Substituted imidazo[2,1-f][1,2,4]triazines, substituted imidazo[1,2-a]pyridines and substituted imidazo[1,2-b]pyridazines as PI3K-gamma inhibitors

A method for treating a disease or disorder in a patient, wherein the disease or disorder is selected from the group consisting of a cardiovascular disease, a neurodegenerative disease, an autoimmune disease, an autoimmune disorder, and cancer, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• X1 is N or CR1;
• X2 is N or CR2;
• X3 is N or CR3;
• X4 is N or CR4;
• X5 is N or CR5;
• X6 is N or CR6;
• X3, X4, X5 and X6 are not simultaneously N;
• R7 is H or C1-6 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halo, OH, oxo, CN, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6-10 aryl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NH2, C1-6 alkyl-NH—O and (C1-6 alkyl)2N—;
• R1, R2, R3, R4, R5, R6 and R8 are each independently selected from H, D, halo, oxo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa1, SRa1, NHORa1, C(O)Ra1, C(O)NRa1Ra1, C(O)ORa1, OC(O)Ra1, OC(O)NRa1Ra1, NHRa1, NRa1Ra1, NRa1 C(O)Ra1, NRa1C(O)ORa1, NRa1C(O)NRa1Ra1, C(═NRa1)Ra1, C(═NRa1)NRa1Ra1, NRa1C(═NRa1)NRa1Ra1, NRa1C(═NOH)NRa1Ra1, NRa1C(═NCN)NRa1Ra1, NRa1S(O)Ra1, NRa1S(O)2Ra1, NRa1S(O)2NRa1Ra1, S(O)Ra1, S(O)NRa1Ra1, S(O)2Ra1, SF5, —P(O)Ra1Ra1, —P(O)(ORa1)(ORa1,B(ORa1)2 and S(O)2NRa1Ra1, wherein the C1-6alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4, R5, R6 and R8 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents;
• R9 is H, D, CN, C(O), NH2, —OH, —COOH, —NH(C1-6 alkyl), —NH(C1-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy, wherein the C1-6 alkyl is optionally substituted with 1, 2 or 3 independently selected Rq substituents;
• R10 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, ORa2, SRa2, NHORa2, C(O)Ra2, C(O)NRa2Ra2, C(O)ORa2, NHRa2, NRa2Ra2, NRa2C(O)Ra2, NRa2C(O)ORa2, NRa2C(O)NRa2Ra2, C(═NRa2)Ra2, C(═NRa2)NRa2Ra2, NRa2C(═NRa2)NRa2Ra2, NRa2S(O)Ra2, NRa2S(O)2Ra2, NRa2S(O)2NRa2Ra2, S(O)Ra2, S(O)NRa2Ra2, S(O)2Ra2, and S(O)2NRa2Ra2, wherein the C1-6 alkyl , C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of R10 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected Rb substituents;
• L is
• wherein each R11 is independently H, C1-6 alkyl, or C3-10 cycloalkyl optionally substituted with 1 or 2 Rq substituents and wherein the single wavy line indicates the point of attachment to R10and the double wavy line indicates the point of attachment to the 6-membered ring A;
• or when L is
• R10 and R11 optionally taken together with the nitrogen atom to which they are attached, form 4 to 14 membered heterocycloalkyl or a 4 to 14 membered heterocycloalkyl-C1-4 alkyl- having 0 to 4 additional heteroatoms as a ring member, each of which is independently selected from N, O and S, wherein the 4 to 14-membered heterocycloalkyl formed by R10, R11 and N is optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected Rb substituents;
• Ra1 and Ra2 are each independently selected from H, D, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of Ra1 and Ra2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rd substituents;
• each Rb substituent is independently selected from D, halo, oxo, C1-4 alkyl, C1-6 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-14 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NRcC(═NOH)NRc, NRcC(═NCN)NRcRc, SF5, —P(O)RcRc, —P(O)(ORc)(ORc), NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc or S(O)2NRcRc;
• wherein the C1-4 alkyl, C1-6 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-and (4-14 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1, 2, or 3 independently selected Rd substituents;
• each Rc is independently selected from H, D, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents;
• each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, NRgC(═NOH)NRgRg, NRgC(═NCN)NRgRg, SF5, —P(O)RgRg, —P(O)(ORg)(ORg), S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg;
• wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rn substituents;
• each Rn is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NRo)NRoRo,NRoC(═NRo)NRoRo, NRoC(═NOH)NRoRo, NroC(═NCN)NRoRo, SF5, —P(O)RoRo, —P(O)(ORo)(ORo), S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo;
• each Rd is independently selected from D, oxo, C1-6 alkyl, C1-6 haloalkyl, halo, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, SF5, —P(O)ReRe, —P(O)(ORe)(ORe), S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wheren the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl -C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rd are each optionally substituted with 1, 2, or 3 independently selected Rf substituents;
• each Rd is independently selected from H, D, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Re are each optionally substituted with 1, 2 or 3 independently selected Rg substituents;
• each Rg is independently selected from H, D, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1, 2 or 3 independently selected Rp substituents;
• each Rp is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, SF5, —P(O)RrRr, —P(O)(ORr)(ORr), S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRr, and S(O)2NRrRr;
• or any two Ra1 substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 independently selected Rh substituents;
• each Rh is independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(═NRi)NRiRi, NRiC(═NRi)NRiRi, NRiC(═NOH)NRiRi, NRiC(═NCN)NRiRi, SF5, —P(O)Ri Ri, —P(O)(ORi)(ORi), S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted by 1, 2, or 3 independently selected Rj substituents;
• each Rj is independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(═NRk)NRkRk, NRkC(═NRk)NRkRk, NRkC(═NOH)NRkRk, NRkC(═NCN)NRkRk, SF5, —P(O)RkRk, —P(O)(ORk)(ORk), S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk;
• or two Rj groups attached to the same carbon atom of the 4to 10-membered heterocycloalkyl taken together with the carbon atom to which they attach form a C3-6 cycloalkyl or 4to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;
• or any two Ra2 substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents;
• or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
• or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
• or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
• or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5- , 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
• or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
• or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
• or any two Rr substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
• each Ri, Rk, Ro or Rr is independently selected from H, D, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, and C2-4 alkynyl of Ri, Rk, Ro or Rr are each optionally substituted with 1, 2 or 3 independently selected Rq substituents;
• each Rq is independently selected from D, OH, CN, —COOH, NH2, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, —CONHR12, —NHC(O)R12, —OC(O)R12, —C(O)OR12, —C(O)R12, —SO2R12, —NHSO2R12, —SO2NHR12 and NR2R2, wherein the C1-6 alkyl, phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl of Rq are each optionally substituted with OH, CN, —COOH, NH2, C1-6 alkoxy, C3-6 cycloalkyl or 4-6 membered heterocycloalkyl;
• and
• each R12 is independently C1-6 alkyl;
• provided that:
• when R7 is C1-6 alkyl, R10-L- is other than cyclopropylsulfamoyl and methanesulfonamido;
• when R7 is cyclopropylmethyl, R10-L- is other than methanesulfonamido;
• when R7 is 2-(4-morpholino)ethyl, R10-L- is other than methanesulfonyl;
• and
• the compound is other than 3-(8-aminoimidazo[1,2-a]pyridin-3-yl)-2-(1H-tetrazol-5-yl)benzenesulfonamide.