted 5,6,7,8-tetrahydro[1,2,4]-triazolo[4,3-a]pyrazinyl, optionally substituted indazolyl, optionally substituted indolinyl, optionally substituted indolyl, optionally substituted isoindolinyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted morpholinyl, optionally substituted oxadiazolyl, optionally substituted oxazolyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted purinyl, optionally substituted pyranyl, optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, optionally substituted pyrrolyl, optionally substituted pyrrolo[3,2-c]pyrimidinyl, optionally substituted pyrrolo[2,3-d]pyrimidinyl, optionally substituted pyrrolo[2,3-b]pyridinyl, optionally substituted octahydropyrrolo[3,4-c]pyrrolyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, optionally substituted quinuclidinyl, optionally substituted quinoxalinyl, optionally substituted thiomorpholinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, optionally substituted thiazolyl, optionally substituted thienyl, optionally substituted tetrazolyl, optionally substituted thiadiazolyl, optionally substituted [1,3,5]triazinyl, optionally substituted triazolyl, or optionally substituted tropanyl;
or
R1 is —Z101-L1-Z102 wherein
Z101 is optionally substituted (C1-C6)alkylene, optionally substituted (C1-C10)heterocyclylene, or optionally substituted (C6-C10)arylene;
L1 is —CH2C(O), —C(O)—, —C(O)CH2—, —N(Ra)—, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)—, -optionally substituted (C1-C4)alkylene-C(O)N(Ra)—, —C(O)N(Ra)—, —N(Ra)C(O)—, —C(O)N(Ra)-optionally substituted (C1-C4)alkylene-, —N(Ra)C(O)-optionally substituted (C1-C4)alkylene-, —C(O)N(Ra)-optionally substituted (C1-C4)alkylene-C(O), —N(Ra)C(O)-optionally substituted (C1-C4)alkylene-C(O)—, —C(O)-optionally substituted (C1-C4)alkylene-N(Ra)C(O)—, —C(O)-optionally substituted (C1-C4)alkylene-C(O)N(Ra)—, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)—, —N(Ra)C(O)-optionally substituted (C1-C4)alkylene, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-C(O)N(Ra)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-N(Ra)S(O)2—, -optionally substituted (C1-C4)alkylene-S(O)2N(Ra)—, —N(Ra)S(O)2CH2—, —S(O)2N(Ra)-optionally substituted (C1-C4)alkylene-, —C(O)N(Ra)S(O)2—, —S(O)2N(Ra)C(O)—, —S(O)2N(Ra)—, —N(Ra)S(O)2—, —O—(C1-C4)alkylene-, (C1-C6)alkylene-O—, —C(O)N(Ra)—(C1-C6)alkylene-C(O)—, or —C(O)—(C1-C6)alkylene-N(Ra)C(O)—;
Z102 is H, —CN, —N(Ra)(Rb), —ORa, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C4)alkoxy, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted bridged (C5-C12)cycloalkyl, or optionally substituted bridged (C2-C10)heterocyclyl;
R2 is H, deuterium, halogen, CF3, CN, ORa, N(Ra)(Rb), OCF3, —C(O)-optionally substituted (C1-C6)alkyl, —C(O)-optionally substituted (C3-C6)cycloalkyl, —S-optionally substituted (C1-C6)alkyl, —S(O)2-optionally substituted (C1-C6)alkyl, —S(O)2N(Ra)(Rb), optionally substituted (C1-C6)alkoxy, —C(O)N(Ra)(Rb), —S(O)2-optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl;
R3 is H or methyl;
R5 is H, deuterium, N(Ra)(Rb), halogen, CN, CF3, ORa, optionally substituted (C1-C6)alkyl, OCF3, —C(O)-optionally substituted (C1-C6)alkyl, —C(O)-optionally substituted (C3-C6)cycloalkyl, —S-optionally substituted (C1-C6)alkyl, —S(O)-optionally substituted (C1-C6)alkyl, —S(O)2-optionally substituted (C1-C6)alkyl, —S(O)2N(Ra)(Rb), optionally substituted (C1-C6)alkyl, or optionally substituted (C1-C6)alkoxy;
R6 is H, deuterium, halogen, CF3, CN, —C(O)—N(Ra)(Rb), —C(O)—ORa, —C(O)-optionally substituted (C1-C6)alkyl, —C(O)-optionally substituted (C3-C6)cycloalkyl, —C(O)-optionally substituted (C6-C10)aryl, —C(O)-optionally substituted (C1-C10)heteroaryl, —C(O)-optionally substituted (C1-C10)heterocyclyl, —S-optionally substituted (C1-C6)alkyl, —S(O)-optionally substituted (C1-C6)alkyl, —S(O)2-optionally substituted (C1-C6)alkyl, —S(O)2N(Ra)(Rb), optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10) heterocyclyl, or optionally substituted (C6-C10)aryl;
or
R6 is —Z201-L2-Z202 wherein
Z201 is optionally substituted (C1-C6)alkylene, optionally substituted (C1-C10)heteroarylene, optionally substituted (C1-C10)heterocyclylene, or optionally substituted (C6-C10)arylene;
L2 is a bond, optionally substituted (C1-C4)alkylene, —CH2C(O), —C(O)—, —C(O)CH2—, —N(Ra)—, —O—, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)—, -optionally substituted (C1-C4)alkylene-C(O)N(Ra)—, —C(O)N(Ra)—, —N(Ra)C(O)—, —C(O)N(Ra)S(O)2—, —S(O)2N(Ra)C(O)—, —C(O)N(Ra)-optionally substituted (C1-C4)alkylene-, —N(Ra)C(O)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-C(O)N(Ra)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-N(Ra)S(O)2—, -optionally substituted (C1-C4)alkylene-S(O)2N(Ra)—, —N(Ra)S(O)2CH2—, —S(O)2N(Ra)-optionally substituted (C1-C4)alkylene-, —S(O)2—, —S(O)2N(Ra)—, —N(Ra)S(O)2—, —(C1-C4)alkylene-O—, or —O—(C1-C4)alkylene-;
Z202 is H, —CN, —N(Ra)(Rb), —ORa, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C4)alkoxy, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted bridged (C5-C12)cycloalkyl, or optionally substituted bridged (C2-C10)heterocyclyl;
R7 is H, deuterium, optionally substituted-(CH2)n—P(═O)(ORa)(ORa), optionally substituted —(CH2)n—O—P(═O)(ORa)(ORa), optionally substituted-(CH2)n—P(═O)(ORa)(Ra), or —CH═CH—P(═O)(ORa)(ORa);
Ra and Rb are each independently H, deuterium, an optionally substituted (C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, an optionally substituted (C1-C10)alkyl-O—(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, an optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted —(C1-C6)alkylene-(C3-C10)cycloalkyl, an optionally substituted —(C1-C6)alkylene-(C6-C10)aryl, optionally substituted —(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted —(C1-C6)alkylene-(C1-C10)heterocyclyl;
Re for each occurrence is independently a bond, an optionally substituted (C1-C10)alkylene, an optionally substituted (C2-C10)alkenylene, an optionally substituted (C2-C10)alkynylene, an optionally substituted —(C1-C10)alkylene-O—(C1-C10)alkylene group, an optionally substituted (C3-C10)cycloalkylene, an optionally substituted (C6-C10)arylene, an optionally substituted (C1-C10)heteroarylene, or an optionally substituted (C1-C10)heterocyclylene;
and
n is 1, 2 or 3;
wherein the optional substituent is selected from the group consisting of:
(C1-C8)alkyl groups, (C2-C8)alkenyl groups, (C2-C8)alkynyl groups, (C3-C10)cycloalkyl groups, halogen, halogenated (C1-C8)alkyl groups, —OH, —S—(C1-C8)alkyl groups, —SH, —NH(C1-C8)alkyl groups, —N((C1-C8)alkyl)2 groups, —NH2, —C(O)NH2, —C(O)NH(C1-C8)alkyl groups, —C(O)N((C1-C8)alkyl)2, —NHC(O)H, —NHC(O)(C1-C8)alkyl groups, —NHC(O)(C3-C8)cycloalkyl groups, —N((C1-C8)alkyl)C(O)H, —N((C1-C8)alkyl)C(O)(C1-C8)alkyl groups, —NHC(O)NH2, —NHC(O)NH(C1-C8)alkyl groups, —N((C1-C8)alkyl)C(O)NH2 groups, —NHC(O)N((C1-C8)alkyl)2 groups, —N((C1-C8)alkyl)C(O)N((C1-C8)alkyl)2 groups, —N((C1-C8)alkyl)C(O)NH((C1-C8)alkyl), —C(O)H, —C(O)(C1-C8)alkyl groups, —CN, —NO2, —S(O)(C1-C8)alkyl groups, —S(O)2N((C1-C8)alkyl)2 groups, —S(O)2NH(C1-C8)alkyl groups, —S(O)2NH(C3-C8)cycloalkyl groups, —S(O)2NH2 groups, —NHS(O)2(C1-C8)alkyl groups, —N((C1-C8)alkyl)S(O)2(C1-C8)alkyl groups, —(C1-C8)alkyl-O—(C1-C8)alkyl groups, —O—(C1-C8)alkyl-O—(C1-C8)alkyl groups, —C(O)OH, —C(O)O(C1-C8)alkyl groups, NHOH, NHO(C1-C8)alkyl groups, —O-halogenated (C1-C8)alkyl groups, —S(O)2-halogenated (C1-C8)alkyl groups, —S-halogenated (C1-C8)alkyl groups, —(C1-C6) heterocyclyl, —(C1-C6) heteroaryl, -phenyl, —NHC(O)O—(C1-C6)alkyl groups, —N((C1-C6)alkyl)C(O)O—(C1-C6)alkyl groups, —C(═NH)—(C1-C6)alkyl groups, —C(═NOH)—(C1-C6)alkyl groups, and —C(═N—O—(C1-C6)alkyl)-(C1-C6)alkyl groups;
provided that R1 and R6 are not both H.

21 more elements

Substituted dihydropyrazolo[3,4-D]pyrrolo[2,3-B]pyridines and methods of use thereof

Life of this patent

Substituted dihydropyrazolo[3,4-D]pyrrolo[2,3-B]pyridines and methods of use thereof

Life of this patent

Abstract

Claims9