Sulfonamide derivative, preparation method therefor and use thereof

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

Sulfonamide derivatives and their preparation methods and uses Technical Field

[0001] The present invention relates to a sulfonamide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, in particular as a CTPS1 inhibitor. Background Art

[0002] Cytidine triphosphate (CTP) is a crucial precursor required for DNA, RNA, and phospholipid metabolism in human cells. CTP is produced through two pathways: salvage synthesis and de novo synthesis. CTP synthetase (CTPS) is the rate-limiting enzyme for de novo CTP synthesis and comprises two isoforms, CTPS1 and CTPS2. CTPS1 and CTPS2 share 74% sequence homology but have distinct physiological roles. CTPS2 is uniformly expressed in all tissues, whereas CTPS1 is expressed at generally low levels across tissues but is rapidly upregulated in activated T cells. Expression of wild-type CTPS1 or addition of exogenous CTP or its nucleoside precursor, cytidine, restores T cell proliferation in CTPS1-deficient cells. This suggests that CTPS1 plays an essential role in the proliferation of both B and T cells and is required for effective immune responses.

[0003] Proliferating cells, such as activated lymphocytes, have a high demand for ribonucleotides, particularly CTP and GTP. CTPS1 is expressed in high quantities upon lymphocyte activation, catalyzing the synthesis of CTP, providing the substrate for lymphocyte proliferation. Furthermore, CTPS1 is less sensitive to feedback inhibition by CTP than CTPS2, endowing CTPS1 with the ability to continuously catalyze CTP synthesis, ultimately expanding the CTP reserve required for lymphocyte proliferation. CTPS1 expression is upregulated in activated lymphocytes to expand the CTP pool and meet the increased demand for nucleic acid and lipid synthesis. The CTP demand of other tissues is met through CTPS2 isoforms and the nucleoside recycling pathway. Therefore, selective inhibition of proliferative CTPS1 is desirable in the treatment of immune diseases and lymphocytic cancers. This makes CTPS1 an ideal target for immunosuppression.

[0004] Lymphoma is one of the most common malignancies in China and is primarily divided into two categories: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). In actual clinical diagnosis, NHL is the most common, accounting for approximately 80% to 90% of confirmed lymphomas. NHL primarily includes diffuse large B-cell lymphoma, peripheral T-cell lymphoma, mantle cell lymphoma, cutaneous T-cell lymphoma, indolent B-cell lymphoma, and NK-cell lymphoma. CTPS1 expression is high in T-cell non-Hodgkin lymphoma and acute T-cell lymphoma. Overexpression of CTPS1 provides a substrate for the excessive proliferation of these T-cell lymphomas, making it a potential target for anticancer drugs.

[0005] While no new CTPS1 inhibitors have been marketed, Step Pharma's STP-938 has entered Phase I / II clinical trials for the treatment of relapsed / refractory B-cell and T-cell lymphomas. Nimbus's CTPS1 small molecule inhibitor is in the discovery phase. Overall, as a cutting-edge research area, CTPS1 remains a promising target for further exploration, and the continued development of new inhibitors is crucial. Summary of the Invention

[0006] In response to the above technical problems, the present invention provides a sulfonamide derivative represented by the general formula (AAI) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0007] in:

[0008] Any two R aa Together with the atoms to which they are attached, they form a ring C, wherein the ring C is optionally further substituted with one or more R 4 replaced by;

[0009] Ring C is selected from 6-membered aryl, 3-5-membered cycloalkyl, 5-7-membered heterocyclyl or 5-6-membered heteroaryl;

[0010] R A Selected from hydrogen atoms or C 1-6 alkyl;

[0011] Ring A is selected from a 6-membered aryl group, a 5- to 6-membered heteroaryl group, or a 5- to 7-membered heterocyclic group;

[0012] Ring B is selected from a 6-membered aryl group or a 5- to 10-membered heteroaryl group;

[0013] L is selected from -C(=O)-, -C(=O)NR a -or-NR b C(=O)-;

[0014] R a 、R b Each independently selected from a hydrogen atom or C 1-6 alkyl;

[0015] X, Y, Z and Q are each independently selected from N or CR c ; and at most two atoms among X, Y, Z, and Q are N atoms at the same time;

[0016] or X and Y, Z and Y independently form a 5-6 membered heteroaryl or a 5-6 membered heterocyclic group; wherein the 5-6 membered heteroaryl or 5-6 membered heterocyclic group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, and 3-5 membered cycloalkyl;

[0017] R c Selected from hydrogen atom, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, and 3-5 membered cycloalkyl;

[0018] R 1 Selected from C 1-6 Alkyl or 3-5 membered cycloalkyl; wherein the C 1-6 The alkyl group or the 3-5 membered cycloalkyl group may be further substituted with one or more alkyl groups selected from halogen, hydroxyl, cyano, 3-5 membered cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted by a haloalkoxy substituent;

[0019] R 2 Each independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy; wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted by one or more radicals selected from halogen, hydroxy, cyano, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent;

[0020] Or, two R 2 It forms a -C(O) with the same carbon atom to which it is attached;

[0021] R 3 Each independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6Alkoxy, 3-5 membered cycloalkyl, C 2-6 Alkenyl, SF5, -C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 wherein the alkyl, alkoxy, alkenyl or cycloalkyl is optionally further substituted by one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0022] R 4 Each is independently selected from hydrogen, cyano, halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-S(O)2NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0023] R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0024] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R10 substituted by a substituent;

[0025] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0026] R 8 、R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0027] m is selected from 0, 1 or 2;

[0028] n is selected from 0, 1 or 2;

[0029] p is selected from 0, 1 or 2;

[0030] q is selected from 0, 1 or 2; and

[0031] r is independently 0, 1 or 2.

[0032] A preferred embodiment of the present invention is a compound of the general formula (AAI) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein Selected from

[0033] wherein t is selected from 0, 1 or 2; Ring C, R 4 , p or q are as defined in the general formula (AAI).

[0034] A preferred embodiment of the present invention is a compound of the general formula (AAI) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of the general formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0035] in:

[0036] X, Y, Z and Q are each independently selected from N or CR c ; and at most two atoms among X, Y, Z, and Q are N atoms at the same time;

[0037] Alternatively, Z and Y form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally further substituted with one or more substituents selected from halogen, hydroxyl, cyano, and 3-5 membered cycloalkyl;

[0038] Alternatively, X and Y form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally further substituted with one or more substituents selected from halogen, hydroxyl, cyano, and 3-5 membered cycloalkyl;

[0039] t is selected from 0, 1 or 2;

[0040] Ring A, Ring B, Ring C, L, R 1 ~R 4 、R A , p, q, m or n are as defined in the general formula (AAI).

[0041] A preferred embodiment of the present invention is a compound of the general formula (AAI) or (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of the general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0042] Among them: Ring A, Ring B, Ring C, L, R 1 ~R 4 , X, Y, Z, Q, p, q, m, n or t are defined as described in the general formula (AI).

[0043] A preferred embodiment of the present invention is a compound of the general formula (AAI), (AI) or (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups:

[0044] A preferred embodiment of the present invention is a compound of formula (AAI), (AI) or (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the following groups:

[0045] A preferred embodiment of the present invention is a compound of the general formula (AAI), (AI) or (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein: L is selected from -C(=O)-, -C(=O)NH- or -NHC(=O)-.

[0046] A preferred embodiment of the present invention is a compound of formula (AAI), (AI) or (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (IIA) or (IIB) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0047] Wherein: X1 is independently selected from N or CR d ;

[0048] X4 are each independently selected from N or CR d ;

[0049] R b are each independently selected from a hydrogen atom or a methyl group;

[0050] R d Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0051] X2 and X3 are each independently selected from N or CR e ;

[0052] j are each independently selected from 0 or 1;

[0053] R e Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0054] Ring C, X, Y, Z, Q, R 1 ~R 4 , p, q or t are as defined in the general formula (AI).

[0055] A preferred embodiment of the present invention is a compound of formula (AAI), (AI) or (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0056] Wherein: X1 is independently selected from N or CR d ;

[0057] R b are each independently selected from a hydrogen atom or a methyl group;

[0058] R d Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0059] X2 and X3 are each independently selected from N or CR e ;

[0060] j are each independently selected from 0 or 1;

[0061] R e Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0062] Ring C, X, Y, Z, Q, R 1 ~R 4 , p, q or t are as defined in the general formula (AI).

[0063] A preferred embodiment of the present invention is a compound of formula (AAI) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV-1) or (IV-2) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0064] Wherein: X1 is independently selected from N or CR d ;

[0065] X4 are each independently selected from N or CR d ;

[0066] R b are each independently selected from a hydrogen atom or a methyl group;

[0067] R d Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0068] X2 and X3 are each independently selected from N or CR e ;

[0069] j are each independently selected from 0 or 1;

[0070] R e Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0071] t is selected from 0, 1 or 2;

[0072] X, Y, Z, Q, or R 1 ~R 4 The definition of is as described in the general formula (AAI).

[0073] A preferred embodiment of the present invention is a compound of the general formula (AAI), (AI) or (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0074] Where: R b are each independently selected from a hydrogen atom or a methyl group;

[0075] Ring B is each independently selected from

[0076] Y1 and Y2 are each independently selected from N or CH;

[0077] j are each independently selected from 0 or 1;

[0078] t is each independently selected from 0, 1 or 2;

[0079] Ring C, X, Y, Z, Q, R 1 ~R 4 , p, q or n are as defined in the general formula (AAI).

[0080] A preferred embodiment of the present invention is a compound of formula (AAI), (AI), (I), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (V-1) or (V-2) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0081] Where: R b are each independently selected from a hydrogen atom or a methyl group;

[0082] X2 and X3 are each independently selected from N or CR e ;

[0083] j are each independently selected from 0 or 1;

[0084] R e Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0085] t is selected from 0, 1 or 2;

[0086] Ring C, X, Y, Z, Q, R 1 ~R 4 , p or q are as defined in the general formula (AAI).

[0087] A preferred embodiment of the present invention is a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein Selected from the following groups:

[0088] R c Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0089] k is independently selected from 0, 1 or 2.

[0090] A preferred embodiment of the present invention is a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (V-1), (V-2), (VA), (VB), (VC) or (VD), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring C is selected from the following groups:

[0091] A preferred embodiment of the present invention is a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atoms, C 1-6 Alkyl, -C(O)R 5 、-C(O)NR 6 R 7 、-S(O)2R 5 、-S(O)2NR 6 R 7 , wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from hydroxy, halogen, cyano or -C(O)OR 8 substituted by a substituent;

[0092] R 5 Each independently selected from C 1-6 Alkyl, 3-5 membered cycloalkyl or 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, 3-5 membered cycloalkyl or 5-6 membered heteroaryl may be further substituted with one or more halogen or C 1-6 substituted by an alkoxy substituent;

[0093] R 6 、R 7 Each independently selected from a hydrogen atom or C 1-6 alkyl;

[0094] R 8 Selected from hydrogen atoms or C 1-6 alkyl.

[0095] A preferred embodiment of the present invention is a compound of formula (AI), (I), (IIA), (IIB), (II), (III), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein Selected from the following groups:

[0096] Where: R 4a Each independently selected from a hydrogen atom or C 1-6 alkyl;

[0097] R 4 The definition of is as described in the general formula (AI).

[0098] A preferred embodiment of the present invention is a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl or 3-5 membered cycloalkyl, wherein the C 1-6 The alkyl group or the 3-5 membered cycloalkyl group may be further substituted with one or more selected from C 1-3 Alkyl, C 1-3 The alkyl group is substituted by an alkoxy group, a halogen group, a hydroxy group or a cyano group.

[0099] A preferred embodiment of the present invention is a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from cyclopropyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl,

[0100] A preferred embodiment of the present invention is a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0101] Or, two R 2 It forms a -C(O) with the same carbon atom to which it is attached.

[0102] A preferred embodiment of the present invention is a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen atom, halogen, cyano, hydroxyl, C1-6 Alkyl, C 1-6 Alkoxy, 3-5 membered cycloalkyl, SF5, C 1-6 Haloalkyl or C 1-6 Halogenated alkoxy.

[0103] A preferred embodiment of the present invention is a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from chloro, trifluoromethoxy, methyl, ethyl or ethoxy.

[0104] A preferred embodiment of the present invention is a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein p is 0 and q is 0.

[0105] A preferred embodiment of the present invention is a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein p is 1 and q is 1 or 2.

[0106] A preferred embodiment of the present invention is a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein p is 2 and q is 0, 1 or 2.

[0107] In a preferred embodiment of the present invention, the compound described by the general formula is selected from:

[0108] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0109] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0110] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0111] The present invention provides a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in preparing a CTPS1 inhibitor.

[0112] The present invention also provides a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in preparing a medicament for treating a disease mediated by CTPS1, wherein the disease mediated by CTPS1 is preferably a lymphoma or a solid tumor; more preferably, relapsed / refractory B-cell and T-cell lymphoma, and most preferably, mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma or indolent B-cell lymphoma.

[0113] The present invention further provides a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing a medicament for treating lymphoma or solid tumors.

[0114] The present invention provides a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in preparing a medicament for treating relapsed / refractory B-cell and T-cell lymphoma.

[0115] The present invention provides a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in preparing a medicament for treating mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma or indolent B-cell lymphoma.

[0116] Accordingly, the present invention also provides a method for preventing or treating a disease mediated by CTPS1, comprising administering to a subject in need thereof a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC), or (VD), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The CTPS1-mediated disease is preferably a lymphoma or a solid tumor; more preferably, relapsed / refractory B-cell and T-cell lymphoma, and most preferably, mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, or indolent B-cell lymphoma.

[0117] The present invention also provides a method for preventing or treating lymphoma or solid tumors, comprising administering to a subject in need thereof a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC), or (VD), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The present invention also provides a method for preventing or treating relapsed / refractory B-cell and T-cell lymphoma, comprising administering to a subject in need thereof a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC), or (VD), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The present invention also provides a method for preventing or treating mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma or indolent B-cell lymphoma, comprising administering to a subject in need thereof a compound of the general formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VA), (VB), (VC) or (VD) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0118] Detailed Description of the Invention

[0119] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0120] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl or C1-C4 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0121] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples of which are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. C2-C4 alkenyl is preferred. The alkenyl group may be optionally substituted or unsubstituted.

[0122] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight chain or branched. 10 The alkynyl group of any of the preceding claims is preferably a C2-C6 alkynyl group, more preferably a C2-C6 alkynyl group, most preferably a C2-C4 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. The alkynyl group may be substituted or unsubstituted.

[0123] "Alkylene" refers to a saturated C1-C 20 A straight-chain or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane, preferably C1-C 10 Alkylene, more preferably C1-C6 alkylene or C1-C4 alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, and the like. The alkylene group may be substituted or unsubstituted.

[0124] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the ring atoms is a carbon atom, including monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably having a 3-10-membered cycloalkyl group or a 3-8-membered cycloalkyl group, such as a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.

[0125] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into single spiro, double spiro or multiple spiroalkyl groups, preferably single spiro and double spiroalkyl groups, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0126] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl group, preferably a bicyclic or tricyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. Non-limiting examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, or tetradecahydrophenanthrenyl.

[0127] "Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures that share two non-directly connected carbon atoms. One or more rings may contain one or more double bonds, but none of the rings have completely conjugated π electrons. It is an aromatic system with preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r,5r)-bicyclo[3.3.2]decyl.

[0128] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring atoms is selected from nitrogen, oxygen, or S(O) r (wherein t is selected from 0, 1 or 2) heteroatoms, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings. Preferably, there is a 5-7 membered monocyclic or 7-10 membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine;

[0129] The heterocyclic group may be substituted or unsubstituted.

[0130] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between the rings, spirocycloalkyl is divided into single spiro heterocyclic group, double spiro heterocyclic group or multiple spiro heterocyclic group, preferably single spiro heterocyclic group and double spiro heterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl.

[0131] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein t is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin.

[0132] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more ring structures that share two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 2-azabicyclo [3.3.2] decyl.

[0133] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0134] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring that may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4- Triazolyl, pyridinyl, pyrimidinyl, pyrazin-2(1H)-onyl, pyrimidin-4(3H)-onyl, pyridazin-3(2H)-onyl, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furo[3,2-b]pyridinyl, furo[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl,.

[0135] Heteroaryl groups can be substituted or unsubstituted.

[0136] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0137] "Nitro" refers to a -NO2 group.

[0138] "Hydroxy" refers to an -OH group.

[0139] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0140] "Amino" refers to -NH2.

[0141] "Cyano" refers to -CN.

[0142] "Benzyl" refers to -CH2-phenyl.

[0143] "Carboxyl" refers to -C(O)OH.

[0144] "Carboxylate" refers to a -C(O)O-alkyl group or a -C(O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0145] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0146] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0147] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0148] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0149] "DMSO" refers to dimethyl sulfoxide.

[0150] "BOC" refers to tert-butoxycarbonyl.

[0151] "Bn" refers to benzyl.

[0152] "THP" refers to 2-tetrahydropyranyl.

[0153] "TFA" refers to trifluoroacetic acid.

[0154] "Ts" refers to p-toluenesulfonyl.

[0155] "Leaving group", or leaving group, is an atom or functional group that breaks away from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that easily accept electrons and have a strong ability to withstand negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break away from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to bind to other atoms, and the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, methylsulfonyl, -OTs or -OH.

[0156] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0157] As used herein, "substituted" or "substituted", unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -OR 6 、-C(O)R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH2NHC(O)OR 6 、-CH2NR 7 R 8 or -S(O)rR 6 substituted by a substituent;

[0158] R 6 is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0159] R 7 and R 8Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0160] Or, R 7 and R 8 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0161] R 9 、R 10 and R 11 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0162] r is selected from 0, 1 or 2;

[0163] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0164] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0165] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0166] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0167] Synthesis method of the compound of the present invention

[0168] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0169] Method 1:

[0170] The present invention provides a method for preparing a compound of general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, the method comprising:

[0171] The compound of formula (II-a) and the compound of formula (II-b) undergo acid-amine condensation or amine ester exchange reaction, and optionally further undergo substitution reaction to obtain the compound of formula (II)

[0172] in:

[0173] Y1 is selected from hydroxy, methoxy or ethoxy;

[0174] X1, X2, X3, X, Y, Z, Q, R 1 ~R 4, p, q, j and t are as defined in the general formula (II).

[0175] Method 2:

[0176] The present invention provides a method for preparing a compound of general formula (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:

[0177] The compound of formula (III-a) undergoes acid-amine condensation or amine ester exchange reaction with the compound (III-b), and optionally further undergoes substitution reaction to obtain the compound of formula (III)

[0178] in:

[0179] Y1 is selected from hydroxy, methoxy or ethoxy;

[0180] X1, X2, X3, X, Y, Z, Q, R 1 ~R 4 , p, q, j and t are as defined in the general formula (III). DETAILED DESCRIPTION

[0181] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0182] Example

[0183] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0184] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0185] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0186] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0187] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise indicated. Commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0188] CD3OD: deuterated methanol.

[0189] CDCl3: deuterated chloroform.

[0190] DMSO-d6: deuterated dimethyl sulfoxide.

[0191] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1 L.

[0192] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0193] The compound was purified using silica gel column chromatography and reverse phase column chromatography, with the eluent system selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; and D: aqueous trifluoroacetic acid and acetonitrile. The volume ratio of the solvents varied depending on the polarity of the compound and could be adjusted by adding a small amount of an acidic or alkaline reagent, such as acetic acid or triethylamine.

[0194] Example 1

[0195] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[0196] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[0197] first step

[0198] 2-chloro-6-ethoxypyrazine

[0199] 2-Chloro-6-ethoxypyrazine

[0200] Under an ice-water bath, sodium hydride (1.76 g, 40.61 mmol, 60% purity) was added to a solution of ethanol (1.62 g, 35.24 mmol) in tetrahydrofuran (50 mL). After 0.5 hour, 2,6-dichloropyrazine 1a (5 g, 33.56 mmol, commercially available) was added. The mixture was then heated to room temperature and stirred for 16 hours. Mass spectrometry confirmed that the starting material had essentially reacted. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 2-chloro-6-ethoxypyrazine 1b (4 g) in a 75.15% yield. MS m / z (ESI): 159.0 [M+1].

[0201] Step 2

[0202] 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine

[0203] 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine

[0204] 2-Chloro-6-ethoxypyrazine 1b (2 g, 12.61 mmol), (6-aminopyridin-3-yl)boronic acid 1c (2.09 g, 15.13 mmol, commercially available), 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (922.78 mg, 1.26 mmol), and potassium carbonate (5.23 g, 37.83 mmol) were added to 1,4-dioxane (60 mL) and water (15 mL). The atmosphere was replaced with argon three times, and the temperature was raised to 95°C and stirred for 3 hours. After the reaction was complete, the solvent was evaporated and the crude product was purified by silica gel column chromatography (eluent: System A) to give 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine 1d (3.5 g) in a yield of 96.26%.

[0205] MS m / z(ESI):217.2[M+1]

[0206] Step 3

[0207] 1-(tert-butyl)3-methyl 2-(2-(methylthio)pyrimidin-4-yl)malonate

[0208] 1-(tert-Butyl)3-methyl 2-(2-(methylthio)pyrimidin-4-yl)malonate

[0209] 4-Chloro-2-(methylthio)pyrimidine 1e (5 g, 31.13 mmol, commercially available), tert-butyl methyl malonate 1f (7.05 g, 40.47 mmol, 6.84 mL, commercially available), and cesium carbonate (25.36 g, 77.82 mmol) were added to N,N-dimethylformamide (45.27 mL), stirred at 70 ° C for 3 hours, cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL) to obtain 1-(tert-butyl) 3-methyl 2-(2-(methylthio)pyrimidin-4-yl)malonate 1g (8 g) with a yield of 86.14%. The crude product was directly used for the next reaction.

[0210] MS m / z(ESI):299.3[M+1]

[0211] Step 4

[0212] methyl 2-(2-(methylthio)pyrimidin-4-yl)acetate

[0213] Methyl 2-(2-(methylthio)pyrimidin-4-yl)acetate

[0214] 1-(tert-Butyl)3-methyl 2-(2-(methylthio)pyrimidin-4-yl)malonate (9 g, 30.17 mmol) was added to dichloromethane (50 mL), and trifluoroacetic acid (34.39 g, 301.65 mmol, 23.24 mL) was slowly added dropwise. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 2-(2-(methylthio)pyrimidin-4-yl)acetate (4 g) in a 66.89% yield.

[0215] MS m / z(ESI):199.2[M+1]

[0216] Step 5

[0217] methyl 2-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[0218] 2-(2-(Methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[0219] Under ice-water bath, sodium hydride (443.90 mg, 11.10 mmol, 60% purity) was slowly added to a solution of methyl 2-(2-(methylthio)pyrimidin-4-yl)acetate 1h (1 g, 5.04 mmol) in N,N-dimethylformamide (8 mL). After 0.5 hour, 1,2-bis(chloromethyl)benzene (971.34 mg, 5.55 mmol) was added. The mixture was stirred at room temperature for 2 hours. Ethyl acetate (3 0 mL) and water (15 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 2-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1i (900 mg) in a yield of 59.40%.

[0220] MS m / z(ESI):301.0[M+1]

[0221] Step 6

[0222] methyl 2-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[0223] 2-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[0224] At room temperature, m-chloroperbenzoic acid (1.44 g, 8.32 mmol) was added to a solution of methyl 2-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1i (1 g, 3.33 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 hours, then neutralized by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give methyl 2-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1j (950 mg) in a yield of 85.85%.

[0225] MS m / z(ESI):333.1[M+1]

[0226] Step 7

[0227] methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[0228] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[0229] Methyl 2-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1j (800 mg, 2.41 mmol), cyclopropanesulfonamide (437.43 mg, 3.61 mmol), and cesium carbonate (1.57 g, 4.81 mmol) were added to N-methylpyrrolidone (5 mL). The reaction mixture was heated to 90°C for 2 hours and then cooled to room temperature. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1k (700 mg) in a yield of 77.88%.

[0230] MS m / z(ESI):374.2[M+1]

[0231] Step 8

[0232] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[0233] 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[0234] Under ice-water bath, trimethylaluminum (2.0 M solution in toluene) (2 M, 187.45 μL) was added to a solution of 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine 1d (30.11 mg, 139.25 μmol) in toluene (1.95 mL), and the mixture was stirred at room temperature for 1 hour. Subsequently, methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1k (40 mg, 107.12 μmol) was added, and the temperature was raised to 90°C for 5 hours. A small amount of methanol and 1N hydrochloric acid were added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane (30 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide 1 (3.48 mg) in a yield of 4.60%.

[0235] MS m / z(ESI):558.2[M+1]

[0236] 1H NMR(400MHz,Chloroform-d)δ9.52(s,1H),8.88(s,1H),8.62–8.42(m,2H),8. 40–8.23(m,2H),8.17(s,1H),7.25(s,1H),7.22–7.14(m,2H),7.07(d,J=5.1H z,1H),4.48(q,J=7.0Hz,2H),4.00(d,J=16.0Hz,2H),3.66(d,J=16.0Hz,2H), 3.21–3.03(m,1H),1.46(t,J=7.0Hz,3H),1.28(s,2H),1.01(d,J=7.6Hz,2H).

[0237] Example 2

[0238] 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[0239] 3-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[0240] first step

[0241] ethyl 3-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0242] 3-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0243] Lithium bistrimethylsilylamide (1 M, 14.01 mL) was added to a solution of 4-chloro-2-(methylthio)pyrimidine 1e (750 mg, 4.67 mmol) and ethyl bicyclo[3.1.0]hexane-3-carboxylate 2a (900.04 mg, 5.84 mmol, commercially available) in tetrahydrofuran (10 mL) at -30°C. The mixture was then stirred at room temperature for 1 hour. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford ethyl 3-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2b (1.25 g) in a 96.17% yield.

[0244] MS m / z(ESI):278.9[M+1]

[0245] Step 2

[0246] ethyl 3-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0247] 3-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0248] At room temperature, m-chloroperbenzoic acid (1.12 g, 6.47 mmol) was added to a solution of ethyl 3-(2-(methylsulfanyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2b (600 mg, 2.16 mmol) in dichloromethane (10 mL). After stirring at room temperature for 2 hours, the mixture was neutralized by adding saturated sodium bicarbonate solution and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give ethyl 3-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2c (330 mg) in a 49.33% yield. MS m / z (ESI): 311.0 [M+1].

[0249] Step 3

[0250] ethyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0251] 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0252] 3-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester 2c (330 mg, 1.06 mmol) and cyclopropanesulfonamide (193.23 mg, 1.59 mmol) were added to N-methylpyrrolidone (3 mL), the temperature was raised to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water (30 mL) was added, and extraction was performed with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester 2d (250 mg) in a yield of 66.91%.

[0253] MS m / z(ESI):352.0[M+1]

[0254] Step 4

[0255] 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[0256] 3-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[0257] At room temperature, trimethylaluminum (2.0 M solution in toluene) (2 M, 958.54 μL) and 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine 1d (142.13 mg, 657.28 μmol) were added to toluene (2 mL), and the mixture was stirred at room temperature for 1 hour. Ethyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2d (192.49 mg, 547.74 μmol) was added, and the temperature was raised to 90°C and stirred for 2 hours. The mixture was cooled to room temperature, quenched by the addition of a small amount of methanol, and the solvent was directly dried to give a crude product. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 2 (12 mg) in a yield of 3.70%.

[0258] MS m / z(ESI):522.2[M+1]

[0259] 1H NMR(400MHz, DMSO-d6)δ10.26(s,1H),9.02(d,J=2.4Hz,1H),8.84(s,1H),8.56–8.44(m,2H), 8.25(s,1H),8.15(d,J=8.8Hz,1H),7.13(d,J=5.3Hz,1H),4.49–4.45(m,2H),3.25(dt,J=8.2, 3.6Hz,1H),2.87(d,J=13.8Hz,2H),2.43(dd,J=13.8,3.5Hz,2H),1.40(q,J=7.0,6.3Hz,5H),1 .07(dt,J=7.0,3.5Hz,2H),0.92(td,J=8.4,5.9Hz,2H),0.47–0.39(m,1H),0.18–0.07(m,1H).

[0260] Example 3

[0261] 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0262] 3-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0263] first step

[0264] 4-(6-ethoxypyrazin-2-yl)aniline

[0265] 4-(6-Ethoxypyrazin-2-yl)aniline

[0266] 2-Chloro-6-ethoxypyrazine 1b (1.52 g, 9.59 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 3a (2 g, 9.13 mmol, commercially available), 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (667.95 mg, 912.88 μmol), and potassium carbonate (3.79 g, 27.39 mmol) were added sequentially to 1,4-dioxane (20 mL) and water (10 mL). The atmosphere was replaced with argon three times. The mixture was heated to 80°C and stirred for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 4-(6-ethoxypyrazin-2-yl)aniline 3b (1.5 g) in a 76.34% yield.

[0267] MS m / z(ESI):216.0[M+1]

[0268] Step 2

[0269] 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0270] 3-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0271] To a solution of 4-(6-ethoxypyrazin-2-yl)aniline 3b (141.48 mg, 657.28 μmol) in toluene (2 mL) was added trimethylaluminum (2.0 M solution in toluene) (2 M, 958.54 μL) at room temperature. After stirring for 1 hour, ethyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2d (192.49 mg, 547.74 μmol) was added, and the mixture was heated to 90°C and stirred for 18 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was directly dried to obtain a crude product. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 3 (65 mg) in a yield of 17.71%.

[0272] MS m / z(ESI):521.2[M+1]

[0273] 1H NMR (400MHz, DMSO-d6) δ11.31(s,1H),9.67(s,1H),8.76(s,1H),8.52(d,J=5.3Hz,1H),8.18( s,1H),8.12–8.03(m,2H),7.75(d,J=8.7Hz,2H),7.03(d,J=5.3Hz,1H),4.47(q,J=7.0Hz,2H), 3.31–3.21(m,1H),2.86(d,J=13.6Hz,2H),2.49–2.38(m,2H),1.41(dt,J=14.0,5.5Hz,5H),1 .09(dt,J=6.7,3.4Hz,2H),0.96(dt,J=7.8,3.6Hz,2H),0.50–0.38(m,1H),0.20–0.11(m,1H).

[0274] Example 4

[0275] (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0276] (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0277] first step

[0278] tert-butyl 2-cyano-2-(2-(methylthio)pyrimidin-4-yl)acetate

[0279] tert-Butyl 2-cyano-2-(2-(methylthio)pyrimidin-4-yl)acetate

[0280] A solution of tert-butyl 2-cyanoacetate (8.79 g, 62.26 mmol) in dimethyl sulfoxide (50 mL) was added dropwise to a solution of sodium hydride (2.54 g, 63.43 mmol, 60% purity) in dimethyl sulfoxide (50 mL) in an ice bath. Stirring was continued for 20 minutes. The gas was released, and 4-chloro-2-(methylthio)pyrimidine 1e (5 g, 31.13 mmol) was added. The mixture was heated to 70°C and stirred for 18 hours. The reaction was complete, and the resulting solid was filtered and dried to afford tert-butyl 2-cyano-2-(2-(methylthio)pyrimidin-4-yl)acetate 4a (7.6 g) in a 92.02% yield. The crude product was used directly in the next reaction.

[0281] MS m / z(ESI):266.3[M+1]

[0282] Step 2

[0283] 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile

[0284] 2-(2-(Methylthio)pyrimidin-4-yl)acetonitrile

[0285] At room temperature, trifluoroacetic acid (32.66 g, 286.43 mmol, 21.93 mL) was added to a solution of tert-butyl 2-cyano-2-(2-(methylthio)pyrimidin-4-yl)acetate 4a (7.6 g, 28.64 mmol) in dichloromethane (100 mL). The mixture was stirred for 4 hours, and the solvent was evaporated. Saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile 4b (3.2 g) in a yield of 67.62%.

[0286] MS m / z(ESI):166.0[M+1]

[0287] Step 3

[0288] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile

[0289] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile

[0290] To a solution of 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile 4b (1 g, 6.05 mmol) in anhydrous ethylene glycol dimethyl ether (8 mL) was added (3aR,6aS)-tetrahydrofuro[3,4-d][1,3,2]dioxythiophene 2,2-dioxide 4c (1.21 g, 7.26 mmol, prepared according to patent publication "WO2005005398") under ice-water bath. The mixture was stirred at room temperature for 1 hour, then heated to 60°C and stirred for 18 hours. After the reaction was complete, water was added to quench the reaction (20 mL), and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile 4d (1.08 g) in a yield of 76.49%.

[0291] MS m / z(ESI):234.1[M+1]

[0292] Step 4

[0293] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0294] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0295] To a solution of (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile 4d (1 g, 4.29 mmol) in dimethyl sulfoxide (10 mL) was added hydrogen peroxide (5 mL, 35%) under ice-cooling. The mixture was stirred at room temperature for 16 hours and poured into ice water. After stirring for 30 minutes, a solid precipitated. The solid was collected by filtration and the filter cake dried to afford (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 4e (1 g) in a 92.83% yield. The crude product was used directly in the next reaction. MS m / z (ESI): 252.0 [M+1]

[0296] Step 5

[0297] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[0298] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[0299] To a mixed solution of (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 4e (1.1 g, 4.38 mmol) in acetic acid (4 mL) and acetic anhydride (8 mL) was added sodium nitrite (3.02 g, 43.77 mmol) under ice-water bath. The mixture was stirred at room temperature for 16 hours. A small amount of water was added to cause solid to precipitate. The solid was filtered under reduced pressure and the filter cake was dried to give (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 4f (600 mg) in a yield of 54.33%.

[0300] Step 6 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0301] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0302] Under ice-water bath, (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 4f (180 mg, 713.47 μmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (599.31 mg, 2.14 mmol), and N-methylimidazole (351.45 mg, 4.28 mmol) were added to anhydrous acetonitrile (5 mL) and stirred at room temperature for 0.5 h. 4-(6-ethoxypyrazin-2-yl)aniline 3b (184 mg, 856.47 μmol) was then added, and the temperature was raised to 60°C and stirred for 18 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H₂O, mobile phase B: CH₃CN) to obtain 4 g (120 mg) of (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide in a 37.42% yield. MS m / z (ESI): 449.8 [M+1].

[0303] Step 7 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0304] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0305] At room temperature, 4 g (120 mg, 266.95 μmol) of (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide and m-chloroperbenzoic acid (108.39 mg, 533.90 μmol, 85% purity) were added to dichloromethane (3 mL) and stirred at room temperature for 18 hours. , saturated sodium bicarbonate solution was added for neutralization, and the mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1R, 5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 4h (60 mg) with a yield of 48.28%. The crude product was directly used for the next reaction.

[0306] MS m / z(ESI):435.1[M+1]

[0307] Step 8

[0308] (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0309] (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0310] Cyclopropanesulfonamide (60.39 mg, 498.42 μmol), (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 4h (120 mg, 249.21 μmol) and cesium carbonate (162.39 mg, 498.42 μmol) were added to N-methylpyrrolidone (2 mL), heated to 90 ° C and stirred for 1 hour, cooled to room temperature, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 4 (12.37 mg), yield 9.50%.

[0311] MS m / z(ESI):462.1[M+1]

[0312] 1H NMR(400MHz,Chloroform-d)δ8.54(s,1H),8.40(s,1H),8.19–7.96(m,3H),7.73(s,2H),7.00(s,1H),4.54(q,J=7.0 Hz,2H),4.35(d,J=9.3Hz,2H),3.97(d,J=9.2Hz,2H),3.13(s,1H),2.59(s,2H),1.47(t,J=7.0Hz,3H),1.33(s,4H).

[0313] Example 5

[0314] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-1-carboxamide

[0315] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-1-carboxamide

[0316] first step

[0317] methyl 2,3-dihydro-1H-indene-1-carboxylate

[0318] 2,3-Dihydro-1H-indene-1-carboxylic acid methyl ester

[0319] To a solution of 2,3-dihydro-1H-indene-1-carboxylic acid 5a (600 mg, 3.70 mmol, commercially available) in dichloromethane (9.73 mL) was added thionyl chloride (880.26 mg, 7.40 mmol, 536.74 μL). The mixture was stirred at room temperature for 2 hours. The solvent was partially removed, and anhydrous methanol (9.73 mL) was added. The mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure, and neutralized with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl 2,3-dihydro-1H-indene-1-carboxylate 5b (560 mg) in an 85.90% yield. The crude product was used directly in the next reaction.

[0320] Step 2

[0321] methyl 1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate

[0322] 1-(2-(Methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester

[0323] To a solution of 4-chloro-2-(methylthio)pyrimidine 1e (400 mg, 2.49 mmol) and methyl 2,3-dihydro-1H-indene-1-carboxylate 5b (438.82 mg, 2.49 mmol) in tetrahydrofuran (23.07 mL) was added lithium bis(trimethylsilylamide) (1 M, 7.47 mL) at -30°C. The mixture was slowly warmed to room temperature and stirred for 1 hour. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: System A) to afford methyl 1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate 5c (530 mg) in a 70.85% yield.

[0324] MS m / z(ESI):301.2[M+1]

[0325] Step 3

[0326] methyl 1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate

[0327] 1-(2-(Methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester

[0328] Methyl 1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate 5c (650 mg, 2.16 mmol) and m-chloroperbenzoic acid (878.67 mg, 4.33 mmol, 85% purity) were added to dichloromethane (7 mL) at room temperature and stirred for 18 hours. After the reaction was complete, saturated sodium bicarbonate was added for neutralization. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: System A) to afford methyl 1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate 5d (460 mg) in a 63.96% yield.

[0329] MS m / z(ESI):333.1[M+1]

[0330] Step 4

[0331] methyl 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate

[0332] 1-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester

[0333] Methyl 1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate 5d (460 mg, 1.38 mmol) and cyclopropanesulfonamide (335.36 mg, 2.77 mmol) were dissolved in N-methylpyrrolidone (3 mL), and cesium carbonate (901.86 mg, 2.77 mmol) was added. The mixture was heated to 90°C and stirred for 18 hours. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by silica gel column chromatography (eluent: System B) to give 1-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester 5e (350 mg) in a yield of 67.72%.

[0334] MS m / z(ESI):374.1[M+1]

[0335] Step 5

[0336] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-1-carboxamide

[0337] 1-(2-(Cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-1-carboxamide

[0338] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (121.05 mg, 562.36 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 702.95 μL) were dissolved in toluene (500.00 μL) and stirred at room temperature for 1 hour. 1-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester 5e (175 mg, 468.63 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. The starting materials were completely reacted and quenched by adding a small amount of methanol. The solvent was directly evaporated to give a crude product. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, and the insoluble solids were removed by filtration. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-1-carboxamide 5 (42 mg) in a yield of 12.19%.

[0339] MS m / z(ESI):556.8[M+1]

[0340] 1H NMR(400MHz,Chloroform-d)δ8.80(s,1H),8.53(d,J=5.4Hz,2H),8.06(s,1H),7.97(d,J=8.4Hz,2H),7.82(s,1H),7.76(d,J=8.2Hz,2H),7 .34(d,J=2.9Hz,3H),7.01(d,J=5.3Hz,1H),4.55(d,J=7.1Hz,2H),3.10(dt,J=17.3,5.8Hz,3H),2.98–2.86(m,2H),1.47(t,J=7.0Hz,3H).

[0341] Example 6

[0342] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0343] 5-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0344] first step

[0345] ethyl 1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[0346] 1-(Tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid ethyl ester

[0347] Ethyl 4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6a (1 g, 5.15 mmol, commercially available), 3,4-dihydro-2H-pyran (1.30 g, 15.45 mmol), and p-toluenesulfonic acid (98.85 mg, 514.85 μmol) were added to tetrahydrofuran (10 mL) and stirred at 80°C for 18 hours. After completion of the reaction, saturated sodium bicarbonate solution was added for neutralization, followed by extraction with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford ethyl 1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6b (1.2 g) in an 83.74% yield.

[0348] MS m / z(ESI):279.1[M+1]

[0349] Step 2

[0350] methyl 5-(2-(methylthio)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[0351] 5-(2-(Methylthio)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester

[0352] To a solution of 4-chloro-2-(methylthio)pyrimidine 1e (0.6 g, 3.74 mmol) and ethyl 1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6b (1.25 g, 4.48 mmol) in tetrahydrofuran (7 mL) was added lithium bistrimethylsilylamide (1 M, 11.21 mL) at -30°C, and the mixture was heated to room temperature and stirred for 1 hour. After the reaction of the starting materials was complete, quenching was performed by adding saturated aqueous ammonium chloride solution. The mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified by silica gel column chromatography (eluent: System A) to afford methyl 5-(2-(methylthio)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6c (831 mg) in a 55.27% yield. MS m / z (ESI): 403.2 [M+1].

[0353] Step 3

[0354] methyl 5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[0355] 5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester

[0356] Methyl 5-(2-(methylthio)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6c (980 mg, 2.43 mmol) and m-chloroperbenzoic acid (988.61 mg, 4.87 mmol, 85% purity) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, saturated sodium bicarbonate was added for neutralization, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (eluent: System A) to give 5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester 6d (500 mg) in a yield of 47.26%.

[0357] MS m / z(ESI):435.1[M+1]

[0358] Step 4

[0359] methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[0360] 5-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester

[0361] Methyl 5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6d (963.18 mg, 2.30 mmol) and cyclopropanesulfonamide (557.36 mg, 4.67 mmol) were added to N-methylpyrrolidone (3 mL), followed by cesium carbonate (1.50 g, 4.60 mmol), and the mixture was heated to 90 °C and stirred for 2 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by silica gel column chromatography (eluent: System A) to give 5-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester 6e (800 mg) in a yield of 75.32%.

[0362] MS m / z(ESI):462.1[M+1]

[0363] Step 5

[0364] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0365] 5-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0366] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (195.88 mg, 910.01 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 1.14 mL) were dissolved in toluene (65.0 μL). After stirring at room temperature for 1 hour, methyl 5-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6e (350 mg, 758.34 μmol) was added, and the temperature was raised to 90°C and stirred for 18 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 6f (150 mg) in a yield of 30.68%.

[0367] MS m / z(ESI):645.1[M+1]

[0368] Step 6

[0369] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0370] 5-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0371] At room temperature, 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 6f (100 mg, 155.10 μmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (1 mL) and stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 6 (27 mg) in a yield of 24.51%.

[0372] MS m / z(ESI):560.8[M+1]

[0373] 1H NMR (400MHz, DMSO-d6) δ9.53 (s, 1H), 8.74 (s, 1H), 8.58 (d, J = 5.3Hz, 1H), 8.17 ( s,1H),8.05(d,J=8.4Hz,2H),7.73(d,J=8.4Hz,2H),7.54(s,1H),7.15(d,J=5.3 Hz,1H),4.46(q,J=7.1Hz,3H),3.35–3.12(m,3H),2.71(s,1H),2.57(d,J=18.1 Hz,3H),1.39(t,J=7.1Hz,3H),1.05(dq,J=10.4,5.0Hz,2H),0.94–0.74(m,2H).

[0374] Example 7

[0375] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0376] 5-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0377] first step

[0378] ethyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[0379] 1-Methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid ethyl ester

[0380] Ethyl 4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6a (1.10 g, 7.72 mmol, 480.77 μL), iodomethane (1.1 g, 7.72 mmol), and cesium carbonate (3.35 g, 10.30 mmol) were added to N,N-dimethylformamide (5 mL) and stirred at room temperature for 18 hours. After the reaction was complete, water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was separated by silica gel column chromatography (eluent: System A) to afford ethyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7a (1 g) in a 93.26% yield.

[0381] MS m / z(ESI):209.1[M+1]

[0382] Step 2

[0383] methyl 1-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[0384] 1-Methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester

[0385] To a solution of 4-chloro-2-(methylthio)pyrimidine 1e (900 mg, 5.60 mmol) and ethyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7a (1.17 g, 5.60 mmol) in tetrahydrofuran (10 mL) was added lithium bistrimethylsilylamide (1 M, 16.81 mL) at -30°C, and the mixture was slowly warmed to room temperature and stirred for 1 hour. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by silica gel column chromatography (eluent: System A) to give 1-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester 7b (800 mg) in a yield of 42.95%.

[0386] MS m / z(ESI):333.9[M+1]

[0387] Step 3

[0388] methyl 1-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[0389] 1-Methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester

[0390] Methyl 1-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7b (800 mg, 2.41 mmol) and m-chloroperbenzoic acid (977.19 mg, 4.81 mmol, 85% purity) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, saturated sodium bicarbonate solution was added for neutralization, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried to afford methyl 1-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7c (400 mg) in a 45.61% yield. The crude product was used directly in the next reaction.

[0391] MS m / z(ESI):365.1[M+1]

[0392] Step 4

[0393] methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[0394] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid methyl ester

[0395] Cyclopropanesulfonamide (532.4 mg, 4.40 mmol) and methyl 1-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7c (764.88 mg, 2.20 mmol) were dissolved in N-methylpyrrolidone (4 mL), and cesium carbonate (1.43 g, 4.39 mmol) was added. The reaction mixture was heated to 90 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7d (750 mg) in an 84.26% yield. MS m / z (ESI): 374.1 [M+1].

[0396] Step 5

[0397] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0398] 5-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[0399] At room temperature, 4-(6-ethoxypyrazin-2-yl)aniline 3b (195.88 mg, 910.01 μmol) was dissolved in toluene (3 mL), followed by the addition of trimethylaluminum (2.0 M solution in toluene) (2 M, 1.14 mL). After stirring at room temperature for 1 hour, methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7d (296.85 mg, 758.34 μmol) was added, and the mixture was heated to 90°C and stirred for 18 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was directly dried to give a crude product. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 7 (98 mg) in a yield of 16.49%.

[0400] MS m / z(ESI):574.8[M+1]

[0401] Example 8

[0402] (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0403] (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0404] first step

[0405] (3aR,6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxathiole 2,2-dioxide

[0406] (3aR,6aS)-Tetrahydro-4H-cyclopenta[d][1,3,2]dioxythiophene 2,2-dioxide

[0407] To a solution of (1R,2S)-cyclopentane-1,2-diol 8a (1.96 g, 19.21 mmol, commercially available) in ethyl acetate (20 mL) was added triethylamine (9.72 g, 96.06 mmol, 13.50 mL). The reaction mixture was cooled to -50°C and a solution of sulfonyl chloride (3.37 g, 24.97 mmol, 2.02 mL) in ethyl acetate (2 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The solid was removed by filtration, and the filtrate was dried. The crude product was purified by silica gel chromatography (eluent: System A) to afford (3aR,6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxythiophene 2,2-dioxide 8b (1.4 g) in a 44.39% yield.

[0408] Step 2

[0409] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[0410] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[0411] Under ice-water bath, sodium hydride (387.37 mg, 9.68 mmol, 1.61 μL, 60% purity) was added to a solution of 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile 4b (800 mg, 4.84 mmol) in anhydrous ethylene glycol dimethyl ether (32 mL). After stirring for 10 minutes, (3aR, 6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxythiophene 2,2-dioxide 8b (953.98 mg, 5.8 The mixture was stirred at room temperature for 1 hour, then heated to 60°C and stirred for 18 hours. Water (10 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by silica gel column chromatography (eluent: System A) to give (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile 8c (790 mg) in a yield of 70.53%.

[0412] MS m / z(ESI):231.9[M+1]

[0413] Step 3

[0414] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0415] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0416] Under ice-water bath, (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile 8c (980 mg, 4.24 mmol) was dissolved in dimethyl sulfoxide (10 mL). Hydrogen peroxide (5 mL, 35%) was then added and stirred at room temperature for 18 hours. The mixture was then heated to 50°C and stirred for another 2 hours, resulting in complete reaction. The reaction mixture was poured into ice water (20 mL). After stirring, a solid precipitated. The solid was filtered under reduced pressure and the filter cake dried to afford (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 8d (700 mg) in a 66.27% yield. The crude product was used directly in the next reaction.

[0417] MS m / z(ESI):249.8[M+1]

[0418] Step 4

[0419] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[0420] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[0421] To a solution of (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 8d (700 mg, 2.81 mmol) in acetic acid (3 mL) and acetic anhydride (6 mL) was added sodium nitrite (1.94 g, 28.08 mmol) under ice-water bath, and the mixture was stirred at room temperature for 18 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried to afford (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 8e (650 mg) in a yield of 92.49%. The crude product was used directly in the next reaction.

[0422] MS m / z(ESI):251.2[M+1]

[0423] Step 5 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0424] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0425] At room temperature, (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 8e (250 mg, 998.74 μmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (838.94 mg, 3.00 mmol) and N-methylimidazole (327.99 mg, 3.99 mmol) were added to a solution of N-methylpyrrolidone (3 mL). After stirring for half an hour, 4-(6-ethoxypyrazin-2-yl)aniline 3b (257 mg, 1.2 mmol) was added. The reaction mixture was heated to 60°C and stirred for 18 hours, and then heated to 120°C and stirred for 3 hours. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 8f (50 mg) in a yield of 11.19%.

[0426] MS m / z(ESI):448.2[M+1]

[0427] Step 6 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0428] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0429] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 8f (50 mg, 111.72 μmol) and m-chloroperbenzoic acid (45.36 mg, 223.44 μmol, 85% purity) were added to dichloromethane (2 mL) and stirred at room temperature for 18 hours. After the reaction was complete, saturated sodium bicarbonate was added for neutralization, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness to obtain 8 g (51 mg) of (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide in a 98.48% yield. The crude product was used directly in the next reaction.

[0430] MS m / z(ESI):464.9[M+1]

[0431] Step 7 (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0432] (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0433] Cyclopropanesulfonamide (26.66 mg, 220.04 μmol), (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 8 g (51 mg, 110.02 μmol) and cesium carbonate (71.69 mg, 220.04 μmol) were added to N-methylpyrrolidone (2 mL), and the reaction was heated to 90 ° C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide 8 (30 mg) in a yield of 40.22%.

[0434] MS m / z(ESI):520.9[M+1]

[0435] 1H NMR (400MHz, DMSO-d6) δ11.16(s,1H),10.49(s,1H),8.76(s,1H),8.41(d,J=5.5Hz,1H),8.19(s,1H),8 .10(d,J=8.5Hz,2H),7.84(d,J=8.4Hz,2H),6.87(d,J=5.4Hz,1H),4.48(q,J=7.0Hz,2H),3.20(dt,J=8. 2,3.6Hz,1H),2.25(d,J=2.9Hz,2H),2.13(dd,J=13.3,8.5Hz,2H),2.06–1.95(m,2H),1.74–1.58(m,1H ), 1.40 (t, J = 7.0Hz, 3H), 1.24 (d, J = 9.0Hz, 2H), 1.04 (q, J = 4.2Hz, 2H), 0.94 (dq, J = 7.6, 4.9, 4.5Hz, 2H).

[0436] Example 9

[0437] 6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0438] 6-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0439] first step

[0440] tert-butyl(3S,4R)-3,4-dihydroxypyrrolidine-1-carboxylate

[0441] tert-Butyl (3S,4R)-3,4-dihydroxypyrrolidine-1-carboxylate

[0442] At room temperature, (3S,4R)-pyrrolidine-3,4-diol 9a (3 g, 21.49 mmol, commercially available), di-tert-butyl dicarbonate (7.04 g, 32.24 mmol), and sodium bicarbonate (18.06 g, 214.93 mmol) were dissolved in dioxane (30 mL) and water (30 mL). The mixture was stirred at room temperature for 18 hours. The insoluble solid was removed by filtration, and the filtrate was directly dried. The crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (3S,4R)-3,4-dihydroxypyrrolidine-1-carboxylate 9b (3.9 g) in a yield of 89.28%.

[0443] MS m / z(ESI):147.1[M+1-56]

[0444] Step 2

[0445] tert-butyl(3aR,6aS)-tetrahydro-5H-[1,3,2]dioxathiolo[4,5-c]pyrrole-5-carboxylate 2,2-dioxide

[0446] tert-Butyl (3aR,6aS)-tetrahydro-5H-[1,3,2]dioxythieno[4,5-c]pyrrole-5-carboxylate 2,2-dioxide

[0447] To a solution of tert-butyl (3S,4R)-3,4-dihydroxypyrrolidine-1-carboxylate 9b (3.90 g, 19.21 mmol) and triethylamine (9.72 g, 96.06 mmol, 13.50 mL) in ethyl acetate (20 mL) was added dropwise a solution of sulfonyl chloride (3.37 g, 24.97 mmol, 2.02 mL) in ethyl acetate (5 mL) at -50°C. The mixture was slowly warmed to room temperature and allowed to react for 18 hours. After the reaction was complete, the solid was removed by filtration, the filtrate was dried, and the crude product was purified by silica gel chromatography (eluent: System A) to afford tert-butyl (3aR,6aS)-tetrahydro-5H-[1,3,2]dioxythieno[4,5-c]pyrrole-5-carboxylate 2,2-dioxide 9c (3 g) in a 58.86% yield.

[0448] Step 3

[0449] tert-butyl(1R,5S)-6-cyano-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0450] tert-Butyl (1R,5S)-6-cyano-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0451] To a solution of 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile 4b (650 mg, 3.93 mmol) in anhydrous ethylene glycol dimethyl ether (28 mL) was added sodium hydride (314.74 mg, 7.87 mmol, 1.61 μL, 60% purity) under ice-water bath. After stirring for 10 minutes, tert-butyl (3aR,6aS)-tetrahydro-5H-[1,3,2]dioxythieno[4,5-c]pyrrole-5-carboxylate 2,2-dioxide 9c (1.57 g, 5.90 mmol) was added. The mixture was stirred at room temperature for 1 hour and then heated to 60°C and stirred for 18 hours. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by silica gel column chromatography (eluent: System A) to give (1R,5S)-6-cyano-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 9d (550 mg) in a yield of 29.44%.

[0452] MS m / z(ESI):333.1[M+1]

[0453] Step 4

[0454] tert-butyl

[0455] (1R,5S)-6-carbamoyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0456] tert-Butyl (1R,5S)-6-carbamoyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0457] To a solution of tert-butyl (1R,5S)-6-cyano-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9d (600 mg, 1.80 mmol) in dimethyl sulfoxide (3 mL) was added sodium hydroxide (144.40 mg, 3.61 mmol) under an ice-water bath. After stirring for 10 minutes, hydrogen peroxide (1.5 mL, 35%) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was quenched by water (20 mL), filtered under reduced pressure, and the filter cake was dried. The crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (1R,5S)-6-carbamoyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9e (410 mg) in a yield of 64.82%.

[0458] MS m / z(ESI):351.0[M+1]

[0459] Step 5

[0460] (1R,5S)-3-(tert-butoxycarbonyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0461] (1R,5S)-3-(tert-Butoxycarbonyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0462] To a solution of tert-butyl (1R,5S)-6-carbamoyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9e (260 mg, 741.94 μmol), acetic acid (1.50 mL) and acetic anhydride (3 mL) in dimethyl sulfoxide (3 mL) was added sodium nitrite (511.94 mg, 7.42 mmol) under ice-water bath, and the mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was poured into water, neutralized with saturated sodium bicarbonate solution, acidified with citric acid, and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: System A) to give (1R,5S)-3-(tert-butoxycarbonyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 9f (150 mg) in a yield of 57.53%.

[0463] Step 6

[0464] tert-butyl

[0465] (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0466] tert-Butyl (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0467] Under ice-water bath, (1R,5S)-3-(tert-butoxycarbonyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 9f (170 mg, 483.75 μmol) was dissolved in N-methylpyrrolidone (2 mL), followed by the addition of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (406.35 mg, 1.45 mmol) and N-methylimidazole (238.30 mg, 2.90 mmol). The mixture was stirred at room temperature for half an hour, and 4-(6-ethoxypyrazin-2-yl)aniline 3b (114 mg, 532.75 μmol) was added. The temperature was raised to 100°C and stirred for 18 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 9 g (200 mg) of tert-butyl (1R, 5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate with a yield of 75.35%.

[0468] MS m / z(ESI):549.1[M+1]

[0469] Step 7

[0470] tert-butyl

[0471] (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0472] tert-Butyl (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0473] At room temperature, 9 g (200 mg, 364.53 μmol) of tert-butyl (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and m-chloroperbenzoic acid (162.82 mg, 801.96 μmol, 85% purity) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate was added for neutralization, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to afford tert-butyl (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9h (50 mg) in a 24.29% yield. The crude product was directly used in the next reaction.

[0474] MS m / z(ESI):565.1 / 581.1[M+1]

[0475] Step 8

[0476] tert-butyl

[0477] (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0478] tert-Butyl (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0479] Tert-butyl (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9h (200 mg, 354.20 μmol), cyclopropanesulfonamide (51.50 mg, 425.04 μmol), and cesium carbonate (230.81 mg, 708.40 μmol) were dissolved in N-methylpyrrolidone (1 mL), heated to 90°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to afford tert-butyl (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9i (30 mg) in a 13.62% yield. MS m / z (ESI): 622.1 [M+1].

[0480] Step 9

[0481] 6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0482] 6-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0483] Tert-butyl (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9i (20 mg, 32.17 μmol) and trifluoroacetic acid (0.5 mL) were dissolved in dichloromethane (1.5 mL) and stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 9 (10 mg) in a yield of 44.02%.

[0484] MS m / z(ESI):522.1[M+1]

[0485] 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.71(s,1H),8.79(s,1H),8.52(d,J=5.4Hz,2H),8.25–8.06(m,3H),7.86(d,J=8.4Hz,2H),6.98(d,J=5.3Hz,1 H),4.48(q,J=7.0Hz,3H),3.77(s,2H),3.64–3.56(m,2H),3.16(d,J=4.8H z, 1H), 2.76 (d, J = 3.5Hz, 2H), 1.40 (t, J = 7.0Hz, 3H), 1.07 (q, J = 4.1Hz, 2H).

[0486] Example 10

[0487] 6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0488] 6-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0489] At room temperature, 6-(2-(cyclopropanesulfonylamino)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 9 (7 mg, 13.42 μmol) and sodium hydroxide (536.82 μg, 13.42 μmol) were added to tetrahydrofuran (1 mL) and stirred for 1 hour. Subsequently, paraformaldehyde (523.92 μg, 17.45 μmol) and formic acid (1.54 mg, 33.55 μmol) were added, and the mixture was heated to 70 ° C and stirred for 5 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The crude product was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H₂O, mobile phase B: CH₃CN) to afford 6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 10 (4.02 mg) in a yield of 44.13%. MS m / z (ESI): 536.1 [M+1].

[0490] Example 11

[0491] 3-acetyl-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0492] 3-Acetyl-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0493] first step

[0494] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile

[0495] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile

[0496] To a solution of tert-butyl (1R,5S)-6-cyano-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9d (2 g, 3.01 mmol) in dichloromethane (20 mL) was added a solution of hydrogen chloride in dioxane (15 mL, 4 M) at room temperature and stirred at room temperature for 5 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the mixture was neutralized by addition of saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried to dryness. The crude product was purified by silica gel column chromatography (eluent: System B) to afford (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile 11a (500 mg) in a yield of 71.55%.

[0497] MS m / z(ESI):232.9[M+1]

[0498] Step 2

[0499] (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile

[0500] (1R,5S)-3-Acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile

[0501] To a solution of (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile 11a (350 mg, 1.51 mmol) and triethylamine (381.14 mg, 3.77 mmol, 529.37 μL) in dichloromethane (3 mL) was added acetyl chloride (141.93 mg, 1.81 mmol, 128.56 μL) under ice-water bath, and the mixture was stirred at room temperature for 18 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile 11b (400 mg) in a yield of 96.77%.

[0502] MS m / z(ESI):274.3[M+1]

[0503] Step 3

[0504] (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0505] (1R,5S)-3-Acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0506] (1R,5S)-3-Acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile 11b (300 mg, 1.09 mmol) was dissolved in dimethyl sulfoxide (3 mL). Sodium hydroxide (87.48 mg, 2.19 mmol) was added under ice-water bath. After stirring for 10 minutes, hydrogen peroxide (1.5 mL) was added. The mixture was stirred at room temperature for 3 hours and quenched with water (20 mL). The mixture was filtered under reduced pressure and the filter cake was dried to give (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 11c (300 mg) in a yield of 93.84%.

[0507] MS m / z(ESI):293.0[M+1]

[0508] Step 4

[0509] (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0510] (1R,5S)-3-Acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0511] To a solution of (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 11c (400 mg, 1.37 mmol), acetic acid (1.50 mL) and acetic anhydride (3 mL) in dimethyl sulfoxide (3 mL) was added sodium nitrite (944.05 mg, 13.68 mmol) under ice-water bath, and the mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was poured into water (5 mL), neutralized with saturated sodium bicarbonate solution, and then acidified with citric acid. The product was extracted with ethyl acetate. Most of the product was in the aqueous phase, which was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 11d (180 mg) in a yield of 44.85%.

[0512] MS m / z(ESI):394.0[M+1]

[0513] Step 5

[0514] (1R,5S)-3-acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0515] (1R,5S)-3-Acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0516] To a solution of (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 11d (180 mg, 613.62 μmol) in N-methylpyrrolidone (2 mL) was added N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (343.63 mg, 1.23 mmol) and N-methylimidazole (201.51 mg, 2.45 mmol) under ice-water bath. The mixture was stirred at room temperature for half an hour, and then 4-(6-ethoxypyrazin-2-yl)aniline 3b (145 mg, 6 The reaction mixture was heated to 100°C and stirred for 18 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by silica gel column chromatography (eluent: System A) to give (1R,5S)-3-acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 11e (300 mg) in a yield of 99.66%.

[0517] MS m / z(ESI):549.1[M+1]

[0518] Step 6

[0519] (1R,5S)-3-acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0520] (1R,5S)-3-Acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0521] (1R,5S)-3-Acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 11e (300 mg, 611.53 μmol) and m-chloroperbenzoic acid (273.14 mg, 1.35 mmol, 85% purity) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added for neutralization, followed by extraction with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to afford (1R,5S)-3-acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 11f (300 mg) in a 96.84% yield. The crude product was used directly in the next reaction.

[0522] MS m / z(ESI):506.8[M+1]

[0523] Step 7

[0524] 3-acetyl-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0525] 3-Acetyl-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0526] (1R,5S)-3-acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 11f (300 mg, 592.21 μmol), cyclopropanesulfonamide (86.10 mg, 710.65 μmol), and cesium carbonate (385.91 mg, 1.18 mmol) were added to N-methylpyrrolidone (1 mL), heated to 90°C and stirred for 1 hour, cooled to room temperature, added with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 3-acetyl-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 11 (55 mg) with a yield of 13.29%.

[0527] MS m / z(ESI):[M+1]563.8

[0528] 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.54(s,1H),8.77(s,1H),8.47(d,J=5.4Hz,1H),8.19 (s,1H),8.13–8.02(m,2H),7.71(d,J=8.7Hz,2H),6.92(d,J=5.5Hz,1H),4.48(q,J=7.0Hz,2H ),4.11(d,J=12.3Hz,1H),3.96(d,J=11.2Hz,1H),3.76(d,J=10.3Hz,1H),3.41(s,3H),3.18( s,1H),2.06–1.94(m,1H),1.70(s,3H),1.40(t,J=7.0Hz,3H),1.24(s,2H),1.09–0.92(m,4H).

[0529] Example 12

[0530] 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0531] 3-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0532] first step

[0533] 4-(6-ethoxypyrazin-2-yl)-2-fluoroaniline

[0534] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline

[0535] 2-Chloro-6-ethoxypyrazine 1b (500 mg, 3.15 mmol), (4-amino-3-fluorophenyl)boronic acid 12a (586.19 mg, 3.78 mmol, commercially available), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (230.70 mg, 315.29 μmol), and potassium carbonate (1.31 g, 9.46 mmol) were added to 1,4-dioxane (10 mL) and water (2.5 mL). The atmosphere was replaced with argon three times, and the temperature was raised to 95°C and stirred for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: System A) to afford 4-(6-ethoxypyrazin-2-yl)-2-fluoroaniline 12b (590 mg) in an 80.23% yield.

[0536] MS m / z(ESI):234.1[M+1]

[0537] Step 2

[0538] 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0539] 3-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0540] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (100 mg, 428.74 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 643.11 μL) were added to toluene (1 mL), and the mixture was stirred at room temperature for 1 hour. 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester 2d (150.67 mg, 428.74 μmol) was then added, and the temperature was raised to 90°C and stirred for 5 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was directly dried to obtain a crude product. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide 12 (22 mg) in a yield of 7.71%.

[0541] MS m / z(ESI):538.8[M+1]

[0542] 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),9.32(s,1H),8.59(s,1H),8.30(d,J=5.4Hz,1H ),8.01(s,1H),7.73(t,J=11.5Hz,2H),7.35(d,J=8.2Hz,1H),6.82(d,J=5.4Hz,1H),4 .24(q,J=7.1Hz,2H),3.04(s,1H),2.62(d,J=13.6Hz,2H),2.22(d,J=13.0Hz,2H),1. 16(q,J=7.4Hz,5H),0.94–0.74(m,4H),0.19(d,J=7.0Hz,1H),-0.00(d,J=5.7Hz,1H).

[0543] Example 13

[0544] 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0545] 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0546] first step

[0547] ethyl 3-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0548] 3-(6-(Methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0549] To a solution of 4-chloro-6-(methylthio)pyrimidine 13a (300 mg, 1.87 mmol, commercially available) and ethyl bicyclo[3.1.0]hexane-3-carboxylate 2a (302.41 mg, 1.96 mmol) in tetrahydrofuran (3.00 mL) was added lithium bistrimethylsilylamide (1 M, 5.60 mL) at -30°C and the mixture was slowly warmed to room temperature for 1 hour. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified by silica gel column chromatography (eluent: System A) to afford ethyl 3-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13b (375 mg) in a 72.13% yield.

[0550] MS m / z(ESI):278.8[M+1]

[0551] Step 2

[0552] ethyl 3-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0553] 3-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0554] Ethyl 3-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13b (500 mg, 1.80 mmol) and m-chloroperbenzoic acid (802.27 mg, 3.95 mmol, 85% purity) were dissolved in dichloromethane (5 mL) at room temperature and stirred for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added for neutralization, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness to afford ethyl 3-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13c (50 mg) in a 9.46% yield. The crude product was used directly in the next reaction.

[0555] MS m / z(ESI):310.8[M+1]

[0556] Step 3

[0557] ethyl 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0558] 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0559] Ethyl 3-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13c (550 mg, 1.77 mmol) and cyclopropanesulfonamide (279.11 mg, 2.30 mmol) were dissolved in N-methylpyrrolidone (3 mL), heated to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give ethyl 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13d (620 mg) in a yield of 99.56%.

[0560] MS m / z(ESI):352.0[M+1]

[0561] Step 4

[0562] 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0563] 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0564] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (126.72 mg, 588.71 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 883.06 μL) were added to toluene (1 mL) at room temperature and stirred for 1 hour. Subsequently, ethyl 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13d (172.40 mg, 490.59 μmol) was added, and the temperature was raised to 90°C and stirred for 2 hours. The mixture was cooled to room temperature, quenched by the addition of a small amount of methanol, and the solvent was directly dried to give a crude product. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 13 (60 mg) in a yield of 18.12%.

[0565] MS m / z(ESI):[M+1]520.8

[0566] 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),9.67(s,1H),8.65(d,J=6.7Hz,2H),8.0 7(s,1H),7.96(d,J=8.4Hz,2H),7.65(d,J=8.3Hz,2H),6.82(s,1H),4.36(q,J =7.1Hz,2H),2.93(s,1H),2.74(d,J=13.6Hz,2H),2.30(d,J=13.4Hz,2H),1.4 2–1.22(m,5H),1.00–0.81(m,4H),0.31(d,J=7.1Hz,1H),0.06–-0.05(m,1H).

[0567] Example 14

[0568] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

[0569] 5-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

[0570] first step

[0571] ethyl 4-(2-methylhydrazineylidene)cyclohexane-1-carboxylate

[0572] Ethyl 4-(2-methylhydrazinylidene)cyclohexane-1-carboxylate

[0573] Ethyl 4-oxocyclohexane-1-carboxylate 14a (2 g, 11.75 mmol, commercially available), methylhydrazine 14b (2.03 g, 14.10 mmol, commercially available), and N,N-diisopropylethylamine (3.80 g, 29.38 mmol, 5.27 mL) were dissolved in ethanol (20 mL). The reaction mixture was heated to 90°C and stirred for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, yielding ethyl 4-(2-methylhydrazinylidene)cyclohexane-1-carboxylate 14c (2 g), which was used directly in the next reaction.

[0574] Step 2

[0575] ethyl 2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

[0576] 2-Methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid ethyl ester

[0577] Ethyl 4-(2-methylhydrazinylidene)cyclohexane-1-carboxylate 14c (2 g, 10.09 mmol) and (chloromethylene)dimethylammonium chloride 14d (1.29 g, 10.09 mmol, commercially available) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 90°C for 18 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified by silica gel column chromatography (eluent: System A) to afford ethyl 2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate 14e (500 mg) in a 23.80% yield.

[0578] MS m / z(ESI):208.9[M+1]

[0579] Step 3

[0580] methyl 2-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

[0581] 2-Methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid methyl ester

[0582] To a solution of 4-chloro-2-(methylthio)pyrimidine 1e (385.64 mg, 2.40 mmol) and ethyl 2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate 14e (500 mg, 1.20 mmol) in tetrahydrofuran (36.42 mL) was added lithium bistrimethylsilylamide (1 M, 3.60 mL) at -30°C, and the mixture was slowly warmed to room temperature and stirred for 1 hour. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate was added for extraction (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by silica gel column chromatography (eluent: System A) to give methyl 2-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate 14f (350 mg) in a yield of 87.71%.

[0583] MS m / z(ESI):333.9[M+1]

[0584] Step 4

[0585] methyl 2-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

[0586] 2-Methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid methyl ester

[0587] 2-Methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid methyl ester 14f (350 mg, 1.05 mmol) and m-chloroperbenzoic acid (470.27 mg, 2.32 mmol, 85% purity) were added to dichloromethane (5 mL). After stirring at room temperature for 2 hours, saturated sodium bicarbonate solution was added for neutralization. The mixture was extracted with dichloromethane (30 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by silica gel column chromatography (eluent: System B) to give 2-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid methyl ester 14g (100 mg) in a yield of 27.26%.

[0588] MS m / z(ESI):349.1[M+1]

[0589] Step 5

[0590] methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

[0591] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid methyl ester

[0592] 14 g (500 mg, 1.44 mmol) of methyl 2-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate and cyclopropanesulfonamide (226.03 mg, 1.87 mmol) were added to N-methylpyrrolidone (2 mL) and stirred at 80°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by silica gel column chromatography (eluent: System B) to obtain 14 g (300 mg) of methyl 5-(2-(cyclopropanesulfonyl)pyrimidin-4-yl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate in a yield of 51.56%.

[0593] MS m / z(ESI):406.1[M+1]

[0594] Step 6

[0595] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

[0596] 5-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

[0597] To a solution of 4-(6-ethoxypyrazin-2-yl)aniline 3b (95.56 mg, 443.93 μmol) in toluene (1.22 mL) was added trimethylaluminum (2.0 M solution in toluene) (2 M, 665.89 μL), and the mixture was stirred at room temperature for 1 hour. Methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate 14h (150 mg, 369.94 μmol) was then added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was directly dried to obtain a crude product. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide 14 (6.9 mg) in a yield of 2.52%.

[0598] MS m / z(ESI):574.8[M+1]

[0599] Example 15

[0600] 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0601] 3-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0602] first step

[0603] ethyl 3-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0604] 3-(4-(Methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0605] To a solution of 2-chloro-4-(methylthio)pyrimidine 15a (374.98 mg, 2.33 mmol, commercially available) and ethyl bicyclo[3.1.0]hexane-3-carboxylate 2a (300 mg, 1.95 mmol) in tetrahydrofuran (3.00 mL) was added lithium bistrimethylsilylamide (1 M, 5.84 mL) at -30°C and the mixture was slowly warmed to room temperature for 1 hour. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified by silica gel column chromatography (eluent: System A) to afford ethyl 3-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15b (300 mg) in a 55.40% yield.

[0606] MS m / z(ESI):278.9[M+1]

[0607] Step 2

[0608] ethyl 3-(4-(methylsulfonyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0609] 3-(4-(Methylsulfonyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0610] Ethyl 3-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15b (500 mg, 1.80 mmol) and m-chloroperbenzoic acid (962.72 mg, 4.74 mmol, 85% purity) were dissolved in dichloromethane (5 mL) at room temperature and stirred for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added for neutralization. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness to afford ethyl 3-(4-(methylsulfonyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15c (600 mg) in an 89.69% yield. The crude product was used directly in the next reaction.

[0611] MS m / z(ESI):310.8[M+1]

[0612] Step 3

[0613] ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0614] 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0615] Ethyl 3-(4-(methylsulfonyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15c (660.00 mg, 2.13 mmol) and cyclopropanesulfonamide (309.17 mg, 2.55 mmol) were dissolved in N-methylpyrrolidone (3 mL), heated to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15d (600 mg) in a yield of 80.29%.

[0616] MS m / z(ESI):352.0[M+1]

[0617] Step 4

[0618] 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0619] 3-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0620] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (110.25 mg, 512.21 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 768.31 μL) were added to toluene (2 mL) at room temperature and stirred for 1 hour. Subsequently, ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15d (150 mg, 426.84 μmol) was added, and the temperature was raised to 90 °C and stirred for 2 hours. The mixture was cooled to room temperature, quenched by the addition of a small amount of methanol, and the solvent was directly dried to give a crude product. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 15 (73 mg) in a yield of 26.53%.

[0621] MS m / z(ESI):[M+1]520.8

[0622] 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),9.63(s,1H),8.75(s,1H),8.49(d,J=5.7Hz,1H),8.17( s,1H),8.05(d,J=8.5Hz,2H),7.77(d,J=8.5Hz,2H),6.78(d,J=5.7Hz,1H),4.47(q,J=7.0Hz,2 H),3.16–3.08(m,1H),2.83(d,J=13.5Hz,2H),2.64–2.55(m,2H),1.39(t,J=7.0Hz,5H),1.05 (dt,J=7.0,3.5Hz,2H),0.83(td,J=7.4,4.7Hz,2H),0.43–0.33(m,1H),0.15(q,J=4.3Hz,1H).

[0623] Example 16

[0624] 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0625] 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0626] first step

[0627] 2-chloro-6-(methylthio)pyrazine

[0628] 2-Chloro-6-(methylthio)pyrazine

[0629] 2,6-Dichloropyrazine 1a (5 g, 33.56 mmol), potassium carbonate (4.64 g, 33.56 mmol) and sodium thiomethoxide (10.59 g, 30.21 mmol, 20% purity) were added to N,N-dimethylformamide (30 mL) and stirred at room temperature for 18 hours. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 2-chloro-6-(methylthio)pyrazine 16a (3.2 g) in a yield of 59.36%.

[0630] MS m / z(ESI):161.2[M+1]

[0631] Step 2

[0632] ethyl 3-(6-(methylthio)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0633] 3-(6-(Methylthio)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0634] To a solution of 2-chloro-6-(methylthio)pyrazine 16a (437.48 mg, 2.72 mmol) and ethyl bicyclo[3.1.0]hexane-3-carboxylate 2a (350 mg, 2.27 mmol) in tetrahydrofuran (3 mL) was added lithium bistrimethylsilylamide (1 M, 6.81 mL) at -30°C, and the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution was added to quench the mixture, and ethyl acetate (20 mL × 3) was added for extraction. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by silica gel column chromatography (eluent: System A) to give ethyl 3-(6-(methylthio)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16b (370 mg) in a yield of 58.56%.

[0635] MS m / z(ESI):278.9[M+1]

[0636] Step 3

[0637] ethyl 3-(6-(methylsulfonyl)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0638] 3-(6-(methylsulfonyl)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0639] Ethyl 3-(6-(methylthio)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16b (370 mg, 1.33 mmol) and m-chloroperbenzoic acid (593.68 mg, 2.92 mmol, 85% purity) were dissolved in dichloromethane (5 mL) at room temperature and stirred for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added for neutralization. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to afford ethyl 3-(6-(methylsulfonyl)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16c (400 mg) in a 96.96% yield. The crude product was used directly in the next reaction.

[0640] MS m / z(ESI):310.8[M+1]

[0641] Step 4

[0642] ethyl 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0643] 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0644] Ethyl 3-(6-(methylsulfonyl)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16c (660.00 mg, 2.13 mmol) and cyclopropanesulfonamide (309.17 mg, 2.55 mmol) were dissolved in N-methylpyrrolidone (3 mL), heated to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water (30 mL) was added, and extraction was performed with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give ethyl 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16d (350 mg) in a yield of 46.84%.

[0645] MS m / z(ESI):352.0[M+1]

[0646] Step 5

[0647] 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0648] 3-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0649] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (110.25 mg, 512.21 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 768.31 μL) were dissolved in toluene (1.5 mL) and stirred at room temperature for 1 hour. Ethyl 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16d (150.00 mg, 426.84 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. The mixture was cooled to room temperature, quenched by the addition of a small amount of methanol, and concentrated under reduced pressure to remove the solvent. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 16 (12 mg) in a yield of 5.24%.

[0650] MS m / z(ESI):520.8[M+1]

[0651] 1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.46(s,1H),8.56(s,1H),8.09(s,1H),7. 99(s,2H),7.89(d,J=8.4Hz,2H),7.57(d,J=8.4Hz,2H),4.28(q,J=7.2Hz,2H),2 .97(s,1H),2.76(d,J=13.6Hz,2H),2.27(d,J=13.4Hz,2H),1.23(dt,J=14.3,7. 3Hz, 5H), 0.94 (s, 2H), 0.77 (d, J = 8.0Hz, 2H), 0.27 (d, J = 7.3Hz, 1H), 0.00 (s, 1H).

[0652] Example 17

[0653] 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0654] 3-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0655] first step

[0656] cyclopropane-1,2-diyldimethanol

[0657] Cyclopropane-1,2-diyldimethanol

[0658] To a suspension of lithium aluminum tetrahydride (6.81 g, 200.74 mmol) in tetrahydrofuran (250 mL) was slowly added a solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione 17a (15 g, 133.83 mmol) in tetrahydrofuran (100 mL) under an ice-water bath. The mixture was then slowly warmed to room temperature and then heated to 70°C with stirring for 18 hours. After the reaction was complete, the mixture was cooled with ice water, and water (6.81 mL) and 15% sodium hydroxide solution (6.81 mL) were added, followed by ethyl acetate (200 mL). After stirring for 30 minutes, the insoluble solid was removed by filtration. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to afford cyclopropane-1,2-diyldimethyl 17b (7 g) in a yield of 51.21%.

[0659] Step 2

[0660] 1,2-bis(bromomethyl)cyclopropane

[0661] 1,2-Bis(bromomethyl)cyclopropane

[0662] Triphenylphosphine (37.25 g, 122.39 mmol) was dissolved in anhydrous acetonitrile (300 mL) under an ice-water bath. Liquid bromine (19.56 g, 122.39 mmol, 6.72 mL) was added dropwise and stirred for 30 minutes. A solution of cyclopropane-1,2-diyldimethanol 17b (5 g, 48.96 mmol) in acetonitrile (50 mL) was then added. The mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was filtered to remove insoluble solids, and the filtrate was concentrated under reduced pressure. Ethyl acetate / petroleum ether (100 mL, 2 / 1) was added and stirred for 1 hour. The insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure to provide 1,2-bis(bromomethyl)cyclopropane 17c (10.1 g) in a 90.51% yield. The crude product was used directly in the next reaction.

[0663] Step 3

[0664] methyl 3-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0665] 3-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid methyl ester

[0666] Methyl 2-(4-bromopyridin-2-yl)acetate 17d (500 mg, 2.17 mmol, commercially available) was added to N,N-dimethylformamide (6 mL), and the argon atmosphere was replaced three times. Under ice-water cooling, sodium hydroxide (199.95 mg, 5.00 mmol) was added. After stirring for 0.5 hour, 1,2-bis(bromomethyl)cyclopropane 17c (643.97 mg, 2.83 mmol) was added, and the mixture was stirred at room temperature for 23 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 3-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17e (490 mg) in a yield of 76.13%.

[0667] Step 4

[0668] methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0669] 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid methyl ester

[0670] Methyl 3-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17e (100 mg, 337.66 μmol), cyclopropanesulfonamide (61.36 mg, 506.48 μmol), cesium carbonate (220.03 mg, 675.31 μmol), allylpalladium chloride (12.35 mg, 33.77 μmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (28.68 mg, 67.53 μmol) were added sequentially to 1,4-dioxane (2 mL). The argon atmosphere was replaced three times, and the temperature was raised to 90 °C and stirred for 2 h. After the reaction was complete, dichloromethane (30 mL) and methanol (5 mL) were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17f (50 mg) in a yield of 44.02%.

[0671] MS m / z(ESI):336.2[M+1]

[0672] Step 5

[0673] 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0674] 3-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0675] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (110.25 mg, 512.21 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 768.31 μL) were dissolved in toluene (1.5 mL) and stirred at room temperature for 1 hour. Methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17f (143.59 mg, 426.84 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 17 (50 mg) in a yield of 17.03%.

[0676] MS m / z(ESI):519.8[M+1]

[0677] 1H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 8.80 (s, 1H), 8.48 (d, J = 5.9Hz, 1H), 8.23 ​​(s, 1H), 8.10(d,J=8.5Hz,2H),7.78(d,J=8.5Hz,2H),7.35(s,1H),7.23(d,J=6.2Hz,1H),4.52 (q,J=7.0Hz,2H),2.95–2.78(m,3H),2.65(d,J=13.7Hz,2H),1.46(dt,J=14.1,5.8Hz, 5H), 1.08 (ddd, J=16.8, 7.2, 3.9Hz, 4H), 0.45 (d, J=4.9Hz, 1H), -0.00 (d, J=4.2Hz, 1H).

[0678] Example 18

[0679] 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0680] 3-(2-(Cyclopropanesulfonamido)pyridin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0681] first step

[0682] methyl 3-(2-bromopyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0683] 3-(2-bromopyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid methyl ester

[0684] Methyl 2-(2-bromopyridin-4-yl)acetate 18a (900 mg, 3.91 mmol, commercially available) was added to N,N-dimethylformamide (6 mL), and the argon atmosphere was replaced three times. Under ice-water cooling, sodium hydroxide (359.91 mg, 9.00 mmol) was slowly added. After stirring for 0.5 hour, 1,2-bis(bromomethyl)cyclopropane 17c (1.16 g, 5.09 mmol) was added. Stirring continued at room temperature for 23 hours. After the reaction was complete, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 3-(2-bromopyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 18b (800 mg) in a 69.05% yield.

[0685] MS m / z(ESI):296.3[M+1]

[0686] Step 2

[0687] methyl 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0688] 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid methyl ester

[0689] Methyl 3-(2-bromopyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 18b (1 g, 3.38 mmol), cyclopropanesulfonamide (613.65 mg, 5.06 mmol), cesium carbonate (2.20 g, 6.75 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (143.77 mg, 337.83 μmol) and allylpalladium(II) chloride dimer (61.77 mg, 168.83 μmol) were added sequentially to 1,4-dioxane (10 mL). The argon atmosphere was replaced three times, and the temperature was raised to 90 °C and stirred for 2 h. After the reaction was complete, dichloromethane (30 mL) and methanol (5 mL) were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give methyl 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 18c (900 mg) in a yield of 79.23%.

[0690] MS m / z(ESI):336.2[M+1]

[0691] Step 3

[0692] 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0693] 3-(2-(Cyclopropanesulfonamido)pyridin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0694] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (122.85 mg, 570.74 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 856.11 μL) were dissolved in toluene (1.5 mL) and stirred at room temperature for 1 hour. Subsequently, methyl 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 18c (160 mg, 475.62 μmol) was added, and the temperature was raised to 90° and stirred for 5 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 18 (54 mg) in a yield of 17.32%.

[0695] MS m / z(ESI):520.8[M+1]

[0696] 1H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 8.63 (d, J = 2.1Hz, 1H), 8.13–7.87 (m, 4H), 7.60 (d d,J=8.5,5.5Hz,2H),6.99–6.84(m,2H),4.35(q,J=7.0Hz,2H),2.98–2.78(m,2H),2.70 (dd,J=14.5,3.9Hz,1H),2.15(d,J=13.9Hz,1H),2.03(d,J=13.1Hz,1H),1.28(q,J=7. 1,6.6Hz,5H),0.86(dd,J=25.5,6.6Hz,4H),0.31(d,J=7.1Hz,1H),0.09–-0.10(m,1H).

[0697] Example 19

[0698] 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0699] 3-(5-(Cyclopropanesulfonamido)pyridazin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0700] first step

[0701] 3-chloro-5-(methylthio)pyridazine

[0702] 3-Chloro-5-(methylthio)pyridazine

[0703] 3,5-Dichloropyridazine 19a (2.2 g, 14.77 mmol, commercially available) and sodium thiomethoxide (6.21 g, 17.72 mmol, 20% purity) were dissolved in tetrahydrofuran (10 mL) and stirred at room temperature for 1 hour. After the reaction was complete, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was added to a 1 / 1 mixture of ethyl acetate and petroleum ether (30 mL) and stirred for 0.5 hour. The mixture was filtered under reduced pressure and the filter cake was dried to afford 3-chloro-5-(methylthio)pyridazine 19b (1.63 g) in a yield of 68.72%.

[0704] MS m / z(ESI):161.0[M+1]

[0705] Step 2

[0706] ethyl 3-(5-(methylthio)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0707] 3-(5-(methylthio)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0708] To a solution of 3-chloro-5-(methylthio)pyridazine 19b (499.98 mg, 3.11 mmol) and ethyl bicyclo[3.1.0]hexane-3-carboxylate 2a (400 mg, 2.59 mmol) in tetrahydrofuran (2 mL) was added lithium bistrimethylsilylamide (1 M, 7.78 mL) at -30°C. The mixture was slowly warmed to room temperature and stirred for 3 hours. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified by silica gel column chromatography (eluent: System A) to afford ethyl 3-(5-(methylthio)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19c (350 mg) in a 48.47% yield.

[0709] MS m / z(ESI):278.9[M+1]

[0710] Step 3

[0711] ethyl 3-(5-(methylsulfonyl)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0712] 3-(5-(methylsulfonyl)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0713] Ethyl 3-(5-(methylthio)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19c (370 mg, 1.33 mmol) and m-chloroperbenzoic acid (431.76 mg, 2.13 mmol, 85% purity) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added for neutralization. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried to afford ethyl 3-(5-(methylsulfonyl)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19d (350 mg) in an 89.45% yield. The crude product was used directly in the next reaction.

[0714] MS m / z(ESI):294.9[M+1]

[0715] Step 4

[0716] ethyl 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0717] 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0718] Ethyl 3-(5-(methylsulfonyl)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19d (400 mg, 1.36 mmol) and cyclopropanesulfonamide (197.56 mg, 1.63 mmol) were dissolved in N-methylpyrrolidone (3 mL) and stirred at 80°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water (30 mL) was added, and extraction was performed with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford ethyl 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19e (300 mg) in a yield of 62.82%.

[0719] MS m / z(ESI):352.0[M+1]

[0720] Step 5

[0721] 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0722] 3-(5-(Cyclopropanesulfonamido)pyridazin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0723] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (122.85 mg, 570.74 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 856.11 μL) were dissolved in toluene (2 mL) and stirred at room temperature for 1 hour. Subsequently, ethyl 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19e (160.47 mg, 475.62 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 19 (8 mg) in a yield of 2.39%.

[0724] MS m / z(ESI):520.8[M+1]

[0725] 1H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 8.76 (d, J = 4.4Hz, 1H), 8.18 (d, J = 5.1H z,1H),8.07(t,J=6.0Hz,2H),7.70(d,J=8.5Hz,3H),4.46(q,J=7.1Hz,2H),3 .09–2.88(m,2H),2.62(s,1H),2.19(t,J=13.5Hz,2H),1.41(dt,J=14.2,5.6 Hz,5H),0.92(t,J=8.2Hz,4H),0.46(t,J=7.3Hz,1H),0.12(d,J=4.6Hz,1H).

[0726] Example 20

[0727] 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0728] 3-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0729] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (41.60 mg, 178.36 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 267.53 μL) were dissolved in toluene (2.00 mL) and stirred at room temperature for 1 hour. Subsequently, methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17f (50 mg, 148.63 μmol) was added, and the temperature was raised to 90 ° C and stirred for 5 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide 20 (21 mg) in a yield of 20.00%.

[0730] MS m / z(ESI):537.8[M+1]

[0731] 1H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.81 (s, 1H), 8.48 (d, J = 5.8Hz, 1H), 8.23 ​​(s, 1H), 8. 02–7.90(m,2H),7.82(d,J=8.2Hz,1H),7.30(d,J=2.1Hz,1H),7.22(d,J=5.9Hz,1H),4.4 6(q,J=7.0Hz,2H),2.89(s,1H),2.82–2.72(m,2H),2.61(d,J=13.7Hz,2H),1.46–1.35(m ,5H),1.04(ddt,J=10.5,4.6,2.4Hz,4H),0.37(d,J=5.7Hz,1H),-0.16(d,J=4.4Hz,1H).

[0732] Example 21

[0733] 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[0734] 3-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[0735] 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine 1d (38.57 mg, 178.36 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 267.53 μL) were dissolved in toluene (2.00 mL) and stirred at room temperature for 1 hour. Subsequently, methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17f (50 mg, 148.63 μmol) was added, and the temperature was raised to 90 ° C and stirred for 5 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 21 (11 mg) in a yield of 11.00%.

[0736] MS m / z(ESI):520.8[M+1]

[0737] 1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.99(d,J=2.4Hz,1H),8.81(s,1H),8.48(dd,J=8.5,2.5Hz,2H),8 .24(s,1H),8.10(d,J=8.8Hz,1H),7.30(d,J=2.1Hz,1H),7.19(dd,J=5.8,2.1Hz,1H),4.46(q,J=7.0Hz ,2H),2.89(dq,J=10.2,3.9,2.8Hz,1H),2.78(dd,J=13.9,4.0Hz,2H),2.61(d,J=13.7Hz,2H),1.40(dt ,J=14.1,7.2Hz,5H),1.02(ddt,J=10.8,8.4,2.4Hz,4H),0.37(q,J=7.2Hz,1H),-0.17(d,J=4.4Hz,1H).

[0738] Example 22

[0739] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide

[0740] 5-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide

[0741] first step

[0742] methyl 4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate

[0743] 4,5,6,7-Tetrahydrobenzo[d]isoxazole-5-carboxylic acid methyl ester

[0744] Ethyl 3-((dimethylamino)methylene)-4-oxocyclohexane-1-carboxylate 22a (10 g, 44.39 mmol, prepared according to patent publication "WO2008011130") and (aminooxy)sulfonic acid 22b (5.52 g, 48.83 mmol, commercially available) were added to methanol (10 mL). The reaction mixture was sealed, heated to 100°C, and stirred for 18 hours. After completion, the solvent was removed by concentration under reduced pressure, and the mixture was neutralized by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate 22c (3.2 g) in a 39.79% yield.

[0745] MS m / z(ESI):181.9[M+1]

[0746] Step 2

[0747] methyl 5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate

[0748] Methyl 5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate

[0749] 4-Chloro-2-(methylthio)pyrimidine 1e (4 g, 24.90 mmol) and methyl 4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate 22c (6.32 g, 34.86 mmol) were dissolved in tetrahydrofuran (30 mL), cooled to -30°C, and lithium bis(trimethylsilylamide) (1 M, 74.71 mL) was added. The reaction mixture was then slowly warmed to room temperature and stirred for 1 hour. The reaction of the starting material was complete, and the reaction was quenched by adding saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by silica gel column chromatography (eluent: System A) to give methyl 5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate 22d (4.2 g) in a yield of 55.23%.

[0750] MS m / z(ESI):306.2[M+1]

[0751] Step 3

[0752] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide

[0753] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide

[0754] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (504.02 mg, 2.34 mmol) and trimethylaluminum (2.0 M solution in toluene) (2M, 3.51 mL) were added to toluene (10 mL) and stirred at room temperature for 1 hour. Subsequently, methyl 5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate 22d (858.00 mg, 2.81 mmol) was added, and the temperature was raised to 90°C and stirred for 18 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System B) to give N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide 22e (200 mg) in a yield of 17.48%.

[0755] MS m / z(ESI):489.1[M+1]

[0756] Step 4

[0757] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylsulfinyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide

[0758] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylsulfinyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide

[0759] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide 22e (200 mg, 409.37 μmol) and m-chloroperbenzoic acid (182.84 mg, 900.60 μmol, 85% purity) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System B) to afford N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylsulfinyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide 22f (120 mg) in a 58.10% yield.

[0760] MS m / z(ESI):505.5[M+1]

[0761] Step 5

[0762] 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide

[0763] 5-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide

[0764] Under ice-water bath, cyclopropanesulfonamide (57.63 mg, 475.66 μmol) and sodium hydride (23.78 mg, 594.58 μmol, 60% purity) were dissolved in N,N-dimethylformamide (2 mL) and stirred for 0.5 h. Subsequently, N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylsulfinyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide 22f (120 mg, 237.83 μmol) was added and the mixture was slowly warmed to room temperature and stirred for 5 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H₂O, mobile phase B: CH₃CN) to afford 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxamide 22 (4.25 mg) in a yield of 1.59%. MS m / z (ESI): 561.7 [M+1].

[0765] Example 23

[0766] 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0767] 3-(5-(Cyclopropanesulfonamido)pyridin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0768] first step

[0769] methyl 3-(5-bromopyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0770] 3-(5-bromopyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylic acid methyl ester

[0771] Methyl 2-(5-bromopyridin-3-yl)acetate 23a (500 mg, 2.17 mmol, commercially available) was added to N,N-dimethylformamide (6 mL), and the argon atmosphere was replaced three times. Under ice-water cooling, sodium hydroxide (199.95 mg, 5.00 mmol) was slowly added. After stirring for 0.5 hour, 1,2-bis(bromomethyl)cyclopropane 17c (643.97 mg, 2.83 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 23 hours. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spun down to dryness. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain methyl 3-(5-bromopyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 23b (600 mg) in a 55.93% yield. MS m / z(ESI):296.3[M+1]

[0772] Step 2

[0773] methyl 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0774] 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylic acid methyl ester

[0775] 3-(5-Bromopyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylic acid methyl ester 23b (800 mg, 2.70 mmol), cyclopropanesulfonamide (392.73 mg, 3.24 mmol), cesium carbonate (1.76 g, 5.40 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (114 mg, 270..06 μmol) and allylpalladium(II) chloride dimer (49.42 mg, 135.06 μmol) were added to 1,4-dioxane (10 mL) in sequence, the argon atmosphere was replaced three times, and the temperature was raised to 90 ° C and stirred for 2 hours. After the reaction was complete, dichloromethane (30 mL) and methanol (5 mL) were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System B) to give methyl 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 23c (230 mg) in a yield of 20.25%.

[0776] MS m / z(ESI):336.2[M+1]

[0777] Step 3

[0778] 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0779] 3-(5-(Cyclopropanesulfonamido)pyridin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0780] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (102.38 mg, 475.62 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 856.11 μL) were dissolved in toluene (1.41 mL) and stirred at room temperature for 1 hour. Subsequently, methyl 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 23c (160.00 mg, 475.62 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid and dichloromethane were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 23 (55 mg) in a yield of 16.79%.

[0781] MS m / z(ESI):520.8[M+1]

[0782] 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.45(d,J=97.4Hz,1H),8.42(dd,J=108.2,46 .5Hz,3H),8.17–7.71(m,4H),7.58(d,J=7.7Hz,2H),4.31(p,J=7.3Hz,2H),3.03(d, J=14.2Hz,1H),2.78(d,J=13.5Hz,1H),2.59–2.47(m,1H),2.10(dd,J=34.2,13.6Hz ,2H),1.29–1.08(m,5H),0.77(d,J=6.5Hz,4H),0.32(t,J=16.5Hz,1H),0.05(m,1H).

[0783] Example 24

[0784] 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[0785] 3-(6-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[0786] 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine 1d (40 mg, 184.98 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 277.47 μL) were added to toluene (2 mL). After stirring at room temperature for 1 hour, ethyl 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13d (62.41 mg, 184.98 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and quenched by the addition of a small amount of methanol. The solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 24 (5.46 mg) in a yield of 4.46%.

[0787] MS m / z(ESI):521.8[M+1]

[0788] 1H NMR(400MHz, DMSO-d6)δ10.18(s,1H),9.00(d,J=2.4Hz,1H),8.83(s,1H),8.52–8.40( m,2H),8.30–8.15(m,2H),6.80(d,J=5.7Hz,1H),4.48(d,J=7.0Hz,2H),3.13–3.07(m,1 H),2.80(d,J=13.6Hz,2H),2.58(dd,J=13.0,10.0Hz,2H),1.40(t,J=7.0Hz,5H),1.06 (dt,J=6.7,3.4Hz,2H),0.91–0.82(m,3H),0.39(d,J=6.6Hz,1H),0.13(d,J=4.7Hz,1H)

[0789] Example 25

[0790] 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0791] 3-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0792] first step

[0793] ethyl 3-(6-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0794] 3-(6-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0795] To a solution of 2-bromo-6-fluoropyridine 25a (547.80 mg, 3.11 mmol, commercially available) and ethyl bicyclo[3.1.0]hexane-3-carboxylate 2a (400 mg, 2.59 mmol) in tetrahydrofuran (5 mL) was added lithium hexamethyldisilazide (1.2 M in tetrahydrofuran, 7.78 mL). The mixture was slowly warmed to room temperature and stirred for 3 hours. After completion of the reaction, saturated ammonium chloride solution (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by silica gel column chromatography (eluent: System A) to afford ethyl 3-(6-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 25b (700 mg) in an 87.00% yield.

[0796] MS m / z(ESI):357.1[M+1]

[0797] Step 2

[0798] ethyl 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0799] 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0800] Ethyl 3-(6-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 25b (800 mg, 2.58 mmol), cyclopropanesulfonamide (468.72 mg, 3.87 mmol), cesium carbonate (1.68 g, 5.16 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (109 mg, 257 μmol) and allylpalladium(II) chloride dimer (47.18 mg, 128.96 μmol) were added sequentially to 1,4-dioxane (10 mL), the argon atmosphere was replaced three times, and the temperature was raised to 90 °C and stirred for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System B) to give ethyl 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 25c (450 mg) in a yield of 49.79%.

[0801] MS m / z(ESI):350.9[M+1]

[0802] Step 3

[0803] 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0804] 3-(6-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0805] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (99.82 mg, 463.73 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 642.08 μL) were added to toluene (1.5 mL) and stirred at room temperature for 1 hour. Subsequently, ethyl 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 25c (125.00 mg, 356.71 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and quenched by the addition of a small amount of methanol. The solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 25 (80 mg) in a yield of 34.64%.

[0806] MS m / z(ESI):519.8[M+1]

[0807] 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.32(s,1H),8.60(s,1H),8.02(s,1H),7.90(d,J=8.3Hz,2H ),7.60(d,J=8.4Hz,2H),7.51(t,J=7.8Hz,1H),6.81(d,J=7.7Hz,1H),6.63(d,J=8.1Hz,1H),4.31 (q,J=7.0Hz,2H),3.13–3.04(m,1H),2.77(d,J=13.4Hz,2H),2.27(d,J=13.2Hz,2H),1.23(t,J=6. 9Hz,5H),0.98–0.89(m,2H),0.83(d,J=7.4Hz,2H),0.24(q,J=7.0Hz,1H),-0.00(q,J=4.3Hz,1H).

[0808] Example 26

[0809] 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0810] 3-(6-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0811] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (82.96 mg, 355.67 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 533.50 μL) were dissolved in toluene (1.73 mL) and stirred at room temperature for 1 hour. Subsequently, ethyl 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13d (100 mg, 296.39 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and quenched by the addition of a small amount of methanol. The solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide 26 (49.42 mg) in a yield of 24.70%.

[0812] MS m / z(ESI):538.8[M+1]

[0813] 1H NMR (400MHz, DMSO-d6) δ9.43(s,1H),8.57(d,J=17.4Hz,2H),7.73(t,J=10.3Hz,2H),7.36(t,J=8.0Hz,1H),6.71(s,1H),4.23(q,J=7.1Hz,2H),2 .84(s,1H),2.60(d,J=13.5Hz,2H),2.17(d,J=13.3Hz,2H),1.20–1.12( m,5H),0.90–0.77(m,4H),0.18(d,J=7.0Hz,1H),-0.01(d,J=5.9Hz,1H).

[0814] Example 27

[0815] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0816] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0817] first step

[0818] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile

[0819] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile

[0820] Under ice-water bath, 2-(6-(methylthio)pyrimidin-4-yl)acetonitrile 27a (700 mg, 4.24 mmol, prepared according to patent publication "WO 2008042639A1") was dissolved in anhydrous ethylene glycol dimethyl ether (28 mL), sodium hydride (372.85 mg, 9.32 mmol, 60% purity) was added, and the mixture was stirred at room temperature for 0.5 hours. (3aR, 6aS)-tetrahydrofuro[3,4-d][1,3,2]dioxythiophene 2,2-dioxide 4c (844.76 mg, 5.08 mmol) was added, and the mixture was heated to 40 ℃. The mixture was warmed to 60°C and stirred for 18 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered and dried. The residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile 27b (520 mg) in a yield of 52.61%.

[0821] MS m / z(ESI):233.2[M+1]

[0822] Step 2

[0823] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0824] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0825] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile 27b (520 mg, 2.23 mmol) was added to dimethyl sulfoxide (3 mL), and sodium hydroxide (178.32 mg, 4.46 mmol) was added under ice-water bath. After stirring for 10 minutes, hydrogen peroxide (1.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was quenched by adding water (10 mL). The solid was collected by filtration and dried to give (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 27c (500 mg) in a yield of 89.26%.

[0826] MS m / z(ESI):251.0[M+1]

[0827] Step 3

[0828] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[0829] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[0830] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 27c (560 mg, 2.23 mmol), acetic acid (1.50 mL), and acetic anhydride (3 mL) were added to dimethyl sulfoxide (3 mL). Sodium nitrite (1.54 g, 22.28 mmol) was added under ice-water bath, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water (10 mL), neutralized with saturated sodium bicarbonate solution, and the pH was adjusted to acidic by adding saturated citric acid solution. The product was extracted with ethyl acetate (20 mL × 3). The aqueous phase was collected and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 27d (210 mg) in a yield of 37.35%.

[0831] MS m / z(ESI):253.0[M+1]

[0832] Step 4 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0833] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0834] Under ice-water bath, (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 27d (210 mg, 832.38 μmol), N-methylpyrrolidone (2 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (466.13 mg, 1.66 mmol) and N-methylimidazole (273.35 mg, 3.33 mmol) were added to a 15 mL single-necked flask and reacted at room temperature for 0.5 h. 4-(6-ethoxypyrazin-2-yl)aniline 3b (197.09 mg, 915.62 μmol) was added, and the temperature was raised to 100°C and stirred for 5 h. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 27e (350 mg) in a yield of 93.54%.

[0835] MS m / z(ESI):450.1[M+1]

[0836] Step 5

[0837] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0838] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0839] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 27e (350 mg, 778.60 μmol) and m-chloroperbenzoic acid (316.15 mg, 1.56 mmol, 85% purity) were added to dichloromethane (5 mL) and stirred at room temperature overnight. Saturated sodium bicarbonate solution was added for neutralization, and the mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 27f (350 mg) with a yield of 96.56%.

[0840] MS m / z(ESI):465.5[M+1]

[0841] Step 6

[0842] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0843] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0844] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 27f (360 mg, 773.32 μmol), cyclopropanesulfonamide (93.69 mg, 773.32 μmol), and cesium carbonate (503.93 mg, 1.55 mmol) were added to N-methylpyrrolidone (1.5 mL) and the temperature was raised to 100 °C for 2 hours. The reaction solution was directly added with water (2 mL) and methanol (2 mL), and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 27 (80 mg) in a yield of 15.83%.

[0845] MS m / z(ESI):523.1[M+1].

[0846] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.76(d,J=21.9Hz,2H),8.20(s,1H),8.11(d,J=8.3Hz,2H),7.82(d,J=8.3Hz,2H),7.01(s,1H), 4.48(q,J=7.0Hz,2H),4.11(d,J=8.9Hz,2H),3.83(d,J=8.8Hz,2H),3.04(s,1H),1.40(t,J=7.0Hz,3H),1.03(dd,J=12.9,6.6Hz,4H).

[0847] Example 28

[0848] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0849] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0850] Step 1: (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[0851] (1R,5S)-6-(4-Bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[0852] Under ice-water bath, 2-(4-bromopyridin-2-yl)acetonitrile 28a (500 mg, 2.54 mmol) was added to anhydrous ethylene glycol dimethyl ether (20 mL), sodium hydride (223.31 mg, 5.58 mmol, 60% purity) was added, and stirred at room temperature for 0.5 hours. (3aR, 6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxythiophene 2,2-dioxide 8b (499 .96 mg, 3.05 mmol), heated to 60 ° C, stirred for 18 hours, added water (50 mL) and ethyl acetate (50 mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile 28b (260 mg) in a yield of 94%.

[0853] MS m / z(ESI):263.0[M+1]

[0854] Step 2

[0855] (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0856] (1R,5S)-6-(4-Bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0857] (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile 28b (260 mg, 988.09 μmol), sodium hydroxide (79.05 mg, 1.98 mmol) and hydrogen peroxide (1.5 mL) were added to dimethyl sulfoxide (1.5 mL) in sequence, and the temperature was raised to 40°C and stirred for 3 hours. The mixture was quenched by the addition of water (10 mL) and stirred for 0.5 hours. The solid was collected by filtration, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the organic phase was combined with the collected solid and dried to give (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide 28c (260 mg) in a yield of 93.59%.

[0858] MS m / z(ESI):281.5[M+1]

[0859] Step 3

[0860] (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[0861] (1R,5S)-6-(4-Bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[0862] (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide 28c (293.18 mg, 1.04 mmol), acetic acid (1.50 mL) and acetic anhydride (3 mL) were added to dimethyl sulfoxide (3 mL). Sodium nitrite (719.53 mg, 10.43 mmol) was added under ice-water bath, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water (10 mL), neutralized with saturated sodium bicarbonate solution, and the pH was adjusted to acidic by adding saturated citric acid solution. The mixture was extracted with ethyl acetate (20 mL × 3). The aqueous phase was collected and purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 28d (210 mg) in a yield of 71.38%.

[0863] MS m / z(ESI):282.0[M+1]

[0864] Step 4 (1R,5S)-6-(4-bromopyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0865] (1R,5S)-6-(4-bromopyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0866] Under ice-water bath, (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 28d (180 mg, 638.00 μmol), N-methylpyrrolidone (1 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (357.28 mg, 1.28 mmol) and N-methylimidazole (209.52 mg, 2.55 mmol) were added to a 15 mL single-necked flask and reacted at room temperature for 0.5 h. 4-(6-ethoxypyrazin-2-yl)aniline 3b (144.20 mg, 669.90 μmol) was added, and the temperature was raised to 65 °C and stirred for 5 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-6-(4-bromopyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide 28e (50 mg) in a yield of 16.35%.

[0867] MS m / z(ESI):480.1[M+1]

[0868] Step 5 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0869] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0870] (1R,5S)-6-(4-bromopyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide 28e (200 mg, 417.22 μmol), cyclopropanesulfonamide (75.82 mg, 625.82 μmol), cesium carbonate (271.87 mg, 834.43 μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (17.72 mg, 41.72 μmol) and allylpalladium(II) chloride dimer (7.63 mg, 20.86 μmol) were added to 1,4-dioxane (3 mL) in sequence, the atmosphere was replaced with argon three times, the temperature was raised to 90°C, stirred for 2 hours, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide 28 (26 mg) with a yield of 97.6%.

[0871] MS m / z(ESI):350.9[M+1]

[0872] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.77(s,1H),8.39(d,J=6.1Hz,1H),8.24–8 .06(m,3H),7.84(d,J=8.4Hz,2H),7.36(s,1H),7.22(d,J=6.1Hz,1H),4.48(q,J= 7.1Hz,2H),2.86(d,J=7.3Hz,1H),2.25–2.10(m,4H),2.01(q,J=10.9Hz,2H),1.6 8(d,J=10.3Hz,1H),1.40(t,J=7.0Hz,3H),1.31–1.15(m,1H),1.16–0.94(m,5H).

[0873] Example 29

[0874] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0875] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0876] first step

[0877] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[0878] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[0879] Under ice-water bath, 2-(6-(methylthio)pyrimidin-4-yl)acetonitrile 27a (800 mg, 4.84 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (20 mL), sodium hydride (426.11 mg, 10.65 mmol, 60% purity) was added, and the mixture was stirred at room temperature for 0.5 hours. (3aR, 6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxythiophene 2,2-dioxide 8b (953 .98 mg, 5.81 mmol), heated to 60 ° C and stirred for 18 hours, water (50 mL) and ethyl acetate (50 mL) were added, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile 29a (600 mg) in a yield of 53.57%.

[0880] MS m / z(ESI):231.2[M+1]

[0881] Step 2

[0882] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0883] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0884] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile 29a (600 mg, 2.59 mmol) was added to dimethyl sulfoxide (3 mL). Sodium hydroxide (207.51 mg, 5.19 mmol) was added under ice-water bath. After stirring for 10 minutes, hydrogen peroxide (1.5 mL) was added. The mixture was stirred at room temperature for 3 hours. Water (10 mL) was added to quench the mixture. The solid was collected by filtration and dried to afford (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 29b (550 mg) in 85.04% yield. MS m / z (ESI): 249.0 [M+1].

[0885] Step 3

[0886] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[0887] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[0888] (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 29b (550 mg, 2.21 mmol), acetic acid (1.50 mL), and acetic anhydride (3 mL) were added to dimethyl sulfoxide (3 mL). Sodium nitrite (1.52 g, 22.06 mmol) was added under ice-water bath, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water (10 mL), neutralized with saturated sodium bicarbonate solution, and the pH was adjusted to acidic by adding saturated citric acid solution. The mixture was extracted with ethyl acetate (20 mL × 3). The aqueous phase was collected and purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 29c (350 mg) in a yield of 63.39%.

[0889] MS m / z(ESI):251.0[M+1]

[0890] Step 4 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0891] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0892] Under ice-water bath, (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 29c (80 mg, 319.60 μmol), N-methylpyrrolidone (1 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (178.97 mg, 639.19 μmol) and N-methylimidazole (104.96 mg, 1.28 mmol) were added to a 15 mL single-necked flask and reacted at room temperature for 0.5 h. 4-(6-ethoxypyrazin-2-yl)aniline 3b (72.23 mg, 335.58 μmol) was added, and the temperature was raised to 100 °C and stirred for 18 h. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 29d (130 mg) in a yield of 90.89%.

[0893] MS m / z(ESI):448.1[M+1]

[0894] Step 5

[0895] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0896] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0897] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 29d (140 mg, 312.81 μmol) and m-chloroperbenzoic acid (101.61 mg, 500.50 μmol, 85% purity) were added to dichloromethane (2 mL) and stirred at room temperature overnight. Saturated sodium bicarbonate solution was added for neutralization, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 29e (140 mg) in a 96.55% yield. MS m / z (ESI): 464.1 [M+1].

[0898] Step 6 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0899] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[0900] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 29e (140 mg, 302.02 μmol), cyclopropanesulfonamide (43.91 mg, 362.42 μmol), and cesium carbonate (196.81 mg, 604.03 μmol) were added to N-methylpyrrolidone (1 mL) and the temperature was raised to 100 °C for 2 h. The reaction solution was cooled to room temperature and directly purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide 29 (40 mg) in a yield of 19.62%.

[0901] MS m / z(ESI):521.3[M+1].

[0902] 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.77(s,1H),8.68(s,1H),8.19(s,1H) ,8.11(d,J=8.4Hz,2H),7.83(d,J=8.4Hz,2H),6.95(s,1H),4.48(d,J=7.0Hz, 2H),3.02(s,1H),2.21(d,J=3.0Hz,2H),2.10(dd,J=13.3,8.5Hz,2H),2.00(d ,J=10.2Hz,2H),1.72–1.61(m,1H),1.40(t,J=7.0Hz,3H),1.10–0.93(m,5H).

[0903] Example 30

[0904] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methylbicyclo[3.1.0]hexane-6-carboxamide

[0905] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methylbicyclo[3.1.0]hexane-6-carboxamide

[0906] first step

[0907] 4-(6-ethoxypyrazin-2-yl)-N-methylaniline

[0908] 4-(6-Ethoxypyrazin-2-yl)-N-methylaniline

[0909] 2-Chloro-6-ethoxypyrazine 1b (340.15 mg, 2.14 mmol), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 30a (500 mg, 2.14 mmol, commercially available), 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (156.94 mg, 214.49 μmol), and potassium carbonate (889.33 mg, 6.43 mmol) were added sequentially to a mixture of 1,4-dioxane (6 mL) and water (3 mL). The atmosphere was replaced with argon three times, and the mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System B) to afford 4-(6-ethoxypyrazin-2-yl)-N-methylaniline 30b (450 mg) in a 91.51% yield.

[0910] MS m / z(ESI):230.0[M+1]

[0911] Step 2 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0912] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0913] Under ice-water bath, (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 29c (80 mg, 319.60 μmol), N-methylpyrrolidone (1 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (178.97 mg, 639.19 μmol) and N-methylimidazole (104.96 mg, 1.28 mmol) were added into a 15 mL single-necked flask and reacted at room temperature for 0.5 h. 4-(6-ethoxypyrazin-2-yl)-N-methylaniline 30b (76.94 mg, 335.58 μmol) was added, and the temperature was raised to 100°C and stirred for 18 h. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 30c (80 mg) in a yield of 54.23%.

[0914] MS m / z(ESI):462.1[M+1]

[0915] Step 3

[0916] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0917] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[0918] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 30c (60 mg, 129.99 μmol) and m-chloroperbenzoic acid (42.23 mg, 207.98 μmol, 85% purity) were added to dichloromethane (2 mL) and stirred at room temperature overnight. Saturated sodium bicarbonate solution was added for neutralization, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1R, 5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 30d (40 mg) with a yield of 64.43%.

[0919] MS m / z(ESI):478.1[M+1]

[0920] Step 4 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methylbicyclo[3.1.0]hexane-6-carboxamide

[0921] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methylbicyclo[3.1.0]hexane-6-carboxamide

[0922] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 30d (60 mg, 125.63 mmol), cyclopropanesulfonamide (18.27 g, 150.76 mmol), and cesium carbonate (81.87 g, 251.27 mmol) were added to N-methylpyrrolidone (1 mL) and the temperature was raised to 90 °C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methylbicyclo[3.1.0]hexane-6-carboxamide 30 (6 mg) in a yield of 7.36%.

[0923] MS m / z(ESI):535.1[M+1]

[0924] 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.69(d,J=10.8Hz,1H),8.26(s,1H),8.19(d,J=8.2Hz,2H),7.54(d,J=8.2Hz,2H),6.97(d,J=14.3Hz,1H) ,4.49(q,J=7.4Hz,2H),3.32(s,3H),3.05(s,1H),2.55(t,J=5.5Hz,2H) ,2.12(t,J=13.0Hz,4H),1.40(q,J=6.4,5.8Hz,4H),1.14–1.00(m,5H).

[0925] Example 31

[0926] 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0927] 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0928] first step

[0929] ethyl 3-(6-((tert-butoxycarbonyl)amino)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0930] Ethyl 3-(6-((tert-butoxycarbonyl)amino)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0931] Tert-butyl (5-chloropyridazin-3-yl)carbamate 31a (700 mg, 3.05 mmol, prepared according to patent publication "WO2022128584 A1") and ethyl bicyclo[3.1.0]hexane-3-carboxylate (564.01 mg, 3.66 mmol, commercially available) were added to tetrahydrofuran (4.69 mL), cooled to -78°C, and lithium bistrimethylsilylamide (1 M, 9.14 mL) was added. The mixture was warmed to room temperature and stirred for 1 hour. Saturated ammonium chloride solution was added to the reaction solution, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to obtain ethyl 3-(6-((tert-butoxycarbonyl)amino)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 31b (900 mg) in an 85.00% yield.

[0932] MS m / z(ESI):348.1[M+1]

[0933] Step 2

[0934] ethyl 3-(6-aminopyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0935] 3-(6-aminopyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0936] Ethyl 3-(6-((tert-Butoxycarbonyl)amino)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 31b (550 mg, 1.58 mmol) was added to a 4M solution of hydrochloric acid in dioxane (5 mL) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to afford ethyl 3-(6-aminopyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 31c (350 mg) in an 89.97% yield.

[0937] MS m / z(ESI):248.0[M+1]

[0938] Step 3

[0939] ethyl 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[0940] 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[0941] 3-(6-aminopyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester 31c (350 mg, 1.42 mmol), 4-dimethylaminopyridine (345.82 mg, 2.83 mmol), cyclopropanesulfonyl chloride (795.92 mg, 5.66 mmol) and pyridine (419.95 μL) were mixed, heated to 70°C, stirred for 2 hours, then heated to 100°C, stirred for 18 hours, and concentrated under reduced pressure. The solvent was evaporated to dryness, and water (10 mL) and saturated citric acid solution (10 mL) were added. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give ethyl 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 31d (150 mg) in a yield of 30.16%.

[0942] MS m / z(ESI):352.1[M+1]

[0943] Step 4

[0944] 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0945] 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide

[0946] Ethyl 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 31d (66.15 mg, 307.32 μmol), toluene (1.81 mL) and a toluene solution of trimethylaluminum (2 M, 460.99 μL) were mixed and stirred at room temperature for 1 hour. 4-(6-ethoxypyrazin-2-yl)aniline 3b (90 mg, 256.10 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. Methanol (1 mL) was added to quench the mixture, and the mixture was concentrated under reduced pressure. Dilute hydrochloric acid (1 M, 2 mL) and dichloromethane (5 mL) were added to the residue, and the insoluble solid was removed by filtration. The filtrate was separated, and the dichloromethane phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide 31 (25 mg) in a yield of 14.92%.

[0947] MS m / z(ESI):521.8[M+1]

[0948] 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),8.63(s,1H),8.06(s,1H),7.95(d,J=8.4Hz,2H),7.57(d,J=8.4Hz,3H),4.34(q,J=7.1Hz,2H),2. 87(d,J=13.5Hz,2H),2.08(d,J=13.4Hz,2H),1.36–1.20(m,6H),0.78(d,J=11.6Hz,4H),0.34(q,J=7.3Hz,1H),-0.00(q,J=4.4Hz,1H).

[0949] Example 32

[0950] 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[0951] 2-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[0952] first step

[0953] methyl 2-(4-bromopyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate

[0954] 2-(4-bromopyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[0955] 2-(4-bromopyridin-2-yl)acetic acid methyl ester 17d (500 mg, 2.17 mmol) was added to N,N-dimethylformamide (1 mL), and the argon was replaced three times. Under ice-water bath cooling, sodium hydroxide (199.95 mg, 5.00 mmol) was slowly added and stirred for 0.5 hours. 1,2-bis(chloromethyl)benzene (494.59 mg, 2.83 mmol) was added and stirred at room temperature for 23 hours. After the reaction was complete, the mixture was added. Ethyl acetate (30 mL) and water (15 mL) were added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: System B) to give methyl 2-(4-bromopyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32a (280 mg) in a yield of 38.78%.

[0956] MS m / z(ESI):333.0[M+1]

[0957] Step 2

[0958] methyl 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate

[0959] 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[0960] Methyl 2-(4-bromopyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32a (230 mg, 692.37 μmol), cyclopropanesulfonamide (125.83 mg, 1.04 mmol), cesium carbonate (451.18 mg, 1.38 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (58.80 mg, 138.47 μmol) and allylpalladium(II) chloride dimer (25.33 mg, 69.24 umol) were added sequentially to 1,4-dioxane (2 mL), the argon atmosphere was replaced three times, and the temperature was raised to 90 °C and stirred for 2 hours. The residue was concentrated under reduced pressure and separated by silica gel column chromatography (eluent: System B) to give methyl 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32b (100 mg) in a yield of 38.78%.

[0961] MS m / z(ESI):373.1[M+1]

[0962] Step 3

[0963] 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[0964] 2-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[0965] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (57.80 mg, 268.50 μmol) was added to toluene (1 mL), and the argon atmosphere was replaced three times. A toluene solution of trimethylaluminum (2 M, 469.88 μL) was slowly added dropwise, and the mixture was stirred for 1 hour. Methyl 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32b (100 mg, 268.50 μmol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was complete, the product was concentrated under reduced pressure and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide 32 (64.54 mg) in a yield of 33.74%.

[0966] MS m / z(ESI):556.2[M+1]

[0967] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.77(s,1H),8.51(d,J=6.2Hz,1H),8.19(s, 1H),8.09(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H),7.40(s,1H),7.35(d,J=6.2Hz,1H ),7.29(d,J=4.2Hz,2H),7.20(d,J=4.3Hz,2H),4.45(t,J=7.1Hz,2H),3.98(d,J=1 6.2Hz,2H),3.58(s,2H),2.88(s,1H),1.39(t,J=7.0Hz,3H),0.99(d,J=9.0Hz,4H).

[0968] Example 33

[0969] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0970] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0971] first step

[0972] (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile

[0973] (1R,5S)-6-(4-Bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile

[0974] Under ice-water bath, 2-(4-bromopyridin-2-yl)acetonitrile 28a (1 g, 5.08 mmol) was added to anhydrous ethylene glycol dimethyl ether (40 mL), sodium hydride (446.63 mg, 11.17 mmol, 60% purity) was added, and stirred at room temperature for 0.5 hours. (3aR, 6aS)-tetrahydrofuro[3,4-d][1,3,2]dioxythiophene 2,2-dioxide 4c (1.26 g, 7 .61 mmol), heated to 60°C and stirred for 18 hours, water (50 mL) and ethyl acetate (50 mL) were added, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile 33a (800 mg) in a yield of 59.46%.

[0975] MS m / z(ESI):265.1[M+1]

[0976] Step 2

[0977] (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0978] (1R,5S)-6-(4-Bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0979] (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile 33a (1.6 g, 6.04 mmol) was added to dimethyl sulfoxide (3 mL), and sodium hydroxide (482.83 mg, 12.07 mmol) was added under ice-water bath. After stirring for 10 minutes, hydrogen peroxide (1.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. Water (10 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 33b (1.2 g) in a yield of 0.23%.

[0980] MS m / z(ESI):283.0[M+1]

[0981] Step 3

[0982] (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[0983] (1R,5S)-6-(4-Bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[0984] (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 33b (1.2 g, 4.24 mmol), acetic acid (1.50 mL), and acetic anhydride (3 mL) were added to dimethyl sulfoxide (3 mL). Sodium nitrite (2.92 g, 42.38 mmol) was added under ice-water bath, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water (10 mL), neutralized with saturated sodium bicarbonate solution, and the pH was adjusted to acidic by adding saturated citric acid solution. The product was extracted with ethyl acetate (20 mL × 3). The aqueous phase was collected and purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 33c (200 mg) in a yield of 16.61%.

[0985] MS m / z(ESI):284.0[M+1]

[0986] Step 4

[0987] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylicacid

[0988] (1R,5S)-6-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[0989] (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 33c (750 mg, 2.64 mmol), cyclopropanesulfonamide (383.81 mg, 3.17 mmol), cesium carbonate (1.72 g, 5.28 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (112 mg, 263 μmol) and allylpalladium(II) chloride dimer (48.29 mg, 131.99 μmol) were added sequentially to 1,4-dioxane (10 mL), the argon atmosphere was replaced three times, and the temperature was raised to 90 °C and stirred for 2 h. The reaction solution was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 33d (110 mg) in a yield of 12.85%.

[0990] MS m / z(ESI):325.0[M+1]

[0991] Step 5

[0992] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0993] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[0994] Under ice-water bath, (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 33d (110 mg, 339.14 μmol), N-methylpyrrolidone (1 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (189.92 mg, 678.28 μmol) and N-methylimidazole (111.37 mg, 1.36 mmole) were added to the mixture. ol) was added to a 15 mL single-necked bottle and reacted at room temperature for 0.5 hours. 4-(6-ethoxypyrazin-2-yl)aniline 3b (87.60 mg, 406.97 μmol) was added and the temperature was raised to 90°C for 2 hours. The reaction solution was cooled to room temperature, and water (10 mL) and EA (10 mL) were added. The extract was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 33 (25 mg) with a yield of 11.50%.

[0995] MS m / z(ESI):522.2[M+1]

[0996] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.77(s,1H),8.39(d,J=6.1Hz,1H),8.23–8.02(m,3H),7.82(d,J=8.3Hz,2H),7.34(s,1H),7.17(d,J=5 .9Hz,1H),4.48(q,J=7.5Hz,2H),4.13(d,J=8.9Hz,2H),3.82(d,J=8.8Hz,2H),2.82(s,1H),2.48(s,2H),1.40(t,J=7.1Hz,3H),1.24(s,1H).

[0997] Example 34

[0998] 2-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[0999] 2-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1000] According to the synthesis method of Example 15 of the present invention, the starting material bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester 2a in Example 15 is replaced with 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester to obtain 2-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide 34.

[1001] MS m / z(ESI):557.1[M+1]

[1002] 1H NMR (400MHz, DMSO-d6) δ9.79(s,1H),8.75(s,1H),8.51(s,1H),8.16(s,1H),8.06(d,J=8. 8Hz,2H),7.78(d,J=8.9Hz,2H),7.23(dd,J=5.4,3.3Hz,2H),7.13(dd,J=5.5,3.2Hz,2H),6 .81(d,J=5.7Hz,1H),4.47(q,J=7.0Hz,2H),3.84(d,J=16.3Hz,2H),3.74(d,J=16.3Hz,2H) ,2.83(td,J=8.1,4.8Hz,1H),1.39(t,J=7.0Hz,3H),1.05–0.96(m,2H),0.81–0.69(m,2H).

[1003] Example 35 and Example 36

[1004] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-6-(4-(N-methylcyclopropanesulfonamido)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 35

[1005] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-6-(4-(N-methylcyclopropanesulfonamido)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 35

[1006] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

[1007] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 36

[1008] first step

[1009] tert-butyl(1R,5S)-6-(4-bromopyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1010] tert-Butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1011] Under ice-water bath, 2-(4-bromopyridin-2-yl)acetonitrile 28a (1 g, 5.08 mmol) was added to anhydrous ethylene glycol dimethyl ether (40 mL), sodium cyanide (446.63 mg, 11.17 mmol, 60% purity) was added, and stirred at room temperature for 0.5 hours. Then, (3aR, 6aS)-tetrahydro-5H-[1,3,2]dioxythieno[4,5-c]pyrrole-5-carboxylic acid 2,2-dioxide tert-butyl ester 9c (1.88 g) was added. , 7.11 mmol), heated to 70 ° C and stirred for 6 hours, water (50 mL) and ethyl acetate (50 mL) were added, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain (1R,5S)-6-(4-bromopyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 35a (1.1 g) in a yield of 59.50%.

[1012] Step 2

[1013] tert-butyl

[1014] (1R,5S)-6-(4-bromopyridin-2-yl)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1015] tert-Butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1016] Tert-butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate 35a (1.1 g, 3.02 mmol) and sodium hydroxide (241.60 mg, 6.04 mmol) were added to dimethyl sulfoxide (3 mL). Hydrogen peroxide (1.5 mL) was added dropwise at room temperature and stirred at room temperature for 2 hours. Water (50 mL) and ethyl acetate (50 mL) were added, the mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 35b (1 g) in a yield of 86.62%.

[1017] MS m / z(ESI):383.0[M+1]

[1018] Step 3 (1R,5S)-6-(4-bromopyridin-2-yl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[1019] (1R,5S)-6-(4-Bromopyridin-2-yl)-3-(tert-butyloxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[1020] To a mixture of tert-butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 35b (1.1 g, 2.88 mmol), acetic acid (3 mL) and acetic anhydride (3 mL) was added sodium nitrite (1.99 g, 28.78 mmol), and the mixture was heated to 45°C and stirred for 5 hours. Water (3 mL) was added to dissolve the mixture, and the mixture was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(4-bromopyridin-2-yl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 35c (700 mg) in a yield of 63.47%.

[1021] MS m / z(ESI):383.0[M+1]

[1022] Step 4

[1023] tert-butyl

[1024] (1R,5S)-6-(4-bromopyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1025] tert-Butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1026] Under ice-water bath, (1R,5S)-6-(4-bromopyridin-2-yl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 35c (340 mg, 887.18 μmol), N-methylpyrrolidone (3 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (496.82 mg, 1.77 mmol) and N-methylimidazole (291.35 mg, 3.55 mmol) were added to a 15 mL single-necked flask and reacted at room temperature for 0.5 h. 4-(6-ethoxypyrazin-2-yl)aniline 3b (210.06 mg, 975.90 μmol) was added, and the temperature was raised to 50°C and stirred for 18 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-6-(4-bromopyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 35d (400 mg) in a yield of 77.67%.

[1027] MS m / z(ESI):580.1[M+1]

[1028] Step 5

[1029] tert-butyl

[1030] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1031] tert-Butyl (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1032] Tert-butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 35d (150 mg, 258.41 μmol), cyclopropanesulfonamide (37.57 mg, 310.09 μmol), cesium carbonate (168.39 mg, 516.82 μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (10.97 mg, 25.84 μmol) and allylpalladium(II) chloride were added. The dimer (4.73 mg, 12.92 μmol) was sequentially added to 1,4-dioxane (4 mL), and the argon atmosphere was replaced three times. The temperature was raised to 90°C, stirred for 2 hours, and concentrated under reduced pressure. The residue was filtered to remove insoluble solids and purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 35e (100 mg) in a yield of 62.34%.

[1033] MS m / z(ESI):621.0[M+1]

[1034] Step 6 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[1035] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[1036] Tert-butyl (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 35e (100 mg, 161.10 μmol) was added to a solution of hydrogen chloride in dioxane (4 M, 5 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was directly used in the next reaction.

[1037] MS m / z(ESI):521.1[M+1]

[1038] Step 7 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-6-(4-(N-methylcyclopropanesulfonamido)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 35

[1039] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-6-(4-(N-methylcyclopropanesulfonamido)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 35

[1040] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

[1041] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 36

[1042] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 35f (60 mg, 115.25 μmol), sodium hydroxide (4.61 mg, 115.25 μmol), paraformaldehyde (3.46 mg, 115.25 μmol) and formic acid (13.25 mg, 288.13 μmol) were added to tetrahydrofuran (5 mL), heated to 80 °C and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-6-(4-(N-methylcyclopropanesulfonamido)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 35 and (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 36.

[1043] Example 35: 5 mg, yield 6.28%.

[1044] MS m / z(ESI):549.2[M+1]

[1045] 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.41(d,J=6.0Hz,1H),8.19(s,1H),8.07(d,J=8.3Hz,2H), 7.88(s,1H),7.72(d,J=8.3Hz,2H),7.32(s,1H),7.21(d,J=5.8Hz,1H),4.48(q,J=7.0Hz,2H),4. 15(d,J=12.2Hz,1H),4.05(d,J=11.3Hz,1H),3.77(dd,J=11.4,3.9Hz,1H),3.39–3.31(m,1H),2 .85(s,1H),2.50(s,6H),2.48–2.35(m,2H),1.40(t,J=7.0Hz,3H),1.00(dd,J=12.8,4.9Hz,4H).

[1046] Example 36: 20 mg, yield 26.22%.

[1047] MS m / z(ESI):535.2[M+1]

[1048] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),10.81(s,1H),8.80(s,1H),8.38(d,J=5.6Hz,1H),8.21 (s,1H),8.15(d,J=8.4Hz,2H),7.87(d,J=8.4Hz,2H),7.26(s,1H),7.17–7.09(m,1H),4.48(q, J=7.0Hz,2H),4.20(s,1H),3.92–3.80(m,1H),3.67(d,J=10.7Hz,1H),3.16(d,J=11.1Hz,1H) ,2.89(s,1H),2.67–2.60(m,1H),2.51–2.48(m,3H),1.41(t,J=7.0Hz,3H),1.03–0.85(m,4H).

[1049] Example 37

[1050] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

[1051] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

[1052] According to the synthesis methods of Examples 9 and 10 of the present invention, the raw material 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile 4b in Example 9 was replaced with 2-(6-(methylthio)pyrimidin-4-yl)acetonitrile 27a to obtain (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 37.

[1053] MS m / z(ESI):536.2[M+1]

[1054] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.50(s,1H),8.21(s,1H),8.15(d,J=8.4Hz,2 H),7.87(d,J=8.4Hz,2H),7.26(s,1H),7.17–7.09(m,1H),4.48(q,J=7.0Hz,2H),4.2 0(s,1H),3.92–3.80(m,1H),3.67(d,J=10.7Hz,1H),3.16(d,J=11.1Hz,1H),2.89(s, 1H),2.67–2.60(m,1H),2.51–2.48(m,3H),1.41(t,J=7.0Hz,3H),1.03–0.85(m,4H).

[1055] Example 38

[1056] 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1057] 3-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1058] Ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15d (54.15 mg, 250.41 μmol) was added to toluene (1.86 mL), followed by a toluene solution of trimethylaluminum (2 M, 409.77 μL), and the mixture was stirred at room temperature for 1 hour. 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine 1d (80 mg, 227.65 μmol) was added, and the mixture was heated to 90°C and stirred for 1.5 hours. The reaction solution was cooled to room temperature, quenched by the addition of methanol (1 mL), and concentrated under reduced pressure. 1 M dilute hydrochloric acid (2 mL) and dichloromethane (5 mL) were added to the residue, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 38 (13 mg) in a yield of 8.86%.

[1059] MS m / z(ESI):522.1M+1].

[1060] 1 H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.92–8.81(m,1H),8.69(s,1H),8.35(d,J=6.4 Hz,2H),8.14–7.97(m,2H),6.67(d,J=5.7Hz,1H),4.32(d,J=7.1Hz,2H),2.97(dt,J=8 .0,3.7Hz,1H),2.67(d,J=13.7Hz,2H),2.47(d,J=13.5Hz,2H),1.26(t,J=6.9Hz,5H) ,0.93(p,J=4.9Hz,2H),0.79–0.69(m,2H),0.30–0.20(m,1H),-0.00(q,J=4.3Hz,1H).

[1061] Example 39

[1062] 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[1063] 3-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide

[1064] Ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15d (58.41 mg, 250.41 μmol) was added to toluene (1.86 mL), followed by a 2M toluene solution of trimethylaluminum (409.77 μL). The mixture was stirred at room temperature for 1 hour. 4-(6-ethoxypyrazin-2-yl)-2-fluoroaniline 12b (80 mg, 227.65 μmol) was then added, and the mixture was heated to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the mixture, and the mixture was concentrated under reduced pressure. 1 M dilute hydrochloric acid (2 mL) and dichloromethane (5 mL) were added to the residue, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-3-carboxamide 39 (13 mg) in a yield of 7.44%.

[1065] MS m / z(ESI):521.8[M+1].

[1066] 1 H NMR(400MHz,DMSO-d6)δ11.28(s,1H),9.41(s,1H),8.83(s,1H),8.52(s,1H),8.24(s,1H),7.95(s,2H),7.80(s,1H),6.84(s,1H) ,4.48(s,2H),3.16(s,1H),2.81(s,2H),2.60(d,J=13.7Hz,2H),1.40(s,5H),1.13(s,2H),1.01(s,2H),0.40(s,1H),0.26(s,1H)

[1067] Example 40

[1068] 2-(3-(cyclopropanesulfonamido)phenyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1069] 2-(3-(Cyclopropanesulfonamido)phenyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1070] first step

[1071] methyl 2-(3-bromophenyl)-2,3-dihydro-1H-indene-2-carboxylate

[1072] 2-(3-bromophenyl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[1073] Methyl 2-(3-bromophenyl)acetate 40a (2.5 g, 10.91 mmol), 1,2-bis(chloromethyl)benzene (2.87 g, 16.37 mmol), and sodium hydride (1.09 g, 27.28 mmol, 60% purity) were added to tetrahydrofuran (50 mL) and stirred at 60°C for 18 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (50 mL) and water (30 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 2-(3-bromophenyl)-2,3-dihydro-1H-indene-2-carboxylate 40b (2.2 g) in a yield of 60.86%.

[1074] MS m / z(ESI):332.1[M+1]

[1075] Step 2

[1076] methyl 2-(3-(cyclopropanesulfonamido)phenyl)-2,3-dihydro-1H-indene-2-carboxylate

[1077] 2-(3-(cyclopropanesulfonamido)phenyl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[1078] 2-(3-Bromophenyl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester 40b (1.1 g, 3.32 mmol), cyclopropanesulfonamide (482.87 mg, 3.99 mmol), cesium carbonate (2.16 g, 6.64 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (141.03 mg, 332.12 μmol) and allylpalladium(II) chloride dimer (60.76 mg, 166.06 μmol) were added sequentially to 1,4-dioxane (4 mL), the argon atmosphere was replaced three times, the temperature was raised to 100 °C and stirred for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Methanol (10 mL) was added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to give methyl 2-(3-(cyclopropanesulfonamido)phenyl)-2,3-dihydro-1H-indene-2-carboxylate 40c (800 mg) in a yield of 64.85%.

[1079] MS m / z(ESI):389.1[M+18]

[1080] Step 3

[1081] 2-(3-(cyclopropanesulfonamido)phenyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1082] 2-(3-(Cyclopropanesulfonamido)phenyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1083] Methyl 2-(3-(cyclopropanesulfonamido)phenyl)-2,3-dihydro-1H-indene-2-carboxylate 40c (122.85 mg, 570.72 μmol) was added to toluene (1.24 mL), and a toluene solution of trimethylaluminum (2 M, 1.03 mL) was added. The mixture was stirred at room temperature for 1 hour. 4-(6-ethoxypyrazin-2-yl)aniline 3b (220 mg, 570.72 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. Methanol (1 mL) was added to quench the reaction mixture, and the mixture was concentrated under reduced pressure. 1 M dilute hydrochloric acid (2 mL) and dichloromethane (5 mL) were added to the residue, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 2-(3-(cyclopropanesulfonamido)phenyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide 40 (160 mg) in a yield of 40.75%.

[1084] MS m / z(ESI):555.1[M+1]

[1085] 1 H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.63(s,1H),8.73(s,1H),8.16(s,1H),8.0 5(d,J=8.6Hz,2H),7.76(d,J=8.6Hz,2H),7.31–7.20(m,3H),7.22–7.10(m,3H),7 .08(dd,J=7.9,2.1Hz,1H),4.46(q,J=7.0Hz,2H),3.90(d,J=15.9Hz,2H),3.36(d ,J=16.0Hz,2H),2.45(d,J=4.6Hz,1H),1.38(t,J=7.0Hz,3H),0.89–0.70(m,4H).

[1086] Example 41

[1087] 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1088] 2-(6-(Cyclopropanesulfonyl)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1089] first step

[1090] methyl 2-(6-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[1091] 2-(6-(Methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[1092] 4-Chloro-6-(methylthio)pyrimidine 13a (328.16 mg, 2.04 mmol) and methyl 2,3-dihydro-1H-indene-2-carboxylate 41a (300 mg, 1.70 mmol, commercially available) were added sequentially to tetrahydrofuran (1 mL), and the argon atmosphere was replaced three times. A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (5.11 mL) was slowly added dropwise at -30°C, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 2-(6-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41b (290 mg) in a 56.71% yield.

[1093] MS m / z(ESI):301.0[M+1]

[1094] Step 2

[1095] methyl 2-(6-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[1096] 2-(6-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[1097] Methyl 2-(6-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41b (290 mg, 965.46 μmol) and m-chloroperbenzoic acid (366.53 mg, 2.12 mmol) were added sequentially to dichloromethane (0.5 mL). The argon atmosphere was replaced three times, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (30 mL) and water (15 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 2-(6-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41c (220 mg) in a yield of 68.56%.

[1098] MS m / z(ESI):333.1[M+1]

[1099] Step 3

[1100] methyl 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[1101] 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester

[1102] Methyl 2-(6-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41c (630 mg, 1.90 mmol), cyclopropanesulfonamide (275.58 mg, 2.27 mmol), and cesium carbonate (1.24 g, 3.79 mmol) were added sequentially to N-methylpyrrolidone (2 mL). The atmosphere was replaced with argon three times, and the mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41d (398 mg) in a 56.23% yield.

[1103] MS m / z(ESI):374.1[M+1]

[1104] Step 4

[1105] 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1106] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (69.17 mg, 321.35 μmol) was added to toluene (1.24 μL), and the argon atmosphere was replaced three times. A toluene solution of trimethylaluminum (2 M, 468.63 μL) was slowly added dropwise and stirred for 0.5 h. Then, methyl 2-(6-(cyclopropanesulfonylamino)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41d (100.00 mg, 267.79 μmol) was added and the temperature was raised to 90 °C and stirred for 5 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide 41 (81 mg) in a yield of 41.90%.

[1107] MS m / z(ESI):557.1[M+1]

[1108] 1 H NMR (400MHz, DMSO-d6) δ9.76 (s, 1H), 8.75 (s, 2H), 8.17 (s, 1H), 8.07 (d, J = 8. 8Hz,2H),7.77(d,J=8.8Hz,2H),7.26(dd,J=5.4,3.3Hz,2H),7.17(dd,J=5.5 ,3.2Hz,2H),6.99(s,1H),4.47(q,J=7.0Hz,2H),3.85(s,2H),3.81(s,2H),3 .50(d,J=16.4Hz,2H),3.01(s,1H),1.39(t,J=7.1Hz,3H),1.07-0.92(m,4H).

[1109] Example 42

[1110] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1111] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1112] first step

[1113] 4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)aniline

[1114] 4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)aniline

[1115] 3-Bromo-5-chloropyrazolo[1,5-a]pyridine 42a (230 mg, 993.62 μmol, according to the published patent “WO2022087634 A1”), (4-aminophenyl)boronic acid 42b (149.68 mg, 1.09 mmol, commercially available), 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (72.70 mg, 99.36 μmol) and potassium carbonate (411.98 mg, 2.98 mmol) were added to a mixed solvent of 1,4-dioxane (2 mL) and water (0.5 mL), and the atmosphere was replaced with argon three times. The temperature was raised to 95°C and stirred for 1.5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)aniline 42c (130 mg) in a yield of 53.69%.

[1116] MS m / z(ESI):244.1[M+1]

[1117] Step 2

[1118] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1119] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1120] 4-(5-Chloropyrazolo[1,5-a]pyridin-3-yl)aniline 42c (61.02 mg, 250.41 μmol) was added to toluene (1.86 mL), and a toluene solution of trimethylaluminum (2 M, 409.77 μL) was added. The mixture was stirred at room temperature for 1 hour. Ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15d (80 mg, 227.65 μmol) was added, and the mixture was heated to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the mixture, and the mixture was concentrated under reduced pressure. 1 M dilute hydrochloric acid (2 mL) and dichloromethane (5 mL) were added to the residue, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 42 (25 mg) in a yield of 15.57%.

[1121] MS m / z(ESI):549.1[M+1]

[1122] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.30(s,1H),8.59(d,J=7.4Hz,1H),8.32(d,J=5.8Hz,1H),8.21(s, 1H),7.84(d,J=2.3Hz,1H),7.54(d,J=8.2Hz,2H),7.43(d,J=8.3Hz,2H),6.80(dd,J=7.4,2.3Hz,1H),6.61 (d,J=5.7Hz,1H),3.03–2.95(m,1H),2.67(d,J=13.4Hz,2H),2.40(d,J=13.4Hz,2H),1.22(dd,J=7.8,4.0 Hz,2H),0.88(d,J=4.2Hz,2H),0.68(dt,J=7.9,3.5Hz,2H),0.20(d,J=6.8Hz,1H),-0.00(d,J=4.4Hz,1H).

[1123] Example 43

[1124] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1125] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1126] first step

[1127] tert-butyl 2-cyano-2-(4-(methylthio)pyrimidin-2-yl)acetate

[1128] tert-Butyl 2-cyano-2-(4-(methylthio)pyrimidin-2-yl)acetate

[1129] Under ice-water bath, tert-butyl 2-cyanoacetate (11.86 g, 84.05 mmol, commercially available) was added to tetrahydrofuran (100 mL), and sodium hydride (4.48 g, 112.06 mmol, 60% purity) was added portionwise. The mixture was stirred at room temperature for 0.5 h, and 2-chloro-4-(methylthio)pyrimidine 15a (9.00 g, 56.03 mmol) was added. The temperature was raised to 75 °C and stirred for 18 h. Water (100 mL) and ethyl acetate (100 mL) were added. The liquids were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 2-cyano-2-(4-(methylthio)pyrimidin-2-yl)acetate 43a (14 g) in a yield of 47.08%.

[1130] MS m / z(ESI):266.3[M+1]

[1131] Step 2

[1132] 2-(4-(methylthio)pyrimidin-2-yl)acetonitrile

[1133] 2-(4-(Methylthio)pyrimidin-2-yl)acetonitrile

[1134] Tert-butyl 2-cyano-2-(4-(methylthio)pyrimidin-2-yl)acetate 43a (14.87 g, 28.02 mmol) and trifluoromethane (10 mL) were added to dichloromethane (30 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to 7-8 by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to dryness. The residue was purified by silica gel column chromatography (eluent: System B) to afford 2-(4-(methylthio)pyrimidin-2-yl)acetonitrile 43b (4.1 g) in an 88.56% yield.

[1135] MS m / z(ESI):166.2[M+1]

[1136] Step 3

[1137] (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[1138] (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[1139] Under ice-water bath, 2-(4-(methylthio)pyrimidin-2-yl)acetonitrile 43b (1 g, 6.05 mmol) was added to anhydrous ethylene glycol dimethyl ether (40 mL), sodium hydride (532.64 mg, 13.32 mmol, 60% purity) was added, and stirred at room temperature for 0.5 hours. (3aR, 6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxythiophene 2,2-dioxide 8b (1.4 The mixture was heated to 65°C and stirred for 6 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the liquids were separated. The organic phase was dried over anhydrous sodium sulfate, filtered and dried. The residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile 43c (700 mg) in a yield of 50.00%.

[1140] MS m / z(ESI):232.0[M+1]

[1141] Step 4

[1142] (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1143] (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1144] (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile 43c (700 mg, 3.03 mmol) and sodium hydroxide (242.09 mg, 6.05 mmol) were added to dimethyl sulfoxide (3 mL), and hydrogen peroxide (3 mL) was added. The temperature was raised to 30°C and stirred for 18 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide 43d (430 mg) in a yield of 56.99%.

[1145] MS m / z(ESI):250.0[M+1]

[1146] Step 5

[1147] (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[1148] (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[1149] (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide 43d (430 mg, 1.72 mmol), acetic acid (2 mL), and acetic anhydride (4 mL) were mixed, and sodium nitrite (1.19 g, 17.25 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was dissolved in water (5 mL) and purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to afford (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 43e (170 mg) in a 39.38% yield. MS m / z(ESI):251.0[M+1]

[1150] Step 6 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1151] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1152] Under ice-water bath, (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 43e (88 mg, 351.56 μmol), N-methylpyrrolidone (2 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (196.87 mg, 703.11 μmol) and N-methylimidazole (115.45 mg, 1.41 mmol) were added to a 15 mL single-necked flask and reacted at room temperature for 0.5 h. 4-(6-ethoxypyrazin-2-yl)aniline 3b (83.24 mg, 386.71 μmol) was added, and the temperature was raised to 90 °C and stirred for 18 h. After the reaction was complete, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide 43f (120 mg) in a 76.27% yield. MS m / z (ESI): 448.0 [M+1].

[1153] Step 7

[1154] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylsulfinyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1155] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylsulfinyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1156] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide 43f (120 mg, 268.13 μmol) and m-chloroperbenzoic acid (97.98 mg, 482.63 μmol, 85% purity) were added to dichloromethane (2 mL) and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added for neutralization, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 43 g (100 mg) of (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylsulfinyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide in an 80.46% yield. MS m / z (ESI): [M+1] 464.0

[1157] Step 8

[1158] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1159] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1160] 43 g (120 mg, 258.87 μmol) of (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylsulfinyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide, cyclopropanesulfonamide (47.05 mg, 388.31 μmol) and cesium carbonate (168.69 mg, 517.74 μmol) were added to N-methylpyrrolidone (1 mL) and the temperature was raised to 90°C for 1 hour. The reaction solution was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL) were added. The pH was adjusted to 6-7 with 1 M dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-carboxamide 43 (25 mg) in a yield of 14.76%.

[1161] MS m / z(ESI):521.2[M+1]

[1162] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),10.31(s,1H),8.76(s,1H),8.42(d,J=5.6Hz,1H),8.18(s, 1H),8.07(d,J=8.3Hz,2H),7.83(d,J=8.4Hz,2H),6.70(d,J=5.6Hz,1H),4.48(q,J=7.1Hz,2H),3. 26–3.15(m,1H),2.21(s,2H),2.12(dd,J=13.2,8.5Hz,2H),2.00(t,J=11.2Hz,2H),1.64(d,J=11. 1Hz,1H),1.40(t,J=7.1Hz,3H),1.09(d,J=12.2Hz,1H),1.05–0.95(m,2H),0.81(d,J=7.7Hz,2H).

[1163] Example 44

[1164] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[1165] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[1166] According to the synthesis method of Example 43 of the present invention, the raw material (3aR,6aS)-tetrahydro-4H-cyclopentadien[d][1,3,2]dioxythiophene 2,2-dioxide 8b in Example 43 is replaced with (3aR,6aS)-tetrahydrofuran[3,4-d][1,3,2]dioxythiophene 2,2-dioxide 4c to obtain (1R,5S)-6-(4-(cyclopropanesulfonyl)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 44.

[1167] MS m / z(ESI):523.2[M+1].

[1168] 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),10.29(s,1H),8.80(s,1H),8.50(d,J=5.6Hz,1H), 8.22(s,1H),8.12(d,J=8.3Hz,2H),7.85(d,J=8.4Hz,2H),6.78(d,J=5.7Hz,1H),4.53(q ,J=7.0Hz,2H),4.17(d,J=8.8Hz,2H),3.88(d,J=8.7Hz,2H),3.37(s,2H),3.30–3.20(m, 1H), 1.45 (t, J=7.0Hz, 3H), 1.05 (dd, J=7.2, 4.3Hz, 2H), 0.86 (tt, J=7.6, 5.1, 4.6Hz, 2H).

[1169] Example 45

[1170] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1171] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1172] first step

[1173] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1174] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1175] Under ice-water bath, (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 29c (85 mg, 339.57 μmol), N-methylpyrrolidone (2 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (190.16 mg, 679.14 μmol) and N-methylimidazole (111.52 mg, 1.36 mmol) were added to a 15 mL single-necked bottle and reacted at room temperature for 0.5 h. Then, 4-(6-ethoxypyrazin-2-yl)-2- Fluoroaniline 12b (87.12 mg, 373.53 μmol) was heated to 90°C and stirred for 18 hours. The reaction solution was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL) were added. The product was extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 45a (60 mg) in a yield of 18.98%.

[1176] MS m / z(ESI):466.0[M+1]

[1177] Step 2

[1178] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylsulfinyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1179] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylsulfinyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[1180] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 45a (60 mg, 128.88 μmol) and m-chloroperbenzoic acid (41.87 mg, 206.21 μmol, 85% purity) were added to dichloromethane (2 mL) and stirred at room temperature for 3 hours. , saturated sodium bicarbonate solution was added for neutralization, and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylsulfinyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 45b (60 mg) with a yield of 96.68%.

[1181] MS m / z(ESI):482.0[M+1]

[1182] Step 3

[1183] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1184] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1185] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylsulfinyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 45b (60 mg, 124.60 μmol), cyclopropanesulfonamide (22.64 mg, 186.90 μmol), and cesium carbonate (81.19 mg, 249.20 μmol) were added to N-methylpyrrolidone (1 mL), and the temperature was raised to 90°C with stirring for 1 hour. The reaction solution was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL) were added. The pH was adjusted to 6-7 with 1 M dilute hydrochloric acid, and the product was extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-6-carboxamide 45 (3.53 mg), with a yield of 4.26%.

[1186] MS m / z(ESI):539.1[M+1]

[1187] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.86(s,1H),8.68(s,1H),8.26(s,1H),8.07–7.93(m,3H),7.01(s,1H),4.49(q,J=7.0Hz,2H),2.21( d,J=3.3Hz,2H),2.12(dd,J=13.3,8.4Hz,2H),2.00(d,J=8.4Hz,3H),1.41(t,J=7.0Hz,3H),1.17(t,J=7.1Hz,2H),1.05(d,J=14.8Hz,4H).

[1188] Example 46

[1189] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1190] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-6-carboxamide

[1191] According to the synthesis method of Example 45 of the present invention, the raw material (1R, 5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 29c in Example 45 is replaced with (1R, 5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 43e to obtain (1R, 5S)-6-(4-(cyclopropanesulfonyl)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicyclo[3.1.0]hexane-6-carboxamide 46.

[1192] MS m / z(ESI):539.1[M+1]

[1193] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),10.06(s,1H),8.83(s,1H),8.41(d,J=5.6Hz,1H),8.23(d, J=2.7Hz,2H),7.97(d,J=10.2Hz,2H),6.70(d,J=5.6Hz,1H),4.49(q,J=7.0Hz,2H),3.21(d,J=8. 2Hz,1H),2.20(d,J=3.0Hz,2H),2.13(dd,J=13.2,8.4Hz,2H),1.98(d,J=11.3Hz,2H),1.64(s,1H ), 1.41 (t, J = 7.0Hz, 3H), 1.17 (d, J = 6.0Hz, 1H), 1.05 (t, J = 3.3Hz, 2H), 0.92 (h, J = 5.2, 4.7Hz, 2H).

[1194] Example 47

[1195] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[1196] (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[1197] According to the synthesis method of Example 45 of the present invention, the raw material 4-(6-ethoxypyrazin-2-yl)-2-fluoroaniline 12b in Example 45 is replaced by 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine 1d to obtain (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 47.

[1198] MS m / z(ESI):524.2[M+1]

[1199] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),9.08(d,J=2.5Hz,1H),8.85(s,1H),8.71(s,1H),8.53(dd,J=8.7,2.5Hz,1H),8.34–8.20(m,2H),6.95(s,1 H),4.49(q,J=7.0Hz,2H),4.11(d,J=9.0Hz,2H),3.82(d,J=8.8Hz,2H),3 .04(s,1H),1.41(t,J=7.0Hz,3H),1.31–1.11(m,2H),1.11–0.91(m,4H).

[1200] Example 48

[1201] N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1202] N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1203] first step

[1204] 5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine

[1205] 5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine

[1206] 3-Bromo-5-chloropyrazolo[1,5-a]pyridine 42a (1.1 g, 4.75 mmol), (6-aminopyridin-3-yl)boronic acid 1c (721.01 mg, 5.23 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (347.71 mg, 475.21 μmol), and potassium carbonate (1.97 g, 14.26 mmol) were added to a mixture of 1,4-dioxane (2 mL) and water (0.5 mL). The atmosphere was replaced with argon three times, and the mixture was heated to 95°C and stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System B) to afford 5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine 48a (900 mg, 3.68 mmol, 77.40% yield). MS m / z(ESI):[M+1]245.1

[1207] Step 2

[1208] N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1209] N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1210] 5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine 48a (114.88 mg, 469.52 μmol) was added to toluene (2 mL), and a toluene solution of trimethylaluminum (2 M, 768.31 μL) was added. The mixture was stirred at room temperature for 1 hour. Ethyl 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16d (150 mg, 426.84 μmol) was added, and the temperature was raised to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the mixture, and the mixture was concentrated under reduced pressure. 1 M dilute hydrochloric acid (2 mL) and dichloromethane (5 mL) were added to the residue, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 48 (3.5 mg) in a yield of 1.10%.

[1211] MS m / z(ESI):550.1[M+1]

[1212] 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.87(s,1H),8.63(d,J=7.4Hz,1H),8.51–8.41 (m,1H),8.32(s,1H),8.18(s,1H),8.04–7.82(m,4H),6.86(dd,J=7.4,2.2Hz,1H),2. 99–2.93(m,1H),2.77(d,J=13.7Hz,2H),2.27(d,J=13.8Hz,2H),1.27(dd,J=8.0,4.2 Hz,2H),0.94–0.88(m,2H),0.80–0.72(m,2H),0.33–0.24(m,1H),0.03–0.05(m,1H).

[1213] Example 49

[1214] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1215] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1216] 4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)aniline 42c (106.79 mg, 438.22 μmol) was added to toluene (1.55 mL), and trimethylaluminum in toluene solution (2 M, 717.09 μL) was added. The mixture was stirred at room temperature for 1 hour. Ethyl 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16d (140 mg, 398.38 μmol) was added, and the temperature was raised to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the mixture, and the mixture was concentrated under reduced pressure. 1 M dilute hydrochloric acid (2 mL) and dichloromethane (5 mL) were added to the residue, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 49 (10 mg) in a yield of 3.53%.

[1217] MS m / z(ESI):549.1[M+1]

[1218] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.50(s,1H),8.76(d,J=7.4Hz,1H),8.39(s,1H),8.25( s,1H),8.15(s,1H),8.02(d,J=2.3Hz,1H),7.69–7.60(m,4H),6.98(dd,J=7.4,2.3Hz,1H),3. 19–3.09(m,1H),2.93(d,J=13.6Hz,2H),2.43(d,J=13.6Hz,2H),1.47–1.39(m,2H),1.10(dt, J=6.6,3.3Hz,2H),0.96(dt,J=7.8,3.6Hz,2H),0.44(d,J=6.4Hz,1H),0.18(d,J=4.5Hz,1H).

[1219] Example 50

[1220] N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1221] N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1222] 5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine 48a (104.44 mg, 426.84 μmol) was added to toluene (2 mL), and a toluene solution of trimethylaluminum (2 M, 768.31 μL) was added. The mixture was stirred at room temperature for 1 hour. Ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15d (150.00 mg, 426.84 μmol) was added, and the temperature was raised to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the mixture, and the mixture was concentrated under reduced pressure. 1 M dilute hydrochloric acid (2 mL) and dichloromethane (5 mL) were added to the residue, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 50 (35 mg) in a yield of 11.11%.

[1223] MS m / z(ESI):550.1[M+1]

[1224] 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.75(s,1H),8.63(d,J=7.4Hz,1H),8.45(d,J=1.7Hz,1H),8.3 8–8.29(m,2H),7.94(dd,J=21.1,2.0Hz,3H),6.86(dd,J=7.4,2.2Hz,1H),6.65(d,J=5.7Hz,1H),2.9 8(s,1H),2.66(d,J=13.6Hz,2H),2.44(dd,J=13.5,3.3Hz,2H),1.24(dt,J=7.8,3.6Hz,2H),0.91(dd ,J=4.7,2.4Hz,2H),0.74(dd,J=7.9,2.7Hz,2H),0.23(td,J=8.0,5.1Hz,1H),0.01(d,J=4.3Hz,1H).

[1225] Example 51

[1226] 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-oxabicyclo[3.1.0]hexane-3-carboxamide

[1227] 3-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-oxabicyclo[3.1.0]hexane-3-carboxamide

[1228] first step

[1229] ethyl 1-(4-iodopyridin-2-yl)cyclopent-3-ene-1-carboxylate

[1230] Ethyl 1-(4-iodopyridin-2-yl)cyclopent-3-ene-1-carboxylate

[1231] Under an ice-water bath, 2-fluoro-4-iodopyridine 51a (279.38 mg, 1.25 mmol, commercially available) and ethyl cyclopent-3-ene-1-carboxylate 51b (263.45 mg, 1.88 mmol, commercially available) were added to tetrahydrofuran (3.81 mL). A 1 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (5.64 mL) was added and stirred at room temperature for 1 hour. The mixture was quenched by the addition of saturated ammonium chloride solution (3 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford ethyl 1-(4-iodopyridin-2-yl)cyclopent-3-ene-1-carboxylate 51c (190 mg) in a 26.51% yield. MS m / z (ESI): 344.1 [M+1].

[1232] Step 2

[1233] ethyl 3-(4-iodopyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate

[1234] 3-(4-iodopyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[1235] Ethyl 1-(4-iodopyridin-2-yl)cyclopent-3-ene-1-carboxylate 51c (2 g, 3.50 mmol) and m-chloroperbenzoic acid (1.42 g, 6.99 mmol, 85% purity) were added to dichloromethane (20 mL) and reacted overnight at room temperature. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford ethyl 3-(4-iodopyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate 51d (780 mg) in a 62.10% yield.

[1236] MS m / z(ESI):360.0[M+1]

[1237] Step 3

[1238] ethyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate

[1239] 3-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester

[1240] Ethyl 3-(4-iodopyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate 51d (780 mg, 2.17 mmol), cyclopropanesulfonamide (315.75 mg, 2.61 mmol), cesium carbonate (1.42 g, 4.34 mmol) and allylpalladium chloride (39.73 mg, 108.59 μmol) were added sequentially to 1,4-dioxane (10 mL), the argon atmosphere was replaced three times, and the temperature was raised to 90 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give ethyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate 51e (270 mg) in a yield of 35.28%.

[1241] MS m / z(ESI):353.0[M+1]

[1242] Step 4

[1243] 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-oxabicyclo[3.1.0]hexane-3-carboxamide

[1244] 3-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-oxabicyclo[3.1.0]hexane-3-carboxamide

[1245] Ethyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate 51e (100 mg, 464.57 μmol) was added to toluene (1.83 mL), and a toluene solution of trimethylaluminum (2 M, 836.23 μL) was added. The mixture was stirred at room temperature for 1 hour. 4-(6-ethoxypyrazin-2-yl)aniline 3b (163.72 mg, 464.57 μmol) was added, and the temperature was raised to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the mixture, and the mixture was concentrated under reduced pressure. 1 M dilute hydrochloric acid (2 mL) and dichloromethane (5 mL) were added to the residue, and the insoluble solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-oxabicyclo[3.1.0]hexane-3-carboxamide 51 (2.3 mg) in a yield of 0.73%.

[1246] MS m / z(ESI):552.1[M+1]

[1247] Example 52

[1248] 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1249] 2-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1250] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (31.31 mg, 134.25 μmol) was added to toluene (1.23 mL), and the argon atmosphere was replaced three times. A toluene solution of trimethylaluminum (2 M, 234.94 μL) was slowly added dropwise, and the mixture was stirred for 1 hour. Methyl 2-(4-(cyclopropanesulfonyl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32b (50 mg, 134.25 μmol) was added, and the mixture was heated to 90°C and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,3-dihydro-1H-indene-2-carboxamide 52 (22.2 mg) in a yield of 22.27%.

[1251] MS m / z(ESI):556.2[M+1]

[1252] 1 H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 8.82 (s, 1H), 8.50 (d, J = 5.8Hz, 1H), 8.24 (s, 1 H),8.02–7.92(m,2H),7.81(t,J=8.2Hz,1H),7.37(s,1H),7.28(dt,J=8.4,4.1Hz,3 H),7.18(dd,J=5.5,3.2Hz,2H),4.47(q,J=7.0Hz,3H),3.92(d,J=16.2Hz,2H),3.59 (d,J=16.2Hz,2H),2.83(q,J=6.6Hz,1H),1.39(t,J=7.0Hz,3H),1.06–0.93(m,4H).

[1253] Example 53

[1254] 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1255] 2-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1256] 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine 1d (29.03 mg, 134.25 μmol) was added to toluene (1.23 mL), and the argon atmosphere was replaced three times. A toluene solution of trimethylaluminum (2 M, 234.94 μL) was slowly added dropwise, and the mixture was stirred for 1 hour. Methyl 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32b (50 mg, 134.25 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide 53 (10.2 mg) in a yield of 9.52%.

[1257] MS m / z(ESI):556.2[M+1]

[1258] 1 H NMR (400MHz, DMSO-d6) δ10.38 (s, 1H), 9.02 (d, J = 2.4Hz, 1H), 8.83 (s, 1H), 8.48 (dd, J = 8. 8,2.5Hz,1H),8.43(d,J=5.8Hz,1H),8.24(s,1H),8.17(d,J=8.8Hz,1H),7.26(td,J=5.5, 2.6Hz,3H),7.15(ddd,J=10.4,5.7,2.6Hz,3H),4.47(d,J=7.1Hz,2H),3.88(d,J=16.3Hz, 2H), 3.56 (d, J=16.3Hz, 2H), 2.79–2.71 (m, 1H), 1.39 (t, J=7.0Hz, 3H), 0.98–0.91 (m, 4H).

[1259] Example 54

[1260] 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1261] 2-(6-(Cyclopropanesulfonyl)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,3-dihydro-1H-indene-2-carboxamide

[1262] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (74.95 mg, 321.35 μmol) was added to toluene (2 mL), and the argon atmosphere was replaced three times. A toluene solution of trimethylaluminum (2 M, 468.63 μL) was slowly added dropwise, and the mixture was stirred for 1 hour. Methyl 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41d (100.00 mg, 267.79 μmol) was added, and the mixture was heated to 90°C and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,3-dihydro-1H-indene-2-carboxamide 54 (23.9 mg) in a yield of 12.12%.

[1263] MS m / z(ESI):575.0[M+1]

[1264] 1H NMR (400MHz, DMSO-d6) δ9.68(s,1H),8.82(d,J=10.4Hz,2H),8.24(s,1H),8.02–7.93(m,2H),7.76(t,J=8.1Hz,1H),7.27(dd,J=5.4,3.3Hz,2H),7.17 (dd,J=5.5,3.2Hz,2H),7.04(s,1H),4.48(q,J=7.0Hz,2H),3.83(d,J=16. 3Hz, 2H), 3.07 (d, J = 28.3Hz, 1H), 1.39 (t, J = 7.0Hz, 3H), 1.12–0.91 (m, 4H).

[1265] Example 55

[1266] 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1267] 2-(6-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1268] 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine 1d (69.49 mg, 321.35 μmol) was added to toluene (2 mL), and the argon atmosphere was replaced three times. A toluene solution of trimethylaluminum (2 M, 468.63 μL) was slowly added dropwise. After stirring for 1 hour, methyl 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41d (100.00 mg, 267.79 μmol) was added, and the temperature was raised to 90°C and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide 55 (1.91 mg) in a yield of 1.01%.

[1269] MS m / z(ESI):558.1[M+1]

[1270] 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.03(d,J=2.4Hz,1H),8.83(s,1H),8.76(s,1 H),8.49(dd,J=8.8,2.5Hz,1H),8.26–8.18(m,2H),7.26(dd,J=5.4,3.3Hz,2H),7.17 (dd,J=5.6,3.2Hz,3H),6.97(s,1H),4.51–4.45(m,2H),3.83(d,J=16.4Hz,2H),3.51 (d,J=16.5Hz,2H),3.04(d,J=19.6Hz,1H),1.39(t,J=7.0Hz,3H),1.05-0.95(m,4H).

[1271] Example 56

[1272] 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrimidin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1273] 2-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrimidin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1274] first step

[1275] 5-(6-ethoxypyrazin-2-yl)pyrimidin-2-amine

[1276] 5-(6-ethoxypyrazin-2-yl)pyrimidin-2-amine

[1277] 2-Chloro-6-ethoxypyrazine 1b (500 mg, 3.15 mmol), (2-aminopyrimidin-5-yl)boronic acid 56a (525.60 mg, 3.78 mmol, commercially available), 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (230.70 mg, 315.29 μmol), and potassium carbonate (1.31 g, 9.46 mmol) were added sequentially to 1,4-dioxane (2 mL) and water (0.5 mL). The atmosphere was replaced with argon three times and stirred at 95°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (eluent: System B) to afford 5-(6-ethoxypyrazin-2-yl)pyrimidin-2-amine 56b (400 mg) in a 58.40% yield.

[1278] MS m / z(ESI):218.0[M+1]

[1279] Step 2

[1280] 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrimidin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1281] 2-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrimidin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1282] 5-(6-Ethoxypyrazin-2-yl)pyrimidin-2-amine 56b (58.33 mg, 268.50 μmol) was added to toluene (1 mL), and the argon atmosphere was replaced three times. Trimethylaluminum (2.0 M solution in toluene) (2 M, 469.88 μg) was slowly added dropwise. After stirring for 1 hour, methyl 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32b (100 mg, 268.50 μmol) was added, and the mixture was stirred at 90°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 2-(4-(cyclopropanesulfonyl)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrimidin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide 56 (17 mg) in a yield of 9.05%.

[1283] MS m / z(ESI):558.1[M+1]

[1284] 1 HNMR(400MHz,DMSO-d6)δ10.60(s,1H),9.30(s,2H),8.87(s,1H),8.43(d, J=5.8Hz,1H),8.30(s,1H),7.29-7.24(m,3H),7.16(ddt,J=8.5,5.8,3.2H z,3H),4.48(q,J=7.0Hz,2H),3.88(d,J=16.3Hz,2H),3.54(d,J=16.3Hz,2 H),2.76(tt,J=7.6,5.2Hz,1H),1.39(t,J=7.0Hz,3H),0.98-0.93(m,4H).

[1285] Example 57

[1286] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1287] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1288] 4-(5-Chloropyrazolo[1,5-a]pyridin-3-yl)aniline 42c (91.54 mg, 375.62 μmol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 614.65 μl) were added to toluene (2.1 mL) and stirred at room temperature for 1 hour. 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester 13d (120 mg, 341.47 μmol) was then added, and the temperature was raised to 90°C and stirred for 1.5 hours. A small amount of methanol (1 mL) was added to quench the reaction, and the solvent was directly dried by spin drying. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (5 mL) were added to the residue, which was filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxamide 57 (25 mg) in a yield of 10.71%.

[1289] MS m / z(ESI):[M+1]549.1.

[1290] 1 HNMR(400MHz,DMSO-d6)δ9.51(s,1H),8.63(d,J=8.5Hz,2H),8.26(s,1H),7.88(s,1H),7.59-7.46(m,4H),6.90-6.78(m, 2H),2.92(s,1H),2.73(d,J=13.5Hz,2H),2.27(d,J=13.3Hz,2H),1.28(s,2H),0.97–0.84(m,5H),0.28(d,J=7.5Hz,1H).

[1291] Example 58

[1292] N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1293] N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1294] 5-(5-Chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine 48a (69.12 mg, 282.51 μmol) and trimethylaluminum (2.0 M in toluene) (2 M, 462.29 μ6) were dissolved in toluene (2.3 mL) and stirred at room temperature for 1 hour. Then, methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17f (90 mg, 256.83 μmol) was added, and the temperature was raised to 90°C and stirred for 1.5 hours. A small amount of methanol (1 mL) was added to quench the reaction, and the solvent was directly dried by rotary evaporation. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (5 mL) were added, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 58 (6 mg / 1) with a yield of 3.31%.

[1295] MS m / z(ESI):[M+1]549.1.

[1296] 1 HNMR(400MHz, DMSO-d6)δ9.90(s,1H),8.62(d,J=7.2Hz,1H),8.48(s,1H),8.29(d,J=16.5Hz,2H),8.04-7.85(m,3H),7.07(s,2H),6.85 (d,J=7.3Hz,1H),2.83–2.66(m,3H),2.24(d,J=13.4Hz,2H),1.26(s,2H),0.85(d,J=11.3Hz,4H),0.29(d,J=7.8Hz,1H),-0.00(s,1H).

[1297] Example 59

[1298] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1299] N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[1300] 4-(5-Chloropyrazolo[1,5-a]pyridin-3-yl)aniline 42c (107.09 mg, 439.46 μg) and trimethylaluminum (2.0 M solution in toluene) (2 M, 719.11 μl) were added to toluene (2.05 mL) and stirred at room temperature for 1 hour. Subsequently, methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17f (140 mg, 399.51 μmol) was added and the temperature was raised to 90 °C and stirred for 1.5 hours. A small amount of methanol (1 mL) was added to quench the reaction, and the solvent was directly dried by spin drying. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (5 mL) were added, filtered, and the liquid was concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 59 (4 mg) with a yield of 1.45%.

[1301] MS m / z(ESI):[M+1]548.1.

[1302] 1HNMR (400MHz, DMSO-d6) δ9.49 (s, 1H), 8.62 (d, J = 7.4Hz, 1H), 8.26 (d, J = 5.3Hz ,2H),7.87(s,1H),7.58-7.45(m,4H),7.02(d,J=6.7Hz,2H),6.84(d,J=7.4Hz, 1H),2.84(d,J=13.5Hz,2H),2.66(d,J=8.1Hz,1H),2.26(d,J=13.3Hz,2H),1.3 2-1.24(m,2H),0.94-0.78(m,4H),0.27(d,J=7.0Hz,1H),0.00(d,J=4.9Hz,1H).

[1303] Example 60

[1304] 6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxamide

[1305] 6-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxamide

[1306] first step

[1307] 2,3-bis(chloromethyl)pyrazine

[1308] 2,3-Bis(chloromethyl)pyrazine

[1309] 2,3-Dimethylpyrazine 60a (500 mg, 4.62 mmol, commercially available), N-chlorosuccinimide (1.54 g, 11.56 mmol), and benzoyl peroxide (112.00 mg, 462.36 μl) were added sequentially to carbon tetrachloride (1 mL). The atmosphere was purged with argon for 2 minutes, then heated to 100°C and stirred for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 2,3-bis(chloromethyl)pyrazine 60b (400 mg) in a 48.87% yield.

[1310] MS m / z(ESI):176.9[M+1]

[1311] Step 2

[1312] methyl 6-(4-bromopyridin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxylate

[1313] 6-(4-bromopyridin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxylic acid methyl ester

[1314] Methyl 2-(4-bromopyridin-2-yl)acetate 17d (320 mg, 1.39 mmol) was added to N,N-dimethylformamide (16 mL), and the argon atmosphere was replaced three times. Under ice-water cooling, sodium hydroxide (255.94 mg, 6.40 mmol) was slowly added. After stirring for 0.5 hour, 2,3-bis(chloromethyl)pyrazine 60b (246.24 mg, 1.39 mmol) was added. The mixture was stirred at room temperature for 23 hours. The reaction solution was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL) were added. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: System B) to give methyl 6-(4-bromopyridin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxylate 60c (240 mg) in a yield of 51.63%.

[1315] MS m / z(ESI):333.9[M+1]

[1316] Step 3

[1317] methyl 6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxylate

[1318] 6-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxylic acid methyl ester

[1319] Methyl 6-(4-bromopyridin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxylate 60c (270 mg, 807.98 μmol), cyclopropanesulfonamide (146.84 mg, 1.21 mmol), cesium carbonate (526.51 mg, 1.62 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (68.62 mg, 161.60 μmol) and allylpalladium(II) chloride dimer (29.56 mg, 807.98 μmol) were added sequentially to 1,4′-dihydro-2′,4′,6′-triisopropylbiphenyl (526.51 mg, 1.62 mmol). The mixture was added to a mixture of 2 mL of dioxane, argon was replaced three times, and the temperature was raised to 90°C with stirring for 2 hours. Water (20 mL) and ethyl acetate (20 mL) were added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: System B) to obtain methyl 6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxylate 60d (260 mg) in a yield of 85.95%.

[1320] MS m / z(ESI):375.0[M+1]

[1321] Step 4

[1322] 6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxamide

[1323] 6-(4-(Cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxamide

[1324] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (50 mg, 232.29 μg / cm2) was added to toluene (2.83 mL) and the argon atmosphere was replaced three times. Trimethylaluminum (2.0 M toluene solution) (2 M, 406.50 μg / cm2) was slowly added dropwise. After stirring for 1 hour, 6-(4-(cyclopropanesulfonylamino)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxylic acid methyl ester 60d (86.97 mg, 232.29 μg / cm2) was added. The mixture was then heated to 90°C and stirred for 5 hours. The product was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyrazine-6-carboxamide 60 (35 mg) with a yield of 21.74%.

[1325] MS m / z(ESI):558.2[M+1]

[1326] 1HNMR(400MHz,DMSO-d6)δ10.58(s,1H),9.88(s,1H),8.76(s,1H),8.36(d, J=10.3Hz,3H),8.17(s,1H),8.08(d,J=8.8Hz,2H),7.79(d,J=8.9Hz,2H),7. 22(s,1H),7.10(dd,J=5.6,2.1Hz,1H),4.47(q,J=7.0Hz,2H),3.94(d,J=17 .2Hz,2H),3.68(d,J=17.2Hz,2H),1.39(t,J=7.0Hz,3H),0.98-0.91(m,4H).

[1327] Example 61

[1328] 2-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyri...

Claims

1. A compound of the general formula (AAI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: Wherein: Any two Rs aa together with the atoms to which they are attached form a ring C, where said ring C is optionally further substituted by one or more Rs 4 ; Ring C is selected from a 6-membered aryl group, a 3- to 5-membered cycloalkyl group, a 5- to 7-membered heterocyclic group or a 5- to 6-membered heteroaryl group; R A selected from a hydrogen atom or a C 1-6 alkyl group; Ring A is selected from a 6-membered aryl group, a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclic group; Ring B is selected from a 6-membered aryl group or a 5- to 10-membered heteroaryl group; L is selected from -C(=O)-, -C(=O)NR a -, or -NR b C(=O)-; R a 、R b each independently selected from a hydrogen atom or a C 1-6 alkyl group; X, Y, Z, and Q are each independently selected from N or CR c ; and at most two of the atoms X, Y, Z, and Q are N atoms simultaneously; Alternatively, X and Y, and Z and Y each independently form a 5- to 6-membered heteroaryl group or a 5- to 6-membered heterocyclic group; wherein the 5- to 6-membered heteroaryl group or 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, 3- to 5-membered cycloalkyl group; R c selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, C 1-6 alkyl or C 1-6 alkoxy; wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl group, a cyano group, and a 3- to 5-membered cycloalkyl group; R 1 selected from C 1-6 alkyl or 3- to 5-membered cycloalkyl; wherein said C 1-6 alkyl or 3- to 5-membered cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, 3- to 5-membered cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy; R 2 Each independently selected from a hydrogen atom, a halogen, a cyano group, a hydroxyl group, C 1-6 alkyl or C 1-6 alkoxy; wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl group, a cyano group, C 1-6 alkyl or C 1-6 alkoxy; Alternatively, two Rs 2 form a -C(O) with the same carbon atom to which they are attached; R 3 Each independently selected from a hydrogen atom, a halogen, a cyano group, a hydroxyl group, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered cycloalkyl group, C 2-6 alkenyl, SF5, -C(O)R 5 , -C(O)OR 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -C(O)NR 6 R 7 , -CH2NHC(O)OR 5 , -CH2NR 6 R 7 or -S(O) r R 5 ; wherein the alkyl, alkoxy, alkenyl or cycloalkyl is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyl, a heterocyclic group, an aryl, a heteroaryl, =O, -C(O)R 8 , -C(O)OR 8 , -OC(O)R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -SO2NR 9 R 10 or -NR 9 C(O)R 10 ; R 4 each independently selected from a hydrogen atom, a cyano group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-S(O)2NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 ; wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 ; R 5 Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O)R 8 , -C(O)OR 8 , -OC(O)R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -SO2NR 9 R 10 or -NR 9 C(O)R 10 ; R 6 and R 7 are each independently selected from a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O)R 8 , -C(O)OR 8 , -OC(O)R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -SO2NR 9 R 10 or -NR 9 C(O)R 10 ; Or, R 6 and R 7 together with the atoms to which they are attached form a 4- to 8-membered heterocyclic group containing one or more N, O or S(O)r, and said 4- to 8-membered heterocyclic group is optionally further substituted by one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 8 , -C(O)OR 8 , -OC(O)R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -SO2NR 9 R 10 or -NR 9 C(O)R 10 ; R 8 、R 9 and R 10 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen atom, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylic acid ester group; m is selected from 0, 1 or 2; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2; q is selected from 0, 1 or 2; and r is each independently 0, 1 or 2.

2. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein selected from where t is selected from 0, 1 or 2; ring C, R 4 , p or q is defined as described in claim 1.

3. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to claim 1 or 2, which is a compound represented by the general formula (AI) or its stereoisomer, tautomer or pharmaceutically acceptable salt: Wherein: X, Y, Z, and Q are each independently selected from N or CR c ; and at most two of X, Y, Z, and Q are N atoms simultaneously; Alternatively, Z and Y form a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, 3- to 5-membered cycloalkyl group; Alternatively, X and Y form a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, 3- to 5-membered cycloalkyl group; t is selected from 0, 1 or 2; Ring A, Ring B, Ring C, L, R 1 ~R 4 , R A , p, q, m or n is defined as described in claim 1.

4. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to claim 3, which is the compound represented by the general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt: Wherein: Ring A, Ring B, Ring C, L, R 1 ~R 4 The definitions of X, Y, Z, Q, p, q, m, n or t are as described in claim 3.

5. The compound according to any one of claims 1-4, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups:

6. The compound according to any one of claims 1-5, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from the following groups:

7. A compound according to any one of claims 1-6, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: L is selected from -C(=O)-, -C(=O)NH- or -NHC(=O)-.

8. A compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-7, which is a compound of the general formula (IIA) or (IIB) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: Wherein: X1 is independently selected from N or CR respectively d ; Each of X4 is independently selected from N or CR d ; R b each independently selected from a hydrogen atom or a methyl group; R d each independently selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group or a C 1-6 haloalkoxy group; X2 and X3 are each independently selected from N or CR e ; j is each independently selected from 0 or 1; R e each independently selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group or a C 1-6 haloalkoxy group; Rings C, X, Y, Z, Q, R 1 ~R 4 The definitions of p, q or t are as described in claim 3.

9. A compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-8, which is a compound of the general formula (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: Wherein: X1 is independently selected from N or CR respectively d ; R b each independently selected from a hydrogen atom or a methyl group; R d each independently selected from a hydrogen atom, a halogen, a cyano group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy; X2 and X3 are each independently selected from N or CR e ; j is each independently selected from 0 or 1; R e each independently selected from a hydrogen atom, a halogen, a cyano group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy; Rings C, X, Y, Z, Q, R 1 ~R 4 The definitions of p, q or t are as described in claim 3.

10. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to claim 1 or 2, which is the compound of general formula (IV-1) or (IV-2) or its stereoisomer, tautomer or pharmaceutically acceptable salt: Wherein: X1 is independently selected from N or CR d ; Each of X4 is independently selected from N or CR d ; R b each independently selected from a hydrogen atom or a methyl group; R d Each independently selected from a hydrogen atom, a halogen, a cyano group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy; X2 and X3 are each independently selected from N or CR e ; j is each independently selected from 0 or 1; R e each independently selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group or a C 1-6 haloalkoxy group; t is selected from 0, 1 or 2; X, Y, Z, Q or R 1 ~R 4 is defined as described in claim 1.

11. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to any one of claims 1-4, which is the compound of general formula (V-A), (V-B), (V-C) or (V-D) or its stereoisomer, tautomer or pharmaceutically acceptable salt: Wherein: R b each independently selected from a hydrogen atom or a methyl group; Ring B is independently selected from Y1 and Y2 are each independently selected from N or CH; j is each independently selected from 0 or 1; t is each independently selected from 0, 1 or 2; Rings C, X, Y, Z, Q, R 1 ~R 4 , p, q or n is defined as described in claim 1.

12. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to any one of claims 11, which is the compound represented by general formula (V-1) or (V-2) or its stereoisomer, tautomer or pharmaceutically acceptable salt: Wherein: R b each independently selected from a hydrogen atom or a methyl group; X2 and X3 are each independently selected from N or CR e ; j is each independently selected from 0 or 1; R e Each independently selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group or a C 1-6 haloalkoxy group; t is selected from 0, 1 or 2; Rings C, X, Y, Z, Q, R 1 ~R 4 The definition of p or q is as described in claim 1.

13. The compound according to any one of claims 1 to 12, or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein is selected from the following groups: R c each independently selected from a hydrogen atom, a halogen, a cyano group, C 1-6 alkoxy group, C 1-6 haloalkyl group or C 1-6 haloalkoxy group; k is each independently selected from 0, 1 or 2.

14. The compound according to any one of claims 1 to 13, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring C is selected from the following groups:

15. The compound according to any one of claims 1 to 14, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 4 is selected from a hydrogen atom, C 1-6 alkyl, -C(O)R 5 -C(O)NR 6 R 7 -S(O)2R 5 -S(O)2NR 6 R 7 wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from hydroxy, halogen, cyano or -C(O)OR 8 ; R 5 each independently selected from C 1-6 alkyl, 3- to 5-membered cycloalkyl or 5- to 6-membered heteroaryl, wherein said C 1-6 alkyl, 3- to 5-membered cycloalkyl or 5- to 6-membered heteroaryl is optionally further substituted by one or more substituents selected from halogen or C 1-6 alkoxy; R 6 、R 7 Each independently represents a hydrogen atom or a C 1-6 alkyl group; R 8 selected from a hydrogen atom or a C 1-6 alkyl group.

16. The compound according to claim 14 or 15, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein is selected from the following groups: Wherein: R 4a each independently selected from a hydrogen atom or a C 1-6 alkyl group; R 4 is defined as described in claim 14.

17. The compound according to any one of claims 1 to 16, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 alkyl or 3- to 5-membered cycloalkyl is optionally further substituted by one or more substituents selected from C 1-3 alkyl, C 1-3 alkoxy, halogen, hydroxy or cyano.

18. The compound according to claim 17, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 is selected from cyclopropyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, 19. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein R 2 is selected from a hydrogen atom, a halogen, a cyano group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy; Alternatively, two Rs 2 form a -C(O) with the same carbon atom to which they are attached.

20. The compound according to any one of claims 1 to 19, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 3 is selected from a hydrogen atom, a halogen, a cyano group, a hydroxyl group, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered cycloalkyl group, SF5, C 1-6 haloalkyl or C 1-6 haloalkoxy.

21. The compound according to claim 20, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 3 is selected from chlorine, trifluoromethoxy, methyl, ethyl or ethoxy.

22. The compound according to any one of claims 1 to 21 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein p is 0 and q is 0.

23. The compound according to any one of claims 1 to 21 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein p is 1 and q is 1 or 2.

24. The compound according to any one of claims 1 to 21 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein p is 2 and q is 0, 1 or 2.

25. A compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein the compound is:

26. A pharmaceutical composition, which contains an effective dose of the compound according to any one of claims 1 to 25 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. Use of the compound according to any one of claims 1 to 25 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26 in the preparation of a CTPS1 inhibitor.

28. Use of the compound according to any one of claims 1 to 25 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26 in the preparation of a medicament for treating a disease mediated by CTPS1, preferably, wherein the disease mediated by CTPS1 is lymphoma or solid tumor.

29. The use according to claim 28, wherein the lymphoma is relapsed / refractory B-cell and T-cell lymphoma.

30. Use according to claim 29, wherein the relapsed / refractory B-cell and T-cell lymphomas are mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, indolent B-cell lymphoma.

31. Use of a compound according to any one of claims 1 to 25, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, in the manufacture of a medicament for treating lymphoma or solid tumor.

32. Use according to claim 31, wherein the lymphoma is relapsed / refractory B-cell and T-cell lymphoma.

33. Use according to claim 32, wherein the relapsed / refractory B-cell and T-cell lymphomas are mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, indolent B-cell lymphoma.

34. Use according to claim 28, wherein the solid tumor is preferably pancreatic cancer.