发明名称 BICYCLIC HETEROAROMATIC CARBOXAMIDE COMPOUNDS USEFUL AS PIM KINASE INHIBITORS
摘要 The present disclosure describes bicyclic heteroaromatic carboxamide derivatives, as well as their compositions and methods of use. The compounds inhibit the activity of the Pim kinases, and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.
申请公布号 US2016009726(A1) 申请公布日期 2016.01.14
申请号 US201514798137 申请日期 2015.07.13
申请人 Incyte Corporation 发明人 Vechorkin Oleg;Li Yun-Long;Zhu Wenyu
分类号 C07D491/048;C07D471/04;C07D487/04;C07D495/04;C07D513/04 主分类号 C07D491/048
代理机构 代理人
主权项 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: CyA is selected from heteroaryl groups of the following Formulae CyA-1 to CyA-3: wherein * indicates the bond connecting CyA and CyB; the moiety represented in Formula (I) by CyC: is a 5-membered heteroaryl or heterocycloalkyl ring wherein: W is A6 or A7; X is A6, A7 or C(O); Y is A6 or A7; Z is C or N; each A6 is independently O, S or NR6; each A7 is independently N or CR7; a and b indicate bonds by which CyC is attached; wherein W, X, Y and Z are selected such that the 5-membered heteroaryl or heterocycloalkyl ring CyC is selected from groups of the following Formulae CyC-1 to CyC-5: wherein, in each of Formulae CyC-1, CyC-2, CyC-3 and CyC-4, at least one A7 is CR7; CyB is an unsubstituted or substituted C3-7 cycloalkyl or an unsubstituted or substituted 4-10 membered heterocycloalkyl, wherein the ring atoms of the heterocycloalkyl forming CyB consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, wherein the substituted C3-7 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming CyB is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, R CyB, C1-6 haloalkyl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1 and S(O)2NRc1Rd1, wherein each RCyB is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-7 cycloalkyl and 4-7 membered heterocycloalkyl, each of which is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)NRc1Rd1, NRc1C(O)ORa1, C(═NRe1)NRc1Rd1, NRc1C(═NRe1)NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, NRc1S(O)2Rb1 and S(O)2NRc1Rd1; R1 is H; and R2 is H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, C(═NRe2)NRc2Rd2, NRc2C(═NRe2)NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2 or S(O)2NRc2Rd2; or R1 and R2 in combination, together with the carbon atoms to which R1 and R2 are attached, form a 5, 6 or 7-membered carbocyclic or heterocyclic ring containing 3 to 7 ring carbon atoms and 0, 1 or 2 ring heteroatoms, each independently selected from N, O and S, wherein the ring formed by the combination of R1 and R2 is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, CN, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2 and oxo; R3 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl or 4-6 membered heterocycloalkyl; R4 is H, halogen or NH2; A5 is N or CR5; R5 is H or halogen; each R6 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy6, or -L6-Cy6; each R7 is independently, at each occurrence, H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy6, -L6-Cy6, halogen, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3 NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3 or S(O)2NRc3Rd3, wherein said C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl forming R6 or R7 are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3 and S(O)2NRc3Rd3; Cy6 is unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-6 cycloalkyl, or unsubstituted or substituted 4-12 membered heterocycloalkyl, wherein the substituted C6-10 aryl, 5-10 membered heteroaryl, C3-6 cycloalkyl or 4-12 membered heterocycloalkyl forming Cy6 is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, RCy6, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, NRc3S(O)2Rb3 and S(O)2NRc3Rd3, wherein each RCy6 is C1-6 alkyl, each of which is independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3 NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3 NRc3S(O)2Rb3 and S(O)2NRc3Rd3; or alternatively, the substituted C6-10 aryl, 5-10 membered heteroaryl, C3-6 cycloalkyl or 4-12 membered heterocycloalkyl forming Cy6 is substituted with unsubstituted C6-10 aryl or C6-10 aryl substituted by 1, 2, 3, 4 or 5 substituents independently selected from halogen, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3 NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3 NRc3S(O)2Rb3 and S(O)2NRc3Rd3; L6 is unsubstituted C1-6 alkylene or C1-6 alkylene substituted with 1, 2 or 3 substituents independently selected from F, Cl, CN, OH, O(C1-6 alkyl), NH2, NH(C1-6 alkyl) and N(C1-6 alkyl)2; or two R6 or R7 groups attached to adjacent ring atoms of CyC in combination, together with the ring atoms of CyC to which they are attached, form a 5, 6 or 7-membered carbocyclic or heterocyclic ring containing 3 to 7 ring carbon atoms and 0, 1 or 2 ring heteroatoms, each independently selected from N, O and S, wherein the ring formed by the combination of two R6 or R7 groups is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, CN, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)NRc3Rd3, NRc3C(O)ORa3 and oxo; Ra1, Rb1, Rc1 and Rd1 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-10 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra1, Rb1, Rc1 and Rd1 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-6 alkyl, halo, CN, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)NRc4Rd4, NRc4C(O)ORa4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, NRc4S(O)2Rb4 and S(O)2NRc4Rd4; or Rc1 and Rd1 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from C1-6 alkyl, halo, CN, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)NRc4Rd4, NRc4C(O)ORa4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, NRc4S(O)2Rb4 and S(O)2NRc4Rd4; Ra2, Rb2, Rc2 and Rd2 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-10 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra2, Rb2, Rc2 and Rd2 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-6 alkyl, halo, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5 and S(O)2NRc5Rd5; or Rc2 and Rd2 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from C1-6 alkyl, halo, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5 and S(O)2NRc5Rd5; Ra3, Rb3, Rc3 and Rd3 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-10 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra3, Rb3, Rc3 and Rd3 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C1-6 alkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, C(═NRe6)NRc6Rd6, NRc6C(═NRe6)NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6 and S(O)2NRc6Rd6; or Rc3 and Rd3 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from C1-6 alkyl, halo, CN, ORa6, SRa6, C(O)Rb6, C(O)NRc6Rd6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)NRc6Rd6, NRc6C(O)ORa6, C(═NRe6)NRc6Rd6, NRc6C(═NRe6)NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, NRc6S(O)2Rb6 and S(O)2NRc6Rd6; Ra4, Rb4, Rc4 and Rd4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-10 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-3 alkyl, 5-10 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-10 membered heterocycloalkyl-C1-3 alkyl forming Ra4, Rb4, Rc4 and Rd4 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C1-6 alkyl), N(C1-6 alkyl)2, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy; or Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C1-6 alkyl), N(C1-6 alkyl)2, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy; Ra5, Rb5, Rc5 and Rd5 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-3 alkyl, 5-6 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-7 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-3 alkyl, 5-6 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-7 membered heterocycloalkyl-C1-3 alkyl forming Ra5, Rb5, Rc5 and Rd5 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C1-6 alkyl), N(C1-6 alkyl)2, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy; or Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C1-6 alkyl), N(C1-6 alkyl)2, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy; Ra6, Rb6, Rc6 and Rd6 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-3 alkyl, 5-6 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-7 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C1-3 alkyl, 5-6 membered heteroaryl-C1-3 alkyl, C3-7 cycloalkyl-C1-3 alkyl and 4-7 membered heterocycloalkyl-C1-3 alkyl forming Ra6, Rb6, Rc6 and Rd6 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C1-6 alkyl), N(C1-6 alkyl)2, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy; or Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C1-6 alkyl), N(C1-6 alkyl)2, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl and C1-6 haloalkoxy; and Re1, Re2, Re3, Re4, Re5 and Re6 are each, independently, H, CN or NO2.
地址 Wilmington DE US