Inhibitors of ephb3 signaling

A compound of Formula (Ia):

• or a pharmaceutically acceptable salt thereof, wherein:
• R5 is 5-14 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1;
• R1 is selected from C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R2 is selected from H and C1-3 alkyl;
• R3 is selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R4 and R7 are each independently selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R6 is selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-6 alkyl, C1-3 haloalkyl, and a reactive electrophilic warhead group, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, and NRc1Rd1;
• Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, C1-6 alkyl, and C1-4 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
• and
• each Rg is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-6 alkoxycarbonyl, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.

A compound of Formula (Ib):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from 5-14 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R2 is selected from H and C1-3 alkyl;
• R3 is selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R5 is selected from H, halo, CN, ORa1, NRc1Rd1, C1-6 alkyl, C1-6 haloalkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1;
• each Cy1 is independently selected from C6-10 aryl, 5-14 membered heteroaryl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected RCy1;
• each RCy1 is independently selected from halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, Cy2, C1-6 alkyl, C1-6 haloalkyl, and oxo, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1;
• each Cy2 is independently selected from C6-10 aryl, 5-14 membered heteroaryl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, each of which is independently selected from 1, 2, or 3 substituents independently selected from RCy2;
• RCy2 is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1 wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected Rg;
• R4 and R7 are each independently selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-3 alkyl, C1-3 haloalkyl, and Cy2, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R6 is selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-6 alkyl, C1-3 haloalkyl, Cy2, and a reactive electrophilic warhead group, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, and NRc1Rd1;
• Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, C1-6 alkyl, and C1-4 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
• and
• each Rg is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-6 alkoxycarbonyl, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.

A compound of Formula (Ic):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R2 is selected from H and C1-3 alkyl;
• R3 is selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• each RCy1 is independently selected from halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, Cy2, C1-6 alkyl, C1-6 haloalkyl, and oxo, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1;
• each Cy2 is independently selected from C6-10 aryl, 5-14 membered heteroaryl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, each of which is independently selected from 1, 2, or 3 substituents independently selected from RCy2;
• RCy2 is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1 wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected Rg;
• R4 and R7 are each independently selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-3 alkyl, C1-3 haloalkyl, and Cy2, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R6 is selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-6 alkyl, C1-3 haloalkyl, Cy2, and a reactive electrophilic warhead group, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, and NRc1Rd1;
• Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, C1-6 alkyl, and C1-4 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
• and
• each Rg is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-6 alkoxycarbonyl, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino, provided that the compound is not:

A compound of Formula (Id):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R2 is selected from H and C1-3 alkyl;
• R3 is selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• each RCy1 is independently selected from halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, Cy2, C1-6 alkyl, C1-6 haloalkyl, and oxo, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1;
• each Cy2 is independently selected from C6-10 aryl, 5-14 membered heteroaryl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, each of which is independently selected from 1, 2, or 3 substituents independently selected from RCy2;
• RCy2 is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1 wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected Rg;
• R4 and R7 are each independently selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-3 alkyl, C1-3 haloalkyl, and Cy2, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R6 is selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-6 alkyl, C1-3 haloalkyl, Cy2, and a reactive electrophilic warhead group, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, and NRc1Rd1;
• Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, C1-6 alkyl, and C1-4 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
• and
• each Rg is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-6 alkoxycarbonyl, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino, provided that the compound is not:

A compound of Formula (If):

• or a pharmaceutically acceptable salt thereof, wherein:
• each R8 is independently selected from halo, CN, ORa1, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• or any two adjacent R8 groups together with the carbon atoms to which they are attached from a ring selected from 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
• R2 is selected from H and C1-3 alkyl;
• R3 is selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R5 is selected from H, halo, CN, ORa1, NRc1Rd1, C1-6 alkyl, C1-6 haloalkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1;
• each Cy1 is independently selected from C6-10 aryl, 5-14 membered heteroaryl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected RCy1;
• each RCy1 is independently selected from halo, CN, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, Cy2, C1-6 alkyl, C1-6 haloalkyl, and oxo, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1;
• each Cy2 is independently selected from C6-10 aryl, 5-14 membered heteroaryl, C3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, each of which is independently selected from 1, 2, or 3 substituents independently selected from RCy2;
• RCy2 is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, and NRc1Rd1 wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected Rg;
• R4 and R7 are each independently selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-3 alkyl, C1-3 haloalkyl, and Cy2, wherein said C1-3 alkyl is optionally substituted with 1 or 2 independently selected Rg;
• R6 is selected from H, halo, CN, ORa1, S(O)2Rb1, S(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, C1-6 alkyl, C1-3 haloalkyl, Cy2, and a reactive electrophilic warhead group, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, ORa1, and NRc1Rd1;
• Ra1, Rb1, Rc1, and Rd1 are each independently selected from H, C1-6 alkyl, and C1-4 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
• and
• each Rg is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-6 alkoxycarbonyl, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.