Indolizine derivatives, composition and methods of use

A compound of formula (I):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• A-B is a 6-5 membered fused indolizine ring system, which is:
• L is selected from NRX, O and S;
• each R1 is independently selected from hydrogen, hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, —CN, —NO2, —NRA1RB1, —ORA1, —S(O)rRA1, —S(O)2ORA1, —OS(O)2RA1, —P(O)RA1RB1, —P(O)(ORA1)(ORB1), —C(O)RA1, —C(O)ORA1, —OC(O)RA1, —C(O)NRA1RB1, —NRA1C(O)RB1, —OC(O)NRA1RB1, —NRA1C(O)ORB1, —NRA1C(O)NRA1RB1, —NRA1C(S)NRA1RB1, —S(O)rNRA1RB1, —NRA1S(O)rRB1, —NRA1S(O)2NRA1RB1, —S(O)(═NRE1)RB1, —N═S(O)RA1RB1, —NRA1S(O)(═NRE1)RB1, —S(O)(═NRE1)NRA1RB1, —NRA1S(O)(═NRE1)NRA1RB1, —C(═NE1)RA1, —C(═N—ORB1)RA1, —C(═NE1RA1RB1, —NRA1C(═NRE1)RB1, and —NRA1C(═NRE1)NRA1RB1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RX;
• each R2 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, —CN, —NO2, —NRA2RB2, —ORA2, —S(O)rRA2, —S(O)2ORA2, —OS(O)2RA2, —P(O)RA2RB2, —P(O)(ORA2)(ORB2), —C(O)RA2, —C(O)ORA2, —OC(O)RA2, —C(O)NRA2RB2, —NRA2C(O)RB2—OC(O)NRA2RB2, —NRA2C(O)ORB2, —NRA2C(O)NRA2RB2, —NRA2C(S)NRA2RB2, —S(O)rNRA2RB2, —NRA2S(O)rRB2, —NRA2S(O)2NRA2RB2, —S(O)(═NRE2)RB2, —N═S(O)RA2RB2, —NRA2S(O)(═NRE2)RB2, —S(O)(═NRE2)NRA2RB2, —NRA2S(O)(═NRE2)NRA2RB2, —C(═NRE2)RA2, —C(═N—ORB2)RA2, —C(═NRE2)NRA2RB2, —NRA2C(═NRE2)RB2 and —NRA2C(═NRE2)NRA2RB2 wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RX;
• each R3 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, —CN, —NO2, —NRA3RB3, —ORA3, —S(O)rRA3, —S(O)2ORA3, —OS(O)2RA3, —P(O)RA3RB3, —P(O)(ORA3)(ORB3), —C(O)RA3, —C(O)ORA3, —OC(O)RA3, —C(O)NRA3RB3, —NRA3C(O)RB3, OC(O)NRA3RB3, —NRA3C(O)ORB3, —NRA3C(O)NRA3RB3, —NRA3C(S)NRA3RB3, —S(O)rNRA3RB3, —NRA3(O)rRB3, —NRA3S(O)2NRA3RB3, —S(O)(═NRE3)RB3, —N═S(O)RA3RB3, —NRA3S(O)(═NRE3)RB3, —S(O)(═NRE3)NRA3RB3, —NRA3S(O)(═NRE3)NRA3RB3, —C(═NRE3)RA3, —C(═N—ORB3)RA3, —C(═NRE3)NRA3RB3, —NRA3C(═NRE3)RB3, and —NRA3C(═NRE3)NRA3RB3, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RX;
• each R4 and R5 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, wherein the said alkyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RX;
• or R4 and R5 together with the carbon atom to which they are attached form a ring of 3 to 7 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RX groups;
• each RA1, RA2, RA3, RB1, RB2 and RB3 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RX;
• or each “RA1 and RB1”, “RA2 and RB2”, or “RA3 and RB3” together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 RX groups;
• each RE1, RE2 and RE3 are independently selected from hydrogen, C1-10 alkyl, CN, NO2, ORa1, SRa1, —S(O)rRa1, —S(O)rNRa1Rb1, —C(O)Ra1, —C(O)ORa1, and —C(O)NRa1Rb1;
• each RX is independently selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, halogen, —CN, —NO2, —(CRc1Rd1)tNRa1Rb1, —(CRc1Rd1)tORb1, —(CRc1Rd1)tS(O)rRb1, —(CRc1Rd1)tS(O)2ORb1, —(CRc1Rd1)tOS(O)2Rb1, —(CRc1Rd1)tP(O)Ra1Ra1, —(CRc1Rd1)tP(O)(ORa1)(ORa1), —(CRc1Rd1)tC(O)Ra1, —(CRc1Rd1)tC(O)ORb1, —(CRc1Rd1)tOC(O)Rb1, —(CRc1Rd1)tC(O)NRa1Rb1, —(CRc1Rd1)tNRa1C(O)Rb1, —(CRc1Rd1)tOC(O)NRa1Rb1, —(CRc1Rd1)tNRa1C(O)ORb1, —(CRc1Rd1)tNRa1C(O)NRa1Rb1, —(CRc1Rd1)tNRa1C(S)NRa1Rb1, —(CRc1Rd1)tS(O)rNRa1Rb1, —(CRc1Rd1)tNRa1S(O)rRb1, —(CRc1Rd1)tNRa1S(O)2NRa1Rb1, —(CRc1Rd1)tS(O)(═NRe1)Rb1, —(CRc1Rd1)N═S(O)Ra1Rb1, —(CRc1Rd1)tNRa1S(O)(═NRe1)Rb1, —(CRc1Rd1)tS(O)(═NRe1)NRa1Rb1, —(CRc1Rd1)NRa1S(O)(═NRe1)NRa1Rb1, —(CRc1Rd1)tC(═NRe1)Ra1, —(CRc1Rd1)tC(═N—ORb1)Ra1, —(CRc1Rd1)tC(═NRe1)NRa1Rb1, —(CRc1Rd1)tNRa1C(═NRe1)Rb1, and —(CRc1Rd1)tNRa1C(═NRe1)NRa1Rb1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RY;
• each Ra1 and each Rb1 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RY;
• or Ra1 and Rb1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2, or 3 RY groups;
• each Rc1 and each Rd1 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RY;
• or Rc1 and Rd1 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2, or 3 RY groups;
• each Re1 is independently selected from hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, —S(O)rRa2, —S(O)rNRa2Rb2, —C(O)Ra2, —C(O)ORa2, and —C(O)NRa2Rb2;
• RY is independently selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, halogen, —CN, —NO2, —(CRc2Rd2)tNRa2Rb2, —(CRc2Rd2)tORb2, —(CRc2Rd2)tS(O)rRb2, —(CRc2Rd2)tS(O)2ORb2, —(CRc2Rd2)tOS(O)2Rb2, —(CRc2Rd2)tP(O)Ra2Rb2, —(CRc2Rd2)tP(O)(ORa2)(ORb2), (CRc2Rd2)tC(O)Ra2, —(CRc2Rd2)tC(O)ORb2, —(CRc2Rd2)tOC(O)Rb2, —(CRc2Rd2)tC(O)NRa1Rb2, —(CRc2Rd2)tNRa2C(O)Rb2, (CRc2Rd2)tOC(O)NRa2Rb2, —(CRc2Rd2)tNRa2C(O)ORb2, —(CRc2Rd2)tNRa2C(O)NRa2Rb2, (CRc2Rd2)tNRa2C(S)NRa2Rb2, —(CRc2Rd2)tS(O)rNRa2Rb2, (CRc2Rd2)tNRa2S(O)rRb2, (CRc2Rd2)tNRa2S(O)2NRa2Rb2, —(CRc2Rd2)tS(O)(═NRe2)Rb2, —(CRc2Rd2)tN═S(O)Ra2Rb2, —(CRc2Rd2)tNRa2S(O)(═NRe2)Rb2, —(CRc2Rd2)tS(O)(═NRe2)NRa2Rb2, —(CRc2Rd2)tNRa2S(O)(═NRe2)NRa2Rb2, —(CRc2Rd2)tC(═NRe2)Ra2, —(CRc2Rd2)tC(═N—ORb2)Ra2, —(CRc2Rd2)tC(═NRe2)NRa2Rb2, —(CRc2Rd2)tNRa2C(═NRe2)Rb2, and —(CRc2Rd2)tNRa2C(═NRe2)NRa1Rb2, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from OH, CN, amino, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
• each Ra2 and each Rb2 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di(C1-10 alkyl)amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
• or Ra2 and Rb2 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
• each Rc2 and each Rd2 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di(C1-10 alkyl)amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
• or Rc2 and Rd2 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di(C1-10 alkyl)amino;
• each Re2 is independently selected from hydrogen, CN, NO2, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, —C(O)C1-4 alkyl, —C(O)C3-10 cycloalkyl, —C(O)OC1-4 alkyl, —C(O)OC3-10 cycloalkyl, —C(O)NH2, —C(O)NH(C1-4 alkyl), —C(O)N(C1-4 alkyl)2, —C(O)NH(C3-10 cycloalkyl), —C(O)N(C3-10 cycloalkyl)2, —S(O)2C1-4 alkyl, —S(O)2C3-10 cycloalkyl, —S(O)2NH2, —S(O)2NH(C1-4 alkyl), —S(O)2N(C1-4 alkyl)2, —S(O)2NH(C3-10 cycloalkyl) and —S(O)2N(C3-10 cycloalkyl)2;
• M is hydrogen, C1-4 alkyl or a pharmaceutically acceptable cation;
• m is independently selected from 0, 1, 2 and 3;
• n is independently selected from 0, 1, 2, and 3;
• o is selected from 1, 2, and 3;
• p is independently selected from 0, 1, 2 and 3;
• each r is independently selected from 0, 1 and 2;
• each t is independently selected from 0, 1, 2, 3 and 4.