HETEROCYCLIC DERIVATIVES AND USE THEREOF

Abstract

Provided are certain URAT1 inhibitors, pharmaceutical compositions thereof, and methods of use thereof.

Claims

1. A compound of formula (I): ##STR00056## or a pharmaceutically acceptable salt thereof, wherein: W is selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; L is selected from —(CR.sup.C0R.sup.D0).sub.uC(O)(CR.sup.C0R.sup.D0).sub.u, —(CR.sup.C0R.sup.D0).sub.uC(O)NR.sup.A0(CR.sup.C0R.sup.D0).sub.t—, —(CR.sup.C0R.sup.D0).sub.uS(O).sub.r(CR.sup.C0R.sup.D0).sub.t— and —(CR.sup.C0R.sup.D0).sub.uS(O).sub.rNR.sup.A0(CR.sup.C0R.sup.D0).sub.t—; X.sup.1 is selected from CR.sup.C1R.sup.D1, NR.sup.A1, O and S(O).sub.r; X.sup.2 and X.sup.3 are independently selected from —(CR.sup.C1R.sup.D1).sub.u—, —(CR.sup.C1R.sup.D1).sub.uO(CR.sup.C1R.sup.D1).sub.t—, —(CR.sup.C1R.sup.D1).sub.uNR.sup.A1(CR.sup.C1R.sup.D1).sub.t—, —(CR.sup.C1R.sup.D1).sub.uS(CR.sup.C1R.sup.D1).sub.t—, —(CR.sup.C1R.sup.D1).sub.uC(O)(CR.sup.C1R.sup.D1).sub.t— and —(CR.sup.C1R.sup.D1).sub.uS(O).sub.r(CR.sup.C1R.sup.D1).sub.t—; Y.sup.1, Y.sup.2 and Y.sup.3 are independently selected from N, NR.sup.1, CR.sup.2, O and S(O).sub.r; R.sup.1 is selected from hydrogen, deuterium, 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.X1; R.sup.2 is selected from hydrogen, deuterium, 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.A2R.sup.B2, —OR.sup.A2, —C(O)R.sup.A2, —C(═NR.sup.E2)R.sup.A2, —C(═N—OR.sup.B2)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, —C(═NR.sup.E2)NR.sup.A2R.sup.B2, —NR.sup.A2C(═NR.sup.E2)R.sup.B2, —OC(O)NR.sup.A2R.sup.B2, —NR.sup.A2C(O)OR.sup.B2, —NR.sup.A2C(O)NR.sup.A2R.sup.B2, —NR.sup.A2C(S)NR.sup.A2R.sup.B2, —NR.sup.A2C(═NR.sup.E2)NR.sup.A2R.sup.B2, S(O).sub.rR.sup.A2, —S(O)(═NR.sup.E2)R.sup.B2, —N═S(O)R.sup.A2R.sup.B2, —S(O).sub.2OR.sup.A2, —OS(O).sub.2R.sup.A2, —NR.sup.A2S(O).sup.rR.sup.B2, —NR.sup.A2S(O)(═NR.sup.E2)R.sup.B2, —S(O).sub.rNR.sup.A2B.sup.B2, —S(O)(═NR.sup.E2)NR.sup.A2R.sup.B2, —NR.sup.A2S(O).sub.2NR.sup.A2R.sup.B2, —NR.sup.A2S(O)(═NR.sup.E2)NR.sup.A2R.sup.B2, —P(O)R.sup.A2R.sup.B2 and —P(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 R.sup.X2; each R.sup.A0 is independently selected from hydrogen, deuterium, 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.X0; each R.sup.A1 is independently selected from hydrogen, deuterium, 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.X1; each R.sup.A1 and R.sup.B2 are independently selected from hydrogen, deuterium, 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.X2; 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, 2 or 3 R.sup.X2 groups; each R.sup.C0 and R.sup.D0 are independently selected from hydrogen, deuterium, 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.X0; or each “R.sup.C0 and R.sup.D0” 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.X0 groups; each R.sup.C1 and R.sup.D1 are independently selected from hydrogen, deuterium, 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.X1; or each “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.X1 groups; each R.sup.E2 are independently selected from hydrogen, deuterium, C.sub.1-10 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 is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X2; each R.sup.X, R.sup.X0, R.sup.X1, R.sup.X2 are independently selected from hydrogen, deuterium, 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)R.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.d1).sub.tNR.sup.a1C(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rR.sup.a1, —(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.a1(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(═NR.sup.e1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.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.d1).sub.tNR.sup.a1S(O).sub.2NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(═R.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, deuterium, 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, deuterium, 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, deuterium, 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.1-4aryl, 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).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, deuterium, 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, 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, deuterium, 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, alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino, 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, deuterium, 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; 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. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the moiety ##STR00057## in Formula (I) is selected from ##STR00058## ##STR00059## wherein R.sup.1 and R.sup.2 are as defined in formula (I).

3. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y.sup.l is NR.sup.1, Y.sup.2 is N and Y.sup.3 is CR.sup.2, the compound has the structure of formula (II), ##STR00060## wherein R.sup.1, R.sup.2, X.sup.1, X.sup.2, X.sup.3, L and W are as defined in formula (I).

4. (canceled)

5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from hydrogen, deuterium, C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X1.

6. (canceled)

7. A compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from hydrogen and methyl.

8. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from hydrogen, deuterium, halogen, OH, CN, NO.sub.2 NH.sub.2, C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X2.

9. (canceled)

10. A compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from hydrogen and methyl.

11. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X.sup.1 is selected from CR.sup.C1R.sup.D1, NR.sup.A1, O, S and S(O).sub.2.

12. A compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the R.sup.C1 and R.sup.D1 in X.sup.1 are independently selected from hydrogen, deuterium, halogen, C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X1.

13. (canceled)

14. A compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the R.sup.A1 in X.sup.1 is selected from hydrogen, deuterium, C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X1.

15. (canceled)

16. A compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the R.sup.C1 and R.sup.D1 in X.sup.1 are independently selected from hydrogen and deuterium, wherein the R.sup.A1 in X.sup.1 is selected from hydrogen, deuterium and methyl.

17. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X.sup.2 and X.sup.3 are independently selected from —(CR.sup.C1R.sup.D1).sub.u—.

18. A compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein each u is independently selected from 0, 1 and 2.

19. A compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein the R.sup.C1 and R.sup.D1 in X.sup.2 or X.sup.3 are independently selected from hydrogen, deuterium, halogen, C.sub.1-10 alkyl and C.sub.3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X1.

20. (canceled)

21. A compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein the R.sup.C1 and R.sup.D1 in X.sup.2 or X.sup.3 are independently selected from hydrogen, deuterium and methyl.

22. A compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the R.sup.C1 and R.sup.D1 in X.sup.2 or X.sup.3 together with the carbon atom(s) to which they are attached form a ring of 3 to 8 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1, 2 or 3 R.sup.X1 groups.

23. A compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein the R.sup.C1 and R.sup.D1 in X.sup.2 or X.sup.3 together with the carbon atom(s) to which they are attached form 3- to 5-membered cycloalkyl.

24. A compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R.sup.C1 and R.sup.D1 in X.sup.2 or X.sup.3 together with the carbon atom(s) to which they are attached form cyclopropyl.

25. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the moiety ##STR00061## in Formula (I) is selected from ##STR00062##

26. (canceled)

27. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is —(CR.sup.C0R.sup.D0).sub.uC(O)(CR.sup.C0R.sup.D0).sub.t—.

28. A compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein L is —C(O)—.

29. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is aryl, wherein aryl is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; or W is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X.

30. (canceled)

31. A compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein W is phenyl, the substituent R.sup.X of phenyl is selected from halogen, CN and —(CR.sup.c1R.sup.d1).sub.tOR.sup.b1.

32. A compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein the substituent R.sup.X of phenyl is selected from Cl, Br, CN and OH.

33. A compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein the moiety ##STR00063## in Formula (I) is selected from ##STR00064##

34. A compound of claim 1, selected from ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## and pharmaceutically acceptable salts thereof.

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

36. A method of treating, ameliorating or preventing a condition, which responds to inhibition of URAT1, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

37. A method of treating a condition mediated by URAT1, comprising administering to a subject in need of such treatment an effective amount of compound of claim 1 or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

[0212] Various methods may be developed for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic routes that others may devise.

[0213] It will be readily recognized that certain compounds of formula (I) have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.

[0214] Ae compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) can be prepared by, for example, reacting the free acid form of the at least one compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of formula (I) are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.

[0215] 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).

[0216] The N-oxides of the 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.

[0217] 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 an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80° C.

[0218] 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.

[0219] 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); Me0H (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); 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).

[0220] 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.

[0221] .sup.1H NMR spectra were recorded on a Varian Mercury Plus 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).

[0222] 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 (60E-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).

Synthetic Schemes

[0223] A compound of formula I and/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.

[0224] In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.

[0225] Synthetic methods for preparing the compounds of the present disclosure 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.

[0226] 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.

[0227] Two synthetic approaches for the construction of the compounds of formula I are shown in Scheme 1. Coupling of fused heterocyclic amines of formula II with intermediates of formula III gives compounds of formula I, which can also be synthesized by via the intramolecular cyclization of intermediates of formula IV.

##STR00026##

[0228] As an illustration of the synthesis of compounds of formula I, one of the synthetic approach of the compounds of formula Ia and Ib is outlined in Scheme 2. Halogenation of II-a with reagents such as NBS gives bromide II-b. Oxidation of amine II-b by H202 gives nitro compounds of formula II-c. S.sub.NAr substitutions of II-c with ethyl 2-mercaptoacetate provides II-d. Hydrolysis of Ester II-d followed by the reduction of the resulting acid with reducing reagents such as ferrous powder gives amino acid II-f. Intramolecular cyclization of II-f with reagents such as POCl.sub.3 gives lactam II-g which can be reduced with BH.sub.3 to give amine II-h. Condensation of amine II-h with III followed by other necessary derivatization reactions leads to compounds of formula Ib. Compounds of formula Ib can be prepared by the oxidization of Ia.

##STR00027## ##STR00028##

[0229] As a further illustration of the preparation of I. One synthetic route of Ic is shown in Scheme 3. The preparation starts with IV-a, which is commercially available or can be synthesized following the procedure known in the literature. Alkylation of IV-a with IV-b in the presence of a base such as Cs.sub.2CO.sub.3 provides ethers of formula IV-c. Nitration of IV-c leads to nitro intermediates of formula IV-d which can converted into intermediates IV-g via reduction of the nitro group and coupling of the resulting amine with III. Ester IV-g can be converted into alcohol IV-h via NaBH.sub.4/CaCl.sub.2 reduction. Cyclization of IV-h via mitsunobu reaction followed by other necessary derivatization reactions to give compounds of formula Ic.

##STR00029##

[0230] 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.

Example 1

(R)-(3,5-dibromo-4-hydroxyphenyl)(1,5-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)methanone (1)

[0231] ##STR00030##

Methyl (R)-2-((1-methyl-1H-pyrazol-4-yl)oxy)propanoate (1a)

[0232] To a mixture of 1-methyl-1H-pyrazol-4-ol (400 mg, 4.08 mmol) and Cs.sub.2CO.sub.3 (2.60 g, 8.00 mmol) in DMF (6.0 mL) was added a solution of methyl (S)-2-((methylsulfonyl)oxy)propanoate (1.00 g, 5.50 mmol) (WO2015/164643, 2015, A1) in DMF (4.0 mL) at 80° C. The mixture was stirred at 80° C. for 45 min. The mixture was diluted with H.sub.2O (100 mL), extracted with EtOAc (3×50 mL), washed with brine, dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by column chromatography on silica gel eluting with Petroleum/EtOAc (10:1˜2:1) to give the title compound methyl (R)-2-((1-methyl-1H-pyrazol-4-yl)oxy)propanoate (1a). MS-ESI (m/z): 185 [M+1].sup.+.

Methyl (R)-2-((1-methyl-5-nitro-1H-pyrazol-4-yl)oxy)propanoate (1b)

[0233] To a mixture of methyl (R)-2((1-methyl-1H-pyrazol-4-yl)oxy)propanoate (1a) (3.68 g, 20.0 mmol) in Con.H.sub.2SO.sub.4 (30.0 mL) was added KNO.sub.3 (3.23 g, 32.0 mmol) in portions under ice-water bath. The mixture was stirred at 0° C. for 20 min. Then the mixture was poured into ice water (350 mL) and extracted with DCM (3×100 mL). The organic phase was washed with saturated NaHCO.sub.3 aqueous solution, concentrated and purified by column chromatography on silica gel eluting with Petroleum/EtOAc (10:1˜4:1) to give the title compound methyl (R)-2-((1-methyl-5-nitro-1H-pyrazol-4-yl)oxy)propanoate (1b). MS-ESI (m/z): 230 [M+1].sup.+.

Methyl (R)-2-((5-amino-1-methyl-1H-pyrazol-4-yl)oxy)propanoate (1c)

[0234] A mixture of methyl (R)-2((1-methyl-5-nitro-1H-pyrazol-4-yl)oxy)propanoate (1b) (2.80 g, 12.2 mmol) and Pd/C (1.00 g) in MeOH (50.0 mL) was stirred at RT under H.sub.2 atmosphere for 6 hours. The reaction mixture was filtered through celite and concentrated to give the crude product of title compound methyl (R)-24(5-amino-1-methyl-1H-pyrazol-4-yl)oxy)propanoate (1c) which was used directly for next step. MS-ESI (m/z): 200 [M+1].sup.+.

2,6-Dibromo-4-methoxybenzoic acid (1d)

[0235] 2,6-dibromo-4-methoxybenzoic acid (1d) was prepared according to the method described in European Journal of Inorganic Chemistry, 2015, 3, 534-541.

Methyl (R)-2-((5-(3,5-dibromo-4-methoxybenzamido)-1-methyl-1H-pyrazol-4-yl)oxy)propanoate (1e)

[0236] To a mixture of 2,6-dibromo-4-methoxybenzoic acid (1d) (2.92 g, 14.0 mmol) in DCM (25 mL) was added (COCl).sub.2 (2M in DCM, 15.0 mL) followed by DMF (0.05 mL), The mixture was stirred at RT for 2 hours. The mixture was concentrated and the residue was dissolved in DCM (10 mL). To a solution of methyl (R)-2-((5-amino-1-methyl-1H-pyrazol-4-yl)oxy)propanoate (1c) (2.50 g, 12.6 mmol) and pyridine (5 mL) in DCM (20 mL) was added the mixture of above solution dropwise under ice-bath, after addition, the mixture was stirred at RT for overnight. The mixture was quenched with H.sub.2O, sequentially washed with 1N HCl (2×50 mL), saturated NaHCO.sub.3 aqueous solution (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel eluting with Petroleum/EtOAc (10:1˜1:1) to give the title compound methyl (R)-2-((5-(3,5-dibromo-4-methoxybenzamido)-1-methyl-1H-pyrazol-4-yl)oxy)propanoate (1e). MS-ESI (m/z): 490, 492, 494 (1:2:1) [M+1].sup.+.

(R)-3,5-dibromo-N-(4-((1-hydroxypropan-2-yl)oxy)-1-methyl-1H-pyrazol-5-yl)-4-methoxybenzamide (1f)

[0237] To a mixture of methyl (R)-2-((5-(3,5-dibromo-4-methoxybenzamido)-1-methyl-1H-pyrazol-4-yl)oxy)propanoate (1e) (3.90 g, 8.00 mmol) and CaCl.sub.2 (1.76 g, 15.9 mmol) in EtOH (50.0 mL) was added NaBH.sub.4 (1.20 g, 31.7 mmol) in portions under ice-water bath. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with water, filtered and the filtrate was extracted with DCM (2×100 mL). 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 DCM/MeOH (20:1) to give the title compound (R)-3,5-dibromo-N-(4-((1-hydroxypropan-2-yl)oxy)-1-methyl-1H-pyrazol-5-yl)-4-methoxybenzamide (1f). MS-ESI (m/z): 462, 464, 466 (1:2:1) [M+1].sup.+.

(R)-(3,5-dibromo-4-methoxyphenyl)(1,5-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)methanone (1g)

[0238] The mixture of (R)-3,5-dibromo-N-(4-((1-hydroxypropan-2-yl)oxy)-1-methyl-1H-pyrazol-5-yl)-4-methoxybenzamide (1f) (2.30 g, 5.00 mmol), PPh.sub.3 (4.58 g, 17.5 mmol) and DIAD (3.03 g, 15.0 mmol) in THF (40.0 mL) was stirred at 0° C.˜RT for 3 h. Then the mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with Petroleum/EtOAc (10:1˜5:1) to give the title compound (R)-(3,5-dibromo-4-methoxyphenyl)(1,5-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)methanone (1g). MS-ESI (m/z): 444, 446, 448 (1:2:1) [M+1].sup.+.

(R)-(3,5-dibromo-4-hydroxyphenyl)(1,5-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)methanone (1)

[0239] The mixture of (R)-(3,5-dibromo-4-methoxyphenyl)(1,5-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)methanone (1g) (3.00 g, 6.77 mmol) and BBr.sub.3 (1M in DCM, 30.0 mL) in DCM (10.0 mL) was stirred at 0° C.˜RT for 2 h. The reaction was quenched with ice water (300 g) and extracted with DCM (2×100 mL). The extracts were washed with brine, dried over MgSO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (100:1˜20:1) to give the title compound (R)-(3,5-dibromo-4-hydroxyphenyl)(1,5-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)methanone (1). MS-ESI (m/z): 430, 432, 434 (1:2:1) [M+1].sup.+.

Example 2

(3,5-Dibromo-4-hydroxyphenyl)(1-methyl-5,6-dihydropyrazolo[4,3-b][1,4]oxazin-7(1H)-yl)methanone (2)

[0240] ##STR00031##

[0241] The title compound 2 was prepared according to the synthetic method of 1 by replacing methyl (S)-2-((methylsulfonyl)oxy)propanoate with methyl 2-bromoacetate. MS-ESI (m/z): 416, 418, 420 (1:2:1) [M+1].sup.+.

[0242] Following essentially the same procedures described for Examples 1˜2 or using similar synthetic methods or strategies, Examples 3˜18 listed in Table 1 were prepared. The structures and names of Examples 3˜19 are given in Table 1.

TABLE-US-00001 TABLE 1 EXAMPLE STRUCTURE NAME DATA 3 [00032] (3,5-dibromo-4-hydroxyphenyl)(5,6- dihydropyrazolo[4,3-b][1,4]oxazin- 7(1H)-yl)methanone MS-ESI (m/z): 402, 404, 406 (1:2:1) [M + 1].sup.+ 4 [00033] (S)-(3,5-dibromo-4-hydroxyphenyl)(5- methyl-5,6-dihydropyrazolo[4,3-b] [1,4]oxazin-7(1H)-yl)methanone MS-ESI (m/z): 416, 418, 420 (1:2:1) [M + 1].sup.+ 5 [00034] (S)-(3,5-dibromo-4-hydroxyphenyl) (1,5-dimethyl-5,6-dihydropyrazolo[4,3- b][1,4]oxazin-7(1H)-yl)methanone MS-ESI (m/z): 430, 432, 434 (1:2:1) [M + 1].sup.+ 6 [00035] (R)-(3,5-dibromo-4-hydroxyphenyl) (5-methyl-5,6-dihydropyrazolo[4,3 -b] [1,4]oxazin-7(1H)-yl)methanone MS-ESI (m/z): 416, 418, 420 (1:2:1) [M + 1].sup.+ 7 [00036] 3-bromo-2-hydroxy-5-(1-methyl-1,5, 6,7-tetrahydropyrazolo[4,3-b][1,4] oxazine-7-carbonyl)benzonitrile MS-ESI (m/z): 363, 365 (1:1) [M + 1]+. 8 [00037] (S)-3-bromo-5-(1,5-dimethyl-1,5,6,7- tetrahydropyrazolo[4,3-b][1,4]oxazine- 7-carbonyl)-2-hydroxybenzonitrile MS-ESI (m/z): 377, 379 (1: 1) [M + 1].sup.+ 9 [00038] (R)-3-bromo-5-(1,5-dimethyl-1,5,6,7- tetrahydropyrazolo[4,3-b][1,4]oxazine- 7-carbonyl)-2-hydroxybenzonitrile MS-ESI (m/z): 377, 379 (1:1) [M + 1].sup.+ 10 [00039] (3,5-dibromo-4-hydroxyphenyl)(1,3- dimethyl-5,6-dihydropyrazolo[4,3-b] [1,4]oxazin-7(1H)-yl)methanone MS-ESI (m/z): 430, 432, 434 (1:2:1) [M + 1].sup.+. 11 [00040] (3,5-dibromo-4-hydroxyphenyl)(1- methyl-1,4,5,6-tetrahydro-7H-pyrazolo [3,4-b]pyridin-7-yl)methanone MS-ESI (m/z): 414, 416, 418 (1:2:1) [M + 1].sup.+. 12 [00041] (3,5-dibromo-4-hydroxyphenyl)(1,5,5- trimethyl-5,6-dihydropyrazolo[4,3-b] [1,4]oxazin-7(1H)-yl)methanone MS-ESI (m/z): 444, 446, 448 (1:2:1) [M + 1].sup.+. 13 [00042] (3,5-dibromo-4-hydroxyphenyl)(1,3,5, 5-tetramethyl-5,6-dihydropyrazolo[4, 3-b][1,4]oxazin-7(1H)-yl)methanone MS-ESI (m/z): 458, 460, 462 (1:2:1) [M + 1].sup.+. 14 [00043] (3,5-dichloro-4-hydroxyphenyl)(1- methyl-5,6-dihydropyrazolo[4,3-b][1,4] oxazin-7(1H)-yl)methanone MS-ESI (m/z): 328 [M + 1].sup.+. 15 [00044] (S)-(3,5-dibromo-4-hydroxyphenyl) (1,3,5-trimethyl-5,6-dihydropyrazolo[4, 3-b][1,4]oxazin-7(1H)-yl)methanone MS-ESI (m/z): 444, 446, 448 (1:2:1) [M + 1].sup.+. 16 [00045] (3,5-dibromo-4-hydroxyphenyl)(1′- methyl-1′H-spiro[cyclopropane-1,5′- pyrazolo[4,3-b][1,4]oxazin]-7′(6′H)-yl) methanone MS-ESI (m/z): 442, 444, 446 (1:2:1) [M + 1].sup.+. 17 [00046] (3,5-dibromo-4-hydroxyphenyl)(1′,3′- dimethyl-1′H-spiro[cyclopropane-1,5′- pyrazolo[4,3-b][1,4]oxazin]-7′(6′H)- yl)methanone MS-ESI (m/z): 456, 458, 460 (1:2:1) [M + 1].sup.+. 18 [00047] (R)-(3,5-dibromo-4-hydroxyphenyl) 1,3,5-trimethyl-5,6-dihydropyrazolo [4,3-b][1,4]oxazin-7(1H)-yl)methanone MS-ESI (m/z): 444, 446, 448 (1:2:1) [M + 1].sup.+. 19 [00048] (3,5-dibromo-4-hydroxyphenyl)(2- methyl-5,6-dihydropyrazolo[4,3-b][1,4] oxazin-7(2H)-yl)methanone MS-ESI (m/z): 416, 418, 420 (1:2:1) [M + 1].sup.+. 20 [00049] (3,5-dibromo-4-hydroxyphenyl)(5,6- dihydropyrazolo[3,4-b][1,4]oxazin- 4(1H)-yl)methanone MS-ESI (m/z): 402, 404, 406 (1:2:1) [M + 1].sup.+. 21 [00050] (3,5-dibromo-4-hydroxyphenyl)(1- methyl-5,6-dihydropyrazolo[3,4-b][1,4] oxazin-4(1H)-yl)methanone MS-ESI (m/z): 416, 418, 420 (1:2:1) [M + 1].sup.+. 22 [00051] (3,5-dibromo-4-hydroxyphenyl)(1- methyl-5,6-dihydropyrazolo[4,3-b][1,4] oxazin-7(1H)-yl-5,5,6,6-d.sub.4)methanone MS-ESI (m/z): 420, 422, 424 (1:2:1) [M + 1].sup.+.

Example 23

(3,5-dibromo-4-hydroxyphenyl)(1,3-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]thiazin-7(1H)-yl)methanone (23)

[0243] ##STR00052##

4-bromo-1,3-dimethyl-1H-pyrazol-5-amine (23a)

[0244] To a stirred solution of 1,3-dimethyl-1H-pyrazol-5-amine (10 g, 90.0 mmol) in DCM (150 mL) was added NBS (16 g, 90 mmol) in 5 portions at 0˜5° C. The resulting mixture was stirred at the same temperature for 1 h under nitrogen atmosphere. The reaction mixture was washed with saturated aqueous NaHCO.sub.3 solution (100 mL). The aqueous layer was extracted with DCM (50 mL×2). The combined DCM phase was washed sequentially with saturated aqueous Na.sub.2SO.sub.3 solution, water and brine, concentrated to give 4-bromo-1,3-dimethyl-1H-pyrazol-5-amine (23a) as crude, which was used in the next step without further purification. MS-ESI(m/z): 190, 192 [M+1].sup.+.

4-bromo-1,3-dimethyl-5-nitro-1H-pyrazole (23b)

[0245] To a stirred solution of 4-bromo-1,3-dimethyl-1H-pyrazol-5-amine (23a) (5.0 g, 26.3 mmol) in con. H.sub.2SO.sub.4 (100 mL) was added H.sub.2O.sub.2/H.sub.2O (30%, 40 mL) dropwise at 5˜30° C. The resulting mixture was stirred at RT for 2 h. Additional H.sub.2O.sub.2/H.sub.2O (30%, 8 mL) was added dropwise to the reaction at 5˜30° C. The mixture was stirred at RT for 2 h before being poured into ice-water. The mixture was extracted with EA (100 mL×3), the combined extracts were washed sequentially with saturated aqueous Na.sub.2SO.sub.3 solution (100 mL) , saturated aqueous NaHCO.sub.3 solution (100 mL), water (100 mL), brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the title compound 4-bromo-1,3-dimethyl-5-nitro-1H-pyrazole (23b) as crude, which was used in the next step without further purification.

ethyl 2-((1,3-dimethyl-5-nitro-1H-pyrazol-4-yl)thio)acetate (23c)

[0246] To a stirred solution of 4-bromo-1,3-dimethyl-5-nitro-1H-pyrazole (23b) (1.0 g, 4.55 mmol) in DMF (10 mL) was added K.sub.2CO.sub.3 (1.26 g, 9.12 mmol), followed by the addition of ethyl 2-mercaptoacetate (0.820 g,6.82 mmol) at RT. The resulting mixture was stirred at RT for 1.5 h under nitrogen atmosphere. Additional ethyl 2-mercaptoacetate (0.547 g, 4.55 mmol) was added to the reaction. The resulting mixture was stirred at RT for 1 h before being diluted with water. The mixture was extracted with EA for 3 times, 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/EA (20:1˜5:1) to give the title compound ethyl 2-((1,3-dimethyl-5-nitro-1H-pyrazol-4-yl)thio)acetate (23c). MS-ESI(m/z):260 [M+1].sup.+.

2((1,3-dimethyl-5-nitro-1H-pyrazol-4-yl)thio)acetic acid (23d)

[0247] To a solution of ethyl 2-((1,3-dimethyl-5-nitro-1H-pyrazol-4-yl)thio)acetate (23c) (0.760 g, 2.93 mmol) in THF (10 mL) and H.sub.2O (10 mL) was added LiOH.H.sub.2O (1.5 g, 35.7 mmol) at RT. The resulting mixture was stirred at RT for 1.5 h. The mixture was then acidified to pH 2˜3 with HCl (2 N), then extracted with DCM, the extracts was washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated to give 2-((1,3-dimethyl-5-nitro-1H-pyrazol-4-yl)thio)acetic acid (23d) as crude, which was used in the next step without further purification. MS-ESI(m/z): 232 [M+1].sup.+.

2-((5-amino-1,3-dimethyl-1H-pyrazol-4-yl)thio)acetic acid (23e)

[0248] To a solution of 2-((1,3-dimethyl-5-nitro-1H-pyrazol-4-yl)thio)acetic acid (23d) (0.62 g, 2.68 mmol) in EtOH (13 mL) and H.sub.2O (3 mL) was added NH.sub.4Cl (1.16 g, 21.7 mmol) followed by the adding of ferrous powder (1.50 g, 26.9 mmol). The resulting mixture was warmed to 45° C. and stirred for 30 min under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was slurried in DCM/MeOH (10:1), then filtered. The filtrate was concentrated to give 2-((5-amino-1,3-dimethyl-1H-pyrazol-4-yl)thio)acetic acid (23e) as crude, which was used in the next step without further purification. MS-ESI(m/z): 202 [M+1].sup.+.

1,3-dimethyl-1,7-dihydropyrazolo[4,3-b][1,4]thiazin-6(5H)-one (23f)

[0249] A solution of 24(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)thio)acetic acid (23e) (234 mg, 1.16 mmol) in POCl.sub.3 (5.9 mL) was stirred at RT for 18 h under nitrogen atmosphere. The mixture was warmed to 40° C. and stirred for 1 h, then warmed to 60˜70° C. and stirred for 1.5 h. After being cooled to RT, the mixture was concentrated in vacuo. The residue was added DCM (15 mL) and saturated aqueous Na.sub.2CO.sub.3 solution (21 mL). After the mixture was basified to pH 8 with Na.sub.2CO.sub.3 (solid), the aqueous layer was extracted with DCM/MeOH (10:1) (15 mL×5). The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated to give the title compound 1,3-dimethyl-1,7-dihydropyrazolo[4,3-b][1,4]thiazin-6(5H)-one (23f) as crude, which was used in the next step without further purification. MS-ESI(m/z):184 [M+1].sup.+.

1,3-dimethyl-1,5,6,7-tetrahydropyrazolo[4,3-b][1,4]thiazine (23g)

[0250] To a stirred suspension of 1,3-dimethyl-1,7-dihydropyrazolo[4,3-b][1,4]thiazin-6(5H)-one (23f) (225 mg, 1.23 mmol) in THF (9.0 mL) was added Borane-methyl sulfide complex (0.98 mL, 9.8 mmol) dropwise at RT under nitrogen atmosphere. The resulting mixture was stirred at RT for 2.5 h. After being cooled to 0° C., the reaction was quenched with MeOH (5.0 mL). The resulting mixture was stirred at 0° C. for 5 min, then added HCl (2 M, 0.87 mL). The mixture was stirred at 0° C. for 5 min. After being neutralized with saturated aqueous Na.sub.2CO.sub.3 solution, the mixture was concentrated and the residue was added DCM/MeOH (10:1) (26 mL) and sonicated for 1 min then filtered, the filtrate was concentrated. The residue was purified by column chromatography on silica gel, eluting with DCM/MeOH (30:1) to give the title compound 1,3-dimethyl-1,5,6,7-tetrahydropyrazolo[4,3-b][1,4]thiazine (23g). MS-ESI(m/z): 170 [M+1].sup.+.

(3,5-dibromo-4-methoxyphenyl)(1,3-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]thiazin-7(1H)-yl)methanone (23h)

[0251] To a solution of 1,3-dimethyl-1,5,6,7-tetrahydropyrazolo[4,3-b][1,4]thiazine (23g) (151 mg, 0.892 mmol) in THF (15mL) was added HMDSLi/THF(1.0 M, 1.57 mmol) dropwise at −72° C. under nitrogen atmosphere. After addition, the reaction mixture was added 3,5-dibromo-4-methoxybenzoyl chloride (439 mg, 1.34 mmol). The resulting mixture was stirred at −72° C. for 10 min and quenched with H.sub.2O (30 mL). The mixture was warmed to RT and extracted with EA (17 mL×3). The extracts were washed sequentially with water (8 mL) and saturated aqueous NaHCO.sub.3 solution (8 mL×3), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EA (4:1) to give the title compound (3,5-dibromo-4-methoxyphenyl)(1,3-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]thiazin-7(1H)-yl)methanone (23h). MS-ESI(m/z): 460, 462, 464 (1:2:1) [M+1].sup.+.

(3,5-dibromo-4-hydroxyphenyl)(1,3-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]thiazin-7(1H)-yl)methanone (23)

[0252] To a solution of (3,5-dibromo-4-methoxyphenyl)(1,3-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]thiazin-7(1H)-yl)methanone (23h) (360 mg, 0.781 mmol) in DMF (14.4 mL) was added LiBr (312 mg, 3.59 mmol) and piperazine (155.0 mg, 1.80 mmol). The resulting mixture was warmed to 100° C. and stirred for overnight under nitrogen atmosphere. After being cooled to RT, the mixture was poured in to water (75 mL). The resulting mixture was acidified to pH 5˜6 with HCl (1 M). The solid was filtered and washed with H.sub.2O (10 mL×2). The solid was dissolved in a mixed solvent of DCM (200 mL) and MeOH (50 mL). The resulting solution was concentrated to about 20 mL. The solid was filtered and washed with MTBE (2 mL×2), and then dried to give (3,5-dibromo-4-hydroxyphenyl)(1,3-dimethyl-5,6-dihydropyrazolo[4,3-b][1,4]thiazin-7(1H)-yl)methanone (23). MS-ESI(m/z): 446, 448, 450 (1:2:1) [M+1].sup.+.

Example 24

(3,5-dibromo-4-hydroxyphenyl)(1,3-dimethyl-4,4-dioxido-5,6-dihydropyrazolo[4,3-b][1,4]thiazin-7(1H)-yl)methanone (24)

[0253] ##STR00053##

[0254] To a suspension of (3,5-dibromo-4-hydroxyphenyl)(1,3-dimethyl-4,4-dioxido-5,6-dihydropyrazolo[4,3-b][1,4]thiazin-7(1H)-yl)methanone (23) (35 mg, 0.0783 mmol) in THF (10 mL) and H.sub.2O (4 mL) was added NaIO.sub.4 (87.2 mg, 0.408 mmol) and RuCL.sub.3.H.sub.2O (4.80 mg, 0.0231 mmol) at 0˜5° C. The resulting mixture was warmed to RT and stirred for 2.5 h. The mixture was concentrated and the residue was purified by preparative TLC eluting with DCM/MeOH (15:1) to give the title compound (3,5-dibromo-4-hydroxyphenyl)(1,3-dimethyl-4,4-dioxido-5,6-dihydropyrazolo[4,3-b][1,4]thiazin-7(1H)-yl)methanone (24). MS-ESI(m/z): 478, 480, 482 (1:2:1) [M+1].sup.+.

[0255] Following essentially the same procedures described for Examples 23˜24 or using similar synthetic methods or strategies. Examples 25˜26 listed in Table 2 were prepared. The structures and names of Examples 25˜26 are given in Table 2.

TABLE-US-00002 TABLE 2 EXAMPLE STRUCTURE NAME DATA 25 [00054] (3,5-dibromo-4-hydroxyphenyl)(1- methyl-5,6-dihydropyrazolo[4,3-b][1,4] thiazin-7(1H)-yl)methanone MS-ESI (m/z): 432, 434, 436 (1:2:1) [M + 1].sup.+. 26 [00055] (3,5-dibromo-4-hydroxyphenyl)(1- methyl-4,4-dioxido-5,6-dihydropyrazolo [4,3-b][1,4]thiazin-7(1H)-yl)methanone MS-ESI (m/z): 464, 466, 468 (1:2:1) [M + 1].sup.+.

URAT1 Inhibitor Activity

[0256] The potency of the compounds of formula (I) as inhibitors of the URAT1 was determined as follow.

[0257] HEK293-URAT1 cell Lines were donated by Japan Fuji Biomedical Research Institute. Negative control cell of HEK293 (MOCK cells) which was transfected with pcDNA3.1 empty vector. HEK293-URAT1 cell lines and MOCK cell lines were cultured in complete growth medium consisting of DMEM supplemented with 10% FBS, penicillin and streptomycin.

[0258] Preparation of working solution: Each stock solutions was diluted to different concentrations (6, 20, 60, 200 and 600 μmol/L) with DMSO as 200× working solution, which was then diluted to 2× compound working solution with HBSS (Cl.sup.− free) buffer. Radiolabeled substrate .sup.14C-Uric acid solution was diluted with HBSS (Cl.sup.− free) buffer to obtain 2× working solution which was mixed with an equal volume of 2× compound working solution to obtain the mixture of radiolabeled substrate and compound working solution.

[0259] HER293-URAT1 and MOCK cells were seeded onto 24-well plates at the density of 1.5×10.sup.6 cells per well. The cells were incubated at 37° C., 5% CO.sub.2 overnight. After cultured for approximately 2 to 3 days, cells were used for the experiments. The culture medium were removed from the wells, and cells were washed with HBSS (Cl.sup.− free) and incubated in 37° C. HBSS (Cl.sup.− free) for 10 min. HBSS was replaced with 500 μL of the mixture of radiolabeled substrate and compound working solution. The final concentration of .sup.14C-Uric acid in the assay was 5.0 μmol/L. Plates were incubated at 37° C., 5% CO.sub.2 for 2 min, and the reaction was stopped by the addition of pre-chilled HBSS (Cl.sup.− free) by washing three times. 400 μL, NaOH (0.1 mmol/L) was added to lyse the cells and the cell lysate was collected to scintillation vials, and 3 ml scintillant (Aquasol-2, PerkinElmer) was added and after mixing completely, the radioactivity was counted by Tri-Carb 2910TR liquid scintillation counter. Each concentration of compounds, positive control and negative control were repeated in two wells (n=2). Inhibition % data were calculated using the formula:

Inhibition=[100×(U−U.sub.0)/(U.sub.c−U.sub.0)]%, and analyzed using Prism5 software. [0260] U.sub.0: Average of signals of MOCK cells; [0261] U.sub.c: Average of signals of radiolabeled substrate. The half inhibition concentration of the tested compounds to URAT1 were analyzed using Prism 5 software.

[0262] Select compounds prepared as described above were assayed according to the biological procedures described herein. The results are given in the Table 3.

TABLE-US-00003 TABLE 3 MDCK HEK293 Example IC.sub.50 (nM) IC.sub.50 (nM) 1 25 62 2 29 69 3 / 130 5 93 40 10 85 <30 11 / 100 12 80 / 13 84 / 14 252 / 15 126 / 16 48 / 17 60 / 18 37 / 19 / 339 20 / 235 21 / 297 23 189 /

CYP Inhibition Assay

[0263] The CYP inhibition assay was conducted using human liver microsomes at 0.200 mg/mL with a marker substrate for CYP2C9. The substrate concentrations employed were similar to published Michaelis-Menten constants (K.sub.m) for each of the respective reactions. The test compounds were added at 8 concentrations (0, 0.0500, 0.150, 0.500, 1.50, 5.00, 15.0, and 50.0 μM). A known inhibitor for the isozyme, at a single concentration (3.00 μM) in duplicates, was selected as the positive control. The reaction in the presence of the organic solvent instead of test compounds served as vehicle control. The final content of organic solvent in all the reactions was up to 0.5% DMSO and 0.5% methanol.

[0264] Reactions were initiated by adding NADPH followed by incubation at 37° C. for 10 minutes. And reactions were terminated by adding a 2-fold volume ice-cold acetonitrile with internal standards. Samples were processed and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS).The results are given in the Table 4.

TABLE-US-00004 TABLE 4 Example CYP2C9 IC.sub.50 (μM) 1 15.5 2 >50 5 18.9 10 16.2 16 4.25 17 10.4 18 16.0