Substituted 2-azabicyclo[3.1.0]hexanes as TRK kinases inhibitors

Abstract

Provided are certain TRK inhibitors of formula (I): ##STR00001##
pharmaceutical compositions thereof, and methods of use thereof.

Claims

1. A compound of formula (I): ##STR00083## or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: formula (I) is formula (Ia) or formula (Ib): ##STR00084## ##STR00085## L is —(CR.sup.C1R.sup.D1).sub.u—, —(CR.sup.C1R.sup.D1).sub.uNR.sup.A1C(O), or —(CR.sup.C1R.sup.D1).sub.uNR.sup.A1S(O).sub.r; R.sup.A1 is hydrogen, C.sub.1-10 alkyl, C.sub.1-4 alkylene-C.sub.3-10 cycloalkyl, C.sub.1-4 alkylene-heterocyclyl, C.sub.1-4 alkylene-aryl, C.sub.1-4 alkylene-heteroaryl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R.sup.X substituents; R.sup.C1 is hydrogen, halogen, C.sub.1-10 alkyl, C.sub.1-4 alkylene-C.sub.3-10 cycloalkyl, C.sub.1-4 alkylene-heterocyclyl, C.sub.1-4 alkylene-aryl, C.sub.1-4 alkylene-heteroaryl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R.sup.X substituents; R.sup.D1 is hydrogen, halogen, C.sub.1-10 alkyl, C.sub.1-4 alkylene-C.sub.3-10 cycloalkyl, C.sub.1-4 alkylene-heterocyclyl, C.sub.1-4 alkylene-aryl, C.sub.1-4 alkylene-heteroaryl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R.sup.X substituents; or R.sup.C1 and R.sup.D1, taken together with the carbon atom(s) to which they are attached, form a 3- to 12-membered ring, wherein the 3- to 12-membered ring optionally contains 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the 3- to 12-membered ring is optionally substituted with one, two, or three independently selected R.sup.X substituents; R.sup.1 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more independently selected R.sup.X substituents; each R.sup.2 is independently hydrogen, halogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C(NR.sup.E2)R.sup.A2, C(NR.sup.E2)NR.sup.A2R.sup.B2, C(NOR.sup.B2)R.sup.A2, C(O)R.sup.A2, C(O)NR.sup.A2R.sup.B2, C(O)OR.sup.A2, NR.sup.A2R.sup.B2, NR.sup.A2C(NR.sup.E2)R.sup.B2, NR.sup.A2C(NR.sup.E2)NR.sup.A2R.sup.B2, NR.sup.A2C(O)R.sup.B2, NR.sup.A2C(O)NR.sup.A2R.sup.B2, NR.sup.A2C(O)OR.sup.B2, NR.sup.A2C(S)NR.sup.A2R.sup.B2, NR.sup.A2S(O).sub.rR.sup.B2, NR.sup.A2S(O)(NR.sup.E2)R.sup.B2, NR.sup.A2S(O)(NR.sup.E2)NR.sup.A2R.sup.B2, NR.sup.A2S(O).sub.2NR.sup.A2R.sup.B2, N═S(O)R.sup.A2R.sup.B2, OR.sup.A2, OC(O)R.sup.A2, OC(O)NR.sup.A2R.sup.B2, OS(O).sub.2R.sup.A2, P(O)R.sup.A2R.sup.B2, P(O)(OR.sup.A2)(OR.sup.B2), S(O).sub.rR.sup.A2, S(O).sub.rNR.sup.A2R.sup.B2, S(O)(NR.sup.E2)R.sup.B2, S(O)(NR.sup.E2)NR.sup.A2R.sup.B2, S(O).sub.2OR.sup.A2, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.X substituents; each R.sup.A2 is independently hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.X substituents; each R.sup.B2 is independently hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.X substituents; or each R.sup.A2 and R.sup.B2, taken together with the atom(s) to which they are attached, independently forms a 4- to 12-membered heterocyclyl, wherein each 4- to 12-membered heterocyclyl optionally and independently contains 1 or 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and further wherein each 4- to 12-membered heterocyclyl is optionally and independently substituted with one, two, or three independently selected R.sup.X substituents; each R.sup.E2 is independently hydrogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C(O)R.sup.a1, C(O)OR.sup.a1, C(O)NR.sup.a1R.sup.b1, OR.sup.a2, SR.sup.a1, S(O).sub.rR.sup.a1, S(O).sub.rNR.sup.a1R.sup.b1, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.Y substituents; R.sup.3 is C(O)R.sup.A3, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R.sup.X substituents; R.sup.A3 is C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R.sup.X substituents; R.sup.4 is hydrogen, halogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C(NR.sup.E4)R.sup.A4C(NR.sup.E4)NR.sup.A4R.sup.B4, C(NOR.sup.B4)R.sup.A4, C(O)R.sup.A4, C(O)NR.sup.A4R.sup.B4, C(O)OR.sup.A4, NR.sup.A4R.sup.B4, NR.sup.A4C(NR.sup.E4)R.sup.B4, NR.sup.A4C(NR.sup.E4)NR.sup.A4R.sup.B4, NR.sup.A4C(O)R.sup.B4, NR.sup.A4C(O)NR.sup.A4R.sup.B4, NR.sup.A4C(O)OR.sup.B4, NR.sup.A4C(S)NR.sup.A4R.sup.B4 NR.sup.A4S(O).sub.rR.sup.B4, NR.sup.A4S(O)(NR.sup.E4)R.sup.B4, NR.sup.A4S(O)(NR.sup.E4)NR.sup.A4R.sup.B4, NR.sup.A4S(O).sub.2NR.sup.A4R.sup.B4, N═S(O)R.sup.A4R.sup.B4 OR.sup.A4, OC(O)R.sup.A4, OC(O)NR.sup.A4R.sup.B4, OS(O).sub.2R.sup.A4, P(O)R.sup.A4R.sup.B4, P(O)(OR.sup.A4)(OR.sup.B4), S(O).sub.rR.sup.A4, S(O).sub.rNR.sup.A4R.sup.B4 S(O)(NR.sup.E4)R.sup.B4, S(O)(NR.sup.E4)NR.sup.A4R.sup.B4, S(O).sub.2OR.sup.A4, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R.sup.X substituents; each R.sup.A4 is independently hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.X substituents; each R.sup.B4 is independently hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.X substituents; or each R.sup.A4 and R.sup.B4, taken together with the atom(s) to which they are attached, independently forms a 4- to 12-membered heterocyclyl, wherein each 4- to 12-membered heterocyclyl optionally and independently contains 1 or 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and further wherein each 4- to 12-membered heterocyclyl is optionally and independently substituted with one, two, or three independently selected R.sup.X substituents; each R.sup.E4 is independently hydrogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C(O)R.sup.a1, C(O)OR.sup.a1, C(O)NR.sup.a1R.sup.b1, OR.sup.a1, S(O).sub.rR.sup.a1, S(O).sub.rNR.sup.a1R.sup.b1, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.Y substituents; each R.sup.X is independently hydrogen, halogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, (CR.sup.c1R.sup.d1).sub.tC(NR.sup.c1)R.sup.a1, (CR.sup.c1R.sup.d1).sub.tC(NR.sup.c1)NR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tC(NOR.sup.b1)R.sup.a1, (CR.sup.c1R.sup.d1).sub.tC(O)R.sup.a1, (CR.sup.c1R.sup.d1).sub.tC(O)NR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tC(O)OR.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(NR.sup.e1)R.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(NR.sup.e1)NR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)R.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)NR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)OR.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(S)NR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.rR.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(NR.sup.e1)R.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(NR.sup.e1)NR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.2NR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tN═S(O)R.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tOR.sup.b1, (CR.sup.c1R.sup.d1).sub.tOC(O)R.sup.b1, (CR.sup.c1R.sup.d1).sub.tOC(O)NR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tOS(O).sub.2R.sup.b1, (CR.sup.c1R.sup.d1).sub.tP(O)R.sup.a1R.sup.b1, P(O)(OR.sup.a1)(OR.sup.b1), (CR.sup.c1R.sup.d1).sub.tS(O).sub.rR.sup.b1, (CR.sup.c1R.sup.d1).sub.tS(O).sub.rNR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tS(O)(NR.sup.e1)R.sup.b1, (CR.sup.c1R.sup.d1).sub.tS(O)(NR.sup.e1)NR.sup.a1R.sup.b1, (CR.sup.c1R.sup.d1).sub.tS(O).sub.2OR.sup.b1, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.Y substituents; each R.sup.a1 is independently hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.Y substituents; each R.sup.b1 is independently hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.Y substituents; or each R.sup.a1 and R.sup.b1, taken together with the atom(s) to which they are attached, independently forms a 4- to 12-membered heterocyclyl, wherein each 4- to 12-membered heterocyclyl optionally and independently contains 1 or 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and further wherein each 4- to 12-membered heterocyclyl is optionally and independently substituted with one, two, or three independently selected R.sup.Y substituents; each R.sup.c1 is independently hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.Y substituents; each R.sup.d1 is independently hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected R.sup.Y substituents; or each R.sup.c1 and R.sup.d1, taken together with the atom(s) to which they are attached, independently forms a 3- to 12-membered ring, wherein each 3- to 12-membered ring optionally and independently contains 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each 3- to 12-membered ring is optionally and independently substituted with one, two, or three independently selected R.sup.Y substituents; each R.sup.e1 is independently hydrogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.1-4 alkylene-C.sub.3-10 cycloalkyl, C(O)R.sup.a2, C(O)NR.sup.a2R.sup.b2, C(O)OR.sup.a2, OR.sup.a2, SR.sup.a2, S(O).sub.rR.sup.a2, S(O).sub.rNR.sup.a2R.sup.b2, or C.sub.3-10 cycloalkyl; each R.sup.Y is independently hydrogen, halogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.1-4 alkylene-heterocyclyl, C.sub.1-4 alkylene-aryl, C.sub.1-4 alkylene-heteroaryl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, (CR.sup.c2R.sup.d2).sub.tC(NR.sup.c2)R.sup.a2, (CR.sup.c2R.sup.d2).sub.tC(NR.sup.c2)NR.sup.a2R.sup.b2, (CR.sup.c2R.sup.d2).sub.tC(NOR.sup.b2)R.sup.a2, (CR.sup.e2R.sup.d2).sub.tC(O)R.sup.a2, (CR.sup.e2R.sup.d2).sub.tC(O)NR.sup.a2R.sup.b2, (CR.sup.c2R.sup.d2).sub.tC(O)OR.sup.b2, (CR.sup.e2R.sup.d2).sub.tNR.sup.a2R.sup.b2, (CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(NR.sup.e2)R.sup.b2, (CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(NR.sup.e2)NR.sup.a2R.sup.b2, (CR.sup.e2R.sup.d2).sub.tNR.sup.a2C(O)R.sup.b2, (CR.sup.e2R.sup.d2).sub.tNR.sup.a2C(O)NR.sup.a2R.sup.b2, (CR.sup.e2R.sup.d2).sub.tNR.sup.a2C(O)OR.sup.b2, (CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(S)NR.sup.a2R.sup.b2, (CR.sup.e2R.sup.d2).sub.tNR.sup.a2S(O).sub.rR.sup.b2, (CR.sup.e2R.sup.d2).sub.tNR.sup.a2S(O)(NR.sup.e2)R.sup.b2, (CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O)(NR.sup.e2)NR.sup.a2R.sup.b2, (CR.sup.e2R.sup.d2).sub.tNR.sup.a2S(O).sub.2NR.sup.a2R.sup.b2, (CR.sup.e2R.sup.d2).sub.tN═S(O)R.sup.a2R.sup.b2, (CR.sup.e2R.sup.d2).sub.tOR.sup.b2, (CR.sup.c2R.sup.d2).sub.tOC(O)R.sup.b2, (CR.sup.c2R.sup.d2).sub.tOC(O)NR.sup.a2R.sup.b2, (CR.sup.c2R.sup.d2).sub.tOS(O).sub.2R.sup.b2, (CR.sup.e2R.sup.d2).sub.tP(O)R.sup.a2R.sup.b2, P(O)(OR.sup.a2)(OR.sup.b2), (CR.sup.e2R.sup.d2).sub.tS(O).sub.rR.sup.b2, (CR.sup.e2R.sup.d2).sub.tS(O).sub.rNR.sup.a2R.sup.b2, (CR.sup.e2R.sup.d2).sub.tS(O)(NR.sup.e2)R.sup.b2, (CR.sup.e2R.sup.d2).sub.tS(O)(NR.sup.e2)NR.sup.a2R.sup.b2, (CR.sup.e2R.sup.d2).sub.tS(O).sub.2OR.sup.b2, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NH.sub.2, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OH, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, and C.sub.3-10 cycloalkyl; each R.sup.a2 is independently hydrogen, C.sub.1-10 alkyl, C.sub.1-4 alkylene-heterocyclyl, C.sub.1-4 alkylene-aryl, C.sub.1-4 alkylene-heteroaryl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NHC.sub.1-10 alkyl, NHC.sub.3-10 cycloalkyl, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NH.sub.2, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OH, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, and C.sub.3-10 cycloalkyl; each R.sup.b2 is independently hydrogen, C.sub.1-10 alkyl, C.sub.1-4 alkylene-heterocyclyl, C.sub.1-4 alkylene-aryl, C.sub.1-4 alkylene-heteroaryl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NHC.sub.1-10 alkyl, NHC.sub.3-10 cycloalkyl, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NH.sub.2, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OH, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, and C.sub.3-10 cycloalkyl; or each R.sup.a2 and R.sup.b2, taken together with the atom(s) to which they are attached, independently forms a 4- to 12-membered heterocyclyl, wherein each 4- to 12-membered heterocyclyl optionally and independently contains 1 or 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and further wherein each 4- to 12-membered heterocyclyl is optionally and independently substituted with one or two substituents independently selected from the group consisting of halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NH.sub.2, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OH, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, and C.sub.3-10 cycloalkyl; each R.sup.c2 is independently hydrogen, halogen, C.sub.1-10 alkyl, C.sub.1-4 alkylene-heterocyclyl, C.sub.1-4 alkylene-aryl, C.sub.1-4 alkylene-heteroaryl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NHC.sub.1-10 alkyl, NHC.sub.3-10 cycloalkyl, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NH.sub.2, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OH, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, and C.sub.3-10 cycloalkyl; each R.sup.d2 is independently hydrogen, halogen, C.sub.1-10 alkyl, C.sub.1-4 alkylene-heterocyclyl, C.sub.1-4 alkylene-aryl, C.sub.1-4 alkylene-heteroaryl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NHC.sub.1-10 alkyl, NHC.sub.3-10 cycloalkyl, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NH.sub.2, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OH, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, and C.sub.3-10 cycloalkyl; or each R.sup.c2 and R.sup.d2, taken together with the atom(s) to which they are attached, independently forms a 3- to 12-membered ring, wherein each 3- to 12-membered ring optionally and independently contains 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each 3- to 12-membered ring is optionally and independently substituted with one or two substituents independently selected from the group consisting of halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, NH.sub.2, NHC.sub.1-10 alkyl, N(C.sub.1-10 alkyl).sub.2, NHC.sub.3-10 cycloalkyl, OH, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, SC.sub.1-10 alkyl, SC.sub.3-10 cycloalkyl, and C.sub.3-10 cycloalkyl; each R.sup.e2 is independently hydrogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.1-4 alkylene-C.sub.3-10 cycloalkyl, C(O)C.sub.1-4 alkyl, C(O)N(C.sub.1-4 alkyl).sub.2, C(O)N(C.sub.3-10 cycloalkyl).sub.2, C(O)OC.sub.1-4 alkyl, C(O)OC.sub.3-10 cycloalkyl, C(O)C.sub.3-10 cycloalkyl, OC.sub.1-10 alkyl, OC.sub.3-10 cycloalkyl, S(O).sub.2C.sub.1-4 alkyl, S(O).sub.2N(C.sub.1-4 alkyl).sub.2, S(O).sub.2N(C.sub.3-10 cycloalkyl).sub.2, S(O).sub.2C.sub.3-10 cycloalkyl, and C.sub.3-10 cycloalkyl; n is 0, 1, 2, 3, or 4; each r is independently 0, 1, or 2; each t is independently 0, 1, 2, 3, or 4; and u is 0.

2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sup.A1 is hydrogen.

3. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sup.1 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or two independently selected R.sup.X substituents.

4. The compound of claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sup.1 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted with one or two independently selected R.sup.X substituents.

5. The compound of claim 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sup.1 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is substituted with one or two substituents independently selected from the group consisting of halogen, CN, NO.sub.2, C.sub.1-10 alkyl, OH, OC.sub.1-10 alkyl, and C.sub.3-10 cycloalkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sup.1 is 2,5-difluorophenyl, 2-chloro-5-fluorophenyl, or 2-methoxy-5-fluoropyridin-3-yl.

7. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R.sup.2 is independently halogen, C.sub.1-10 alkyl, or C.sub.3-10 cycloalkyl, wherein each C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl is optionally and independently substituted with one or more independently selected R.sup.X substituents.

8. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sup.3 is C(O)R.sup.A3, heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R.sup.X substituents.

9. The compound of claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sup.3 is: ##STR00086## each of which is optionally substituted with one or more independently selected R.sup.X substituents.

10. The compound of claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R.sup.X is independently halogen, CN, NO.sub.2, C.sub.1-10 alkyl, C(O)OC(CH.sub.3).sub.3, OH, OCH.sub.3, C.sub.3-10 cycloalkyl, or aryl, wherein each C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, and aryl is optionally and independently substituted with one or more independently selected R.sup.Y substituents.

11. The compound of claim 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R.sup.Y is an independently selected halogen substituent.

12. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R.sup.4 is hydrogen, halogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C(O)R.sup.A4, C(O)NR.sup.A4R.sup.B4, C(O)OR.sup.A4, NR.sup.A4R.sup.B4, NR.sup.A4C(O)R.sup.B4, NR.sup.A4C(O)NR.sup.A4R.sup.B4, NR.sup.A4C(O)OR.sup.B4, NR.sup.A4S(O).sub.rR.sup.B4, NR.sup.A4S(O).sub.2NR.sup.A4R.sup.B4, OR.sup.A4, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R.sup.X substituents.

13. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 0 or 1.

14. The compound of claim 1, wherein the compound is of formula (II): ##STR00087## or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: formula (II) is formula (IIa) or formula (IIb): ##STR00088## ##STR00089##

15. The compound of claim 14, wherein the compound is of formula (III): ##STR00090## or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: formula (III) is formula (IIIa) or formula (IIIb): ##STR00091## ##STR00092## wherein: R.sup.A1 is hydrogen, C.sub.1-10 alkyl, or C.sub.3-10 cycloalkyl, wherein the C.sub.1-10 alkyl or C.sub.3-10 cycloalkyl is optionally substituted with one or more independently selected R.sup.X substituents.

16. The compound of claim 14, wherein the compound is of formula (IV): ##STR00093## or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: formula (IV) is formula (IVa) or formula (IVb): ##STR00094## ##STR00095##

17. The compound of claim 1, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of: ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

19. A method for inhibiting tropomyosin receptor kinase activity in a subject, wherein the method comprises administering to the subject in need thereof an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 18.

20. The method of claim 19, wherein the subject has a cell-proliferative disorder.

21. The method of claim 19, wherein the method further comprises administering to the subject in need thereof an effective amount of a second therapeutic agent.

22. A compound selected from the group consisting of: ##STR00103## or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

(1) Various methods may be developed for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic routes that others may devise.

(2) It will be readily recognized that certain compounds of formula (I) have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.

(3) The compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) can be prepared by, for example, reacting the free acid form of the at least one compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of formula (I) are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.

(4) The free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc).

(5) The N-oxides of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80° C. Alternatively, the N-oxides of the compounds of formula (I) can be prepared from the N-oxide of an appropriate starting material.

(6) Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in a suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80° C.

(7) Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

(8) As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); μL (microliters); psi (pounds per square inch); M (molar); mM (millimolar); i.v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography); Rt (retention time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THE (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et20 (diethyl ether); EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); tBu (tert-butyl); HPLC (high pressure liquid chomatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF (tetra-n-butylammonium fluoride); m-CPBA (meta-chloroperbenzoic acid).

(9) References to ether or Et.sub.2O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions were conducted under an inert atmosphere at RT unless otherwise noted.

(10) .sup.1H NMR spectra were recorded on a Varian Mercury Plus 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).

(11) Low-resolution mass spectra (MS) and compound purity data were acquired on a Shimadzu LC/MS single quadrapole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD). Thin-layer chromatography was performed on 0.25 mm Superchemgroup silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical Co., Ltd).

(12) Synthetic Schemes

(13) A compound of formula (I) or a pharmaceutically acceptable salt thereof may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided below and in the examples. Other reaction schemes could be readily devised by those skilled in the art in view of the present disclosure.

(14) In the reactions described herein after it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.

(15) Synthetic methods for preparing the compounds of the present invention are illustrated in the following Schemes and Examples. Starting materials are commercially available or may be made according to procedures known in the art or as illustrated herein.

(16) The intermediates shown in the following schemes are either known in the literature or may be prepared by a variety of methods familiar to those skilled in the art.

(17) As an illustration, the compound of formula II of the present disclosure can be prepared as shown in Scheme 1. Starting from the intermediates IV, which is either commercially available or known in the literature. VI is prepared by the coupling of IV with the intermediates V through a substitution reaction. Reduction of VI under standard conditions such as zinc dust and NH.sub.4Cl gives VII. Finally, the compounds of formula II can be prepared by reacting VII with R.sub.3COOH in the presence of a coupling reagent or with CDI followed by amino substitution.

Scheme 1

(18) As an illustration, one of the synthetic approaches of the compounds of formula III of the present disclosure in outlined in Scheme 2. As shown in the Scheme, the intermediates IX is prepared by the coupling of the commercially available VIII with the intermediates V through a substitution reaction. Hydrolysis of ester IX gives carboxylic acid X. Intermediate of formula III can be obtained from X via transformations such as sequential condensation and intramolecular cyclization reaction.

Scheme 2

(19) As an illustration of the preparation of intermediates of formula V, one synthetic route of compounds of formula Va is shown in Scheme 3. Starting from Va-A, which is either commercially available or known in the literature. Lactone Va-B can be prepared by treating Va-A with (S)-2-(chloromethyl)oxirane. Hydrolysis of Va-B gives compounds of formula Va-C which can be further transformed into Va-D. Oxidation of Va-D gives aldehyde Va-E. Intermediate Va-H can be prepared from aldehyde Va-E by reacting with wittig reagent followed by hydrolysis of ester and hydroboration-oxidation of alkene. Protecting of free hydroxyl group of Va-H gives compounds of formula Va-I which can be further transformed into Va-J via Curtius rearrangement. Intermediate Va-M can be obtained via a three-step sequence of cleavage of the protecting groups of Va-J, mesylation of hydroxyl group of Va-L, and intramolecular cyclization in the presence of a base. Finally, deprotecting of Va-M leads to compounds of formula Va.

Scheme 3

(20) In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

Example 1

(S)—N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (1)

(21) ##STR00040##

(1R,5S)-1-(2,5-difluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (1a

(22) To a solution of 2-(2,5-difluorophenyl)acetonitrile (5.00 g, 32.7 mmol) and (S)-2-(chloromethyl)oxirane (4.50 g, 49.0 mmol) in THE (40 mL) was added NaHMDS (42.0 ml, 81.8 mmol) dropwise at −20° C. The mixture was stirred at −15° C. for 3 h. The reaction was quenched with water and concentrated. To the mixture was added EtOH (30 mL) and KOH (5.50 g, 38.2 mmol) and stirred at 80° C. overnight. The mixture was adjusted with conc. HCl to pH=2˜3 and then was stirred at 60° C. for 2 h. The mixture was extracted with EtOAc. The organic phase was washed with saturated NaHCO.sub.3 aqueous solution, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel to give title compound (1R,5S)-1-(2,5-difluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (1a). MS-ESI (m/z): 211 [M+1].sup.+.

(1R,2S)-1-(2,5-difluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carboxylic acid (1b

(23) To a solution of (1R,5S)-1-(2,5-difluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (1a) (4.20 g, 20.0 mmol) in MeOH/THF (16/16 mL) at RT was added LiOH (4.20 g, 100 mmol). After stirred at RT for 3 h, the reaction was quenched with water and adjusted with 6 N HCl to pH=4˜5. The mixture was extracted with EtOAc (4×80 mL). The extracts were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of (1R,2S)-1-(2,5-difluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carboxylic acid (1b), which was used for next step without further purification. MS-ESI (m/z): 229 [M+1].sup.+.

Ethyl (1R,2S)-1-(2,5-difluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carboxylate (1c

(24) A mixture of (1R,2S)-1-(2,5-difluorophenyl)-2-(hydroxymethyl)cyclopropane-1-carboxylic acid (1b) (100 mg, 0.439 mmol), KHCO.sub.3 (57.0 mg, 0.570 mmol) and EtBr (144 mg, 1.32 mmol) in DMF (5 mL) was stirred at 23° C. for 4 h. The reaction was quenched with water and extracted with EtOAc. The extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of ethyl (1R,2S)-1-(2,5-difluorophenyl)-2-(hydroxymethyl) cyclopropane-1-carboxylate (1c), which was used for next step without further purification. MS-ESI (m/z): 257 [M+1].sup.+.

Ethyl (1R,2S)-1-(2,5-difluorophenyl)-2-formylcyclopropane-1-carboxylate (1d

(25) To a solution of ethyl (1R,2S)-1-(2,5-difluorophenyl)-2-(hydroxymethyl)-cyclopropane-1-carboxylate (1c) (98.0 mg, 0.380 mmol) in DCM (4 mL) was added DMP (243 mg, 0.570 mmol) at RT. The mixture was stirred at RT for 4 h and quenched with saturated NaHCO.sub.3 aqueous solution. The mixture was extracted with DCM. The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and the solvent was concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (10:1) to give title compound ethyl (1R,2S)-1-(2,5-difluorophenyl)-2-formylcyclopropane-1-carboxylate (1d). MS-ESI (m/z): 255 [M+1]+.

Ethyl (1R,2R)-1-(2,5-difluorophenyl)-2-vinylcyclopropane-1-carboxylate (1e

(26) To a solution of ethyl (1R,2S)-1-(2,5-difluorophenyl)-2-formylcyclopropane-1-carboxylate (1d) (100 mg, 0.394 mmol) and methyltriphenylphosphonium iodide (207 mg, 0.512 mmol) in DCM (3 mL) was added t-BuOK (62.0 mg, 0.552 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. The mixture was evaporated to give the crude product of ethyl (1R,2R)-1-(2,5-difluorophenyl)-2-vinylcyclopropane-1-carboxylate (1e), which was used for next step directly.

(1R,2R)-1-(2,5-difluorophenyl)-2-vinylcyclopropane-1-carboxylic acid (1f

(27) A mixture of ethyl (1R,2R)-1-(2,5-difluorophenyl)-2-vinylcyclopropane-1-carboxylate (1e) (99.3 mg, 0.394 mmol) and NaOH (158 mg, 3.94 mmol) in MeOH (1 mL) was stirred at 55° C. for 4 h. The reaction was quenched with water and washed with DCM. The aqueous layer was acidified with HCl to pH=3˜4. The mixture was extracted with EtOAc. The extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, and the solvent was concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (5:1) to give the title compound (1R,2R)-1-(2,5-difluorophenyl)-2-vinylcyclopropane-1-carboxylic acid (1f). MS-ESI (m/z): 225 [M+1].sup.+.

(1R,2R)-1-(2,5-difluorophenyl)-2-(2-hydroxyethyl)cyclopropane-1-carboxylic acid (1g

(28) To a solution of (1R,2R)-1-(2,5-difluorophenyl)-2-vinylcyclopropane-1-carboxylic acid (1f) (30.0 mg, 0.134 mmol) in THE (1 mL) was added a solution of BH.sub.3 in THF (0.33 mL, 0.33 mmol) dropwise at 0° C. The mixture was stirred at RT for 0.2 h. Then NaOH (6 N, 0.2 mL) and H.sub.2O.sub.2 (30%, 152 mg, 1.34 mmol) was added to the mixture at RT and stirred at RT for 20 min. The reaction was quenched with water and washed with DCM. The aqueous layer was acidified with HCl to pH=3-4. The mixture was extracted with EtOAc. The extracts were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, and the solvent was concentrated to give the crude product of (1R,2R)-1-(2,5-difluorophenyl)-2-(2-hydroxyethyl)cyclopropane-1-carboxylic acid (1g), which was used for next step directly. MS-ESI (m/z): 243 [M+1].sup.+.

(1R,2R)-2-(2-((tert-butyidimethylsilyl)oxy)ethyl)-1-(2,5-difluorophenyl)cyclopropane-1-carboxylic acid (1h

(29) To a solution of (1R,2R)-1-(2,5-difluorophenyl)-2-(2-hydroxyethyl) cyclopropane-1-carboxylic acid (1g) (385 mg, 1.60 mmol) in DCM/DMF (4 mL/2 mL) was added TBSCl (483 mg, 3.20 mmol) and imidazole (433 mg, 6.40 mmol) at 0° C. The mixture was stirred at 20° C. for overnight and concentrated. The mixture was diluted with saturated Na.sub.2CO.sub.3 aqueous solution (30 mL), and the mixture was washed with EtOAc. The aqueous layer was acidified with HCl to pH=3-4 and was extracted with EtOAc. The extracts were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of (1R,2R)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(2,5-difluorophenyl)cyclopropane-1-carboxylic acid (1h), which was used for next step directly. MS-ESI (m/z): 357 [M+1].sup.+.

Benzyl ((1R,2R)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(2,5-difluorophenyl)cyclopropyl)carbamate (1i

(30) To a solution of (1R,2R)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(2,5-difluorophenyl)cyclopropane-1-carboxylic acid (1h) (383 mg, 1.08 mmol) and BnOH (1.17 g, 10.8 mmol) in Toluene (8 mL) was added DPPA (446 mg, 1.62 mmol) and TEA (273 mg, 2.70 mmol) at RT. The mixture was stirred at 85° C. for overnight. The reaction was quenched with water and the mixture was extracted with EtOAc. The extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, and the solvent was concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (20:1) to give the title compound benzyl ((1R,2R)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(2,5-difluorophenyl)cyclopropyl)carbamate (1i). MS-ESI (m/z): 462 [M+1].sup.+.

Benzyl ((1R,2R)-1-(2,5-difluorophenyl)-2-(2-hydroxyethyl)cyclopropyl) carbamate (1j

(31) To a solution of benzyl ((1R,2R)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(2,5-difluorophenyl)cyclopropyl)carbamate (1i) (15.0 mg, 0.033 mmol) in THF (1 mL) was added TBAF (1M, 0.16 mL) at RT. The mixture was stirred at 25° C. for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc. The extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of benzyl ((1R,2R)-1-(2,5-difluorophenyl)-2-(2-hydroxyethyl)cyclopropyl)carbamate (1j), which was used for next step directly. MS-ESI (m/z): 348 [M+1].sup.+.

2-((1R,2R)-2-(((benzyloxy)carbonyl)amino)-2-(2,5-difluorophenyl)cyclopropyl)ethyl methanesulfonate (1k

(32) To a solution of benzyl ((1R,2R)-1-(2,5-difluorophenyl)-2-(2-hydroxyethyl) cyclopropyl)carbamate (1j) (246 mg, 0.710 mmol) and MsCl (122 mg, 1.06 mmol) in DCM (2 mL) was added TEA (180 mg, 1.76 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. The reaction was quenched with water and the mixture was extracted with DCM. The extracts were washed sequentially with 1 N HCl, water and brine, dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of 2-((1R,2R)-2-(((benzyloxy)carbonyl)amino)-2-(2,5-difluorophenyl)-cyclopropyl)ethyl methanesulfonate (1k), which was used for next step directly. MS-ESI (m/z): 426 [M+1]+.

Benzyl (1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

(33) To a solution of 2-((1R,2R)-2-(((benzyloxy)carbonyl)amino)-2-(2,5-difluorophenyl)cyclopropyl)ethyl methanesulfonate (1k) (302 mg, 0.710 mmol) in DMF (6 mL) was added NaH (60% in oil, 43 mg) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The reaction was quenched with water. The mixture was extracted with EtOAc and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (15:1˜10:1) to give title compound benzyl (1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1l). MS-ESI (m/z): 330 [M+1]+.

(1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane (1m

(34) A mixture of benzyl (1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1l) (40.0 mg, 0.122 mmol) and conc. HCl (1 mL) in MeOH/CH.sub.3CN (0.1 mL/0.5 mL) was stirred at 60° C. for overnight. The mixture was basified with aq. NaOH to pH=10, and the aq. phase was extracted with DCM. The extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product of (1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane (1m), which was used for next step directly. MS-ESI (m/z): 196 [M+1]+.

5-Chloro-3-nitropyrazolo[1,5-a]pyrimidine (1n

(35) 5-Chloro-3-nitropyrazolo[1,5-a]pyrimidine (In) was prepared according to the method described in US 20170281632A1. MS-ESI (m/z): 199 [M+1]+.

5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-nitropyrazolo[1,5-a]pyrimidine (1o

(36) To a solution of (1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexane (1m) (27 mg, 0.138 mmol) and TEA (35 mg, 0.345 mmol) in DMF (1.5 mL) was added 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine (in) (36 mg, 0.18 mmol) at RT. The mixture was stirred at 50° C. for 1.5 h under N.sub.2 atmosphere. The reaction was quenched with water and the mixture was extracted with EtOAc. The extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (1.5:1) to give the title compound 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]-hexan-2-yl)-3-nitropyrazolo[1,5-a]pyrimidine (1o). MS-ESI (m/z): 358 [M+1].sup.+.

5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-amine (1p

(37) A mixture of 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-nitropyrazolo[1,5-a]pyrimidine (1o) (15 mg, 0.042 mmol), NH.sub.4C.sub.1 (23 mg, 0.42 mmol) and Fe powder (12 mg, 0.21 mmol) in EtOH/H.sub.2O (1 mL/1 mL) was heated at 70° C. for 1 h. The reaction was quenched with saturated NaHCO.sub.3 aqueous solution and extracted with EtOAc (2×30 mL). The extracts were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (25:1) to give the title compound 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl) pyrazolo[1,5-a]pyrimidin-3-amine (1p). MS-ESI (m/z): 328 [M+1].sup.+.

(S)—N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (1)

(38) To a solution of 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]-hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-amine (1p) (11 mg, 0.035 mmol) in DCM (3 mL) at RT was added CDI (11 mg, 0.070 mmol). The mixture was stirred at RT for 2 h. Then, (S)-pyrrolidin-3-ol (6.0 mg, 0.070 mmol) was added. The mixture was stirred at RT for 3 h. The reaction was quenched with water. The mixture was extracted with DCM (3×10 mL). The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and evaporated. The residue was purified by column chromatography on silica gel, eluting with DCM/MeOH (20:1) to give the title compound (S)—N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (1). MS-ESI (m/z): 441 [M+1].sup.+.

Example 2

(S)—N-(5-((1R,5S)-1-(2-chloro-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (2)

(39) ##STR00041##

(40) The title compound (S)—N-(5-((1R,5S)-1-(2-chloro-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (2) was prepared according to the synthetic method of 1 by replacing 2-(2,5-difluorophenyl)-acetonitrile with 2-(2-chloro-5-fluorophenyl)acetonitrile. MS-ESI (m/z): 457 [M+1].sup.+.

Example 3

(R)—N-(5-((1R,5S)-1-(2-chloro-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (3)

(41) ##STR00042##

(42) The title compound (R)—N-(5-((1R,5S)-1-(2-chloro-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (3) was prepared according to the synthetic method of 1 by replacing 2-(2,5-difluorophenyl) acetonitrile and (S)-pyrrolidin-3-ol with 2-(2-chloro-5-fluorophenyl)acetonitrile and (R)-pyrrolidin-3-ol. MS-ESI (m/z): 457 [M+1]+.

Example 4

(43) (S)—N-(6-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (4)

(44) ##STR00043##

(45) The title compound (S)—N-(6-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo-[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (4) was prepared according to the synthetic method of 1 by replacing 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine (in) with 6-chloro-3-nitroimidazo[1,2-b]pyridazine. MS-ESI (m/z): 441 [M+1].sup.+.

Example 5

2-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-5-isopropyl-1,3,4-oxadiazole (5

(46) ##STR00044##

Ethyl 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate (5a

(47) The title compound ethyl 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo-[3.1.0]hexan-2-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate (5a) was prepared according to the synthetic method of 1o by replacing 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine (in) with ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate. MS-ESI (m/z): 385 [M+1].sup.+.

5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5b

(48) A mixture of ethyl 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]-hexan-2-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate (5a) (1.22 g, 3.18 mmol) and LiOH (763 mg, 31.8 mmol) in MeOH (30 mL) was stirred at 70° C. for overnight. The reaction mixture was diluted with water and acidified with HCl to pH=6. The mixture was extracted with DCM. The extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5b), which was used for next step directly. MS-ESI (m/z): 357 [M+1].sup.+.

Isobutyrohydrazide (5c

(49) Isobutyrohydrazide (5c) was prepared according to the method described in WO2016/097869.

5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-N′-isobutyrylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (5d

(50) A mixture of isobutyrohydrazide (5c) (233 mg, 1.68 mmol), 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5b) (300 mg, 0.842 mmol), DIPEA (435 mg, 3.37 mmol) and HATU (480 mg, 1.26 mmol) in DMF (10 mL) was stirred at RT for overnight. The reaction was quenched with water and extracted with EtOAc. The extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (1:1) to give the title compound 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-N-isobutyrylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (5d). MS-ESI (m/z): 441 [M+1]+.

2-(5-((1R,5S)-1-(2,5-difluorophenol)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-5-isopropyl-1,3,4-oxadiazole (5)

(51) To a solution of 5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]-hexan-2-yl)-N′-isobutyrylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (5d) (70.0 mg, 0.160 mmol) in DCM (2 mL) was added pyridine (29 mg, 0.37 mmol) at 0° C. To the reaction mixture was added Tf.sub.2O (95 mg, 0.34 mmol) at −10° C. The mixture was stirred at −10° C. for 1 h, then warmed to 0° C. and stirred at 0° C. for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (1:4) to give the title compound 2-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-5-isopropyl-1,3,4-oxadiazole (5). MS-ESI (m/z): 423 [M+1].sup.+.

(52) Following essentially the same procedures described for Examples 1-5 or using similar synthetic methods or strategies, Examples 6-43 listed in Table 1 were prepared. The structures and names of Examples 6-43 are given in Table 1.

(53) TABLE-US-00001 TABLE 1 EXAMPLE STRUCTURE NAME DATA 6 (S)-N-(5-((1S,5R)-l-(2,5-difluorophenyl)-2- azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide MS-ESI (m/z): 441 [M + 1].sup.+ 7 (R)-N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2- azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide MS-ESI (m/z): 441 [M + 1].sup.+ 8 (R)-N-(6-((1R,5S)-1-(2,5-difluorophenyl)-2- azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazin- 3-yl)-3-hydroxypyrrolidine-1-carboxamide MS-ESI (m/z): 441 [M + 1].sup.+ 9 (S)-N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2- azabicyclo[3.1.0]hexan-2-yl)pyrazolo [1,5-a]pyrimidin-3-yl)- 3-methoxypyrrolidine-1-carboxamide MS-ESI (m/z): 455 [M + 1].sup.+ 10 (R)-N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2- azabicyclo[3.1.0]hexan-2-yl)pyrazolo [1,5-a]pyrimidin-3-yl)- 3-fluoropyrrolidine-1-carboxamide MS-ESI (m/z): 443 [M + 1].sup.+ 11 0 (R)-N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2- azabicyclo[3.1.0]hexan-2-yl)pyrazolo [1,5-a]pyrimidin-3-yl)- 3-fluoropyrrolidine-l-carboxamide MS-ESI (m/z): 443 [M + 1].sup.+ 12 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 3,3-difluoropyrrolidine-1-carboxamide MS-ESI (m/z): 461 [M + 1].sup.+ 13 tert-butyl 6-((5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate MS-ESI (m/z): 552 [M + 1].sup.+ 14 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 2,6-diazaspiro[3.3]heptane-2-carboxamide MS-ESI (m/z): 452 [M + 1].sup.+ 15 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl) picolinamide MS-ESI (m/z): 433 [M + 1].sup.+ 16 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)-6-methylpicolinamide MS-ESI (m/z): 447 [M + 1].sup.+ 17 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 3-methylpicolinamide MS-ESI (m/z): 447 [M + 1].sup.+ 18 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1,0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 5-methylpicolinamide MS-ESI (m/z): 447 [M + 1].sup.+ 19 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 5-fluoropicolinamide MS-ESI (m/z): 451 [M + 1].sup.+ 20 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 5-methylpyrimidine-2-carboxamide MS-ESI (m/z): 448 [M + 1].sup.+ 21 0 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 5-fluoropyrimidine-2-carboxamide MS-ESI (m/z): 452 [M + 1].sup.+ 22 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 5-methylpyrimidine-2-carboxamide MS-ESI (m/z): 448 [M + 1].sup.+ 23 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1,0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 5-methylpyrazine-2-carboxainide MS-ESI (m/z): 448 [M + 1].sup.+ 24 5-chloro-N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2- azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a] pyrimidin-3-yl)picolinamide MS-ESI (m/z): 468 [M + 1].sup.+ 25 2-(tert-butyl)-5-(5-((1R,5S)-1-(2,5-difluorophenyl)- 2-azabicyclo[3.1,0]hexan-2-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-1,3,4-oxadiazole MS-ESI (m/z): 437 [M + 1].sup.+ 26 2-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)-5-isopropyl-1,3,4-thiadiazole MS-ESI (m/z): 439 [M + 1].sup.+ 27 2-(tert-butyl)-5-(5-((1R,5S)-1-(2,5-difluorophenyl)- 2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-1,3,4-thiadiazole MS-ESI (m/z): 453 [M + 1].sup.+ 28 2-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)isoindolin-1-one MS-ESI (m/z): 444 [M + 1].sup.+ 29 2-cyclopropyl-5-(5-((1R,5S)-1-(2,5-difluorophenyl)- 2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-1,3,4-thiadiazole MS-ESI (m/z): 437 [M + 1].sup.+ 30 2-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 5-(trifluoromethyl)-1,3,4-thiadiazole MS-ESI (m/z): 465 [M + 1].sup.+ 31 0 5-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)-2-isopropylthiazole MS-ESI (m/z): 438 [M + 1].sup.+ 32 2-cyclopropyl-5-(5-((1R,5S)-1-(2,5-difluorophenyl)- 2-azabicyclo[3.1,0]hexan-2-yl)pyrazolo[1,5-a] pyrimidin-3-yl)thiazole MS-ESI (m/z): 436 [M + 1].sup.+ 33 5-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)-2-(trifluoromethyl)thiazole MS-ESI (m/z): 464 [M + 1].sup.+ 34 2-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3- yl)-5-isopropylthiazole MS-ESI (m/z): 438 [M + 1].sup.+ 35 5-cyclopropyl-2-(5-((1R,5S)-1-(2,5-difluorophenyl)- 2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a] pyrimidin-3-yl)thiazole MS-ESI (m/z): 436 [M + 1].sup.+ 36 (5)-N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin- 3-yl)-3-hydroxypyrrolidine-2,2,5,5-d.sub.4-l- carboxamide MS-ESI (m/z): 445 [M + 1].sup.+ 37 (S)-N-(5-((1R,5S)-1-(5-fluoro-2-methoxypyridin- 3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1- carboxamide MS-ESI (m/z): 454 [M + 1].sup.+ 38 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 4-methylbenzamide MS-ESI (m/z): 446 [M + 1].sup.+ 39 N-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)- 4-methylbenzenesulfonamide MS-ESI (m/z): 482 [M + 1].sup.+ 40 (5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl) ((S)-3-hydroxypyrrolidin-1-yl)methanone MS-ESI (m/z): 426 [M + 1].sup.+ 41 0 N.sup.1-(5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-y l)pyrazolo[1,5-a]pyrimidin-3- yl)-N.sup.2,N.sup.2-dimethyloxalamide MS-ESI (m/z): 427 [M + 1].sup.+ 42 cyclopentyl (5-((1R,5S)-1-(2,5-difluorophenyl)-2-azabicyclo [3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl) carbamate MS-ESI (m/z): 440 [M + 1].sup.+ 43 (1R,5S)-1-(2,5-difluorophenyl)-N-(5-((1R,5S)-1- (2,5-difluorophenyl)-2-azabicyclo[3.1.0]hexan-2- yl)pyrazolo[1,5-a]pyrimidin-3-yl)-2-azabicyclo [3.1.0]hexane-2-carboxamide MS-ESI (m/z): 549 [M + 1].sup.+
Biological Activity

(54) MTS testing kit was purchased from Promega (Madison, Wis., USA). The RPMI-1640, Fetal bovine serum and Penicillin-Streptomycin were purchased from Gibco (San Francisco, Calif., USA). Dimethyl sulfoxide (DMSO) and Puromycin were purchased from Sigma (St. Louis, Mo., USA). Mouse interleukin-3 (IL-3) was purchased from Cell signaling Technology (Boston, Mass., USA).

(55) To investigate whether a compound is able to inhibit the activity of TRK in cells, a mechanism-based assay using KM12 cells was developed. In this assay, inhibition of TRK was detected by the inhibition of KM12 cells proliferation. KM12 cells were cultured in culture flasks to 40-80% confluence in RPMI-1640 plus 10% fetal bovine serum. Cells were collected and plated onto 96-well plates at 1000 cells/well. Plates were incubated at 37° C., with 5% CO.sub.2 for 4 h. Compounds were added to the plates, the final compound concentrations were 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM. Place plates at 37° C., with 5% CO.sub.2 for KM12 cells 72 h. 20 μl MTS/100 μl medium mixture solution were added to each well and incubate the plates for exactly 2 h. Stop the reaction by adding 25 μl 10% SDS per well. Measure absorbance at 490 nm and 650 nm (reference wavelength). IC50 was calculated using GraphPad Prism 5.0.

(56) To investigate whether a compound is able to inhibit the activity of TRK fusion mutation in cells, a mechanism-based assay using engineered Ba/F3 cell lines stably overexpressing oncogenic rearrangement or gene mutation of TRK (TPM3-TRKA, TPM3-TRKA-G595R, AFAP1-TRKB, ETV6-TRKC and ETV6-TRKC-G623R) were developed. In this assay, inhibition of TRK fusion mutation was detected by the cell proliferation inhibition of engineered Ba/F3 cells. Engineered Ba/F3 cells were cultured in culture flasks to 40-80% confluence in RPMI-1640 supplemented with 10% fetal bovine serum, 2 ug/mL puromycin. Cells were collected and plated onto 96-well plates at desired cell density (Ba/F3-TPM3-TRKA: 3×104/mL, Ba/F3-TPM3-TRKA-G595R: 1×105/mL, Ba/F3-AFAP1-TRKB: 1×105/mL, Ba/F3-ETV6-TRKC: 3×104/mL, Ba/F3-ETV6-TRKC-G623R: 3×104/mL). Plates were incubated at 37° C., with 5% CO.sub.2 for 4 h. Compounds were then added to the plates with the final compound concentrations of 10000, 3333, 1111, 270, 123, 41.2, 13.7, 4.6 and 1.5 nM. Plates were incubated at 37° C., with 5% CO.sub.2 for 72 h. A mixture of 20 μl MTS/100 μl medium were added to each well and the plates were incubated at 37° C., with 5% CO.sub.2 for exactly 2 h. The reaction was stopped by adding 25 μl of 10% SDS per well. The absorbance was measured at 490 nm and 650 nm (reference wavelength). IC50 was calculated using GraphPad Prism 5.0 software.

(57) Select compounds prepared as described above were assayed according to the biological procedures described herein. The results are given in the table 2.

(58) TABLE-US-00002 TABLE 2 KM12 IC.sub.50 ETV6-TRKC TPM3-TRKA- TPM3-TRKA ETV6-TRKC- AFAP1-TRKB Example (nM) IC.sub.50 (nM) G595R IC.sub.50 (nM) IC.sub.50 (nM) G623R IC.sub.50 (nM) IC.sub.50 (nM) 1 1 1 / 3 / 14 2 42 7 / 44 / / 3 36 17 / 47 / / 4 2 1 / 5 / / 5 9 / 40 6 / / 7 20 3 / 3 / / 8 25 5 / 5 / / 9 42 4 / / / / 10 23 2 / / / / 11 53 / / / / / 12 2 9 / / / / 15 1 1 18 1 / / 16 1 1  5 1 / / 17 1 1 / 2 / / 18 2 1 / 33 / / 19 1 1 / 2 / / 20 6 1 67 14 / / 21 24 1 / 10 / / 22 1 1 / 1 / / 24 38 16 / / / / 26 4 1 15 2 6 / 27 11 11 21 2 20 / 28 / 2 / 19 / /