HETEROCYCLIC SULFOXIMINE COMPOUND AND INTERMEDIATE THEREOF, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF

Abstract

The present invention relates to a heterocyclic sulfoximine compound represented by formula (I), and racemates, enantiomers, pharmaceutically acceptable salts or solvates thereof. Also disclosed herein are an intermediate compound for synthesizing the compound, a preparation method therefor, and a pharmaceutical composition comprising the compound and use thereof. The compound is RET, RET mutant, or RET fusion protein inhibitor, capable of treating diseases caused by abnormal activity of RET, RET mutant, or RET fusion protein, for example, tumors.

Claims

1. A heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof, a molecular structure of the compound is represented by formula (I) ##STR00128## in the formula: Cy is (Ia) or (Ib) ##STR00129## * represents an attachment point between Cy and the rest of the molecular structure represented by formula (I); X is N or C—R; Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are the same or different, and each independently represents N or C—R′; Z is N or C—R″; R, R′ or R″ are the same or different, and each independently selected from hydrogen, deuterium, halogen, CN, OR.sup.a, NR.sup.bR.sup.c, S(═O).sub.wR.sup.d, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; one or more hydrogens in R, R′ or R″ are optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCH.sub.3, OCF.sub.3 or CF.sub.3; R.sup.1 and R.sup.2 are the same or different, and each independently selected from one or two of the same or different hydrogen, deuterium, halogen, CN, NO.sub.2, OR.sup.a, NR.sup.bR.sup.c, S(═O).sub.wR.sup.d, CO.sub.2R.sup.e, CONR.sup.bR.sup.c, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl, wherein one or more hydrogens in the C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl are optionally substituted by the same or different G.sup.1; R.sup.3 is selected from hydrogen, deuterium, S(═O).sub.wR.sup.d, S(═O).sub.wNR.sup.fR.sup.g, C(═O)R.sup.h, C(═O)NR.sup.iR.sup.j, C(═O)OR.sup.k, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; one or more hydrogens in R.sup.3 are optionally substituted by the same or different G.sup.2; R.sup.4 and R.sup.5 are the same or different, and each independently selected from hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; when R.sup.4 and R.sup.5 represent two same or different C.sub.1-12 alkyl groups, the two same or different C.sub.1-12 alkyl groups are connected to each other and form a heteroalicycle together with the S atom to which the two same or different C.sub.1-12 alkyl groups are commonly connected, the heteroalicycle optionally contains one or more additional heteroatoms selected from O, N or S(═O).sub.w; one or more hydrogens in R.sub.4 and R.sub.5 are optionally substituted by the same or different G.sup.3; R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j or R.sup.k is each independently selected from hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; one or more hydrogens in R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, or R.sup.k are optionally substituted by the same or different G.sup.4; R.sup.b and R.sup.c are the same or different, when R.sup.b and R.sup.c represent two same or different C.sub.1-12 alkyl groups connected to the same nitrogen atom, the two same or different C.sub.1-12 alkyl groups are optionally connected with each other, and form a heteroalicycle together with the nitrogen atom, the heteroalicycle optionally contains one or more additional heteroatoms selected from O, N or S(═O).sub.w; R.sup.f and R.sup.g are the same or different, when R.sup.f and R.sup.g represent two same or different C.sub.1-12 alkyl groups connected to the same nitrogen atom, the two same or different C.sub.1-12 alkyl groups are optionally connected with each other, and form a heteroalicycle together with the nitrogen atom, the heteroalicycle optionally contains one or more additional heteroatoms selected from O, N or S(═O).sub.w; R.sup.i and R.sup.j are the same or different, when R.sup.i and R.sup.j represent two same or different C.sub.1-12 alkyl groups connected to the same nitrogen atom, the two same or different C.sub.1-12 alkyl groups are optionally connected with each other, and form a heteroalicycle together with the nitrogen atom, the heteroalicycle optionally contains one or more additional heteroatoms selected from O, N or S(═O).sub.w; G.sup.1, G.sup.2, G.sup.3 and G.sup.4 are the same or different, and each independently selected from one or more same or different deuterium, halogen, CN, NO.sub.2, OH, OCF.sub.3, CF.sub.3, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, R.sup.6O—, R.sup.7R.sup.8N—, R.sup.6S(═O).sub.w—, R.sup.7R.sup.8NS(═O).sub.w—, R.sup.6C(═O)—, R.sup.7R.sup.8NC(═O)—, R.sup.6OC(═O)—, R.sup.6C(═O)O—, R.sup.7R.sup.8NC(═O)O—, R.sup.6C(═O)NR.sup.9—, R.sup.7R.sup.8NC(═O)NR.sup.9—, R.sup.6OC(═O)NR.sup.9—, R.sup.6S(═O).sub.wNR.sup.9—, R.sup.7R.sup.8NS(═O).sub.wNR.sup.9—, R.sup.7R.sup.8NC(═NR.sup.10)NR.sup.9—, R.sup.7R.sup.8NC(═CHNO.sub.2)NR.sup.9—, R.sup.7R.sup.8NC(═N—CN)NR.sup.9—, R.sup.7R.sup.8NC(═NR.sup.10)—, R.sup.6S(═O)(═NR.sup.10)NR.sup.9—, or R.sup.7R.sup.8NS(═O)(═NR.sup.10)—, wherein one or more hydrogens in the C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl are optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCF.sub.3, CF.sub.3, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, R.sup.6O—, R.sup.7R.sup.8N—, R.sup.6S(═O).sub.w—, R.sup.7R.sup.8NS(═O).sub.w—, R.sup.6C(═O)—, R.sup.7R.sup.8NC(═O)—, R.sup.6OC(═O)—, R.sup.6C(═O)O—, R.sup.7R.sup.8NC(═O)O—, R.sup.6C(═O)NR.sup.9—, R.sup.7R.sup.8NC(═O)NR.sup.9—, R.sup.6OC(═O)NR.sup.9—, R.sup.6S(═O).sub.wNR.sup.9—, R.sup.7R.sup.8NS(═O).sub.wNR.sup.9—, R.sup.7R.sup.8NC(═NR.sup.10)NR.sup.9—, R.sup.7R.sup.8NC(═CHNO.sub.2)NR.sup.9—, R.sup.7R.sup.8NC(═N—CN)NR.sup.9—, R.sup.7R.sup.8NC(═NR.sup.10)—, R.sup.6S(═O)(═NR.sup.10)NR.sup.9— or R.sup.7R.sup.8NS(═O)(═NR.sup.10)—; R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are the same or different, and each independently selected from hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; when R.sup.7 and R.sup.8 are two same or different C.sub.1-12 alkyl groups connected to the same nitrogen atom, the two same or different C.sub.1-12 alkyl groups are connected to each other, and form a heteroalicycle together with the nitrogen atom, the heteroalicycle optionally comprises one or more additional heteroatoms selected from O, N or S(═O).sub.w; and one or more hydrogens in R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are further optionally substituted by the same or different deuterium, halogen, OH, CN, NO.sub.2, OCH.sub.3, OCF.sub.3, C.sub.1-12 alkyl or C.sub.3-12 cycloalkyl; and w is 0, 1 or 2.

2. The heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 1, wherein the structural formula of the compound is (IIa) or (IIb) ##STR00130## wherein, X, Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 have the same definitions as described in claim 1.

3. The heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 1, wherein, the structural formula of the compound is (IIIa), (IIIb), (IIIc) or (IIId): ##STR00131## wherein, X is N or C—R; Y.sup.1 and Y.sup.4 are the same or different N or C—R′; R.sup.a is selected from hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; one or more hydrogens in R.sup.a are optionally substituted by the same or different G.sup.1; R and R′ are each independently selected from hydrogen, deuterium, halogen, CN, C.sub.1-12 alkyl, OH or C.sub.1-12 alkyl-O—, one or more hydrogens in the C.sub.1-12 alkyl groups are optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCH.sub.3, OCF.sub.3 or CF.sub.3; Ar represents C.sub.6-12 aryl or C.sub.5-12 heteroaryl; one or more hydrogens in Ar are optionally substituted by the same or different G.sup.1; and R.sup.3, R.sup.4, R.sup.5 and G.sup.1 have the same definitions as described in claim 1.

4. The heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 1, wherein, the structural formula of the compound is (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg) or (IVh): ##STR00132## wherein, Y.sup.1 represents N or CH; R.sup.a is selected from hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; one or more hydrogens in R.sup.a are optionally substituted by the same or different G.sup.1; Ar represents C.sub.6-12 aryl or C.sub.5-12 heteroaryl; one or more hydrogens in Ar are optionally substituted by the same or different G.sup.1; R.sup.3 represents hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, S(═O).sub.wR.sup.d, S(═O).sub.wNR.sup.fR.sup.g, C(═O)R.sup.h, C(═O)NR.sup.iR.sup.j or C(═O)OR.sup.k; one or more hydrogens in R.sup.3 are optionally substituted by the same or different G.sup.2; R.sup.d, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, or R.sup.k is each independently selected from hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; one or more hydrogens in R.sup.d, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j or R.sup.k are further optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCH.sub.3, OCF.sub.3, C.sub.1-12 alkyl or C.sub.3-12cycloalkyl; R.sup.f and R.sup.g are the same or different, when R.sup.f and R.sup.g represent two same or different C.sub.1-12 alkyl groups connected to the same nitrogen atom, the two same or different C.sub.1-12 alkyl groups are optionally connected with each other, and form a heteroalicycle together with the nitrogen atom, the heteroalicycle optionally comprises one or more additional heteroatoms selected from O, N or S(═O).sub.w; R.sup.i and R.sup.j are the same or different, when R.sup.i and R.sup.j represent two same or different C.sub.1-12 alkyl groups connected to the same nitrogen atom, the two same or different C.sub.1-12 alkyl groups are optionally connected with each other, and form a heteroalicycle together with the nitrogen atom, the heteroalicycle optionally comprises one or more additional heteroatoms selected from O, N or S(═O).sub.w; R.sup.4 and R.sup.5 are the same or different, and each independently selected from hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; when R.sup.4 and R.sup.5 each represent a same or different C.sub.1-12 alkyl groups, the two C.sub.1-12 alkyl groups are connected to each other, and form a heteroalicycle together with the sulfur atom to which the two C.sub.1-12 alkyl groups are commonly connected, the heteroalicycle optionally comprises one or more additional heteroatoms selected from O, N or S(═O).sub.w; one or more hydrogens in R.sup.4 and R.sup.5 are optionally substituted by the same or different G.sup.3; and w, G.sup.1, G.sup.2 and G.sup.3 have the same definitions as described in claim 1.

5. The heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 4, wherein, R.sup.a is selected from hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; one or more hydrogens in R.sup.a are optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, CH.sub.3, OCH.sub.3, OCF.sub.3, CF.sub.3; preferably, R.sup.a is selected from hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl or C.sub.2-12 alkynyl; more preferably, R.sup.a is selected from hydrogen or C.sub.1-12 alkyl.

6. The heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 4, wherein, Ar represents C.sub.6-12 aryl or C.sub.5-12 heteroaryl; one or more hydrogens in Ar are optionally substituted by the same or different hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; preferably, Ar represents C.sub.5-12 heteroaryl; one or more hydrogens in Ar are optionally substituted by the same or different hydrogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; more preferably, one or more hydrogens in Ar are optionally substituted by the same or different hydrogen or C.sub.1-12 alkyl.

7. The heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 4, wherein, R.sup.3 represents hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.5-12 heteroaryl or —C(═O)O—C.sub.1-12 alkyl; one or more hydrogens in R.sup.3 are optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCF.sub.3, CF.sub.3, C.sub.1-12 alkyl-O, C.sub.3-12 cycloalkyl-O, C.sub.3-12 heteroalicyclyl-O, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl or —C(═O)O—C.sub.1-12 alkyl, wherein one or more hydrogens in the C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl or —C(═O)O—C.sub.1-12 alkyl are further optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCF.sub.3, CF.sub.3, C.sub.1-12 alkyl, C.sub.1-12 alkyl-O, C.sub.3-12 cycloalkyl-O or C.sub.3-12 heteroalicyclyl-O; preferably, R.sup.3 represents hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.5-12 heteroaryl or —C(═O)O—C.sub.1-12 alkyl; and one or more hydrogens in R.sup.3 are optionally substituted by the same or different deuterium, C.sub.1-12 alkyl-O, C.sub.3-12 cycloalkyl-O, C.sub.3-12 heteroalicyclyl-O, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl or —C(═O)O—C.sub.1-12 alkyl, wherein one or more hydrogens in the C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, or —C(═O)O—C.sub.1-12 alkyl are further optionally substituted by the same or different deuterium, C.sub.1-12 alkyl-O, C.sub.3-12 cycloalkyl-O or C.sub.3-12 heteroalicyclyl-O.

8. The heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 4, wherein, R.sup.4 and R.sup.5 are the same or different, and each independently selected from C.sub.1-12 alkyl or C.sub.6-12 aryl; one or more hydrogens in R.sup.4 and R.sup.5 are optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCF.sub.3, CF.sub.3, C.sub.1-12 alkyl-O, C.sub.3-12 cycloalkyl-O, C.sub.3-12 heteroalicyclyl-O, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl, wherein one or more hydrogens in the C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl are further optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCF.sub.3, CF.sub.3, C.sub.1-12 alkyl, C.sub.1-12 alkyl-O, C.sub.3-12 cycloalkyl-O or C.sub.3-12 heteroalicyclyl-O; preferably, R.sup.4 and R.sup.5 are the same or different, and each independently selected from C.sub.1-6 alkyl or C.sub.6 aryl; and one or more hydrogens in R.sup.4 and R.sup.5 are optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCF.sub.3, CF.sub.3, C.sub.1-12 alkyl-O, C.sub.3-12 cycloalkyl-O, C.sub.3-12 heteroalicyclyl-O, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl, wherein one or more hydrogens in the C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl are further optionally substituted by the same or different deuterium, halogen, CN, NO.sub.2, OH, OCF.sub.3, CF.sub.3, C.sub.1-12 alkyl, C.sub.1-12 alkyl-O, C.sub.3-12 cycloalkyl-O or C.sub.3-12 heteroalicyclyl-O.

9. The heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 1, wherein, the structural formula of the compound is any one of the following: ##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182## ##STR00183##

10. A pharmaceutical composition comprising at least one of heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 1.

11. The pharmaceutical composition according to claim 10, further comprising at least one pharmaceutically acceptable carrier or diluent.

12. The pharmaceutical composition according to claim 10, wherein, the preparation forms of the pharmaceutical composition comprise: oral preparation, injection, anal plug, nostril inhalation, eye drops or skin patch.

13. A method for treating a disease caused by abnormal activity of RET, RET mutant, or RET fusion proteins, wherein the method comprises administering the heterocyclic sulfoximine compound, or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof according to claim 1.

14. The method for treating a disease caused by abnormal activity of RET, RET mutant, or RET fusion proteins according to claim 13, wherein, the disease is tumor, the tumor is selected from solid tumor and liquid tumor, preferably, the tumor is selected from one or any combination of lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, colorectal cancer, anal area cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or ureter cancer, kidney cancer, adrenal cancer, renal cell carcinoma, renal pelvis cancer, brain glioma, brain stem glioma, neuroendocrine glioma, glioma, central nervous system (CNS) neoplasms, spinal axis tumor, pituitary adenoma, gastrointestinal stromal tumor, colorectal cancer, non-small cell lung cancer, small cell lung cancer, mastocytosis, glioma, sarcoma, and lymphoma.

15. An intermediate compound for synthesizing the heterocyclic sulfoximine compound according to claim 1, wherein the structural formula of the intermediate compound is (Va), (Vb), (Vc), (Vd) or (Ve) ##STR00184## wherein: L and T are independently selected from chlorine, bromine, iodine, F.sub.3C—SO.sub.3, a boronic acid group, a boronic ester group, or a boronic acid salt group; PG is selected from hydrogen, (tert-butoxy)C(═O)—, (benzyloxy)C(═O)—, (p-methylbenzyloxy)C(═O)— or benzyl; PP is an N protecting group; R.sup.33 is selected from hydrogen, (tert-butoxy)C(═O)—, (benzyloxy)C(═O)—, (p-methylbenzyloxy)C(═O)—, benzyl, trifluoroacetyl, acetyl, S(═O).sub.wR.sup.d, S(═O).sub.wNR.sup.fR.sup.g, C(═O)R.sup.h, C(═O)NR.sup.iR.sup.j, C(═O)OR.sup.k, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl, wherein one or more hydrogens in the C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl are optionally substituted by the same or different G.sup.2; R.sup.44 and R.sup.55 are the same or different, and each independently selected from C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; when R.sup.44 and R.sup.55 represent two same or different C.sub.1-12 alkyl groups, the two same or different C.sub.1-12 alkyl groups are connected to each other, and form a heteroalicycle together with the sulfur atom to which the two C.sub.1-12 alkyl groups are commonly connected, the heteroalicycle optionally comprises one or more additional heteroatoms selected from O, N or S(═O).sub.w; one or more hydrogens in R.sup.44 and R.sup.55 are optionally substituted by the same or different G.sup.3; in the structural formula (Vd), when PG is (benzyloxy)C(═O)—, R.sup.44 and R.sup.55 are not methyl at the same time; G.sup.2, G.sup.3, R.sup.d, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k and w have the same definitions as described in claim 1; preferably, the boronic acid group, boronic ester group or boronic acid salt group is selected from (HO).sub.2B, (CH.sub.3O).sub.2B, (CH.sub.3CH.sub.2O).sub.2B, (isopropyl-O).sub.2B, ##STR00185## BF.sub.3K or BF.sub.3Na; and PP is selected from Boc, CBZ, trifluoroacetyl, acetyl, Bn or PMB.

16. A synthetic method for synthesizing the intermediate compound according to claim 15, comprising Steps 1-4 or Steps 1-3 and 5-7, ##STR00186## wherein: L′ is selected from chlorine, bromine, iodine, of F.sub.3C—SO.sub.3; M is selected from a boronic acid group, a boronic ester group or a boronic acid salt group; PP has the same definition as described in claim 15; R.sup.3a is selected from S(═O).sub.wR.sup.d, S(═O).sub.wNR.sup.g, C(═O)R.sup.h, C(═O)NR.sup.iR.sup.j, C(═O)OR.sup.k, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl, wherein one or more hydrogens in the C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl are optionally substituted by the same or different G.sup.2; G.sup.2, R.sup.d, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k and w have the same definitions as described in claim 1; Step 1: reacting a compound of formula A-1 with a compound of formula A-2 to obtain a compound of formula A-3; Step 2: reacting the compound of formula A-3 with an oxidant to obtain a compound of formula A-4; Step 3: reacting the compound of formula A-4 with an amino compound PP-NH.sub.2 with a protective group under a rhodium catalyst to obtain a compound of formula A-5; Step 4: subjecting the compound of formula A-8 to a boronation reaction to obtain an intermediate compound represented by formula A-6; or Step 5: removing the protective group PP on the N atom in the compound of formula A-5 to obtain a compound of formula A-7; Step 6: subjecting the compound of formula A-7 to an alkylation reaction or an acylation reaction to obtain a compound A-8; Step 7: subjecting the compound of formula A-8 to a boronation reaction to obtain an intermediate compound represented by formula A-9; preferably, M is selected from (HO).sub.2B, (CH.sub.3O).sub.2B, (CH.sub.3CH.sub.2O).sub.2B, (isopropyl-O).sub.2B, ##STR00187## BF.sub.3K or BF.sub.3Na.

17. A method for preparing the heterocyclic sulfoximine compound according to claim 1, comprising Step 1 or Steps 2-4, ##STR00188## wherein: R.sup.1, R.sup.2 and X have the same definitions as described in claim 1; LG.sup.2 represents chlorine, bromine, iodine, or F.sub.3C—SO.sub.3; PP has the same definition as described in claim 15; M and R.sup.3a have the same definitions as described in claim 16; Step 1: subjecting a compound of formula B-1 to a Suzuki reaction with a compound of formula A-9 to obtain a heterocyclic sulfoximine compound represented by formula B-2; or Step 2: subjecting a compound of formula B-1 to a Suzuki reaction with a compound of formula A-6 to obtain a compound of formula B-3; Step 3: removing a protecting group PP in the compound of formula B-3 to obtain a compound of formula B-4; Step 4: subjecting the compound of formula B-4 to a reaction to obtain a heterocyclic sulfoximine compound represented by formula B-2; preferably, in Step 4, the compound of formula B-4 is subjected to an alkylation, an acylation or an arylation reaction to introduce a R.sup.3a substituent to obtain a heterocyclic sulfoximine compound represented by the formula B-2.

18. A synthetic method for synthesizing the intermediate compound according to claim 15, comprising Steps 1-2, ##STR00189## wherein: LG.sup.1 is selected from fluorine, chlorine, bromine, iodine, H.sub.3C—SO.sub.3, F.sub.3C—SO.sub.3, C.sub.6H.sub.4SO.sub.3, p-CH.sub.3C.sub.6H.sub.4—SO.sub.3 or p-O.sub.2NC.sub.6H.sub.4—SO.sub.3; R.sup.4a and R.sup.5a are the same or different, each independently selected from hydrogen, deuterium, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-12 heteroalicyclyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.6-12 aryl, or C.sub.5-12 heteroaryl; when R.sup.4a and R.sup.5a represent two same or different C.sub.1-12 alkyl groups, the two same or different C.sub.1-12 alkyl groups are connected to each other, and form a heteroalicycle together with the sulfur atom to which the two C.sub.1-12 alkyl groups are commonly connected, the heteroalicycle optionally comprises one or more additional heteroatoms selected from O, N or S(═O).sub.w; one or more hydrogens in R.sup.4a and R.sup.5a are further optionally substituted by the same or different G.sup.3; G.sup.3 and w have the same definitions as described in claim 1; PP has the same definition as described in claim 15; Step 1: subjecting a compound of formula C-1 to nucleophilic substitution with a compound of formula C-3, or subjecting a compound of formula C-2 to reductive amination with a compound of formula C-3, to obtain a compound of formula C-4; Step 2: removing a protecting group PP in the compound of formula C-4 to obtain an intermediate compound represented by formula C-5.

19. A method for preparing the heterocyclic sulfoximine compound according to claim 1, comprising Steps 1-2 or Steps 1, and 3-4, ##STR00190## wherein: R.sup.1, R.sup.2, X have the same definitions as described in claim 1, LG.sup.2 has the same definition as described in claim 17, R.sup.4a and R.sup.5a have the same definitions as described in claim 18; Step 1: subjecting a compound of formula B-1 to Suzuki reaction with a compound of formula D-1 to obtain a compound of formula D-2; Step 2: subjecting the compound of formula D-2 and a compound of formula C-5 to a nucleophilic substitution in the presence of a base to generate a heterocyclic sulfoximine compound represented by formula D-3; or Step 3: subjecting the compound of formula D-2 and a compound of formula D-4 to a nucleophilic substitution in the presence of a base to generate a compound of formula D-5; Step 4: subjecting the compound of formula D-5 to reductive amination with a compound of formula C-3 to obtain a heterocyclic sulfoximine compound represented by formula D-3.

20. A method for treating a disease caused by abnormal activity of RET, RET mutant, or RET fusion proteins, wherein the method comprises administering the pharmaceutical composition according to claim 10.

Description

DETAILED DESCRIPTION

[0197] The present invention will be described in further detail below in conjunction with specific Examples, but not intended to limit the scope of the present invention.

[0198] The English abbreviations and corresponding Chinese meanings appearing in the Examples are listed below. If an abbreviation not listed here appears in the Examples, it represents the generally accepted meaning.

[0199] h: hour(s)

[0200] rt: room temperature

[0201] ° C.: degree Celsius

[0202] TLC: Thin Layer Chromatography

[0203] HPLC: High Performance Liquid Chromatography

[0204] LC-MS: Liquid Chromatography-Mass Spectrometry

[0205] g: gram(s)

[0206] mg: milligram(s)

[0207] mmol: millimole(s)

[0208] nM: nanomolar (concentration unit)

[0209] μM: micromolar (concentration unit)

[0210] M: mole (concentration unit)

[0211] mL: milliliter(s)

[0212] (M+H).sup.+: Molecular ion peak in mass spectrum

[0213] m/z: mass-to-charge ratio

[0214] NMR: Nuclear Magnetic Resonance Spectroscopy

[0215] δ: chemical shift

[0216] DMSO-d.sub.6: hexadeuterated dimethyl sulfoxide

[0217] CDCl.sub.3: deuterated chloroform

[0218] CD.sub.3OD: deuterated methanol

[0219] DMSO: dimethyl sulfoxide

[0220] DMF: N,N-dimethylformamide

[0221] DMA: N,N-dimethylacetamide

[0222] MeOH: methanol

[0223] EtOAc: ethyl acetate

[0224] DCM: dichloromethane

[0225] Dioxane: dioxane

[0226] DCE: 1,2-dichloroethane

[0227] HCl: hydrogen chloride or hydrochloric acid

[0228] TFA: trifluoroacetic acid

[0229] AcOH: acetic acid

[0230] KOAc: potassium acetate

[0231] NaHCO.sub.3: sodium bicarbonate

[0232] Na.sub.2CO.sub.3: sodium carbonate

[0233] K.sub.2CO.sub.3: potassium carbonate

[0234] Cs.sub.2CO.sub.3: cesium carbonate

[0235] K.sub.3PO.sub.4: potassium phosphate

[0236] Pd/C: palladium on carbon

[0237] DIPEA: diisopropylethylamine

[0238] BBr.sub.3: boron tribromide

[0239] NaIO.sub.4: sodium periodate

[0240] PhI(OAc).sub.2: (diacetoxyiodo)benzene

[0241] MgO: magnesium oxide

[0242] Na.sub.2SO.sub.4: sodium sulfate

[0243] Na.sub.2S.sub.2O.sub.3: sodium thiosulfate

[0244] NH.sub.3.H.sub.2O: ammonia water

[0245] BocNH.sub.2: tert-butyl carbamate

[0246] NaB(OAc).sub.3H: sodium triacetoxyborohydride

[0247] NaBH.sub.3CN: sodium cyanoborohydride

[0248] Rh.sub.2(OAc).sub.4: rhodium(II) acetate dimer

[0249] Pd(PPh.sub.3).sub.4: Tetra(triphenylphosphine)palladium(0)

[0250] Pd.sub.2(dba).sub.3: tris(dibenzylideneacetone)dipalladium(0)

[0251] Pd(dppf)Cl.sub.2: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0252] Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene

[0253] XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0254] PhN(Tf).sub.2: N,N′-bis(trifluoromethylsulfonyl)aniline

[0255] Pin.sub.2B.sub.2 or B.sub.2Pin.sub.2: bis(pinacol) diboron

[0256] 4 Å MS: molecular sieve with a pore size of 4 Å

[0257] General Experimental Conditions:

[0258] .sup.1H NMR and .sup.13C NMR spectra were obtained by Varian 300 or 400 MHz or Bruker 300 or 400 MHz instrument (with deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol and the like as solvents, with or without tetramethylsilane as an internal standard). Mass spectra were obtained by liquid chromatography-mass spectrometry combined instrument (Waters or Agilent in the United States). High performance liquid chromatography was performed using a high performance liquid chromatography instrument of Waters company or Agilent company, unless otherwise specified.

[0259] Starting materials, reagents, and solvents were purchased from the following suppliers: Sigma-Aldrich, Milwaukee, Wis., USA; Acros, Morris Plains, N.J., USA; Frontier Scientific, Logan, Utah, USA; Alfa Aesar, Ward Hill, Mass., USA; Shanghai Aladdin Bio-Chem Technology Co., Ltd, Shanghai, China; Shanghai Macklin Bio-Chemical Co., Ltd., Shanghai, China; WuXi LabNetwork, Shanghai, China, and the like, or were synthesized by methods reported in the literatures. Unless otherwise specified, the solvent is generally not dried, and the products of the suppliers are directly used or are used after being dried through molecular sieves.

Intermediate 1: 4-bromo-6-hydroxypyrazolo[1,5-a]pyridin-3-carbonitrile (Int-1)

[0260] ##STR00088##

[0261] Int-1 (CAS #: 2068065-05-2) was prepared according to the method reported in the literature (WO2019075092).

Intermediate 2: 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carbonitrile (Int-2)

[0262] ##STR00089##

[0263] 2,2-Dimethyloxirane (3.03 g, 3.73 mL, 42.0 mmol) was added to a mixture of 4-bromo-6-hydroxypyrazolo[1,5-a]pyridin-3-carbonitrile (Int-1, 10.0 g, 42.0 mmol) and K.sub.2CO.sub.3 (17.4 g, 126 mmol) in DMF (50 mL). The resulting mixture was stirred at 85° C. for 12 h, and TLC showed that the reaction was completed. After cooling to room temperature, the reaction mixture was poured into water (400 mL) and stirred for 1 h. The product was collected by filtration and dried to give 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carbonitrile (Int-2, 11.0 g, yield: 84%) as a brown solid.

Intermediate 3: 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carbonitrile (Int-3)

[0264] ##STR00090##

[0265] Int-3 (CAS #: 2222653-74-7) was prepared according to the method reported in the literature (WO2019075108).

Intermediate 4: S,S-dimethyllsulfoximine (Int-4)

[0266] ##STR00091##

[0267] Int-4 (CAS #: 1520-31-6) was purchased from WuXi LabNetwork.

Intermediate 5: (S)-(+)-S-methyl-S-phenylsulfonimide (Int-5)

[0268] ##STR00092##

[0269] Int-5 (CAS #: 33903-50-3) was prepared according to the method reported in the literature (M. R. Yadav et al, Chem. Eur. J. 2012, 18, 5541-5545).

Intermediate 6: (R)-(−)—S-methyl-S-phenylsulfonimide (Int-6)

[0270] ##STR00093##

[0271] Int-6 (CAS #: 60933-65-5) was prepared according to the method reported in the literature (H. Zhao et al, Mol. Catalysis 2018, 455, 210-213).

Intermediate 7: tert-butyl (1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)carboxylate (Int-7)

[0272] ##STR00094##

Step 1: 4-(5-bromopyridin-2-yl)thiomorpholine (Int-7.3)

[0273] A mixture of 5-bromo-2-chloropyridine (Int-7.1, 38.0 g, 197 mmol) and thiomorpholine (Int-7.2, 102.0 g, 93.5 mL, 987 mmol) was stirred at 100° C. for 16 h, and TLC showed that the reaction was completed. After cooling to room temperature, saturated NaHCO.sub.3 solution (400 mL) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate (3×350 mL). The organic layers were combined, washed with water (500 mL) and saturated brine (500 mL) in turn, dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=50:1 to 5:1) to obtain 4-(5-bromopyridin-2-yl)thiomorpholine (Int-7.3, 30.0 g, yield: 58%) as a colorless oily liquid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.18 (d, J=2.4 Hz, 1H), 7.51-7.54 (m, 1H), 6.51 (d, J=9.2 Hz, 3H), 3.90-3.92 (m, 4H), 2.64-2.66 (m, 4H). Mass spectrum (ESI) m/z: 259 (M+H, .sup.79Br).sup.+, 261 (M+H, .sup.81Br).sup.+.

Step 2: 4-(5-bromopyridin-2-yl)thiomorpholine-1-oxide (Int-7.4)

[0274] NaIO.sub.4 (27.2 g, 127 mmol) was added to a mixture of 4-(5-bromopyridin-2-yl)thiomorpholine (Int-7.3, 30.0 g, 116 mmol) in MeOH (300 mL) and water (300 mL) at 0° C. The resulting mixture was stirred at 0-10° C. for 16 h, and TLC showed that the reaction was completed. The reaction mixture was filtered, the aqueous layer was extracted with DCM (3×200 mL), the organic layers were combined and washed successively with saturated Na.sub.2S.sub.2O.sub.3 solution (200 mL) and saturated brine (200 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-(5-bromopyridin-2-yl)thiomorpholine-1-oxide (Int-7.4, 25.8 g, yield: 74.5%) as a white solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.23 (d, J=2.4 Hz, 1H), 7.60 (dd, J=2.4, 8.8 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.08-4.19 (m, 4H), 2.74-2.80 (m, 4H). Mass spectrum (ESI) m/z: 275.1 (M+H, .sup.79Br).sup.+, 277.1 (M+H, .sup.81Br).sup.+.

Step 3: tert-butyl (4-(5-bromopyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Int-7.5)

[0275] Under nitrogen gas, Rh.sub.2(OAc).sub.4 (1.20 g, 2.73 mmol) was added to a mixture of tert-butyl 4-(5-bromopyridin-2-yl)thiomorpholine-1-oxide (Int-7.4, 15.0 g, 54.5 mmol), amino carboxylate (12.8 g, 109 mmol), magnesium oxide (8.79 g, 218 mmol), and PhI(OAc).sub.2 (26.3 g, 81.8 mmol) in 1,2-dichloroethane (40 mL). The resulting mixture was stirred at 40° C. for 5 h, and TLC showed that the reaction was completed. After cooling to room temperature, the reaction mixture was filtered, the filtrate was diluted with water (100 ml), and extracted with DCM (2×100 mL). The organic layers were combined, dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=10:1 to 1:1) to obtain tert-butyl (4-(5-bromopyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Int-7.5, 11.5 g, yield: 54%), as a colorless oily liquid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.25 (d, J=2.0 Hz, 1H), 7.65 (dd, J=2.0, 8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 4.18-4.35 (m, 2H), 4.00 (ddd, J=2.0, 8.4, 14.4 Hz, 2H), 3.63 (dd, J=6.7, 14.4 Hz, 2H), 3.23-3.35 (m, 2H), 1.50 (s, 9H). Mass spectrum (ESI) m/z: 289.9 (M+H−100, .sup.79Br).sup.+, 291.9 (M+H−100, .sup.8′Br).sup.+.

Step 4: tert-butyl (1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)carboxylate (Int-7)

[0276] Under nitrogen gas, Pd(dppf)Cl.sub.2 (562 mg, 0.769 mmol) was added to a mixture of tert-butyl (4-(5-bromopyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Int-7.5, 3.00 g, 7.69 mmol), potassium acetate (2.26 g, 23.1 mmol) and bis(pinacol) diboron (Pin.sub.2B.sub.2, 5.86 g, 23.1 mmol) in dioxane (30 mL). The resulting mixture was stirred at 80° C. for 12 h, and LC-MS showed that the reaction was completed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and filtered, and the filtrate was concentrated under reduced pressure to obtain crude product, which was washed with petroleum ether (80 mL) to obtain tert-butyl (1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)carboxylate (Int-7, 3.2 g, crude product) as a dark brown solid. It was used in the next reaction without further purification. Mass spectrum (ESI) m/z: 438.4 (M+H).sup.+.

Intermediate 8: tert-butyl 4-(1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)piperidin-1-carboxylate (Int-8)

[0277] ##STR00095##

Step 1: 4-(5-bromopyridin-2-yl)-1-iminothiomorpholine-1-oxide (Int-8.1)

[0278] At 0° C., trifluoroacetic acid (5 mL, 67.5 mmol) was added to a solution of tert-butyl (4-(5-bromopyridin-2-yl)-1-oxothiomorpholine-1-imino) carboxylate (Int-7.5, 1.50 g, 3.84 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 1 h, and TLC showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in methyl tert-butyl ether (20 mL). The solid product 4-(5-bromopyridin-2-yl)-1-iminothiomorpholine-1-oxide (Int-8.1, 1.2 g, crude product) was collected by filtration as a yellow solid. The crude product was basified with saturated aqueous sodium carbonate to obtain the free base, which was used in the next reaction without further purification. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.24 (d, J=2.4 Hz, 1H), 7.80 (dd, J=2.6, 9.0 Hz, 1H), 7.04 (d, J=9.2 Hz, 1H), 4.47 (d, J=15.4 Hz, 2H), 3.65-3.76 (m, 2H), 3.52-3.61 (m, 2H), 3.40-3.49 (m, 2H).

Step 2: tert-butyl 4-(4-(5-bromopyridin-2-yl)-1-oxothiomorpholine-1-imino)piperidin-1-ylcarboxylate (Int-8.4)

[0279] 2-Methylpyridin-borane complex (Int-8.3, 221 mg, 2.07 mmol) was added to a mixture of 4-(5-bromopyridin-2-yl)-1-iminothiomorpholine-1-oxide (Int-8.1, 0.50 g, 1.72 mmol), tert-butyl 4-oxopiperidin-1-carboxylate (Int-8.2, 1.37 g, 6.89 mmol) and AcOH (1 mL, 17.5 mmol) in MeOH (3 mL). The resulting reaction mixture was stirred at 25° C. for 4 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=30:1 to 1:1) to obtained tert-butyl 4-(4-(5-bromopyridin-2-yl)-1-oxothiomorpholine-1-imino)piperidin-1-ylcarboxylate (Int-8.4, 0.34 g, yield: 41.7%) as a yellow solid. Analytical data: Mass spectrum (ESI) m/z: 473.1 (M+H, .sup.79Br).sup.+, 475.1 (M+H, .sup.81Br).sup.+.

Step 3: tert-butyl 4-(1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)piperidin-1-ylcarboxylate (Int-8)

[0280] Under nitrogen gas, Pd(dppf)Cl.sub.2 (52.6 mg, 0.0718 mmol) was added to a mixture of tert-butyl 4-(4-(5-bromopyridin-2-yl)-1-oxothiomorpholine-1-imino)piperidin-1-ylcarboxylate (Int-8.4, 340 mg, 0.718 mmol), potassium acetate (211 mg, 2.15 mmol) and bis(pinacol) diboron(Pin.sub.2B.sub.2, 547 mg, 2.15 mmol) in dioxane (5 mL). The resulting mixture was stirred at 80° C. for 12 h, and LC-MS showed that the reaction was completed. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and dried to obtain tert-butyl 4-(1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)piperidin-1-ylcarboxylate (Int-8, 360 mg, crude product, yield: 96%) as a brown solid. It was used in the next reaction without further purification. Analytical data: Mass spectrum (ESI) m/z: 521.3 (M+H).sup.+.

Intermediate 9: N-(dimethyloxo-λ.SUP.4.-sulfinyl)-4-piperidinamine (Int-9)

[0281] ##STR00096##

Step 1: benzyl 4-[(dimethylloxo-λ.SUP.4.-sulfinyl)amino]piperidin-1-ylcarboxylate (Int-9.2)

[0282] NaB(OAc).sub.3H (45.5 g, 215 mmol) was added to a solution of S,S-dimethyllsulfoximine (Int-4, 5.0 g, 53.7 mmol) and benzyl 4-oxopiperidin-1-carboxylate (Int-9.1, 25.0 g, 107 mmol) in 1,2-dichloroethane (250 mL). The resulting mixture was stirred at 35° C. for 12 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with water, adjusted to about 8 of pH with saturated aqueous sodium bicarbonate solution, extracted with DCM (3×200 mL). The organic layers were combined, dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=5:1 to 1:1) to obtain benzyl 4-[(dimethylloxo-λ.sup.4-sulfinyl)amino]piperidin-1-ylcarboxylate (Int-9.2, 5.3 g, yield: 32%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=7.19-7.28 (m, 5H), 5.04 (s, 2H), 3.80-3.91 (m, 2H), 3.30 (m, 1H), 2.91-2.97 (m, 2H), 2.94 (s, 6H), 1.69-1.72 (m, 2H), 1.43-1.46 (m, 2H). Mass spectrum (ESI) m/z: 311.0 (M+H).sup.+.

Step 2: N-(dimethyloxo-λ.SUP.4.-sulfinyl)-4-piperidinamine (Int-9)

[0283] 10% Pd/C (400 mg) was added to a solution of benzyl 4-[(dimethyloxo-λ.sup.4-sulfinyl)amino]piperidin-1-ylcarboxylate (Int-9.2, 2.0 g, 6.44 mmol) in MeOH (30 mL). The resulting mixture was hydrogenated at room temperature for 1 h, and TLC showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(dimethyloxo-λ.sup.4-sulfinyl)-4-piperidinamine (Int-9, 1.10 g, yield: 96%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=3.47 (br, m, 1H), 3.81-3.95 (m, 2H), 3.20 (m, 1H), 3.01 (s, 6H), 2.80-2.83 (m, 2H), 1.90-1.93 (m, 2 H), 1.58-1.62 (m, 2H).

Intermediate 10: N—((S)-methyl-oxo-phenyl-λ.SUP.4.-sulfinyl)-4-piperidinamine (Int-10)

[0284] ##STR00097##

Step 1: tert-butyl 4-(((S)-methyl-oxo-phenyl-λ.SUP.4.-sulfinyl)amino)piperidin-1-ylcarboxylate (Int-10.1)

[0285] The acetic acid (14 mL, 244 mmol) and 2-methylpyridin-borane complex (Int-8.3, 3.62 g, 33.8 mmol) were added to a solution of (S)-(+)-S-methyl-S-phenylsulfonimide (Int-5, 3.50 g, 22.6 mmol) and tert-butyl 4-oxopiperidin-1-ylcarboxylate (Int-8.2, 22.5 g, 112 mmol) in MeOH (50 mL) and DCM (25 mL). The resulting mixture was stirred at 40° C. for 5 h, and LC-MS showed that the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with DCM(3×50 mL). The organic layers were combined, dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=10:1 to DCM:MeOH=10:1) to obtain tert-butyl 4-(((S)-methyl-oxo-phenyl-λ.sup.4-sulfinyl)amino)piperidin-1-ylcarboxylate (Int-10.1, 1.7 g, yield: 22%). Analytical data: Mass spectrum (ESI) m/z: 339.4 (M+H).sup.+.

Step 2: N—((S)-methyl-oxo-phenyl-λ.SUP.4.-sulfinyl)-4-piperidinamine (Int-10)

[0286] At 0° C., trifluoroacetic acid (5 mL, 67.5 mmol) was added to a solution of tert-butyl 4-(((S)-methyl-oxo-phenyl-λ.sup.4-sulfinyl)amino)piperidin-1-ylcarboxylate (Int-10.1, 1.5 g, 4.43 mmol) in DCM (15 mL). The resulting mixture was stirred at room temperature for 2 h, and TLC showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure to obtain a crude product (2.2 g), which was basified with saturated NaHCO.sub.3 solution to give N—((S)-methyl-oxo-phenyl-λ.sup.4-sulfinyl)-4-piperidinamine (Int-10), as a yellow oily liquid, which was used in the next reaction without further purification. Analytical data: Mass spectrum (ESI) m/z: 239 (M+H).sup.+.

Intermediate 11: N—((R)-methyl-oxo-phenyl-λ.SUP.4.-sulfinyl)-4-piperidinamine (Int-11)

[0287] ##STR00098##

Step 1: tert-butyl 4-(((R)-methyl-oxo-phenyl-λ.SUP.4.-sulfinyl)amino)piperidin-1-ylcarboxylate (Int-11.1)

[0288] The acetic acid (10.4 mL, 182 mmol) and 2-methylpyridin-borane complex (Int-8.3, 2.78 g, 26 mmol) were added to a solution of (R)-(−)—S-methyl-S-phenylsulfonimide (Int-6, 2.70 g, 17.3 mmol) and tert-butyl 4-oxopiperidin-1-carboxylate (Int-8.2, 17.3 g, 86.7 mmol) in MeOH (50 mL) and DCM (25 mL). The resulting mixture was stirred at 40° C. for 2 h, and LC-MS showed that the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×50 mL). The organic layers were combined, dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=10:1 to DCM:MeOH=10:1) to obtain tert-butyl 4-(((R)-methyl-oxo-phenyl-λ.sup.4-sulfinyl)amino)piperidin-1-ylcarboxylate (Int-11.1, 1.6 g, yield: 24%). Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=7.91-7.93 (m, 2H), 7.55-7.59 (m, 3H), 4.74 (d, J=8.0 Hz, 2H), 3.84-3.89 (m, 2H), 3.08 (s, 3H), 3.04 (m, 1H), 2.74-2.80 (m, 2H), 1.59-1.61 (m, 2H), 1.43 (s, 9H). Mass spectrum (ESI) m/z: 339.1 (M+H).sup.+.

Step 2: N—((R)-methyl-oxo-phenyl-λ.SUP.4.-sulfinyl)-4-piperidinamine (Int-11)

[0289] At 0° C., trifluoroacetic acid (6.09 mL, 82.2 mmol) was added to a solution of tert-butyl 4-(((R)-methyl-oxo-phenyl-λ.sup.4-sulfinyl)amino)piperidin-1-ylcarboxylate (Int-11.1, 1.6 g, 4.2 mmol) in DCM (16 mL). The resulting mixture was stirred at room temperature for 2 h, and TLC showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure to obtain a crude product (2.2 g), which was basified with saturated NaHCO.sub.3 solution to give N—((R)-methyl-oxo-phenyl-λ.sup.4-sulfinyl)-4-piperidinamine (Int-11), as a yellow oily liquid, which was used in the next reaction without further purification. Analytical data: Mass spectrum (ESI) m/z: 239 (M+H).sup.+.

Intermediate 12: 3-cyano-6-(1-methyl-1H-pyrazole-4-yl) pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (Int-12)

[0290] ##STR00099##

Step 1: 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-3-carbonitrile (Int-12.3)

[0291] Under nitrogen gas, Pd(PPh.sub.3).sub.4 (3.64 g, 3.15 mmol) was added to a mixture of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridin-3-carbonitrile (CAS #: (2068065-16-5), which was prepared according to the method reported in the literature (WO2019075092), Int-12.1, 15.0 g, 63.0 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (Int-12.2, 15.7 g, 75.6 mmol) in dioxane (150 mL) and aqueous Na.sub.2CO.sub.3 solution (2 M, 94.5 mL, 189 mmol). The resulting mixture was stirred at 80° C. for 12 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, and the filter cake was washed with water (3×100 mL) and DCM (100 mL). The aqueous phases were combined, adjusted to about 5 of pH with 1M HCl. The solid product was collected by filtration, washed with water (2×50 mL), and dried to give 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-3-carbonitrile (Int-12.3, 11.1 g, yield: 42%), as a brown solid. It was used in the next reaction without further purification. Analytical data: Mass spectrum (ESI) m/z: 240.1 (M+H).sup.+.

Step 2: 3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (Int-12)

[0292] Diisopropylethylamine (7.43 mL, 42.6 mmol) was added to a suspension of 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-3-carbonitrile (Int-12.3, 5.10 g, 21.3 mmol) in N,N-dimethyllacetamide (50 mL), and then N-phenyl-bis(trifluoro methanesulfonimide) (Int-12.4, 8.38 g, 23.5 mmol) was added. The resulting solution was stirred at room temperature for 2 h, and LC-MS showed that the reaction was completed. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2×200 mL). The organic layers were combined, dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=10:1 to 1:1) to obtain 3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (Int-12, 5.40 g, yield: 25%). Analytical data: Mass spectrum (ESI) m/z: 372.1 (M+H).sup.+.

Intermediate 13: 4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-3-carbonitrile (Int-13)

[0293] ##STR00100##

[0294] Int-13 (CAS #: 2068064-98-0) was prepared according to the method reported in the literature (WO2017011776). Analytical data: Mass spectrum (ESI) m/z: 319.1 (M+H).sup.+.

Intermediate 14: 3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl trifluoromethanesulfonate (Int-14)

[0295] ##STR00101##

Step 1: 4-(benzyloxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-14.2)

[0296] Under nitrogen gas, Pd.sub.2(dba).sub.3 (2.12 g, 2.32 mmol) and XPhos (2.21 g, 4.64 mmol) were added to a mixture of 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-14.1, CAS #: 1650547-68-4, which was prepared according to the method reported in WO2015017610, 13.2 g, 46.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (Int-12.2, 10.6 g, 51.0 mmol) in K.sub.3PO.sub.4 aqueous solution (2M, 69.5 mL, 139 mmol) and dioxane (130 mL). The resulting mixture was stirred at 80° C. for 2 h, and LC-MS showed that the reaction was completed. The reaction mixture was diluted with water (250 mL), extracted with DCM (3×200 mL). The organic layers were combined, washed with saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The trituration with petroleum ether:ethyl acetate=5:1 at room temperature was performed for 5 minutes to give 4-(benzyloxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-14.2, 9.0 g, yield: 53%, purity: 98.6%), as a yellow solid. Analytical data: Mass spectrum(ESI) m/z: 331.1 (M+H).sup.+.

Step 2: 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-14.3)

[0297] A solution of BBr.sub.3 (12.9 mL, 33.7 g, 134 mmol) in DCM (135 mL) was added to a solution of 4-(benzyloxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-14.2, 9.0 g, 26.9 mmol) in DCM (135 mL) at −78° C. under nitrogen gas. The resulting mixture was stirred at room temperature for 1.25 h, and TLC showed that the reaction was completed. The reaction was quenched with water (500 mL) and the solid product was collected by filtration to give 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-14.3, 7 g, crude product), as a yellow solid. It was used in the next reaction without further purification. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=12.07 (m, 1H), 8.53 (t, J=10.0 Hz, 1H), 8.33 (d, J=9.2 Hz, 1H), 8.22-8.27 (m, 1H), 8.08 (s, 1H), 3.88 (s, 3H). Mass spectrum (ESI) m/z: 241.1 (M+H).sup.+.

Step 3: 3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl trifluoromethanesulfonate (Int-14)

[0298] N-phenyl-bis(trifluoro methanesulfonimide) (Int-12.4, 9.67 g, 27.1 mmol) and diisopropylethylamine (8.34 mL, 47.9 mmol) were added to a solution of 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-14.3, 5.0 g, 20.8 mmol) in N,N-dimethyllacetamide (50 mL). The resulting mixture was stirred at room temperature for 8 h, and TLC showed that the reaction was completed. The resultant of reaction was diluted with water (100 mL), and the product was collected by filtration to give 3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl trifluoromethanesulfonate (Int-14, 1.0 g, yield: 9.8%), as a yellow solid. It was used in the next reaction without further purification. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.57 (s, 1H), 8.93 (m, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 3.92 (s, 3H). Mass spectrum (ESI) m/z: 373.0 (M+H).sup.+.

Intermediate 15: 4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-15)

[0299] ##STR00102##

[0300] Under nitrogen gas, Pd.sub.2(dba).sub.3 (84.3 mg, 0.092 mmol) and XPhos (87.7 mg, 0.184 mmol) were added to a mixture of 3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl trifluoromethanesulfonate (Int-14, 901 mg, 1.84 mmol) and (6-fluoropyridin-3-yl)boronic acid (Int-15.1, 311 mg, 2.21 mmol) in aqueous K.sub.3PO.sub.4 solution(2M, 2.76 mL, 5.52 mmol) and dioxane (10 mL). The resulting mixture was degassed and stirred at 80° C. for 2 h, and LC-MS showed that the reaction was completed. After cooling to 0° C., the reaction mixture was diluted with water (50 mL), extracted with DCM (2×100 mL). The organic layers were combined, washed with saturated brine (200 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent: dichloromethane:methanol=1:0 to 100:1) to obtain 4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-15, 300 mg, yield: 43%), as a yellow solid. Analytical data: Mass spectrum (ESI) m/z: 319.9 (M+H).sup.+.

Example 1

tert-butyl (4-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Ex.1)

[0301] ##STR00103##

[0302] Under nitrogen gas, Pd(dppf)Cl.sub.2 (209 mg, 0.286 mmol) was added to a mixture of tert-butyl (1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)carboxylate (Int-7, 2.50 g, 5.72 mmol), 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carbonitrile (Int-2, 886 mg, 2.86 mmol, 1 eq) and Na.sub.2CO.sub.3 (606 mg, 5.72 mmol) in water (15 mL) and dioxane (25 mL). The resulting mixture was stirred at 80° C. for 12 h, and LC-MS showed that the reaction was completed. After cooling to room temperature, the reaction mixture was filtered, the filtrate was diluted with water (30 ml), and extracted with DCM (3×30 mL). The organic layers were combined, washed with saturated brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 1% to 25%, 9 minutes) to obtain tert-butyl (4-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Ex. 1, 1.30 g, yield: 84%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.39 (s, 1H), 8.19-8.20 (m, 2H), 7.80 (d, J=7.0 Hz, 1H), 7.19 (s, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.38-4.42 (m, 2H), 4.08 (dd, J=8.0, 13.2 Hz, 2H), 3.87 (s, 2H), 3.67-3.70 (m, 2H), 3.28-3.48 (m, 2H), 1.50 (s, 9H), 1.39 (s, 6H). Mass spectrum (ESI) m/z: 441.2 (M+H−100).sup.+.

Example 2: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-imino-1-oxo thiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex.2)

[0303] ##STR00104##

[0304] Trifluoroacetic acid (5 mL, 67.5 mmol) was added to a solution of tert-butyl (4-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Ex. 1, 1.30 g, 2.40 mmol) in DCM (10 mL). The resulting mixture was stirred at 25° C. for 1 h, and LC-MS showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was washed with petroleum ether, dissolved in MeOH, and neutralized by dropwise addition of NH.sub.3.H.sub.2O. The obtained solid product was collected by filtration and dried to obtain 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-imino-1-oxothiomorpholinyl)pyridine-3-yl)pyrazolo[1,5-a]pyridin-3-carbonitrile (Ex. 2, 26 mg, yield: 2.4%, purity: 98.7%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ−8.69 (s, 1H), 8.57 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.85 (dd, J=2.4, 8.8 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 4.70 (s, 1H), 4.29 (d, J=16.0 Hz, 2H), 3.87-3.93 (m, 5H), 2.97-3.02 (m, 4H), 1.22 (s, 6H). Mass spectrum (ESI) m/z: 441.1 (M+H).sup.+.

Example 3: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-((6-methoxypyridin-3-yl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 3)

[0305] ##STR00105##

[0306] Under nitrogen gas, Xantphos (20.9 mg, 0.036 mmol) and Pd.sub.2(dba).sub.3 (16.5 mg, 0.018 mmol) were added to a mixture of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 2, 159 mg, 0.361 mmol), 5-bromo-2-methoxypyridine (67.8 mg, 0.361 mmol) and Cs.sub.2CO.sub.3 (353 mg, 1.08 mmol) in dioxane (1 mL). The resulting mixture was stirred at 100° C. for 5 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 1% to 25%, 9 minutes) to give 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-((6-methoxypyridin-3-yl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 3, 30 mg, yield: 14.6%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.69 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.88-7.89 (m, 2H), 7.39 (dd, J=2.8, 8.8 Hz, 1H), 7.34 (d, J 2.0 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 4.71 (s, 1H), 4.43 (d, J=15.4 Hz, 2H), 3.87-3.90 (m, 4H), 3.79 (s, 3H), 3.39-3.42 (m, 2H), 3.19-3.24 (m, 2H), 1.23 (s, 6H). Mass spectrum(ESI) m/z: 548.2 (M+H).sup.+.

Example 4: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-(isobutylimino)-1-oxothiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 4)

[0307] ##STR00106##

[0308] NaBH.sub.3CN (42.5 mg, 0.676 mmol) was added to a mixture of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 2, 199 mg, 0.451 mmol), isobutyraldehyde (163 mg, 0.206 mL, 2.25 mmol), and 4 Å molecular sieves (200 mg) in MeOH (2 mL). The resulting mixture was stirred at 25° C. for 12 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column:Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 1% to 25%, 9 minutes) to obtain 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-(isobutylimino)-1-oxothiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 4, 30 mg, yield: 13%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.69 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.86 (dd, J=2.4, 8.8 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 4.71 (s, 1H), 4.27-4.32 (m, 2H), 3.81-3.85 (m, 4H), 3.19 (dd, J=3.6, 12.4 Hz, 2H), 2.97-3.02 (m, 2H), 2.79 (d, J=6.4 Hz, 2H), 1.66 (dt, J=6.6, 13.2 Hz, 1H), 1.22 (s, 6H), 0.90 (d, J=6.8 Hz, 6H). Mass spectrum (ESI) m/z: 497.3 (M+H).sup.+.

Example 5: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-(((6-methoxypyridin-3-yl)methyl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 5)

[0309] ##STR00107##

[0310] It was prepared using the same method as Example 4 (Ex. 4). Analytical data: Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.68 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.86 (dd, J=2.4, 8.8 Hz, 1H), 7.70 (dd, J=2.4, 8.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.71 (s, 1H), 4.28-4.32 (m, 2H), 4.18 (s, 2H), 3.83-3.92 (m, 4H), 3.82 (s, 3H), 3.25-3.28 (m, 2H), 3.04-3.10 (m, 2H), 1.23 (s, 6H). Mass spectrum (ESI) m/z: 562.2 (M+H).sup.+.

Example 6: tert-butyl 4-(4-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)piperidine-1-carboxylate (Ex. 6)

[0311] ##STR00108##

[0312] Under nitrogen gas, Pd(dppf)Cl.sub.2 (33.7 mg, 0.046 mmol) was added to a mixture of tert-butyl 4-(1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)piperidine-1-carboxylate (Int-8, 360 mg, 0.692 mmol), 4-bromo-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-carbonitrile (Int-2, 143 mg, 0.461 mmol) and Na.sub.2CO.sub.3 (97.7 mg, 0.922 mmol) in water (0.5 mL) and dioxane (2 mL). The resulting mixture was stirred at 80° C. for 12 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 1% to 25%, 9 minutes) to obtain tert-butyl 4-(4-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)piperidine-1-carboxylate (Ex. 6, 107 mg, yield: 37%), as a yellow solid. Analytical data: Mass spectrum (ESI) m/z: 624.3 (M+H).sup.+.

Example 7: 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-oxo-1-(piperidin-4-ylimino)thiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 7)

[0313] ##STR00109##

[0314] At 0° C., trifluoroacetic acid (0.332 mL, 4.46 mmol) was added to a solution of tert-butyl 4-(4-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)piperidine-1-carboxylate (Ex. 6, 110 mg, 0.172 mmol) in DCM (1.5 mL). The resulting mixture was stirred at room temperature for 0.5 h, and TLC showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 1% to 25%, 9 minutes) to obtain 6-(2-hydroxy-2-methylpropoxy)-4-(6-(1-oxo-1-(piperidin-4-ylimino)thiomorpholinyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 7, 49.8 mg, yield: 55%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, CD.sub.3OD): δ=8.48 (d, J=2.0 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.33 (s, 1H), 7.86 (dd, J=2.4, 8.8 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 4.36 (dd, J=3.8, 14.6 Hz, 2H), 4.10-4.13 (m, 2H), 3.92 (s, 2H), 3.72 (m, 1H), 3.31-3.40 (m, 4H), 3.09-3.13 (m, 2H), 2.05-2.10 (m, 2H), 1.72-1.82 (m, 2H), 1.36 (s, 6H). Mass spectrum (ESI) m/z: 524.3 (M+H).sup.+.

Example 8: 4-(6-(4-((dimethyloxo-λ.SUP.4.-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 8)

[0315] ##STR00110##

[0316] A mixture of N-(dimethyloxo-λ.sup.4-sulfinyl)-4-piperidinamine (Int-9, 200 mg, 1.13 mmol), 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Int-3, 473 mg, 1.13 mmol) and K.sub.2CO.sub.3 (313 mg, 2.27 mmol) in DMSO(2 mL) was stirred at 90° C. for 12 h, and LC-MS showed that the reaction was completed. The solid product was collected by filtration and purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 1% to 25%, 9 minutes) to obtain 4-(6-(4-((dimethyloxo-λ.sup.4-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 8, 40 mg, yield: 17%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, CD.sub.3OD): δ=8.43 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 8.26 (dd, J=2.0, 12.4 Hz, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 4.31 (d, J=13.2 Hz, 2H), 3.91 (s, 2H), 3.54 (m, 1H), 3.13 (s, 6H), 3.08-3.12 (m, 2H), 1.92 (d, J=10.0 Hz, 2H), 1.54-1.64 (m, 2H), 1.35 (s, 6H). Mass spectrum (ESI) m/z: 483.2 (M+H).sup.+.

Example 9: 4-(6-(4-(((S)—S-methyl-S-phenyl-oxo-λ.SUP.4.-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 9)

[0317] ##STR00111##

[0318] A mixture of N—((S)-methyl-oxo-phenyl-λ.sup.4-sulfinyl)-4-piperidinamine (Int-10, 541 mg, 2.27 mmol), 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Int-3, 123 mg, 0.306 mmol) and K.sub.2CO.sub.3 (414.6 mg, 4.0 mmol) in DMSO (2 mL) was stirred at 90° C. for 2 h, and LC-MS showed that the reaction was completed. After cooling to room temperature, the solid product was collected by filtration, which was purified by preparative HPLC (column: Shim-pack C18 150*25*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 16% to 49%, 11 minutes) to obtain 4-(6-(4-(((S)—S-methyl-S-phenyl-oxo-λ.sup.4-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 9, 36.9 mg, yield: 12%), as a light brown solid. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.66 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.91 (dd, J=1.6, 8.4 Hz, 2H), 7.65-7.72 (m, 4H), 7.28 (d, J=2.0 Hz, 1H), 6.91 (d, J=9.2 Hz, 1H), 4.71 (s, 1H), 4.10-4.16 (m, 2H), 3.86 (s, 2H), 3.14 (s, 3H), 2.99-3.06 (m, 2H), 1.36-1.82 (m, 5H), 1.22 (s, 6H). Mass spectrum (ESI) m/z: 545.2 (M+H).sup.+.

Example 10: 4-(6-(4-(((R)—S-methyl-S-phenyl-oxo-λ.SUP.4.-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 10)

[0319] ##STR00112##

[0320] A mixture of N—[(R)-methyl-oxo-phenyl-λ.sup.4-sulfinyl]-4-piperidinamine (Int-11, 183 mg, 0.519 mmol), 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Int-3, 127 mg, 0.307 mmol) and K.sub.2CO.sub.3 (207 mg, 2.0 mmol) in DMSO (2 mL) was stirred at 90° C. for 2 h, and LC-MS showed that the reaction was completed. After cooling to room temperature, the solid product was collected by filtration, which was purified by preparative HPLC (column: Shim-pack C18 150*25*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 16% to 49%, 11 minutes) to obtain 4-(6-(4-(((R)—S-methyl-S-phenyl-oxo-λ.sup.4-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 10, 40 mg, yield: 18%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.66 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.91 (dd, J=1.6, 8.4 Hz, 2H), 7.65-7.72 (m, 4H), 7.28 (d, J=2.0 Hz, 1H), 6.91 (d, J=9.2 Hz, 1H), 4.71 (s, 1H), 4.10-4.16 (m, 2H), 3.86 (s, 2H), 3.14 (s, 3H), 2.99-3.06 (m, 2H), 2.51-2.52 (m, 1H), 1.36-1.75 (m, 4H), 1.22 (s, 6H). Mass spectrum (ESI) m/z: 545.2 (M+H).sup.+.

Example 11: tert-butyl (4-(5-(3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Ex. 11)

[0321] ##STR00113##

[0322] Under nitrogen gas, Pd(dppf)Cl.sub.2 (394 mg, 0.539 mmol) was added to a solution of 3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (Int-12, 2.0 g, 5.39 mmol) and tert-butyl (1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)carboxylate (Int-7, 2.83 g, 6.46 mmol) in dioxane (20 mL) and aqueous Na.sub.2CO.sub.3 solution (2 M, 8.08 mL, 16.16 mmol). The resulting mixture was stirred at 80° C. for 12 h, and TLC showed that the reaction was completed. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with DCM (2×50 mL). The organic layers were combined, dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent:petroleum ether:ethyl acetate=10:1 to 1:1) to obtain tert-butyl (4-(5-(3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Ex. 11, 1.90 g, yield: 65.6%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.68 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.27 (s, 1H), 7.83 (dd, J=2.4, 8.8 Hz, 1H), 7.81 (s, 1H), 7.71 (s, 1H), 7.43 (d, J=1.6 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 4.40-4.45 (m, 2H), 4.10-4.13 (m, 2H), 4.01 (s, 3H), 3.66-3.68 (m, 2H), 3.34-3.38 (m, 2H), 1.51 (s, 9H). Mass spectrum (ESI) m/z: 533.2 (M+H).sup.+, 433.1 (M+H−100).sup.+.

Example 12: 4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 12)

[0323] ##STR00114##

[0324] Trifluoroacetic acid (7.84 mL, 106 mmol) was added to a solution of tert-butyl (4-(5-(3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Ex. 11, 1.90 g, 3.53 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 1 h, and TLC showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure to obtain a residue, and the residue was suspended in methyl tert-butyl ether (20 mL) at room temperature, and the solid product, 4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriletrifluoroacetate (Ex. 12.TFA, 2.40 g, crude product), was collected from the filtrate as a yellow solid. The solid product was used in the next reaction without further purification, a small part of which was purified using preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 1% to 25%, 9 minutes) to obtain a free base sample (Ex. 12) with >99% purity for biological activity assays. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.25 (d, J=1.2 Hz, 1H), 8.65 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.89-7.92 (m, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 4.29-4.32 (m, 2H), 3.88 (s, 3H), 3.86-3.90 (m, 3H), 2.98-3.04 (m, 4H). Mass spectrum (ESI) m/z: 433.1 (M+H).sup.+.

Example 13: 4-(6-(1-(isobutylimino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 13)

[0325] ##STR00115##

[0326] 2-Methylpyridin-boronic acid complex (Int-8.3, 143 mg, 1.33 mmol) was added to a mixture of 4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile trifluoroacetate (Ex. 12.TFA, 500 mg, 0.887 mmol), isobutyraldehyde (256 mg, 0.323 mL, 3.55 mmol) and acetic acid (242 mg, 0.23 mL, 4.03 mmol) in MeOH (3 mL). The resulting mixture was stirred at room temperature for 12 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 17% to 47%, 9 minutes) to obtain 4-(6-(1-(isobutylimino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 13, 30 mg, yield: 6.8%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.67 (d, J=1.6 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 7.82 (dd, J=2.8, 7.2 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.43 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 4.29-4.31 (m, 2H), 4.06-4.11 (m, 2H), 4.01 (s, 3H), 3.19-3.21 (m, 2H), 3.12-3.15 (m, 2H), 2.92 (d, J=6.8 Hz, 2H), 1.78 (m, 1H), 0.98 (d, J=6.4 Hz, 6H). Mass spectrum(ESI) m/z: 489.2 (M+H).sup.+.

Example 14: 4-(6-(1-(((6-methoxypyridin-3-yl)methyl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 14)

[0327] ##STR00116##

[0328] 2-Methylpyridin-boronic acid complex (Int-8.3, 143 mg, 1.33 mmol) was added to a mixture of 4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile trifluoroacetate (Ex. 12.TFA, 500 mg, 0.887 mmol), 6-methoxynicotinaldehyde (487 mg, 3.55 mmol) and acetic acid (249 mg, 0.237 mL, 4.15 mmol) in MeOH (3 mL). The resulting mixture was stirred at 40° C. for 12 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 17% to 47%, 9 minutes) to obtain 4-(6-(1-(((6-methoxypyridin-3-yl)methyl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 14, 249 mg, yield: 50.5%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.67 (d, J=1.6 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.80-7.82 (m, 2H), 7.70-7.73 (m, 2H), 7.43 (d, J=1.6 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.26-4.30 (m, 4H), 4.09-4.12 (m, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.10-3.16 (m, 4H). Mass spectrum (ESI) m/z: 554.3 (M+H).sup.+.

Example 15: 4-(6-(1-((6-methoxypyridin-3-yl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 15)

[0329] ##STR00117##

[0330] Under nitrogen gas, Pd.sub.2(dba).sub.3 (21.2 mg, 0.023 mmol) was added to a mixture of 4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 12, 200 mg, 0.462 mmol), 5-bromo-2-methoxypyridine (87 mg, 0.462 mmol), Cs.sub.2CO.sub.3 (452 mg, 1.39 mmol) and Xantphos (26.8 mg, 0.046 mmol) in dioxane (5 mL). The resulting mixture was stirred at 100° C. for 5 h, and LC-MS showed that the reaction was completed. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 20% to 50%, 9 minutes) to obtain 4-(6-(1-((6-methoxypyridin-3-yl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex.15, 60 mg, yield: 23%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.67 (d, J=1.6 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.28 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.81-7.85 (m, 2H), 7.71 (s, 1H), 7.42-7.45 (m, 2H), 6.91 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 4.45-4.49 (m, 2H), 4.03-4.07 (m, 2H), 4.01 (s, 3H), 3.91 (s, 3H), 3.34-3.36 (m, 2H), 3.21-3.26 (m, 2H). Mass spectrum (ESI) m/z: 540.3 (M+H).sup.+.

Example 16: 4-(6-(4-((dimethyloxo-λ.SUP.4.-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 16)

[0331] ##STR00118##

[0332] A mixture of N-(dimethyloxo-λ.sup.4-sulfinyl)-4-piperidinamine (Int-9, 166 mg, 0.942 mmol), 4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Int-13, 300 mg, 0.942 mmol) and K.sub.2CO.sub.3 (261 mg, 1.88 mmol) in DMSO (3 mL) was stirred at 90° C. for 12 h, and LC-MS showed that the reaction was completed. After cooling to room temperature, the solid product was collected by filtration, and purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 1% to 25%, 9 minutes) to obtain 4-(6-(4-((dimethyloxo-λ.sup.4-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 16, 25 mg, yield: 5.4%), as a light brown solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.63 (s, 1H), 8.36 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 7.79 (s, 1H), 7.73 (dd, J=2.4, 8.8 Hz, 1H), 7.69 (s, 1H), 7.39 (d, J=1.6 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 4.28 (d, J=13.2 Hz, 2H), 4.00 (s, 3H), 3.50 (s, 1H), 3.15 (t, J=10.8 Hz, 2H), 3.07 (s, 6H), 1.93 (dd, J=3.6, 13.2 Hz, 2H), 1.68-1.75 (m, 2H). Mass spectrum (ESI) m/z: 475.3 (M+H).sup.+.

Example 17: 4-(6-(4-(((S)—S-methyl-S-phenyl-oxo-λ.SUP.4.-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 17)

[0333] ##STR00119##

[0334] A mixture of N—((S)-methyl-oxo-phenyl-λ.sup.4-sulfinyl)-4-piperidinamine (Int-10, 225 mg, 0.942 mmol), 4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Int-13, 100 mg, 0.314 mmol) and K.sub.2CO.sub.3 (174 mg, 1.26 mmol) in DMSO (2 mL) was stirred at 90° C. for 12 h, and LC-MS showed that the reaction was completed. The solid product was collected by filtration, and purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 12% to 42%, 10 minutes) to obtain 4-(6-(4-(((S)—S-methyl-S-phenyl-oxo-λ.sup.4-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 17, 44 mg, yield: 26%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.62 (d, J=1.6 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 7.95-8.01 (m, 2H), 7.79 (s, 1H), 7.57-7.73 (m, 5H), 7.38 (d, J=1.6 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.23 (d, J=4.0 Hz, 2H), 4.00 (s, 3H), 3.22 (m, 1H), 3.11 (s, 3H), 3.01-3.11 (m, 2H), 1.97-2.00 (m, 1H), 1.72-1.84 (m, 3H). Mass spectrum (ESI) m/z: 537.1 (M+H).sup.+.

Example 18: 4-(6-(4-(((R)—S-methyl-S-phenyl-oxo-λ.SUP.4.-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 18)

[0335] ##STR00120##

[0336] A mixture of N—((R)-methyl-oxo-phenyl-λ.sup.4-sulfinyl)-4-piperidinamine (Int-11, 225 mg, 0.942 mmol), 4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Int-13, 100 mg, 0.314 mmol) and K.sub.2CO.sub.3 (217 mg, 1.57 mmol) in DMSO (2 mL) was stirred at 90° C. for 12 h, and LC-MS showed that the reaction was completed. After cooling to room temperature, the solid product was collected by filtration and purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 12% to 42%, 10 minutes) to obtain 4-(6-(4-(((R)—S-methyl-S-phenyl-oxo-λ.sup.4-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Ex. 18, 27 mg, yield: 16%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.62 (d, J=1.6 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.25 (s, 1H), 7.96-7.98 (m, 2H), 7.79 (s, 1H), 7.57-7.73 (m, 5H), 7.38 (d, J=1.6 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.23 (td, J=4.8, 9.2 Hz, 2H), 4.00 (s, 3H), 3.21 (m, 1H), 3.11 (s, 3H), 2.95-3.08 (m, 2H), 1.92-2.07 (m, 1H), 1.72-1.86 (m, 3H). Mass spectrum(ESI) m/z: 537.1 (M+H).sup.+.

Example 19: tert-butyl (4-(5-(3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Ex. 19)

[0337] ##STR00121##

[0338] Under nitrogen gas, Pd.sub.2(dba).sub.3 (24.6 mg, 0.0269 mmol) and XPhos (25.6 mg, 0.0537 mmol) were added to a mixture of 3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl trifluoromethanesulfonate (Int-14, 0.20 g, 0.537 mmol) and tert-butyl (1-oxo-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)thiomorpholine-1-imino)carboxylate (Int-7, 258 mg, 0.591 mmol) in aqueous K.sub.3PO.sub.4 solution (2.0 M, 0.806 mL, 1.61 mmol) and dioxane (5 mL). The resulting mixture was stirred at 80° C. for 12 h, and LC-MS showed that the reaction was completed. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent:DCM:ethyl acetate=15:1 to 5:1, and then DCM:MeOH=50:1) to obtain tert-butyl (4-(5-(3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Ex. 19, 110 mg, 0.206 mmol, yield: 38%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.83 (d, J=2.8 Hz, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.87-8.01 (m, 2H), 6.94 (d, J=8.8 Hz, 1H), 4.47 (dd, J=4.0, 14.4 Hz, 2H), 4.32-4.34 (m, 2H), 4.01 (s, 3H), 3.68-3.71 (m, 2H), 3.34-3.39 (m, 2H), 1.51 (s, 9H). Mass spectrum (ESI) m/z: 434.2 (M+H−100).sup.+.

Example 20: 4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 20)

[0339] ##STR00122##

[0340] Trifluoroacetic acid (1 mL, 13.5 mmol) was added to a solution of tert-butyl (4-(5-(3-cyano-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)pyridin-2-yl)-1-oxothiomorpholine-1-imino)carboxylate (Ex. 19, 100 mg, 0.187 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 h, and TLC showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 17% to 41%, 8 minutes) to obtain 4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 20, 35 mg, yield: 43%), as a white solid. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.33 (s, 1H), 8.83 (s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.38 (s, 1H), 8.11-8.14 (m, 2H), 7.21 (d, J=8.8 Hz, 1H), 4.34 (dd, J=1.6, 14.8 Hz, 2H), 3.81-3.99 (m, 6H), 2.96-3.11 (m, 4H). Mass spectrum (ESI) m/z: 434.1 (M+H).sup.+.

Example 21: 4-(6-(1-(((6-methoxypyridin-3-yl)methyl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 21)

[0341] ##STR00123##

[0342] 2-Methylpyridin-boronic acid complex (Int-8.3, 180 mg, 1.68 mmol) was added to a solution of 4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 20, 0.50 g, 1.15 mmol), 6-methoxynicotinaldehyde (614 mg, 4.48 mmol) and acetic acid (0.299 mL, 5.23 mmol) in MeOH (10 mL). The resulting mixture was stirred at 40° C. for 12 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 18% to 48%, 9 minutes) to obtain 4-(6-(1-(((6-methoxypyridin-3-yl)methyl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 21, 27 mg, yield: 4.3%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.81 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.08-8.21 (m, 2H), 7.99 (d, J=8.8 Hz, 2H), 7.68 (dd, J=2.8, 8.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.31-4.34 (m, 2H), 4.29 (s, 2H), 4.00-4.16 (m, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.10-3.16 (m, 4H). Mass spectrum (ESI) m/z: 555.2 (M+H).sup.+.

Example 22: 4-(6-(1-((6-methoxypyridin-3-yl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 22)

[0343] ##STR00124##

[0344] Under nitrogen gas, Xantphos (52.8 mg, 0.091 mmol) and Pd.sub.2(dba).sub.3 (41.8 mg, 0.0457 mmol) were added to a suspension of 4-(6-(1-imino-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 20, 0.50 g, 0.913 mmol), 5-bromo-2-methoxypyridine (172 mg, 0.913 mmol) and Cs.sub.2CO.sub.3 (892 mg, 2.74 mmol) in dioxane (5 mL). The resulting mixture was stirred at 100° C. for 5 h, and LC-MS showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 22% to 52%, 9 minutes) to obtain 4-(6-(1-((6-methoxypyridin-3-yl)imino)-1-oxothiomorpholinyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 22, 52.5 mg, yield: 10%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.83 (d, J=2.4 Hz, 1H), 8.58 (s, 1H), 8.37 (s, 1H), 8.15 (dd, J=2.4, 8.8 Hz, 1H), 7.93-8.07 (m, 3H), 7.43 (dd, J=2.8, 8.8 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 4.52 (d, J=16.0 Hz, 2H), 4.08 (dd, J=9.6, 12.8 Hz, 2H), 4.01 (s, 3H), 3.91 (s, 3H), 3.38 (dd, J=2.4, 12.0 Hz, 2H), 3.15-3.27 (m, 2H). Mass spectrum (ESI) m/z: 541.2 (M+H).sup.+.

Example 23: 4-(6-(4-((dimethyloxo-λ.SUP.4.-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 23)

[0345] ##STR00125##

[0346] A mixture of N-(dimethyloxo-λ.sup.4-sulfinyl)-4-piperidinamine (Int-9, 51.6 mg, 0.292 mmol), 4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Int-15, 100 mg, 0.266 mmol) and K.sub.2CO.sub.3 (73.5 mg, 0.532 mmol) in DMSO (2 mL) was stirred at 90° C. for 3 h, and LC-MS showed that the reaction was completed. The solid product was collected by filtration, and purified by preparative HPLC (column: Shim-pack C18 150*25*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 11% to 31%, 10 minutes) to obtain 4-(6-(4-((dimethyloxo-λ.sup.4-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 23, 27 mg, yield: 21%), as a yellow solid. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.28 (s, 1H), 8.82 (s, 1H), 8.64 (d, J=2.3 Hz, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 8.02 (dd, J=2.5, 8.9 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 4.13-4.22 (m, 2H), 3.90 (s, 3H), 3.31 (s, 3H), 3.15 (s, 6H), 1.65-1.82 (m, 2H), 1.38-1.54 (m, 2H). Mass spectrum (ESI) m/z: 476.2 (M+H).sup.+.

Example 24: 4-(6-(4-(((S)—S-methyl-S-phenyl-oxo-λ.SUP.4.-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 24)

[0347] ##STR00126##

[0348] Compound Ex.24 was prepared by the method as described in Example 23. Analytical data: .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.28 (s, 1H), 8.82 (s, 1H), 8.64 (d, J=2.4 Hz, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 8.01 (dd, J=2.8, 8.8 Hz, 1H), 7.91-7.93 (m, 2H), 7.65-7.70 (m, 3H), 6.98 (d, J=8.8 Hz, 1H), 4.16 (m, 2H), 3.90 (s, 3H), 3.31 (s, 3H), 3.15 (s, 3H), 3.10-3.20 (m, 2H), 1.79-1.83 (m, 1H), 1.64-1.68 (m, 1H), 1.41-1.54 (m, 2H). Mass spectrum (ESI) m/z: 538.1 (M+H).sup.+.

Example 25: 4-(6-(4-(((R)—S-methyl-S-phenyl-oxo-λ.SUP.4.-sulfinyl)amino)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (Ex. 25)

[0349] ##STR00127##

[0350] Compound Ex.25 was prepared by the method as described in Example 23. Analytical data: .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=8.78 (d, J=2.4 Hz, 1H), 8.51 (s, 1H), 8.33 (s, 1H), 7.96-8.01 (m, 5H), 7.61-7.66 (m, 3H), 6.77 (d, J=8.8 Hz, 1H), 4.26-4.32 (m, 2H), 3.99 (s, 3H), 3.24 (m, 1H), 3.08-3.15 (m, 2H), 3.13 (s, 3H), 1.97 (m, 1H), 1.61-1.78 (m, 3H). Mass spectrum (ESI) m/z: 538.0 (M+H).sup.+.

Example 26: Determination of Biochemical IC.SUB.50 .Values of RET Kinase and its Mutants and Fusions

[0351] The determination of biochemical inhibitory activity of the compounds prepared in the Examples of the present invention on wild-type RET kinase, RET(V804M) mutant and RET-CCDC6 fusions was entrusted to American Reaction Biology Corporation (One Great Valley Parkway, Suite 2, Malvern, Pa. 19355, USA). For detailed test methods, the following references were referred to: T. Anastassiadis, S. W. Deacon, K. Devarajan, H. Ma, J. R. Peterson. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotech. 2011, 29(11), 1039-1045.

[0352] I. General Conditions for Determination:

[0353] The compounds of the present invention were dissolved in dimethyl sulfoxide (DMSO) to prepare 10 mM stock solutions, and ten different doses by 3-fold serial dilutions from 10 mM were prepared. The ATP concentration used in this determination was 1 μM.

[0354] II. Reagents Used:

[0355] Base reaction buffer: 20 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer (Hepes, pH 7.5), 10 mM magnesium chloride, 1 mM ethylene glycol-bis(3-aminoethylether)-N,N,N′,N′-tetraacetic acid (EGTA), 0.02% Brij™-35 (purchased from ThermoFisher Scientific), 0.02 mg/mL bovine serum albumin (BSA), 0.1 mM sodium orthovanadate (Na.sub.3VO.sub.4), 2 mM dithiothreitol (DTT), 1% dimethyl sulfoxide (DMSO).

[0356] III. Reaction Steps:

[0357] a) adding the corresponding substrate to a freshly prepared base reaction buffer;

[0358] b) adding necessary cofactors;

[0359] c) adding kinase and shake gently;

[0360] d) adding the compounds in DMSO using Acoustic technology (Echo550; nanoliter range) and incubating at room temperature for 20 minutes;

[0361] e) adding 33P-ATP (specific activity 10 μCi/μL) to initiate the reaction;

[0362] f) incubating the kinase reaction at room temperature for 2 hours;

[0363] g) spotting the resultant of reaction on P81 ion exchange paper (purchased from Whatman);

[0364] h) detecting kinase activity by filter binding assay.

[0365] IV. Acquiring and Processing Data:

[0366] The filter was washed extensively with 0.75% phosphoric acid to remove unbound phosphate, and after subtracting the background derived from the control reaction containing the inactive enzyme, the kinase activity was expressed as: the remaining kinase activity of the compound test group accounted for a percent of blank test control group (DMSO). IC.sub.50 values were generated using Prism (GraphPad software).

[0367] V. Measurement Results:

[0368] The biochemical IC.sub.50 values of the compounds prepared in the Examples of the present invention against wild-type RET kinases, RET(V804M) mutants and RET-CCDC6 fusions were listed in Table 1:

TABLE-US-00005 TABLE 1 Biochemical IC.sub.50 (nM) Example RET RET (V804M) RET-CCDC6 Ex. 2 4.23 21.2 2.81 Ex. 3 1.66 3.78 0.993 Ex. 4 6.74 55.7 4.59 Ex. 5 3.62 17.9 2.09 Ex. 7 18.1 165 12.6 Ex. 8 9.45 63.6 5.89 Ex. 9 14.2 138 8.14 Ex. 10 6.18 36.0 4.59 Ex. 12 0.849 5.55 0.523 Ex. 13 0.89 5.10 0.416 Ex. 14 0.657 5.21 0.336 Ex. 15 0.759 1.72 0.518 Ex. 16 1.16 5.55 0.619 Ex. 17 1.49 10.6 0.776 Ex. 18 0.907 4.72 0.501 Ex. 20 1.16 7.91 0.677 Ex. 21 1.02 7.83 0.528 Ex. 22 0.673 3.24 0.410 Ex. 23 4.09 25.0 2.16 Ex. 24 4.06 26.3 1.93 Ex. 25 2.02 10.6 1.15

[0369] It can be seen from the above data that the compounds in the present invention have strong inhibitory activity on wild-type RET kinase, representative RET (V804M) of mutant RET kinase and representative RET-CCDC6 of fusion RET kinase, in which IC.sub.50 value is less than 100 nM, and individual results were less than 1 nM, reaching the picomolar scale.

[0370] It should be noted that there are many mutants of RET kinase, and multiple fusion proteins can also be formed. These mutants and fusion proteins include, but not limited to, RET(A883F), RET(E762Q), RET(G691S), RET(L790F), RET(M918T), RET(R749T), RET(R813Q), RET(R912P), RET(S891A), RET(S904A), RET(S904F), RET(V804M), RET(V778I), RET(V804E), RET(V804L), RET-KIF5B, RET(G810R)-KIF5B, RET(V804L)-KIF5B, RET(V804M)-KIF5B, RET(Y791F), RET(Y806H), RET-BCR, RET-KIF5B(Kex15Rex14), RET-CCDC6, RET-NCOA4(PTC3), RET-PRKAR1A(PTC2). Example 26 determined the inhibitory activity of some compounds of the present invention on the representative RET (V804M) of the mutant RET kinase and the representative RET-CCDC6 of the fusion RET kinase. These results are not used to limit the protection scope of the present invention. The compounds in the present invention that have inhibitory activity against other RET mutants or fusions other than these two types also belong to the protection scope of the present invention.

Example 27: Determination of IC.SUB.50 .Values for Phospho-RET and Phospho-ERK in Tumor Cells

[0371] The determination of inhibitory activity of the compounds prepared in the examples of the present invention on Phospho-RET and Phospho-ERK in tumor cells was entrusted to the American Reaction Biology Corporation (Address: One Great Valley Parkway, Suite 2, Malvern, Pa. 19355, USA).

[0372] I. General Conditions for Determination:

[0373] The compounds of the present invention were dissolved in dimethyl sulfoxide (DMSO) to prepare 10 mM stock solutions, and ten different doses by 3-fold serial dilutions from 10 mM were prepared. An ELISA assay format was used in the test.

[0374] II. Reagents and Cell Culture:

[0375] PathScan® Phospho-Ret (panTyr) and p44/42 MAPK (Thr202/Tyr204) (ERK) Sandwich ELISA kits were purchased from Cell Signaling Technology. The LC-2/ad lung cancer cell line was purchased from Sigma-Aldrich. The LC-2/ad cells were cultured in RPMI-1640: F-12K (1:1). The medium was supplemented with 10% fetal bovine serum (FBS), 100 μg/mL penicillin and 100 μg/mL streptomycin, and the cultures were maintained at 37° C. in a humidified atmosphere of 5% CO.sub.2 and 95% air.

[0376] III. Reaction Steps:

[0377] a) 1.5×10.sup.4 LC-2/ad cells were seeded in the wells of a 96-well tissue culture plate overnight;

[0378] b) the cells were treated with DMSO or the test compound in DMSO (the initial concentration was 1 μM, and ten doses by 3-fold serial dilutions) for one hour;

[0379] c) the cells were washed once with 200 μL ice-cold phosphate buffered saline (PBS) and washed with 100 μL/well of cell lysis buffer (1% NP-40, 20 mM Tris/pH=8.0, 137 mM NaCl, 10% glycerol, 2 mM EDTA, protease/phosphatase inhibitor mixture). The plate was shaken for 1 minute, then placed on a rocking platform at 4° C. for 30 minutes;

[0380] d) 80 μL/well of lysate was added to the appropriate wells of each ELISA plate and the plate was incubated overnight at 4° C. on a rocking platform;

[0381] e) the contents of the plate were discarded into a container and the wells were washed for four times with 200 μL/well of 1×ELISA wash buffer;

[0382] f) 100 μL of reconstituted Phospho-Ret(panTyr) or Phospho-ERK(Thr202/Tyr204; p44/42MAPK) detection antibody was added to the appropriate wells and the plate was incubated at 37° C. for 1 hour;

[0383] g) the washing procedure was repeated and 100 μL of reconstituted HRP-linked secondary antibody was added to each well of two plates and the plates were incubated at 37° C. for 30 minutes;

[0384] h) the washing procedure was repeated, 100 μL of TMB substrate was added to each well, and the plates were incubated at 37° C. for 45 minutes;

[0385] i) 100 μL of STOP solution was added to each well and the plate was gently shaken for a few seconds.

[0386] IV. Acquiring and Processing Data:

[0387] Absorbance was read at 460 nm using an Envision 2104 Multilabel Reader (purchased from PerkinElmer, Santa Clara, Calif., USA); IC.sub.50 curves were plotted and IC.sub.50 values were calculated based on a sigmoidal dose-response equation using GraphPad Prism 4 software.

[0388] V. Measurement Results:

[0389] The IC.sub.50 values of the compounds prepared in the examples of the present invention to Phospho-RET and Phospho-ERK in LC-2/ad lung cancer tumor cells were listed in Table 2:

TABLE-US-00006 TABLE 2 Cell IC.sub.50(nM) LC-2/ad lung cancer cells Example Phospho-RET Phospho-ERK LOXO292* 6.08 >1000 Ex. 12 11.5 246 Ex. 13 16.3 6.55 Ex. 14 11.5 82.5 Ex. 15 0.51 321 Ex. 16 66.4 7.19 Ex. 18 7.10 6.83 Ex. 20 91.4 7.77 Ex. 21 21.3 6.42 Ex. 25 84.7 9.27 LOXO292* is a RET inhibitor in clinical trials and is used here as a positive control.

[0390] From the data listed in Table 2, it can be seen that some of the compounds synthesized in the Examples of the present invention have a strong inhibitory effect on Phospho-RET and Phospho-ERK in tumors cells, in which IC.sub.50 value is less than 100 nM, and individual results were less than 1 nM, reaching the picomolar scale. Interestingly, compared with the positive control LOXO292, the compounds in the present invention have much stronger inhibitory activity on Phospho-ERK, wherein the IC.sub.50 value of the former is >1000 nM, while IC.sub.50 values of the compounds of the present invention are mostly lower than single digit nM. This also shows that the compounds in the present invention have obvious advantages over LOXO292 in inhibiting the key tumor-driven target ERK in tumor cells.

[0391] Although the present invention has been described in detail with general descriptions, specific embodiments and tests above, some modifications or improvements can be made on the basis of the present invention, which will be obvious to a person skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention belong to the scope of protection of the present invention.

INDUSTRIAL APPLICABILITY

[0392] The present invention provides a heterocyclic sulfoximine compound represented by formula (I), or a racemate, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof Δt the same time, also disclosed are an intermediate compound for synthesizing the compound, a preparation method therefor, and a pharmaceutical composition comprising the compound and use thereof. The compound is RET, RET mutant, or RET fusion protein inhibitors, capable of treating diseases caused by abnormal activity of RET, RET mutant, or RET fusion proteins, for example, tumors and the like.