Compounds, compositions and methods

A method for treating an inflammatory disorder, the method comprising administering an effective amount of a compound of Formula I,

• or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof to a subject in need thereof, wherein:
• Y is N or CH;
• n is 1 or 2;
• m is 0, 1, 2, 3, 4, or 5;
• p is 0, 1, 2, or 3;
• A is aryl, heteroaryl, C3-10 cycloalkyl, or heterocyclyl;
• each of R1 and R2 is independently hydrogen, deuterium, halo, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl or aryl;
• wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z1;
• or
• R1 and R2 taken together with the atoms to which they are attached form a C3-10 cycloalkyl;
• wherein the C3-10 cycloalkyl is optionally substituted with one, two, three, four, or five Z2;
• R3 in each instance is independently deuterium, halo, hydroxy, cyano, nitro, azido, oxo, C1-12 alkyl, —OR5, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R4, —C(═O)OR4, —OC(═O)OR4, —OC(═O)R4, —C(═O)NR4R5, —OC(═O)NR4R5, —NR4C(═O)NR5R6, —S(═O)1-2R4, —S(═O)1-2OR4, —OS(═O)1-2R4, —S(═O)1-2NR4, —NR4S(═O)1-2R5, —NR4S(═O)1-2NR4R5, —NR4R5, —NR4C(═O)R5, or —NR4C(═O)OR5;
• wherein each C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, three, four, or five Z3;
• R4, R5, and R6 in each instance are independently C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 haloalkyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
• wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 haloalkyl, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z4;
• or
• two of R4, R5, and R6 taken together with the atoms to which they are attached form a heterocyclyl;
• wherein the heterocyclyl is optionally substituted with one, two, three, four, or five Z5;
• R14 is bonded to either ring of the fused bicyclic ring and, in each instance, is independently halo or haloalkyl, or two R14 bonded to the same carbon atom may be taken together with the atom to which they are attached to form a C3-10 cycloalkyl or heterocyclyl;
• wherein the C3-10 cycloalkyl or heterocyclyl is optionally substituted with one, two, three, four, or five Z6;
• each of Z1, Z2, Z3, Z4, Z5, and Z6 are independently deuterium, halo, hydroxy, cyano, nitro, azido, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R11, —C(═O)OR11, —OC(═O)OR11, —OC(═O)R11, —C(═O)NR11R12, —OC(═O)NR11R12, —NR11C(═O)NR12R13, —S(═O)1-2R11, —S(═O)1-2OR11, —S(═O)1-2NR11, —NR11S(═O)1-2R12, —NR11S(═O)1-2NR12R13, —NR11R12, —NR11C(═O)R12, or —NR11C(═O)OR12;
• wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three substituents independently selected from deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C1-12 alkyl, C1-12 alkoxy, C1-12 haloalkyl, C1-12 haloalkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• and
• R11, R12, and R13 in each instance are independently C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
• wherein each C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C1-12 alkoxy, C3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z11;
• or
• two of R11, R12, and R13 are taken together with the atoms to which they are attached to form a heterocyclyl;
• wherein the heterocyclyl is optionally substituted with one, two, three, four or five Z12;
• wherein each of Z11 and Z12 is independently deuterium, halo, hydroxy, cyano, oxo, amino or C1-12 alkyl;
• wherein the C1-12 alkyl is optionally substituted with one, two or three halo, hydroxyl, amino or oxo, provided that
• when n is 1, Y is CH, and both of R1 and R2 are hydrogen, then A is not heterocyclyl substituted with oxo;
• and
• when n is 2, Y is CH, and one of R1 or R2 is iodo, or both of R1 or R2 are hydrogen, then A is not 4-chlorophenyl, 2,6-difluoropyridin-3-yl, phenyl, or phenyl substituted with 1, 2 or 3 fluoro;
• and
• the compound is not chosen from (3R,8aR)-6-chloro-3-(4-fluorophenyl)hexahydroindolizin-5(1H)one:
• (3R,6S,8aS)-6-methyl-3-phenylhexahydroindolizin-5(1H)-one;
• hexahydro-6-methyl-3-phenyl-5(1H)-indolizinone;
• and 6-[(2-bromo-1H-indol-3-yl)methyl]hexahydro-3-(4-hydroxyphenyl)-5(1H)-indolizinone.