Compounds and methods of use

A compound of Formula I

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is independently a member selected from the group consisting of C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and halogen;
• the subscript n is an integer from 0 to 2, wherein when n is 0 then X1 is —CH2—, —C(H)(Ra)—,
• X1 is a member selected from the group consisting of —CH2—, —C(H)(Ra)—, —C(Ra)2—, —O—, —N(H)—, —N(Ra)—, —N(C(O)Ra)—, —N(C(O)ORa—, —N(S(O)2Ra)—, —N(S(O)Ra)—, —S—, —S(O)—, and —S(O)2—, wherein Ra is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, and halogen;
• X2a, X2b and X2c are each independently selected from the group consisting of C(H), C(R2), and N, wherein at least one of X2a and X2b is C(H) or C(R2);
• wherein R2 is independently selected from the group consisting of —ORb, —NRbRc, —SRb, —C(O)ORc, —C(O)NRbRc, —NRbC(O)Rd, —S(O)2Rd, —S(O)Rd, —S(O)2NRbRc, —Rd, halogen, —CN, and —NO2, wherein Rb and Rc are each independently selected from the group consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 haloalkyl, or optionally Rb and Rc, together with the atom to which each is attached, are combined to form a 3- to 7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S as ring vertices;
• and Rd is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
• A is a member selected from the group consisting of:
• wherein R3 is independently selected from the group consisting of —NReRf, —ORe, —CN, —NO2, halogen, —C(O)ORe, —C(O)NReRf, —NReC(O)Rf, —NReS(O)2Rg, —NReS(O)Rg, —S(O)2Rg, —S(O)Rg, and —Rg, wherein Re and Rf at each occurrence are each independently selected from the group consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and —(CH2)1-4 phenyl, or Re and Rf, or Re and Rg together with the atom to which each is attached, are optionally combined to form a 3- to 7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S as ring vertices;
• and Rg is selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 haloalkyl;
• B is a member selected from the group consisting of:
• wherein Y is N, C(H), or C(R4a);
• X3 is N(H), N(C1-3 alkyl), O, or S;
• R4a, if present, is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, and —CN;
• R4b, at each occurrence, is independently selected from the group consisting of —C(O)ORj, —C(O)NRhRi, —C(O)Ri, —NRhC(O)Ri, —NRhC(O)NRhRi, —OC(O)NRhRi, —NRhC(O)ORj, —C(═NORh)NRhRi, —NRhC(═NCN)NRhRi, —NRhS(O)2NRhRi, —S(O)2Rj, —S(O)2NRhRi, —N(Rh)S(O)2Ri, —NRhC(═NRi)NRhRi, —C(═S)NRhRi, —C(═NRh)NRhRi, halogen, —NO2, and —CN, wherein Rh and Ri at each occurrence are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl, phenyl, and —(CH2)1-4-phenyl, or Rh and Ri, or Rh and Rj, together with the atom to which each is attached are optionally combined to form a 3- to 7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S as ring vertices;
• Rj is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, and —(CH2)1-4 phenyl;
• or in the alternative, R4b is selected from the group consisting of
• wherein Rk is selected from C1-6 alkyl, C1-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl and C1-6 haloalkyl;
• L is absent or is a member selected from the group consisting of C6-10 arylene-C1-6 heteroalkylene, C5-9 heteroarylene-C1-6 heteroalkylene, C1-6 heteroalkylene, C1-6 alkylene, C1-6 haloalkylene, C2-6 alkenylene, C2-6 alkynylene, —NH—, —S—, and —O—, wherein the alkylene, alkenylene, alkynylene or heteroalkylene portions of the L group are substituted with 0 to 4 R5a substituents selected from the group consisting of halogen, —Rm, and ═O, and the aromatic portions of the L group are substituted with 0 to 4 R5b substituents selected from the group consisting of halogen, —ORn, —NRnRo, —Rn, —NO2, and CN;
• wherein Rm is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, and C1-6 haloalkyl, and optionally any two R5a substituents attached to the same or different atoms of L can be combined to form a 5- to 7-membered carbocyclic ring or a 5- to 7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S as ring vertices;
• and wherein Rn and Ro, at each occurrence, are selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl, and wherein optionally Rn and Ro, together with the atoms to which each is attached, are combined to form a 3- to 7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S as ring vertices;
• E is hydrogen or halogen;
• or in the alternative E is selected from the group consisting of phenyl, C5-6 heteroaryl, C3-7 heterocycloalkyl, and C3-7 cycloalkyl, and optionally fused to E are 1 or 2 rings independently selected from the group consisting of a 3- to 7-membered carbocyclic ring, a 3- to 7-membered heterocyclic ring, a benzene ring, and a 5- to 6-membered heteroaromatic ring, wherein E and each ring optionally fused to E are independently substituted with 0 to 5 R6 substituents selected from the group consisting of halogen, —NRpRq, —SRp, —ORp, —C(O)ORp, —C(O)NRpRq, —C(O)Rp, —NRpC(O)Rq, —OC(O)Rr, —NRpC(O)NRpRq, —OC(O)NRpRq, —NRpC(O)ORr, —C(═NORp)NRpRq, —NRpC(═N—CN)NRpRq, —NRpS(O)2NRpRq, —S(O)2Rr, —S(O)2NRpRq, —Rr, —Rs, —NO2, —N3, ═O, —CN, —Z1—NRpRq, —Z1—SRp, —Z1—ORp, —Z1—C(O)ORp, —Z1—C(O)NRpRq, —Z1—C(O)Rp, —Z1—NRpC(O)Rq, —Z1—OC(O)Rr, —Z1—NRpC(O)NRpRq, —Z1—OC(O)NRpRq, —Z1—NRpC(O)ORr, —Z1—C(═NORp)NRpRq, —Z1—NRpC(═N—CN)NRpRq, —Z1—NRpS(O)2NRpRq, —Z1—S(O)2Rr, —Z1—S(O)2NRpRq, —Z1—NO2, —Z1—N3, —Z1—Rs, and —Z1—CN;
• wherein Z1 is selected from the group consisting of C1-6 alkylene, C2-6 alkenylene, C2-4, alkynylene, C1-6 heteroalkylene, C3-7 cycloalkylene, and C3-7 heterocycloalkylene;
• Rp and Rq are each independently selected from hydrogen, C1-4, alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, phenyl, and —(CH2)1-4-phenyl;
• Rr is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, phenyl, and —(CH2)1-4-phenyl;
• optionally within each R6 substituent Rp and Rq or Rp and Rr, together with the atom to which each is attached, are optionally combined to form a 3- to 7-membered heterocyclic ring optionally comprising 1 to 2 heteroatoms selected from N, O and S as ring vertices;
• Rs is selected from the group consisting of phenyl, C5-6 heteroaryl, C3-7 heterocycloalkyl, and C3-7 cycloalkyl, and optionally fused to Rs are 1 or 2 rings each independently selected from the group consisting of a 5- to 7-membered carbocyclic ring, a 5- to 7-membered heterocyclic ring, a benzene ring, and a 5- to 6-membered heteroaromatic ring, and wherein Rs and each ring optionally fused to Rs are each independently substituted with 0 to 5 R7 substituents selected from the group consisting of halogen, —NRtRu, —SRt, —ORt, —C(O)ORt, —C(O)NRtRu, —C(O)Rt, —NRtC(O)Ru, —OC(O)Rv, —NRtC(O)NRtRu, —OC(O)NRtRr, —NRtC(O)ORv, —C(═NORt)NRtRu, —NRtC(═N—CN)NRtRu, —NRtS(O)2NRtRu, —S(O)2Rv, —S(O)2NRtRu, —Rv, —NO2, —N3, ═O, —CN, —Z2—NRtRu, —Z2—SRt, —Z2—ORt, —Z2—C(O)ORt, —Z2—C(O)NRtRu, —Z2—C(O)Rv, —Z2—NRtC(O)Ru, —Z2—OC(O)Rv, —Z2—NRtC(O)NRtRu, —Z2—OC(O)NRtRu, —Z2—NRtC(O)ORv, —Z2—C(═NORt)NRtRu, —Z2—NRtC(═N—CN)NRtRu, —Z2—NRtS(O)2NRtRu, —Z2—S(O)2Rv, —Z2S(O)2NRtRu, —Z2—NO2, —Z2—N3, and —Z—CN;
• wherein Z2 is selected from the group consisting of C1-6 alkylene, alkenylene, C2-6 alkynylene, and C1-6 heteroalkylene;
• Rt and Ru are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)1-4-phenyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl;
• Rv is selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, and —(CH2)1-4-phenyl;
• and within each R7 substituent, Rt and Ru or Rt and Rv, together with the atom to which each is attached, optionally are combined to form a 3- to 7-membered heterocyclic ring having 1 to 2 heteroatoms selected from N, O and S as ring vertices.