Macrocyclic compounds as TRK kinases inhibitors

Abstract

Provided are certain TRK inhibitors, pharmaceutical compositions thereof, and methods of use thereof.

Claims

1. A compound of formula (I): ##STR00144## or a pharmaceutically acceptable salt thereof, wherein X is selected from CR.sup.X and N; Y is selected from O and N, wherein when Y is O, R.sup.4 is absent; Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.6 and Z.sup.7 are independently selected from CR.sup.X and N; Z.sup.4 and Z.sup.5 are independently selected from C and N, wherein when one of Z.sup.4 and Z.sup.5 is N, then the other of Z.sup.4 and Z.sup.5 is C; L is selected from —(CR.sup.CR.sup.D).sub.u—, —(CR.sup.CR.sup.D).sub.uO(CR.sup.CR.sup.D).sub.t—, —(CR.sup.CR.sup.D).sub.uNR.sup.A(CR.sup.CR.sup.D).sub.t— and —(CR.sup.CR.sup.D).sub.uS(CR.sup.CR.sup.D).sub.t—; each R.sup.1 is independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, NO.sub.2, —NR.sup.A1R.sup.B1, —OR.sup.A1, —C(O)R.sup.A1, —C(═NR.sup.E1)R.sup.A1, —C(═N—OR.sup.B1)R.sup.A1, —C(O)OR.sup.A1, —OC(O)R.sup.A1, —C(O)NR.sup.A1R.sup.B1, —NR.sup.A1C(O)R.sup.B1, —C(═NR.sup.E1)NR.sup.A1R.sup.B1, —NR.sup.A1C(═NR.sup.E1)R.sup.B1, —OC(O)NR.sup.A1R.sup.B1, —NR.sup.A1C(O)OR.sup.B1, —NR.sup.A1C(O)NR.sup.A1R.sup.B1, —NR.sup.A1C(S)NR.sup.A1R.sup.B1, —NR.sup.A1C(═NR.sup.E1)NR.sup.A1R.sup.B1, —S(O).sub.rR.sup.A1, —S(O)(═NR.sup.E1)R.sup.B1, —N═S(O)R.sup.A1R.sup.B1, —S(O).sub.2OR.sup.A1, —OS(O).sub.2R.sup.A1, —NR.sup.A1S(O).sub.rR.sup.B1, —NR.sup.A1S(O)(═NR.sup.E1)R.sup.B1, —S(O).sub.rNR.sup.A1R.sup.B1, —S(O)(═NR.sup.E1)NR.sup.A1R.sup.B1, —NR.sup.A1S(O).sub.2NR.sup.A1R.sup.B1, —NR.sup.A1S(O)(═NR.sup.E1)NR.sup.A1R.sup.B1, —P(O)R.sup.A1R.sup.B1, and —P(O)(OR.sup.A1)(OR.sup.B1), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; R.sup.2 is selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, —NR.sup.A2R.sup.B2, —OR.sup.A2, —C(O)R.sup.A2, —C(O)OR.sup.A2, —OC(O)R.sup.A2, —C(O)NR.sup.A2R.sup.B2, —NR.sup.A2C(O)R.sup.B2 and —S(O).sub.rR.sup.A2, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; each R.sup.3 and R.sup.3′ are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, —NR.sup.A3R.sup.B3, —OR.sup.A3, —C(O)R.sup.A3, —C(O)OR.sup.A3, —OC(O)R.sup.A3, —C(O)NR.sup.A3R.sup.B3, —NR.sup.A3C(O)R.sup.B3, and —S(O).sub.rR.sup.A3, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; or “R.sup.2 and R.sup.3,” or “R.sup.2 and R.sup.3′” together with the carbon atoms to which they are attached form a C.sub.5-7 cycloalkyl or heterocyclic ring of 3 to 7 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X groups; or R.sup.3 and R.sup.3′ together with the carbon atoms to which they are attached form a C.sub.3-7 cycloalkyl or heterocyclic ring of 4 to 7 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X groups; R.sup.4 is selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; or R.sup.3 and R.sup.4 together with the atoms to which they are attached form a heterocyclic ring of 4 to 7 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X groups; R.sup.5 is selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl and C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; R.sup.6 is selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl and C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; or R.sup.5 and R.sup.6 together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X groups; each R.sup.A, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.B1, R.sup.B2 and R.sup.B3 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; or each “R.sup.A1 and R.sup.B1”, “R.sup.A2 and R.sup.B2” and “R.sup.A3 and R.sup.B3”, together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X groups; R.sup.C and R.sup.D are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; or R.sup.C and R.sup.D together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R.sup.X groups; R.sup.E1 is selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, —S(O).sub.rR.sup.a1, —C(O)R.sup.a1, C(O)OR.sup.a1, —C(O)NR.sup.a1R.sup.b1 and —S(O).sub.rNR.sup.a1R.sup.b1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.Y; each R.sup.X is independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, halogen, CN, NO.sub.2, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(O)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(═NR.sup.e1)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(═N—OR.sup.b1)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(O)OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOC(O)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(═NR.sup.e1)NR.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.tOC(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(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(S)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.a1).sub.tR.sup.a1C(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O)(═NR.sup.e1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tN═S(O)R.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.2OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOS(O).sub.2R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.a1) R.sup.a1S(O)(═NR.sup.e1)R.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)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.a1).sub.tNR.sup.a1S(O).sub.2NR.sup.a1R.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.tP(O)R.sup.a1R.sup.b1 and —(CR.sup.c1R.sup.d1).sub.tP(O)(OR.sup.a1)(OR.sup.b1) wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.Y; each R.sup.a1 and each R.sup.b1 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.Y; or R.sup.a1 and R.sup.b1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.Y groups; each R.sup.c1 and each R.sup.d1 are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.Y; or R.sup.c1 and R.sup.d1 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R.sup.Y groups; each R.sup.e1 is independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, CN, NO.sub.2, —OR.sup.a2, —SR.sup.a2, —S(O).sub.rR.sup.a2, —C(O)R.sup.a2, —C(O)OR.sup.a2, —S(O).sub.rNR.sup.a2R.sup.b2 and —C(O)NR.sup.a2R.sup.b2; each R.sup.Y is independently selected from C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, halogen, CN, NO.sub.2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(O)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(═NR.sup.e2)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(═N—OR.sup.b2)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(O)OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOC(O)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(O)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(═NR.sup.e2)NR.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.tOC(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(O)OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(S)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.rR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O)(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tN═S(O)R.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.2OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOS(O).sub.2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O).sub.rR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O)(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.rNR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O)(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O).sub.2NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O)(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tP(O)R.sup.a2R.sup.b2 and —(CR.sup.c2R.sup.d2).sub.tP(O)(OR.sup.a2)(OR.sup.b2), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from OH, CN, amino, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.a2 and each R.sup.b2 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino, di(C.sub.1-10 alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; or R.sup.a2 and R.sup.b2 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.c2 and each R.sup.d2 are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino, di(C.sub.1-10 alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; or R.sup.c2 and R.sup.d2 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.e2 is independently selected from hydrogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, —C(O)C.sub.1-4 alkyl, —C(O)C.sub.3-10 cycloalkyl, —C(O)OC.sub.1-4 alkyl, —C(O)OC.sub.3-10 cycloalkyl, —C(O)N(C.sub.1-4 alkyl).sub.2, —C(O)N(C.sub.3-10 cycloalkyl).sub.2, —S(O).sub.2C.sub.1-4 alkyl, —S(O).sub.2C.sub.3-10 cycloalkyl, —S(O).sub.2N(C.sub.1-4 alkyl).sub.2 and —S(O).sub.2N(C.sub.3-10 cycloalkyl).sub.2; m is selected from 0, 1, 2, 3 and 4; n is selected from 1, 2, 3 and 4; p is selected from 1, 2, 3 and 4; each r is independently selected from 0, 1 and 2; each t is independently selected from 0, 1, 2, 3 and 4; each u is independently selected from 0, 1, 2, 3 and 4.

2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein n is 1 or 2 and R.sup.3 and R.sup.3′ are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, —OR.sup.A3 and C.sub.3-10 cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from R.sup.X.

3. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein n is 1 or 2 and R.sup.3 and R.sup.3′ are independently selected from hydrogen, fluorine, methyl and OH.

4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein n is 1 or 2 and R.sup.3′ is hydrogen, shown as formula (II): ##STR00145##

5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sup.3 and R.sup.3′ together with the carbon atoms to which they are attached form a C.sub.3-7 cycloalkyl or heterocyclic ring of 4 to 7 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X groups.

6. The compound of claim 5 or the pharmaceutically acceptable salt thereof, wherein R.sup.3 and R.sup.3′ together with the carbon atoms to which they are attached form cyclopropyl or cyclobutyl.

7. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein X is CH; or X is N.

8. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, halogen and CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from R.sup.X.

9. The compound of claim 8 or the pharmaceutically acceptable salt thereof, wherein R.sup.1 is fluorine and m is 1.

10. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein L is selected from —(CR.sup.CR.sup.D).sub.uO(CR.sup.CR.sup.D).sub.t—, —CR.sup.CR.sup.D—, —NR.sup.A— and —(CR.sup.CR.sup.D).sub.uS(CR.sup.CR.sup.D).sub.t—.

11. The compound of claim 10 or the pharmaceutically acceptable salt thereof, wherein L is selected from —O—, —CH.sub.2—, —NH— and —S—.

12. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sup.2 is independently selected from hydrogen, C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from R.sup.X.

13. The compound of claim 12 or the pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from hydrogen and methyl.

14. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is O and R.sup.4 is absent.

15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is N.

16. The compound of claim 15 or the pharmaceutically acceptable salt thereof, wherein R.sup.4 is selected from hydrogen, C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from R.sup.X.

17. The compound of claim 16 or the pharmaceutically acceptable salt thereof, wherein R.sup.4 is selected from hydrogen and methyl.

18. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sup.3 and R.sup.4 together with the atoms to which they are attached form a heterocyclic ring of 4 to 7 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with R.sup.X.

19. The compound of claim 18 or the pharmaceutically acceptable salt thereof, wherein R.sup.3 and R.sup.4 together with the atoms to which they are attached form ##STR00146##

20. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl and heterocyclyl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R.sup.X.

21. The compound of claim 20 or the pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 are independently selected from hydrogen, methyl, CD.sub.3 and ethyl.

22. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with R.sup.X.

23. The compound of claim 22 or the pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring without additional heteroatom.

24. The compound of claim 23 or the pharmaceutically acceptable salt thereof, wherein the substructure of Formula (III) ##STR00147## in Formula (I) is ##STR00148## wherein the symbol indicates the point of attachment to the rest of the molecule.

25. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein p is 1.

26. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Z.sup.4 is N and Z.sup.5 is C; or Z.sup.4 is C and Z.sup.5 is N.

27. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Z.sup.1 and Z.sup.7 are N, and Z.sup.2, Z.sup.3 and Z.sup.6 are CR.sup.X, R.sup.X is selected from hydrogen, halogen, OH, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heteroaryl-C.sub.1-4 alkyl, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1R.sup.b1 and —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)R.sup.b1.

28. The compound of claim 27 or the pharmaceutically acceptable salt thereof, wherein R.sup.X is selected from hydrogen, NH.sub.2, ##STR00149##

29. The compound of claim 1, selected from ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158## and pharmaceutically acceptable salts thereof.

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

31. A method of treating a cell-proliferative disorder, comprising administering to a subject in need of such treatment an effective amount of the compound of claim 1 or the pharmaceutically acceptable salt, wherein the cell-proliferative disorder is selected from the group consisting of lung, pancreatic, breast, ovarian, colorectal, thyroid cancer, glioma, melanoma, and epidermoid cancer.

Description

EXAMPLES

(1) Various methods may be developed for synthesizing a compound of formula (I)/(II) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing a compound of formula (I)/(II) or a pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that a compound of formula (I)/(II) 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)/(II) 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)/(II) 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) A compound of formula (I)/(II) 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)/(II) 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)/(II) are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of formula (I)/(II) 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 a 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); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxy ethane); 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); Et.sub.2O (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 Bruker AV 600. 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)/(II) 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 hydroxyl, amino, imino, thio or carboxyl 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, one synthesis of compounds of formula (I)/(II) of the present disclosure is shown in Scheme 1. Starting from the intermediates III, which is either commercially available or known in the literature. Intermediate of formula V is prepared by the coupling of III with the intermediates IV using such coupling conditions as Buchwald amination reaction or amination conditions known in the literature. Intermediate of formula VII can be obtained from the appropriately functionalized intermediates V via substitution or cross coupling reactions with intermediates of formula VI. Sequential Hydrolysis of ester VII gives carboxylic acid VIII. Finally, the compounds of formula (I)/(II) can be prepared from VIII by the cleavage of the protecting group and intramolecular cyclization reaction in the presence of coupling reagents.

(18) ##STR00030##

(19) As an illustration of the preparation of intermediates of formula IV, one synthetic route of compounds of formula IVa is shown in Scheme 2. Starting from IVa-A, which is either commercially available or known in the literature. Amino alcohols IVa-B can be prepared by treating IVa-A with but-3-en-1-ol via Kulinkovich reaction. Selective protection of amino group gives compounds of formula IVa-C which can be further transformed into IVa-D. Finally, Intermediate of formula IVa can be obtained from IVa-D through intramolecular cyclization in the presence of a base followed by deprotection of the protecting group on the amino.

(20) ##STR00031##

(21) As a further illustration of the preparation of intermediates of formula IV, a preparation of compound of formula IVb is illustrated in Scheme 3. Starting from IVb-A, which is either commercially available or known in the literature. Hydrolysis of of IVb-A results in carboxylic acid IVb-B, and then reduction of IVb-B provides IVb-C. Intermediate of formula IVb-F can be obtained via a three-step sequence of mesylation of hydroxyl group of IVb-C, substitution reaction and cyclopropanation reaction. Hydrolysis of IVb-F gives compounds of formula IVb-G which can be further transformed into IVb-H via Curtius rearrangement. Finally, selective deprotecting of IVb-H leads to compounds of formula IVb.

(22) ##STR00032##

(23) Another illustration of the preparation of intermediates of formula IV is shown is Scheme 4 which demonstrates preparation of compound of formula IVc. Starting from IVc-A, which is either commercially available or known in the literature. Lactone IVc-B can be prepared by treating IVc-A with (5)-2-(chloromethyl)oxirane. Ammonolysis of IVc-B gives compounds of formula IVc-C which can be further transformed into compounds of formula IVc-D via Curtius rearrangement followed by intramolecular cyclization. Hydrolysis of IVc-D results in amino alcohols IVc-E. Selective protection of the amino group in IVc-E leads to IVc-F. Mesylation of the hydroxyl group in IVc-F into a leaving Group gives IVc-G which can be further transformed into compounds of formula IVc-H through a substitution reaction. Lactam IVc-K can be obtained via a three-step sequence of conversion of the cyano group in IVc-H into the amide group, the cleavage of the protecting groups of IVc-I and intramolecular cyclization. Finally, the reduction of lactam IVc-K leads to compounds of formula IVc.

(24) ##STR00033##

(25) 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.

Preparation of Intermediates

Intermediate A

1-(5-Fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-ium trifluoroacetate (A)

(26) ##STR00034##

2-(Benzyloxy)-5-fluorobenzonitrile (A-1)

(27) The title compound 2-(benzyloxy)-5-fluorobenzonitrile (A-1) was prepared according to the method described in WO 2007/89646.

2-(2-Amino-2-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)ethan-1-ol (A-2)

(28) To a solution of Ti(O-i-Pr).sub.4 (4.80 mL, 16.0 mmol) in Et.sub.2O (40 mL) was added cyclohexylmagnesium chloride (20.0 mL, 40.0 mmol) dropwise at −78° C. and the resulting mixture was stirred at −78° C. for 20 min. Then a solution of but-3-en-1-ol (0.668 mL, 8.0 mmol) and 2-(benzyloxy)-5-fluorobenzonitrile (A-1) (3.64 g, 16.0 mmol) in Et.sub.2O (430 mL) was added to the mixture. The reaction mixture was warmed to RT, and stirred at RT for overnight. The mixture was cooled to 0° C., quenched with 1 N NaOH aqueous solution and extracted with EtOAc (2×100 mL). The organic phase was washed sequentially with water (20 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (3:1˜1:3) to give the title compound 2-(2-amino-2-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)ethan-1-ol (A-2). MS-ESI (m/z): 302 [M+1].sup.+.

tert-Butyl (1-(2-(benzyloxy)-5-fluorophenyl)-2-(2-hydroxyethyl)cyclopropyl) carbamate (A-3)

(29) To a solution of 2-(2-amino-2-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)ethan-1-ol (A-2) (1.10 g, 3.66 mmol) in DCM (26 mL) was added (Boc).sub.2O (0.958 g, 4.39 mmol) and Et.sub.3N (1.02 mL, 7.3 mmol) at 0° C. After addition, the mixture was warmed to RT and stirred at RT for overnight. The reaction was quenched with water, and the mixture was extracted with DCM. 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 (5:1˜2:1) to give the title compound tert-butyl (1-(2-(benzyloxy)-5-fluorophenyl)-2-(2-hydroxyethyl)cyclopropyl) carbamate (A-3). MS-ESI (m/z): 402 [M+1].sup.+.

2-(2-(2-(Benzyloxy)-5-fluorophenyl)-2-((tert-butoxycarbonyl)amino)cyclopropyl) ethyl methane sulfonate (A-4)

(30) To a solution of tert-butyl (1-(2-(benzyloxy)-5-fluorophenyl)-2-(2-hydroxyethyl)cyclopropyl)carbamate (A-3) (1.10 g, 2.74 mmol) in DCM (30 mL) was added MsCl (0.300 mL, 4.65 mmol) and Et.sub.3N (1.02 mL, 7.3 mmol) at 0° C. The mixture was stirred at 0° C. for 40 min. The reaction was quenched with water and extracted with DCM. The extracts were washed sequentially with water, 0.5 N HCl and brine, dried over Na.sub.2SO.sub.4, and concentrated to give the title compound 2-(2-(2-(benzyloxy)-5-fluorophenyl)-2-((tert-butoxycarbonyl)amino)-cyclopropyl)ethyl methanesulfonate (A-4). MS-ESI (m/z): 480 [M+1].sup.+.

tert-Butyl 1-(2-(benzyloxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (A-5)

(31) To a solution of 2-(2-(2-(benzyloxy)-5-fluorophenyl)-2-((tert-butoxycarbonyl)-amino)cyclopropyl)ethyl methanesulfonate (A-4) (1.27 g, 2.65 mmol) in DMF (15 mL) was added NaH (159 mg, 4.00 mmol) at 0° C. After addition, the mixture was warmed to RT and stirred at RT for 1.5 h. The reaction was cooled to 0° C., quenched with water and extracted with EtOAc. The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (12:1˜5:1) to give the title compound tert-butyl 1-(2-(benzyloxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (A-5). MS-ESI (m/z): 384 [M+1].sup.+.

tert-Butyl 1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (A-6)

(32) The mixture of tert-butyl 1-(2-(benzyloxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]-hexane-2-carboxylate (A-5) (0.19 g, 0.50 mmol) and Pd/C (10%, 190 mg) in MeOH (20 mL) was stirred at RT for overnight at the atmosphere of H.sub.2 (1 atm). Then the mixture was filtered, and the filtrate was concentrated to give the title compound tert-butyl 1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (A-6). MS-ESI (m/z): 294 [M+1].sup.+.

1-(5-Fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-iumtrifluoroacetate (A)

(33) To a solution of tert-butyl 1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (A-6) (12.6 mg, 0.043 mmol) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 0.5 h, and concentrated to give 1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-ium trifluoroacetate (A) as crude, which was used in next step without further purification. MS-ESI (m/z): 194 [M+1].sup.+.

Intermediate B

1-(2-(Benzyloxy)-5-fluorophenyl)cyclopropan-1-amine (B)

(34) ##STR00035##

(35) To a solution of 2-(benzyloxy)-5-fluorobenzonitrile (A-1) (1.13 g, 5.00 mmol) in Et.sub.2O (25 mL) was added Ti(O-i-Pr).sub.4 (1.81 mL, 5.50 mmol) and EtMgCl (11.0 mL, 11.0 mmol) dropwise at −78° C. and the resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was warmed to RT. Then BF.sub.3.OEt.sub.2 (1.27 mL, 10.0 mmol) was added, the mixture was stirred at RT for 1 h. The mixture was quenched with 1 N HCl aqueous solution (15 mL), then 10% NaOH aqueous solution (45 mL) was added. The mixture was extracted with EtOAc (2×50 mL). The organic phase was washed sequentially with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (5:1˜1:1) to give the title compound 1-(2-(benzyloxy)-5-fluorophenyl)cyclopropan-1-amine (B). MS-ESI (m/z): 258 [M+1].sup.+.

Intermediate C

1-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexane trifluoroacetate (C)

(36) ##STR00036##

2-(Benzyloxy)-5-fluoro Nicotinonitrile (C-1)

(37) To a solution of 2-chloro-5-fluoronicotinonitrile (1.57 g, 10.0 mmol) and phenylmethanol (1.20 g, 11.0 mmol) in dioxane (100 mL) was added Pd(OAc).sub.2 (225 mg, 1.00 mmol), Cs.sub.2CO.sub.3 (4.89 g, 15.0 mmol) and [1,1′-binaphthalen]-2-yldi-tert-butylphosphane (800 mg, 2.00 mmol). Then the resulting mixture was heated at 70° C. for 4 h at the atmosphere of N.sub.2. The mixture was concentrated and the residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (50:1) to give the title compound 2-(benzyloxy)-5-fluoronicotinonitrile (C-1). MS-ESI (m/z): 229 [M+1].sup.+.

2-(2-Amino-2-(2-(benzyloxy)-5-fluoropyridin-3-yl)cyclopropyl)ethan-1-ol (C-2)

(38) To a solution of Ti(O-i-Pr).sub.4 (2.56 g, 9.00 mmol) in Et.sub.2O (25 mL) was added cyclohexylmagnesium chloride (11.3 mL, 22.5 mmol) dropwise at −78° C. and the resulting mixture was stirred at −78° C. for 20 min. Then a solution of but-3-en-1-ol (325 mg, 4.50 mmol) and 2-(benzyloxy)-5-fluoronicotinonitrile (C-1) (2.05 g, 9.00 mmol) in Et.sub.2O (25 mL) was added to the mixture. The reaction mixture was warmed to RT, and stirred at RT for overnight. The mixture was cooled to 0° C., quenched with 1 N NaOH aqueous solution and extracted with EtOAc (2×60 mL). The organic phase was washed sequentially with water (20 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (2:1˜1:1) to give the title compound 2-(2-amino-2-(2-(benzyloxy)-5-fluoropyridin-3-yl)cyclopropyl)ethan-1-ol (C-2). MS-ESI (m/z): 303 [M+1].sup.+.

Tert-butyl (1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-(2-hydroxyethyl)cyclopropyl) carbamate (C-3)

(39) To a solution of 2-(2-amino-2-(2-(benzyloxy)-5-fluoropyridin-3-yl)cyclopropyl)-ethan-1-ol (C-2) (130 mg, 0.430 mmol) in DCM (5 mL) was added (Boc).sub.2O (113 mg, 0.520 mmol) and Et.sub.3N (65 mg, 0.65 mmol) at 0° C. After addition, the mixture was warmed to RT and stirred at RT for overnight. The reaction was quenched with water, and the mixture was extracted with DCM. 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 (3:1) to give the title compound tert-butyl (1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-(2-hydroxyethyl)-cyclopropyl)carbamate (C-3). MS-ESI (m/z): 403 [M+1].sup.+.

2-(2-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-2-((tert-butoxycarbonyl)amino)-cyclopropyl)ethyl methanesulfonate (C-4)

(40) To a solution of tert-butyl (1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-(2-hydroxyethyl)cyclopropyl)carbamate (C-3) (239 mg, 0.590 mmol) in DCM (10 mL) was added MsCl (82 mg, 0.71 mmol) and Et.sub.3N (90 mg, 0.89 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with water and extracted with DCM. The extracts were washed sequentially with water, sat. NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4, and concentrated to give the title compound 2-(2-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-((tert-butoxycarbonyl)amino)-cyclopropyl)ethyl methanesulfonate (C-4). MS-ESI (m/z): 481 [M+1].sup.+.

tert-Butyl 1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexane-2-carb oxylate (C-5)

(41) To a solution of 2-(2-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-((tert-butoxycarbonyl)amino)cyclopropyl)ethyl methanesulfonate (C-4) (341 mg, 0.590 mmol) in DMF (5 mL) was added NaH (48.0 mg, 1.19 mmol) at 0° C. After addition, the mixture was warmed to RT and stirred at RT for overnight. The reaction was cooled to 0° C., quenched with water and extracted with EtOAc. The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (10:1) to give the title compound tert-butyl 1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (C-5). MS-ESI (m/z): 385 [M+1].sup.+.

1-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexane trifluoroacetate (C)

(42) To a solution of tert-butyl 1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (C-5) (50 mg, 0.13 mmol) in DCM (5 mL) was added TFA (1.8 mL) at 0° C. After that, the mixture was stirred at RT for 1 h, and concentrated to give 1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexane trifluoroacetate (C) as crude, which was used in next step without further purification. MS-ESI (m/z): 285 [M+1].sup.+.

Intermediate D

Ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)pyrazolo-[1,5-a]-pyrimidine-3-carboxylate (D)

(43) ##STR00037##

5-Fluoro-2-methoxynicotinonitrile (D-1)

(44) To a solution of 3-bromo-5-fluoro-2-methoxypyridine (7.085 g, 34.39 mmol) in DMF (60 mL) was added Zn(CN).sub.2 (8.076 g, 68.79 mmol), zinc powder (67.0 mg, 1.03 mmol), 1,1′-bis(diphenyphosphino)ferrocene (DPPF) (825 mg, 1.49 mmol) and Pd.sub.2(dba).sub.3 (945 mg, 1.03 mmol). The mixture was heated at 100° C. under N.sub.2 for 7 h. The mixture was cooled to RT, diluted with water (350 mL) and extracted with EtOAc (2×100 mL). The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and the solvents were evaporated to give yellow solid. This was purified by column chromatography on silica gel to give 5-fluoro-2-methoxynicotinonitrile (D-1). MS-ESI (m/z): 153 [M+1].sup.+.

5-Fluoro-2-methoxy nicotinic Acid (D-2)

(45) To a solution of 5-fluoro-2-methoxynicotinonitrile (D-1) (2.95 g, 19.4 mmol) in MeOH (35 mL) was added 5 N NaOH (17 mL). The mixture was heated at reflux for 5 h. The mixture was cooled to RT, diluted with water (50 mL), and acidified with cone. HCl to pH=2˜3. The mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give 5-fluoro-2-methoxynicotinic acid (D-2). MS-ESI (m/z): 172 [M+1].sup.+.

(5-Fluoro-2-methoxypyridin-3-yl)methanol (D-3)

(46) To a suspension of 5-fluoro-2-methoxynicotinic acid (D-2) (2.95 g, 17.0 mmol) in THF (35 mL) was added BH.sub.3-SMe.sub.2 (2.0 M in THF, 17 mL, 34 mmol). The mixture was stirred at RT for 1 h. The mixture was slowly quenched with water (100 mL) and extracted with EtOAc. The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give (5-fluoro-2-methoxypyridin-3-yl)methanol (D-3). MS-ESI (m/z): 158 [M+1].sup.+.

(5-Fluoro-2-methoxypyridin-3-yl)methyl methanesulfonate (D-4)

(47) To a solution of (5-fluoro-2-methoxypyridin-3-yl)methanol (D-3) (2.44 g, 15.5 mmol) in DCM (35 mL) at RT was added TEA (2.79 mL) followed by MsCl (1.87 g, 16.3 mmol). The mixture was stirred at RT for 1 h. The mixture was diluted with water (100 mL) and extracted with EtOAc. The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give (5-fluoro-2-methoxypyridin-3-yl)methyl methanesulfonate (D-4). MS-ESI (m/z): 236 [M+1].sup.+.

2-(5-Fluoro-2-methoxypyridin-3-yl)acetonitrile (D-5)

(48) To a solution of (5-fluoro-2-methoxypyridin-3-yl)methyl methanesulfonate (D-4) (3.00 g, 12.8 mmol) in DMSO (30 mL) at RT was added NaCN (1.88 g, 38.3 mmol). The mixture was stirred at RT for 2 h. The mixture was diluted with water (100 mL) 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 and eluted with 5% 15% ethyl acetate in hexanes to give 2-(5-fluoro-2-methoxypyridin-3-yl)acetonitrile (D-5). MS-ESI (m/z): 167 [M+1].sup.+.

1-(5-Fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carbonitrile (D-6)

(49) To a solution of 2-(5-fluoro-2-methoxypyridin-3-yl)acetonitrile (D-5) (1.89 g, 11.4 mmol) in DMF (15 mL) at 0° C. was added NaH (60%, 1.37 g, 34.2 mmol). The mixture was stirred at 0° C. for 10 min. 1,2-Dibromoethane (4.28 g, 22.8 mmol) in DMF (5 mL) was added at 0° C. The mixture was stirred at RT for 1 h. The reaction was diluted with water (100 mL) 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 and eluted with 10% ethyl acetate in hexane to give 1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carbonitrile (D-6). MS-ESI (m/z): 193 [M+1].sup.+.

1-(5-Fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carboxylic Acid (D-7)

(50) To a solution of 1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carbonitrile (D-6) (1.96 g, 10.2 mmol) in EtOH (45 mL) was added 5 N NaOH (22 mL). The mixture was heated at reflux for 8 h. The mixture was cooled to RT, diluted with water (50 mL), and acidified with cone. HCl to pH=2˜3. The mixture was extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give 1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carboxylic acid (D-7). MS-ESI (m/z): 212 [M+1].sup.+.

Methyl (1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropyl)carbamate (D-8)

(51) To a solution of 1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropane-1-carboxylic acid (D-7) (2.12 g, 10.1 mmol) in toluene (10 mL) was added Et.sub.3N (1.12 g, 11.1 mmol) followed by DPPA (3.04 g, 11.1 mmol). The mixture was heated at 100° C. for 2 h. Then MeOH (10 mL) was added. The mixture was heated at 80° C. for additional 2 h. The mixture was cooled to RT, diluted with water (100 mL) and extracted with EtOAc. The extracts were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated. The residue was purified by column chromatography on silica gel and eluted with 20% ethyl acetate in hexanes to give methyl (1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropyl) carbamate (D-8). MS-ESI (m/z): 241 [M+1].sup.+.

1-(5-Fluoro-2-methoxypyridin-3-yl)cyclopropan-1-amine (D-9)

(52) A solution of (1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropyl)carbamate (D-8) (640 mg, 2.67 mmol) in 32% HBr—HOAc (3 mL) was stirred at RT for 8 h. The mixture was diluted with saturated aqueous NaHCO.sub.3 (50 mL) 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, eluted with 30-50% EtOAc in hexanes to give 1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropan-1-amine (D-9). MS-ESI (m/z): 183 [M+1].sup.+.

Ethyl 5-((1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D-10)

(53) To a solution of 1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropan-1-amine (D-9) (197 mg, 1.03 mmol) and ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1a) (WO 2017/007759) (232 mg, 1.03 mmol) in n-butanol (3.5 mL) was added DIPEA (529 mg, 4.10 mmol). The mixture was heated at 110° C. for 8 h. The mixture was cooled to RT, diluted with water (30 mL) 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 and eluted with 40% ethyl acetate in hexane to give ethyl 5-((1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropyl) amino)pyrazolo-[1,5-a]pyrimidine-3-carboxylate (D-10). MS-ESI (m/z): 372 [M+1].sup.+.

Ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D)

(54) To a solution of ethyl 5-((1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropyl)-amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D-10) (294 mg, 0.792 mmol) in HOAc (1.5 mL) was added 32% HBr—HOAc (1.5 mL). The mixture was heated at 90° C. for 2 h. The mixture was cooled to RT, diluted with saturated aqueous NaHCO.sub.3 (50 mL) 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 and eluted with 4% MeOH in DCM to give ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D). MS-ESI (m/z): 358 [M+1].sup.+.

Intermediate E

1-(2-(Benzyloxy)-5-fluorophenyl)-N-methylcyclopropan-1-amine 2,2,2-trifluoroacetate (E)

(55) ##STR00038##

tert-Butyl (1-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)carbamate (E-1)

(56) To a solution of 1-(2-(benzyloxy)-5-fluorophenyl)cyclopropan-1-amine (B) (0.24 g, 0.93 mmol) in DCM (15 mL) was added (Boc).sub.2O (0.304 g, 1.39 mmol) and Et.sub.3N (0.39 mL, 2.78 mmol) at RT and stirred for overnight. The reaction was quenched with water, and the mixture was extracted with DCM. 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 (20:1˜5:1) to give the title compound tert-butyl (1-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)-carbamate (E-1). MS-ESI (m/z): 358 [M+1].sup.+.

tert-Butyl (1-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)(methyl)carbamate (E-2)

(57) To a solution of tert-butyl (1-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl) carbamate (E-1) (0.27 g, 0.91 mmol) in DMF (5 mL) was added NaH (54.0 mg, 1.36 mmol) at 0° C. After 15 mins, CH.sub.3I (0.20 mL, 3.2 mmol) was added, the mixture was further stirred for 1 h. The reaction was quenched with water and extracted with EtOAc. The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (20:1˜5:1) to give the title compound tert-butyl (1-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)(methyl)carbamate (E-2). MS-ESI (m/z): 372 [M+1].sup.+.

1-(2-(Benzyloxy)-5-fluorophenyl)-N-methylcyclopropan-1-amine 2,2,2-trifluoroacetate (E)

(58) To a solution of tert-butyl (1-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl) (methyl)carbamate (E-2) (137 mg, 0.370 mmol) in DCM (2.5 mL) was added TFA (0.6 mL) at 0° C. The mixture was stirred at RT for 1 h, and concentrated to give 1-(2-(benzyloxy)-5-fluorophenyl)-N-methylcyclopropan-1-amine 2,2,2-trifluoroacetate (E) as crude, which was used in next step without further purification. MS-ESI (m/z): 272 [M+1].sup.+.

Intermediate F

Ethyl 6-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo-[1,2-b]pyridazine-3-carboxylate (F)

(59) ##STR00039##

Ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (F-1)

(60) The title compound ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (F-1) was prepared according to the method described in US 2012/0065184.

Ethyl 6-(1-(2-(benzyloxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazine-3-carboxylate (F-2)

(61) The mixture of 1-(2-(benzyloxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexane (170 mg, 0.600 mmol), ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (F-1) (220 mg, 1.20 mmol) and KF (348 mg, 6.00 mmol) in DMSO (5 mL) was stirred at 120° C. for 24 h. The reaction was cooled to RT, quenched with water and extracted with EtOAc. The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (5:1˜1:1) to give the title compound ethyl 6-(1-(2-(benzyloxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazine-3-carboxylate (F-2). MS-ESI (m/z): 473 [M+1].sup.+.

Ethyl 6-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo-[1,2-b]pyridazine-3-carboxylate (F)

(62) The mixture of ethyl 6-(1-(2-(benzyloxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazine-3-carboxylate (F-2) (75 mg, 0.16 mmol) and Pd/C (10%, 25 mg) in MeOH (2 mL) was stirred at RT for 3 h at the atmosphere of H.sub.2 (1 atm). Then the mixture was filtered, and the filtrate was concentrated to give the title compound ethyl 6-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazine-3-carboxylate (F). MS-ESI (m/z): 383 [M+1].sup.+.

Intermediate G

Ethyl 6-(1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo-f[2-b]pyridazine-S-carboxylate (G)

(63) ##STR00040##

(64) The title compound ethyl 6-(1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo-[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazine-3-carboxylate (G) was prepared according to the synthetic method of Intermediate F by replacing 1-(2-(benzyloxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexane with 1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexane. MS-ESI (m/z): 384 [M+1].sup.+.

Intermediate H

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

(65) ##STR00041##

2-(5-Fluoro-2-methoxyphenyl)acetonitrile (H-1)

(66) A mixture of 2-(bromomethyl)-4-fluoro-1-methoxybenzene (6.00 g, 27.4 mmol), NaCN (4.00 g, 81.6 mmol) and n-Bu.sub.4NI (1.01 g, 2.74 mmol) in DCM/H.sub.2O (60 mL/60 mL) was stirred at RT for 6 hours. The reaction was quenched with saturated NaHCO.sub.3 aqueous solution and extracted with DCM. The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and evaporated to give the crude product. This was purified by column chromatography on silica gel, eluting with PE/EtOAc (10:1˜6:1) to give the product of 2-(5-fluoro-2-methoxyphenyl)acetonitrile (H-1).

(1R,5S) 1-(5-fluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one (H-2)

(67) To a mixture of (5)-2-(chloromethyl)oxirane (3.38 mL, 39.1 mmol) and 2-(5-fluoro-2-methoxyphenyl)acetonitrile (H-1) (4.300 g, 26.06 mmol) in THF (36 mL) was added NaHMDS (32.5 mL, 65.2 mmol) dropwise at −15° C. The mixture was stirred at −15° C. for 3 h. The reaction was quenched with water (40 mL) and stirred for 5 min. The mixture was concentrated. The residue was diluted with EtOH (35 mL), and KOH (5.4 g) were added. Then the mixture was stirred at 80° C. for overnight. The reaction mixture was cooled to r.t. and cone. HCl (25 mL) were added. The mixture was stirred at 60° C. for 3 h. The mixture was extracted with EtOAc. The extracts were washed sequentially with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (1R,5S)-1-(5-fluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one (H-2). MS-ESI (m/z): 223 [M+1].sup.+.

(1R,2S)-1-(5-fluoro-2-methoxyphenyl)-2-(hydroxymethyl)cyclopropane-1-carboxamide (H-3)

(68) A mixture of (1R,5S)-1-(5-fluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one (H-2) (2.09 g, 9.41 mmol) in NH.sub.3/MeOH (7 N/20 mL) was stirred at r.t. for 3 h. The mixture was concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (3:1˜1:1) to give the title compound (1R,2S)-1-(5-fluoro-2-methoxyphenyl)-2-(hydroxymethyl)cyclopropane-1-carboxamide (H-3). MS-ESI (m/z): 240 [M+1].sup.+.

(1R,6S)-1-(5-fluoro-2-methoxyphenyl)-4-oxa-2-azabicyclo[4.1.0]heptan-3-one (H-4)

(69) To a solution of (1R,2S)-1-(5-fluoro-2-methoxyphenyl)-2-(hydroxymethyl)-cyclopropane-1-carboxamide (H-3) (675 mg, 2.82 mmol) in CH.sub.3CN (30 mL) was added phenyl-λ.sup.3-iodanediyl diacetate (1.36 g, 4.23 mmol) at 0° C. The mixture was warmed to r.t. and stirred at RT for 13 h. The reaction was quenched with water and extracted with EtOAc. The extracts were washed sequentially with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give the title compound (1R,6S)-1-(5-fluoro-2-methoxyphenyl)-4-oxa-2-azabicyclo[4.1.0]heptan-3-one (H-4). MS-ESI (m/z): 238 [M+1].sup.+.

((1S,2R)-2-amino-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methanol (H-5)

(70) A mixture of (1R,6S)-1-(5-fluoro-2-methoxyphenyl)-4-oxa-2-azabicyclo[4.1.0]heptan-3-one (H-4) (480 mg, 2.02 mmol) and NaOH (400 mg, 10.0 mmol) in EtOH/H.sub.2O (3 mL/3 mL) was stirred at 70° C. for overnight. The reaction mixture was cooled to r.t. and concentrated. The residue was washed with PE and extracted with EtOAc. The extracts were washed sequentially with water and brine, dried and concentrated to give the title compound ((1S,2R)-2-amino-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methanol (H-5). MS-ESI (m/z): 212 [M+1].sup.+.

((1S,2R)-2-(benzylideneamino)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methanol (H-6)

(71) The mixture of ((1S,2R)-2-amino-2-(5-fluoro-2-methoxyphenyl)cyclopropyl) methanol (H-5) (250 mg, 1.18 mmol) and benzaldehyde (152 mg, 1.42 mmol) in DCM was stirred at RT for overnight. The mixture was extracted with DCM. The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give the crude product of the title compound ((1S,2R)-2-(((E)-benzylidene)amino)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)-methanol (H-6). MS-ESI (m/z): 300 [M+1].sup.+.

((1S,2R)-2-(benzylideneamino)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl) methyl methanesulfonate (H-7)

(72) The mixture of ((1S,2R)-2-(benzylideneamino)-2-(5-fluoro-2-methoxyphenyl) cyclopropyl)methanol (H-6) (352 mg, 1.17 mmol), MsCl (137 μL, 1.75 mmol) and Et.sub.3N (326 μL, 2.34 mmol) in DCM (15 mL) was stirred at 0° C. for 1.5 hours. The mixture was extracted with DCM. The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give the crude product of the title compound ((1S,2R)-2-(((E)-benzylidene)amino)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)-methyl methanesulfonate (H-7). MS-ESI (m/z): 378 [M+1].sup.+.

2-((1R,2R)-2-(benzylideneamino)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl) acetonitrile (H-8)

(73) The mixture of ((1S,2R)-2-(benzylideneamino)-2-(5-fluoro-2-methoxyphenyl) cyclopropyl)methyl methanesulfonate (H-7) (200 mg, 0.530 mmol) and NaCN (116 mg, 2.42 mmol) in DMF (6 mL) was stirred at 45° C. for 4 hours. The reaction mixture was cooled to r.t. and extracted with EtOAc. The extracts were washed sequentially with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give the crude product of the title compound 2-((1R,2R)-2-(((E)-benzylidene)amino)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)acetonitrile (H-8). MS-ESI (m/z): 309 [M+1].sup.+.

2-((1R,2R)-2-(benzylideneamino)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl) acetamide (H-9)

(74) A mixture of 2-((1R,2R)-2-(benzylideneamino)-2-(5-fluoro-2-methoxyphenyl) cyclopropyl)acetonitrile (H-8) (2.67 g, 8.66 mmol) and K.sub.2CO.sub.3 (3.00 g, 21.0 mmol) in DMSO (80 mL) was added dropwise H.sub.2O.sub.2 (30%, 20 mL, 172 mmol) under ice water bath in portions for 4 times and stirred at RT for overnight. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The extracts were washed sequentially with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give the crude product of the title compound 2-((1R,2R)-2-(((E)-benzylidene)amino)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)acetamide (H-9). MS-ESI (m/z): 327 [M+1].sup.+.

2-((1R,2R)-2-amino-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)acetamide (H-10)

(75) To a mixture of 2-((1R,2R)-2-(((E)-benzylidene)amino)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)acetamide (H-9) (616 mg, 1.89 mmol) in CH.sub.3CN (6 mL) was added HCl (1 N, 10 mL) at 0° C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was extracted with PE/EtOAc (1:1) and washed with HCl (1 N, 10 mL). The combined aqueous layers were washed with PE/EtOAc (1:1). The aqueous layer were adjusted to pH=8˜9 using saturated aqueous Na.sub.2CO.sub.3 and extracted with EtOAc (4×80 mL), dried over Na.sub.2SO.sub.4, and concentrated to give the crude product of the title compound 2-((1R,2R)-2-amino-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)acetamide (H-10). MS-ESI (m/z): 239 [M+1].sup.+.

(1R,5R)-1-(5-fluoro-2-methoxyphenyl)-2-azabicyclo[3.1.0]hexan-3-one (H-11)

(76) A mixture of 2-((1R,2R)-2-amino-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)-acetamide (H-10) (327 mg, 1.37 mmol) and cone. HCl (1 mL, 12 mmol) in MeOH (6.5 mL) was stirred at 60° C. for 5 h. The reaction mixture was cooled to 0° C., Na.sub.2CO.sub.3 (1.100 g, 10.38 mmol) and water (13 mL) were added. The mixture was stirred at 60° C. for 3 h. The reaction mixture was cooled to r.t. and extracted with DCM, the extracts were washed sequentially with HCl (1 N), water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give the crude product of the title compound (1R,5R)-1-(5-fluoro-2-methoxyphenyl)-2-azabicyclo[3.1.0]hexan-3-one (H-11). MS-ESI (m/z): 222 [M+1].sup.+.

(1R,5S)-1-(5-fluoro-2-methoxyphenyl)-2-azabicyclo[3.1.0]hexane (H-12)

(77) To a mixture of (1R,5R)-1-(5-fluoro-2-methoxyphenyl)-2-azabicyclo[3.1.0]hexan-3-one (H-11) (247 mg, 1.12 mmol) in dry THF (10 mL) was added borane dimethyl sulfide complex solution (10 M, 0.67 mL) dropwise at 0° C. Then the mixture was warmed to 60° C. and stirred for 12 h. The reaction mixture was cooled to r.t., quenched with MeOH (7 mL) and HCl aqueous (6 N, 6 mL). The mixture was stirred at RT for 1 h. The mixture was extracted with EtOAc (2×15 mL), the aqueous layer were adjusted to pH=10 using NaOH (1.08 g) and extracted with EtOAc. The extracts were washed sequentially with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give the crude product of the title compound (1R,5S)-1-(5-fluoro-2-methoxyphenyl)-2-azabicyclo[3.1.0]hexane (H-12). MS-ESI (m/z): 208 [M+1].sup.+.

Ethyl 5-((1R,5S)-1-(5-fluoro-2-methoxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H-131

(78) A mixture of (1R,5S)-1-(5-fluoro-2-methoxyphenyl)-2-azabicyclo-[3.1.0]hexane (H-12) (120 mg, 0.580 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1a) (WO 2017/007759) (177 mg, 0.700 mmol) and DIPEA (0.50 mL, 2.9 mmol) in n-BuOH (4 mL) was stirred at 125° C. for 19 h. The reaction mixture was cooled to RT and extracted with EtOAc. The extracts were washed sequentially with water and brine, dried over Na.sub.2SO.sub.4, concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (5:1˜3:1) to give the product of ethyl 5-((1R,5S)-1-(5-fluoro-2-methoxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H-13). MS-ESI (m/z): 397 [M+1].sup.+.

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

(79) To a solution of ethyl 5-((1R,5S)-1-(5-fluoro-2-methoxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H-13) (0.15 g, 0.38 mmol) in DCM (15 mL) was added BBr.sub.3 (0.64 mL, 0.65 mmol) at 0° C. and stirred at the same temperature for 1.5 h. Then additional BBr.sub.3 (0.64 mL, 0.65 mmol) was added and stirred at 0° C. for 2 h. The reaction was quenched with water. The mixture was extracted with DCM. The extracts were sequentially with saturated NaHCO.sub.3, water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give the crude product of the title compound ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H). MS-ESI (m/z): 383 [M+1].sup.+.

Intermediate I

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

(80) ##STR00042##

(81) The title compound I was prepared according to the synthetic method of H by replacing 2-(5-fluoro-2-methoxyphenyl)acetonitrile (H-1) with 2-(5-fluoro-2-methoxypyridin-3-yl)acetonitrile (D-5). MS-ESI (m/z): 384 [M+1].sup.+.

Intermediate J

Ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (J)

(82) ##STR00043##

Ethyl 5-((1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (J-1)

(83) To a solution of ethyl 5-((1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropyl)amino)-pyrazolo[1,5-a]pyrimidine-3-carboxylate (D-10) (331 mg, 0.892 mmol) in DMF (5 mL) was added NaH (60%, 71.4 mg, 1.78 mmol) at RT and stirred for 10 min. Then Mel (253 mg, 1.75 mmol) was added dropwise and stirred for 50 min. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×). The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give ethyl 5-((1-(5-fluoro-2-methoxypyridin-3-yl) cyclopropyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (J-1) as crude, which was used in next step without further purification. MS-ESI (m/z): 386 [M+1].sup.+.

Ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (J)

(84) The title compound J was prepared according to the synthetic method of D by replacing ethyl 5-((1-(5-fluoro-2-methoxypyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D-10) with ethyl 5-((1-(5-fluoro-2-methoxypyridin-3-yl) cyclopropyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (J-1). MS-ESI (m/z): 372 [M+1].sup.+.

Example 1

(1.SUP.3.E,1.SUP.4.E,6R)-3.SUP.5.-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-azabicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (1)

(85) ##STR00044##

Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1a)

(86) The title compound ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1a) was prepared according to the method described in WO 2017/007759.

Ethyl 5-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate (1b)

(87) The mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1a) (82.0 mg, 0.360 mmol), 1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-ium trifluoroacetate (A) (96.0 mg, 0.330 mmol) and DIPEA (0.40 mL, 2.4 mmol) in n-BuOH (3 mL) was stirred at 120° C. for 6 h. The reaction was cooled to RT, quenched with water and extracted with EtOAc. The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (3:1˜1:1) to give the title compound ethyl 5-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1b). MS-ESI (m/z): 383 [M+1].sup.+.

(R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (1c)

(88) The title compound (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (1c) was prepared according to the method described in J. Org. Chem. 2010, 75, 2718-2721.

Ethyl 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1d)

(89) To a solution of ethyl 5-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]-hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1b) (54.0 mg, 0.142 mmol) in DMF (3 mL) was added Cs.sub.2CO.sub.3 (278 mg, 0.852 mmol). The mixture was heated to 70° C. and stirred for 30 min. Then (ethyl (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (1c) (107 mg, 0.426 mmol) was added. The mixture was stirred at 70° C. for overnight. The mixture was cooled to RT, diluted 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 ethyl 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)-propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1d). MS-ESI (m/z): 540 [M+1].sup.+.

5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1e)

(90) A mixture of ethyl 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1d) (38 mg, 0.071 mmol) and LiOH.H.sub.2O (40 mg, 0.95 mmol) in MeOH/H.sub.2O (2 mL/0.2 mL) was stirred at 70° C. for 4 h. The mixture was cooled to RT and concentrated. The residue was acidified to pH=3˜4 with 0.5 N HCl aqueous solution and extracted with EtOAc. The extracts were was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give the title compound 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1e). MS-ESI (m/z): 512 [M+1].sup.+.

(2R)-1-(2-(2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]Hexan-1-yl)-4-fluorophenoxy)propan-2-aminium Trifluoroacetate (1f)

(91) To a solution of 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1e) (35 mg, 0.069 mmol) in DCM (2 mL) at 0° C. was added TFA (2 mL). The mixture was stirred at RT for 45 min, and concentrated to give (2R)-1-(2-(2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-4-fluorophenoxy)propan-2-aminium trifluoroacetate (1f) as crude, which was used in next step without further purification. MS-ESI (m/z): 412 [M+1].sup.+.

(1.SUP.3.E,1.SUP.4.E,6R)-3.SUP.5.-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (1)

(92) To a solution of (2R)-1-(2-(2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-4-fluorophenoxy)propan-2-aminium trifluoroacetate (1f) (26.8 mg, 0.0650 mmol) in DMF (11 mL) at RT was added HATU (30 mg, 0.078 mmol). Then a solution of DIPEA (0.11 mL, 0.65 mmol) in DMF was added dropwise to the mixture at RT and the resulting mixture was stirred for overnight. The mixture was diluted with water (10 mL) and extracted with EtOAc. The extracts were washed with brine (40 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by preparative TLC, eluting with DCM/MeOH (20:1) to give (1.sup.3E,1.sup.4E,6R)-3.sup.5-fluoro-6-methyl-4-oxa-2.sup.2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (1). MS-ESI (m/z): 394 [M+1].sup.+.

Example 2

(R,3′E,4′E)-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)-benzenacyclononaphan]-9′-one (2)

(93) ##STR00045##

Ethyl 5-((1-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)amino)pyrazolo[1,5-a]-pyrimidine-3-carboxylate (2a)

(94) The title compound ethyl 5-((1-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)-amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (2a) was prepared according to the synthetic method of ethyl 5-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate (1b) by replacing 1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-ium trifluoroacetate (A) with 1-(2-(benzyloxy)-5-fluorophenyl)-cyclopropan-1-amine (B). MS-ESI (m/z): 447 [M+1].sup.+.

Ethyl 5-((1-(5-fluoro-2-hydroxyphenyl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (2b)

(95) The title compound ethyl 5-((1-(5-fluoro-2-hydroxyphenyl)cyclopropyl)amino)-pyrazolo[1,5-a]pyrimidine-3-carboxylate (2b) was prepared according to the synthetic method of tert-butyl 1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (A-6) by replacing tert-butyl 1-(2-(benzyloxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (A-5) with ethyl 5-((1-(2-(benzyloxy)-5-fluorophenyl)cyclopropyl)amino)pyrazolo[1,5-a]-pyrimidine-3-carboxylate (2a). MS-ESI (m/z): 357 [M+1].sup.+.

(R,3′E,4′E)-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5.3)-pyrazolo[1,5-a]pyrimidina-4(1,2)-benzenacyclononaphan]-9′-one (2)

(96) The title compound (R,3′E,4′E)-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)-benzenacyclononaphan]-9′-one (2) was prepared according to the synthetic method of 1 by replacing ethyl 5-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1b) with ethyl 5-((1-(5-fluoro-2-hydroxyphenyl)cyclopropyl)amino)pyrazolo-[1,5-a]pyrimidine-3-carboxylate (2b). MS-ESI (m/z): 368 [M+1].sup.+.

Example 3

(1.SUP.3.E,1.SUP.4.E,5S)-3.SUP.5.-fluoro-5-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (3)

(97) ##STR00046##

(98) The title compound (1.sup.4E,1.sup.4E,5S)-3.sup.5-fluoro-5-methyl-4-oxa-2.sup.2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (3) was prepared according to the synthetic method of example 1 by replacing (R)-2-((tert-butoxycarbonyl)-amino)propyl methanesulfonate (1c) with (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate. MS-ESI (m/z): 394 [M+1].sup.+.

Example 4

(S,3′E,4E)-5′-fluoro-6′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(7,2)-benzenacyclononaphan]-9′-one (4)

(99) ##STR00047##

(100) The title compound (S,3′E,4′E)-5′-fluoro-6′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)-benzenacyclononaphan]-9′-one (4) was prepared according to the synthetic method of example 2 by replacing (R)-2-((tert-butoxycarbonyl)-amino)propyl methanesulfonate (1c) with (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate. MS-ESI (m/z): 368 [M+1].sup.+.

Example 5

(1.SUP.3.E,1.SUP.4.E,6R)-3.SUP.5.-fluoro-6-methyl-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (5)

(101) ##STR00048##

Ethyl 5-(1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5a)

(102) The mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1a) (44 mg, 0.20 mmol), 1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexane trifluoroacetate (C) (37 mg, 0.13 mmol) and DIPEA (98 mg, 0.78 mmol) in n-BuOH (3.5 mL) was stirred at 120° C. for 12 h. The reaction was cooled to r.t., quenched with water and extracted with EtOAc. The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (3:1) to give the title compound ethyl 5-(1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5a). MS-ESI (m/z): 474 [M+1].sup.+.

Ethyl 5-(1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5b)

(103) To a solution of ethyl 5-(1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2-azabicyclo hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5a) (69 mg, 0.15 mmol) in DCM (5 mL) was added TFA (5 mL) at RT and stirred at RT for 21 h. The reaction mixture was concentrated, quenched with water and extracted with DCM. The extracts were washed sequentially with water and sat. NaHCO.sub.3, dried over Na.sub.2SO.sub.4. The solvents were evaporated to give ethyl 5-(1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5b) as crude, which was used in next step without further purification. MS-ESI (m/z): 384 [M+1].sup.+.

Ethyl 5-(1-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5c)

(104) To a solution of ethyl 5-(1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]-hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5b) (40 mg, 0.10 mmol) in DCM (8 mL) was added Tf.sub.2O (88.4 mg, 0.310 mmol) and pyridine (83 mg, 1.0 mmol) at 0° C. The mixture was stirred at RT for overnight. The reaction was quenched with water and extracted with DCM. The extracts were washed sequentially with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (3:1) to give the title compound ethyl 5-(1-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)-pyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5c). MS-ESI (m/z): 516 [M+1].sup.+.

tert-Butyl (R)-but-3-yn-2-ylcarbamate (5d)

(105) The title compound tert-butyl (R)-but-3-yn-2-ylcarbamate (5d) was prepared according to the method described in WO 2006/065703.

Ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5e)

(106) To a solution of ethyl 5-(1-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5c) (23 mg, 0.045 mmol) and tert-butyl (R)-but-3-yn-2-ylcarbamate (5d) (30.2 mg, 0.180 mmol) in DMF (0.5 mL) was added Pd(PPh.sub.3).sub.2C.sub.1-2 (6.3 mg, 0.0089 mmol), CuI (1.7 mg, 0.0089 mmol) and DIPEA (29 mg, 0.22 mmol). The resulting mixture was heated at 80° C. for 18 h at the atmosphere of N.sub.2. The reaction was cooled to RT, quenched with water and extracted with EtOAc. The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EtOAc (1.5:1) to give the title compound ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]-hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5e). MS-ESI (m/z): 535 [M+1].sup.+.

Ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[5-a]pyrimidine-3-carboxylate (5f)

(107) The mixture of ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5e) (20 mg, 0.037 mmol) and Pd(OH).sub.2/C (20%, 8 mg) in MeOH (5 mL) was stirred at RT for 5 h at the atmosphere of H.sub.2 (1 atm). Then the mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC, eluting with DCM/MeOH (30:1) to give the title compound ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5f). MS-ESI (m/z): 539 [M+1].sup.+.

5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5 g)

(108) A mixture of ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5f) (12 mg, 0.022 mmol) and LiOH.H.sub.2O (10 mg, 0.22 mmol) in MeOH/H.sub.2O (5 mL/1 mL) was stirred at 70° C. for 17 h. The mixture was cooled to RT and concentrated. The residue was acidified to pH=4˜5 with 1 N HCl aqueous solution and extracted with EtOAc. The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give the title compound 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]p yrimidine-3-carboxylic acid (5 g). MS-ESI (m/z): 511 [M+1].sup.+.

(2R)-4-(3-(2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-5-fluoropyridin-2-yl)butan-2-aminium 2,2,2-trifluoroacetate (5h)

(109) To a solution of 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5 g) (11.4 mg, 0.0220 mmol) in DCM (6 mL) at 0° C. was added TFA (2 mL). The mixture was stirred at RT for 40 min, and concentrated to give (2R)-4-(3-(2-(3-carboxypyrazolo[1,5-a]-pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-5-fluoropyridin-2-yl)butan-2-aminium 2,2,2-trifluoroacetate (5h) as crude, which was used in next step without further purification. MS-ESI (m/z): 411 [M+1].sup.+.

(1.SUP.3.E,1.SUP.4.E,6R)-3.SUP.5.-fluoro-6-methyl-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (5)

(110) To a solution of (2R)-4-(3-(2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-5-fluoropyridin-2-yl)butan-2-aminium 2,2,2-trifluoroacetate (5h) (10 mg, 0.022 mmol) in DMF (10 mL) at RT was added FDPP (9.0 mg, 0.022 mmol) and DIPEA (30.0 mg, 0.22 mmol). The resulting mixture was stirred at RT for overnight. Then the mixture was diluted with water (50 mL) and extracted with EtOAc. The extracts were washed with brine (40 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by preparative TLC, eluting with DCM/MeOH (25:1) to give the title compound (1.sup.3E,1.sup.4E,6R)-3.sup.5-fluoro-6-methyl-2.sup.2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (5). MS-ESI (m/z): 393 [M+1].sup.+.

Example 6

(1.SUP.3.E,1.SUP.4.E,6R)-3.SUP.5.-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]-pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (6)

(111) ##STR00049##

Ethyl 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (6a)

(112) To a solution of ethyl 5-(1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5b) (15 mg, 0.039 mmol) in DMF (4 mL) was added Cs.sub.2CO.sub.3 (102 mg, 0.313 mmol). The mixture was heated to 70° C. and stirred for 30 min. Then (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (1c) (60 mg, 0.24 mmol) was added, the mixture was stirred at 70° C. for 3 h. After that the mixture was cooled to RT, diluted 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 preparative TLC eluting with DCM/MeOH (30:1) to give the title compound ethyl 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate (6a). MS-ESI (m/z): 541 [M+1].sup.+.

5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic Acid (6b)

(113) A mixture of ethyl 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (6a) (28 mg, 0.052 mmol) and LiOH.H.sub.2O (22 mg, 0.52 mmol) in MeOH/H.sub.2O (5 mL/1 mL) was stirred at 70° C. for 17 h. The mixture was cooled to RT and concentrated. The residue was acidified to pH=5 with 1 N HCl aqueous solution and extracted with DCM. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give the title compound 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxylic acid (6b). MS-ESI (m/z): 513 [M+1].sup.+.

(2R)-1-((3-(2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-5-fluoropyridin-2-yl)oxy)propan-2-aminium 2,2,2-trifluoroacetate (6c)

(114) To a solution of 5-(1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (6b) (26.5 mg, 0.0520 mmol) in DCM (2 mL) at 0° C. was added TFA (0.7 mL). The mixture was stirred at RT for 40 min, and concentrated to give (2R)-1-((3-(2-(3-carboxypyrazolo-[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-5-fluoropyridin-2-yl)oxy)propan-2-aminium 2,2,2-trifluoroacetate (6c) as crude, which was used in next step without further purification. MS-ESI (m/z): 413 [M+1].sup.+.

(1.SUP.3.E,1.SUP.4.E,6R)-3.SUP.5.-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1 (5.3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (6)

(115) To a solution of (2R)-1-((3-(2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-5-fluoropyridin-2-yl)oxy)propan-2-aminium 2,2,2-trifluoroacetate (6c) (21.4 mg, 0.0520 mmol) in DMF (15 mL) at RT was added FDPP (20.0 mg, 0.0520 mmol) and DIPEA (65.0 mg, 0.520 mmol). The resulting mixture was stirred at RT for 18 h. Then the mixture was diluted with water (100 mL) and extracted with EtOAc. The extracts were washed with brine (40 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by preparative TLC eluting with DCM/MeOH (20:1) to give the title compound (1.sup.3E,1.sup.4E,6R)-3.sup.5-fluoro-6-methyl-4-oxa-2.sup.2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (6). MS-ESI (m/z): 395 [M+1].sup.+.

Example 7

(1.SUP.3.E,1.SUP.4.E,5S)-3.SUP.5.-fluoro-5-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (7)

(116) ##STR00050##

(117) The title compound (1.sup.3E,1.sup.4E,5S)-3.sup.5-fluoro-5-methyl-4-oxa-2.sup.2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (7) was prepared according to the synthetic method of example 6 by replacing (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (1c) with (R)-1-((tert-butoxy-carbonyl)-amino)propan-2-yl methanesulfonate. MS-ESI (m/z): 395 [M+1].sup.+.

Example 8

(R,3′E,4′E)-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (8)

(118) ##STR00051##

5-((1-(5-Fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (8a)

(119) To a solution of ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)-pyrazolo[1,5-a]pyrimidine-3-carboxylate (D) (36 mg, 0.10 mmol) in THF-MeOH (1:1, 1.5 mL) was added 5 N NaOH (1 mL). The mixture was stirred at RT for 16 h. The mixture was acidified with 3N HCl to pH=2˜3. The mixture was loaded on silica gel column and eluted with 10% MeOH in DCM to give 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)pyrazolo-[1,5-a]pyrimidine-3-carboxylic acid (8a). MS-ESI (m/z): 330 [M+1].sup.+.

(R)-5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)-N-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (8b)

(120) To a solution of 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (8a) (32.2 mg, 0.0980 mmol) in DMF (1.0 mL) was added D-alaninol (14.7 mg, 0.196 mmol), HATU (56.0 mg, 0.147 mmol) and DIPEA (25.0 mg, 0.196 mmol). The mixture was stirred at RT for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc. The extracts were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated. The residue was purified by column chromatography on silica gel, eluting with 5-10% MeOH in DCM to give (R)-5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)-N-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (8b). MS-ESI (m/z): 387 [M+1].sup.+.

(R,3′E,4′E)-5′-fluoro-7′-methyl-2′-(methylsulfonyl)spiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5.3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (8c)

(121) To a solution of (R)-5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)-N-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (8b) (13.6 mg, 0.0352 mmol) in DCM (0.5 mL) was added methanesulfonyl chloride (23 mg, 0.20 mmol) and TEA (35 mg, 0.35 mmol). The mixture was stirred at RT for 5 h. The mixture was diluted with water (5 mL) and extracted with EtOAc. The extracts were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated. The residue was purified by column chromatography on silica gel, and eluted with 5% MeOH in DCM to give (R,3′E,4′E)-5′-fluoro-7′-methyl-2′-(methylsulfonyl)spiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (8c). MS-ESI (m/z): 447 [M+1].sup.+.

(7′R,E)-3a′-bromo-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (8d)

(122) To a solution of (R,3′E,4′E)-5′-fluoro-7′-methyl-2′-(methylsulfonyl)spiro-[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (8c) (7.5 mg, 0.017 mmol) in 32% HBr—HOAc (0.5 mL). The mixture was heated at 85° C. for 1 h. The solvents were evaporated to give crude (7′R,E)-3a′-bromo-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (8d), which was used in next step without further purification. MS-ESI (m/z): 449/451 (1:1) [M+1].sup.+.

(R,3′E,4′E)-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (8)

(123) To a solution of above crude (7′R,E)-3a′-bromo-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (8d) in MeOH (0.5 mL) was added 5 N NaOH (0.5 mL). The mixture was stirred at RT for 4 h. The mixture was diluted with water and extracted with DCM. The extracts were washed with brine, dried (Na.sub.2SO.sub.4), and the solvents were evaporated. The residue was purified by column chromatography on a silica gel, eluting with DCM-MeOH—NH.sub.4OH (92:7:1) to give (R,3′E,4′E)-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (8). MS-ESI (m/z): 369 [M+1].sup.+.

Example 9

(S,3′E,4′E)-5′-fluoro-6′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (9)

(124) ##STR00052##

(R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (9a)

(125) To a solution of tert-butyl (R)-(2-hydroxypropyl)carbamate (780 mg, 4.46 mmol) in DCM (10 mL) was added methanesulfonyl chloride (536 mg, 4.68 mmol) and TEA (744 mg, 7.37 mmol). The mixture was stirred at RT for 2 h. The solvents were evaporated, the residue was dissolved in EtOAc (50 mL). The solution was washed with water and brine, dried (Na.sub.2SO.sub.4), and concentrated to give (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (9a). MS-ESI (m/z): 276 [M+23].sup.+.

Ethyl (S)-5-((1-(2-((1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (9b)

(126) To a solution of ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)-amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D) (47.0 mg, 0.132 mmol) in DMF (1 mL) was added (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (9a) (50.0 mg, 0.197 mmol) and Cs.sub.2CO.sub.3 (52.0 mg, 0.158 mmol). The mixture was heated at 70° C. for 3 h. The mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried (Na.sub.2SO.sub.4), and the solvents were evaporated. The residue was purified by silica gel chromatography, eluting with 30% EtOAc in hexane to give ethyl (5)-5-((1-(2-((1-((tert-butoxycarbonyl)amino)-propan-2-yl)oxy)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (9b). MS-ESI (m/z): 515 [M+1].sup.+.

(S)-5-((1-(2-((1-aminopropan-2-yl)oxy)-5-fluoropyridin-3-yl)cyclopropyl)amino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (9c)

(127) To a solution of ethyl (5)-5-((1-(2-((1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (9b) (27.1 mg, 0.0527 mmol) in 1:1 MeOH-THF (1.5 mL) was added 5 N NaOH (1 mL). The mixture was heated at 60° C. for 4 h. The mixture was cooled to RT, diluted with water (6 mL), acidified with 3 N HCl to pH=3˜4, and extracted with EtOAc. The extracts were dried (Na.sub.2SO.sub.4), and the solvent was evaporated to give the crude acid. The crude acid was dissolved in DCM (1 mL) and TFA (0.5 mL) was added. The mixture was stirred at RT for 1 h. The solvents were evaporated to give the crude amino acid as TFA salt of (5)-5-((1-(2-((1-aminopropan-2-yl)oxy)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (9c). MS-ESI (m/z): 387 [M+1].sup.+.

(S,3′E,4′E)-5′-fluoro-6′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (9)

(128) To a solution of (5)-5-((1-(2-((1-aminopropan-2-yl)oxy)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (9c) (10 mg, 0.026 mmol) in DMF (0.3 mL) was added HATU (14.8 mg, 0.0390 mmol) and DIPEA (13.4 mg, 0.104 mmol). The mixture was stirred at RT for 14 h. The mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried (Na.sub.2SO.sub.4), and the solvents were evaporated. The residue was purified by preparative TLC on silica gel, eluting with 90:10:0.5 DCM-MeOH—NH.sub.4OH to give (S,3′E,4′E)-5′-fluoro-6′-methylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (9). MS-ESI (m/z): 369 [M+1].sup.+.

Example 10

(R,3′E,4′E)-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (10)

(129) ##STR00053##

Ethyl 5-((1-(5-fluoro-2-(((trifluoromethyl(sulfonyl)oxy)pyridin-3-yl)cyclopropyl)-amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10a)

(130) To a solution of ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl) amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D) (105 mg, 0.294 mmol) in DCM (20 mL) at 0° C. was added pyridine (231 mg, 2.92 mmol) and triflic anhydride (248 mg, 0.879 mmol). The mixture was stirred at RT for 1 h. The reaction was diluted with water and extracted with DCM (2×). The extracts were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated. The crude product was purified by silica gel chromatography, eluting with 30% EtOAc in hexane to give ethyl 5-((1-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10a). MS-ESI (m/z): 490 [M+1].sup.+.

Ethyl (R)-5-((1-(2-(3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10b)

(131) To a solution of 5-((1-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)cyclopropyl)amino) pyrazolo[1,5-a]pyrimidine-3-carboxylate (10a) (112 mg, 0.229 mmol) and tert-butyl (R)-but-3-yn-2-ylcarbamate (77.4 mg, 0.460 mmol) in DMF (4 mL) was added CuI (8.8 mg, 0.046 mmol), Pd(PPh.sub.3).sub.2C.sub.1-2 (32.3 mg, 0.0460 mmol), and diisopropylamine (58 mg, 0.57 mmol). The mixture was heated at 80° C. for 2 h. After cooling to RT, the reaction was diluted with water and extracted with EtOAc (2×). The extracts were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated. The residue was purified by silica gel chromatography, eluting with 40% EtOAc in hexane to give ethyl (R)-5-((1-(2-(3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10b). MS-ESI (m/z): 509 [M+1].sup.+.

Ethyl (R)-5-((1-(2-(3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10c)

(132) To a solution of ethyl (R)-5-((1-(2-(3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10b) (116 mg, 0.228 mmol) in MeOH (5 mL) was added Pd(OH).sub.2 on carbon (20%, contain 50% H.sub.2O, 60 mg). The mixture was stirred at 1 atmosphere of H.sub.2 for 2 h. The catalyst was removed by filtration and the filter cake was washed with MeOH. The filtrate was concentrated. The residue was purified by silica gel chromatography, eluting with 40% EtOAc in hexane to give ethyl (R)-5-((1-(2-(3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10c). MS-ESI (m/z): 513 [M+1].sup.+.

(R)-5-((1-(2-(3-aminobutyl)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo-[1,5-a]pyrimidine-3-carboxylate acid (10d)

(133) To a solution of ethyl (R)-5-((1-(2-(3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (10c) (91.4 mg, 0.178 mmol) in 1:1 MeOH-THF (4.5 mL) was added 5 N NaOH (3 mL). The mixture was heated at 60° C. for 3 h. The mixture was cooled to RT, diluted with water (20 mL), acidified with 3 N HCl to pH=3˜4, and extracted with EtOAc. The extracts were dried (Na.sub.2SO.sub.4), and the solvents were evaporated to give the crude acid. The crude acid was dissolved in 4 N HCl-dioxane (3 mL). The mixture was stirred at RT for 1 h. The solvents were evaporated to give the crude amino acid as HCl salt of (R)-5-((1-(2-(3-aminobutyl)-5-fluoropyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (10d). MS-ESI (m/z): 385 [M+1].sup.+.

(R,3′E,4′E)-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (10)

(134) To a solution of (R)-5-((1-(2-(3-aminobutyl)-5-fluoropyridin-3-yl)cyclopropyl) amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid hydrochloride (10d) (20 mg, 0.044 mmol) in DMF (2 mL) was added DIPEA (49 mg, 0.38 mmol). FDPP (40 mg, 0.104 mmol) was added in 4 portions during 3 h. The mixture was stirred at RT for 14 h. The mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried (Na.sub.2SO.sub.4), and the solvents were evaporated. The residue was purified by preparative TLC on silica gel, eluting with 90:10:0.5 DCM-MeOH—NH.sub.4OH to give (R,3′E,4′E)-5′-fluoro-7′-methylspiro[cyclopropane-1,3′-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphan]-9′-one (10). MS-ESI (m/z): 367 [M+1].sup.+.

Example 11

(R,3′E,4′E)-5′-fluoro-2′7′-dimethylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5.3)-pyrazolo[1,5-a]pyrimidina-4(1,2)-benzenacyclononaphan]-9′-one (111

(135) ##STR00054##

(136) The title compound (R,3′E,4′E)-5′-fluoro-2′,7′-dimethylspiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)-benzenacyclononaphan]-9′-one (11) was prepared according to the synthetic method of example 2 by replacing 1-(2-(benzyloxy)-5-fluorophenyl)-cyclopropan-1-amine (B) with 1-(2-(benzyloxy)-5-fluorophenyl)-A-methylcyclopropan-1-amine 2,2,2-trifluoroacetate (E). MS-ESI (m/z): 382 [M+1].sup.+.

Example 12

(1.SUP.3.E,1.SUP.4.E,6R)-3.SUP.5.-fluoro-6-methyl-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (12A and 12B)

(137) ##STR00055##

Ethyl 5-(1-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-azabicyclo-[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (12a)

(138) The title compound ethyl 5-(1-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)-phenyl)-2-azabicyclo-[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (12a) was prepared according to the synthetic method of ethyl 5-(1-(5-fluoro-2-(((trifluoromethyl)sulfonyl) oxy)-pyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]-pyrimidine-3-carboxylate (5c) by replacing ethyl 5-(1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (5b) with ethyl 5-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1b). MS-ESI (m/z): 515 [M+1].sup.+.

Ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (12b-A and 12b-B)

(139) To a solution of ethyl 5-(1-(5-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)phenyl-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (12a) (84 mg, 0.16 mmol) and tert-butyl (R)-but-3-yn-2-ylcarbamate (5d) (110 mg, 0.650 mmol) in DMF (2.0 mL) was added Pd(PPh.sub.3).sub.2C.sub.1-2 (23.0 mg, 0.0327 mmol), CuI (6.2 mg, 0.033 mmol) and DIPEA (105 mg, 0.820 mmol). Then the resulting mixture was heated at 80° C. for 18 h at the atmosphere of N.sub.2. The reaction was cooled to RT, quenched with water and extracted with EtOAc. The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by preparative TLC to give the title compound ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino) but-1-yn-1-yl)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate (12b-A) (upper spot) and ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate (12b-B) (lower spot). Both compounds shown MS-ESI (m/z): 534 [M+1].sup.+.

(1.SUP.3.E,1.SUP.4.E,6R)-3.SUP.5.-fluoro-6-methyl-2.SUP.2.,7-diaza-1(5.3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (12A and 12B)

(140) The title compound (1.sup.3E, 1.sup.4E,6R)-3.sup.5-fluoro-6-methyl-2.sup.2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (12A and 12B) was prepared according to the synthetic method of 5 by replacing ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluoropyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl) pyrazolo[1,5-a]pyrimidine-3-carboxylate (5e) with ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino) but-1-yn-1-yl)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate (12b-A) or ethyl 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate (12b-B). MS-ESI (m/z): 392 [M+1].sup.+.

Example 13

(6R,E)-3-fluoro-6-methyl-4-oxa-2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (13)

(141) ##STR00056##

(142) The title compound (6R,E)-3.sup.5-fluoro-6-methyl-4-oxa-2.sup.2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (13) was prepared according to the synthetic method of example 1 by replacing ethyl 5-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1b) with ethyl 6-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazine-3-carboxylate (F). MS-ESI (m/z): 394 [M+1].sup.+.

Example 14

(6R,E)-3-fluoro-6-methyl-4-oxa-2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina-3(3,2)-pyridina-2(2.1)-bicyclo[3.1.0]hexanacyclooctphan-8-one (141

(143) ##STR00057##

(144) The title compound (6R,E)-3.sup.5-fluoro-6-methyl-4-oxa-2.sup.2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (14) was prepared according to the synthetic method of example 1 by replacing ethyl 5-(1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1b) with ethyl 6-(1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazine-3-carboxylate (G). MS-ESI (m/z): 395 [M+1].sup.+.

Example 15

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,6R)-3.SUP.5.-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (15]

(145) ##STR00058##

Ethyl 5-((1R,5S)-1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (15a)

(146) To a solution of ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H) (120 mg, 0.320 mmol) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (626 mg, 1.92 mmol), the mixture was stirred at 70° C. for 30 min. To the reaction mixture was added (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (238 mg, 0.960 mmol) at 70° C. and stirred at 70° C. for overnight. The reaction mixture was cooled to RT, diluted 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 (5:1˜1:1) to give the title compound ethyl 5-((1R,5S)-1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (15a). MS-ESI (m/z): 540 [M+1].sup.+.

5-((1R,5S)-1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (15b)

(147) To a solution of ethyl 5-((1R,5S)-1-(2-((R)-2-((tert-butoxycarbonyl)amino)-propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (15a) (77.0 mg, 0.143 mmol) in MeOH (4 mL) was added a solution of LiOH (133 mg, 3.17 mmol) in H.sub.2O (0.7 mL) and stirred at 70° C. overnight and concentrated. The residue was adjusted PH=3˜4 by 0.5 N HCl and extracted with EtOAc. The extracts were washed sequentially with H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and concentrated to give 5-((1R,5S)-1-(2-((R)-2-((tert-butoxycarbonyl)-amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (15b), which was used for next step directly. MS-ESI (m/z): 512 [M+1].sup.+.

(R)-1-(2-((1R,5S)-2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]Hexan-1-yl)-4-fluorophenoxy)propan-2-aminium 2,2,2-trifluoroacetate (15c)

(148) To a solution of 5-((1R,5S)-1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (15b) (72 mg, 0.14 mmol) in DCM (5 mL) was added TFA (4 mL) at 0° C. Then the mixture was warmed to r.t. and stirred for 40 min. The reaction mixture was evaporated to give the crude product of (R)-1-(2-((1R,5S)-2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-4-fluorophenoxy)propan-2-aminium 2,2,2-trifluoroacetate (15c), which was used for next step directly. MS-ESI (m/z): 412 [M+1].sup.+.

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,6R)-3.SUP.5.-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (15)

(149) A mixture of (R)-1-(2-((1R,5S)-2-(3-carboxypyrazolo[1,5-a]pyrimidin-5-yl)-2-azabicyclo[3.1.0]hexan-1-yl)-4-fluorophenoxy)propan-2-aminium 2,2,2-trifluoroacetate (15c) (194 mg, 0.143 mmol), FDPP (55.0 mg, 0.143 mmol) and DIPEA (0.300 mL, 1.82 mmol) in DMF (40 mL) was stirred at RT for overnight. The mixture was diluted 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 preparative TLC to give the title compound (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S,6R)-3.sup.5-fluoro-6-methyl-4-oxa-2.sup.2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (15). .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.87 (d, 1H), 8.27-8.26 (m, 2H), 7.14 (dd, 1H), 6.87-6.85 (m, 1H), 6.72 (dd, 1H), 6.20 (d, 1H), 4.54 (brs, 1H), 4.41 (q, 1H), 4.24 (d, 1H), 4.06 (dd, 1H), 3.73-3.69 (m, 1H), 2.66-2.60 (m, 1H), 2.31 (t, 1H), 2.14-2.10 (m, 1H), 1.74-1.70 (m, 1H), 1.47 (d, 3H), 1.33 (t, 1H).MS-ESI (m/z): 394 [M+1].sup.+.

Example 16

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S)-3.SUP.5.-fluoro-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]Hexana-3(1,2)-benzeneacyclooctaphan-8-one (16)

(150) ##STR00059##

(151) The title compound 16 was prepared according to the syndetic method of 15 by replacing (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate with 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate. .sup.1H NMR (600 MHZ, CDCl.sub.3): δ 9.59 (s, 1H), 8.27-8.26 (m, 2H), 7.14 (dd, 1H), 6.86 (dt, 1H), 6.77 (dd, 1H), 6.21 (d, 1H), 4.45-4.41 (m, 1H), 4.37-4.34 (m, 1H), 4.18-4.16 (m, 1H), 4.08-4.06 (m, 1H), 3.67-3.64 (m, 1H), 3.58-3.53 (m, 1H), 2.66-2.60 (m, 1H), 2.28-2.26 (m, 1H), 2.17-2.13 (m, 1H), 1.71-1.67 (m, 1H), 1.26 (t, 1H). MS-ESI (m/z): 380 [M+1].sup.+.

Example 17

(3′E,4′E)-5′-fluoro-2′-methyldispiro[cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridinacyclononaphane-7′,1″-cyclopropan]-9′-one (17)

(152) ##STR00060##

(153) The title compound 17 was prepared according to the synthetic method of 15 by replacing ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H) and (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate with ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)(methyl)amino) pyrazolo[1,5-a]pyrimidine-3-carboxylate (J) and (1-((tert-butoxycarbonyl)amino)cyclopropyl) methyl methanesulfonate. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.30 (s, 1H), 8.29 (d, 1H), 8.27 (s, 1H), 7.87 (d, 1H), 7.61 (dd, 1H) 6.26 (d, 1H), 4.85 (d, 1H), 3.56 (d, 1H), 3.48 (s, 3H), 2.61-2.57 (m, 1H), 2.39-2.35 (m, 1H), 1.47-1.40 (m, 2H), 1.03-1.00 (m, 2H), 0.93-0.92 (m, 1H), 0.77-0.73 (m, 1H). MS-ESI (m/z): 395 [M+1].sup.+.

Example 18

(2.SUP.1.R,2.SUP.5.S,6R,E)-3-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1(6,3j-imidazo[1,2-b]pyridazina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (18)

(154) ##STR00061##

(155) The title compound 18 was prepared according to the synthetic method of 15 by replacing 2-(5-fluoro-2-methoxyphenyl)acetonitrile (H-1) and ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1a) with 2-(5-fluoro-2-methoxypyridin-3-yl)acetonitrile (D-5) and ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (F-1). .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.96 (d, 1H), 8.18 (s, 1H), 7.87 (d, 1H), 7.79 (d, 1H), 7.61 (dd, 1H), 6.75 (d, 1H), 4.96 (dd, 1H), 4.65-4.62 (m, 1H), 4.37-4.33 (m, 1H), 4.14 (d, 1H), 3.40 (q, 1H), 2.67-2.61 (m, 1H), 2.30 (t, 1H), 2.26-2.23 (m, 1H), 1.73-1.71 (m, 1H), 1.50 (d, 3H), 1.38 (t, 1H). MS-ESI (m/z): 395 [M+1].sup.+.

Example 19

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,6R)-3.SUP.5.-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (19)

(156) ##STR00062##

(157) The title compound 19 was prepared according to the synthetic method of 15 by replacing 2-(5-fluoro-2-methoxyphenyl)acetonitrile (H-1) with 2-(5-fluoro-2-methoxypyridin-3-yl)acetonitrile (D-5). .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.47 (d, 1H), 8.28-8.27 (m, 2H), 7.86 (d, 1H), 7.49 (dd, 1H), 6.21 (d, 1H), 4.95 (dd, 1H), 4.51-4.50 (m, 1H), 4.38-4.33 (m, 1H), 4.07 (dd, 1H), 3.65-3.61 (m, 1H), 2.69-2.63 (m, 1H), 2.27 (t, 1H), 2.22-2.17 (m, 1H), 1.78-1.74 (m, 1H), 1.47 (d, 3H), 1.32 (t, 1H). MS-ESI (m/z): 395 [M+1].sup.+.

Example 20

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,6R)-3.SUP.5.-fluoro-6-methyl-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (20)

(158) ##STR00063##

(159) The title compound 20 was prepared according to the synthetic method of 10 by replacing ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D) with ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (I). .sup.1H NMR (600 MHz, CDCl.sub.3): δ 8.29 (d, 1H), 8.26 (d, 1H), 8.24 (s, 1H), 8.06 (d, 1H), 7.37 (dd, 1H), 6.24 (d, 1H), 4.35-4.31 (m, 1H), 4.29-4.26 (m, 1H), 3.72-3.67 (m, 1H), 3.57 (q, 1H), 2.81-2.77 (m, 2H), 2.68-2.63 (m, 1H), 2.33-2.29 (m, 1H), 2.06-2.01 (m, 2H), 1.68-1.67 (m, 1H), 1.49 (t, 1H), 1.40 (d, 3H). MS-ESI (m/z): 393 [M+1].sup.+.

Example 21

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,5R)-3.SUP.3.-fluoro-5-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (21)

(160) ##STR00064##

Ethyl 5-((I R,5S)-1-(2-(((R)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 121a)

(161) To a solution of ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H) (1.50 g, 3.93 mmol) and tert-butyl (5)-(2-hydroxypropyl)carbamate (1.03 g, 5.90 mmol) in THF (66 mL) was added PPh.sub.3 (1.55 g, 5.90 mmol) at r.t. under N.sub.2 atmosphere. Then DIAD (1.27 g, 5.90 mmol) was added dropwise. The mixture was stirred at 30° C. for overnight. The reaction mixture was concentrated and redisolved in EtOAc. The solution was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (200:1˜100:1) to give the title compound ethyl 5-((1R,5S)-1-(2-(((R)-1-((tert-butoxycarbonyl)-amino)propan-2-yl)oxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (21a). MS-ESI (m/z): 540 [M+1].sup.+.

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,5R)-3.SUP.5.-fluoro-5-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (21)

(162) The title compound 21 was prepared according to the synthetic method of 15 by replacing ethyl 5-((1R,5S)-1-(2-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (15a) with ethyl 5-((1R,5S)-1-(2-(((R)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)-5-fluorophenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (21a). .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.23 (s, 1H), 8.29-8.28 (m, 2H), 7.13 (dd, 1H), 6.90-6.87 (m, 1H), 6.80-6.79 (m, 1H), 6.23 (d, 1H), 4.73-4.72 (m, 1H), 4.31-4.27 (m, 1H), 3.87-3.80 (m, 2H), 3.59-3.55 (m, 1H), 2.62-2.61 (m, 1H), 2.30-2.28 (m, 1H), 2.20-2.17 (m, 1H), 1.70-1.68 (m, 1H), 1.56 (d, 3H), 1.22 (t, 1H). MS-ESI (m/z): 394 [M+1].sup.+.

Example 22

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,5S)-3.SUP.5.-fluoro-5-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.10]hexana-3(1,2)-benzenacyclooctaphan-8-one (22)

(163) ##STR00065##

(164) The title compound 22 was prepared according to the synthetic method of 21 by replacing tert-butyl (5)-(2-hydroxypropyl)carbamate with tert-butyl (R)-(2-hydroxypropyl)-carbamate. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.67 (s, 1H), 8.28-8.26 (m, 2H), 7.13 (dd, 1H), 6.86-6.83 (m, 1H), 6.80-6.78 (m, 1H), 6.21 (d, 1H), 4.56-4.53 (m, 1H), 4.36-4.33 (m, 1H), 4.10-4.06 (m, 1H), 3.64-3.60 (m, 1H), 3.31-3.27 (m, 1H), 2.67-2.61 (m, 1H), 2.32-2.29 (m, 1H), 2.20-2.15 (m, 1H), 1.71-1.67 (m, 1H), 1.49 (d, 3H), 1.23 (t, 1H). MS-ESI (m/z): 394 [M+1].sup.+.

Example 23

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S)-35-fluoro-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (23)

(165) ##STR00066##

(166) The title compound 23 was prepared according to the synthetic method of 15 by replacing ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H) and (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate with ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]-hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (I) and 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.19 (brs, 1H), 8.29-8.28 (m, 2H), 7.87 (d, 1H), 7.50 (dd, 1H), 6.22 (d, 1H), 5.01-4.98 (m, 1H), 4.34-4.30 (m, 2H), 4.05-4.01 (m, 1H), 3.65-3.55 (m, 2H), 2.69-2.63 (m, 1H), 2.26-2.20 (m, 2H), 1.76-1.72 (m, 1H), 1.27 (t, 1H). MS-ESI (m/z): 381 [M+1].sup.+.

Example 24

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,6S)-35-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzenacyclooctaphan-8-one (24)

(167) ##STR00067##

(168) The title compound 24 was prepared according to the synthetic method of 15 by replacing (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate with (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate. .sup.1H NMR (600 MHZ, CDCl.sub.3): δ 9.40 (s, 1H), 8.28-8.26 (m, 2H), 7.16 (dd, 1H), 6.88-6.85 (m, 2H), 6.20 (d, 1H), 4.39-4.31 (m, 2H), 4.18-4.16 (m, 1H), 4.09-4.06 (m, 1H), 3.69-3.66 (m, 1H), 2.63-2.58 (m, 1H), 2.21 (t, 1H), 2.11-2.07 (m, 1H), 1.68-1.63 (m, 4H), 1.20 (t, 1H). MS-ESI (m/z): 394 [M+1].sup.+.

Example 25

(169) (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S,5R)-3.sup.5-fluoro-5-methyl-4-oxa-2.sup.2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (25)

(170) ##STR00068##

(171) The title compound 25 was prepared according to the synthetic method of 21 by replacing ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H) with ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (I). .sup.1H NMR (600 MHz, CDCl.sub.3): δ 8.84 (d, 1H), 8.30-8.28 (m, 2H), 7.80 (d, 1H), 7.44 (dd, 1H), 6.22 (d, 1H), 4.71-4.70 (m, 1H), 4.26-4.22 (m, 1H), 4.01 (t, 1H), 3.90-3.86 (m, 1H), 3.49-3.44 (m, 1H), 2.67-2.65 (m, 1H), 2.29-2.26 (m, 1H), 2.21-2.19 (m, 1H), 1.82 (d, 3H), 1.74-1.71 (m, 1H), 1.21 (t, 1H). MS-ESI (m/z): 395 [M+1].sup.+.

Example 26

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,5S)-3.SUP.5.-fluoro-5-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (26)

(172) ##STR00069##

(173) The title compound 26 was prepared according to the synthetic method of 21 by replacing ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H) and tert-butyl (5)-(2-hydroxypropyl)carbamate with ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (I) and tert-butyl (R)-(2-hydroxypropyl)carbamate. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.38 (d, 1H), 8.28-8.27 (m, 2H), 7.85 (d, 1H), 7.48 (dd, 1H), 6.21 (d, 1H), 5.32-5.28 (m, 1H), 4.36-4.32 (m, 1H), 4.15-4.11 (m, 1H), 3.61-3.57 (m, 1H), 3.29-3.26 (m, 1H), 2.69-2.63 (m, 1H), 2.26-2.19 (m, 2H), 1.75-1.71 (m, 1H), 1.48 (d, 3H), 1.25 (t, 1H). MS-ESI (m/z): 395 [M+1].sup.+.

Example 27

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,6R)-3.SUP.5.-fluoro-6-methyl-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0]hexana-3(1,2)-benzeneacyclooctaphan-8-one (271

(174) ##STR00070##

(175) The title compound 27 was prepared according to the synthetic method of 10 by replacing ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl) amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D) with ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H). .sup.1H NMR (600 MHz, CDCl.sub.3): δ 8.26-8.24 (m, 3H), 7.18 (t, 1H), 7.05 (dd, 1H), 6.88 (dt, 1H), 6.23 (d, 1H), 4.38-4.34 (m, 1H), 4.26-4.22 (m, 1H), 3.67-3.59 (m, 2H), 2.75-2.71 (m, 1H), 2.70-2.63 (m, 1H), 2.24-2.19 (m, 3H), 1.98-1.96 (m, 1H), 1.65-1.62 (m, 1H), 1.45-1.43 (m, 4H). MS-ESI (m/z): 392 [M+1].sup.+.

Example 28

(1.SUP.3.E,1.SUP.4.E,2.SUP.1.R,2.SUP.5.S,6S)-3.SUP.5.-fluoro-6-methyl-4-oxa-2.SUP.2.,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (28)

(176) ##STR00071##

(177) The title compound 28 was prepared according to the synthetic method of 15 by replacing ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxyphenyl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (H) and (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate with ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]-hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (I) and (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate. .sup.1H NMR (600 MHz, CDCl.sub.3): δ 9.09 (brs, 1H), 8.30-8.28 (m, 2H), 7.89 (d, 1H), 7.52 (dd, 1H), 6.21 (d, 1H), 5.08 (dd, 1H), 4.36-4.33 (m, 1H), 4.29-4.27 (m, 1H), 4.26-4.19 (m, 1H), 3.61-3.56 (m, 1H), 2.68-2.62 (m, 1H), 2.22-2.14 (m, 2H), 1.74-1.70 (m, 1H), 1.57 (d, 3H), 1.21 (t, 1H). MS-ESI (m/z): 395 [M+1].sup.+.

Example 29

(2.SUP.1.R,2.SUP.5.S,6R,E)-3.SUP.5.-fluoro-6-methyl-2.SUP.2.,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina-3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (29)

(178) ##STR00072##

(179) The title compound 29 was prepared according to the synthetic method of 10 by replacing ethyl 5-((1-(5-fluoro-2-hydroxypyridin-3-yl)cyclopropyl) amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (D) with ethyl 5-((1R,5S)-1-(5-fluoro-2-hydroxypyridin-3-yl)-2-azabicyclo[3.1.0]hexan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (I). .sup.1H NMR (600 MHZ, CDCl.sub.3): δ 8.65 (d, 1H), 8.30 (d, 1H), 8.13 (s, 1H), 7.77 (d, 1H), 7.49 (dd, 1H), 6.78 (d, 1H), 4.45-4.43 (m, 1H), 4.36-4.32 (m, 1H), 3.62-3.58 (m, 1H), 3.42 (q, 1H), 2.87-2.77 (m, 2H), 2.63-2.60 (m, 1H), 2.33-2.30 (m, 1H), 2.10-2.03 (m, 2H), 1.66-1.64 (m, 1H), 1.54 (t, 1H), 1.38 (d, 3H). MS-ESI (m/z): 393 [M+1].sup.+.

(180) Following essentially the same procedures described for Examples 1-29, Examples 30-100 listed in Table 1 were prepared from the appropriate starting materials which are commercially available or known in the literature. The structures and names of Examples 30-100 are given in Table 1.

(181) TABLE-US-00001 TABLE 1 EXAMPLE STRUCTURE NAME DATA 30 (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S,6S)-35-fluoro-6-methyl-2.sup.2,7- diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)- pyridina-2(2,1)-bicyclo[3.1.0]hexana- cyclooctaphan-8- one MS-ESI (m/z): 393 [M + 1].sup.+ 31 (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S,6S)-35-fluoro-6-methyl-2.sup.2,7- diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)- bicyclo[3.1.0]hexana-3(1,2)-benzenecyclo- octaphan-8-one MS-ESI (m/z): 392 [M + 1].sup.+ 32 (5S,E)-3.sup.5-fluoro-5-methyl-4-oxa-2.sup.2,7- diaza-1(6,3)-imidazo[1,2-b]pyridazina-2(2,1)- bicyclo[3.1.0]hexana-3(1,2)-benzenacyclo- octaphan-8-one MS-ES (m/z): 394 [M + 1].sup.+ 33A/ 33B (6R,E)-3.sup.5-fluoro-6-methyl-2.sup.2,7-diaza-1(6,3)- imidazo[1,2-b]pyridazina-2(2,1)- bicyclo[3.1.0]hexana-3(1,2)-benzena- cyclooctaphan-8-one MS-ESI (m/z): 392 [M + 1].sup.+ 34 (5S,E)-3.sup.5-fluoro-5-methyl-4-oxa-2.sup.2,7- diaza-1(6,3)-imidazo[1,2-b]pyridazina-3(3,2)- pyridina-2(2,1)-bicyclo[3.1.0]- hexanacyclooctaphan-8-one MS-ESI (m/z): 395 [M + 1].sup.+ 35 (6R,E)-3.sup.5-fluoro-6-methyl-2.sup.2,7-diaza-1(6,3)- imidazo[1,2-b]pyridazina-3(3,2)- pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclo- octaphan-8-one MS-ESI (m/z): 393 [M + 1].sup.+ 36 (2.sup.1R,2.sup.5S,6R,E)-3.sup.5-fluoro-6-methyl-4-oxa- 2.sup.2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina- 2(2,1)-bicyclo[3.1.0]hexana-3(1,2)- benzenacyclooctaphan-8-one MS-ESI (m/z): 394 [M + 1].sup.+ 37 0 (2.sup.1R,2.sup.5S,6R,E)-3.sup.5-fluoro-6-methyl-2.sup.2,7- diaza-1(6,3)-imidazo[1,2-b]pyridazina-2(2,1)- bicyclo[3.1.0]hexana-3(1,2)-benzena- cyclooctaphan-8-one MS-ESI (m/z): 392 [M + 1].sup.+ 38 (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S,6R)-3.sup.5-fluoro-6-methyl- 4-oxa-2.sup.4,7-diaza-1(5,3)-pyrazolo[1,5-a] pyrimidina-2(4,5)-bicyclo[3.1.0]hexana- 3(1,2)-benzenacyclooctaphan-8-one MS-ESI (m/z): 394 [M + 1].sup.+ 39 (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S,6R)-3.sup.5-fluoro-6,7- dimethyl-4-oxa-2.sup.2,7-diaza-1(5,3)-pyrazolo [1,5-a]pyrimidina-2(2,1)-bicyclo[3.1.0] hexana-3(1,2)-benzenacyclooctaphan-8-one MS-ESI (m/z): 408 [M + 1].sup.+ 40 (3′E,4′E)-5′-fluorospiro[cyclopropane-1,3′- 5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a] pyrimidina-4(1,2)-benzena- cyclononaphan]-9′-one MS-ESI (m/z): 354 [M + 1].sup.+ 41 (3′E,4′E)-5′-fluorodispiro[cyclopropane- 1,3′-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a] pyrimidina-4(3,2)-pyridina- cyclononaphane-7′,1″-cyclopropan]-9′- one MS-ESI (m/z): 381 [M + 1].sup.+ 42 (R,3′E,4′E)-5′-fluoro-6′-methylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclononaphan]-9′-one MS-ESI (m/z): 369 [M + 1].sup.+ 43 (S,3′E,4′E)-5′-fluoro-7′-methylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclononaphan]-9′-one MS-ESI (m/z): 369 [M + 1].sup.+ 44 (3′E,4′E)-5′-fluorospiro[cyclopropane-1,3′- 5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a] pyrimidina-4(3,2)-pyridinacyclononaphan]- 9′-one MS-ESI (m/z): 355 [M + 1].sup.+ 45 (S,3′E,4′E)-5′-fluoro-2′,6′-dimethylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclononaphan]-9′-one MS-ESI (m/z): 383 [M + 1].sup.+ 46 (R,3′E,4′E)-5′-fluoro-2′,6′-dimethylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphan]-9′-one MS-ESI (m/z): 383 [M + 1].sup.+ 47 0 (7′R,E)-5′-fluoro-2′,7′-dimethylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(6,3)- imidazo[1,2-b]pyridazina-4(3,2)-pyridina- cyclononaphan]-9′-one MS-ESI (m/z): 383 [M + 1].sup.+ 48 (R,3′E,4′E)-5′-fluoro-2′,7′-dimethylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclononaphan]-9′-one MS-ESI (m/z): 383 [M + 1].sup.+ 49 (S,3′E,4′E)-5′-fluoro-2′,7′-dimethylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphan]-9′-one MS-ESI (m/z): 383 [M + 1].sup.+ 50 (3′E,4′E)-5′-fluoro-2′-methylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclononaphan]-9′-one MS-ESI (m/z): 369 [M + 1].sup.+ 51 (R,3′E,4′E)-5′-fluoro-2′,7′-dimethylspiro- [cyclopropane-1,3′-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclononaphan]-9′-one MS-ESI (m/z): 381 [M + 1].sup.+ 52 (7′R,E)-5′-fluoro-2′,7′-dimethylspiro- [cyclopropane-1,3′-2,8-diaza-1(6,3)-imidazo [1,2-b]pyridazina-4(3,2)-pyridinacyclo- nonaphan]-9′-one MS-ESI (m/z): 381 [M + 1].sup.+ 53 (7′R,E)-5′-fluoro-2′,7′-dimethylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(6,3)- imidazo[1,2-b]pyridazina-4(1,2)- benzenacyclononaphan]-9′-one MS-ESI (m/z): 382 [M + 1].sup.+ 54 (3′E,4′E)-5′-fluoro-2′-methylspiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenacyclononaphan]-9′-one MS-ESI (m/z): 368 [M + 1].sup.+ 55 (R,3′E,4′E)-5′-fluoro-2′,7′-dimethylspiro [cyclopropane-1,3′-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenecyclononaphan]-9′-one MS-ESI (m/z): 380 [M + 1].sup.+ 56 (7′R,E)-5′-fluoro-2′,7′-dimethylspiro- [cyclopropane-1,3′-2,8-diaza-1(6,3)- imidazo[1,2-b]pyridazina-4(1,2)- benzenacyclononaphan]-9′-one MS-ESI (m/z): 380 [M + 1].sup.+ 57 00 (S,3′E,4′E)-2′-ethyl-5′-fluoro-6′-methyl- spiro[cyclopropane-1,3′-5-oxa-2,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenacyclononaphan]-9′-one MS-ESI (m/z): 396 [M + 1].sup.+ 58 01 (R,3′E,4′E)-2′-ethyl-5′-fluoro-6′-methyl- spiro[cyclopropane-1,3′-5-oxa-2,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenacyclononaphan]-9′-one MS-ESI (m/z): 396 [M + 1].sup.+ 59 02 (R,3′E,4′E)-2′-ethyl-5′-fluoro-7′-methyl- spiro[cyclopropane-1,3′-5-oxa-2,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenacyclononaphan]-9′-one MS-ESI (m/z): 396 [M + 1].sup.+ 60 03 (S,3′E,4′E)-2′-ethyl-5′-fluoro-7′-methyl- spiro[cyclopropane-1,3′-5-oxa-2,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenacyclononaphan]-9′-one MS-ESI (m/z): 396 [M + 1].sup.+ 61 04 (3′E,4′E)-2′-ethyl-5′-fluorospiro- [cyclopropane-1,3′-5-oxa-2,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenacyclononaphan]-9′-one MS-ESI (m/z): 382 [M + 1].sup.+ 62 05 (S,3′E,4′E)-2′-ethyl-5′-fluoro-6′-methylspiro [cyclopropane-1,3′-5-oxa-2,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononphan]-9′-one MS-ESI (m/z): 397 [M + 1].sup.+ 63 06 (R,3′E,4′E)-2′-ethyl-5′-fluoro-6′-methyl- spiro[cyclopropane-1,3′-5-oxa-2,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphan]-9′-one MS-ESI (m/z): 397 [M + 1].sup.+ 64 07 (R,3′E,4′E)-2′-ethyl-5′-fluoro-7′-methylspiro [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphan]-9′-one MS-ESI (m/z): 397 [M + 1].sup.+ 65 08 (S,3′E,4′E)-2′-ethyl-5′-fluoro-7′-methylspiro [cyclopropane-1,3′-5-oxa-2,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphan]-9′-one MS-ESI (m/z): 397 [M + 1].sup.+ 66 09 (3′E,4′E)-2′-ethyl-5′-fluorospiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphan]-9′-one MS-ESI (m/z): 383 [M + 1].sup.+ 67 0 (3′E,4′E)-5′-fluorospiro[cyclopropane-1,3′- 5-oxa-2,9-diaza-1(5,3)-pyrazolo[1,5-a] pyrimidina-4(3,2)-pyridinacyclodecaphan]- 10′-one MS-ESI (m/z): 369 [M + 1].sup.+ 68 (3′E,4′E)-5′-fluoro-2′-methylspiro- [cyclopropane-1,3′-5-oxa-2,9-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclodecaphan]-10′-one MS-ESI (m/z): 383 [M + 1].sup.+ 69 (3′E,4′E)-5′-fluoro-2′-methyldispiro- [cyclopropane-1,3′-5-oxa-2,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenacyclononaphane-7′,1″-cyclopropan]- 9′-one MS-ESI (m/z): 394 [M + 1].sup.+ 70 (1′R,3′E,4′E,5′S)-5′-fluorospiro- [cyclopropane-1,6′-4-oxa-2.sup.2,7-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-3(3,2)- pyridina-2(2,1)-bicyclo[3.1.0]hexanacyclo- octaphan]-8′-one MS-ESI (m/z): 407 [M + 1].sup.+ 71 (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S)-3.sup.5-fluoro-2.sup.2,7-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-2(2,1)- bicyclo[3.1.0]hexana-3(1,2)-benzenacyclo- octaphan-8-one MS-ESI (m/z): 378 [M + 1].sup.+ 72 (2.sup.1R,2.sup.5S,5S,E)-3.sup.5-fluoro-5-methyl-4-oxa- 2.sup.2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina- 3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0] hexanacyclooctaphan-8-one MS-ESI (m/z): 395 [M + 1].sup.+ 73 (S,3′E,4′E)-4′-fluoro-8′-methylspiro- [cyclopropane-1,7′-5-oxa-8-aza-1(3,5)- pyrazolo[1,5-a]pyrimidina-3(1,2)- pyrrolidina-6(1,2)-benzenacyclooctaphan]-2′- one MS-ESI (m/z): 408 [M + 1].sup.+ 74 (R,3′E,4′E)-4′-fluoro-8′-methylspiro- [cyclopropane-1,7′-5-oxa-8-aza-1(3,5)- pyrazolo[1,5-a]pyrimidina-3(1,2)- pyrrolidina-6(1,2)-benzenacyclooctaphan]- 2′-one MS-ESI (m/z): 408 [M + 1].sup.+ 75 (3′E,4′E)-5′-fluoro-2′-methyldispiro- [cyclobutane-1,7′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphane-3′,1″-cyclopropan]- 9′-one MS-ESI (m/z): 409 [M + 1].sup.+ 76 (1.sup.3E,1.sup.4E,2.sup.1E,2.sup.1R,2.sup.5S)-3.sup.5-fluoro-4-oxa-2.sup.2,8- diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexana- cyclononaphan-9-one MS-ESI (m/z): 395 [M + 1].sup.+ 77 0 (1′R,3′E,4′E,5′S)-5′-fluorospiro- [cyclopropane-1,6′-2.sup.2,7-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina- 2(2,1)-bicyclo[3.1.0]hexanacyclooctaphan]- 8′-one MS-ESI (m/z): 405 [M + 1].sup.+ 78 (1′R,5′S,E)-5′fluorospiro[cyclopropane- 1,6′-2.sup.2,7-diaza-1(6,3)-imidazo[1,2-b] pyridazina-3(3,2)-pyridina-2(2,1)-bicyclo [3.1.0]hexanacyclooctaphan]-8′-one MS-ESI (m/z): 405 [M + 1].sup.+ 79 (1′R,3′E,4′E,5′S)-5′-fluorospiro- [cyclopropane-1,6′-4-oxa-2.sup.2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-3(3,2)- pyridina-2(2,1)-bicyclo[3.1.0]hexana- cyclononaphan]-9′-one MS-ESI (m/z): 421 [M + 1].sup.+ 80 (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S)-3.sup.5-fluoro-6,6-dimethyl- 4-oxa-2.sup.2,8-diaza-1(5,3)-pyrazolo[1,5-a] pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo [3.1.0]hexanacyclononaphan-9-one MS-ESI (m/z): 423 [M + 1].sup.+ 81 (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S)-3.sup.5,6,6-trifluoro-4-oxa- 2.sup.2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0] hexanacyclononaphan-9-one MS-ESI (m/z): 431 [M + 1].sup.+ 82 (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S)-3.sup.5,6-difluoro-4-oxa-2.sup.2, 8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0] hexanacyclononaphan-9-one MS-ESI (m/z): 413 [M + 1].sup.+ 83 (1.sup.3E,1.sup.4E,2.sup.1R,2.sup.5S)-3.sup.5-fluoro-6-hydroxy-4- oxa-2.sup.2,8-diaza-1(5,3)-pyrazolo[1,5-a] pyrimidina-3(3,2)-pyridina-2(2,1)-bicyclo [3.1.0]hexanacyclononaphan-9-one MS-ESI (m/z): 411 [M + 1].sup.+ 84 (3′E,4′E)-5′-fluoro-2′-methyldispiro- [cyclobutane-1,7′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenacyclononaphane-3′,1″-cyclopropan]- 9′-one MS-ES (m/z): 408 [M + 1].sup.+ 85 (3′E,4′E)-5′-fluoro-2′-methyldispiro- [cyclopropane-1,3′-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphane-7′,1″-cyclopropan]- 9′-one MS-ESI (m/z): 393 [M + 1].sup.+ 86 (3′E,4′E)-5′-fluoro-2′-methyldispiro- [cyclopropane-1,3′-5-thia-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclononaphane-7′,1″-cyclopropan]-9′- one MS-ESI (m/z): 411 [M + 1].sup.+ 87 0 (3′E,4′E)-5′-fluoro-2′-methylspiro- [cyclopropane-1,3′-2,5,8-triaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphan]-9′-one MS-ESI (m/z): 368 [M + 1].sup.+ 88 (3′E,4′E)-5′-fluoro-2′-methylspiro- [cyclopropane-1,3′-5,8-dioxa-2-aza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(1,2)- benzenacyclononaphan]-9′-one MS-ESI (m/z): 369 [M + 1].sup.+ 89 (3′E,4′E)-5′-fluoro-2′-(methyl-d.sub.3)dispiro [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(1,2)-benzena- cyclononaphan-7′,1″-cyclopropan]-9′-one MS-ESI (m/z): 397 [M + 1].sup.+ 90 (3′E,4′E)-4′-fluoro-8′-methylspiro- [cyclopropane-1,7′-5-oxa-8-aza-1(3,5)- pyrazolo[1,5-a]pyrimidina-3(1,2)-azetidina- 6(1,2)-benzenacyclooctaphan]-2′-one MS-ESI (m/z): 394 [M + 1].sup.+ 91 (3′E,4′E)-5′-fluoro-2′-(methyl-d.sub.3)dispiro- [cyclopropane-1,3′-5-oxa-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclononaphane-7′,1″-cyclopropan]-9′-one MS-ESI (m/z): 398 [M + 1].sup.+ 92 (3′E,4′E)-5′-fluoro-2′-methyldispiro- [cyclopropane-1,3′-5-oxa-2,9-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclodecaphane-7′,1″-cyclopropan]-10′- one MS-ESI (m/z): 409 [M + 1].sup.+ 93 (3′E,4′E)-5′-fluoro-2′,7′,7′-trimethylspiro- [cyclopropane-1,3′-5-oxa-2,9-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclodecaphan]-10′-one MS-ESI (m/z): 411 [M + 1].sup.+ 94 (3′E,4′E)-5′,7′,7′-trifluoro-2′-methylspiro- [cyclopropane-1,3′-5-oxa-2,9-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(4,3)-pyridina- cyclodecaphan]-10′-one MS-ESI (m/z): 419 [M + 1].sup.+ 95 (3′E,4′E)-5′,7′-difluoro-2′-methylspiro- [cyclopropane-1,3′-5-oxa-2,9-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)-pyridina- cyclodecaphan]-10′-one MS-ESI (m/z): 401 [M + 1].sup.+ 96 (3′E,4′E)-5′-fluoro-7′-hydroxy-2′-methyl- spiro[cyclopropane-1,3′-5-oxa-2,9-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclodecaphan]-10′-one MS-ESI (m/z): 399 [M + 1].sup.+ 97 0 (3′E,4′E)-5′-fluoro-2′-(methyl-d.sub.3)-dispiro [cyclopropane-1,3′-2,8-diaza-1(5,3)- pyrazolo[1,5-a]pyrimidina-4(3,2)- pyridinacyclononaphane-7′,1″- cyclopropan]-9′-one MS-ESI (m/z): 396 [M + 1].sup.+ 98 (1′R,3′E,4′E,5′S)-2′-amino-5′-fluorospiro- [cyclopropane-1,6′-4-oxa-2.sup.2,7-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)- pyridina-2(2,1)-bicyclo[3.1.0]- hexanacyclooctaphan]-8′-one MS-ESI (m/z): 422 [M + 1].sup.+ 99 N-((1′R,3′E,4′E,5′S)-5′-fluoro-8′-oxospiro [cyclopropane-1,6′-4-oxa-2.sup.2,7-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0] hexanacyclooctaphan]-2′-yl)acetamide MS-ESI (m/z): 464 [M + 1].sup.+ 100  2-amino-N-((1′R,3′E,4′E,5′S)-5′-fluoro-8′- oxospiro[cyclopropane-1,6′-4-oxa-2.sup.2,7- diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(2,1)-bicyclo[3.1.0]hexana- cyclooctaphan]-2′-yl)acetamide MS-ESI (m/z): 479 [M + 1].sup.+
Biological Activity

(182) 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).

(183) 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). IC.sub.50 was calculated using GraphPad Prism 5.0.

(184) 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: 3×10.sup.4/mL, Ba/F3-TPM3-TRKA-G595R: 1×10.sup.5/mL, Ba/F3-AFAP1-TRKB: 1×10.sup.5/mL, Ba/F3-ETV6-TRKC: 3×10.sup.4/mL, Ba/F3-ETV6-TRKC-G623R: 3×10.sup.4/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). IC.sub.50 was calculated using GraphPad Prism 5.0 software.

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

(186) TABLE-US-00002 TABLE 2 KM12 IC.sub.50 TPM3-TRKA TPM3-TRKA-G595R ETV6-TRKC ETV6-TRKC-G623R Example (nM) IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM)  1 1 / / / /  2 1 / / / /  3 1 / / 1 /  4 1 / / / /  5 1 / / / /  6 1 / / / /  7 1 / / / /  8 4 3 67 1 39  9 7 / / / / 10 1 / / / / 11 1 / 36 / 41  12A 1 / / / /  12B 2 / / / / 13 1 / / / / 14 1 / / / / 15 1 1 1 1 1 16 1 1 1 1 2 17 1 1 5 / 1 18 1 1 1 1 2 19 1 1 1 1 1 20 1 1 1 1 1 21 1 1 / / 1 22 1 1 1 1 1 23 1 1 4 / 5 24 1 1 1 1 4 25 2 / / / 7 26 1 / / / 1 27 1 1 1 1 1 28 1 1 / / 6 29 1 1 1 1 1 30 1 1 / / 2 31 1 1 1 1 3 32 1 / / / /  33A 1 / / / /  33B 1 / / / / 34 1 / / / / 35 1 / / / / 36 6 2 17 3 13 37 9 1 10 3 8 38 3 1 1 2 23 39 1 1 1 1 17 41 1 1 30 / 26 42 3 / / / / 44 35 18 / 26 / 45 2 3 25 1 15 47 2 / 26 / 23 48 2 / 14 / 12 50 10 11 / 2 68 51 3 / 72 / 44 53 30 / / / / 54 9 13 / / 62 55 5 / / / 87 56 3 / / / / 59 1 17 / / / 62 13 46 / / / 64 2 6 / / 68 66 34 60 / 15 / 67 10 23 / / / 68 10 8 53 / 33 69 1 / 1 / 4 70 / / 1 / 1 71 1 / 1 / 1 72 / / 3 / 5 75 / / 25 / 19 76 / / / / 1 77 1 / 1 / 1 78 1 / 3 / 1 79 / / / / 1 80 / / / / 4 81 / / / / 1 82 / / / / 1 83 / / / / 1 84 / / 46 / 29 85 / / 15 / 45 86 1 / 1 / 1 89 / / / / 1 91 / / / / 2 92 / / / / 5 93 / / / / 32 94 / / / / 25 95 / / / / 1 96 / / / / 4 97 / / / / 25 98 / / / / 1