Sulfonamide derivative, preparation method therefor and use thereof

Abstract

The present invention relates to a sulfonamide derivative, a preparation method therefor, and a medical use of a pharmaceutical composition containing the derivative. Specifically, the present invention relates to a sulfonamide derivative represented by general formula (AAI), a preparation method therefor, and a pharmaceutically acceptable salt thereof, as well as a use thereof as a therapeutic agent, particularly as a CTPS1 inhibitor, the definitions of the substituents in the general formula (AAI) being the same as the definitions in the description.

Description

FIELD

[0001] The present disclosure relates to a sulfonamide derivative, a preparation method therefor, a pharmaceutical composition containing the derivative, and use thereof as a therapeutic agent, particularly as a CTPS1 inhibitor. BACKGROUND

[0002] Cytidine triphosphate (CTP) is an important precursor required for DNA, RNA, and phospholipid metabolism in human cells. CTP is produced through two pathways: a salvage synthesis pathway and a de novo synthesis pathway. CTP synthase (CTPS) is a rate-limiting enzyme for the de novo synthesis of CTP, and includes two subtypes: CTPS1 and CTPS2. CTPS1 and CTPS2 have 74% sequence homology but have different physiological roles. CTPS2 is uniformly expressed in various tissues, whereas CTPS1 is generally expressed at low levels in most tissues but is rapidly upregulated in activated T cells. By expressing wild-type CTPS1 or adding exogenous CTP or its nucleotide precursor cytidine, T cell proliferation is restored in CTPS1-deficient cells. It is indicated that CTPS1 plays an essential role in the proliferation of B cells and T cells and is necessary for an effective immune response.

[0003] Proliferating cells, such as activated lymphocytes, have a high demand for ribonucleotides, particularly CTP and GTP. CTPS1 is highly expressed after lymphocyte activation and catalyzes the synthesis of CTP, providing a material basis for lymphocyte proliferation. Meanwhile, CTPS1 has reduced sensitivity to CTP feedback inhibition compared to CTPS2, which confers on CTPS1 the ability to continuously catalyze CTP synthesis, ultimately expanding the CTP reserve required during lymphocyte proliferation. CTPS1 is upregulated in activated lymphocytes to expand the CTP pool, meeting the increased demand for nucleic acid and lipid synthesis. The demand for CTP in other tissues is met through the CTPS2 subtype and nucleotide salvage pathways. Therefore, selective inhibition of proliferative CTPS1 is desirable in the treatment of immune diseases and lymphocyte cancers, which makes CTPS1 an ideal target for immunosuppression.

[0004] Lymphoma is one of the most common malignancies in China, and is mainly divided into two categories: Hodgkin Lymphoma (HL) and non-Hodgkin Lymphoma (NHL). In actual clinical diagnosis, NHL is more common, with about 80% to 90% of diagnosed lymphomas being NHL. NHL mainly 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. In T-cell non-Hodgkin lymphoma and acute T-cell lymphoma, CTPS1 expression levels are relatively high, and CTPS1 overexpression provides a material basis for the excessive proliferation of these T-cell lymphomas, thus serving as a target for anticancer drugs.

[0005] To date, no novel CTPS1-targeting inhibitors have been marketed. Currently, STP-938 developed by Step Pharma has entered Phase I / II clinical studies for the treatment of relapsed / refractory B-cell and T-cell lymphomas, and a small molecule CTPS1 inhibitor developed by Nimbus is in the discovery stage. Overall, as a relatively cutting-edge research direction, there is still enormous room for exploration in CTPS1-related research, and it is highly necessary to continue developing new inhibitors. SUMMARY

[0006] In view of the foregoing, the present disclosure provides a sulfonamide derivative represented by formula (AAI):

[0007] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;

[0008] wherein:

[0009] any two Raa, together with the atoms to which they are attached, form a ring C, wherein ring C is optionally further substituted by one or more R4;

[0010] ring C is selected from the group consisting of a 6-membered aryl, a 3- to 5- membered cycloalkyl, a 5- to 7- membered heterocyclyl, and a 5- to 6- membered heteroaryl;

[0011] RA is selected from the group consisting of a hydrogen atom and a C1-6 alkyl;

[0012] ring A is selected from the group consisting of a 6-membered aryl, a 5- to 6- membered heteroaryl, and a 5- to 7- membered heterocyclyl;

[0013] ring B is selected from the group consisting of a 6-membered aryl and a 5- to 10membered heteroaryl;

[0014] L is selected from the group consisting of -C(=O)-, -C(=O)NRa-, and -NRbC(=O)-;

[0015] Ra and Rb are each independently selected from the group consisting of a hydrogen atom and a C1-6 alkyl;

[0016] X, Y, Z, and Q are each independently selected from the group consisting of N and CRc; and at most two of X, Y, Z, and Q are simultaneously N atoms;

[0017] alternatively, X and Y, Z and Y each independently form a 5- to 6- membered heteroaryl or a 5- to 6- membered heterocyclyl; wherein the 5- to 6- membered heteroaryl or 5- to 6membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, and 3- to 5- membered cycloalkyl;

[0018] Rc is selected from the group consisting of a hydrogen atom, halogen, hydroxy, cyano, C1-6 alkyl, and C1-6 alkoxy; wherein the C1-6 alkyl or C1-6 alkoxy is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, and 3- to 5- membered cycloalkyl;

[0019] R1 is selected from the group consisting of C1-6 alkyl and 3- to 5- membered cycloalkyl; wherein the C1-6 alkyl or 3- to 5- membered cycloalkyl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, 3- to 5membered cycloalkyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;

[0020] each R2 is independently selected from the group consisting of a hydrogen atom, halogen, cyano, hydroxy, C1-6 alkyl, and C1-6 alkoxy; wherein the C1-6 alkyl or C1-6 alkoxy is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-6 alkyl, and C1-6 alkoxy;

[0021] alternatively, two R2, together with the same carbon atom to which they are attached, form a -C(O);

[0022] R3 is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, 3- to 5- membered cycloalkyl, C2-6 alkenyl, SF5, -C(O)R5, -C(O)OR5, -NHC(O)R5, -NHC(O)OR5, -NR6R7, -C(O)NR6R7, -CH2NHC(O)OR5, -CH2NR6R7, and -S(O)rR5; wherein the alkyl, alkoxy, alkenyl, or cycloalkyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10, and -NR9C(O)R10;

[0023] R4 is each independently selected from the group consisting of a hydrogen atom, cyano, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5, -C(O)R5,  -C(O)OR5,  -NHC(O)R5,  -NHC(O)OR5,  -NR6R7,  -C(O)NR6R7,  -S(O)2NR6R7, -CH2NHC(O)OR5, -CH2NR6R7, and -S(O)rR5; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10, and -NR9C(O)R10;

[0024] R5 is each independently selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10, and -NR9C(O)R10;

[0025] R6 and R7 are each independently selected from the group consisting of a hydrogen atom, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10, and -NR9C(O)R10;

[0026] alternatively, R6 and R7, together with the atoms to which they are attached, form a 4- to 8- membered heterocyclyl, wherein the 4- to 8- membered heterocyclyl contains one or more N, O, or S(O)r, and the 4- to 8- membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10, and -NR9C(O)R10;

[0027] R8, R9, and R10 are each independently selected from the group consisting of a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, and carboxylate;

[0028] m is selected from the group consisting of 0, 1, and 2;

[0029] n is selected from the group consisting of 0, 1, and 2;

[0030] p is selected from the group consisting of 0, 1, and 2;

[0031] q is selected from the group consisting of 0, 1, and 2; and

[0032] r is each independently 0, 1, or 2.

[0033] In a preferred embodiment, the present disclosure provides a compound represented by formula (AAI), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, g(R4)t q ;

[0034] wherein t is selected from the group consisting of 0, 1, and 2; and ring C, R4, p, or q are as defined in formula (AAI).

[0035] In a preferred embodiment, the present disclosure provides a compound represented by formula (AAI), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (AI):

[0036] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;

[0037] wherein:

[0038] X, Y, Z, and Q are each independently selected from the group consisting of N and CRc; and at most two of X, Y, Z, and Q are simultaneously N atoms;

[0039] alternatively, Z and Y form a 5- to 6- membered heteroaryl, wherein the 5- to 6membered heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, and 3- to 5- membered cycloalkyl;

[0040] alternatively, X and Y form a 5- to 6- membered heteroaryl, wherein the 5- to 6membered heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, and 3- to 5- membered cycloalkyl;

[0041] t is selected from the group consisting of 0, 1, and 2; and

[0042] ring A, ring B, ring C, L, R1 to R4, RA, p, q, m, and n are as defined in formula (AAI).

[0043] In a preferred embodiment, the present disclosure provides a compound of formula (AAI) or (AI), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (I):

[0044] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;

[0045] wherein: ring A, ring B, ring C, L, R1 to R4, X, Y, Z, Q, p, q, m, n, and t are as defined in formula (AI).

[0046] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), or (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of: and

[0048] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), or (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of:

[0049] and

[0050] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), or (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: L is selected from the group consisting of -C(=O)-, -C(=O)NH-, and -NHC(=O)-.

[0051] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), or (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IIA) or (IIB):

[0052] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;

[0053] wherein: each X1 is independently selected from the group consisting of N and CRd;

[0054] X4 is each independently selected from the group consisting of N and CRd;

[0055] Rb is each independently selected from the group consisting of a hydrogen atom and methyl;

[0056] Rd is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;

[0057] X2 and X3 are each independently selected from the group consisting of N and CRe;

[0058] j is each independently selected from the group consisting of 0 and 1;

[0059] Re is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and

[0060] ring C, X, Y, Z, Q, R1 to R4, p, q, and t are as defined in formula (AI).

[0061] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), or (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or (III):

[0062] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;

[0063] wherein: each X1 is independently selected from the group consisting of N and CRd;

[0064] Rb is each independently selected from the group consisting of a hydrogen atom and methyl;

[0065] Rd is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;

[0066] X2 and X3 are each independently selected from the group consisting of N and CRe;

[0067] j is each independently selected from the group consisting of 0 and 1;

[0068] Re is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and

[0069] ring C, X, Y, Z, Q, R1 to R4, p, q, and t are as defined in formula (AI).

[0070] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV-1) or (IV-2):

[0071] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof

[0072] wherein: each X1 is independently selected from the group consisting of N and CRd;

[0073] X4 is each independently selected from the group consisting of N and CRd;

[0074] Rb is each independently selected from the group consisting of a hydrogen atom and methyl;

[0075] Rd is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;

[0076] X2 and X3 are each independently selected from the group consisting of N and CRe;

[0077] j is each independently selected from the group consisting of 0 and 1;

[0078] Re is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;

[0079] t is selected from the group consisting of 0, 1, and 2; and

[0080] X, Y, Z, Q, and R1 to R4 are as defined in formula (AAI).

[0081] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), or (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof which is a compound of formula (V-A), (V-B), (V-C), or (V-D):

[0082] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;

[0083] wherein: each Rb is independently selected from the group consisting of a hydrogen atom and methyl;

[0084] ring B is each independently selected from the group consisting of and

[0085] Y1 and Y2 are each independently selected from the group consisting of N and CH;

[0086] j is each independently selected from the group consisting of 0 and 1;

[0087] t is each independently selected from the group consisting of 0, 1, and 2; and

[0088] ring C, X, Y, Z, Q, R1 to R4, p, q, and n are as defined in formula (AAI).

[0089] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (V-1) or (V-2):

[0090] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof

[0091] wherein: each Rb is independently selected from the group consisting of a hydrogen atom and methyl;

[0092] X2 and X3 are each independently selected from the group consisting of N and CRe;

[0093] j is each independently selected from the group consisting of 0 and 1;

[0094] Re is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;

[0095] t is selected from the group consisting of 0, 1, and 2; and

[0096] ring C, X, Y, Z, Q, R1 to R4, p, and q are as defined in formula (AAI).

[0097] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Y      is selected from the group consisting of: X / Vl Xy"N<XX Xy^^yX Xy^XXX ll +(Rc)k II J-(RC) H X / rcx Tl X(Rc)k II 4-(Rc)k

[0098] '    , N N     ,   "^(R\            , ^(Rc)k (Rc) / , and ;k

[0099] Rc is each independently selected from the group consisting of hydrogen atom, halogen, cyano, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and

[00100] k is each independently selected from the group consisting of 0, 1, and 2.

[00101] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from the group consisting of:

[00102] HN-N and

[00103] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of hydrogen atom, C1-6 alkyl, -C(O)R5, -C(O)NR6R7, -S(O)2R5, and -S(O)2NR6R7, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, cyano, and -C(O)OR8;

[00104] R5 is each independently selected from the group consisting of C1-6 alkyl, 3- to 5membered cycloalkyl, and 5- to 6- membered heteroaryl, wherein the C1-6 alkyl, 3- to 5membered cycloalkyl, or 5- to 6- membered heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen and C1-6 alkoxy;

[00105] R6 and R7 are each independently selected from the group consisting of a hydrogen atom and C1-6 alkyl; and

[00106] R8 is selected from the group consisting of a hydrogen atom and C1-6 alkyl.

[00107] In a preferred embodiment, the present disclosure provides a compound of formula (AI), (I), (IIA), (IIB), (II), (III), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a G¥R4)l tautomer, or a pharmaceutically acceptable salt thereof, wherein              is selected from the group consisting of:

[00108] and

[00109] wherein: R4a is each independently selected from the group consisting of a hydrogen atom and C1-6 alkyl; and

[00110] R4 is as defined in formula (AI).

[00111] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of C1-6 alkyl and 3- to 5- membered cycloalkyl, wherein the C1-6 alkyl or 3- to 5- membered cycloalkyl is optionally further substituted by one or more substituents selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, halogen, hydroxy, and cyano.

[00112] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of cyclopropyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, \ ,         0  ,           , and      F.

[00113] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;

[00114] alternatively, two R2, together with the same carbon atom to which they are attached, form a -C(O).

[00115] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of hydrogen atom, halogen, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, 3 to 5- membered cycloalkyl, SF5, C1-6 haloalkyl, and C1-6 haloalkoxy.

[00116] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of chloro, trifluoromethoxy, methyl, ethyl, and ethoxy.

[00117] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein p is 0, and q is 0.

[00118] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein p is 1, and q is 1 or 2.

[00119] In a preferred embodiment, the present disclosure provides a compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein p is 2, and q is 0, 1, or 2.

[00120] In a preferred embodiment of the present disclosure, the compound of general formula is selected from the group consisting of: Compound No. Structure Name Example 1 o XNxX f I O N- / 1 o^N^X        hn^ X         o "v N 2-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(5-(6-ethoxypyrazin -2-yl)pyridin-2-yl)-2,3-dihydro- 1H-indene-2-carboxamide Example 2 H           H 0 / N. X ,N.    o \ h n r X \^OX,N. x>; / N  0 I^N OZ V xx 3-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(5-(6-ethoxypyrazin -2-yl)pyridin-2-yl)bicyclo[3.1.0]he xane-3-carboxamide Example 3 h XX h o / N. X _N. .N, / / r%     X<           Q \^O N^XX o X / N "X7 T J 3-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 4 o.? IZ '° ° 2k\ / =o z z \\ / / / ~Q (1R,5S)-6-(2-(cyclopropanesulfona mido)pyrimidin-4-yl)-N-(4-(6-etho xypyrazin-2-yl)phenyl)-3-oxabicycl o[3.1.0]hexane-6-carboxamide Example 5 H XX / H o \              / N. X ,1 / .N^. / / 1                 II               n r”                      , °V'NX / ^ 0 XN ° T J 1-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-2,3-dihydro- 1H-inde ne-1 -carboxamide Example 6 HN^\ H X / / / - fX 1 nX\ cxN / f        hn^ X >      oX N 5-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-4,5,6,7-tetrahydro- 1H -indazole-5 -carboxamide Example 7 xN^n H X / / -. ^nXX N O 7 x o^N / f         hn^' X >        0^7 N 5-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-1 -methyl-4,5,6,7-tetr ahydro-1H-indazole-5-carboxamide Example 8 O„P IZ '° / XX^ )= o z z \\ / / / ^° (1R,5S)-6-(2-(cyclopropanesulfona mido)pyrimidin-4-yl)-N-(4-(6-etho xypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-6-carboxamide Example 9 H N H V     H 0 \^°^NXX^ 0 X / N o' ""V 6-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-3-azabicyclo[3.1.0]he xane-6-carboxamide Example 10 1 N H V    H Q ^x     >4 _N,      / / x^O. n J   o XX oz >7 T J 6-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-3-methyl-3-azabicycl o[3.1.0]hexane-6-carboxamide Example 11 o,P XC4)X IZ ° o       )=o IZ z z \\ / / o 3-acetyl-6-(2-(cyclopropanesulfona mido)pyrimidin-4-yl)-N-(4-(6-etho xypyrazin-2-yl)phenyl)-3-azabicycl o[3.1.0]hexane-6-carboxamide Example 12 f H kJ H 0 / N. X _N. _N' / / r%             ><k        Q \^O N^jXX 0 Xx^N O' 'X? T J 3-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-fluorophenyl)bicyclo[3.1.0 ]hexane-3-carboxamide Example 13 o.k IZ ° Jp IZ z z \\ / / o ? 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 14 / n-n / / A h LJ h o \^O N^JXX o Xx / N o' X J 5-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-2-methyl-4,5,6,7-tetr ahydro-2H-indazole-5-carboxamide Example 15 o z z ZI O=( / T^ 4 O. 4T 4'° 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 16 IZ ° z z \\ / / ^"■■4^=0 IZ z z \\ / / o ? 3-(6-(cyclopropanesulfonamido)pyr azin-2-yl)-N-(4-(6-ethoxypyrazin-2 -yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 17 o.4 Xc / K IZ ° ^--4^=0 IZ z z \\ / / o 3-(4-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(4-(6-ethoxypyrazin-2 -yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 18 H 44 H o ,N. X     4 ii         n       44 s. Xx4vXJ ° ^-N ° ^47 V 3-(2-(cyclopropanesulfonamido)pyr idin-4-yl)-N-(4-(6-ethoxypyrazin-2 -yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 19 o.4 Xc / K IZ ° <nrz IZ z z \\ / / o 3 -(5-(cyclopropanesulfonamido)pyr idazin-3-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 20 < o z z ZI o=( o. 4T 4'° 3-(4-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(4-(6-ethoxypyrazin-2 -yl)-2-fluorophenyl)bicyclo[3.1.0]h exane-3-carboxamide Example 21 H kJ H o o n^JF oz Y7 T J 3-(4-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(5-(6-ethoxypyrazin-2 -yl)pyridin-2-yl)bicyclo[3.1.0]hexa ne-3-carboxamide Example 22 O-N / H kJ H 0 / VNV<VNvN' '' \ / O N JJ 0 XX o'X T J 5-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-4,5,6,7-tetrahydroben zo[d]isoxazole-5-carboxamide Example 23 N J>^ N / / ° ^o^nXx o x y oz Y          N N^ 3 -(5-(cyclopropanesulfonamido)pyr idin-3-yl)-N-(4-(6-ethoxypyrazin-2 -yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 24 < o xk ZT oX V) z \ Ox / ZT ws <r 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(5-(6-ethoxypyrazin -2-yl)pyridin-2-yl)bicyclo[3.1.0]he xane-3-carboxamide Example 25 O.P IZ ° CX IZ z z \\ / / o ? 3-(6-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(4-(6-ethoxypyrazin-2 -yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 26 x^Xyl \^0x ,N„       0 NVN O V T J N^ 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-fluorophenyl)bicyclo[3.1.0 ]hexane-3-carboxamide Example 27 0 hA / h       H H \            ,N. Xx     N <0 1           [I j ¥ h °X / N\¥¥¥  0 N^N 0 v I Y "N (1R,5S)-6-(6-(cyclopropanesulfona mido)pyrimidin-4-yl)-N-(4-(6-etho xypyrazin-2-yl)phenyl)-3-oxabicycl o[3.1.0]hexane-6-carboxamide Example 28 hA / H       H H \             N ACN. <0 o N. ¥  0 V I Y N (1R,5S)-6-(4-(cyclopropanesulfona mido)pyridin-2-yl)-N-(4-(6-ethoxy pyrazin-2-yl)phenyl)bicyclo[3.1.0] hexane-6-carboxamide Example 29 HA / H \ / H    H r, \                                <.o 1         f J ¥ H J °\ / N\¥\¥  0 N^N 0 v I Y (1R,5S)-6-(6-(cyclopropanesulfona mido)pyrimidin-4-yl)-N-(4-(6-etho xypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-6-carboxamide Example 30 hA / \  \ / “H H 1      Pl ¥ h 1  h^<7 °\ / N\¥\¥ o N^N O v I Y N (1R,5S)-6-(6-(cyclopropanesulfona mido)pyrimidin-4-yl)-N-(4-(6-etho xypyrazin-2-yl)phenyl)-N-methylbi cyclo[3.1.0]hexane-6-carboxamide Example 31 ¥ X^s IZ ° / =O IZ z z \\ / / o 3-(6-(cyclopropanesulfonamido)pyr idazin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)bicyclo[3.1.0]hexane-3-carboxamide Example 32 ¥ IZ ° L L X y=o TZ Z   Z \\ / / o ? 2-(4-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(4-(6-ethoxypyrazin-2 -yl)phenyl)-2,3-dihydro- IH-indene-2-carboxamide Example 33 o hA / h       H H \              N           Nk <£> ।       h j n   h       uX O  N. X 0 v I Y (1R,5S)-6-(4-(cyclopropanesulfona mido)pyridin-2-yl)-N-(4-(6-ethoxy pyrazin-2-yl)phenyl)-3-oxabicyclo[ 3.1.0]hexane-6-carboxamide Example 34 H           H 0 / N. X _N.     / 7 r X>X X< yX x / xq \XXN^Jl^X o      6' '"V V.......... 2-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-2,3-dihydro- 1H-inde ne-2-carboxamide Example 35 1 N H«\    / H \ / -H   ।  „ x   z^NXX^NV'0 1        fl T H H        nX7 °\xNxX\X 0 N^X ° T Y N (1R,5S)-N-(4-(6-ethoxypyrazin-2-y l)phenyl)-3-methyl-6-(4-(N-methyl cyclopropanesulfonamido)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide Example 36 1 N hA / H \ / H H X           N \^XX / -^ / N <.0 ।          fi j n h n "'X? °\xN\^XX 0 N. X o v I Y N (1R,5S)-6-(4-(cyclopropanesulfona mido)pyridin-2-yl)-N-(4-(6-ethoxy pyrazin-2-yl)phenyl)-3 -methyl-3 -az abicyclo[3.1.0]hexane-6-carboxami de Example 37 > rxYYxx °^zNxXX o N.    0 v I Y (1R,5S)-6-(6-(cyclopropanesulfona mido)pyrimidin-4-yl)-N-(4-(6-etho xypyrazin-2-yl)phenyl)-3-methyl-3 -azabicyclo[3.1.0]hexane-6-carboxa mide Example 38 H 4 3 H o N NXXXN N^ / / 'XXN'XXX o xJ o' XNX 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(5-(6-ethoxypyrazin -2-yl)pyridin-2-yl)bicyclo[3.1.0]he xane-3-carboxamide Example 39 A IZ ° / =O IZ z z \\ / / O 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-fluorophenyl)bicyclo[3.1.0 ]hexane-3-carboxamide Example 40 A Xc / K IZ ° o IZ Z  Z \\ / / o 2-(3-(cyclopropanesulfonamido)ph enyl)-N-(4-(6-ethoxypyrazin-2-yl)p henyl)-2,3-dihydro-1H-indene-2-ca rboxamide Example 41 H AA H 0 _n. X xx _n, / r T n r h         / A / Ox / N. / ^  0 N^N O' V PA 2-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-2,3-dihydro- 1H-inde ne-2-carboxamide Example 42 C\         H (J A   ^XxPX M H r> / A r J              / P Pn\PA o pj ox N=P N-(4-(5-chloropyrazolo[ 1,5-a]pyrid in-3-yl)phenyl)-3-(4-(cyclopropane sulfonamido)pyrimidin-2-yl)bicycl o[3.1.0]hexane-3-carboxamide Example 43 hA / H \ / H H \           AA-n^ / n-q<-° i       n i n h p uX 0\x-NxAPA O N. A 0 v I J 'N (1R,5S)-6-(4-(cyclopropanesulfona mido)pyrimidin-2-yl)-N-(4-(6-etho xypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-6-carboxamide Example 44 0 hX / H       H H 0 N^A o V I J "N (1R,5S)-6-(4-(cyclopropanesulfona mido)pyrimidin-2-yl)-N-(4-(6-etho xypyrazin-2-yl)phenyl)-3-oxabicycl o[3.1.0]hexane-6-carboxamide Example 45 c hA / H VH H \      Asxx N. AAN <0 i      h i n ¥ x n^a 0 N^N 0 v 1 J 'N (1R,5S)-6-(6-(cyclopropanesulfona mido)pyrimidin-4-yl)-N-(4-(6-etho xypyrazin-2-yl)-2-fluorophenyl)bic yclo[3.1.0]hexane-6-carboxamide Example 46 c hA / f H VH H \      Ax / N, X ,NX ,N. 1         h i n    h A °x / nxA\A o n^A o v I J (1R,5S)-6-(4-(cyclopropanesulfona mido)pyrimidin-2-yl)-N-(4-(6-etho xypyrazin-2-yl)-2-fluorophenyl)bic yclo[3.1.0]hexane-6-carboxamide Example 47 0 hA / H \ / H    H r> \     ^n\ / n\AA / ^ / n'cA’ i             fl A n ii । °\^N\A\A ° N^-N ° v T T (1R,5S)-6-(6-(cyclopropanesulfona mido)pyrimidin-4-yl)-N-(5-(6-etho xypyrazin-2-yl)pyridin-2-yl)-3-oxa bicyclo[3.1.0]hexane-6-carboxamid e Example 48 Cl               H 4 3      H 0 \     / n^nCAAn N X fxIJ 5 X y rfA XnA^   n N-(5-(5-chloropyrazolo[ 1,5-a]pyrid in-3-yl)pyridin-2-yl)-3-(6-(cyclopro panesulfonamido)pyrazin-2-yl)bicy clo[3.1.0]hexane-3-carboxamide Example 49 Cl               H 4 3      H o \ x^xX / AA nAu ity / \7 Xn-V^ n N-(4-(5-chloropyrazolo[ 1,5-a]pyrid in-3-yl)phenyl)-3-(6-(cyclopropane sulfonamido)pyrazin-2-yl)bicyclo[3 .1.0]hexane-3-carboxamide Example 50 O'? "c / ^ IZ '° XX iz z^3 ZH r j O N-(5-(5-chloropyrazolo[ 1,5-a]pyrid in-3-yl)pyridin-2-yl)-3-(4-(cyclopro panesulfonamido)pyrimidin-2-yl)bi cyclo[3.1.0]hexane-3-carboxamide Example 51 0 >9 0 N^J 6' ~\7 XX^ 3-(4-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(4-(6-ethoxypyrazin-2 -yl)phenyl)-6-oxabicyclo [3.1.0]hex ane-3-carboxamide Example 52 < o ^x z z ZT O=( X J J cZ O. / ZT Wx <r 2-(4-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(4-(6-ethoxypyrazin-2 -yl)-2-fluorophenyl)-2,3 -dihydro-1 H-indene-2-carboxamide Example 53 o ^x z z ZT O=X X J J xx o. / ZT cox 4'° 2-(4-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(5-(6-ethoxypyrazin-2 -yl)pyridin-2-yl)-2,3-dihydro- 1H-in dene-2-carboxamide Example 54 ( o ^x z z ZT O=( X J J o Z \ O. / ZT 4'° 2-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-fluorophenyl)-2,3-dihydro-1H-indene-2-carboxamide Example 55 o YX z z ZT O=^ X J J o z \ o. / ZI 4'° 2-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(5-(6-ethoxypyrazin -2-yl)pyridin-2-yl)-2,3-dihydro- 1H-indene-2-carboxamide Example 56 H XX H o X      / f 1 II ।                          '' -----7 ° NV ° V T J 2-(4-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(5-(6-ethoxypyrazin-2 -yl)pyrimidin-2-yl)-2,3 -dihydro- 1H -indene-2-carboxamide Example 57 % .yA-X \\ XXAX o NVN 0 V J N-(4-(5-chloropyrazolo[ 1,5-a]pyrid in-3-yl)phenyl)-3-(6-(cyclopropane sulfonamido)pyrimidin-4-yl)bicycl o[3.1.0]hexane-3-carboxamide Example 58 Cl\_ / Av^yV^y^ / (XXJ o M o\7 N-(5-(5-chloropyrazolo[ 1,5-a]pyrid in-3-yl)pyridin-2-yl)-3-(4-(cyclopro panesulfonamido)pyridin-2-yl)bicy clo[3.1.0]hexane-3-carboxamide Example 59 o,A TZ'"0 ^\ / —z )=o IZ XT N-(4-(5-chloropyrazolo[ 1,5-a]pyrid in-3-yl)phenyl)-3-(4-(cyclopropane sulfonamido)pyridin-2-yl)bicyclo[3 .1.0]hexane-3-carboxamide Example 60 o w z z ZT yo o. / ZI <r 6-(4-(cyclopropanesulfonamido)pyr idin-2-yl)-N-(4-(6-ethoxypyrazin-2 -yl)phenyl)-6,7-dihydro-5H-cyclop enta[b]pyrazine-6-carboxamide Example 61 H           H 0 N N                N , / / ^°v»vU o XJ xx 2-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(5-(6-ethoxypyrazin -2-yl)pyridin-2-yl)-2,3-dihydro- 1H-indene-2-carboxamide Example 62 C\                      9 7=\  \ J n r Y s Y \\ k.           0 NK > 0 | ^<7           F N-(5-(5-chloropyrazolo[ 1,5-a]pyrid in-3-yl)pyridin-2-yl)-3-(4-((difluor omethyl)sulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxa mide Example 63 c\ C /          0 n ,h 6' Y N J N-(5-(5-chloropyrazolo[ 1,5-a]pyrid in-3-yl)pyridin-2-yl)-3-(6-(cyclopro panesulfonamido)pyrimidin-4-yl)bi cyclo[3.1.0]hexane-3-carboxamide Example 64 H k /    H o X .NxXy\A / / rf X Y K Y S. ,F II 1                        ' / X / °xNX / Vk O N<^ 0 1 T T            F TT 3-(4-((difluoromethyl)sulfonamido) pyridin-2-yl)-N-(5-(6-ethoxypyrazi n-2-yl)pyridin-2-yl)bicyclo[3.1.0]h exane-3-carboxamide Example 65 IZ ° z z \\ / / TZ z^^ z z \\ / / o ? 3-(6-(cyclopropanesulfonamido)pyr azin-2-yl)-N-(5-(6-ethoxypyrazin-2 -yl)pyridin-2-yl)bicyclo[3.1.0]hexa ne-3-carboxamide Example 66 ( o 2   2 21 CK / ZT / -O N-(4-(6-ethoxypyrazin-2-yl)phenyl )-3-(6-(methylsulfonamido)pyrimid in-4-yl)bicyclo[3.1.0]hexane-3-carb oxamide Example 67 O.V IZ '° b> ^=o IZ z z \\ / / o ? N-(4-(6-ethoxypyrazin-2-yl)phenyl )-3-(6-((1 -methylethyl)sulfonamido )pyrimidin-4-yl)bicyclo[3.1.0]hexa ne-3-carboxamide Example 68 o.X Xc / K IZ '° Jb IZ z z \\ / / o 2-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)octahydrop entalene-2 -carboxamide Example 69 H           H 0 N ^>y\ / N Xz / Jb 0 NX C? N-(4-(6-ethoxypyrazin-2-yl)phenyl )-3-(6-(ethylsulfonamido)pyrimidin -4-yl)bicyclo[3.1.0]hexane-3-carbo xamide Example 70 o.X IZ ° b> yo IZ z z \\ / / O ) N-(4-(6-ethoxypyrazin-2-yl)phenyl )-3-(6-((1 -methylcyclopropane)-1 -s ulfonamido)pyrimidin-4-yl)bicyclo [3.1.0]hexane-3-carboxamide Example 71 IZ ° bp IZ z z \\ / / o ) N-(4-(6-ethoxypyrazin-2-yl)phenyl )-3-(6-((trifluoromethyl)sulfonamid o)pyrimidin-4-yl)bicyclo[3.1.0]hex ane-3-carboxamide Example 72 H N H k /    H 0 _N. X     _N^ / / IlY YYY 0 N<^N O V T J 5-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)octahydrocyclopenta[ c]pyrrole-5-carboxamide Example 73 \ o cxS 'w, IZ ° IZ z z \\ / / o ) N-(4-(6-ethoxypyrazin-2-yl)phenyl )-3-(6-((2-methoxyethyl)sulfonami do)pyrimidin-4-yl)bicyclo[3.1.0]he xane-3-carboxamide Example 74 1 N H ky    h o X    .N^ / / Hl V    H     z 0 N<X °' v 5-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-2-methyloctahydrocy clopenta[c]pyrrole-5-carboxamide Example 75 Ck / "OT^ IZ ° / =O IZ z z \\ / / O ) 3-(6-((cyanomethyl)sulfonamido)p yrimidin-4-yl)-N-(4-(6-ethoxypyraz in-2-yl)phenyl)bicyclo[3.1.0]hexan e-3-carboxamide Example 76 ( o z z ZI / T^ z \ o. / 21 C / K <K N-(4-(6-ethoxypyrazin-2-yl)phenyl )-3-(6-((1 -fluorocyclopropane)-1 -su lfonamido)pyrimidin-4-yl)bicyclo[ 3.1.0]hexane-3-carboxamide Example 77 O.P IZ ° IZ o ? 3-(6-(cyclopropanesulfonamido)-2-methylpyrimidin-4-yl)-N-(4-(6-eth oxypyrazin-2-yl)phenyl)bicyclo[3.1 .0]hexane-3-carboxamide Example 78 “A l=\ ° \\ / / z—( )=O IZ A J J A' ZI Ck / A° N-(2-(4-(cyclopropanesulfonamido )pyrimidin-2-yl)-2,3-dihydro- 1H-in den-2-yl)-4-(6-ethoxypyrazin-2-yl) benzamide Example 79 □A IZ ° )=\ / X / ° IZ z z \\ / / o 3-(6-(cyclopropanesulfonamido)-2-methoxypyrimidin-4-yl)-N-(4-(6-et hoxypyrazin-2-yl)phenyl)bicyclo[3. 1.0]hexane-3-carboxamide Example 80 oA IZ ° ^=o IZ aA\ ,z J f / 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(5-methoxypyraz olo[1,5-a]pyridin-3-yl)phenyl)bicyc lo[3.1.0]hexane-3-carboxamide Example 81 °\ A IZ xo Ai A~~z ° A o A~z \ V zAA^ 3 -(5-(cyclopropanesulfonamido)pyr azolo[1,5-a]pyrimidin-7-yl)-N-(4-( 6-ethoxypyrazin-2-yl)phenyl)bicycl o[3.1.0]hexane-3-carboxamide Example 82 oA IZ ° Q ° j X A. / ^=0 IZ z z \\ / / o 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-8-oxabicyclo[3.2.1]o ctane-3 -carboxamide Example 83 9 / )   H r iT n if        s. H N^N °' xx N-(3-(6-(cyclopropanesulfonamido )pyrimidin-4-yl)bicyclo[3.1.0]hexa n-3-yl)-4-(6-ethoxypyrazin-2-yl)be nzamide Example 84 ''C / K IZ ° ^=o IZ  O— z z / / o 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-methoxyphenyl)bicyclo[3. 1.0]hexane-3-carboxamide Example 85 TZ ° fi z z / / O 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-methylphenyl)bicyclo[3.1. 0]hexane-3-carboxamide Example 86 1N H O Ho / N. X _N. .KI, / / r Y n k Y X / Ox / Xf / 0 N<X ° X N-(2-cyano-4-(6-ethoxypyrazin-2-y l)phenyl)-3-(4-(cyclopropanesulfon amido)pyrimidin-2-yl)bicyclo[3.1.0 ]hexane-3-carboxamide Example 87 0        0 V X J N 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2,6-difluorophenyl)bicyclo[3 .1.0]hexane-3-carboxamide Example 88 H 4 3 H o n n^XXjm ^ / Nx / / 0 N^J) 0 A / U..... 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(5-(6-ethoxypyrazin -2-yl)-3-methylpyridin-2-yl)bicyclo [3.1.0]hexane-3-carboxamide Example 89 H \ /    H Q . ° , / \. ^ ° XX °' X7 XT N 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(5-(6-ethoxypyrazin -2-yl)-3-fluoropyridin-2-yl)bicyclo[ 3.1.0]hexane-3-carboxamide Example 90 .p IZ ° k z z / / O 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-fluoro-5-methylphenyl)bic yclo[3.1.0]hexane-3-carboxamide Example 91 < o z z Ko \_ / o ZI O= / / '"■b. p O. P1 "co., <r 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-(trifluoromethoxy)phenyl) bicyclo[3.1.0]hexane-3-carboxamid e Example 92 .P IZ ° cP IZ z z o 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2,3-dimethylphenyl)bicyclo[ 3.1.0]hexane-3-carboxamide Example 93 9 O H r iT n y A s. H Pn 0' >7 Pp N-(3-(2-(cyclopropanesulfonamido )pyrimidin-4-yl)bicyclo[3.1.0]hexa n-3-yl)-4-(6-ethoxypyrazin-2-yl)be nzamide Example 94 O,P z6 z o^ z z K o ? N-(3-(4-(cyclopropanesulfonamido )pyrimidin-2-yl)bicyclo[3.1.0]hexa n-3-yl)-4-(6-ethoxypyrazin-2-yl)be nzamide Example 95 \                  n / \       H 0 \                 O / >       M H 1 XZV S^—7 \=N   S^ / 'N V ' 0 V CMP H n^n N-7 N-(3-(6-(cyclopropanesulfonamido )pyrimidin-4-yl)bicyclo[3.1.0]hexa n-3-yl)-5-(6-ethoxypyrazin-2-yl)thi azole-2-carboxamide Example 96 X iP '° o / = o IZ Xi J f oA^ 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(5-ethoxypyrazol o[1,5-a]pyridin-3-yl)phenyl)bicyclo [3.1.0]hexane-3-carboxamide Example 97 x rr^^ / v VX / I 0 N<^N 0 V X—N 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(5-methylpyrazol o[1,5-a]pyridin-3-yl)phenyl)bicyclo [3.1.0]hexane-3-carboxamide Example 98 O.P IZ ° z z \\ / / ZI z z \\ / / o ) N-(3-(6-(cyclopropanesulfonamido )pyrazin-2-yl)bicyclo[3.1.0]hexan-3-yl)-4-(6-ethoxypyrazin-2-yl)benz amide Example 99 z z / / ZI op A\ y ° । Cp ZI O=« / < / ° 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-fluorophenyl)-8-oxabicycl o[3.2.1]octane-3-carboxamide Example 100 z z \\ / / ZI oX X ° 1 Cp ZI O=cn / \x < / ° 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)-2-methoxyphenyl)-8-oxabicy clo[3.2.1]octane-3-carboxamide Example 101 O X P)=O / IZ X) / V—\ >=z I o A AA / = o IZ z y O z z O\__ 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(5-(6-ethoxypyrazin -2-yl)pyridin-2-yl)-8-oxabicyclo[3. 2.1]octane-3-carboxamide Example 102 'o z z \\ z ZI O=( ,A\ VO | z= / o ZI O=< / / \x — / o N-(4-(6-ethoxypyrazin-2-yl)phenyl )-3-(6-(ethylsulfonamido)pyrimidin -4-yl)-8-oxabicyclo[3.2.1 ]octane-3 -carboxamide Example 103 o xw=o / IZ Vz o AA\ )= Z 1 o A XA )= O IZ ( A '—z 3-(6-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(3-(6-ethoxypyrazin -2-yl)phenyl)-8-oxabicyclo[3.2.1]o ctane-3 -carboxamide Example 104 o %=o / IZ 0 I o A \ZA )= o IZ z z _ 3-(2-(cyclopropanesulfonamido)pyr imidin-4-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-8-oxabicyclo[3.2.1]o ctane-3 -carboxamide Example 105 o Za XO)=O / IZ AA z y AA\ z 1 o X v> a° IZ ^^^Va z z O__ 3-(4-(cyclopropanesulfonamido)pyr imidin-2-yl)-N-(4-(6-ethoxypyrazin -2-yl)phenyl)-8-oxabicyclo[3.2.1]o ctane-3 -carboxamide Example 106 ^°\       9 4) h / =N.       X XA / / ° Z   \ / / r   n Af 'A s. v / / \\ 1'      H II                  --7 O V N-(2-(4-(cyclopropanesulfonamido )pyrimidin-2-yl)-2,3-dihydro- 1H-in den-2-yl)-5-(6-ethoxypyrazin-2-yl)t hiazole-2-carboxamide Example 107 O / A %=o / IZ ^A z z I O A \A )= o IZ <''^Va z z O__ 3-(6-(cyclopropanesulfonamido)pyr azin-2-yl)-N-(4-(6-ethoxypyrazin-2 -yl)phenyl)-8-oxabicyclo[3.2.1]octa ne-3-carboxamide Example 108 IZ ° z z \\ / / X N-(3-(6-(cyclopropanesulfonamido )pyrazin-2-yl)bicyclo[3.1.0]hexan-3-yl)-5-(6-ethoxypyrazin-2-yl)thiaz ole-2-carboxamide Example 109 ^0     0 O  H XAyXxnYN's° h XJ^ °' Az N-(3-(2-(cyclopropanesulfonamido )pyrimidin-4-yl)bicyclo[3.1.0]hexa n-3-yl)-5-(6-ethoxypyrazin-2-yl)thi azole-2-carboxamide Example 110 U 0   H o ^hk X X   ,N„ o f Y NnY X_ H      II      I Z / x—7 \ / O, ,N,           N^N o V J\T N-(3-(6-(cyclopropanesulfonamido )pyrimidin-4-yl)bicyclo[3.1.0]hexa n-3-yl)-5-(6-ethoxypyrazin-2-yl)pic olinamide Example 111 nX Vn m      o \7 N-(3-(4-(cyclopropanesulfonamido )pyrimidin-2-yl)bicyclo[3.1.0]hexa n-3-yl)-5-(6-ethoxypyrazin-2-yl)thi azole-2-carboxamide Example 112 0          H An s A        ° < xno NO on    nON 0 5-(6-ethoxypyrazin-2-yl)-N-(3-(6-( ethylsulfonamido)pyrimidin-4-yl)bi cyclo[3.1.0]hexan-3-yl)thiazole-2-c arboxamide Example 113 \ 0            Q /  \ AN S ^A      n ? < / H mVya N-k / Vn m N^N O 5-(6-ethoxypyrazin-2-yl)-N-(3-(6-( methylsulfonamido)pyrimidin-4-yl) bicyclo[3.1.0]hexan-3-yl)thiazole-2 -carboxamide Example 114 o° IZ / —z\ X i ° z =( v_k / o z \ O. / ZI <r N-(( 1R,5S)-3 -(6-(cyclopropanesulf onamido)pyrimidin-4-yl)-8-oxabicy clo[3.2.1]octan-3 -yl)-5-(6-ethoxypy razin-2-yl)thiazole-2-carboxamide Example 115 oY IZ ° Yz f) / Z ZI °A .z N-(3-(6-(cyclopropanesulfonamido )pyrimidin-4-yl)bicyclo[3.1.0]hexa n-3-yl)-5-(6-ethoxypyrazin-2-yl)-1, 3,4-thiadiazole-2-carboxamide Example 116 °\       ° H H A=N       AA^^^N, / / ° 4 \ /      n >i y^ s. Up H 1^1 A? N-(( 1R,5S)-3 -(6-(cyclopropanesulf onamido)pyrimidin-4-yl)-8-oxabicy clo[3.2.1]octan-3 -yl)-2-(6-ethoxypy razin-2-yl)thiazole-5-carboxamide Example 117 Cl 0 °          H N A S ^A AaA-^ N - / / 0 । y_ / y n i y y_ n^Vn h n^n o' >7 5-(5-chloropyrazolo[1,5-a]pyridin-3 -yl)-N-(( 1R,5S)-3 -(6-(cyclopropan esulfonamido)pyrimidin-4-yl)- 8 -ox abicyclo[3.2.1]octan-3 -yl)thiazole-2-carboxamide Example 118 \             z°\ °\        9 AA h / =N    A XSyN' / / ° <x \__ / 7T N X Y S. N-A^vK h IIJ N-(( 1R,5S)-3 -(4-(cyclopropanesulf onamido)pyrimidin-2-yl)-8-oxabicy clo[3.2.1]octan-3 -yl)-5-(6-ethoxypy razin-2-yl)thiazole-2-carboxamide Example 119 °. H I J H o N N Y><Y N N - O' y^O^N^JyA o Ci / N o' A / (1R,5S)-3 -(2-(cyclopropanesulfonam ido)pyrimidin-4-yl)-N-(5-(6-ethoxyp yrazin-2-yl)pyridin-2-yl)-8-oxabicycl o[3.2.1]octane-3-carboxamide Example 120 \           r> A    H 0 Ay^v 3'-- / svA « J o V /  \—Z II H n^Y \\    Yn N—' N-(3-(4-(cyclopropanesulfonamido)p yridin-2-yl)bicyclo[3.1.0]hexan-3-yl) -5-(6-ethoxypyrazin-2-yl)thiazole-2-carboxamide Example 121 ° Ay / N -'>aLn y / N' o U^n o' A / y.......... (1R,5S)-3 -(2-(cyclopropanesulfonam ido)pyrimidin-4-yl)-N-(4-(6-ethoxyp yrazin-2-yl)-2-methoxyphenyl)-8-ox abicyclo[3.2.1]octane-3-carboxamide Example 122 o l" H I J       H o ,N. X ,N. .N. / / fif nT V / / sv^ 0 Xx ° v XX (1R,5S)-3 -(2-(cyclopropanesulfonam ido)pyrimidin-4-yl)-N-(4-(6-ethoxyp yrazin-2-yl)-2-fluorophenyl)-8-oxabi cyclo[3.2.1]octane-3-carboxamide Example 123 n /  \      H 0 Cl       \\ VvX S^-7 )=\ ,SV N Y ' o V / \_y ” H n^n v   VN N—7 5-(5 -chloropyridin-3 -yl)-N-(3 -(6 -(cy clopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexan-3-yl)thiazole-2-carboxamide Example 124 / 3 XX N x * . / ^v«JU s M / ~v xx (1R,5S)-3 -(4-(cyclopropanesulfonam ido)pyrimidin-2-yl)-N-(5-(6-ethoxyp yrazin-2-yl)pyridin-2-yl)-8-oxabicycl o[3.2.1]octane-3-carboxamide Example 125 / / ^y / \YXz~Y 0 X 0 V XNX (1R,5S)-3 -(4-(cyclopropanesulfonam ido)pyrimidin-2-yl)-N-(4-(6-ethoxyp yrazin-2-yl)-2-fluorophenyl)-8-oxabi cyclo[3.2.1]octane-3-carboxamide Example 126 XJxX B p I Y Y T Y Yx ° n<Y ° v Xx (1R,5S)-3 -(4-(cyclopropanesulfonam ido)pyrimidin-2-yl)-N-(4-(6-ethoxyp yrazin-2-yl)-2-methoxyphenyl)-8-ox abicyclo[3.2.1]octane-3-carboxamide Example 127 \                  n / \       H 0 \              Q I /     N. " yi YY / ^X Xn sXX Y ' o V C / MJ h n^n N—J N-(3-(6-(cyclopropanesulfonamido)p yrimidin-4-yl)bicyclo[3.1.0]hexan-3-yl)-5-(6-ethoxypyrazin-2-yl)thiophen e-2-carboxamide Example 128 \                n            H  0 \              ° L Z      N " 0                  \\ Vn sX^m V \ 0 V \\ N—J   [ N-(3-(6-(cyclopropanesulfonamido)p yrimidin-4-yl)bicyclo[3.1.0]hexan-3-yl)-5-(6-ethoxypyrazin-2-yl)-4-meth ylthiazole-2-carboxamide Example 129 H \ /    H 0 ,N.    X , N.    A II 1              ' / ^ \zOxzNvA / 0     0 T J N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-3-(4-(methylsulfonamido)pyri midin-2-yl)bicyclo[3.1.0]hexane-3 -c arboxamide Example 130 F         n l\ H ,° f-4~f     1 X / X ?^-7 >=N sXn V \ o V GHj h n^n N--' N-(3-(6-(cyclopropanesulfonamido)p yrimidin-4-yl)bicyclo[3.1.0]hexan-3-yl)-5-(6-(trifluoromethyl)pyrazin-2-y l)thiazole-2-carboxamide Example 131 \           n / \    H ° \               ° L z      n " 0                  l\ \=N   SX^N  \\  \ o V \ Z II H    <          v v / /  \^N N--' N-(3-(2-(cyclopropanesulfonamido)p yridin-4-yl)bicyclo[3.1.0]hexan-3-yl) -5-(6-ethoxypyrazin-2-yl)thiazole-2-carboxamide Example 132 n / \      H 0 O / /       n " —0       it KZV 5'^-? \=N SN \\   \ o \ / F        11 H          u \\     V^N N--' N-(3-(6-(cyclopropanesulfonamido)p yrimidin-4-yl)bicyclo[3.1.0]hexan-3-yl)-5-(6-methoxypyrazin-2-yl)thiazol e-2-carboxamide Example 133 rFr- / f.. •xx / o. ,N. A^ / N 0 N^N 0 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-3-(6-(ethylsulfonamido)pyrimi din-4-yl)bicyclo[3.1.0]hexane-3-carb oxamide Example 134 H           H 0 / N. X'V Il J H 1*^ V \ / 0. / N. / X0 N^ / N 0Z V X J ° N 3-(6-(cyclopropanesulfonamido)pyri midin-4-yl)-N-(4-(6-ethoxypyrazin-2 -yl)-2-methoxyphenyl)bicyclo[3.1.0] hexane-3-carboxamide Example 135 O,X ''X IZ '° )=o z z \\ / / o ? 3-(4-(cyclopropanesulfonamido)pyri din-2-yl)-N-(4-(6-ethoxypyrazin-2-yl )-2-methoxyphenyl)bicyclo[3.1.0]he xane-3-carboxamide Example 136 ^0        / \ \ .,         H X X      H o XX S^nX<.N N, / / u \\ X—X « Y T if N—VN 0       0 \ / 3-(4-(cyclopropanesulfonamido)pyri midin-2-yl)-N-(5-(6-ethoxypyrazin-2 -yl)thiazol-2-yl)bicyclo[3.1.0]hexane -3-carboxamide

[00121] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[00122] Note: If there is a discrepancy between the drawn structure and the name given for the structure, the drawn structure shall prevail.

[00123] Further, the present disclosure provides a pharmaceutical composition comprising an effective dose of the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[00124] The present disclosure provides a use of the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the manufacture of a CTPS1 inhibitor.

[00125] The present disclosure further provides a use of the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the manufacture of a medicament for treating a disease mediated by CTPS1, wherein the disease mediated by CTPS1 is preferably lymphoma or solid tumor; more preferably relapsed / refractory B-cell or T-cell lymphoma; most preferably mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, or indolent B-cell lymphoma.

[00126] The present disclosure further provides a use of the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the manufacture of a medicament for treating lymphoma or solid tumor.

[00127] The present disclosure provides a use of the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the manufacture of a medicament for treating relapsed / refractory B-cell and T-cell lymphoma.

[00128] The present disclosure provides a use of the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the manufacture of 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.

[00129] Accordingly, the present disclosure further provides a method for preventing or treating a disease mediated by CTPS1, comprising administering to a subject in need thereof the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof; wherein the disease mediated by CTPS1 is preferably lymphoma or solid tumor; more preferably relapsed / refractory B-cell or T-cell lymphoma; most preferably mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, or indolent B-cell lymphoma.

[00130] The present disclosure further provides a method for preventing or treating lymphoma or solid tumor, comprising administering to a subject in need thereof the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof. The present disclosure further provides a method of preventing or treating relapsed / refractory B-cell and T-cell lymphoma, comprising administering to a subject in need thereof the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof. The present disclosure further 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 the compound of formula (AAI), (AI), (I), (IIA), (IIB), (II), (III), (IV-1), (IV-2), (V-1), (V-2), (V-A), (V-B), (V-C), or (V-D), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof. DETAILED DESCRIPTION

[00131] Unless stated to the contrary, certain terms used in the specification and claims of the present disclosure are defined as follows:

[00132] "Alkyl," when used as a group or as part of a group, refers to a C1-C20 linear or branched aliphatic hydrocarbon group. It is preferably C1-C10 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, and the like. Alkyl may be substituted or unsubstituted.

[00133] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl,        * and the like; preferably C2-C4 alkenyl. Alkenyl may be optionally substituted or unsubstituted.

[00134] "Alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which may be linear or branched. Preferably C2-C10 alkynyl, more preferably C2-C6 alkynyl, most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl may be substituted or unsubstituted.

[00135] "Alkylene" refers to a saturated C1-C20 linear or branched aliphatic hydrocarbon group having two radicals derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, preferably C1-C10 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. Alkylene may be substituted or unsubstituted.

[00136] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more ring-forming atoms are carbon atoms, including monocyclic, polycyclic, fused, bridged, and spiro rings, preferably having 3- to 10- membered cycloalkyl or 3- to 8- membered cycloalkyl, for example 5- to 7- membered monocyclic or 7- to 10- membered bicyclic or tricyclic rings. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl. Cycloalkyl may be substituted or unsubstituted.

[00137] "Spirocycloalkyl" refers to a 5- to 18- membered polycyclic group having two or more ring structures, wherein monocyclic rings share one carbon atom (called a spiro atom) with each other, containing one or more double bonds in the rings, but no ring having a fully conjugated n-electron aromatic system. Preferably 6- to 14- membered, more preferably 7- to 10- membered. According to the number of spiro atoms shared between rings, spirocycloalkyl is divided into monospiro, dispiro or polispirocycloalkyl, preferably monospiro and dispirocycloalkyl, preferably 4- / 5-, 4- / 6-, 5- / 5- or 5- / 6- membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[00138] "Fused cycloalkyl" refers to a 5- to 18- membered all-carbon polycyclic group containing two or more ring structures sharing a pair of carbon atoms with each other, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated n-electron aromatic system, preferably 6- to 12- membered, more preferably 7- to 10- membered. According to the number of constituent rings, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5- / 5- or 5- / 6membered bicyclic alkyl. 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 tetradecahydrophenanthryl.

[00139] "Bridged cycloalkyl" refers to a 5- to 18- membered all-carbon polycyclic group containing two or more ring structures sharing two non-directly connected carbon atoms with each other, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated n-electron aromatic system, preferably 6- to 12- membered, more preferably 7-to 10- membered. Preferably 6- to 14- membered, more preferably 7- to 10- membered. According to the number of constituent rings, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, 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, (1r,5r)-bicyclo[3.3.2]decyl.

[00140] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably in the present disclosure and refer to a non-aromatic heterocyclic group in which one or more ring-forming atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and S(O)r (wherein t is selected from the group consisting of 0, 1, and 2), including monocyclic, polycyclic, fused, bridged, and spiro rings. Preferably having 5- to 7- membered monocyclic or 7- to 10- membered bicyclic or tricyclic rings, which may contain 1, 2, or 3 atoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholino, oxetanyl, thiomorpholino, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholino, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl,      piperazin-2-one,      8-oxa-3-aza-bicyclo[3.2.1]octyl,      piperazinyl, hexahydropyrimidinyl;

[00141] heterocyclyl may be substituted or unsubstituted.

[00142] "Spiraheterocyclyl" refers to a polycyclic group having 5 to 18 members and two or more ring structures, wherein the rings share a single atom with each other, and the rings contain one or more double bonds but no ring has a fully conjugated n-electron aromatic system, wherein one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and S(O)t (where t is selected from the group consisting of 0, 1, and 2), and the remaining ring atoms are carbon. Preferably 6- to 14- membered, more preferably 7- to 10- membered. According to the number of spiro atoms shared between rings, spiroheterocyclyl is divided into monospiroheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl, preferably monospiroheterocyclyl or dispiroheterocyclyl. More preferably 4- / 4- membered, 4- / 5- membered, 3- / 5- membered, 3- / 6- membered, 4- / 6- membered, 5- / 5- membered, or 5- / 6- membered monospiroheterocyclyl. Non-limiting examples of "spiraheterocyclyl" include, but are not limited to:   1,7-dioxaspiro[4.5]decanyl,   2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, and 5-oxaspiro[2.4]heptyl.

[00143] "Fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, wherein one or more rings may contain one or more double bonds but no ring has a fully conjugated n-electron aromatic system, wherein one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and S(O)r (where t is selected from the group consisting of 0, 1, and 2), and the remaining ring atoms are carbon. Preferably 6- to 14- membered, more preferably 7- to 10- membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 5- / 5- membered or 5- / 6- membered bicyclic fused heterocyclyl. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, and octahydrobenzo[b][1,4]dioxinyl.

[00144] "Bridged heterocyclyl" refers to a polycyclic group having 5 to 14 members or 5 to 18 members, and containing two or more ring structures sharing two non-adjacent atoms with each other, wherein one or more rings may contain one or more double bonds but no ring has a fully conjugated n-electron aromatic system, wherein one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and S(O)t (where t is selected from the group consisting of 0, 1, and 2), and the remaining ring atoms are carbon. Preferably 6- to 14- membered, more preferably 7- to 10- membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[00145] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings can be connected together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably aryl is C6-C10 aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl may be substituted or unsubstituted.

[00146] "Heteroaryl" refers to an aromatic 5- to 6- membered monocycle or 8- to 10- membered bicycle, which can contain 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, 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, furan[3,2-b]pyridinyl, furan[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, and 2H-pyrrolo[3,4-c]pyridinyl.

[00147] Heteroaryl can be substituted or unsubstituted.

[00148] "Alkoxy" refers to a group of (alkyl-O-). wherein alkyl is as defined in the present disclosure, preferably C1-C6 alkoxy. Examples thereof include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[00149] "Nitro" refers to a -NO2 group.

[00150] "Hydroxy" refers to a -OH group.

[00151] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[00152] "Amino" refers to -NH2.

[00153] "Cyano" refers to -CN.

[00154] "Benzyl" refers to -CH2-phenyl.

[00155] "Carboxy" refers to -C(O)OH.

[00156] "Carboxylate" group refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[00157] "Hydroxyalkyl" refers to an alkyl group substituted by hydroxy, wherein alkyl is as defined above.

[00158] "Aminoalkyl" refers to an alkyl group substituted by amino, wherein alkyl is as defined above.

[00159] "Haloalkyl" refers to an alkyl group substituted by a halogen, wherein alkyl is as defined above.

[00160] "Haloalkoxy" refers to an alkoxy group substituted by a halogen, wherein alkoxy is as defined above.

[00161] "DMSO" refers to dimethyl sulfoxide.

[00162] "BOC" refers to tert-butoxycarbonyl.

[00163] "Bn" refers to benzyl.

[00164] "THP" refers to 2-tetrahydropyranyl.

[00165] "TFA" refers to trifluoroacetic acid.

[00166] "Ts" refers to p-toluenesulfonyl.

[00167] "Leaving group" refers to an atom or functional group that dissociates from a larger molecule in a chemical reaction, and is a term applied in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by a nucleophile is referred to as a substrate, and the atom or group that breaks away from the substrate molecule with a pair of electrons is referred to as a leaving group. Groups that readily accept electrons and have a strong ability to bear negative charge are good leaving groups. The smaller the pKa of the conjugate acid of a leaving group, the more easily the leaving group dissociates from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group has an increased tendency to exist in the form of an anion (or an electrically neutral leaving group) without binding to other atoms. Common leaving groups include, but are not limited to, halogen, methylsulfonyl, -OTs, or -OH.

[00168] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, being independently replaced by a corresponding number of substituents. It is understood that substituents are only located at their possible chemical positions, and a person skilled in the art can determine possible or impossible substitutions (through experiment or theory) without undue effort. For example, an amino or hydroxy group having free hydrogen may be unstable when bound to a carbon atom having an unsaturated (e.g., olefinic) bond.

[00169] "Substitution" or "substituted" as described in the present disclosure, unless otherwise specified, refers to a group that may be substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, =O, -OR6, -C(O)R6, -C(O)OR6, -NHC(O)R6, -NHC(O)OR6, -NR7R8, -C(O)NR7R8, -CH2NHC(O)OR6, -CH2NR7R8, and -S(O)rR6;

[00170] R6 is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR10R11, -C(O)NR10R11, -SO2NR10R11, and -NR10C(O)R11;

[00171] R7 and R8 are each independently selected from the group consisting of a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR10R11, -C(O)NR10R11, -SO2NR10R11, and -NR10C(O)R11;

[00172] alternatively, R7 and R8, together with the atoms to which they are attached, form a 4- to 8- membered heterocyclyl, wherein the 4- to 8- membered heterocyclyl contains one or more N, O, or S(O)r, and the 4- to 8- membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR10R11, -C(O)NR10R11, -SO2NR10R11, and -NR10C(O)R11;

[00173] R9, R10, and R11 are each independently selected from the group consisting of a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, and carboxylate;

[00174] r is selected from the group consisting of 0, 1, and 2.

[00175] Compounds of the present disclosure may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure, 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 disclosure.

[00176] Unless otherwise specified, the structures described in the present disclosure also include all isomers of such structures (e.g., diastereomers, enantiomers, and atropisomers and geometric (conformational) isomer forms; for example, the R and S configurations at each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers of the compounds of the present disclosure as well as enantiomer mixtures, diastereomer mixtures, and geometric (conformational) isomer mixtures are all within the scope of the present disclosure.

[00177] "Pharmaceutically acceptable salt" refers to certain salts of the above-mentioned compounds that retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salt of the compound represented by formula (I) may be a metal salt or an amine salt formed with an appropriate acid.

[00178] "Pharmaceutical composition" refers to a mixture containing one or more compounds described in the present disclosure or physiologically pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism and promote absorption of the active ingredient to exert biological activity. Synthesis methods of compounds of the present disclosure

[00179] In order to achieve the object of the present disclosure, the following technical solutions are adopted:

[00180] Method 1:

[00181] The present disclosure provides a method for preparing a compound of formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, comprising:

[00182] performing an acid-amine condensation reaction or an amine-ester exchange reaction with a compound of formula (II-a) and a compound of formula (II-b), and optionally further performing a substitution reaction, to obtain a compound of formula (II);

[00183] wherein:

[00184] Y1 is selected from the group consisting of hydroxy, methoxy, and ethoxy;

[00185] X1, X2, X3, X, Y, Z, Q, R1 to R4, p, q, j, and t are as defined in formula (II).

[00186] Method 2:

[00187] The present disclosure provides a method for preparing a compound of formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, comprising:

[00188] performing an acid-amine condensation reaction or an amine-ester exchange reaction with a compound of formula (III-a) and a compound of formula (III-b), and optionally further performing a substitution reaction, to obtain a compound of formula (III);

[00189] wherein:

[00190] Y1 is selected from the group consisting of hydroxy, methoxy, and ethoxy;

[00191] X1, X2, X3, X, Y, Z, Q, R1 to R4, p, q, j, and t are as defined in formula (III). Detailed Description of Embodiments

[00192] The present disclosure is further described below in conjunction with examples, however, these examples are not intented to limit the scope of the present disclosure. Examples

[00193] The examples provide the preparation of representative compounds of formula (I) and relevant structural characterization data. It should be noted that the following examples are for illustrating the present disclosure and not limiting the present disclosure. 1H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm. Tetramethylsilane was used as an internal standard (0.00 ppm). The representation of 1H NMR: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets. When coupling constants were provided, the unit was Hz.

[00194] Mass spectra were measured using an LC / MS instrument, and the ionization mode may be ESI or APCI.

[00195] For thin layer chromatography (TLC), Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The specifications of silica gel plates used for thin-layer chromatography (TLC) were 0.15 mm to 0.2 mm, and the specification of those used for separation and purification by thin layer chromatography was 0.4 mm to 0.5 mm.

[00196] For column chromatography, Yantai Huanghai silica gel of 200 to 300 mesh was generally used as a carrier.

[00197] In the following examples, unless otherwise specified, all temperatures are presented in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or are synthesized according to known methods. Commercially available starting materials and reagents are used directly without further purification. Unless otherwise specified, 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.

[00198] CD3OD: deuterated methanol.

[00199] CDCl3: deuterated chloroform.

[00200] DMSO-d6: deuterated dimethyl sulfoxide.

[00201] Argon atmosphere refers to a reaction flask connected to an argon balloon having a volume of about 1 L.

[00202] In the examples, unless otherwise specified, solutions in reactions referred to aqueous solutions.

[00203] Compounds were purified using silica gel column chromatography and reverse-phase column chromatography. The eluent systems were selected from the group consisting of A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; and D: trifluoroacetic acid aqueous solution and acetonitrile system. The volume ratios of solvents varied depending on the polarity of the compound, and small amounts of acidic or basic reagents such as acetic acid or triethylamine may also be added for adjustment. Example 1 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-di hydro-1H-indene-2-carboxamide Step 1 2-chloro-6-ethoxypyrazine

[00204] Under 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 hours, 2,6-dichloropyrazine 1a (5 g, 33.56 mmol, commercially available) was added. The mixture was heated to room temperature and stirred for 16 hours. Mass spectrometry showed that the starting material was basically completely reacted. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: System A) to obtain 2-chloro-6-ethoxypyrazine 1b (4 g) with a yield of 75.15%.

[00205] MS m / z (ESI): 159.0 [M+1] Step 2 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine

[00206] 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)ferrocene palladium(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 mixture was subjected to argon exchange three times, heated to 95°C, and stirred for 3 hours. After the reaction was completed, the solvent was evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine 1d (3.5 g) with a yield of 96.26%.

[00207] MS m / z (ESI): 217.2 [M+1] Step 3 1-(tert-butyl) 3-methyl 2-(2-(methylthio)pyrimidin-4-yl)malonate

[00208] 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). The mixture was stirred at 70°C for 3 hours, cooled to room temperature, and quenched by adding water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was 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 in the next step.

[00209] MS m / z (ESI): 299.3 [M+1] Step 4 methyl 2-(2-(methylthio)pyrimidin-4-yl)acetate

[00210] 1-(Tert-butyl) 3-methyl 2-(2-(methylthio)pyrimidin-4-yl)malonate 1g (9 g, 30.17 mmol) was added to dichloromethane (50 mL). Trifluoroacetic acid (34.39 g, 301.65 mmol, 23.24 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 2-(2-(methylthio)pyrimidin-4-yl)acetate 1h (4 g) with a yield of 66.89%.

[00211] MS m / z (ESI): 199.2 [M+1] Step 5 methyl 2-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[00212] 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 hours, 1,2-bis(chloromethyl)benzene (971.34 mg, 5.55 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (30 mL) and water (15 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was 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-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1i (900 mg) with a yield of 59.40%.

[00213] MS m / z (ESI): 301.0 [M+1] Step 6 methyl 2-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[00214] At room temperature, meta-chloroperoxybenzoic 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). After stirring at room temperature for 2 hours, saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phase was 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 2-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1j (950 mg) with a yield of 85.85%.

[00215] MS m / z (ESI): 333.1[M+1] Step 7 methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[00216] 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 mixture was heated to 90°C and the reaction was performed for 2 hours, then cooled to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was 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 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1k (700 mg) with a yield of 77.88%.

[00217] MS m / z (ESI): 374.2 [M+1] Step 8 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-di hydro-1H-indene-2-carboxamide

[00218] Under ice-water bath, trimethylaluminum (2.0 M solution in toluene) (2 M, 187.45 pL) was added to a solution of 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine 1d (30.11 mg, 139.25 pmol) in toluene (1.95 mL). The mixture was stirred at room temperature for 1 hour, then methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 1k (40 mg, 107.12 pmol) was added, and the mixture was heated to 90°C and the reaction was performed for 5 hours. A small amount of methanol and 1 N hydrochloric acid were added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A:   0.05% TFA +   H2O,   mobile phase B:   CH3CN)   to obtain 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-di hydro-1H-indene-2-carboxamide 1 (3.48 mg) with a yield of 4.60%.

[00219] MS m / z (ESI): 558.2 [M+1]

[00220] 1H NMR (400 MHz, Chloroform-d) 8 9.52 (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 = 5.1 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 4.00 (d, J = 16.0 Hz, 2H), 3.66 (d, J = 16.0 Hz, 2H), 3.21 - 3.03 (m, 1H), 1.46 (t, J = 7.0 Hz, 3H), 1.28 (s, 2H), 1.01 (d, J = 7.6 Hz, 2H). Example 2 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo [3.1.0]hexane-3-carboxamide Step 1 ethyl 3-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00221] At -30°C, lithium bis(trimethylsilyl)amide (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). The mixture was heated to room temperature and stirred for 1 hour. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was 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       ethyl 3-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2b (1.25 g) with a yield of 96.17%.

[00222] MS m / z (ESI): 278.9 [M+1] Step 2 ethyl 3-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00223] At room temperature, meta-chloroperoxybenzoic acid (1.12 g, 6.47 mmol) was added to a solution of ethyl 3-(2-(methylthio)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, saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was 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 ethyl 3-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2c (330 mg) with a yield of 49.33%.

[00224] MS m / z (ESI): 311.0 [M+1] Step 3 ethyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00225] Ethyl 3-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2c (330 mg, 1.06 mmol) and cyclopropanesulfonamide (193.23 mg, 1.59 mmol) were added to N-methylpyrrolidone (3 mL). The mixture was heated to 80°C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was 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        ethyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2d (250 mg) with a yield of 66.91%.

[00226] MS m / z (ESI): 352.0 [M+1] Step 4 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo [3.1.0]hexane-3-carboxamide

[00227] At room temperature, trimethylaluminum (2.0 M solution in toluene) (2 M, 958.54 pL) and 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine 1d (142.13 mg, 657.28 pmol) were added to toluene (2 mL). 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 pmol) was added, and the mixture was heated to 90°C and stirred for 2 hours. The mixture was cooled to room temperature, and a small amount of methanol was added to quench the reaction. The solvent was directly evaporated to dryness by rotation to obtain a crude product. Dilute hydrochloric acid and dichloromethane were added, and 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 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) with a yield of 3.70%.

[00228] MS m / z (ESI): 522.2 [M+1]

[00229] 1H NMR (400 MHz, DMSO-d6) 8 10.26 (s, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H), 8.56-8.44 (m, 2H), 8.25 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 5.3 Hz, 1H), 4.49-4.45 (m, 2H), 3.25 (dt, J = 8.2, 3.6 Hz, 1H), 2.87 (d, J = 13.8 Hz, 2H), 2.43 (dd, J = 13.8, 3.5 Hz, 2H), 1.40 (q, J = 7.0, 6.3 Hz, 5H), 1.07 (dt, J = 7.0, 3.5 Hz, 2H), 0.92 (td, J = 8.4, 5.9 Hz, 2H), 0.47-0.39 (m, 1H), 0.18-0.07 (m, 1H). Example 3 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-3-carboxamide Step 1 4-(6-ethoxypyrazin-2-yl)aniline

[00230] 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)ferrocene palladium(II) dichloride (667.95 mg, 912.88 pmol), and potassium carbonate (3.79 g, 27.39 mmol) were sequentially added to 1,4-dioxane (20 mL) and water (10 mL). The mixture was subjected to argon exchange three times and heated to 80°C with stirring for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 4-(6-ethoxypyrazin-2-yl)aniline 3b (1.5 g) with a yield of 76.34%.

[00231] MS m / z (ESI): 216.0 [M+1] Step 2 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-3-carboxamide

[00232] At room temperature, trimethylaluminum (2.0 M toluene solution) (2 M, 958.54 pL) was added to a solution of 4-(6-ethoxypyrazin-2-yl)aniline 3b (141.48 mg, 657.28 pmol) in toluene       (2       mL).       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 pmol) was added, and the mixture was heated to 90°C and stirred for 18 hours. After the reaction was completed, a small amount of methanol was added to quench the reaction, and the solvent was directly evaporated to dryness by rotation 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 x 21.2 mm I.D.; 5 pm, 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) with a yield of 17.71%.

[00233] MS m / z (ESI): 521.2 [M+1]

[00234] 1H NMR (400 MHz, DMSO-d6) 8 11.31 (s, 1H), 9.67 (s, 1H), 8.76 (s, 1H), 8.52 (d, J = 5.3 Hz, 1H), 8.18 (s, 1H), 8.12-8.03 (m, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 5.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.31 - 3.21 (m, 1H), 2.86 (d, J = 13.6 Hz, 2H), 2.49 - 2.38 (m, 2H), 1.41 (dt, J = 14.0, 5.5 Hz, 5H), 1.09 (dt, J = 6.7, 3.4 Hz, 2H), 0.96 (dt, J = 7.8, 3.6 Hz, 2H), 0.50 - 0.38 (m, 1H), 0.20 - 0.11 (m, 1H). Example 4 (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-o xabicyclo[3.1.0]hexane-6-carboxamide Step 1 tert-butyl 2-cyano-2-(2-(methylthio)pyrimidin-4-yl)acetate

[00235] Under an ice bath, 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) with continuous stirring 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. After the reaction was completed, the generated solid was filtered, and the filter cake was dried to obtain tert-butyl 2-cyano-2-(2-(methylthio)pyrimidin-4-yl)acetate 4a (7.6 g) with a yield of 92.02%. The crude product was directly used in the next step.

[00236] MS m / z (ESI): 266.3 [M+1] Step 2 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile

[00237] 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). After stirring for 4 hours, the solvent was evaporated to dryness by rotation. Saturated sodium bicarbonate solution was added to neutralize the mixture to neutral, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The residue was purified by silica gel column chromatography (eluent: System B) to obtain 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile 4b (3.2 g) with a yield of 67.62%.

[00238] MS m / z (ESI): 166.0 [M+1] Step 3 (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile

[00239] Under ice-water bath, (3aR,6aS)-tetrahydrofuro[3,4-d][1,3,2]dioxathiole 2,2-dioxide 4c (1.21 g, 7.26 mmol, prepared according to published patent "WO2005005398") was added 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). The mixture was stirred at room temperature for 1 hour, then heated to 60°C and stirred for 18 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The residue was purified by silica gel column chromatography (eluent: System B) to obtain (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile 4d (1.08 g) with a yield of 76.49%.

[00240] MS m / z (ESI): 234.1 [M+1] Step 4 (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[00241] Under an ice bath, hydrogen peroxide (5 mL, 35%) was added 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). The mixture was stirred at room temperature for 16 hours, then poured into ice water. After stirring for 30 minutes, a solid precipitated. The solid was collected by filtration, and the filter cake was dried to obtain (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 4e (1 g) with a yield of 92.83%. The crude product was directly used in the next step.

[00242] MS m / z (ESI): 252.0 [M+1] Step 5 (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[00243] Under ice-water bath, sodium nitrite (3.02 g, 43.77 mmol) was added to a mixed solution of acetic acid (4 mL) and acetic anhydride (8 mL) containing (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 4e (1.1 g, 4.38 mmol). The mixture was stirred at room temperature for 16 hours, then poured into a small amount of water. A solid precipitated, and the mixture was filtered under reduced pressure. The filter              cake              was              dried              to              obtain (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 4f (600 mg) with a yield of 54.33%. 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

[00244] 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 pmol), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (599.31 mg, 2.14 mmol), and N-methylimidazole (351.45 mg, 4.28 mmol) were added to anhydrous acetonitrile (5 mL). The mixture was stirred at room temperature for 0.5 hours, then 4-(6-ethoxypyrazin-2-yl)aniline 3b (184 mg, 856.47 umol) was added, and the mixture was heated to 60°C and stirred for 18 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 um, 20 mL / min; mobile phase A: 0.05% TFA + H2O,        mobile        phase        B:         CH3CN)        to        obtain (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1. 0]hexane-6-carboxamide 4g (120 mg) with a yield of 37.42%.

[00245] MS m / z (ESI): 449.8 [M+1] 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

[00246] At                              room                              temperature, (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1. 0]hexane-6-carboxamide 4g (120 mg, 266.95 pmol) and meta-chloroperoxybenzoic acid (108.39 mg, 533.90 pmol, 85% purity) were added to dichloromethane (3 mL). The mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was 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 in the next step.

[00247] MS m / z (ESI): 435.1 [M+1] Step 8 (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-o xabicyclo[3.1.0]hexane-6-carboxamide

[00248] Cyclopropanesulfonamide        (60.39        mg,        498.42        pmol), (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 pmol), and cesium carbonate (162.39 mg, 498.42 pmol) were added to N-methylpyrrolidone (2 mL). The mixture was heated to 90°C and stirred for 1 hour, then cooled to room temperature. The crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / 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-o xabicyclo[3.1.0]hexane-6-carboxamide 4 (12.37 mg) with a yield of 9.50%.

[00249] MS m / z (ESI): 462.1 [M+1]

[00250] 1H NMR (400 MHz, Chloroform-d) 8 8.54 (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 = 9.3 Hz, 2H), 3.97 (d, J = 9.2 Hz, 2H), 3.13 (s, 1H), 2.59 (s, 2H), 1.47 (t, J = 7.0 Hz, 3H), 1.33 (s, 4H). Example 5 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro -1H-indene-1-carboxamide Step 1 methyl 2,3-dihydro-1H-indene-1-carboxylate

[00251] 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 pL). The mixture was stirred at room temperature for 2 hours. Part of the solvent was removed, and anhydrous methanol (9.73 mL) was added. The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain methyl 2,3-dihydro-1H-indene-1-carboxylate 5b (560 mg) with a yield of 85.90%. The crude product was directly used in the next step. Step 2 methyl 1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate

[00252] At -30°C, lithium bis(trimethylsilyl)amide (1 M, 7.47 mL) was added 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). The mixture was slowly heated to room temperature and stirred for 1 hour. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent:   System A) to obtain methyl 1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate 5c (530 mg) with a yield of 70.85%.

[00253] MS m / z (ESI): 301.2 [M+1] Step 3 methyl 1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate

[00254] At                  room                  temperature,                  methyl 1-(2-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate 5c (650 mg, 2.16 mmol) and meta-chloroperoxybenzoic acid (878.67 mg, 4.33 mmol, 85% purity) were added to dichloromethane (7 mL). The mixture was stirred at room temperature for 18 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain methyl 1-(2-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate 5d (460 mg) with a yield of 63.96%.

[00255] MS m / z (ESI): 333.1 [M+1] Step 4 methyl 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate

[00256] 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). Cesium carbonate (901.86 mg, 2.77 mmol) was added subsequently. The mixture was heated to 90°C and stirred for 18 hours. After the reaction was completed, the mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System                B)                to                obtain                methyl 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate 5e (350 mg) with a yield of 67.72%.

[00257] MS m / z (ESI): 374.1 [M+1] Step 5 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro -1H-indene-1-carboxamide

[00258] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (121.05 mg, 562.36 umol) and trimethylaluminum (2.0 M toluene solution) (2 M, 702.95 pL) were dissolved in toluene (500.00 pL). The mixture was      stirred      at      room      temperature      for      1      hour.      Methyl 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-1-carboxylate 5e (175 mg, 468.63 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. All starting materials were completely reacted. A small amount of methanol was added to quench the reaction, and the solvent was directly evaporated to dryness by rotation 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 x 21.2 mm I.D.; 5 um, 20 mL / min; mobile phase A: 0.05% TFA + H2O,        mobile        phase        B:         CH3CN)        to        obtain 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro -1H-indene-1-carboxamide 5 (42 mg) with a yield of 12.19%.

[00259] MS m / z (ESI): 556.8 [M+1]

[00260] 1H NMR (400 MHz, Chloroform-d) 8 8.80 (s, 1H), 8.53 (d, J = 5.4 Hz, 2H), 8.06 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 2.9 Hz, 3H), 7.01 (d, J = 5.3 Hz, 1H), 4.55 (d, J = 7.1 Hz, 2H), 3.10 (dt, J = 17.3, 5.8 Hz, 3H), 2.98 - 2.86 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H). Example 6 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetr ahydro-1H-indazole-5-carboxamide Step 1 ethyl 1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[00261] 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 pmol) were added to tetrahydrofuran (10 mL), and the mixture was heated to 80°C and stirred for 18 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to neutralize the mixture, followed by extraction with ethyl acetate (20 mL*3). The combined organic phases were washed with a 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 obtain ethyl 1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6b (1.2 g) with a yield of 83.74%.

[00262] MS m / z (ESI): 279.1 [M+1] Step 2 methyl 5-(2-(methylthio)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5 -carboxylate

[00263] At -30°C, lithium bis(trimethylsilyl)amide (1 M, 11.21 mL) was added 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), and then the mixture was heated to room temperature and stirred for 1 hour. After the starting materials were completely reacted, an aqueous solution of saturated ammonium chloride was added to quench the reaction, followed by extraction with ethyl acetate (20 mL*3). The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System A) to                                       obtain                                       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) with a yield of 55.27%. MS m / z (ESI): 403.2 [M+1] Step 3 methyl 5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazo le-5-carboxylate

[00264] 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 meta-chloroperoxybenzoic 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 completed, a saturated sodium bicarbonate solution was added to neutralize the mixture, followed by extraction with dichloromethane (20 mL*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 obtain                                                                             methyl 5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazo le-5-carboxylate 6d (500 mg) with a yield of 47.26%.

[00265] MS m / z (ESI): 435.1 [M+1] Step 4 methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[00266] Methyl 5-(2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazo le-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 addition of 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 completed, water (20 mL) was added, followed by extraction with ethyl acetate (20 mL*3). The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6e (800 mg) with a yield of 75.32%.

[00267] MS m / z (ESI): 462.1 [M+1] Step 5 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-(tetrahydr o-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

[00268] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (195.88 mg, 910.01 umol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 1.14 mL) were dissolved in toluene (65.0 uL) and stirred at room temperature for 1 hour, followed by addition of methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6e (350 mg, 758.34 umol), and the mixture was heated to 90°C and stirred for 18 hours. After the reaction was completed, a small amount of methanol was added to quench the reaction, followed by addition of dilute hydrochloric acid and dichloromethane. The insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (separation column: AKZONOBEL Kromasil; 250*21.2 mm I.D.; 5 ^m, 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)-1-(tetrahydr o-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 6f (150 mg) with a yield of 30.68%.

[00269] MS m / z (ESI): 645.1 [M+1] Step 6 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetr ahydro-1H-indazole-5-carboxamide

[00270] At                              room                              temperature, 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-(tetrahydr o-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 6f (100 mg, 155.10 umol) and trifluoroacetic acid (1 mL) were added to dichloromethane (1 mL), and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 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 I.D.; 5 um. 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)-4,5,6,7-tetr ahydro-1H-indazole-5-carboxamide 6 (27 mg) with a yield of 24.51%.

[00271] MS m / z (ESI): 560.8 [M+1]

[00272] 1H NMR (400 MHz, DMSO-d6) 8 9.53 (s, 1H), 8.74 (s, 1H), 8.58 (d, J = 5.3 Hz, 1H), 8.17 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.15 (d, J = 5.3 Hz, 1H), 4.46 (q, J = 7.1 Hz, 3H), 3.35 - 3.12 (m, 3H), 2.71 (s, 1H), 2.57 (d, J = 18.1 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.05 (dq, J = 10.4, 5.0 Hz, 2H), 0.94 - 0.74 (m, 2H). Example 7 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-methyl-4, 5,6,7-tetrahydro-1H-indazole-5-carboxamide Step 1 ethyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[00273] Ethyl 4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 6a (1.10 g, 7.72 mmol, 480.77 pL), 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 the mixture was stirred at room temperature for 18 hours. After the reaction was completed, water (20 mL) was added, 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 evaporated to dryness by rotation. The crude product was separated by silica gel column chromatography (eluent: System A) to obtain ethyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7a (1 g) with a yield of 93.26%.

[00274] MS m / z (ESI): 209.1 [M+1] Step 2 methyl 1-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[00275] At -30°C, lithium bis(trimethylsilyl)amide (1 M, 16.81 mL) was added 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), and the mixture was slowly heated to room temperature and stirred for 1 hour. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mLx3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain methyl 1-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7b (800 mg) with a yield of 42.95%.

[00276] MS m / z (ESI): 333.9 [M+1] Step 3 methyl 1-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

[00277] 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 meta-chloroperoxybenzoic acid (977.19 mg, 4.81 mmol, 85% purity) were dissolved in dichloromethane (10 mL), and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (20 mLx3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation to obtain methyl 1-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate 7c (400 mg) with a yield of 45.61%, and the crude product was directly used in the next step.

[00278] MS m / z (ESI): 365.1 [M+1] Step 4 methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-5-carb oxylate

[00279] 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), followed by addition of cesium carbonate (1.43 g, 4.39 mmol). 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 x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. 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-carb oxylate 7d (750 mg) with a yield of 84.26%.

[00280] MS m / z (ESI): 374.1 [M+1] Step 5 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-1-methyl-4, 5,6,7-tetrahydro-1H-indazole-5-carboxamide

[00281] At room temperature, 4-(6-ethoxypyrazin-2-yl)aniline 3b (195.88 mg, 910.01 umol) was dissolved in toluene (3 mL), followed by 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-carb oxylate 7d (296.85 mg, 758.34 pmol) was added. 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 evaporated to dryness by rotation to obtain the crude product. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (separation column: AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 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)-1-methyl-4, 5,6,7-tetrahydro-1H-indazole-5-carboxamide 7 (98 mg) with a yield of 16.49%.

[00282] MS m / z (ESI): 574.8 [M+1] Example 8 (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bic yclo[3.1.0]hexane-6-carboxamide Step 1 (3aR,6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxathiole 2,2-dioxide

[00283] 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 was cooled to -50°C, and a solution of sulfuryl chloride (3.37 g, 24.97 mmol, 2.02 mL) in ethyl acetate (2 mL) was added dropwise. The reaction was slowly heated to room temperature and stirred for 18 hours. Solid was removed by filtration, and the filtrate was evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain (3aR,6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxathiole 2,2-dioxide 8b (1.4 g) with a yield of 44.39%. Step 2 (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[00284] Under ice-water bath, sodium hydride (387.37 mg, 9.68 mmol, 1.61 pL, 60% purity) was added to a solution of 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile 4b (800 mg, 4.84 mmol) in anhydrous dimethoxyethane (32 mL). After stirring for 10 minutes, (3aR,6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxathiole 2,2-dioxide 8b (953.98 mg, 5.81 mmol) was added. The mixture was stirred at room temperature for 1 hour, then heated to 60°C and stirred for an additional 18 hours. Water (10 mL) was added to quench the reaction, 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 evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography          (eluent:          System          A)          to          obtain (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile 8c (790 mg) with a yield of 70.53%.

[00285] MS m / z (ESI): 231.9 [M+1] Step 3 (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[00286] 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), followed by addition of hydrogen peroxide (5 mL, 35%). The mixture was stirred at room temperature for 18 hours, then heated to 50°C and stirred for an additional 2 hours, after which the starting material was completely consumed. The reaction mixture was poured into ice-water (20 mL), and a solid precipitated after stirring. The mixture was filtered under reduced pressure, and the filter cake was dried to obtain (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 8d (700 mg) with a yield of 66.27%. The crude product was directly used in the next step.

[00287] MS m / z (ESI): 249.8 [M+1] Step 4 (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[00288] 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) in ice-water bath was added sodium nitrite (1.94 g, 28.08 mmol), and the mixture was stirred at room temperature for 18 hours. Water (10 mL) was added to the reaction mixture, 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 evaporated to dryness by rotation to obtain (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 8e (650 mg) with a yield of 92.49%. The crude product was used directly in the next step.

[00289] MS m / z (ESI): 251.2 [M+1] Step 5 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexa ne-6-carboxamide

[00290] (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 8e (250 mg, 998.74 umol), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (838.94 mg, 3.00 mmol), and N-methylimidazole (327.99 mg, 3.99 mmol) were added to N-methylpyrrolidone (3 mL) at room temperature. After stirring for half an hour, 4-(6-ethoxypyrazin-2-yl)aniline 3b (257 mg, 1.2 mmol) was added, and the reaction was heated to 60°C and stirred for 18 hours, then heated to 120°C and stirred for 3 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mLx3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250^21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA+H2O,        mobile        phase        B:        CH3CN)       to        obtain (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexa ne-6-carboxamide 8f (50 mg) with a yield of 11.19%.

[00291] MS m / z (ESI): 448.2 [M+1] Step 6 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0] hexane-6-carboxamide

[00292] (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 umol) and meta-chloroperoxybenzoic acid (45.36 mg, 223.44 umol, 85% purity) were added to dichloromethane (2 mL) and stirred at room temperature for 18 hours. After completion of the reaction, saturated sodium bicarbonate solution was added to neutralize the mixture until the mixture became neutral, and the mixture was extracted with dichloromethane (20 mLx3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to             dryness             by             rotation             to             obtain (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0] hexane-6-carboxamide 8g (51 mg) with a yield of 98.48%. The crude product was used directly in the next step.

[00293] MS m / z (ESI): 464.9 [M+1] Step 7 (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bic yclo[3.1.0]hexane-6-carboxamide

[00294] Cyclopropanesulfonamide        (26.66        mg,        220.04        umol), (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0] hexane-6-carboxamide 8g (51 mg, 110.02 pmol), and cesium carbonate (71.69 mg, 220.04 pmol) were added to N-methylpyrrolidone (2 mL), and the reaction was heated to 90°C and stirred for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mLx3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250x21.2 mm I.D.; 5 um. 20 mL / 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)bic yclo[3.1.0]hexane-6-carboxamide 8 (30 mg) with a yield of 40.22%.

[00295] MS m / z (ESI): 520.9 [M+1]

[00296] 1H NMR (400 MHz, DMSO-d6) 8 11.16 (s, 1H), 10.49 (s, 1H), 8.76 (s, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.19 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 5.4 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.20 (dt, J = 8.2, 3.6 Hz, 1H), 2.25 (d, J = 2.9 Hz, 2H), 2.13 (dd, J = 13.3, 8.5 Hz, 2H), 2.06 - 1.95 (m, 2H), 1.74 - 1.58 (m, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.24 (d, J = 9.0 Hz, 2H), 1.04 (q, J = 4.2 Hz, 2H), 0.94 (dq, J = 7.6, 4.9, 4.5 Hz, 2H). Example 9 6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicycl o[3.1.0]hexane-6-carboxamide H Step 1 tert-butyl (3S,4R)-3,4-dihydroxypyrrolidine-1-carboxylate

[00297] (3S,4R)-pyrrolidin-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 1,4-dioxane (30 mL) and water (30 mL) at room temperature and stirred at room temperature for 18 hours. Insoluble solid was removed by filtration, and the filtrate was directly evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography       (eluent:       System       A)       to       obtain       tert-butyl (3S,4R)-3,4-dihydroxypyrrolidine-1-carboxylate 9b (3.9 g) with a yield of 89.28%.

[00298] MS m / z (ESI): 147.1 [M+1-56] Step 2 tert-butyl (3aR,6aS)-tetrahydro-5H-[1,3,2]dioxathiolo[4,5-c]pyrrole-5-carboxylate 2,2-dioxide

[00299] At -50°C, a solution of sulfonyl chloride (3.37 g, 24.97 mmol, 2.02 mL) in ethyl acetate (5     mL)     was     added     dropwise     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). The reaction mixture was allowed to slowly warm to room temperature and was stirred for 18 h. Upon completion of the reaction, solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl (3aR,6aS)-tetrahydro-5H-[1,3,2]dioxathiolo[4,5-c]pyrrole-5-carboxylate 2,2-dioxide 9c (3 g) with a yield of 58.86%. Step 3 tert-butyl (1R,5S)-6-cyano-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[00300] Under ice-water bath, sodium hydride (314.74 mg, 7.87 mmol, 1.61 pL, 60% purity) was added to a solution of 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile 4b (650 mg, 3.93 mmol) in anhydrous dimethoxyethane (28 mL). After stirring for ten minutes, tert-butyl (3aR,6aS)-tetrahydro-5H-[1,3,2]dioxathiolo[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 h, then heated to 60°C and stirred for 18 h. Upon completion of the reaction, water (10 mL) was added to quench the reaction, 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 concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent:  System A) to obtain tert-butyl (1R,5S)-6-cyano-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9d (550 mg) with a yield of 29.44%.

[00301] MS m / z (ESI): 333.1 [M+1] Step 4 tert-butyl (1R,5S)-6-carbamoyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[00302] Under ice-water bath, sodium hydroxide (144.40 mg, 3.61 mmol) was added 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). After stirring for ten minutes, hydrogen peroxide (1.5 mL, 35%) was added, and the mixture was stirred at room temperature for 3 h. Water (20 mL) was added to quench the reaction, and the mixture was filtered under reduced pressure. The filter cake was dried, and the crude product was purified by silica gel column chromatography       (eluent:       System       A)       to       obtain       tert-butyl (1R,5S)-6-carbamoyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9e (410 mg) with a yield of 64.82%.

[00303] MS m / z (ESI): 351.0 [M+1] Step 5 (1R,5S)-3-(tert-butoxycarbonyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-c arboxylic acid

[00304] Under ice-water bath, sodium nitrite (511.94 mg, 7.42 mmol) was added 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 pmol), acetic acid (1.50 mL), and acetic anhydride (3 mL) in dimethyl sulfoxide (3 mL). The mixture was stirred at room temperature for 18 h. Upon completion of the reaction, the reaction mixture was poured into water, neutralized with saturated sodium bicarbonate solution, acidified with citric acid, 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 concentrated. The crude product was purified by silica gel column       chromatography       (eluent:       System       A)       to       obtain (1R,5S)-3-(tert-butoxycarbonyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-c arboxylic acid 9f (150 mg) with a yield of 57.53%. Step 6 tert-butyl (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azab icyclo[3.1.0]hexane-3-carboxylate

[00305] Under                                ice-water                                bath, (1R,5S)-3-(tert-butoxycarbonyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-c arboxylic acid 9f (170 mg, 483.75 pmol) was dissolved in N-methylpyrrolidone (2 mL), followed by addition of N,N,N',N'-tetramethylchloroformamidinium 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, then 4-(6-ethoxypyrazin-2-yl)aniline 3b (114 mg, 532.75 umol) was added. The temperature was raised to 100°C, and the mixture was stirred for 18 h. Upon completion of the reaction, water (20 mL) was added to the reaction mixture, which 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 evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent:            System            A)            to            obtain            tert-butyl (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azab icyclo[3.1.0]hexane-3-carboxylate 9g (200 mg) with a yield of 75.35%.

[00306] MS m / z (ESI): 549.1 [M+1] Step 7 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

[00307] At                  room                  temperature,                  tert-butyl (1R,5S)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carbamoyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azab icyclo[3.1.0]hexane-3-carboxylate 9g (200 mg, 364.53 pmol) and meta-chloroperoxybenzoic acid (162.82 mg, 801.96 gmol, 85% purity) were dissolved in dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 h. Upon completion of the reaction, saturated sodium bicarbonate solution was added to neutralize, 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 evaporated to dryness by rotation                         to                         obtain                         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) with a yield of 24.29%. The crude product was directly used in the next step.

[00308] MS m / z (ESI): 565.1 / 581.1 [M+1] Step 8 tert-butyl (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)car bamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[00309] 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 pmol), cyclopropanesulfonamide (51.50 mg, 425.04 pmol), and cesium carbonate (230.81 mg, 708.40 pmol) 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 x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by preparative liquid chromatography (column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain tert-butyl (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)car bamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9i (30 mg) with a yield of 13.62%.

[00310] MS m / z (ESI): 622.1 [M+1] Step 9 6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicycl o[3.1.0]hexane-6-carboxamide

[00311] Tert-butyl (1R,5S)-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)car bamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 9i (20 mg, 32.17 pmol) 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 under reduced pressure. The crude product was purified by preparative liquid chromatography (column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN)                                   to                                   obtain 6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicycl o[3.1.0]hexane-6-carboxamide 9 (10 mg) with a yield of 44.02%.

[00312] MS m / z (ESI): 522.1 [M+1]

[00313] 1H NMR (400 MHz, DMSO-d6) 8 10.85 (s, 1H), 9.71 (s, 1H), 8.79 (s, 1H), 8.52 (d, J = 5.4 Hz, 2H), 8.25 - 8.06 (m, 3H), 7.86 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 5.3 Hz, 1H), 4.48 (q, J = 7.0 Hz, 3H), 3.77 (s, 2H), 3.64 - 3.56 (m, 2H), 3.16 (d, J = 4.8 Hz, 1H), 2.76 (d, J = 3.5 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H), 1.07 (q, J = 4.1 Hz, 2H). Example 10 6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

[00314] 6-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3 -azabicyclo[3.1.0]hexane-6-carboxamide 9 (7 mg, 13.42 umol) and sodium hydroxide (536.82 ug, 13.42 umol) were added to tetrahydrofuran (1 mL) at room temperature and stirred for 1 hour. Subsequently, paraformaldehyde (523.92 ug, 17.45 umol) and formic acid (1.54 mg, 33.55 umol) were added, and the mixture was heated to 70°C and stirred for 5 hours. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by preparative liquid chromatography (column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 um, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 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) with a yield of 44.13%.

[00315] MS m / z (ESI): 536.1 [M+1] Example 11 3-acetyl-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide Step 1 (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile

[00316] A solution of hydrogen chloride in dioxane (15 mL, 4 M) was added 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) at room temperature, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the residue 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 evaporated to dryness by rotation. The crude product was purified by silica gel     column     chromatography     (eluent:      System     B)     to      obtain (1R,5S)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile 11a (500 mg) with a yield of 71.55%.

[00317] MS m / z (ESI): 232.9 [M+1] Step 2 (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile

[00318] 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 pL) in dichloromethane (3 mL) in ice-water bath was added acetyl chloride (141.93 mg, 1.81 mmol, 128.56 pL), and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, 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 evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent:     System B) to obtain (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile 11b (400 mg) with a yield of 96.77%.

[00319] MS m / z (ESI): 274.3 [M+1] Step 3 (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[00320] (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboni trile 11b (300 mg, 1.09 mmol) was dissolved in dimethyl sulfoxide (3 mL). Sodium hydroxide (87.48 mg, 2.19 mmol) was added in ice-water bath, and the mixture was stirred for 10 minutes. Hydrogen peroxide (1.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. Water (20 mL) was added to quench the reaction, and the mixture was filtered under reduced     pressure.      The      filter      cake     was      dried     to      obtain (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 11c (300 mg) with a yield of 93.84%.

[00321] MS m / z (ESI): 293.0 [M+1] Step 4 (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[00322] 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) in ice-water bath was added sodium nitrite (944.05 mg, 13.68 mmol), and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction mixture was poured into water (5 mL), neutralized with saturated sodium bicarbonate solution, acidified with citric acid, and extracted with ethyl acetate. Most of the product was in the aqueous phase. The aqueous phase was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250*21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O,        mobile        phase        B:         CH3CN)        to        obtain (1R,5S)-3-acetyl-6-(2-(methylthio)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 11d (180 mg) with a yield of 44.85%.

[00323] MS m / z (ESI): 394.0 [M+1] Step 5 (1R,5S)-3-acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabic yclo[3.1.0]hexane-6-carboxamide

[00324] 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 umol) in N-methylpyrrolidone (2 mL) in ice-water bath were added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (343.63 mg, 1.23 mmol) and N-methylimidazole (201.51 mg, 2.45 mmol). The mixture was stirred at room temperature for half an hour. Then 4-(6-ethoxypyrazin-2-yl)aniline 3b (145 mg, 672.62 umol) was added, and the mixture was heated to 100°C and stirred for 18 hours. Water (20 mL) was added to the reaction mixture, 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 evaporated to dryness by rotation. The crude product was purified by silica gel     column     chromatography     (eluent:      System     A)     to     obtain (1R,5S)-3-acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylthio)pyrimidin-4-yl)-3-azabic yclo[3.1.0]hexane-6-carboxamide 11e (300 mg) with a yield of 99.66%.

[00325] MS m / z (ESI): 549.1 [M+1] Step 6 (1R,5S)-3-acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-az abicyclo[3.1.0]hexane-6-carboxamide

[00326] (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 pmol) and meta-chloroperoxybenzoic 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 completed, saturated sodium bicarbonate solution was added to neutralize, and the mixture was extracted with dichloromethane (20 mLx3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to              dryness              by             rotation             to              obtain (1R,5S)-3-acetyl-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3-az abicyclo[3.1.0]hexane-6-carboxamide 11f (300 mg) with a yield of 96.84%. The crude product was directly used in the next step. MS m / z (ESI): 506.8 [M+1] Step 7 3-acetyl-6-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

[00327] (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     pmol), cyclopropanesulfonamide (86.10 mg, 710.65 pmol), and cesium carbonate (385.91 mg, 1.18 mmol) were added to N-methylpyrrolidone (1 mL). The mixture was heated to 90°C and stirred for 1 hour, then cooled to room temperature. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mLx3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250x21.2 mm I.D.; 5 pm, 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%.

[00328] MS m / z (ESI): [M+1] 563.8

[00329] 1H NMR (400 MHz, DMSO-d6) 8 11.23 (s, 1H), 10.54 (s, 1H), 8.77 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.19 (s, 1H), 8.13 - 8.02 (m, 2H), 7.71 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 5.5 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 4.11 (d, J = 12.3 Hz, 1H), 3.96 (d, J = 11.2 Hz, 1H), 3.76 (d, J = 10.3 Hz, 1H), 3.41 (s, 3H), 3.18 (s, 1H), 2.06 - 1.94 (m, 1H), 1.70 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H), 1.24 (s, 2H), 1.09 - 0.92 (m, 4H). Example 12 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bic yclo[3.1.0]hexane-3-carboxamide Step 1 4-(6-ethoxypyrazin-2-yl)-2-fluoroaniline

[00330] 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)ferrocene palladium(II) dichloride (230.70 mg, 315.29 pmol), and potassium carbonate (1.31 g, 9.46 mmol) were added to 1,4-dioxane (10 mL) and water (2.5 mL). The mixture was subjected to argon exchange three times, and the reaction mixture was heated to 95°C and stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: System A) to obtain 4-(6-ethoxypyrazin-2-yl)-2-fluoroaniline 12b (590 mg) with a yield of 80.23%.

[00331] MS m / z (ESI): 234.1 [M+1] Step 2 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bic yclo[3.1.0]hexane-3-carboxamide

[00332] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline   12b   (100 mg, 428.74 pmol) and trimethylaluminum (2.0 M toluene solution) (2 M, 643.11 pL) were added to toluene (1 mL) and stirred at room temperature for 1 hour, followed by addition of ethyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 2d (150.67 mg, 428.74 pmol), and the reaction mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, a small amount of methanol was added to quench the reaction, and the solvent was directly removed by rotary evaporation to obtain a crude product. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, 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 x 21.2 mm I.D.; 5 pm, 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)bic yclo[3.1.0]hexane-3-carboxamide 12 (22 mg) with a yield of 7.71%.

[00333] MS m / z (ESI): 538.8 [M+1]

[00334] 1H NMR (400 MHz, DMSO-d6) 8 11.06 (s, 1H), 9.32 (s, 1H), 8.59 (s, 1H), 8.30 (d, J = 5.4 Hz, 1H), 8.01 (s, 1H), 7.73 (t, J = 11.5 Hz, 2H), 7.35 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 5.4 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.04 (s, 1H), 2.62 (d, J = 13.6 Hz, 2H), 2.22 (d, J = 13.0 Hz, 2H), 1.16 (q, J = 7.4 Hz, 5H), 0.94 - 0.74 (m, 4H), 0.19 (d, J = 7.0 Hz, 1H), -0.00 (d, J = 5.7 Hz, 1H). Example 13 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-3-carboxamide Step 1 ethyl 3-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00335] At -30°C, lithium bis(trimethylsilyl)amide (1 M, 5.60 mL) was added to a tetrahydrofuran (3.00 mL) 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), and the reaction mixture was slowly heated to room temperature and the reaction was performed for 1 hour. After the reaction was completed, a saturated ammonium chloride solution was added to quench the reaction, 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, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain ethyl 3-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13b (375 mg) with a yield of 72.13%.

[00336] MS m / z (ESI): 278.8 [M+1] Step 2 ethyl 3-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00337] At                   room                   temperature,                   ethyl 3-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13b (500 mg, 1.80 mmol) and meta-chloroperoxybenzoic acid (802.27 mg, 3.95 mmol, 85% purity) were dissolved in dichloromethane (5 mL) and stirred for 2 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to neutralize the mixture, followed by extraction with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation to obtain ethyl 3-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13c (50 mg) with a yield of 9.46%. The crude product was directly used in the next step without further purification.

[00338] MS m / z (ESI): 310.8 [M+1] Step 3 ethyl 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00339] 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), and the mixture was heated to 80°C with stirring for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and water was added. The mixture was extracted with ethyl acetate (30 mL*3). The combined organic phase was 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       ethyl 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 13d (620 mg) with a yield of 99.56%.

[00340] MS m / z (ESI): 352.0 [M+1] Step 4 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-3-carboxamide

[00341] At room temperature, 4-(6-ethoxypyrazin-2-yl)aniline 3b (126.72 mg, 588.71 umol) and trimethylaluminum (2.0 M solution in toluene) (2 M, 883.06 pL) were added to toluene (1 mL) 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 pmol) was added, and the mixture was heated to 90°C with stirring for 2 hours. The mixture was cooled to room temperature, and a small amount of methanol was added to quench the reaction. The solvent was directly evaporated to dryness by rotation to obtain a crude product. Dilute hydrochloric acid and dichloromethane were added, and 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 I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN)                                   to                                   obtain 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-3-carboxamide 13 (60 mg) with a yield of 18.12%.

[00342] MS m / z (ESI): [M+1] 520.8

[00343] 1H NMR (400 MHz, DMSO-d6) 8 11.23 (s, 1H), 9.67 (s, 1H), 8.65 (d, J = 6.7 Hz, 2H), 8.07 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 6.82 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.93 (s, 1H), 2.74 (d, J = 13.6 Hz, 2H), 2.30 (d, J = 13.4 Hz, 2H), 1.42 - 1.22 (m, 5H), 1.00 - 0.81 (m, 4H), 0.31 (d, J = 7.1 Hz, 1H), 0.06 - -0.05 (m, 1H). Example 14 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-4, 5,6,7-tetrahydro-2H-indazole-5-carboxamide n-nZ II / 5 Step 1 ethyl 4-(2-methylhydrazineylidene)cyclohexane-1-carboxylate

[00344] 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), and the reaction was heated to 90°C with stirring for 18 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove the solvent to obtain ethyl 4-(2-methylhydrazineylidene)cyclohexane-1-carboxylate 14c (2 g), and the crude product was directly used in the next step. Step 2 ethyl 2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

[00345] Ethyl 4-(2-methylhydrazineylidene)cyclohexane-1-carboxylate 14c (2 g, 10.09 mmol) and (chloromethylene)dimethyliminium chloride 14d (1.29 g, 10.09 mmol, commercially available) were dissolved in N,N-dimethylformamide (5 mL), and the mixture was heated to 90°C with stirring for 18 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography       (eluent:       System       A)       to       obtain       ethyl 2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate 14e (500 mg) with a yield of 23.80%.

[00346] MS m / z (ESI): 208.9 [M+1] Step 3 methyl 2-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

[00347] At -30°C, lithium bis(trimethylsilyl)amide (1 M, 3.60 mL) was added 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), and the mixture was slowly heated to room temperature with stirring for 1 hour. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mLx3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent:    System A) to obtain methyl 2-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate     14f (350 mg) with a yield of 87.71%.

[00348] MS m / z (ESI): 333.9 [M+1] Step 4 methyl 2-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

[00349] Methyl 2-methyl-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate     14f (350 mg, 1.05 mmol) and meta-chloroperoxybenzoic acid (470.27 mg, 2.32 mmol, 85% purity) were added to dichloromethane (5 mL). The mixture was stirred at room temperature for 2 h, then neutralized by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System B) to                                       obtain                                       methyl 2-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate 14g (100 mg) with a yield of 27.26%.

[00350] MS m / z (ESI): 349.1 [M+1] Step 5 methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carb oxylate

[00351] Methyl 2-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate 14g (500 mg, 1.44 mmol) and cyclopropanesulfonamide (226.03 mg, 1.87 mmol) were added to N-methylpyrrolidone (2 mL). The mixture was heated to 80°C and stirred for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) was added to the reaction mixture. 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 evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System B) to obtain methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carb oxylate 14h (300 mg) with a yield of 51.56%.

[00352] MS m / z (ESI): 406.1 [M+1] Step 6 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-4, 5,6,7-tetrahydro-2H-indazole-5-carboxamide

[00353] Trimethylaluminum (2.0 M solution in toluene) (2 M, 665.89 pL) was added to a solution of 4-(6-ethoxypyrazin-2-yl)aniline 3b (95.56 mg, 443.93 pmol) in toluene (1.22 mL). The mixture was stirred at room temperature for 1 h, then methyl 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-4,5,6,7-tetrahydro-2H-indazole-5-carb oxylate 14h (150 mg, 369.94 pmol) was added. The mixture was heated to 90°C and stirred for 5 h. After the reaction was complete, a small amount of methanol was added to quench the reaction, and the solvent was directly evaporated to dryness by rotation to obtain the 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 (column: AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 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) with a yield of 2.52%.

[00354] MS m / z (ESI): 574.8 [M+1] Example 15 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-3-carboxamide Step 1 ethyl 3-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00355] Lithium bis(trimethylsilyl)amide (1 M, 5.84 mL) was added 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) at -30°C. The mixture was slowly heated to room temperature over 1 h. After the reaction was complete, the mixture was quenched by adding saturated ammonium chloride solution. 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 evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography        (eluent:        System        A)        to        obtain        ethyl 3-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15b (300 mg) with a yield of 55.40%.

[00356] MS m / z (ESI): 278.9 [M+1] Step 2 ethyl 3-(4-(methylsulfonyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00357] Ethyl 3-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15b (500 mg, 1.80 mmol) and meta-chloroperoxybenzoic acid (962.72 mg, 4.74 mmol, 85% purity) were dissolved in dichloromethane (5 mL) at room temperature and stirred for 2 h. After the reaction was complete, saturated sodium bicarbonate solution was added to neutralize the mixture. 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      concentrated      under      reduced      pressure      to      obtain      ethyl 3-(4-(methylsulfonyl)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15c (600 mg) with a yield of 89.69%. The crude product was directly used in the next step without further purification.

[00358] MS m / z (ESI): 310.8 [M+1] Step 3 ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00359] 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), the temperature was raised to 80°C and the mixture was stirred for 2 hours. After the reaction was completed, 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        obtain        ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15d (600 mg) in a yield of 80.29%.

[00360] MS m / z (ESI): 352.0 [M+1] Step 4 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1. 0]hexane-3-carboxamide

[00361] At room temperature, 4-(6-ethoxypyrazin-2-yl)aniline 3b (110.25 mg, 512.21 umol) and trimethylaluminum (2.0 M toluene solution) (2 M, 768.31 pL) were added to toluene (2 mL) 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 umol) was added, the temperature was raised to 90°C and the mixture was stirred for 2 hours. The mixture was cooled to room temperature, quenched by adding a small amount of methanol, and the solvent was directly evaporated to dryness by rotation to obtain a crude product. Dilute hydrochloric acid and dichloromethane were added, insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (separation column: AKZONOBEL Kromasil; 250^21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN)                                   to                                   obtain 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%.

[00362] MS m / z (ESI): [M+1] 520.8

[00363] 1H NMR (400 MHz, DMSO-d6) 8 11.25 (s, 1H), 9.63 (s, 1H), 8.75 (s, 1H), 8.49 (d, J = 5.7 Hz, 1H), 8.17 (s, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 5.7 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.16 - 3.08 (m, 1H), 2.83 (d, J = 13.5 Hz, 2H), 2.64 - 2.55 (m, 2H), 1.39 (t, J = 7.0 Hz, 5H), 1.05 (dt, J = 7.0, 3.5 Hz, 2H), 0.83 (td, J = 7.4, 4.7 Hz, 2H), 0.43 - 0.33 (m, 1H), 0.15 (q, J = 4.3 Hz, 1H). Example 16 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0] hexane-3-carboxamide Step 1 2-chloro-6-(methylthio)pyrazine

[00364] 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 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 obtain 2-chloro-6-(methylthio)pyrazine 16a (3.2 g) in a yield of 59.36%.

[00365] MS m / z (ESI): 161.2 [M+1] Step 2 ethyl 3-(6-(methylthio)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00366] At -30°C, lithium bis(trimethylsilyl)amide (1 M, 6.81 mL) was added 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). The mixture was heated to room temperature and stirred for 3 hours. Saturated ammonium chloride solution was added to quench the reaction, and extraction was performed with ethyl acetate (20 mLx3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain ethyl 3-(6-(methylthio)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16b (370 mg) in a yield of 58.56%.

[00367] MS m / z (ESI): 278.9 [M+1] Step 3 ethyl 3-(6-(methylsulfonyl)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00368] At                   room                   temperature,                   ethyl 3-(6-(methylthio)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16b (370 mg, 1.33 mmol) and meta-chloroperoxybenzoic acid (593.68 mg, 2.92 mmol, 85% purity) were dissolved in dichloromethane (5 mL) and stirred for 2 h. After the reaction was completed, a saturated sodium bicarbonate solution was added to neutralize, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness             by             rotation             to             obtain             ethyl 3-(6-(methylsulfonyl)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16c (400 mg) with a yield of 96.96%. The crude product was directly used in the next step.

[00369] MS m / z (ESI): 310.8 [M+1] Step 4 ethyl 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00370] 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 h. After the reaction was completed, the mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with a 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                 ethyl 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 16d (350 mg) with a yield of 46.84%.

[00371] MS m / z (ESI): 352.0 [M+1] Step 5 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0] hexane-3-carboxamide

[00372] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (110.25 mg, 512.21 umol) and trimethylaluminum (2.0 M toluene solution) (2 M, 768.31 pL) were dissolved in toluene (1.5 mL) and stirred at room temperature                  for                  1                  h.                  Ethyl 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate  16d  (150.00 mg, 426.84 umol) was added, and the mixture was heated to 90°C and stirred for 5 h. The mixture was cooled to room temperature, and a small amount of methanol was added to quench the reaction. 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 x 21.2 mm I.D.; 5 um, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to                                                                                         obtain 3-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0] hexane-3-carboxamide 16 (12 mg) with a yield of 5.24%.

[00373] MS m / z (ESI): 520.8 [M+1]

[00374] 1H NMR (400 MHz, DMSO-d6) 8 10.93 (s, 1H), 9.46 (s, 1H), 8.56 (s, 1H), 8.09 (s, 1H), 7.99 (s, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 4.28 (q, J = 7.2 Hz, 2H), 2.97 (s, 1H), 2.76 (d, J = 13.6 Hz, 2H), 2.27 (d, J = 13.4 Hz, 2H), 1.23 (dt, J = 14.3, 7.3 Hz, 5H), 0.94 (s, 2H), 0.77 (d, J = 8.0 Hz, 2H), 0.27 (d, J = 7.3 Hz, 1H), 0.00 (s, 1H). Example 17 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide Step 1 cyclopropane-1,2-diyldimethanol

[00375] Under ice-water bath, a solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione 17a (15 g, 133.83 mmol) in tetrahydrofuran (100 mL) was slowly added to a suspension of lithium aluminum hydride (6.81 g, 200.74 mmol) in tetrahydrofuran (250 mL). The mixture was slowly heated to room temperature and then heated to 70°C with stirring for 18 h. After the reaction was completed, the mixture was cooled with ice water, and water (6.81 mL) and 15% sodium hydroxide solution (6.81 mL) were added. Ethyl acetate (200 mL) was subsequently added, and the mixture was stirred for 30 min. The insoluble solid was removed by filtration, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain cyclopropane-1,2-diyldimethanol 17b (7 g) with a yield of 51.21%. Step 2 1,2-bis(bromomethyl)cyclopropane

[00376] Under ice-water bath, triphenylphosphine (37.25 g, 122.39 mmol) was dissolved in anhydrous acetonitrile (300 mL). Liquid bromine (19.56 g, 122.39 mmol, 6.72 mL) was added dropwise, and the mixture was stirred for 30 min. A solution of cyclopropane-1,2-diyldimethanol 17b (5 g, 48.96 mmol) in acetonitrile (50 mL) was added, and the mixture was slowly heated to room temperature and stirred for 18 h. The reaction mixture was filtered to remove the insoluble solid, and the filtrate was concentrated under reduced pressure. Ethyl acetate / petroleum ether (100 mL, 2 / 1) was added, and the mixture was stirred for 1 h. The insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1,2-bis(bromomethyl)cyclopropane 17c (10.1 g) with a yield of 90.51%. The crude product was directly used in the next step. Step 3 methyl 3-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00377] 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 mixture was subjected to argon exchange three times. Under cooling with ice-water bath, sodium hydroxide (199.95 mg, 5.00 mmol) was added. After stirring for 0.5 hours, 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 completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was 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) with a yield of 76.13%. Step 4 methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00378] Methyl 3-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17e  (100 mg, 337.66 pmol), cyclopropanesulfonamide (61.36 mg, 506.48 pmol), cesium carbonate (220.03 mg, 675.31 pmol), allylpalladium chloride (12.35 mg, 33.77 pmol), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (28.68 mg, 67.53 umol) were sequentially added to 1,4-dioxane (2 mL). The mixture was subjected to argon exchange 3 times and heated to 90°C with stirring for 2 hours. After the reaction was completed, dichloromethane (30 mL) and methanol (5 mL) were added, and 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       obtain       methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17f (50 mg) with a yield of 44.02%.

[00379] MS m / z (ESI): 336.2 [M+1] Step 5 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide

[00380] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (110.25 mg, 512.21 umol) and trimethylaluminum (2.0 M toluene solution) (2 M, 768.31 uL) 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 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, 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 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide 17 (50 mg) with a yield of 17.03%.

[00381] MS m / z (ESI): 519.8 [M+1]

[00382] 1H NMR (400 MHz, DMSO-d6) 8 9.47 (s, 1H), 8.80 (s, 1H), 8.48 (d, J = 5.9 Hz, 1H), 8.23 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.35 (s, 1H), 7.23 (d, J = 6.2 Hz, 1H), 4.52 (q, J = 7.0 Hz, 2H), 2.95 - 2.78 (m, 3H), 2.65 (d, J = 13.7 Hz, 2H), 1.46 (dt, J = 14.1, 5.8 Hz, 5H), 1.08 (ddd, J = 16.8, 7.2, 3.9 Hz, 4H), 0.45 (d, J = 4.9 Hz, 1H), -0.00 (d, J = 4.2 Hz, 1H). Example 18 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide Step 1 methyl 3-(2-bromopyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00383] 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 mixture was subjected to argon exchange three times. Under cooling with ice-water bath, sodium hydroxide (359.91 mg, 9.00 mmol) was slowly added. After stirring for 0.5 hours, 1,2-bis(bromomethyl)cyclopropane 17c (1.16 g, 5.09 mmol) was added. The mixture was stirred at room temperature for 23 hours. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was 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-(2-bromopyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 18b (800 mg) with a yield of 69.05%.

[00384] MS m / z (ESI): 296.3 [M+1] Step 2 methyl 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00385] 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 umol), and allylpalladium(II) chloride dimer (61.77 mg, 168.83 umol) were sequentially added to 1,4-dioxane (10 mL). The mixture was subjected to argon exchange 3 times and heated to 90°C with stirring for 2 hours. After the reaction was completed, dichloromethane (30 mL) and methanol (5 mL) were added, and 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       obtain       methyl 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 18c (900 mg) with a yield of 79.23%.

[00386] MS m / z (ESI): 336.2 [M+1] Step 3 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide

[00387] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (122.85 mg, 570.74 umol) and trimethylaluminum (2.0 M toluene solution) (2 M, 856.11 uL) 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 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 3-(2-(cyclopropanesulfonamido)pyridin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide 18 (54 mg) with a yield of 17.32%.

[00388] MS m / z (ESI): 520.8 [M+1]

[00389] 1H NMR (400 MHz, DMSO-d6) 8 9.56 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.13-7.87 (m, 4H), 7.60 (dd, J = 8.5, 5.5 Hz, 2H), 6.99-6.84 (m, 2H), 4.35 (q, J = 7.0 Hz, 2H), 2.98-2.78 (m, 2H), 2.70 (dd, J = 14.5, 3.9 Hz, 1H), 2.15 (d, J = 13.9 Hz, 1H), 2.03 (d, J = 13.1 Hz, 1H), 1.28 (q, J = 7.1, 6.6 Hz, 5H), 0.86 (dd, J = 25.5, 6.6 Hz, 4H), 0.31 (d, J = 7.1 Hz, 1H), 0.09 - -0.10 (m, 1H). Example 19 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0 ]hexane-3-carboxamide Step 1 3-chloro-5-(methylthio)pyridazine

[00390] 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 completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was added to ethyl acetate / petroleum ether = 1 / 1 (30 mL) mixed solvent and stirred for 0.5 hours. The mixture was filtered under reduced pressure, and the filter cake was dried to obtain 3-chloro-5-(methylthio)pyridazine 19b (1.63 g) with a yield of 68.72%.

[00391] MS m / z (ESI): 161.0 [M+1] Step 2 ethyl 3-(5-(methylthio)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00392] At -30°C, lithium bis(trimethylsilyl)amide (1 M, 7.78 mL) was added 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). The mixture was slowly heated to room temperature and stirred for 3 hours. After the reaction was completed, saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column     chromatography     (eluent:     System     A)     to     obtain     ethyl 3-(5-(methylthio)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19c (350 mg) with a yield of 48.47%.

[00393] MS m / z (ESI): 278.9 [M+1] Step 3 ethyl 3-(5-(methylsulfonyl)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00394] Ethyl 3-(5-(methylthio)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19c (370 mg, 1.33 mmol) and meta-chloroperoxybenzoic 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 completed, saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation to obtain ethyl 3-(5-(methylsulfonyl)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19d (350 mg) with a yield of 89.45%. The crude product was directly used in the next step.

[00395] MS m / z (ESI): 294.9 [M+1] Step 4 ethyl 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00396] 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). The mixture was heated to 80°C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was 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        ethyl 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19e (300 mg) with a yield of 62.82%.

[00397] MS m / z (ESI): 352.0 [M+1] Step 5 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0 ]hexane-3-carboxamide

[00398] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (122.85 mg, 570.74 umol) and trimethylaluminum (2.0 M toluene solution) (2 M, 856.11 pL) were dissolved in toluene (2 mL). The mixture was stirred        at        room        temperature        for        1        hour.        Ethyl 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 19e (160.47 mg, 475.62 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, a small amount of methanol was added to quench the reaction. The mixture was 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 3-(5-(cyclopropanesulfonamido)pyridazin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0 ]hexane-3-carboxamide 19 (8 mg) with a yield of 2.39%.

[00399] MS m / z (ESI): 520.8 [M+1]

[00400] 1H NMR (400 MHz, DMSO-d6) 8 9.85 (s, 1H), 8.76 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 5.1 Hz, 1H), 8.07 (t, J = 6.0 Hz, 2H), 7.70 (d, J = 8.5 Hz, 3H), 4.46 (q, J = 7.1 Hz, 2H), 3.09 -2.88 (m, 2H), 2.62 (s, 1H), 2.19 (t, J = 13.5 Hz, 2H), 1.41 (dt, J = 14.2, 5.6 Hz, 5H), 0.92 (t, J = 8.2 Hz, 4H), 0.46 (t, J = 7.3 Hz, 1H), 0.12 (d, J = 4.6 Hz, 1H). Example 20 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicycl o[3.1.0]hexane-3-carboxamide

[00401] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (41.60 mg, 178.36 pmol) and trimethylaluminum (2.0 M toluene solution) (2 M, 267.53 pL) were dissolved in toluene (2.00 mL). The mixture was stirred at room temperature for 1 hour. Methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17f (50 mg, 148.63 pmol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, a small amount of methanol was added to quench the reaction. The mixture was 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bicycl o[3.1.0]hexane-3-carboxamide 20 (21 mg) with a yield of 20.00%.

[00402] MS m / z (ESI): 537.8 [M+1]

[00403] 1H NMR (400 MHz, DMSO-d6) 8 9.30 (s, 1H), 8.81 (s, 1H), 8.48 (d, J = 5.8 Hz, 1H), 8.23 (s, 1H), 8.02-7.90 (m, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 4.46 (q, J = 7.0 Hz, 2H), 2.89 (s, 1H), 2.82 - 2.72 (m, 2H), 2.61 (d, J = 13.7 Hz, 2H), 1.46 - 1.35 (m, 5H), 1.04 (ddt, J = 10.5, 4.6, 2.4 Hz, 4H), 0.37 (d, J = 5.7 Hz, 1H), -0.16 (d, J = 4.4 Hz, 1H). Example 21 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo[3. 1.0]hexane-3-carboxamide

[00404] 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine 1d (38.57 mg, 178.36 umol) and trimethylaluminum (2.0 M toluene solution) (2 M, 267.53 pL) were dissolved in toluene (2.00 mL). The mixture was stirred at room temperature for 1 hour. Methyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 17f (50 mg, 148.63 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, a small amount of methanol was added to quench the reaction. The mixture was 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 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) with a yield of 11.00%.

[00405] MS m / z (ESI): 520.8 [M+1]

[00406] 1H NMR (400 MHz, DMSO-d6) 8 9.65 (s, 1H), 8.99 (d, J = 2.4 Hz, 1H), 8.81 (s, 1H), 8.48 (dd, J = 8.5, 2.5 Hz, 2H), 8.24 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 5.8, 2.1 Hz, 1H), 4.46 (q, J = 7.0 Hz, 2H), 2.89 (dq, J = 10.2, 3.9, 2.8 Hz, 1H), 2.78 (dd, J = 13.9, 4.0 Hz, 2H), 2.61 (d, J = 13.7 Hz, 2H), 1.40 (dt, J = 14.1, 7.2 Hz, 5H), 1.02 (ddt, J = 10.8, 8.4, 2.4 Hz, 4H), 0.37 (q, J = 7.2 Hz, 1H), -0.17 (d, J = 4.4 Hz, 1H). Example 22 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetr ahydrobenzo[d]isoxazole-5-carboxamide O~N Step 1 methyl 4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate

[00407] Ethyl 3-((dimethylamino)methylene)-4-oxocyclohexane-1-carboxylate 22a (10 g, 44.39 mmol, prepared according to published patent "WO2008011130") and (aminooxy)sulfonic acid 22b (5.52 g, 48.83 mmol, commercially available) were added to methanol (10 mL). The reaction was sealed and heated to 100°C with stirring for 18 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic phase was 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) with a yield of 39.79%.

[00408] MS m / z (ESI): 181.9 [M+1] Step 2 methyl 5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate

[00409] 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). The mixture was cooled to -30°C, and lithium bis(trimethylsilyl)amide (1 M, 74.71 mL) was added. The reaction was slowly heated to room temperature and stirred for 1 hour. The starting material was completely reacted. Saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain methyl 5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]isoxazole-5-carboxylate 22d (4.2 g) with a yield of 55.23%.

[00410] MS m / z (ESI): 306.2 [M+1] Step 3 N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[d] isoxazole-5-carboxamide

[00411] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (504.02 mg, 2.34 mmol) and trimethylaluminum (2.0 M toluene solution) (2 M, 3.51 mL) were added to toluene (10 mL). The mixture was stirred at         room         temperature          for          1          hour.          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 mixture was heated to 90°C with stirring for 18 hours. After the reaction was completed, 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          obtain 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) with a yield of 17.48%.

[00412] MS m / z (ESI): 489.1 [M+1] Step 4 N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylsulfinyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenz o[d]isoxazole-5-carboxamide

[00413] N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylthio)pyrimidin-4-yl)-4,5,6,7-tetrahydr obenzo[d]isoxazole-5-carboxamide 22e (200 mg, 409.37 pmol) and meta-chloroperoxybenzoic acid (182.84 mg, 900.60 pmol, 85% purity) were dissolved in dichloromethane (5 mL). The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (eluent:     System B) to obtain N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylsulfinyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenz o[d]isoxazole-5-carboxamide 22f (120 mg) with a yield of 58.10%.

[00414] MS m / z (ESI): 505.5 [M+1] Step 5 5-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4,5,6,7-tetr ahydrobenzo[d]isoxazole-5-carboxamide

[00415] Under ice-water bath, cyclopropanesulfonamide (57.63 mg, 475.66 pmol) and sodium hydride (23.78 mg, 594.58 pmol, 60% purity) were dissolved in N,N-dimethylformamide (2 mL). The          mixture          was          stirred          for          0.5          hours. N-(4-(6-ethoxypyrazin-2-yl)phenyl)-5-(2-(methylsulfinyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrobenz o[d]isoxazole-5-carboxamide 22f (120 mg, 237.83 pmol) was added, and the mixture was slowly heated to room temperature and stirred for 5 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was 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 (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 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)-4,5,6,7-tetr ahydrobenzo[d]isoxazole-5-carboxamide 22 (4.25 mg) with a yield of 1.59%.

[00416] MS m / z (ESI): 561.7 [M+1] Example 23 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide Step 1 methyl 3-(5-bromopyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00417] Methyl 2-(5-bromopyridin-3-yl)acetate 23a (500 mg, 2.17 mmol, commercially available) was added to N,N-dimethylformamide (6 mL). The mixture was subjected to argon exchange three times. Under cooling with ice-water bath, sodium hydroxide (199.95 mg, 5.00 mmol) was slowly added. After stirring for 0.5 hours, 1,2-bis(bromomethyl)cyclopropane 17c (643.97 mg, 2.83 mmol) was added, and the mixture was slowly heated to room temperature and stirred for 23 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. 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) with a yield of 55.93%.

[00418] MS m / z (ESI): 296.3 [M+1] Step 2 methyl 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00419] Methyl 3-(5-bromopyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 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 pmol), and allylpalladium(II) chloride dimer (49.42 mg, 135.06 umol) were sequentially added to 1,4-dioxane (10 mL). The mixture was subjected to argon exchange 3 times and heated to 90°C with stirring for 2 hours. After the reaction was completed, dichloromethane (30 mL) and methanol (5 mL) were added, and 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       obtain       methyl 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)bicyclo[3.1.0]hexane-3-carboxylate 23c (230 mg) with a yield of 20.25%.

[00420] MS m / z (ESI): 336.2 [M+1] Step 3 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide

[00421] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (102.38 mg, 475.62 umol) and trimethylaluminum (2.0 M toluene solution) (2 M, 856.11 uL) 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 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, 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 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 3-(5-(cyclopropanesulfonamido)pyridin-3-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide 23 (55 mg) with a yield of 16.79%.

[00422] MS m / z (ESI): 520.8 [M+1]

[00423] 1H NMR (400 MHz, DMSO-d6) 8 10.00 (s, 1H), 9.45 (d, J = 97.4 Hz, 1H), 8.42 (dd, J = 108.2, 46.5 Hz, 3H), 8.17-7.71 (m, 4H), 7.58 (d, J = 7.7 Hz, 2H), 4.31 (p, J = 7.3 Hz, 2H), 3.03 (d, J = 14.2 Hz, 1H), 2.78 (d, J = 13.5 Hz, 1H), 2.59-2.47 (m, 1H), 2.10 (dd, J = 34.2, 13.6 Hz, 2H), 1.29-1.08 (m, 5H), 0.77 (d, J = 6.5 Hz, 4H), 0.32 (t, J = 16.5 Hz, 1H), 0.05 (m, 1H). Example 24 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo [3.1.0]hexane-3-carboxamide

[00424] 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine 1d (40 mg, 184.98 pmol) and trimethylaluminum (2.0 M toluene solution) (2 M, 277.47 uL) were added to toluene (2 mL) and stirred        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 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, and a small amount of methanol was added to quench the reaction. The solvent was removed by concentration under reduced pressure. Dilute hydrochloric acid (1 mL, 1 M) and dichloromethane (10 mL) were added, and 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA     +      H2O,      mobile     phase      B:      CH3CN)      to      obtain 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) with a yield of 4.46%.

[00425] MS m / z (ESI): 521.8 [M+1]

[00426] 1H NMR (400 MHz, DMSO-d6) 8 10.18 (s, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.83 (s, 1H), 8.52-8.40 (m, 2H), 8.30-8.15 (m, 2H), 6.80 (d, J = 5.7 Hz, 1H), 4.48 (d, J = 7.0 Hz, 2H), 3.133.07 (m, 1H), 2.80 (d, J = 13.6 Hz, 2H), 2.58 (dd, J = 13.0, 10.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 5H), 1.06 (dt, J = 6.7, 3.4 Hz, 2H), 0.91-0.82 (m, 3H), 0.39 (d, J = 6.6 Hz, 1H), 0.13 (d, J = 4.7 Hz, 1H). Example 25 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide Step 1 ethyl 3-(6-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00427] At -30°C, lithium hexamethyldisilazide (1.2 M tetrahydrofuran solution) (1 M, 7.78 mL) was added 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). The mixture was slowly heated to room temperature and stirred for 3 hours. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain ethyl 3-(6-bromopyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 25b (700 mg) with a yield of 87.00%.

[00428] MS m / z (ESI): 357.1 [M+1] Step 2 ethyl 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00429] 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 umol), and allylpalladium(II) chloride dimer (47.18 mg, 128.96 umol) were sequentially added to 1,4-dioxane (10 mL). The mixture was subjected to argon exchange three times and heated to 90°C with stirring for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography        (eluent:        System        B)        to        obtain        ethyl 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 25c (450 mg) with a yield of 49.79%.

[00430] MS m / z (ESI): 350.9 [M+1] Step 3 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide

[00431] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (99.82 mg, 463.73 umol) and trimethylaluminum (2.0 M toluene solution) (2 M, 642.08 uL) 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 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, and a small amount of methanol was added to quench the reaction. 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A:   0.05% TFA + H2O, mobile phase B:   CH3CN) to obtain 3-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]h exane-3-carboxamide 25 (80 mg) with a yield of 34.64%.

[00432] MS m / z (ESI): 519.8 [M+1]

[00433] 1H NMR (400 MHz, DMSO-d6) 8 10.51 (s, 1H), 9.32 (s, 1H), 8.60 (s, 1H), 8.02 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 4.31 (q, J = 7.0 Hz, 2H), 3.13 - 3.04 (m, 1H), 2.77 (d, J = 13.4 Hz, 2H), 2.27 (d, J = 13.2 Hz, 2H), 1.23 (t, J = 6.9 Hz, 5H), 0.98 - 0.89 (m, 2H), 0.83 (d, J = 7.4 Hz, 2H), 0.24 (q, J = 7.0 Hz, 1H), -0.00 (q, J = 4.3 Hz, 1H). Example 26 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bic yclo[3.1.0]hexane-3-carboxamide 13d 26

[00434] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline  12b  (82.96 mg, 355.67 pmol) and trimethylaluminum (2.0 M toluene solution) (2 M, 533.50 pL) 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 pmol) was added, and the mixture was heated to 90°C and stirred for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, and a small amount of methanol was added to quench the reaction. 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A:   0.05% TFA + H2O, mobile phase B:   CH3CN)   to obtain 3-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bic yclo[3.1.0]hexane-3-carboxamide 26 (49.42 mg) with a yield of 24.70%.

[00435] MS m / z (ESI): 538.8 [M+1]

[00436] 1H NMR (400 MHz, DMSO-d6) 8 9.43 (s, 1H), 8.57 (d, J = 17.4 Hz, 2H), 7.73 (t, J = 10.3 Hz, 2H), 7.36 (t, J = 8.0 Hz, 1H), 6.71 (s, 1H), 4.23 (q, J = 7.1 Hz, 2H), 2.84 (s, 1H), 2.60 (d, J = 13.5 Hz, 2H), 2.17 (d, J = 13.3 Hz, 2H), 1.20 - 1.12 (m, 5H), 0.90 - 0.77 (m, 4H), 0.18 (d, J = 7.0 Hz, 1H), -0.01 (d, J = 5.9 Hz, 1H). Example 27 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-o xabicyclo[3.1.0]hexane-6-carboxamide Step 1 (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile

[00437] Under ice-water bath, 2-(6-(methylthio)pyrimidin-4-yl)acetonitrile 27a (700 mg, 4.24 mmol, prepared according to published patent "WO 2008042639A1") was dissolved in anhydrous dimethoxyethane (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]dioxathiole 2,2-dioxide 4c (844.76 mg, 5.08 mmol) was added, and the mixture was heated to 60°C and stirred for 18 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was partitioned. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The residue was purified by silica gel column chromatography (eluent:   System  B) to obtain (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile 27b (520 mg) with a yield of 52.61%.

[00438] MS m / z (ESI): 233.2 [M+1] Step 2 (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[00439] (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). Under ice-water bath, sodium hydroxide (178.32 mg, 4.46 mmol) was added, and the mixture was stirred 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 reaction, and the solid was collected by filtration and                         dried                         to                         obtain (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 27c (500 mg) with a yield of 89.26%.

[00440] MS m / z (ESI): 251.0 [M+1] Step 3 (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[00441] (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). Under ice-water bath, sodium nitrite (1.54 g, 22.28 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and neutralized with saturated sodium bicarbonate solution. Saturated citric acid solution was added to adjust the pH to acidic. The mixture was extracted with ethyl acetate (20 mL x 3). The aqueous phase was collected and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A:   0.05% TFA +   H2O,   mobile phase B:   CH3CN)   to obtain (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 27d (210 mg) with a yield of 37.35%.

[00442] MS m / z (ESI): 253.0 [M+1] 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

[00443] 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 pmol), N-methylpyrrolidone (2 mL), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (466.13 mg, 1.66 mmol), and N-methylimidazole (273.35 mg, 3.33 mmol) were added to a 15 mL single-neck flask. The reaction was performed at room temperature for 0.5 hours. 4-(6-Ethoxypyrazin-2-yl)aniline 3b (197.09 mg, 915.62 umol) was added, and the mixture was heated to 100°C and stirred for 5 hours. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined 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 obtain (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) with a yield of 93.54%.

[00444] MS m / z (ESI): 450.1 [M+1] Step 5 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)-3-oxabicyclo[ 3.1.0]hexane-6-carboxamide

[00445] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)-3-oxabic yclo[3.1.0]hexane-6-carboxamide 27e (350 mg, 778.60 umol) and meta-chloroperoxybenzoic acid (316.15 mg, 1.56 mmol, 85% purity) were added to dichloromethane (5 mL). The mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under                reduced                pressure                to                obtain (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%.

[00446] MS m / z (ESI): 465.5 [M+1] Step 6 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-o xabicyclo[3.1.0]hexane-6-carboxamide

[00447] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)-3-ox abicyclo[3.1.0]hexane-6-carboxamide 27f (360 mg, 773.32 pmol), cyclopropanesulfonamide (93.69 mg, 773.32 pmol), and cesium carbonate (503.93 mg, 1.55 mmol) were added to N-methylpyrrolidone (1.5 mL). The mixture was heated to 100°C and the reaction was performed for 2 hours. The reaction mixture was directly added to water (2 mL) and methanol (2 mL) and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 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-o xabicyclo[3.1.0]hexane-6-carboxamide 27 (80 mg) with a yield of 15.83%.

[00448] MS m / z (ESI): 523.1 [M+1].

[00449] 1H NMR (400 MHz, DMSO-d6) 8 10.42 (s, 1H), 8.76 (d, J = 21.9 Hz, 2H), 8.20 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.01 (s, 1H), 4.48 (q, J = 7.0 Hz, 2H), 4.11 (d, J = 8.9 Hz, 2H), 3.83 (d, J = 8.8 Hz, 2H), 3.04 (s, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.03 (dd, J = 12.9, 6.6 Hz, 4H). Example 28 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicycl o[3.1.0]hexane-6-carboxamide Step 1 (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[00450] Under ice-water bath, 2-(4-bromopyridin-2-yl)acetonitrile 28a (500 mg, 2.54 mmol) was added to anhydrous dimethoxyethane (20 mL). Sodium hydride (223.31 mg, 5.58 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]dioxathiole 2,2-dioxide 8b (499.96 mg, 3.05 mmol) was added, and the mixture was heated to 60°C and stirred for 18 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The residue was purified by silica gel column chromatography (eluent:   System  B) to obtain (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile 28b (260 mg) with a yield of 94%.

[00451] MS m / z (ESI): 263.0 [M+1] Step 2 (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[00452] (1R,5S)-6-(4-Bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile 28b (260 mg, 988.09 pmol), sodium hydroxide (79.05 mg, 1.98 mmol), and hydrogen peroxide (1.5 mL) were sequentially added to dimethyl sulfoxide (1.5 mL). The mixture was heated to 40°C and stirred for 3 hours. Water (10 mL) was added to quench the reaction, and the mixture was stirred for 0.5 hours. The solid was collected by filtration. The aqueous phase was extracted with ethyl acetate (10 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation, then combined with the collected solid and dried to obtain (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide 28c (260 mg) with a yield of 93.59%.

[00453] MS m / z (ESI): 281.5 [M+1] Step 3 (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[00454] (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). Under ice-water bath, sodium nitrite (719.53 mg, 10.43 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and neutralized with saturated sodium bicarbonate solution. Saturated citric acid solution was added to adjust the pH to acidic. The mixture 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 I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA     +      H2O,      mobile     phase      B:      CH3CN)      to      obtain (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 28d (210 mg) with a yield of 71.38%.

[00455] MS m / z (ESI): 282.0 [M+1] Step 4 (1R,5S)-6-(4-bromopyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-car boxamide

[00456] Under                                ice-water                                bath, (1R,5S)-6-(4-bromopyridin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 28d (180 mg, 638.00 pmol),    N-methylpyrrolidone    (1 mL),    N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (357.28 mg, 1.28 mmol), and N-methylimidazole (209.52 mg, 2.55 mmol) were added to a 15 mL single-neck flask. The reaction was performed at room temperature for 0.5 hours. 4-(6-Ethoxypyrazin-2-yl)aniline 3b (144.20 mg, 669.90 umol) was added, and the mixture was heated to 65°C and stirred for 5 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined 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 obtain (1R,5S)-6-(4-bromopyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0]hexane-6-car boxamide 28e (50 mg) with a yield of 16.35%.

[00457] MS m / z (ESI): 480.1 [M+1] Step 5 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicycl o[3.1.0]hexane-6-carboxamide

[00458] (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 umol), cyclopropanesulfonamide (75.82 mg, 625.82 umol),       cesium       carbonate       (271.87       mg,       834.43       umol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl   (17.72 mg, 41.72 umol), and allylpalladium(II) chloride dimer (7.63 mg, 20.86 umol) were sequentially added to 1,4-dioxane (3 mL). The mixture was subjected to argon exchange three times and heated to 90°C with stirring for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 um, 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)bicycl o[3.1.0]hexane-6-carboxamide 28 (26 mg) with a yield of 97.6%.

[00459] MS m / z (ESI): 350.9 [M+1]

[00460] 1H NMR (400 MHz, DMSO-d6) 8 10.53 (s, 1H), 8.77 (s, 1H), 8.39 (d, J = 6.1 Hz, 1H), 8.24 - 8.06 (m, 3H), 7.84 (d, J = 8.4 Hz, 2H), 7.36 (s, 1H), 7.22 (d, J = 6.1 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.86 (d, J = 7.3 Hz, 1H), 2.25 - 2.10 (m, 4H), 2.01 (q, J = 10.9 Hz, 2H), 1.68 (d, J = 10.3 Hz, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.31 - 1.15 (m, 1H), 1.16 - 0.94 (m, 5H). Example 29 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bic yclo[3.1.0]hexane-6-carboxamide Step 1 (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[00461] Under ice-water bath, 2-(2-(methylthio)pyrimidin-4-yl)acetonitrile 27a (800 mg, 4.84 mmol) was dissolved in anhydrous dimethoxyethane (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]dioxathiole 2,2-dioxide 8b (953.98 mg, 5.81 mmol) was added, and the mixture was heated to 60°C and stirred for 18 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The residue was purified by silica gel column chromatography (eluent: System B) to obtain (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carbonitrile 29a (600 mg) with a yield of 53.57%.

[00462] MS m / z (ESI): 231.2 [M+1] Step 2 (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide

[00463] (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). Under ice-water bath, sodium hydroxide (207.51 mg, 5.19 mmol) was added. 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 reaction. The solid was collected by filtration and dried to obtain (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxamide 29b (550 mg) with a yield of 85.04%. MS m / z (ESI): 249.0 [M+1] Step 3 (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[00464] (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). Under ice-water bath, sodium nitrite (1.52 g, 22.06 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and neutralized with saturated sodium bicarbonate solution. Saturated citric acid solution was added to adjust the pH to acidic. The mixture was extracted with ethyl acetate (20 mL x 3). The aqueous phase was collected and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA     +      H2O,      mobile     phase      B:      CH3CN)      to      obtain (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 29c (350 mg) with a yield of 63.39%.

[00465] MS m / z (ESI): 251.0 [M+1] Step 4 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexa ne-6-carboxamide

[00466] 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 pmol), N-methylpyrrolidone (1 mL), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (178.97 mg, 639.19 pmol), and N-methylimidazole (104.96 mg, 1.28 mmol) were added to a 15 mL single-neck flask. The reaction was performed at room temperature for 0.5 hours. 4-(6-Ethoxypyrazin-2-yl)aniline 3b (72.23 mg, 335.58 umol) was added, and the mixture was heated to 100°C and stirred for 18 hours. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined 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 obtain (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexa ne-6-carboxamide 29d (130 mg) with a yield of 90.89%.

[00467] MS m / z (ESI): 448.1 [M+1] Step 5 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyclo[3.1.0] hexane-6-carboxamide

[00468] (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 umol) and meta-chloroperoxybenzoic acid (101.61 mg, 500.50 umol, 85% purity) were added to dichloromethane (2 mL) and stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to                                                                                         obtain (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) with a yield of 96.55%.

[00469] MS m / z (ESI): 464.1 [M+1] Step 6 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bic yclo[3.1.0]hexane-6-carboxamide

[00470] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicyc lo[3.1.0]hexane-6-carboxamide 29e (140 mg, 302.02 pmol), cyclopropanesulfonamide (43.91 mg, 362.42 pmol), and cesium carbonate (196.81 mg, 604.03 pmol) were added to N-methylpyrrolidone (1 mL). The mixture was heated to 100°C and the reaction was performed for 2 hours. The reaction mixture was cooled to room temperature and directly purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 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)bic yclo[3.1.0]hexane-6-carboxamide 29 (40 mg) with a yield of 19.62%.

[00471] MS m / z (ESI): 521.3 [M+1].

[00472] 1H NMR (400 MHz, DMSO- d6) 8 10.47 (s, 1H), 8.77 (s, 1H), 8.68 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 4.48 (d, J = 7.0 Hz, 2H), 3.02 (s, 1H), 2.21 (d, J = 3.0 Hz, 2H), 2.10 (dd, J = 13.3, 8.5 Hz, 2H), 2.00 (d, J = 10.2 Hz, 2H), 1.72 -1.61 (m, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.10 - 0.93 (m, 5H). Example 30 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methylbicyclo[3.1.0]hexane-6-carboxamide Step 1 4-(6-ethoxypyrazin-2-yl)-N-methylaniline

[00473] 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)ferrocene palladium(II) dichloride (156.94 mg, 214.49 pmol), and potassium carbonate (889.33 mg, 6.43 mmol) were sequentially added to a mixed solvent of 1,4-dioxane (6 mL) and water (3 mL). The mixture was subjected to argon exchange three times and heated to 80°C with stirring 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 obtain 4-(6-ethoxypyrazin-2-yl)-N-methylaniline 30b (450 mg) with a yield of 91.51%.

[00474] MS m / z (ESI): 230.0 [M+1] 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

[00475] 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 pmol), N-methylpyrrolidone (1 mL), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (178.97 mg, 639.19 pmol), and N-methylimidazole (104.96 mg, 1.28 mmol) were added to a 15 mL single-neck flask. The reaction was performed at room temperature for 0.5 hours. 4-(6-Ethoxypyrazin-2-yl)-N-methylaniline 30b (76.94 mg, 335.58 umol) was added, and the mixture was heated to 100°C and stirred for 18 hours. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined 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                        obtain (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) with a yield of 54.23%.

[00476] MS m / z (ESI): 462.1 [M+1] Step 3 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicy clo[3.1.0]hexane-6-carboxamide

[00477] (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 umol) and meta-chloroperoxybenzoic acid (42.23 mg, 207.98 umol, 85% purity) were added to dichloromethane (2 mL). The mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under                reduced                pressure                to                obtain (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-methyl-6-(6-(methylsulfonyl)pyrimidin-4-yl)bicy clo[3.1.0]hexane-6-carboxamide 30d (40 mg) with a yield of 64.43%.

[00478] MS m / z (ESI): 478.1 [M+1] 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

[00479] (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). The mixture was heated to 90°C and the reaction was performed for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 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)-N-methylbicyclo[3.1.0]hexane-6-carboxamide 30 (6 mg) with a yield of 7.36%.

[00480] MS m / z (ESI): 535.1 [M+1]

[00481] 1H NMR (400 MHz, DMSO- d6) 8 8.84 (s, 1H), 8.69 (d, J = 10.8 Hz, 1H), 8.26 (s, 1H), 8.19 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 14.3 Hz, 1H), 4.49 (q, J = 7.4 Hz, 2H), 3.32 (s, 3H), 3.05 (s, 1H), 2.55 (t, J = 5.5 Hz, 2H), 2.12 (t, J = 13.0 Hz, 4H), 1.40 (q, J = 6.4, 5.8 Hz, 4H), 1.14 - 1.00 (m, 5H). Example 31 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0 ]hexane-3-carboxamide Step 1 ethyl 3-(6-((tert-butoxycarbonyl)amino)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00482] Tert-butyl (5-chloropyridazin-3-yl)carbamate 31a (700 mg, 3.05 mmol, prepared according    to    published    patent    "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). The mixture was cooled to -78°C, and lithium bis(trimethylsilyl)amide (1 M, 9.14 mL) was added. The mixture was heated to room temperature and stirred for 1 hour. Saturated ammonium chloride solution was added to the reaction mixture, 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) with a yield of 85.00%.

[00483] MS m / z (ESI): 348.1[M+1] Step 2 ethyl 3-(6-aminopyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00484] 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 4 M solution of hydrochloric acid in dioxane (5 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain ethyl 3-(6-aminopyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 31c (350 mg) with a yield of 89.97%.

[00485] MS m / z (ESI): 248.0 [M+1] Step 3 ethyl 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate

[00486] Ethyl 3-(6-aminopyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 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 uL) were mixed. The mixture was heated to 70°C and stirred for 2 hours, then heated to 100°C and stirred for 18 hours. The mixture was concentrated under reduced pressure and the solvent was evaporated to dryness by rotation. Water (10 mL) and saturated citric acid solution (10 mL) were added, and the mixture was extracted with dichloromethane (20 mL x 3). The combined 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 obtain ethyl 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 31d (150 mg) with a yield of 30.16%.

[00487] MS m / z (ESI): 352.1 [M+1] Step 4 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0 ]hexane-3-carboxamide

[00488] Ethyl 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)bicyclo[3.1.0]hexane-3-carboxylate 31d  (66.15 mg, 307.32 pmol), toluene (1.81 mL), and a solution of trimethylaluminum in toluene (2 M, 460.99 pL) were mixed and stirred at room temperature for 1 hour. 4-(6-Ethoxypyrazin-2-yl)aniline 3b (90 mg, 256.10 pmol) was added, and the mixture was heated to 90°C and stirred for 5 hours. Methanol (1 mL) was added to quench the reaction, and the mixture was directly concentrated under reduced pressure. Dilute hydrochloric acid (1 M, 2 mL) and dichloromethane (5 mL) were added to the residue. Insoluble solid was removed by filtration, and the filtrate was separated. 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 3-(6-(cyclopropanesulfonamido)pyridazin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bicyclo[3.1.0 ]hexane-3-carboxamide 31 (25 mg) with a yield of 14.92%.

[00489] MS m / z (ESI): 521.8 [M+1]

[00490] 1H NMR (400 MHz, DMSO-d6) 8 9.71 (s, 1H), 8.63 (s, 1H), 8.06 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 3H), 4.34 (q, J = 7.1 Hz, 2H), 2.87 (d, J = 13.5 Hz, 2H), 2.08 (d, J = 13.4 Hz, 2H), 1.36 - 1.20 (m, 6H), 0.78 (d, J = 11.6 Hz, 4H), 0.34 (q, J = 7.3 Hz, 1H), -0.00 (q, J = 4.4 Hz, 1H). Example 32 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1 H-indene-2-carboxamide Step 1 methyl 2-(4-bromopyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate

[00491] Methyl 2-(4-bromopyridin-2-yl)acetate 17d (500 mg, 2.17 mmol) was added to N,N-dimethylformamide (1 mL). The mixture was subjected to argon exchange three times. Under cooling with ice-water bath, sodium hydroxide (199.95 mg, 5.00 mmol) was slowly added, and the mixture was stirred for 0.5 hours. 1,2-Bis(chloromethyl)benzene (494.59 mg, 2.83 mmol) was added, and the mixture was stirred at room temperature for 23 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was 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     B)     to     obtain     methyl 2-(4-bromopyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32a (280 mg) with a yield of 38.78%.

[00492] MS m / z (ESI): 333.0 [M+1] Step 2 methyl 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate

[00493] Methyl 2-(4-bromopyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32a (230 mg, 692.37 pmol), 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 umol), and allylpalladium(II) chloride dimer (25.33 mg, 69.24 umol) were sequentially added to 1,4-dioxane (2 mL). The mixture was subjected to argon exchange 3 times and heated to 90°C with stirring for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:   System B) to obtain methyl 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylate 32b (100 mg) with a yield of 38.78%.

[00494] MS m / z (ESI): 373.1 [M+1] Step 3 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1 H-indene-2-carboxamide

[00495] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (57.80 mg, 268.50 umol) was added to toluene (1 mL). The mixture was subjected to argon exchange three times. A toluene solution of trimethylaluminum (2 M, 469.88 uL) 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 umol) was added, and the mixture was heated to 90°C with stirring for 5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to                                                                                         obtain 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1 H-indene-2-carboxamide 32 (64.54 mg) with a yield of 33.74%.

[00496] MS m / z (ESI): 556.2 [M+1]

[00497] 1H NMR (400 MHz, DMSO- d6) 8 10.13 (s, 1H), 8.77 (s, 1H), 8.51 (d, J = 6.2 Hz, 1H), 8.19 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.40 (s, 1H), 7.35 (d, J = 6.2 Hz, 1H), 7.29 (d, J = 4.2 Hz, 2H), 7.20 (d, J = 4.3 Hz, 2H), 4.45 (t, J = 7.1 Hz, 2H), 3.98 (d, J = 16.2 Hz, 2H), 3.58 (s, 2H), 2.88 (s, 1H), 1.39 (t, J = 7.0 Hz, 3H), 0.99 (d, J = 9.0 Hz, 4H). Example 33 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxa bicyclo[3.1.0]hexane-6-carboxamide Step 1 (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile

[00498] Under ice-water bath, 2-(4-bromopyridin-2-yl)acetonitrile 28a (1 g, 5.08 mmol) was added to anhydrous dimethoxyethane (40 mL). Sodium hydride (446.63 mg, 11.17 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]dioxathiole 2,2-dioxide 4c (1.26 g, 7.61 mmol) was added, and the mixture was heated to 60°C and stirred for 18 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was partitioned. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The residue was purified by silica gel     column     chromatography     (eluent:      System     B)     to     obtain (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carbonitrile 33a (800 mg) with a yield of 59.46%.

[00499] MS m / z (ESI): 265.1 [M+1] Step 2 (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[00500] (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). Under ice-water bath, sodium hydroxide (482.83 mg, 12.07 mmol) was added. 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 reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 33b (1.2 g) with a yield of .23%.

[00501] MS m / z (ESI): 283.0 [M+1] Step 3 (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[00502] (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). Under ice-water bath, sodium nitrite (2.92 g, 42.38 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and neutralized with saturated sodium bicarbonate solution. Saturated citric acid solution was added to adjust the pH to acidic, and the mixture was extracted with ethyl acetate (20 mL x 3). The aqueous phase was collected and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA     +      H2O,      mobile     phase      B:      CH3CN)      to      obtain (1R,5S)-6-(4-bromopyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 33c (200 mg) with a yield of 16.61%.

[00503] MS m / z (ESI): 284.0 [M+1] Step 4 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[00504] (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-diter-butylphosphino-2',4',6'-triisopropylbiphenyl (112 mg, 263 pmol), and allylpalladium(II) chloride dimer (48.29 mg, 131.99 pmol) were sequentially added to 1,4-dioxane (10 mL). The mixture was subjected to argon exchange 3 times and heated to 90°C with stirring for 2 hours. The reaction mixture was cooled to room temperature, and insoluble material 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase               B:                CH3CN)               to               obtain (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 33d (110 mg) with a yield of 12.85%.

[00505] MS m / z (ESI): 325.0 [M+1] Step 5 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-oxa bicyclo[3.1.0]hexane-6-carboxamide

[00506] 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 pmol),    N-methylpyrrolidone    (1 mL), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (189.92 mg, 678.28 pmol), and N-methylimidazole (111.37 mg, 1.36 mmol) were added to a 15 mL single-neck flask. The reaction was performed at room temperature for 0.5 hours. 4-(6-Ethoxypyrazin-2-yl)aniline 3b (87.60 mg, 406.97 pmol) was added, and the mixture was heated to 90°C and the reaction was performed for 2 hours. The reaction mixture was cooled to room temperature. Water (10 mL) and ethyl acetate (10 mL) were added, and the mixture was extracted and partitioned. 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 x 21.2 mm I.D.; 5 pm, 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)-3-oxa bicyclo[3.1.0]hexane-6-carboxamide 33 (25 mg) with a yield of 11.50%.

[00507] MS m / z (ESI): 522.2 [M+1]

[00508] 1H NMR (400 MHz, DMSO-d6) 8 10.39 (s, 1H), 8.77 (s, 1H), 8.39 (d, J = 6.1 Hz, 1H), 8.23 - 8.02 (m, 3H), 7.82 (d, J = 8.3 Hz, 2H), 7.34 (s, 1H), 7.17 (d, J = 5.9 Hz, 1H), 4.48 (q, J = 7.5 Hz, 2H), 4.13 (d, J = 8.9 Hz, 2H), 3.82 (d, J = 8.8 Hz, 2H), 2.82 (s, 1H), 2.48 (s, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.24 (s, 1H). Example 34 2-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro -1H-indene-2-carboxamide

[00509] According to the synthesis method of Example 15 of the present disclosure, ethyl bicyclo[3.1.0]hexane-3-carboxylate 2a as the starting material in Example 15 was replaced with methyl              2,3-dihydro-1H-indene-2-carboxylate              to              obtain 2-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro -1H-indene-2-carboxamide 34.

[00510] MS m / z (ESI): 557.1 [M+1]

[00511] 1H NMR (400 MHz, DMSO-d6) 8 9.79 (s, 1H), 8.75 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.23 (dd, J = 5.4, 3.3 Hz, 2H), 7.13 (dd, J = 5.5, 3.2 Hz, 2H), 6.81 (d, J = 5.7 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.84 (d, J = 16.3 Hz, 2H), 3.74 (d, J = 16.3 Hz, 2H), 2.83 (td, J = 8.1, 4.8 Hz, 1H), 1.39 (t, J = 7.0 Hz, 3H), 1.05 - 0.96 (m, 2H), 0.81 - 0.69 (m, 2H). Examples 35 and 36 (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 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-met hyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 36 Step 1 tert-butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate

[00512] Under ice-water bath, 2-(4-bromopyridin-2-yl)acetonitrile 28a (1 g, 5.08 mmol) was added to anhydrous dimethoxyethane (40 mL). Sodium cyanide (446.63 mg, 11.17 mmol, 60% purity) was added, and the mixture was stirred at room temperature for 0.5 hours. (3aR,6aS)-tert-butyl tetrahydro-5H-[1,3,2]dithiolo[4,5-c]pyrrole-5-carboxylate 2,2-dioxide 9c (1.88 g, 7.11 mmol) was added, and the mixture was heated to 70°C and stirred for 6 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was partitioned. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The residue was purified by silica gel column chromatography (eluent: System B) to obtain tert-butyl    (1R,5S)-6-(4-bromopyridin-2-yl)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate 35a (1.1 g) with a yield of 59.50%. Step 2 tert-butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[00513] 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 the mixture was stirred at room temperature for 2 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was partitioned. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain    tert-butyl (1R,5S)-6-(4-bromopyridin-2-yl)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 35b (1 g) with a yield of 86.62%.

[00514] MS m / z (ESI): 383.0 [M+1] Step 3 (1R,5S)-6-(4-bromopyridin-2-yl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxyli c acid

[00515] 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) were mixed. Sodium nitrite (1.99 g, 28.78 mmol) was added, 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (1R,5S)-6-(4-bromopyridin-2-yl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxyli c acid 35c (700 mg) with a yield of 63.47%.

[00516] MS m / z (ESI): 383.0 [M+1] Step 4 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

[00517] Under                                ice-water                                bath, (1R,5S)-6-(4-bromopyridin-2-yl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxyli c acid 35c   (340 mg, 887.18 pmol),   N-methylpyrrolidone   (3 mL), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (496.82 mg, 1.77 mmol), and N-methylimidazole (291.35 mg, 3.55 mmol) were added to a 15 mL single-neck flask. The reaction was performed at room temperature for 0.5 hours. 4-(6-Ethoxypyrazin-2-yl)aniline 3b (210.06 mg, 975.90 pmol) was added, and the mixture was heated to 50°C and stirred for 18 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined 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                obtain                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 (400 mg) with a yield of 77.67%.

[00518] MS m / z (ESI): 580.1 [M+1] Step 5 tert-butyl (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carba moyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[00519] 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 pmol), cyclopropanesulfonamide (37.57 mg, 310.09     pmol),     cesium     carbonate     (168.39     mg,     516.82     pmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl   (10.97 mg, 25.84 umol), and allylpalladium(II) chloride dimer (4.73 mg, 12.92 umol) were sequentially added to 1,4-dioxane (4 mL). The mixture was subjected to argon exchange 3 times, heated to 90°C, and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was filtered to remove insoluble solid. The residue was purified by silica gel column chromatography (eluent: System                 B)                 to                 obtain                 tert-butyl (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carba moyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 35e (100 mg) with a yield of 62.34%.

[00520] MS m / z (ESI): 621.0 [M+1] Step 6 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-aza bicyclo[3.1.0]hexane-6-carboxamide

[00521] Tert-butyl (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-((4-(6-ethoxypyrazin-2-yl)phenyl)carba moyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 35e (100 mg, 161.10 pmol) was added to a solution of hydrogen chloride in dioxane (4 M, 5 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was directly used in the next step.

[00522] MS m / z (ESI): 521.1 [M+1] 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 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-met hyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 36

[00523] (1R,5S)-6-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phen yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide 35f (60 mg, 115.25 pmol), sodium hydroxide (4.61 mg, 115.25 pmol), paraformaldehyde (3.46 mg, 115.25 pmol), and formic acid (13.25 mg, 288.13 umol) were added to tetrahydrofuran (5 mL). The mixture was heated to 80°C and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to                                                                                         obtain (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-met hyl-3-azabicyclo[3.1.0]hexane-6-carboxamide 36.

[00524] Example 35: 5 mg, with a yield of 6.28%.

[00525] MS m / z (ESI): 549.2 [M+1]

[00526] 1H NMR (400 MHz, DMSO-d6) 8 8.77 (s, 1H), 8.41 (d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.88 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 7.21 (d, J = 5.8 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 4.15 (d, J = 12.2 Hz, 1H), 4.05 (d, J = 11.3 Hz, 1H), 3.77 (dd, J = 11.4, 3.9 Hz, 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 = 7.0 Hz, 3H), 1.00 (dd, J = 12.8, 4.9 Hz, 4H).

[00527] Example 36: 20 mg, with a yield of 26.22%.

[00528] MS m / z (ESI): 535.2 [M+1]

[00529] 1H NMR (400 MHz, DMSO-d6) 8 10.96 (s, 1H), 10.81 (s, 1H), 8.80 (s, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.21 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.17 -7.09 (m, 1H), 4.48 (q, J = 7.0 Hz, 2H), 4.20 (s, 1H), 3.92 - 3.80 (m, 1H), 3.67 (d, J = 10.7 Hz, 1H), 3.16 (d, J = 11.1 Hz, 1H), 2.89 (s, 1H), 2.67 - 2.60 (m, 1H), 2.51 - 2.48 (m, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.03 - 0.85 (m, 4H). Example 37 (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

[00530] According to the synthesis methods of Examples 9 and 10 of the present disclosure,the 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.

[00531] MS m / z (ESI): 536.2 [M+1]

[00532] 1H NMR (400 MHz, DMSO-d6) 8 10.81 (s, 1H), 9.50 (s, 1H), 8.21 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.17 - 7.09 (m, 1H), 4.48 (q, J = 7.0 Hz, 2H), 4.20 (s, 1H), 3.92 - 3.80 (m, 1H), 3.67 (d, J = 10.7 Hz, 1H), 3.16 (d, J = 11.1 Hz, 1H), 2.89 (s, 1H), 2.67 - 2.60 (m, 1H), 2.51 - 2.48 (m, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.03 - 0.85 (m, 4H). Example 38 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)bicyclo [3.1.0]hexane-3-carboxamide

[00533] Ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15d (54.15 mg, 250.41 pmol) was added to toluene (1.86 mL). A solution of trimethylaluminum in toluene (2 M, 409.77 pL) was added, and the mixture was stirred at room temperature for 1 hour. 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine 1d (80 mg, 227.65 pmol) was added, and the mixture was heated to 90°C and stirred for 1.5 hours. The reaction mixture was cooled to room temperature, and methanol (1 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure. Dilute hydrochloric acid (1 M, 2 mL) and dichloromethane (5 mL) were added to the residue. The insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 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) with a yield of 8.86%.

[00534] MS m / z (ESI): 522.1 [M+1].

[00535] 1H NMR (400 MHz, DMSO-d6) 8 10.03 (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 = 5.7 Hz, 1H), 4.32 (d, J = 7.1 Hz, 2H), 2.97 (dt, J = 8.0, 3.7 Hz, 1H), 2.67 (d, J = 13.7 Hz, 2H), 2.47 (d, J = 13.5 Hz, 2H), 1.26 (t, J = 6.9 Hz, 5H), 0.93 (p, J = 4.9 Hz, 2H), 0.79 - 0.69 (m, 2H), 0.30 - 0.20 (m, 1H), -0.00 (q, J = 4.3 Hz, 1H). Example 39 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bic yclo[3.1.0]hexane-3-carboxamide F 39

[00536] Ethyl 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxylate 15d (58.41 mg, 250.41 pmol) was added to toluene (1.86 mL). A solution of trimethylaluminum in toluene (2 M, 409.77 pL) was added, and the mixture was stirred at room temperature for 1 hour. 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (80 mg, 227.65 pmol) was added, and the mixture was heated to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. Dilute hydrochloric acid (1 M, 2 mL) and dichloromethane (5 mL) were added to the residue. The insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)bic yclo[3.1.0]hexane-3-carboxamide 39 (13 mg) with a yield of 7.44%.

[00537] MS m / z (ESI): 521.8 [M+1].

[00538] 1H NMR (400 MHz, DMSO- d6) 8 11.28 (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 = 13.7 Hz, 2H), 1.40 (s, 5H), 1.13 (s, 2H), 1.01 (s, 2H), 0.40 (s, 1H), 0.26 (s, 1H). Example 40 2-(3-(cyclopropanesulfonamido)phenyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-ind ene-2-carboxamide Step 1 methyl 2-(3-bromophenyl)-2,3-dihydro-1H-indene-2-carboxylate

[00539] 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). The mixture was heated to 60°C and stirred for 18 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (50 mL) and water (30 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was 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) with a yield of 60.86%.

[00540] MS m / z (ESI): 332.1 [M+1]. Step 2 methyl 2-(3-(cyclopropanesulfonamido)phenyl)-2,3-dihydro-1H-indene-2-carboxylate

[00541] Methyl 2-(3-bromophenyl)-2,3-dihydro-1H-indene-2-carboxylate 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 umol), and allylpalladium(II) chloride dimer (60.76 mg, 166.06 umol) were sequentially added to 1,4-dioxane (4 mL). The mixture was subjected to argon exchange 3 times and heated to 100°C with stirring for 1 hour. The reaction mixture 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 obtain methyl 2-(3-(cyclopropanesulfonamido)phenyl)-2,3-dihydro-1H-indene-2-carboxylate 40c (800 mg) with a yield of 64.85%.

[00542] MS m / z (ESI): 389.1 [M+18]. Step 3 2-(3-(cyclopropanesulfonamido)phenyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-ind ene-2-carboxamide

[00543] Methyl  2-(3-(cyclopropanesulfonamido)phenyl)-2,3-dihydro-1H-indene-2-carboxylate 40c (122.85 mg, 570.72 pmol) was added to toluene (1.24 mL). A solution of trimethylaluminum in toluene (2 M, 1.03 mL) was added, and the mixture was stirred at room temperature for 1 hour. 4-(6-Ethoxypyrazin-2-yl)aniline 3b (220 mg, 570.72 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. Methanol (1 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. Dilute hydrochloric acid (1 M, 2 mL) and dichloromethane (5 mL) were added to the residue. The insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 2-(3-(cyclopropanesulfonamido)phenyl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro-1H-ind ene-2-carboxamide 40 (160 mg) with a yield of 40.75%.

[00544] MS m / z (ESI): 555.1 [M+1]

[00545] 1H NMR (400 MHz, DMSO-d6) 8 9.71 (s, 1H), 9.63 (s, 1H), 8.73 (s, 1H), 8.16 (s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.31 - 7.20 (m, 3H), 7.22 - 7.10 (m, 3H), 7.08 (dd, J = 7.9, 2.1 Hz, 1H), 4.46 (q, J = 7.0 Hz, 2H), 3.90 (d, J = 15.9 Hz, 2H), 3.36 (d, J = 16.0 Hz, 2H), 2.45 (d, J = 4.6 Hz, 1H), 1.38 (t, J = 7.0 Hz, 3H), 0.89 - 0.70 (m, 4H). Example 41 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro -1H-indene-2-carboxamide 41 Step 1 methyl 2-(6-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[00546] 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 sequentially added to tetrahydrofuran (1 mL). The mixture was subjected to argon exchange three times. At -30°C, a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 5.11 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:    System A) to obtain methyl 2-(6-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41b (290 mg) with a yield of 56.71%.

[00547] MS m / z (ESI): 301.0 [M+1] Step 2 methyl 2-(6-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[00548] Methyl  2-(6-(methylthio)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate  41b (290 mg, 965.46 pmol) and meta-chloroperoxybenzoic acid (366.53 mg, 2.12 mmol) were sequentially added to dichloromethane (0.5 mL). The mixture was subjected to argon exchange three times and stirred at room temperature for 16 hours. Ethyl acetate (30 mL) and water (15 mL) were added to the reaction mixture, and the mixture was partitioned. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated       under       reduced       pressure       to       obtain       methyl 2-(6-(methylsulfonyl)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41c (220 mg) with a yield of 68.56%.

[00549] MS m / z (ESI): 333.1 [M+1] Step 3 methyl 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate

[00550] 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 sequentially added to N-methylpyrrolidone (2 mL). The mixture was subjected to argon exchange three times and heated to 80°C with stirring 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 obtain methyl 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate 41d (398 mg) with a yield of 56.23%.

[00551] MS m / z (ESI): 374.1 [M+1] Step 4 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro -1H-indene-2-carboxamide

[00552] 4-(6-Ethoxypyrazin-2-yl)aniline 3b (69.17 mg, 321.35 umol) was added to toluene (1.24 pL). The mixture was subjected to argon exchange three times. A solution of trimethylaluminum in toluene (2 M, 468.63 uL) was slowly added dropwise, and the mixture was stirred                  for                  0.5                  hours.                  Methyl 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylate       41d (100.00 mg, 267.79 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 um, 20 mL / min; mobile phase A: 0.05% TFA + H2O,        mobile        phase        B:         CH3CN)        to        obtain 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2,3-dihydro -1H-indene-2-carboxamide 41 (81 mg) with a yield of 41.90%.

[00553] MS m / z (ESI): 557.1 [M+1]

[00554] 1H NMR (400 MHz, DMSO-d6) 8 9.76 (s, 1H), 8.75 (s, 2H), 8.17 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.26 (dd, J = 5.4, 3.3 Hz, 2H), 7.17 (dd, J = 5.5, 3.2 Hz, 2H), 6.99 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.85 (s, 2H), 3.81 (s, 2H), 3.50 (d, J = 16.4 Hz, 2H), 3.01 (s, 1H), 1.39 (t, J = 7.1 Hz, 3H), 1.07-0.92 (m, 4H). Example 42 N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide Step 1 4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)aniline

[00555] 3-Bromo-5-chloropyrazolo[1,5-a]pyridine 42a  (230 mg, 993.62 gmol, prepared according to published patent WO2022087634 A1), (4-aminophenyl)boronic acid 42b (149.68 mg, 1.09 mmol, commercially available), 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride (72.70 mg, 99.36 pmol), 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). The mixture was subjected to argon exchange three times and heated to 95°C with stirring for 1.5 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 obtain 4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)aniline 42c (130 mg) with a yield of 53.69%.

[00556] MS m / z (ESI): 244.1 [M+1] Step 2 N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)bicyclo[3.1.0]hexane-3-carboxamide

[00557] 4-(5-Chloropyrazolo[1,5-a]pyridin-3-yl)aniline 42c (61.02 mg, 250.41 pmol) was added to toluene (1.86 mL). A toluene solution of trimethylaluminum (2 M, 409.77 uL) was added, and 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 umol) was added, and the mixture was heated to 90°C with stirring for 1.5 hours. Methanol (1 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. Dilute hydrochloric acid (1 M, 2 mL) and dichloromethane (5 mL) were added to the residue. The insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A:   0.05% TFA + H2O, mobile phase B:   CH3CN) to obtain 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) with a yield of 15.57%.

[00558] MS m / z (ESI): 549.1 [M+1]

[00559] 1H NMR (400 MHz, DMSO-d6) 8 11.09 (s, 1H), 9.30 (s, 1H), 8.59 (d, J = 7.4 Hz, 1H), 8.32 (d, J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 6.80 (dd, J = 7.4, 2.3 Hz, 1H), 6.61 (d, J = 5.7 Hz, 1H), 3.03-2.95 (m, 1H), 2.67 (d, J = 13.4 Hz, 2H), 2.40 (d, J = 13.4 Hz, 2H), 1.22 (dd, J = 7.8, 4.0 Hz, 2H), 0.88 (d, J = 4.2 Hz, 2H), 0.68 (dt, J = 7.9, 3.5 Hz, 2H), 0.20 (d, J = 6.8 Hz, 1H), -0.00 (d, J = 4.4 Hz, 1H). Example 43 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bic yclo[3.1.0]hexane-6-carboxamide Step 1 tert-butyl 2-cyano-2-(4-(methylthio)pyrimidin-2-yl)acetate

[00560] Under ice-water bath, tert-butyl 2-cyanoacetate (11.86 g, 84.05 mmol, commercially available) was added to tetrahydrofuran (100 mL). Sodium hydride (4.48 g, 112.06 mmol, 60% purity) was added in batches, and the mixture was stirred at room temperature for 0.5 hours. 2-Chloro-4-(methylthio)pyrimidine 15a (9.00 g, 56.03 mmol) was added, and the mixture was heated to 75°C with stirring for 18 hours. Water (100 mL) and ethyl acetate (100 mL) were added, and the mixture was partitioned. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain    tert-butyl 2-cyano-2-(4-(methylthio)pyrimidin-2-yl)acetate 43a (14 g) with a yield of 47.08%.

[00561] MS m / z (ESI): 266.3 [M+1] Step 2 2-(4-(methylthio)pyrimidin-2-yl)acetonitrile

[00562] Tert-butyl 2-cyano-2-(4-(methylthio)pyrimidin-2-yl)acetate 43a (14.87 g, 28.02 mmol) and trifluoroacetic acid (10 mL) were added to dichloromethane (30 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to the residue to adjust pH to 7 to 8, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The residue was purified by silica gel column chromatography (eluent: System B) to obtain 2-(4-(methylthio)pyrimidin-2-yl)acetonitrile 43b (4.1 g) with a yield of 88.56%.

[00563] MS m / z (ESI): 166.2 [M+1] Step 3 (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile

[00564] Under ice-water bath, 2-(4-(methylthio)pyrimidin-2-yl)acetonitrile 43b (1 g, 6.05 mmol) was added to anhydrous dimethoxyethane (40 mL). Sodium hydride (532.64 mg, 13.32 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]dioxathiole 2,2-dioxide 8b (1.49 g, 9.08 mmol) was added, and the mixture was heated to 65°C and stirred for 6 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness by rotation. The residue was purified by silica gel  column chromatography (eluent:   System B) to obtain (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carbonitrile 43c (700 mg) with a yield of 50.00%.

[00565] MS m / z (ESI): 232.0 [M+1] Step 4 (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide

[00566] (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). Hydrogen peroxide (3 mL) was added, and the mixture was heated to 30°C and stirred for 18 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 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          obtain (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxamide 43d  (430 mg) with a yield of 56.99%.

[00567] MS m / z (ESI): 250.0 [M+1] Step 5 (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid

[00568] (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. Sodium nitrite (1.19 g, 17.25 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added to dissolve the reaction mixture, and the mixture was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (1R,5S)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 43e (170 mg) with a yield of 39.38%.

[00569] MS m / z (ESI): 251.0 [M+1] Step 6 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexa ne-6-carboxamide

[00570] 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 pmol), N-methylpyrrolidone (2 mL), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (196.87 mg, 703.11 pmol), and N-methylimidazole (115.45 mg, 1.41 mmol) were added to a 15 mL single-neck flask. The reaction was performed at room temperature for 0.5 hours. 4-(6-Ethoxypyrazin-2-yl)aniline 3b (83.24 mg, 386.71 umol) was added, and the mixture was heated to 90°C and stirred for 18 hours. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined 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 obtain (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylthio)pyrimidin-2-yl)bicyclo[3.1.0]hexa ne-6-carboxamide 43f (120 mg) with a yield of 76.27%.

[00571] MS m / z (ESI): 448.0 [M+1] Step 7 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylsulfinyl)pyrimidin-2-yl)bicyclo[3.1.0]h exane-6-carboxamide

[00572] (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 umol) and meta-chloroperoxybenzoic acid (97.98 mg, 482.63 umol, 85% purity) were added to dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under                reduced                pressure                to                obtain (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylsulfinyl)pyrimidin-2-yl)bicyclo[3.1.0]h exane-6-carboxamide 43g (100 mg) with a yield of 80.46%.

[00573] MS m / z (ESI): [M+1] 464.0 Step 8 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bic yclo[3.1.0]hexane-6-carboxamide

[00574] (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-(4-(methylsulfinyl)pyrimidin-2-yl)bicycl o[3.1.0]hexane-6-carboxamide 43g (120 mg, 258.87 umol), cyclopropanesulfonamide (47.05 mg, 388.31 pmol), and cesium carbonate (168.69 mg, 517.74 pmol) were added to N-methylpyrrolidone (1 mL). The mixture was heated to 90°C and the reaction was performed for 1 hour. The reaction mixture was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL) were added. The pH was adjusted to 6 to 7 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3). 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to                                                                                         obtain (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)bic yclo[3.1.0]hexane-6-carboxamide 43 (25 mg) with a yield of 14.76%.

[00575] MS m / z (ESI): 521.2 [M+1]

[00576] 1H NMR (400 MHz, DMSO-d6) 8 11.14 (s, 1H), 10.31 (s, 1H), 8.76 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.18 (s, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 5.6 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.26 - 3.15 (m, 1H), 2.21 (s, 2H), 2.12 (dd, J = 13.2, 8.5 Hz, 2H), 2.00 (t, J = 11.2 Hz, 2H), 1.64 (d, J = 11.1 Hz, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.09 (d, J = 12.2 Hz, 1H), 1.05 - 0.95 (m, 2H), 0.81 (d, J = 7.7 Hz, 2H). Example 44 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-o xabicyclo[3.1.0]hexane-6-carboxamide

[00577] According to the synthesis method of Example 43 of the present disclosure, (3aR,6aS)-tetrahydro-4H-cyclopenta[d][1,3,2]dioxathiole 2,2-dioxide 8b in Example 43 was replaced with (3aR,6aS)-tetrahydrofuro[3,4-d][1,3,2]dioxathiole 2,2-dioxide 4c to obtain (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-3-o xabicyclo[3.1.0]hexane-6-carboxamide 44.

[00578] MS m / z (ESI): 523.2 [M+1].

[00579] 1H NMR (400 MHz, DMSO-d6) 8 11.25 (s, 1H), 10.29 (s, 1H), 8.80 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.22 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 5.7 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 4.17 (d, J = 8.8 Hz, 2H), 3.88 (d, J = 8.7 Hz, 2H), 3.37 (s, 2H), 3.30 - 3.20 (m, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.05 (dd, J = 7.2, 4.3 Hz, 2H), 0.86 (tt, J = 7.6, 5.1, 4.6 Hz, 2H). Example 45 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluoroph enyl)bicyclo[3.1.0]hexane-6-carboxamide Step 1 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3. 1.0]hexane-6-carboxamide

[00580] 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 umol), N-methylpyrrolidone (2 mL), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (190.16 mg, 679.14 umol), and N-methylimidazole (111.52 mg, 1.36 mmol) were added to a 15 mL single-neck flask. The reaction was performed at room temperature for 0.5 hours. 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (87.12 mg, 373.53 umol) was added, and the mixture was heated to 90°C and stirred for 18 hours. The reaction mixture 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 x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (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) with a yield of 18.98%.

[00581] MS m / z (ESI): 466.0 [M+1] Step 2 (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylsulfinyl)pyrimidin-4-yl)bicycl o[3.1.0]hexane-6-carboxamide

[00582] (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 umol) and meta-chloroperoxybenzoic acid (41.87 mg, 206.21 umol, 85% purity) were added to dichloromethane (2 mL). The mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under                reduced                pressure                to                obtain (1R,5S)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-6-(6-(methylsulfinyl)pyrimidin-4-yl)bicycl o[3.1.0]hexane-6-carboxamide 45b (60 mg) with a yield of 96.68%.

[00583] MS m / z (ESI): 482.0 [M+1] Step 3 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluoroph enyl)bicyclo[3.1.0]hexane-6-carboxamide

[00584] (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 pmol), cyclopropanesulfonamide (22.64 mg, 186.90 pmol), and cesium carbonate (81.19 mg, 249.20 pmol) were added to N-methylpyrrolidone (1 mL). The mixture was heated to 90°C and stirred for 1 hour. The reaction mixture was cooled to room temperature. Water (20 mL) and ethyl acetate (20 mL) were added, and the pH was adjusted to 6 to 7 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3). 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 x 21.2 mm I.D.; 5 pm, 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)-2-fluoroph enyl)bicyclo[3.1.0]hexane-6-carboxamide 45 (3.53 mg) with a yield of 4.26%.

[00585] MS m / z (ESI): 539.1 [M+1]

[00586] 1H NMR (400 MHz, DMSO- d6) 8 10.27 (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 = 7.0 Hz, 2H), 2.21 (d, J = 3.3 Hz, 2H), 2.12 (dd, J = 13.3, 8.4 Hz, 2H), 2.00 (d, J = 8.4 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.17 (t, J = 7.1 Hz, 2H), 1.05 (d, J = 14.8 Hz, 4H). Example 46 (1R,5S)-6-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluoroph enyl)bicyclo[3.1.0]hexane-6-carboxamide

[00587] According to the synthesis method of Example 45 of the present disclosure, (1R,5S)-6-(6-(methylthio)pyrimidin-4-yl)bicyclo[3.1.0]hexane-6-carboxylic acid 29c in Example 45                       was                       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-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluoroph enyl)bicyclo[3.1.0]hexane-6-carboxamide 46.

[00588] MS m / z (ESI): 539.1 [M+1]

[00589] 1H NMR (400 MHz, DMSO-d6) 8 11.12 (s, 1H), 10.06 (s, 1H), 8.83 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.23 (d, J = 2.7 Hz, 2H), 7.97 (d, J = 10.2 Hz, 2H), 6.70 (d, J = 5.6 Hz, 1H), 4.49 (q, J = 7.0 Hz, 2H), 3.21 (d, J = 8.2 Hz, 1H), 2.20 (d, J = 3.0 Hz, 2H), 2.13 (dd, J = 13.2, 8.4 Hz, 2H), 1.98 (d, J = 11.3 Hz, 2H), 1.64 (s, 1H), 1.41 (t, J = 7.0 Hz, 3H), 1.17 (d, J = 6.0 Hz, 1H), 1.05 (t, J = 3.3 Hz, 2H), 0.92 (h, J = 5.2, 4.7 Hz, 2H). Example 47 (1R,5S)-6-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-y l)-3-oxabicyclo[3.1.0]hexane-6-carboxamide

[00590] According to the synthesis method of Example 45 of the present disclosure, 4-(6-ethoxypyrazin-2-yl)-2-fluoroaniline 12b in Example 45 was replaced with 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-y l)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 47.

[00591] MS m / z (ESI): 524.2 [M+1]

[00592] 1H NMR (400 MHz, DMSO-d6) 8 11.07 (s, 1H), 9.08 (d, J = 2.5 Hz, 1H), 8.85 (s, 1H), 8.71 (s, 1H), 8.53 (dd, J = 8.7, 2.5 Hz, 1H), 8.34 - 8.20 (m, 2H), 6.95 (s, 1H), 4.49 (q, J = 7.0 Hz, 2H), 4.11 (d, J = 9.0 Hz, 2H), 3.82 (d, J = 8.8 Hz, 2H), 3.04 (s, 1H), 1.41 (t, J = 7.0 Hz, 3H), 1.31 - 1.11 (m, 2H), 1.11 - 0.91 (m, 4H). Example 48 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 Step 1 5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine

[00593] 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)ferrocene palladium(II) dichloride (347.71 mg, 475.21 pmol), and potassium carbonate (1.97 g, 14.26 mmol) were added to a mixed solvent of 1,4-dioxane (2 mL) and water (0.5 mL). The mixture was subjected to argon exchange three times and heated to 95°C with stirring for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to obtain 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 Step 2 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

[00594] 5-(5-Chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine 48a (114.88 mg, 469.52 pmol) was added to toluene (2 mL). A solution of trimethylaluminum in toluene (2 M, 768.31 pL) was added, and 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 pmol) was added, and the mixture was heated to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the reaction, 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 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA     +      H2O,      mobile     phase      B:      CH3CN)      to      obtain 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) with a yield of 1.10%.

[00595] MS m / z (ESI): 550.1 [M+1]

[00596] 1H NMR (400 MHz, DMSO-d6) 8 10.86 (s, 1H), 9.87 (s, 1H), 8.63 (d, J = 7.4 Hz, 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, 2.2 Hz, 1H), 2.99 - 2.93 (m, 1H), 2.77 (d, J = 13.7 Hz, 2H), 2.27 (d, J = 13.8 Hz, 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). Example 49 N-(4-(5-chloropyrazolo[1,5-a]pyridin-3-yl)phenyl)-3-(6-(cyclopropanesulfonamido)pyrazin-2-yl) bicyclo[3.1.0]hexane-3-carboxamide 42c                                                                  49

[00597] 4-(5-Chloropyrazolo[1,5-a]pyridin-3-yl)aniline 42c (106.79 mg, 438.22 pmol) was added to toluene (1.55 mL). A solution of trimethylaluminum in toluene (2 M, 717.09 uL) was added, and 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 umol) was added, and the mixture was heated to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the reaction, 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 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA     +      H2O,      mobile      phase      B:      CH3CN)     to      obtain 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) with a yield of 3.53%.

[00598] MS m / z (ESI): 549.1 [M+1]

[00599] 1H NMR (400 MHz, DMSO-d6) 8 11.08 (s, 1H), 9.50 (s, 1H), 8.76 (d, J = 7.4 Hz, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.69 - 7.60 (m, 4H), 6.98 (dd, J = 7.4, 2.3 Hz, 1H), 3.19 - 3.09 (m, 1H), 2.93 (d, J = 13.6 Hz, 2H), 2.43 (d, J = 13.6 Hz, 2H), 1.47 - 1.39 (m, 2H), 1.10 (dt, J = 6.6, 3.3 Hz, 2H), 0.96 (dt, J = 7.8, 3.6 Hz, 2H), 0.44 (d, J = 6.4 Hz, 1H), 0.18 (d, J = 4.5 Hz, 1H). Example 50 N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(4-(cyclopropanesulfonamido)pyrimid in-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 0 15d

[00600] 5-(5-Chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine 48a (104.44 mg, 426.84 pmol) was added to toluene (2 mL). A solution of trimethylaluminum in toluene (2 M, 768.31 uL) was added, and 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 umol) was added, and the mixture was heated to 90°C and stirred for 1.5 hours. Methanol (1 mL) was added to quench the reaction, 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 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA     +      H2O,      mobile     phase      B:      CH3CN)     to      obtain N-(5-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(4-(cyclopropanesulfonamido)pyrimid in-2-yl)bicyclo[3.1.0]hexane-3-carboxamide 50 (35 mg) with a yield of 11.11%.

[00601] MS m / z (ESI): 550.1 [M+1]

[00602] 1H NMR (400 MHz, DMSO-d6) 8 11.08 (s, 1H), 9.75 (s, 1H), 8.63 (d, J = 7.4 Hz, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.38 - 8.29 (m, 2H), 7.94 (dd, J = 21.1, 2.0 Hz, 3H), 6.86 (dd, J = 7.4, 2.2 Hz, 1H), 6.65 (d, J = 5.7 Hz, 1H), 2.98 (s, 1H), 2.66 (d, J = 13.6 Hz, 2H), 2.44 (dd, J = 13.5, 3.3 Hz, 2H), 1.24 (dt, J = 7.8, 3.6 Hz, 2H), 0.91 (dd, J = 4.7, 2.4 Hz, 2H), 0.74 (dd, J = 7.9, 2.7 Hz, 2H), 0.23 (td, J = 8.0, 5.1 Hz, 1H), 0.01 (d, J = 4.3 Hz, 1H). Example 51 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-oxabicyclo[ 3.1.0]hexane-3-carboxamide Step 1 ethyl 1-(4-iodopyridin-2-yl)cyclopent-3-ene-1-carboxylate

[00603] Under 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 solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 5.64 mL) was added, and the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution (3 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture 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 obtain ethyl 1-(4-iodopyridin-2-yl)cyclopent-3-ene-1-carboxylate 51c (190 mg) with a yield of 26.51%.

[00604] MS m / z (ESI): 344.1 [M+1] Step 2 ethyl 3-(4-iodopyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate

[00605] Ethyl 1-(4-iodopyridin-2-yl)cyclopent-3-ene-1-carboxylate 51c (2 g, 3.50 mmol) and meta-chloroperoxybenzoic acid (1.42 g, 6.99 mmol, 85% purity) were added to dichloromethane (20 mL), and the reaction was performed at room temperature overnight. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was partitioned. 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 obtain ethyl 3-(4-iodopyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate 51d (780 mg) with a yield of 62.10%.

[00606] MS m / z (ESI): 360.0 [M+1] Step 3 ethyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate

[00607] 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 pmol) were sequentially added to 1,4-dioxane (10 mL). The mixture was subjected to argon exchange 3 times and heated to 90°C with stirring for 2 hours. The reaction mixture was cooled to room temperature, and 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase            B:            CH3CN)            to            obtain            ethyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate 51e (270 mg) with a yield of 35.28%.

[00608] MS m / z (ESI): 353.0 [M+1] Step 4 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-6-oxabicyclo[ 3.1.0]hexane-3-carboxamide

[00609] Ethyl 3-(4-(cyclopropanesulfonamido)pyridin-2-yl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate 51e (100 mg, 464.57 pmol) was added to toluene (1.83 mL). A solution of trimethylaluminum in toluene (2 M, 836.23 pL) was added, and the mixture was stirred at room temperature for 1 hour. 4-(6-Ethoxypyrazin-2-yl)aniline 3b (163.72 mg, 464.57 pmol) was added, and the mixture was heated to 90°C with stirring for 1.5 hours. Methanol (1 mL) was added to quench the reaction, 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 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 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 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) with a yield of 0.73%.

[00610] MS m / z (ESI): 552.1 [M+1] Example 52 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,3-d ihydro-1H-indene-2-carboxamide

[00611] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (31.31 mg, 134.25 pmol) was added to toluene (1.23 mL). The mixture was subjected to argon exchange 3 times. A solution of trimethylaluminum in toluene (2 M, 234.94 pL) 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 pmol) was added, and the mixture was heated to 90°C with stirring for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2,3-d ihydro-1H-indene-2-carboxamide 52 (22.2 mg) with a yield of 22.27%.

[00612] MS m / z (ESI): 556.2 [M+1]

[00613] 1H NMR (400 MHz, DMSO-d6) 8 9.91 (s, 1H), 8.82 (s, 1H), 8.50 (d, J = 5.8 Hz, 1H), 8.24 (s, 1H), 8.02-7.92 (m, 2H), 7.81 (t, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.28 (dt, J = 8.4, 4.1 Hz, 3H), 7.18 (dd, J = 5.5, 3.2 Hz, 2H), 4.47 (q, J = 7.0 Hz, 3H), 3.92 (d, J = 16.2 Hz, 2H), 3.59 (d, J = 16.2 Hz, 2H), 2.83 (q, J = 6.6 Hz, 1H), 1.39 (t, J = 7.0 Hz, 3H), 1.06-0.93 (m, 4H). Example 53 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihy dro-1H-indene-2-carboxamide

[00614] 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine 1d (29.03 mg, 134.25 pmol) was added to toluene (1.23 mL). The mixture was subjected to argon exchange 3 times. A solution of trimethylaluminum in toluene (2 M, 234.94 pL) 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 pmol) was added, and the mixture was heated to 90°C with stirring for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-dihy dro-1H-indene-2-carboxamide 53 (10.2 mg) with a yield of 9.52%.

[00615] MS m / z (ESI): 556.2 [M+1]

[00616] 1H NMR (400 MHz, DMSO-d6) 8 10.38 (s, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.83 (s, 1H), 8.48 (dd, J = 8.8, 2.5 Hz, 1H), 8.43 (d, J = 5.8 Hz, 1H), 8.24 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.26 (td, J = 5.5, 2.6 Hz, 3H), 7.15 (ddd, J = 10.4, 5.7, 2.6 Hz, 3H), 4.47 (d, J = 7.1 Hz, 2H), 3.88 (d, J = 16.3 Hz, 2H), 3.56 (d, J = 16.3 Hz, 2H), 2.79 - 2.71 (m, 1H), 1.39 (t, J = 7.0 Hz, 3H), 0.98 - 0.91 (m, 4H). Example 54 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2, 3-dihydro-1H-indene-2-carboxamide

[00617] 4-(6-Ethoxypyrazin-2-yl)-2-fluoroaniline 12b (74.95 mg, 321.35 umol) was added to toluene (2 mL). The mixture was subjected to argon exchange three times. A toluene solution of trimethylaluminum (2 M, 468.63 uL) 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 umol) was added, and the mixture was heated to 90°C and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 um, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 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) with a yield of 12.12%.

[00618] MS m / z (ESI): 575.0 [M+1]

[00619] 1H NMR (400 MHz, DMSO-d6) 8 9.68 (s, 1H), 8.82 (d, J = 10.4 Hz, 2H), 8.24 (s, 1H), 8.02 - 7.93 (m, 2H), 7.76 (t, J = 8.1 Hz, 1H), 7.27 (dd, J = 5.4, 3.3 Hz, 2H), 7.17 (dd, J = 5.5, 3.2 Hz, 2H), 7.04 (s, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.83 (d, J = 16.3 Hz, 2H), 3.07 (d, J = 28.3 Hz, 1H), 1.39 (t, J = 7.0 Hz, 3H), 1.12 - 0.91 (m, 4H). Example 55 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-di hydro-1H-indene-2-carboxamide

[00620] 5-(6-Ethoxypyrazin-2-yl)pyridin-2-amine 1d (69.49 mg, 321.35 pmol) was added to toluene (2 mL). The mixture was subjected to argon exchange three times. A solution of trimethylaluminum (2 M, 468.63 pL) in toluene 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 pmol) was added, and the mixture was heated to 90°C and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 2-(6-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2,3-di hydro-1H-indene-2-carboxamide 55 (1.91 mg) with a yield of 1.01%.

[00621] MS m / z (ESI): 558.1 [M+1]

[00622] 1H NMR (400 MHz, DMSO- d6) 8 10.48 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.83 (s, 1H), 8.76 (s, 1H), 8.49 (dd, J = 8.8, 2.5 Hz, 1H), 8.26 - 8.18 (m, 2H), 7.26 (dd, J = 5.4, 3.3 Hz, 2H), 7.17 (dd, J = 5.6, 3.2 Hz, 3H), 6.97 (s, 1H), 4.51 - 4.45 (m, 2H), 3.83 (d, J = 16.4 Hz, 2H), 3.51 (d, J = 16.5 Hz, 2H), 3.04 (d, J = 19.6 Hz, 1H), 1.39 (t, J = 7.0 Hz, 3H), 1.05 - 0.95 (m, 4H). Example 56 2-(4-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrimidin-2-yl)-2,3-di hydro-1H-indene-2-carboxamide Step 1 5-(6-ethoxypyrazin-2-yl)pyrimidin-2-amine

[00623] 2-Chloro-6-et...

Claims

1. A compound of formula (AAI):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;wherein:any two Raa, together with the atoms to which they are attached, form a ring C, wherein ring C is optionally further substituted by one or more R4;ring C is selected from the group consisting of a 6-membered aryl, a 3- to 5- membered cycloalkyl, a 5- to 7- membered heterocyclyl, and a 5- to 6- membered heteroaryl;RA is selected from the group consisting of a hydrogen atom and a C1-6 alkyl;ring A is selected from the group consisting of a 6-membered aryl, a 5- to 6- membered heteroaryl, and a 5- to 7- membered heterocyclyl;ring B is selected from the group consisting of a 6-membered aryl and a 5- to 10- membered heteroaryl;L is selected from the group consisting of -C(=O)-, -C(=O)NRa-, and -NRbC(=O)-;Ra and Rb are each independently selected from the group consisting of a hydrogen atom and a C1-6 alkyl;X, Y, Z, and Q are each independently selected from the group consisting of N and CRc; and at most two of X, Y, Z, and Q are simultaneously N atoms;alternatively, X and Y, Z and Y each independently form a 5- to 6- membered heteroaryl or a 5- to 6- membered heterocyclyl; wherein the 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl is optionally further substituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, cyano, and 3- to 5- membered cycloalkyl;Rc is selected from the group consisting of a hydrogen atom, halogen, hydroxy, cyano, C1-6 alkyl, and C1-6 alkoxy; wherein the C1-6 alkyl or C1-6 alkoxy is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, and 3- to 5- membered cycloalkyl;R1 is selected from the group consisting of C1-6 alkyl and 3- to 5- membered cycloalkyl; wherein the C1-6 alkyl or 3- to 5- membered cycloalkyl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, 3- to 5membered cycloalkyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;R2 is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, hydroxy, C1-6 alkyl, and C1-6 alkoxy; wherein the C1-6 alkyl or C1-6 alkoxy is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-6 alkyl, and C1-6 alkoxy;alternatively, two R2, together with the same carbon atom to which they are attached, form a -C(O);R3 is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, 3- to 5- membered cycloalkyl, C2-6 alkenyl, SF5, -C(O)R5, -C(O)OR5, -NHC(O)R5, -NHC(O)OR5, -NR6R7, -C(O)NR6R7, -CH2NHC(O)OR5, -CH2NR6R7, and -S(O)rR5; wherein the alkyl, alkoxy, alkenyl, or cycloalkyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10, and -NR9C(O)R10;R4 is each independently selected from the group consisting of a hydrogen atom, cyano, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR5, -C(O)R5,  -C(O)OR5,  -NHC(O)R5,  -NHC(O)OR5,  -NR6R7,  -C(O)NR6R7,  -S(O)2NR6R7,-CH2NHC(O)OR5, -CH2NR6R7, and -S(O)rR5; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10,-SO2NR9R10, and -NR9C(O)R10;R5 is each independently selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10, -C(O)NR9R10, -SO2NR9R10, and -NR9C(O)R10;R6 and R7 are each independently selected from the group consisting of a hydrogen atom, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10,-C(O)NR9R10, -SO2NR9R10, and -NR9C(O)R10;alternatively, R6 and R7, together with the atoms to which they are attached, form a 4- to 8membered heterocyclyl, wherein the 4- to 8- membered heterocyclyl contains one or more N, O, or S(O)r, and the 4- to 8- membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R10,-C(O)NR9R10, -SO2NR9R10, and -NR9C(O)R10;R8, R9, and R10 are each independently selected from the group consisting of a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, and carboxylate;m is selected from the group consisting of 0, 1, and 2;n is selected from the group consisting of 0, 1, and 2;p is selected from the group consisting of 0, 1, and 2;q is selected from the group consisting of 0, 1, and 2; andr is each independently 0, 1, or 2.

2. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereofaccording to claim 1, whereinis selected from the group consisting ofandwherein t is selected from the group consisting of 0, 1, and 2; and ring C, R4, p, and q are as defined in claim 1.

3. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound of formula (AI):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;wherein:X, Y, Z, and Q are each independently selected from the group consisting of N and CRc; and at most two of X, Y, Z, and Q are simultaneously N atoms;alternatively, Z and Y form a 5- to 6- membered heteroaryl, wherein the 5- to 6- membered heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, and 3- to 5- membered cycloalkyl;alternatively, X and Y form a 5- to 6- membered heteroaryl, wherein the 5- to 6- membered heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, and 3- to 5- membered cycloalkyl;t is selected from the group consisting of 0, 1, and 2; andring A, ring B, ring C, L, R1 to R4, RA, p, q, m, and n are as defined in claim 1.

4. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to claim 3, which is a compound of formula (I):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;wherein: ring A, ring B, ring C, L, R1 to R4, X, Y, Z, Q, p, q, m, n, and t are as defined in claim 3.

5. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein ring A is selected from the group consisting of:

6. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring B is selected from the group consisting of:

7. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: L is selected from the group consisting of -C(=O)-, -C(=O)NH-, and -NHC(=O)-.

8. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is a compound of formula (IIA) or (IIB):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;wherein each X1 is independently selected from the group consisting of N and CRd;X4 is each independently selected from the group consisting of N and CRd;Rb is each independently selected from the group consisting of a hydrogen atom and methyl;Rd is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;X2 and X3 are each independently selected from the group consisting of N and CRe;j is each independently selected from the group consisting of 0 and 1;Re is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; andring C, X, Y, Z, Q, R1 to R4, p, q, and t are as defined in claim 3.

9. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, which is a compound of formula (II) or (III):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;wherein each X1 is independently selected from the group consisting of N and CRd;Rb is each independently selected from the group consisting of a hydrogen atom and methyl;Rd is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;X2 and X3 are each independently selected from the group consisting of N and CRe;j is each independently selected from the group consisting of 0 and 1;Re is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; andring C, X, Y, Z, Q, R1 to R4, p, q, and t are as defined in claim 3.

10. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound of formula (IV-1) or (IV-2):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;wherein each X1 is independently selected from the group consisting of N and CRd;X4 is each independently selected from the group consisting of N and CRd;Rb is each independently selected from the group consisting of a hydrogen atom and methyl;Rd is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;X2 and X3 are each independently selected from the group consisting of N and CRe;j is each independently selected from the group consisting of 0 and 1;Re is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;t is selected from the group consisting of 0, 1, and 2; andX, Y, Z, Q, and R1 to R4 are as defined in claim 1.

11. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound of formula (V-A), (V-B), (V-C), or (V-D):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;wherein each Rb is independently selected from the group consisting of a hydrogen atom and methyl;ring B is each independently selected from the group consisting of      N      ,. N-V"N      ,^-        , and               ;Y1 and Y2 are each independently selected from the group consisting of N and CH;j is each independently selected from the group consisting of 0 and 1;t is each independently selected from the group consisting of 0, 1, and 2; andring C, X, Y, Z, Q, R1 to R4, p, q, and n are as defined in claim 1.

12. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to claim 11, which is a compound of formula (V-1) or (V-2):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereofwherein each Rb is independently selected from the group consisting of a hydrogen atom and methyl;X2 and X3 are each independently selected from the group consisting of N and CRe;j is each independently selected from the group consisting of 0 and 1;Re is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;t is selected from the group consisting of 0, 1, and 2; andring C, X, Y, Z, Q, R1 to R4, p, and q are as defined in claim 1.

13. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltmT v z. ,x thereof according to any one of claims 1 to 12, wherein     Y      is selected from the groupconsisting of:Rc is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; andk is each independently selected from the group consisting of 0, 1, and 2.

14. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein ring C is selected from the group consisting of:and15. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R4 is selected from the group consisting of a hydrogen atom, C1-6 alkyl, -C(O)R5, -C(O)NR6R7, -S(O)2R5, and -S(O)2NR6R7; wherein the C1-6 alkyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, cyano, and -C(O)OR8;R5 is each independently selected from the group consisting of C1-6 alkyl, 3- to 5- membered cycloalkyl, and 5- to 6- membered heteroaryl, wherein the C1-6 alkyl, 3- to 5- membered cycloalkyl, or 5- to 6- membered heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen and C1-6 alkoxy;R6 and R7 are each independently selected from the group consisting of a hydrogen atom andC1-6 alkyl; andR8 is selected from the group consisting of a hydrogen atom and C1-6 alkyl.

16. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt O(R4)tthereof according to claim 14 or 15, wherein     <A      is selected from the group consistingof:wherein: R4a is each independently selected from the group consisting of a hydrogen atom and C1-6 alkyl; andR4 is as defined in claim 14.

17. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R1 is selected from the group consisting of C1-6 alkyl and 3- to 5- membered cycloalkyl, wherein the C1-6 alkyl or 3- to 5- membered cycloalkyl is optionally further substituted by one or more substituents selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, halogen, hydroxy, and cyano.

18. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to claim 17, wherein R1 is selected from the group consisting of cyclopropyl,methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl,and19. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof according to any one of claims 1 to 18, wherein R2 is selected from the group consisting of a hydrogen atom, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;alternatively, two R2, together with the same carbon atom to which they are attached, form a -C(O).

20. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R3 is selected from the group consisting of a hydrogen atom, halogen, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, 3 to 5- membered cycloalkyl, SF5, C1-6 haloalkyl, and C1-6 haloalkoxy.

21. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to claim 20, wherein R3 is selected from the group consisting of chloro, trifluoromethoxy, methyl, ethyl, and ethoxy.

22. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein p is 0 and q is 0.

23. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein p is 1 and q is 1 or 2.

24. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein p is 2 and q is 0, 1, or 2.

25. The compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein the compound is:

26. A pharmaceutical composition comprising an effective dose of the compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, and a pharmaceutically acceptable carrier.

27. Use of the compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, or the pharmaceutical composition according to claim 26, in the manufacture of a CTPS1 inhibitor.

28. Use of the compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, or the pharmaceutical composition according to claim 26, in the manufacture of a medicament for treating a disease mediated by CTPS1; preferably, 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. The use according to claim 29, wherein the relapsed / refractory B-cell and T-cell lymphoma is mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, or indolent B-cell lymphoma.

31. Use of the compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, or the pharmaceutical composition according to claim 26, in the manufacture of a medicament for treating lymphoma or solid tumor.

32. The use according to claim 31, wherein the lymphoma is relapsed / refractory B-cell and T-cell lymphoma.

33. The use according to claim 32, wherein the relapsed / refractory B-cell and T-cell lymphoma is mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, or indolent B-cell lymphoma.

34. The use according to claim 28, wherein the solid tumor is preferably pancreatic cancer.