3-(5-amino-pyrazin-2-yl)-benzenesulfonamide derivatives and related compounds as PI3K-gamma kinase inhibitors

A compound of Formula (I):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• X1 is N or CR1;
• X6 is N or CR6;
• Ring A is a C5-10 bridged bicycloalkyl which is optionally substituted by 1, 2, 3, or 4 independently selected R2 groups;
• Y1 is a C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein the C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl and 4-14 membered heterocycloalkyl of Y1 are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;
• R1, R5, R6, and R7 are each independently selected from H, D, halo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, 4-14 membered heterocycloalkyl-C1-6 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRk)Ra, C(═NRk)NRaRa, NRaC(═NRk)NRaRa NRaC(═NOH)NRaRa, NRaC(═NCN)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, S(O)(═NRk)Ra, SF5, —P(O)RaRa, —P(O)(ORa)(ORa), B(ORa)2 and S(O)2NRaRa, wherein the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 5-14 membered heterocycloalkyl-C1-4 alkyl- of R1, R5, R6 and R7 are each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;
• each R2 is independently selected from D, OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, cyano-C1-6 alkyl, HO—C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, —O-carbamyl, —O—C1-6 alkylcarbamyl, —O-di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino;
• R8 is selected from H, D, CN, OH, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
• R9 is selected from H, D, halo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, 4-14 membered heterocycloalkyl-C1-6 alkyl-, CN, NO2, ORn, SRn, NHORn, C(O)Rn, C(O)NRnRn, C(O)ORn, OC(O)Rn, OC(O)NRnRn, NRnRn, NRnC(O)Rn, NRnC(O)ORn, NRnC(O)NRnRn, C(═NRk)Rn, C(═NRk)NRnRn, NRnC(═NRk)NRnRn, NRnC(═NOH)NRnRn, NRnC(═NCN)NRnRn, NRnS(O)Rn, NRnS(O)2Rn, NRnS(O)2NRnRn, S(O)Rn, S(O)NRnRn, S(O)2Rn, S(O)(═NRk)Rn, SF5, —P(O)RnRn, —P(O)(ORn)(ORn), B(ORn)2 and S(O)2NRnRn, wherein the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-4 alkyl- of R9 are each optionally substituted with 1, 2, 3, or 4 independently selected Rm substituents;
• each Ra is independently selected from H, D, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-6 alkyl-, wherein the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl- and 4-14 membered heterocycloalkyl-C1-6 alkyl- of Ra is each optionally substituted with 1, 2, 3, or 4 independently selected Rb substituents;
• each Rb is independently selected from D, halo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, 4-14 membered heterocycloalkyl-C1-6 alkyl-, CN, NO2, ORc, SRc, NHORc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NRcRc, NRcC(O)Rc, NRc(O)ORc, NRc(O)NRcRc, C(═NRk)Rc, C(═NRk)NRcRc, NRc(═NRk)NRcRc, NRc(═NOH)NRcRc, NRc(═NCN)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc, S(O)(═NRk)Rc, SF5, —P(O)RcRc, —P(O)(ORc)(ORc), B(ORc)2 and S(O)2NRcRc, wherein the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-4 alkyl- of Rb is each optionally substituted with 1, 2, 3, or 4 independently selected Rd substituents;
• each Rc is independently selected from H, D, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-6 alkyl-, wherein the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl- and 4-14 membered heterocycloalkyl-C1-6 alkyl- of Rc is each optionally substituted with 1, 2, 3, or 4 independently selected Rd substituents;
• each Rd is independently selected from D, halo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, 4-14 membered heterocycloalkyl-C1-6 alkyl-, CN, NO2, ORe, SRe, NHORe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NReRe, NReC(O)Re, NReC(O)ORe, NReC(O)NReRe, C(═NRk)Re, C(═NRk)NReRe, NReC(═NRk)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, NReS(O)Re, NReS(O)2Re, NReS(O)2NReRe, S(O)Re, S(O)NReRe, S(O)2Re, S(O)(═NRk)Re, SF5, —P(O)ReRe, —P(O)(ORe)(ORe), B(ORe)2 and S(O)2NReRe, wherein the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-4 alkyl- of Rd is each optionally substituted with 1, 2, 3, or 4 independently selected Rf substituents;
• each Re is independently selected from H, D, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-6 alkyl-, wherein the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl- and 4-14 membered heterocycloalkyl-C1-6 alkyl- of Re is each optionally substituted with 1, 2, 3, or 4 independently selected Rf substituents;
• each Rf is independently selected from D, halo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, 4-14 membered heterocycloalkyl-C1-6 alkyl-, CN, NO2, ORg, SRg, NHORg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NRgRg, NRgC(O)Rg, NRgC(O)ORg, NRgC(O)NRgRg, C(═NRk)Rg, C(═NRk)NRgRg, NRgC(═NRk)NRgRg, NRgC(═NOH)NRgRg, NRgC(═NCN)NRgRg, NRgS(O)Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, S(O)(═NRk)Rg, SF5, —P(O)RgRg, —P(O)(ORg)(ORg), B(ORg)2 and S(O)2NRgRg, wherein the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-4 alkyl- of Rf is each optionally substituted with 1, 2, 3, or 4 independently selected Rh substituents;
• each Rg is independently selected from H, D, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-6 alkyl-, wherein the 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+-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl- and 4-14 membered heterocycloalkyl-C1-6 alkyl- of Rg is each optionally substituted with 1, 2, 3m or 4 independently selected Rh substituents;
• each Rh is independently selected from H, D, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-6 alkyl-, wherein the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl- and 4-14 membered heterocycloalkyl-C1-6 alkyl- of Rh is each optionally substituted with 1 or 2 independently selected Ri substituents;
• each Ri is independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl-, C3-10 cycloalkyl-C1-6 alkyl-, 5-14 membered heteroaryl-C1-6 alkyl-, and 4-14 membered heterocycloalkyl-C1-6 alkyl-;
• each Rk is independently selected from H, CN, OH, C1-4 alkyl, and C1-4 alkoxy;
• each Rm is independently selected from D, OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, cyano-C1-6 alkyl, HO—C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, —O-carbamyl, —O—C1-6 alkylcarbamyl, —O-di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino;
• and
• each Rn is independently selected from H, D, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl;
• or any two Rn substituents, together with the atom to which they attached form a 4-, 5-, 6, or 7-membered heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted by 1, 2, 3, or 4 independently selected Rm groups.