WO2023143355A1

WO2023143355A1 - Azacycle amide derivative, preparation methods and medicinal uses thereof

Info

Publication number: WO2023143355A1
Application number: PCT/CN2023/073091
Authority: WO
Inventors: Gang Liu; Hugh Y. Zhu; Avinash KHANNA
Original assignee: Hansoh Bio Llc; Shanghai Hansoh Biomedical Co., Ltd.; Jiangsu Hansoh Pharmaceutical Group Co., Ltd.
Priority date: 2022-01-28
Filing date: 2023-01-19
Publication date: 2023-08-03

Abstract

The present invention provide compounds of formula (I-a), the preparation method thereof, pharmaceutcal compositions comprising the compounds, and the pharmaceutical uses for the treatment of cancer, autoimmune diseases, inflammatory disorders, or fibrosis.

Description

AZACYCLE AMIDE DERIVATIVE, PREPARATION METHODS AND MEDICINAL USES THEREOF

FIELD OF THE INVENTION

The present invention belongs to the field of medicine, and relates to azacycle amide derivative, preparation methods thereof, pharmaceutical compositions comprising the compounds, and medical uses thereof.

BACKGROUD OF THE INVENTION

Bruton's tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine kinases that is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. The function of BTK in signaling pathways activated by the engagement of the B cell receptor (BCR) and FCεR1 on mast cells is well established. BTK is a key enzyme in BCR activation and plays a critical role in the maturation of B cells in bone marrow and in lymphoid tissues. Functional mutations in BTK in human result in a primary immunodeficiency disease (X-linked agammaglobulinemia, XLA) characterized by a defect in B cell development with a block between pro-and pre-B cell stages. The result is an almost complete absence of B lymphocytes, causing a pronounced reduction of serum immunoglobulin of all classes. Furthermore, engagement of the BCR induces signaling through BTK and its downstream substrate PLCγ2, which activates the NFκB, a transcription factor that is essential for the development of innate and adaptive immune responses. BTK protein and mRNA are significantly over expressed in chronic lymphocytic leukemia (CLL) compared with normal B-cells. Although BTK is not always constitutively active in CLL cells, B-cell receptor (BCR) or CD40 signaling is accompanied by effective activation of this pathway. Other diseases with an important role for dysfunctional B cells are B cell malignancies, such as Non-Hodgkin's Lymphomas, such as chronic lymphocytic leukemia (CLL) , mantle cell leukemia (MCL) , follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) , and multiple myeloma (MM) .

The reported role of BTK in BCR signaling, and in the regulation of proliferation and apoptosis of B cells, indicates the potential for BTK inhibitors in the treatment of B cell lymphomas.

Ibrutinib (ibr) , the first inhibitor of BTK, was approved by the US Food and Drug Administration (FDA) in 2013, has long been used to treat B-cell malignancies such as MCL, CLL, and has demonstrated high response rates in both relapsed/refractory and treatment naive CLL. However, in some cases, for example, mutations of BTK can lead to ibrutinib-resistant diseases ibrutinib treatment is discontinued due to progression of leukemia, or Richter Transformation (progression of CLL into an aggressive form of tumor with poor prognosis) . Mutations within the kinase domain of BTK (e.g., at C481) disrupt ibrutinib binding and are the most common mechanism of ibrutinib resistance. Further Btk inhibitors are disclosed in WO2017103611, WO 2013010136, US 9090621, WO 2015127310, WO 2015095099 and US 2014221333.

This suggests that new inhibitors and/or alternative therapeutic targets are needed. Loxo 305, an oral BTK inhibitor, is currently in Phase 1/2. A phase 1 trial of the next-generation Bruton tyrosine kinase (BTK) inhibitor LOXO-305 has demonstrated safety and provided evidence of its efficacy in heavily pretreated patients with B-cell malignancies, including some with acquired resistance to other BTK inhibitors and venetoclax. LOXO-305 is designed to non-covalently bind to BTK, regardless of C481 status. However, LOXO-305 has less than ideal solubility. Thus, there is an urgent need in the art for new generation BTK inhibitors.

SUMMARY OF THE INVENTION

The present invention, in one aspect, provides a compound of formula (I-a) :

or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

wherein:

A is 5-10 membered heterocyclyl or 5-10 membered heteroaryl;

L is bond, NH, O or S;

R₁ is independently selected from the group consisting of hydrogen, deuterium, oxo, halogen, amino, cyano, hydroxy, alkyl, alkylamino, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylamino, heterocyclylamino, arylamino, heteroarylamino, - (CHR_a) _nS (O) ₂R_b, - (CHR_a) _nC (O) R_b, - (CHR_a) _nNR_bR_c and - (CHR_a) _nC (O) NR_bR_c, wherein each of the alkyl, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylamino, heterocyclylamino, arylamino and heteroarylamino at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH₂) _mNR_dR_e, - (CH₂) _mOR_d,

- (CH₂) _mC (O) R_d and - (CH₂) _mC (O) NR_dR_e;

R_a is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy and deuteroalkyl;

R_b and R_c are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein each of the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

or, R_b and R_c are together with the N atom to which they are bound form heterocyclyl, wherein the heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

R_d and R_e are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein each of the cycloalkyl and heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl and hydroxyalkyl;

R₂ is selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₃ is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₄ and R₅ are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl;

x is 0, 1, 2 or 3;

y is 0, 1, 2 or 3;

z is 1, 2, 3 or 4,

m is 0, 1, 2, 3 or 4; and

n is 0, 1, 2, 3 or 4.

In some embodiments, the present invention provides a compound of formula (I-a) :

wherein:

A is 5-10 membered heterocyclyl or 5-10 membered heteroaryl;

L is bond, NH, O or S;

R₁ is independently selected from the group consisting of hydrogen, deuterium, oxo, halogen, amino, cyano, hydroxy, alkyl, alkylamino, alkoxy, haloalkyl, hydroxyalkyl, halohydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylamino, heterocyclylamino, arylamino, heteroarylamino, - (CHR_a) _nS (O) ₂R_b, - (CHR_a) _nC (O) R_b, - (CHR_a) _nNR_bR_c and - (CHR_a) _nC (O) NR_bR_c, wherein each of the alkyl, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylamino, heterocyclylamino, arylamino and heteroarylamino at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH₂) _mNR_dR_e, - (CH₂) _mOR_d, - (CH₂) _mC (O) R_d and - (CH₂) _mC (O) NR_dR_e;

R_a is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, halohydroxyalkyl, deuteroalkoxy and deuteroalkyl;

R₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyloxy;

x is 0, 1, 2 or 3;

y is 0, 1, 2 or 3;

z is 1, 2, 3 or 4,

m is 0, 1, 2, 3 or 4; and

n is 0, 1, 2, 3 or 4.

In some embodiments, A is

is a single bond or a double bond;

thesymbol indicates the point of attachment to L;

M₁, M₃ and M₄ are independently selected from O, S, –CR_a-, C (O) , –NR_a-and –N-;

M₂ and M₅ are independently selected from absent, O, S, –CR_a-, C (O) , –NR_a-and –N-;

M₆, M₇, M₈ and M₉ are independently selected from absent, CH₂, CH, NH, N and O, wherein CH₂, CH and NH is independently unsubstituted or substituted by R₁;

when one of M₆, M₇, M₈ and M₉ is absent, the others are absent.

In some embodiments, R_a is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy and deuteroalkyl, wherein the hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

In some embodiments, at most one of M₂ and M₅ is absent.

In some embodiments, wherein, A is 5-6 membered aryl or heteroaryl.

In some embodiments, wherein, A is
thesymbol indicates the point of attachment to L.

In some embodiments, L is NH.

In some embodiments, the compound of formula (I-a) being a compound of formula (I) , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, including tautomers, cis-or trans-isomers, mesomers, racemates, enantiomers, diastereomers, and mixtures thereof:

wherein:

M₁ and M₂ are independently selected from –CR_a-and –N-;

R₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkylamino, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, - (CHR_a) _nS (O) ₂R_b, - (CHR_a) _nC (O) R_b, - (CHR_a) _nNR_bR_c and - (CHR_a) _nC (O) NR_bR_c, wherein each of the alkyl, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH₂) _mNR_dR_e, - (CH₂) _mOR_d, - (CH₂) _mC (O) R_d and - (CH₂) _mC (O) NR_dR_e;

x is 0, 1, 2 or 3;

y is 0, 1, 2 or 3;

z is 1, 2, 3 or 4,

m is 0, 1, 2, 3 or 4; and

n is 0, 1, 2, 3 or 4.

In some embodiments, R_a is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, halohydroxyalkyl, deuteroalkoxy and deuteroalkyl, wherein the hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

In some embodiments, the compound of formula (I-a) being a compound of formula (II) , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, including tautomers, cis-or trans-isomers, mesomers, racemates, enantiomers, diastereomers, and mixtures thereof:

wherein,

R₈ is hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the C_3-8 cycloalkyl and 4-8 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

B is C_3-8 cycloalkyl or 4-9 membered heterocyclyl; optionally, unsubstituted or substituted with one or more substituents;

L₁ is bond, - (CH₂) _n-, -CHR_f-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

R_f is R_aa, –C (O) NR_aaR_bb, –NC (O) R_aa or NR_aaR_bb,

R_aa and R_bb are independently selected from hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl; or, R_aa and R_bb with the N atom to which they are bound form 4-8 membered heterocyclyl, optionally, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl and C_1-6 hydroxyalkyl;

A, R₂, R₃, R₄, R₅, R₆, n, y and z are defined as formula (I-a) .

In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, including tautomers, cis-or trans-isomers, mesomers, racemates, enantiomers, diastereomers, and mixtures thereof:

wherein,

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

B is C_3-8 cycloalkyl or 4-8 membered heterocyclyl; optionally, unsubstituted or substituted with one or more substituents;

L₁ is bond, - (CH₂) _n-, -CHR_f-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

R_f is R_aa, –C (O) NR_aaR_bb, –NC (O) R_aa or NR_aaR_bb,

A, R₂, R₃, R₄, R₅, R₆, n, y and z are defined as formula (I-a) .

In some embodiments, B is C_3-8 cycloalkyl or 4-9 membered heterocyclyl containing 1, 2 or 3 of heteroatoms selected from N, O or S (O) ₂, optionally, B is unsubstituted or substituted with one or more substituents selected from the group of hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl;

In some embodiments, B is:
optionally, B is unsubstituted or substituted with one or more substituents selected from the group of hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl.

In some embodiments, R_a is hydrogen, deuterium and halogen.

In some embodiments, M₁ and M₂ are independently selected from –CH-and –N-;

In some embodiments, R₁ is independently selected from hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkylamino, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 deuteroalkoxy, C_1-6 deuteroalkyl, -C_0-6 alkyl (C_3-8 cycloalkyl) , -C_0-6 alkyl (4-10 membered heterocyclyl) , -C_0-6 alkyl (C_6-10 aryl) , -C_0-6 alkyl (5-10 membered heteroaryl) , -S (O) ₂R_b, -C (O) R_b, - (CH₂) _nNR_bR_c and -C (O) NR_bR_c, wherein each of the C_1-6 alkyl, C_1-6 alkylamino, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 deuteroalkoxy, C_1-6 deuteroalkyl, -C_0-6 alkyl (C_3-8 cycloalkyl) , -C_0-6 alkyl (4-10 membered heterocyclyl) , -C_0-6 alkyl (C_6-10 aryl) and –C_0-6 alkyl (5-10 membered heteroaryl) at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl, 4-10 membered heterocyclyl, - (CH₂) _nNR_dR_e, - (CH₂) _nOR_d, -C (O) R_d and -C (O) NR_dR_e;

R_b and R_c are independently selected from the group consisting of hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-10 membered heterocyclyl, wherein each of the C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-10 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-10 membered heterocyclyl;

or, R_b and R_c are together with the N atom to which they are bound form 4-10 heterocyclyl, wherein the 4-10 heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl and C_1-6 hydroxyalkyl;

R_d and R_e are independently selected from the group consisting of hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-10 membered heterocyclyl, wherein each of the C_3-8 cycloalkyl and 4-10 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl and C_1-6 hydroxyalkyl.

In some embodiments, R₁ is independently selected from C_1-6 alkyl, -C_0-3 alkyl (C_3-6 cycloalkyl) , -C_0-3 alkyl (4-8 membered heterocyclyl) , -S (O) ₂R_b, - (CH₂) _nNR_bR_c and -C (O) NR_bR_c; wherein each of the -C_0-3 alkyl (C_3-6 cycloalkyl) and -C_0-3 alkyl (4-8 membered heterocyclyl) at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, - (CH₂) _nOR_d and -C (O) R_d;

or, R_b and R_c are together with the N atom to which they are bound form 4-6 membered heterocyclyl containing 1, 2 or 3 of heteroatoms selected from N or O, wherein the heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl and C_1-6 hydroxyalkyl;

R_d is independently selected from the group consisting of hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, wherein the cycloalkyl and heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl.

In some embodiments, R₁ is independently selected from -C_0-3 alkyl (C_3-6 cycloalkyl) and-C_0-3 alkyl (4-8 membered heterocyclyl containing 1, 2 or 3 of heteroatoms selected from N or O) , optionally, R₁ is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, - (CH₂) _nOR_d and -C (O) R_d;

R_d is independently selected from the group consisting of hydrogen, deuterium, halogen, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, wherein the cycloalkyl and heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl.

In some embodiments, R₁ is:
andoptionally, R₁ is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, - (CH₂) _nOC_1-3 alkyl and -C (O) C_1-3 alkyl.

In some embodiments, R₁ is hydrogen, halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl.

In some embodiments, R₁ is:
andoptionally, R₁ is unsubstituted or substituted with one or more substituents selected from the group consisting of -F, -Cl, -Br, -CN, -CH₃, -CH₂CH₃, -CH (CH₃) ₂, -CF₃, -CH₂F, -CH₂CH₂F, -CH₂CF₃, - (CH₂) ₂OCH₃, and

In some embodiments, R₂ is selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy and C₁-C₃ hydroxyalkyl.

In some embodiments, R₂ is hydrogen or deuterium.

In some embodiments, R₃ is hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl and C₁-C₃ hydroxyalkyl.

In some embodiments, R₄ and R₅ are independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl and C₁-C₃ hydroxyalkyl.

In some embodiments, R₄ and R₅ are hydrogen.

In some embodiments, R₆ is independently selected from the group consisting of hydrogen, halogen, C₁-C₃ alkyl and C₁-C₃ alkoxy.

In some embodiments, R₆ is independently selected from the group consisting of H, F, Cl, CH₃, OCH₃, OCD₃ and

In some embodiments, R₆ is independently selected from the group consisting of H, F and OCH₃.

In some embodiments, the compound of formula (I-a) being a compound of formula (II-a) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein,

R₇ is independently selected from the group consisting of hydrogen, oxo, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl and C_1-6 alkoxy;

R₈ is selected from the group consisting of hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

X₁ is N or CH;

X₂ is O, S, S (O) ₂, N or CH, when X₂ is O, S, or S (O) ₂, L₂ and R₈ are absent;

L₁ is bond, - (CH₂) _n-, -CHR_f-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

R_f is R_aa, –C (O) NR_aaR_bb, –NC (O) R_aa or NR_aaR_bb,

R_aa and R_bb are independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl;

or, R_aa and R_bb with the N atom to which they are bound form 4-6 membered heterocyclyl, optionally, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

M₁ and M₄ are independently selected from the group consisting of O, S, CR_a, C (O) , NR_a and N;

M₃ is C or N;

M₂ and M₅ are independently selected from the group consisting of absent, O, S, CR_a, C (O) , NR_aand N;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2;

R_a, R₂, R₃, R₄, R₅, R₆, n, y and z are defined as formula (I) .

wherein,

R₇ is independently selected from the group consisting of hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl and C_1-6 alkoxy;

R₈ is hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_3-8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the C_3-8 cycloalkyl and 4-8 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

X₁ is N or CH;

X₂ is O, N or CH, when X₂ is O, L₂ and R₈ are absent;

L₁ is bond, - (CH₂) _n-, -CHR_f-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

R_f is R_aa, –C (O) NR_aaR_bb, –NC (O) R_aa or NR_aaR_bb,

R_aa and R_bb are independently selected from hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl; or, R_aa and R_bb with the N atom to which they are bound form 4-6 membered heterocyclyl, optionally, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

M₁ and M₄ are independently selected from O, S, –CR_a-, C (O) , –NR_a-and –N-;

M₃ is C or N;

M₂ and M₅ are independently selected from absent, O, S, –CR_a-, C (O) , –NR_a-and –N-, at most one of M₂ and M₅ is absent;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2;

R₂, R₃, R₄, R₅, R₆, n, y and z are defined as formula (I-a) .

In some embodiments, the compound of formula (I-a) being a compound of formula (II-a-1) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein,

M₁, M_2, M_3, M₄ and M₅ are independently selected from the group consisting of N or CR^a;

R^a is independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, hydroxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_1-6 deuteroalkoxy and C_1-6 deuteroalkyl, wherein C_1-6 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl, C_4-7 heterocyclyl, C_6-12 aryl, and C_5-6 heteroaryl;

X₁ is N, C, or CH;

X₂ is N, C, or CH;

each of X₃ and X₄ is independently selected from the group consisting of bond, NR_a, CR_a or C (R_a) ₂;

R₃ is hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; R₄, and R₅ are selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₁-C₆ hydroxyalkyl;

R₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkoxy;

R₇ is independently selected from the group consisting of hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl and C_1-3 alkoxy;

or, two of R₇ are together with the atom to which they are bound form 3-6 cycloalkyl or 4-7 heterocyclyl, wherein 3-6 cycloalkyl or 4-7 heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

R₈ is hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of the C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_3-6 cycloalkyl and 4-6 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

p is 1, 2 or 3;

y is 1, 2 or 3;

z is 1, 2 or 3.

In some embodiments, the compound of formula (I-a) being a compound of formula (II-a-2) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein,

X₁ is N or CH;

X₂ is N or CH;

R₈ is hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of the C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_3-6 cycloalkyl and 4-6 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

p is 1, 2 or 3;

y is 1, 2 or 3;

z is 1, 2 or 3.

In some embodiments, the compound of formula (II-a) being a compound of formula (II-a-1) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

In some embodiments, for the formula (II-a-1) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

L₁ is bond, NH, O or -CHR_f-;

R_a is hydrogen, deuterium, halogen or C_1-3 alkyl;

M₁, M₂, M₃, M₄, M₅, R₇, s and t are defined as formula (II-a) .

In some embodiments, the compound of formula (I-a) being a compound of formula (II-b) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein,

M₁ is O, S, –CR_a-, C (O) , –NR_a-or –N-;

M₃ and M₄ are independently selected from C and N;

M₆, M₇, M₈ and M₉ are independently selected from absent, CH₂, CH, NH, N and O;

R₁, R₂, R₃, R₄, R₅, R₆, x, y and z are defined as formula (I-a) .

In some embodiments, the compound of formula (II-b) being a compound of formula (II-b-1) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

M₁ is O, S, –CR_a-, C (O) , –NR_a-or –N-;

R_a is hydrogen, deuterium, halogen or C_1-3 alkyl;

M₃ and M₄ are independently selected from C and N;

R₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy and C₁-C₃ hydroxyalkyl.

In some embodiments, the compound of formula (I) being a compound of formula (II-c) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein,

L₁ is bond, - (CH₂) _n-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

X₁ is N or CH;

X₂ is O, N or CH, when X₂ is O, L₂ and R₈ are absent;

R₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy and C₁-C₃ hydroxyalkyl;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

x is 0, 1 or 2;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2;

M₁, M₂, R₂, R₃, R₄, R₅, R₆, n, y and z are defined in formula (I) .

In some embodiments, the compound of formula (II-c) being a compound of formula (III-a) - (III-d) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

In some embodiments, for the compound of formula (III-a) or (III-b) , wherein:

M₁ is –CR^a-or –N-;

M₂ is –CR^a-or –N-;

R^a is hydrogen, deuterium, halogen or C_1-3 alkyl;

L₁ is bond, - (CH₂) _n-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

X₁ is N or CH;

X₂ is O, N or CH, when X₂ is O, L₂ and R₈ are absent;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

R₈ is hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_3-6cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, wherein each of the C_3-6 cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

n is 1, 2 or 3;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2.

In some embodiments, for the compound of formula (III-a) - (III-d) , wherein:

M₁ is –CH-or –N-;

M₂ is –CH-or –N-;

R_a is hydrogen, deuterium, halogen or C_1-3 alkyl;

L₁ is bond, - (CH₂) _n-, O, -C (O) -, -NHC (O) -or –C (O) NH-;

X₁ is N or CH;

X₂ is O, N or CH, when X₂ is O, L₂ and R₈ are absent;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

n is 1, 2 or 3;

x is 0, 1 or 2;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2.

In some embodiments, for the compound of formula (III-a) - (III-d) , wherein:

M₁ is –CR^a-or –N-;

M₂ is –CR^a-or –N-;

R^a is hydrogen, deuterium, halogen or C_1-3 alkyl;

L₁ is bond, - (CH₂) _n-, -C (O) -, -O-, -NHC (O) -or –C (O) NH-;

X₁ is N or CH;

X₂ is O, N or CH, when X₂ is O, L₂ and R₈ are absent;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

R₈ is selected from the group consisting of hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_1-3 hydroxyalkyl, C_3-6cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, wherein each of the C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

n is 1, 2 or 3;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2.

In some embodiments, R^a is independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, hydroxy, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_1-3 hydroxyalkyl, C_1-3 deuteroalkoxy and C_1-3 deuteroalkyl, wherein C_1-3 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-3 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl, and C_4-6 heterocyclyl.

In some embodiments, R^a independently selected from the group consisting of hydrogen, deuterium, halogen, and C_1-3 hydroxyalkyl, wherein the C_1-3 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-3 alkyl, C_2-4 alkenyl and C_3-6 cycloalkyl.

In some embodiments, R^a independently selected from the group consisting of hydrogen, deuterium, halogen, and C_1-3 hydroxyalkyl.

In some embodiments, the compound of formula (II-c) being a compound of (III-b-1) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

M₁ is –CH-or –N-;

M₂ is –CH-or –N-;

R^a is hydrogen, deuterium, halogen, C_1-3 alkyl C_1-3 haloalkyl, C_1-3 alkoxy, C_1-3 hydroxyalkyl, C_1-3 deuteroalkoxy and C_1-3 deuteroalkyl, wherein the C_1-3 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-3 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl, and C_4-6 heterocyclyl;

X₁ is N or CH;

X₂ is N or CH;

R₈ is C_3-6 cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, wherein each of the C_3-6 cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

x is 0, 1 or 2;

p is 1, 2 or 3.

In some embodiments, the compound of formula (I) being a compound of (IV) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wheein,

R_e is independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, or 4-8 membered heterocyclyl;

L₁ is bond, - (CH₂) _n-, -CHR_f-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

R_f is R_aa, –C (O) NR_aaR_bb, –NC (O) R_aa or NR_aaR_bb,

R_aa and R_bb are independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl;

X₁ is N or CH;

n is 0, 1, 2, 3 or 4;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2;

z is 0 or 1.

In some embodiments, the compound of formula (I) being a compound of (V) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wheein,

L₁ is bond, - (CH₂) _n-, -CHR_f-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

R_f is R_aa, –C (O) NR_aaR_bb, –NC (O) R_aa or NR_aaR_bb,

X₁ is N or CH;

n is 0, 1, 2, 3 or 4;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2;

z is 0 or 1.

In some embodiments, for the compound of formula (IV) , wherein:

M₁ is –CR^a-or –N-;

R^a is hydrogen, deuterium, halogen, C_1-3 alkyl or C_1-3 hydroxyalkyl;

L₁ is bond, - (CH₂) _n-, -C (O) -, -O-, -NHC (O) -or –C (O) NH-;

X₁ is N or CH;

X₂ is O, N or CH, when X₂ is O, L₂ and R₈ are absent;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

n is 1, 2 or 3;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2.

In some embodiments, for the compound of formula (IV) or formula (V) , wherein:

R_e is independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, or C₃-C₆ cycloalkyl;

M₁ is -CR^a-or –N-, preferable, M₁ is -CR^a-;

R^a is hydrogen, deuterium, halogen, C_1-3 alkyl or C_1-3 hydroxyalkyl, wherein the C_1-3 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, and C_3-6 cycloalkyl;

L₁ is bond, - (CH₂) _n-, -C (O) -, -O-, -NHC (O) -or –C (O) NH-, preferable, L₁ is bond;

X₁ is N or CH;

X₂ is O, N or CH, when X₂ is O, L₂ and R₈ are absent;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-, preferable, L₂ is bond or - (CH₂) _n-;

n is 1, 2 or 3;

p is 1, 2 or 3;

s is 1;

t is 1.

In some embodiments, for the compound of formula (IV) or formula (V) , wherein:

M₁ is -CR^a-;

R^a is hydrogen, deuterium, halogen, C_1-3 alkyl or C_1-3 hydroxyalkyl, wherein the C_1-3 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-3 alkyl, and C_3-6 cycloalkyl;

L₁ is bond;

X₁ is N or CH;

X₂ is N or CH;

L₂ is bond, or - (CH₂) _n-;

R₈ is selected from the group consisting of hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, and C_1-3 hydroxyalkyl;

n is 1, 2 or 3;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2.

In some embodiments, for the compound of formula (IV) or formula (V) , being a compound of (IV-a) , (IV-b) , (V-a) , or formula (V-b) , or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

The present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of any formula, or a tautomer, cis-or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

In an embodiment, the amount of the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salts thereof, is about 0.1-99%, 1-94.5%, 2-89.5%, 5-74.5%, 10-49.5%, 10.1-49%, 10.2-48.5%, 10.3-48%, 10.4-47.5%, 10.5-47%, 10.6-46.5%, 10.7-46%, 10.8-45.5%, 10.9-45%, 11-44.5%, 11.1-44%, 11.2-43.5%, 11.3-43%, 11.4-42.5%, 11.5-42%, 11.6-41.5%, 11.7-41%, 11.8-40.5%, 11.9-40%, 12-39.5%, 12.1-39%, 12.2-38.5%, 12.3-38%, 12.4-37.5%, 12.5-37%, 12.6-36.5%, 12.7-36%, 12.8-35.5%, 12.9-35%, 13-34.5%, 13.1-34%, 13.2-33.5%, 13.3-33%, 13.4-32.5%, 13.5-32%, 13.6-31.5%, 13.7-31%, 13.8-30.5%, 13.9-30%, 14-29.5%, 14.1-29%, 14.2-28.5%, 14.3-28%, 14.4-27.5%, 14.5-27%, 14.6-26.5%, 14.7-26%, 14.8-25.5%, 14.9-25%, 15-24.5%, 15.1-24%, 15.2-23.5%, 15.3-23%, 15.4-22.5%, 15.5-22%, 15.6-21.5%, 15.7-21%, 15.8-20.5%, 15.9-20%, 16-19.5%, or 16.5-17%by weight of free base. In an embodiment, the unit dosage of the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salts thereof, is 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000m by weight of free base.

In another aspect, the present invention relates to a method for treatment of a condition which is modulated by Bruton's tyrosine kinase (BTK) comprising administering a therapeutically effective amount of a compound any formula or a pharmaceutical composition comprising the same. Usually conditions that are modulated by BTK are conditions that would be treated by the inhibition of BTK using a compound of the present invention. A compound of any formula disclosed herein may be for use in the treatment of a condition treatable by the inhibition of BTK.

In another aspect, the present invention relates to a method for treatment of a condition selected from solid cancer, lymphoma, leukemia, autoimmune diseases, inflammatory disorders, or fibrosis comprising administering a therapeutically effective amount of a compound any formula or a pharmaceutical composition comprising the same.

In an embodiment the method may be for treating a specific condition selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, small lymphocytic lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, Sjogren's syndrome and disorders associated with renal transplant.

In another aspect, the present invention relates to a method for preparing a compound of formula (III-b) , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by comprising the following step:

reacting the compound of formula (b) with (a) to obtain the compound of formula (c) , and formula (III-b) is obtained by hydrolysis reaction;

wherein,

X is halogen,

M₁, M₂, X₁, X₂, L₁, L₂, R₇, R₈, s, t and x are defined as formula (III-b) .

DETAILED DESCRIPTION OF THE INVENTION

Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term. “Alkyl” refers to a saturated aliphatic hydrocarbon group including C₁-C₂₀ straight chain and branched chain groups. Preferably an alkyl group is an alkyl having 1 to 12, sometimes preferably 1 to 6, sometimes more preferably 1 to 4, carbon atoms. Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2, 2-dimethylpentyl, 3, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2, 2-dimethylhexyl, 3, 3-dimethylhexyl, 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 2-diethylpentyl, n-decyl, 3, 3-diethylhexyl, 2, 2-diethylhexyl, and the isomers of branched chain thereof. More preferably an alkyl group is a lower alkyl having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group (s) can be substituted at any available connection point, preferably the substituent group (s) is one or more substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.

“Alkenyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc., preferably C_2-20 alkenyl, more preferably C_2-12 alkenyl, and most preferably C_2-6 alkenyl. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.

“Alkynyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl etc., preferably C_2-20 alkynyl, more preferably C_2-12 alkynyl, and most preferably C_2-6 alkynyl. The alkynyl group can be substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

“Alkylene” refers to a saturated linear or branched aliphatic hydrocarbon group, wherein having 2 residues derived by removing two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms. The straight or branched chain group containing 1 to 20 carbon atoms, preferably has 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH₂-) , 1, 1-ethylene (-CH (CH₃) -) , 1, 2-ethylene (-CH₂CH₂) -, 1, 1-propylene (-CH (CH₂CH₃) -) , 1, 2-propylene (-CH₂CH (CH₃) -) , 1, 3-propylene (-CH₂CH₂CH₂-) , 1, 4-butylidene (-CH₂CH₂CH₂CH₂-) etc. The alkylene group can be substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

“Alkenylene” refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C_2-20 alkenylene, more preferably C_2-12 alkenylene, and most preferably C_2-6 alkenylene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH₂-, -CH=CHCH₂CH₂-, -CH₂CH=CHCH₂-etc. The alkenylene group can be substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

“Alkynylene” refers to an alkynyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, preferably C_2-20 alkynylene, more preferably C_2-12 alkynylene, and most preferably C_2-6 alkynylene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH≡CH-, -CH≡CHCH₂-, -CH≡CHCH₂CH₂-, -CH₂CH≡CHCH₂-etc. The alkynylene group can be substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

“Cycloalkyl” refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.

“Spiro Cycloalkyl” refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom) , wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably a spiro cycloalkyl is 6 to 14 membered, and more preferably 7 to 10 membered. According to the number of common spiro atoms, a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl. Representative examples of spiro cycloalkyl include, but are not limited to the following substituents:
and

“Fused Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, a fused cycloalkyl group is 6 to 14 membered, more preferably 7 to 10 membered. According to the number of membered rings, fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and preferably refers to a bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyls include, but are not limited to, the following substituents:
and

“Bridged Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings can have one or more double bonds, but have no completely conjugated pi-electron system. Preferably, a bridged cycloalkyl is 6 to 14 membered, and more preferably 7 to 10 membered. According to the number of membered rings, bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents:
and

The cycloalkyl can be fused to the ring of an aryl, heteroaryl or heterocyclic alkyl, wherein the ring bound to the parent structure is cycloalkyl. Representative examples include, but are not limited to indanylacetic, tetrahydronaphthalene, benzocycloheptyl and so on. The cycloalkyl is optionally substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.

“Heterocyclyl” refers to a 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) _m (wherein m is 0, 1, or 2) as ring atoms, but excluding -O-O-, -O-S- or -S-S- in the ring, the remaining ring atoms being C. Preferably, heterocyclyl is a 3 to 12 membered having 1 to 4 heteroatoms; more preferably a 3 to 10 membered having 1 to 3 heteroatoms; more preferably a 4 to 8 membered having 1 to 3 heteroatoms; most preferably a 5 to 6 membered having 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, azabutyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and so on. Polycyclic heterocyclyl includes the heterocyclyl having a spiro ring, fused ring or bridged ring.

“Spiro heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom) , wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) _m (wherein m is 0,1 or 2) as ring atoms, the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably a spiro heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered. According to the number of common spiro atoms, spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl. Representative examples of spiro heterocyclyl include, but are not limited to the following substituents:
and

“Fused Heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with the other ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) _p (wherein p is 0, 1, or 2) as ring atoms, the remaining ring atoms being C. Preferably a fused heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered. According to the number of membered rings, fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably refers to bicyclic or tricyclic fused heterocyclyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocyclyl include, but are not limited to, the following substituents:
and

“Bridged Heterocyclyl” refers to a 5 to 14 membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, the rings can have one or more double bonds, but have no completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O, and S (O) _m (wherein m is 0, 1, or 2) as ring atoms, the remaining ring atoms being C. Preferably a bridged heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered. According to the number of membered rings, bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to, the following substituents:
and

The ring of said heterocyclyl can be fused to the ring of an aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl. Representative examples include, but are not limited to the following substituents:
andetc.

The heterocyclyl is optionally substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio.

“Aryl” refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi-electron system. Preferably aryl is 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl can be fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl. Representative examples include, but are not limited to, the following substituents:
and

The aryl group can be substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

“Heteroaryl” refers to an aryl system having 1 to 4 heteroatoms selected from the group consisting of O, S and N as ring atoms and having 5 to 14 annular atoms. Preferably a heteroaryl is 5-to 10-membered, more preferably 5-or 6-membered, for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. Representative examples include, but are not limited to, the following substituents:
and

The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio and -NR⁹R¹⁰.

“Alkoxy” refers to both an -O- (alkyl) and an -O- (unsubstituted cycloalkyl) group, wherein the alkyl is defined as above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxyl can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

“Bond” refers to a covalent bond using a sign of “-” .

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

“Hydroxy” refers to an -OH group.

“Halogen” refers to fluoro, chloro, bromo or iodo atoms.

“Amino” refers to a -NH₂ group.

“Cyano” refers to a -CN group.

“Nitro” refers to a -NO₂ group.

“Oxo group” refers to a =O group.

“Carboxyl” refers to a -C (O) OH group.

“Alkoxycarbonyl” refers to a -C (O) O (alkyl) or (cycloalkyl) group, wherein the alkyl and cycloalkyl are defined as above.

“Optional” or “optionally” means that the event or circumstance described subsequently can, but need not, occur, and the description includes the instances in which the event or circumstance may or may not occur. For example, “the heterocyclic group optionally substituted by an alkyl” means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.

“Substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. It goes without saying that the substituents exist in their only possible chemical position. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.

A “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity.

“Pharmaceutically acceptable salts” refer to salts of the compounds of the invention, such salts being safe and effective when used in a mammal and have corresponding biological activity.

EXAMPLES

The following examples serve to illustrate the invention, but the examples should not be considered as limiting the scope of the invention. If specific conditions for the experimental method are not specified in the examples of the present invention, they are generally in accordance with conventional conditions or recommended conditions of the raw materials and the product manufacturer. The reagents without a specific source indicated are commercially available, conventional reagents.

The structure of each compound was identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS) . NMR chemical shifts (δ) were given in 10^-6 (ppm) . NMR was determined by Varian Mercury 300 MHz, Bruker Avance III 400MHz machine. The solvents used were deuterated-dimethyl sulfoxide (DMSO-d₆) , deuterated-chloroform (CDCl₃) and deuterated-methanol (CD₃OD) .

High performance liquid chromatography (HPLC) was determined on an Agilent 1200DAD high pressure liquid chromatography spectrometer (Sunfire C18 150×4.6 mm chromatographic column) and a Waters 2695-2996 high pressure liquid chromatography spectrometer (Gimini C18 150×4.6 mm chromatographic column) .

Chiral High performance liquid chromatography (HPLC) is determined on SFC Thar 80 (waters. )

MS is determined by a SHIMADZU (ESI) liquid chromatography-mass spectrometer (manufacturer: Shimadzu, type: LC-20AD, LCMS-2020) .

The average rates of kinase inhibition, and the IC₅₀ values were determined by Victor Nivo multimode plate reader (PerkinElmer, USA) .

The thin-layer silica gel plates used in thin-layer chromatography were Yantai Xinnuo silica gel plate. The dimension of the plates used in TLC was 0.15 mm to 0.2 mm, and the dimension of the plates used in thin-layer chromatography for product purification was 0.4 mm to 0.5 mm.

Column chromatography generally used Qingdao Haiyang 200 to 300 mesh silica gel as carrier.

The known starting material of the invention can be prepared by the conventional synthesis method in the prior art, or can be purchased from ABCR GmbH &Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari chemical Company, etc.

Unless otherwise stated in the examples, the following reactions were placed under argon atmosphere or nitrogen atmosphere.

The term “argon atmosphere” or “nitrogen atmosphere” means that a reaction flask was equipped with a balloon having 1 L of argon or nitrogen.

The term “hydrogen atmosphere” means that a reaction flask was equipped with a balloon having 1 L of hydrogen.

MS is mass spectroscopy with (+) referring to the positive mode which generally gives a M+1 (or M+H) absorption where M = the molecular mass.

EXAMPLES

INTERMEDIATE

INT1: Methyl 3-bromo-1- (4-cyanophenyl) -4-iodo-1H-pyrazole-5-carboxylate

Step 1. (Z) -2- (2- (4-Cyanophenyl) hydrazineylidene) acetic acid, INT1-1.

To a solution of 4-hydrazineylbenzonitrile hydrochloride (100 g, 0.59 mol) in aqueous hydrochloric acid (20%, 590 mL) was carefully added a solution of glyoxylic acid solution, (50 wt. %in H₂O, 118 mL, mol) and the resultant mixture stirred at room temperature for 16 h. The solids were collected by vacuum filtration, rinsed with H₂O and dried. The crude product was recrystallized from acetonitrile to provide INT1-1 (92.0 g, 82%) as a yellow solid.

C₉H₇N₃O₂ Calc (M+H) ⁺: 190.0 m/z, ESI-MS (M+H) ⁺: 190.1 m/z.

Step 2. (4-Cyanophenyl) carbonohydrazonic dibromide, INT1-2.

To a solution of INT1-1 (92.0 g, 0.49 mol) in DCM (1 L) at 0 ℃ was added NBS (173 g, 0.97 mol) portionwise. under N₂. The reaction mixture stirred at room temperature for 2h and was then washed with saturated aqueous sodium thiosulfate (1 x 500 mL) . The organic phase was dried over Na2SO4, filtered, and then used immediately in the next step without further concentration, purification or analysis.

Step 3. Methyl 3-bromo-1- (4-cyanophenyl) -1H-pyrazole-5-carboxylate, INT1-3.

The filtrate containing INT1-2 was diluted with DMF (1 L) . To this solution under N₂ was added DIPEA (62.8 g, 0.49 mol) , followed by dropwise addition of methyl propiolate (205 g, 2.43 mol) . The resultant mixture stirred at room temperature for 2 h. The solids were collected by vacuum filtration, washed with DCM (3 x 100 mL) and dried under vacuum to provide INT1-3 (60.0 g, 40%as a grey solid, which was used in the next step without further purification.

C₁₂H₈BrN₃O₂ Calc (M+H) ⁺: 306.0, 308.0 m/z, ESI-MS (M+H) ⁺: 305.8, 307.8 m/z.

Step 4. Methyl 3-bromo-1- (4-cyanophenyl) -4-iodo-1H-pyrazole-5-carboxylate, INT1

A solution of INT1-3 (1.00 g, 3.27 mmol) and NIS (808 mg, 3.59 mmol) in TFA (20 mL) was stirred at room temperature for 3 h. The reaction mixture was carefully diluted with H₂O (5 mL) and the mixture concentrated in vacuo. The residue obtained was dissolved in EtOAc (20 mL) and the organic solution successively washed with saturated aqueous NaHCO₃ (20 mL) and brine (50 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified by FCC on silica gel (DCM: EA=80: 1) to provide INT1 (530 mg, 38%) as a yellow solid.

C₁₂H₇BrIN₃O₂ Calc (M+H) ⁺: 431.9, 433.9 m/z, ESI-MS (M+H) ⁺: 431.6, 433.5 m/z.

INT2:

N- (4- (4-amino-5-cyano-1H-pyrazol-1-yl) benzyl) -5-fluoro-2-methoxybenzamide

Step 1. ethyl 4- (dimethylamino) -2-oxobut-3-enoate, INT2-3

Ethyl pyruvate (2.8 kg, 24.11 mol) and DMFDEA (3.55 kg, 24.11 mol) were added to stirred DCM (60 L) . The mixture was stirred at 20-30 ℃ for 4 h. LC-MS showed full conversion and formation of ethyl 4- (dimethylamino) -2-oxobut-3-enoate. The reaction mixture was then concentrated to afford crude ethyl 4- (dimethylamino) -2-oxobut-3-enoate, INT2-3 3.70 kg as an oil, 89.6%yield, which is used in the next step without further purification.

Mass calc. C8H13NO3 for: 171.1; found: 172.2 [M+H] ⁺, ESI.

Step 2. ethyl 1- (4-cyanophenyl) -1H-pyrazole-5-carboxylate, INT2-5

ethyl 4- (dimethylamino) -2-oxobut-3-enoate (3.70 kg, crude, assuming 21.61 mol) was added to stirred DMF (50 L) and cooled to 10-15 ℃. HCl (conc. Aq, 1000 mL) was added. 4-Hydrazinylbenzonitrile (hydrochloride, 2.44 kg, 14.41 mol) was added in 3 portions, 30 min between each portion. The reaction mixture was warmed to 25-35℃. after the 3^rd portion was added, and stirred for 24 h. LC-MS showed full conversion and formation of ethyl 1- (4-cyanophenyl) -1H-pyrazole-5-carboxylate. Water (100 L) was added to the reaction mixture and stirred for another 2 h. The precipitation was filtered out and washed by water, and dried in an air blowing thermostatic at 50 ℃ for 24 h, to afford ethyl 1- (4-cyanophenyl) -1H-pyrazole-5-carboxylate, INT2-5 2213 g, 63.6%yield (based on INT2-4) .

Mass calc. C13H11N3O2 for: 241.1; found: 242.2 [M+H] ⁺, ESI.

Step 3. ethyl 1- (4-cyanophenyl) -4-nitro-1H-pyrazole-5-carboxylate, INT2-6

Ethyl 1- (4-cyanophenyl) -1H-pyrazole-5-carboxylate (900 g, 3.73 mol) was added to stirred TFAA (7 L) and cooled to -10～-15 ℃. HNO₃ (red fuming, 940 g) was added dropwise. The reaction was maintained below -5 ℃ while adding. The reaction mixture was stirred at -10-0 ℃ for 1 h. LC-MS showed full conversion and formation of ethyl 1- (4-cyanophenyl) -4-nitro-1H-pyrazole-5-carboxylate. To the reaction mixture was added a mixture of water (10 L) and ice shard (10 L) and kept below 20 ℃. The precipitation was filtered out and washed with water until filtrate was neutral, and dried in an air blowing thermostatic at 50 ℃ for 24 h, to afford ethyl 1- (4-cyanophenyl) -4-nitro-1H-pyrazole-5-carboxylate, INT2-6 832 g, 77.7%yield. Mass calc. C13H10N4O4 for: 286.1; found: 285.1 [M-H] ^-, ESI.

Step 4. ethyl 1- (4- (aminomethyl) phenyl) -4-nitro-1H-pyrazole-5-carboxylate, INT2-7

Ethyl 1- (4-cyanophenyl) -4-nitro-1H-pyrazole-5-carboxylate (688 g, 2.40 mol) was added to stirred THF (4.5 L) and cooled to 0-5 ℃. Borane THF complex (1M, 4.8 L, 4.8 mol) was added dropwise and the reaction was kept below 5 ℃. After addition of borane, the reaction mixture was raised to 35 ℃ and stirred for 2 h. LC-MS showed full conversion and formation of ethyl 1- (4- (aminomethyl) phenyl) -4-nitro-1H-pyrazole-5-carboxylate. The reaction mixture was cooled to 0 ℃, and ethanol (1.5 L) was added dropwise, and the reaction was kept below 10 ℃. After addition of ethanol the reaction mixture was stirred at 35 ℃ for 3 h. The reaction mixture was then concentrated under vacuum. To the residue was added a mixture of DCM/MeOH (6: 1, 20 L) and HCl (aq, 0.2 N, 20 L) and partitioned. The organic phase was extracted HCl (aq, 0.2 N, 5 L) . The combined aq phase was adjusted to pH > 7 by NaHCO₃ (aq, sat) and extracted by added a mixture of DCM/MeOH (6: 1, 30 L) and another extraction by DCM (5 L) . The combined organic phase was concentrated under vacuum to afford ethyl 1- (4- (aminomethyl) phenyl) -4-nitro-1H-pyrazole-5-carboxylate, INT2-7 357 as an oil, 51%yield, which is directly used in the next step without further purification.

Mass calc. C13H14N4O4 for: 290.1; found: 291.2 [M+H] ⁺, ESI.

Step 5. ethyl 1- (4- ( ( (5-fluoro-2-methoxybenzoyl) oxy) methyl) phenyl) -4-nitro-1H-pyrazole-5-carb oxylate, INT2-9

5-Fluoro-2-methoxybenzoic acid (703 g, 4.13 mol) was added to stirred DCM (15 L) and cooled to 0-10 ℃. EDCI (782 g, 3.79 mol) and HOBt (512 g, 3.79 mol) was added and stirred at 0-10 ℃ for 30 min. Pyridine (354 g, 4.48 mol) was added, followed by Ethyl 1- (4- (aminomethyl) phenyl) -4-nitro-1H-pyrazole-5-carboxylate (1000 g, 3.45 mol) in DCM 10 L. The reaction was raised to 25-30 ℃ and stirred for another 24 h, LC-MS showed full conversion and formation of ethyl 1- (4- ( ( (5-fluoro-2-methoxybenzoyl) oxy) methyl) phenyl) -4-nitro-1H-pyrazole-5-carboxy late. To the reaction mixture was added HCl (1N, 10 L) and stirred for 30 min and partitioned. The organic phase was extracted by another portion of HCl (1N, 5 L) . To the combined organic phase was added NaHCO₃ (aq, sat) until aq phase pH > 7, and was partitioned. The organic phase was dried over anhydrous Na2SO4 and filtered, and concentrated to afford ethyl 1- (4- ( ( (5-fluoro-2-methoxybenzoyl) oxy) methyl) phenyl) -4-nitro-1H-pyrazole-5-carb oxylate, INT2-9 1510 g, 89.9%yield, which is directly used in the next step without further purification.

Mass calc. C21H18FN3O7 for: 443.1; found: 444.2 [M+H] ⁺, ESI.

Step 6. 1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4-nitro-1H-pyrazole-5-carbox amide, INT2-10

Ethyl 1- (4- ( ( (5-fluoro-2-methoxybenzoyl) oxy) methyl) phenyl) -4-nitro-1H-pyrazole-5-carboxy late (1510 g, 3.41 mol) was dissolved in MeOH (1 L) and transferred to a 10 L autoclave. NH₃ (7 M in MeOH, 7 L, 49 mol) was added. The autoclave was heated at 80 ℃ for 24 h. The reaction mixture was cooled to 50 ℃ and pressure was released. The reaction mixture was transferred out and stirred for another 2 h to allow to cool to 20 ℃ and precipitation formed. The precipitation was filtered out and washed by cold MeOH and dried to afford 1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4-nitro-1H-pyrazole-5-carbox amide, INT2-9 870 g, 61.7%yield.

Mass calc. C19H16FN5O5 for: 413.1; found: 414.2 [M+H] ⁺, ESI.

Step 7. N- (4- (5-cyano-4-nitro-1H-pyrazol-1-yl) benzyl) -5-fluoro-2-methoxybenzamide, INT2-11

1- (4- ( (5-Fluoro-2-methoxybenzamido) methyl) phenyl) -4-nitro-1H-pyrazole-5-carboxam ide (700 g, 1.69 mol) was added to POCl3 (1.6 L) . The reaction mixture was stirred at 70 ℃ for 10 h. LC-MS showed full conversion and formation of N- (4- (5-cyano-4-nitro-1H-pyrazol-1-yl) benzyl) -5-fluoro-2-methoxybenzamide. The reaction mixture was then cooled to 40 ℃ and poured into a mixture of water (5 L) and ice shard (5 L) , and kept below 5 ℃ and stirred for 2 h. The precipitation was filtered out and washed with water until filtrate was neutral and dried in an air blowing thermostatic at 50 ℃ for 16 h to afford crude INT2-11. The crude was added to 2.5 V MeOH and reflux for 1 h and then allowed to cool to r. t. naturally while stirring over 2 h. The precipitated was filtered and dried under vacuum at 50 ℃ for 12 h to afford N- (4- (5-cyano-4-nitro-1H-pyrazol-1-yl) benzyl) -5-fluoro-2-methoxybenzamide, INT2-11 500 g, 74.8%yield.

Mass calc. C19H14FN5O4 for: 395.1; found: 396.2 [M+H] ⁺, ESI.

Step 8. N- (4- (4-amino-5-cyano-1H-pyrazol-1-yl) benzyl) -5-fluoro-2-methoxybenzamide, INT2

N- (4- (5-cyano-4-nitro-1H-pyrazol-1-yl) benzyl) -5-fluoro-2-methoxybenzamide (500 g, 1.26 mol) was added to THF (8 L) , and Pd/C (10%Pd on carbon, wet, ～55%water, 250 g) was added. The atmosphere in the reactor was swapped to N₂ thrice and then swapped to H2 thrice. The reaction was then stirred under 1 atm of H₂ pressure at r. t. for 26 h. LC-MS showed full conversion and formation of N- (4- (4-amino-5-cyano-1H-pyrazol-1-yl) benzyl) -5-fluoro-2-methoxybenzamide. The reaction was filtered, and concentrated under vacuum. The residue was added to 1.5 V MeOH and refluxed for 1 h, and allowed to cool to r. t. while stirring in 2 h. The precipitate was filtered out and dried under vacuum at 50 ℃ for 12 h to afford N- (4- (4-amino-5-cyano-1H-pyrazol-1-yl) benzyl) -5-fluoro-2-methoxybenzamide,

INT2, 320 g, 69.5%yield.

Mass calc. C19H16FN5O2 for: 365.1; found: 365.2 [M+H] ⁺, ESI.

1H NMR (400 MHz, DMSO-d6) δ 8.88 (t, J = 6.1 Hz, 1H) , 7.58-7.55 (m, 2H) , 7.53-7.46 (m, 3H) , 7.40 (s, 1H) , 7.34 (ddd, J = 9.1, 7.9, 3.3 Hz, 1H) , 7.18 (dd, J = 9.1, 3.3 Hz, 1H) , 5.61 (br, 2H) , 4.54 (d, J = 6.2 Hz, 2H) , 3.89 (s, 3H) . 19F NMR (376 MHz, DMSO-d6) δ -123.

INT3:

4-amino-1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-carb oxamide

Step 1. 4-Amino-1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-car boxamide, INT3

1- (4- ( (5-Fluoro-2-methoxybenzamido) methyl) phenyl) -4-nitro-1H-pyrazole-5-carboxam ide (100 g, 241.92 mmol) was added to THF (1.5 L) , and Pd/C (10%Pd on carbon, wet, ～55%water, 40 g) was added. The atmosphere in the reactor was swapped to N2 thrice and then swapped to H₂ thrice. The reaction was then stirred under 1 atm of H2 pressure at r.t. for 20 h. LC-MS showed full conversion and formation of 4-Amino-1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-carboxa mide. The reaction mixture was filtered. The filter cake was refluxed with acetonitrile (400 mL) and filtered (repeated 5 times) . The combined filtrated was concentrated under vacuum. The residue was added to 1.5 V MeOH and refluxed for 1 h, and allowed to cool to r. t. while stirring in 2 h. The precipitate was filtered out and dried under vacuum at 50 ℃ for 12 h to afford 4-Amino-1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-carb oxamide, INT3, 50 g, 53.6%yield. Mass calc. C19H18FN5O3 for: 383.1; found: 384.2 [M+H] ⁺, ESI.

1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 6.1 Hz, 1H) , 7.51 (dd, J = 9.2, 3.3 Hz, 1H) , 7.38-7.28 (m, 7H) , 7.18 (dd, J = 9.2, 4.3 Hz, 1H) , 6.97 (br, 1H) , 4.69 (br, 2H) , 4.52 (d, J = 6.1 Hz, 2H) , 3.89 (s, 3H) .

Example 1

1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- ( (4- (piperidin-4-yl) phenyl) amino) -1H-pyrazole-5-carboxamide TFA salt

Step 1: tert-butyl

4- (4- ( (3-bromo-1- (4-cyanophenyl) -5- (methoxycarbonyl) -1H-pyrazol-4-yl) amino) phenyl) piperidine-1-carboxylate

A solution of INT1 (150 mg, 0.35 mmol) , compound 1 (125 mg, 0.45 mmol) , Pd (OAc) ₂ (8 mg, 0.035 mmol) , Xantphos (33 mg, 0.07 mmol) and Cs₂CO₃ (340 mg, 1.04 mmol) in toluene (7 mL) was irradiated in the microwave for 60 min at 100 ℃ under N₂. The mixture was concentrated in vacuum and dissolved in EA (30 mL) , then filtered, the filtrate was washed with brine (10 mL) . The organic phase was dried over anhydrous Na₂SO₄. After filtration, the solvent was removed in vacuum and the residue was purified by flash column (eluent: DCM/EA = 98: 2 -95: 5) chromatography on silica gel to give compound 2 (73 mg, yield: 36.42%) as a light yellow solid.

MS: m/z = 601.7, 603.7 (M+Na, ESI⁺) .

Step 2: tert-butyl 4- (4- ( (3-bromo-5-carbamoyl-1- (4-cyanophenyl) -1H-pyrazol-4-yl) amino) phenyl) piper idine-1-carboxylate

A solution of compound 2 (1.10 g, 1.90 mmol) in NH₃/MeOH (20 mL, 7N) in a sealed tube was stirred at 50℃ for 16 h. The mixture was concentrated in vacuum to give compound 3 (1.08 g, crude) as a light yellow solid, which was used for the next step without purification. MS: m/z = 586.8, 588.8 (M+Na, ESI⁺) .

Step 3: tert-butyl 4- (4- ( (1- (4- (aminomethyl) phenyl) -5-carbamoyl-1H-pyrazol-4-yl) amino) phenyl) piperidine-1-carboxylate

A solution of compound 3 (1.08 g, 1.91 mmol) , NH₃. H₂O (4.00 mL, 25%) and Raney Nickel (1.12 g, 90%) in EtOH (80 mL) was stirred at 25℃ under H₂ for 16 h. The mixture was filtered, the filtrate was concentrated in vacuum to give compound 4 (800 mg, crude) as a light yellow solid, which was used for the next step without purification.

MS: m/z = 512.9 (M+Na, ESI⁺) .

Step 4: tert-butyl 4- (4- ( (5-carbamoyl-1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazol-4-yl) amino) phenyl) piperidine-1-carboxylate

A solution of compound 4 (800 mg, 1.63 mmol) , compound 5 (277 mg, 1.63 mmol) , EDCI (468 mg, 2.44 mmol) , HOBt (330 mg, 2.44 mmol) and DIEA (631 mg, 4.88 mmol) in DCM (20 mL) was stirred at rt for 2 h. Diluted with DCM (40 mL) , washed with brine (20 mL) . The organic phase was dried over anhydrous Na₂SO₄. After filtration, the solvent was concentrated in vacuum and the residue was purified by flash column (eluent: DCM/MeOH = 98: 2 -95: 5) chromatography on silica gel to give compound 6 (750 mg, 71.56%) as a light yellow solid. MS: m/z = 664.8 (M+Na, ESI⁺) .

Step 5:

A solution of compound 6 (750 mg, 1.17 mmol) and TFA (3 mL) in DCM (5 mL) was stirred at rt for 2 h. The mixture was concentrated in vacuum and the residue was recrystallization from DCM/PE to give Example 1 (610 mg, 79.63%) .

MS: m/z = 542.9 (M+H, ESI⁺) .

¹H NMR (400 MHz, CD₃OD) δ 7.72 (s, 1H) , 7.59 (dd, J = 9.2, 3.2 Hz, 1H) , 7.46 (dd, J = 20.0, 8.5 Hz, 4H) , 7.26 –7.20 (m, 1H) , 7.16 –7.09 (m, 3H) , 6.89 (d, J = 8.5 Hz, 2H) , 4.65 (s, 2H) , 3.93 (s, 3H) , 3.45 (d, J = 12.6 Hz, 2H) , 3.09 (t, J = 11.8 Hz, 2H) , 2.85 – 2.71 (m, 1H) , 2.02 (d, J = 13.8 Hz, 2H) , 1.90 –1.76 (m, 2H) .

The compounds in the table below (Table 1) were prepared by similarly following the procedures described above.

Table 1

Example 2

B193:

1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- ( (5- (4-methylpiperazin-1-yl) -6- (2, 2, 2-trifluoro-1-hydroxyethyl) pyridin-2-yl) amino) -1H-pyrazole-5-carboxamide

Step 1. 6-chloro-3- (4-methylpiperazin-1-yl) picolinaldehyde, B193-1-2.

A solution of B193-1-1 (1.00 g, 6.30 mmol) , 1-methylpiperazine (630 mg, 6.30 mmol) and K₂CO₃ (2.60 g, 18.90 mmol) in DMF (10 mL) was stirred at 80℃ under N₂ for 1 h. The mixture was quenched with a saturated ammonium chloride solution and extracted with EA (20 mL*3) . The organic phase was dried over anhydrous Na₂SO₄. After filtration, the solvent was removed in vacuum to purify by flash (EA/DCM=1: 5) to give compound B193-1-2 (1.20 g, yield: 80%) as a light-yellow oil. MS: m/z =240.0, 242.0 (M+H, ESI+) .

Step 2. 1- (6-chloro-3- (4-methylpiperazin-1-yl) pyridin-2-yl) -2, 2, 2-trifluoroethan-1-ol.

A solution of B193-1-2 (300 mg, 1.25 mmol) , CsF (285 mg, 1.87 mmol) and TMSCF₃ (267 mg, 1.87 mmol) in THF (3 mL) was stirred at 25℃ under N₂ for 2 h. The mixture was quenched with a saturated ammonium chloride solution and extracted with DCM (10 mL*3) . The organic phase was dried over anhydrous Na₂SO₄. After filtration, the solvent was concentrated in vacuum and the residue was purified by flash column (eluent: DCM/MeOH = 10: 1) chromatography on silica gel to give compound B193-1-3 (227 mg) as a light-yellow oil.

MS: m/z =310.0, 312.0 (M+H, ESI+) .

Step 3. 1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- ( (5- (4-methylpiperazin-1-yl) -6- (2, 2, 2-trifluoro-1-hydroxyethyl) pyridin-2-yl) amino) -1H-pyrazole-5-carboxamide

A solution of B193-1-3 (227 mg, 0.73 mmol) , INT3 (233 mg, 0.60 mmol) , Cs₂CO₃ (594 mg, 1.82 mmol) , t-BuXPhos (72 mg, 0.090 mmol) and t-BuXPhos Pd G3 (78 mg, 0.18 mmol) in t-BuOH/THF (1: 1, 10 mL) was stirred at 80℃ for 16 h. The mixture was diluted with DCM (50 mL) , washed with brine (20 mL) . The organic phase was dried over anhydrous Na₂SO₄. After filtration, the solvent was concentrated in vacuum and the residue was purified by flash column (eluent: DCM/MeOH = 10: 1) chromatography on silica gel to give compound B193 (138 mg, yield: 28.6%) as a yellow solid.

MS: m/z = 657.1 (M+H, ESI+) .

Step 4. (S) -1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- ( (5- (4-methylpiperazin-1-yl) -6- (2, 2, 2-trifluoro-1-hydroxyethyl) pyridin-2-yl) amino) -1H-pyrazole-5-carboxamide

B193 (138 mg) was sepatated by SFC (Apparatus: SFC Thar prep80; Column: CHIRALPAK AS-H 250 mm *20 mm, 5 μm; Modifier: 40%IPA (NH4OH 0.2%) ; Total Flow: 40 g/min; column temperature: 25 ℃, Retention time (min) : 5.59, 7.61) to give B193-1 (43.2 mg) and B193-2 (38.5 mg) .

B193-1 MS: m/z = 657.3 (M+1, ESI+) .

¹H NMR (400 MHz, MeOD) δ 8.51 (s, 1H) , 7.73 (d, J = 8.9 Hz, 1H) , 7.63 (dd, J = 9.2, 3.2 Hz, 1H) , 7.56-7.46 (m, 4H) , 7.31-7.22 (m, 1H) , 7.21-7.13 (m, 1H) , 6.90 (d, J = 8.8 Hz, 1H) , 5.63-5.58 (m, 1H) , 4.70 (s, 2H) , 3.98 (s, 3H) , 3.05-2.95 (m, 2H) , 2.95-2.86 (m, 2H) , 2.72-2.58 (m, 4H) , 2.38 (s, 3H) .

B193-2 MS: m/z = 657.3 (M+1, ESI+) .

¹H NMR (400 MHz, MeOD) δ 8.50 (s, 1H) , 7.72 (d, J = 8.8 Hz, 1H) , 7.62 (dd, J = 9.2, 3.2 Hz, 1H) , 7.55-7.47 (m, 4H) , 7.28 –7.22 (m, 1H) , 7.20-7.14 (m, 1H) , 6.89 (d, J = 8.8 Hz, 1H) , 5.64-5.57 (m, 1H) , 4.69 (s, 2H) , 3.97 (s, 3H) , 3.12-2.94 (m, 2H) , 2.95-2.84 (m, 2H) , 2.70-2.53 (m, 4H) , 2.37 (s, 3H) .

The compounds in the table below (Table 2) were prepared by similarly following the procedures described above.

Table 2

Example 3

B196:

4- ( (6- (cyclopropyl (hydroxy) methyl) -5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-carboxamide

Step 1. (6-chloro-3- (4-methylpiperazin-1-yl) pyridin-2-yl) (cyclopropyl) methanol To a solution of B193-1-2 (300 mg, 1.25 mmol) in THF (3 mL) , cyclopropylmagnesium bromide (218 mg, 1.50 mmol) was stirred at 0℃ under N₂ for 2 h. The mixture was quenched with a saturated ammonium chloride solution and extracted with EA (20 mL*3) . The organic phase was dried over anhydrous Na2SO4. After filtration, the solvent was concentrated in vacuum and the residue was purified by flash column (eluent: DCM/MeOH = 10: 1) chromatography on silica gel to give the titled compound B196-1-1 (166 mg, 47%) as a light-yellow oil. MS: m/z =281.9, 283.9 (M+H, ESI+) .

Step 2: 4- ( (6- (cyclopropyl (hydroxy) methyl) -5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-carboxamide

A solution of B196-1-1 (166 mg, 0.58 mmol) , INT3 (206 mg, 0.53 mmol) , Cs2CO3 (525 mg, 1.61 mmol) , t-BuXPhos (68 mg, 0.16 mmol) and t-BuXPhos Pd G3 (64 mg, 0.08 mmol) in t-BuOH/THF (1: 1, 10 mL) was stirred at 80℃ for 16 h. The mixture was diluted with DCM (50 mL) and washed with brine (20 mL) . The organic phase was dried over anhydrous Na2SO4. After filtration, the solvent was concentrated in vacuum and the residue was purified by flash column (eluent: DCM/MeOH = 10: 1) chromatography on silica gel to give compound B196 (56 mg, 15%) as a yellow solid.

MS: m/z = 629.3 (M+H, ESI+) .

Step 3: (S) / (R) -4- ( (6- (cyclopropyl (hydroxy) methyl) -5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-carboxamide, B196-1

B196 (56 mg) was sepatated by SFC (Apparatus: SFC Thar prep80; Column: CHIRALPAK AS-H 250 mm *20 mm, 5 μm; Modifier: 40%IPA (NH4OH 0.2%) ; Total Flow: 40 g/min; column temperature: 25 ℃, Retention time (min) : 3.07, 3.52) to give B196-1 (19.42 mg) and B196-2 (16.59 mg) .

B196-1 MS: m/z = 629.3 (M+1, ESI+) .

₁HNMR (400 MHz, MeOD) δ 8.46 (s, 1H) , 7.65 –7.58 (m, 2H) , 7.56-7.48 (m, 4H) , 7.31 –7.23 (m, 1H) , 7.21-7.14 (m, 1H) , 6.75 (d, J = 8.7 Hz, 1H) , 4.69 (s, 2H) , 4.52 (d, J = 7.8 Hz, 1H) , 3.97 (s, 3H) , 3.07-2.95 (m, 2H) , 2.89 –2.80 (m, 2H) , 2.73-2.45 (m, 4H) , 2.37 (s, 3H) , 1.46 –1.34 (m, 1H) , 0.61 –0.38 (m, 4H) .

B196-2 MS: m/z = 629.3 (M+1, ESI+) .

¹HNMR (400 MHz, MeOD) δ 8.45 (s, 1H) , 7.65 –7.58 (m, 2H) , 7.56-7.47 (m, 4H) , 7.30-7.22 (m, 1H) , 7.20-7.14 (m, 1H) , 6.75 (d, J = 8.7 Hz, 1H) , 4.68 (s, 2H) , 4.51 (d, J =7.9 Hz, 1H) , 3.96 (s, 3H) , 3.06 –2.97 (m, 2H) , 2.89 –2.80 (m, 2H) , 2.78 –2.47 (m, 4H) , 2.38 (s, 3H) , 1.45 –1.35 (m, 1H) , 0.64 –0.35 (m, 4H) .

The compounds in the table below (Table3) were prepared by similarly following the procedures described above.

Table 3

Example 4

B333:

1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- ( (6- (1-methoxyethyl) -5- (4- ( 2-methoxyethyl) piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrazole-5-carboxamide

Step 1.6-chloro-3- (4- (2-methoxyethyl) piperazin-1-yl) picolinaldehyde

A mixture of 6-chloro-3-fluoropicolinaldehyde (100g, 626.78mmol) , 1- (2-methoxyethyl) piperazine (108.47g, 752.14mmol) , K₂CO₃ (216.24g, 1.57mol) in DMF (500ml) was stirred at 80℃ for 2h. LC-MS showed full conversion. The reaction mixture was concentrated under reduced pressure, Then 500ml water was added to the residue and extracted with CH₂Cl₂ for three times and dried with Na₂SO₄, The combined was filtered and the filtrate was evaporated to afford B333-1-1 (170g) as yellow oil with the yield of 95.6%, which was used to next step directly. Mass calc. C₁₃H₁₈ClN₃O₂ for 283.11, found: 284.21 (M+H) + ESI.

Step 2.1- (6-chloro-3- (4- (2-methoxyethyl) piperazin-1-yl) pyridin-2-yl) ethan-1-ol To a mixture of B333-1-1 (170g, 599.11mmol) in dry THF (750ml) under N₂, CH₃MgBr (3 mol/L in MeTHF) was added dropwise at -20℃. Then the mixture was kept stirring at the temperature for another 2 hours. LC-MS showed full conversion. The mixture was poured into ice water and extracted with CH₂Cl₂ for three times. The organic layer was washed with water for 2 times and dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified with column chromatography (CH₂Cl₂/MeOH = 20: 1) to get red oil 130g with yield of 72.38%. The red oil was separated by chiral chromatography to get B333-1-2 (61g, yield: 46.9%) , which was used to next step. Mass calc. C₁₄H₂₂ClN₃O₂ for 299.14, found: 300.32 (M+H) + ESI.

Step 3. 1- (6-chloro-2- (1-methoxyethyl) pyridin-3-yl) -4- (2-methoxyethyl) piperazine NaH (9.77g, 244.17mmol, 60%purity) was added to B333-1-2 (61g, 203.47mmol) in THF (1000ml) slowly at 0℃, which was kept stirring for another 30 min. Then CH₃I (34.66g, 244.17mmol) was added dropwise into the slurry mixture. After dropping, the mixture was moved to r. t. and kept stirring for another 2 hours. LC-MS showed full conversion. Saturated ammonium solution was added and extracted with EA (500ml *2) , The EA layer was washed with water, dried with Na₂SO₄, filtered and concentrated to get red oil which was purified by column chromatography (CH₂Cl₂/MeOH = 20: 1) to afford B333-1-3 (56g) with the yield of 87.7%. Mass calc. C₁₅H₂₄ClN₃O₂ for 313.16, found: 314.32 (M+H) + ESI.

Step 4.1- (6-chloro-2- (1-methoxyethyl) pyridin-3-yl) -4- (2-methoxyethyl) piperazine

A mixture of Pd₂ (dba) ₃ (21.3 g, 23.26 mmol) , XantPhos (15.84 g, 27.37 mmol) , INT2 (50 g, 136.85 mmol) , B333-1-3 (42.95 g, 136.85 mmol) and Cs₂CO₃ (111.47 g, 342.13 mmol) in 1, 4-dioxane (500 mL) was de-gassed and stirred at 85 ℃ for 16 hours under N₂. LC-MS showed full conversion. The reaction mixture was filtered through diatomite and concentrated under reduced pressure to afford an oil residue, which was used to next step directly. Mass calc. C₃₄H₃₉FN₈O₄ for 642.31, found: 643.32 (M+H) + ESI.

Step 5. 1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- ( (6- (1-methoxyethyl) -5- (4- (2-methoxyethyl) piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrazole-5-carboxamide

To a solution of B333-1-4 in EtOH (600mL) was added NaOH dropwise (19.92 g NaOH in 100 mL water) . The mixture was heated to 70 ℃ and stirred for 1 h. LC-MS showed full conversion. The reaction mixture was cooled to room temperature and poured to water (500 mL) , and extracted with DCM (500 mL × 2) . The organic phase was combined and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated in a mixed solvent (EtOH: CH₂Cl₂: n-heptane = 40 mL: 20 mL: 80 mL) at room temperature for 3 h, and filtered to afford the crude product. The crude was triturated with a mixed solvent (EtOH: CH₂Cl₂: heptane = 20 mL: 5 mL: 40 mL) at r. t. for 30 minutes, and filtered to afford B333 after vacuum drying at 50 ℃ for 6 hours. 36 g, 53.5%yield 2 steps, 99.3%210 nm, 99.2%254 nm. Mass calc. C₃₄H₄₁FN₈O₅ for 660.32, found: 661.32 (M+H) + ESI.

Step 6. (S)/ (R) -1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- ( (6- (1-methoxyethyl) -5- (4- (2-methoxyethyl) piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrazole-5-carboxamide

B333 was sepatated by SFC (Apparatus: SFC Thar prep80; Column: CHIRALPAK AS-H 250 mm *20 mm, 5 μm; Modifier: 40%IPA (NH4OH 0.2%) ; Total Flow: 40 g/min; column temperature: 25 ℃, Retention time (min) : 3.07, 3.52) to give B333-1 and B333-2.

Mass calc. C₃₄H₄₁FN₈O₅ for 660.32, found: 661.32 (M+H) + ESI.

¹H-NMR (DMSO-d6, 400Hz) : 1.36 (d, J=6.38Hz ) , 2.57 (m, 4H) , 2.75 (m, 4H) , 3.12 (s, 3H) , 3.35 (s, 3H) , 3.45 (t, J=5.8Hz, 2H) , 3.89 (s, 3H) , 4.54 (d, J=6.12Hz, 2H) , 4.96 (m,1H) , 6.79 (d, J=8.75 Hz, 1H) , 7.2 (m, 1H) , 7.35 (m, 1H) , 7.47 (s, 4H) , 7.51 (m, 1H) , 7.53 (m, 1H) , 8.33 (d, 2H) , 8.86 (t, J=6.1Hz, 1H) ,

Example 5

B334:

1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- ( (5- (4- (2-methoxyethyl) piperazin-1-yl) -6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazole-5-carboxamide

Step 1. (6-chloro-3- (4- (2-methoxyethyl) piperazin-1-yl) pyridin-2-yl) methanol

To a stirring mixture of B333-1-1 (80g, 281.94 mmol) in MeOH (400ml) , NaBH₄ (16.0g, 422.9 mmol) was added in portions at 0℃, then the slurring mixture was moved to r. t. and kept stirring for another 2 hours. LC-MS showed full conversion. Water (1L) was added and extracted with DCM (600ml *2) , the organic layer was washed with water for 2 times, and combined to dry with Na₂SO₄, filtered and concentrated under reduced pressure to afford crude, which was purified by column chromatography (DCM: MeOH = 10: 1) to get B334-1 (55g) with the yield of 68.3%. Mass calc. C₁₃H₂₀ClN₃O₂ for 285.12, found: 286.13 (M+H) + ESI.

Step 2. 1- (6-chloro-2- (methoxymethyl) pyridin-3-yl) -4- (2-methoxyethyl) piperazine

NaH (913.75mg, 2.85mmol, 60%purity) was added to B334-1 (5.44g, 19.04mmol) in THF (100 ml) in portions at 0℃, which was kept stirring for another 30 min. Then CH₃I (3.38g, 23.80mmol) was added dropwise into the slurry mixture. After dropping, the mixture was moved to r. t. and kept stirring for another 2 hours. LC-MS showed full conversion. Saturated ammonium solution was added and extracted with DCM (100ml *2) . The DCM layer was washed with water, dried with Na₂SO₄, filtered and concentrated to get red oil which was purified by column chromatography (CH₂Cl₂/MeOH = 20: 1) to afford B334-2 (4.2g) with the yield of 73.7%. Mass calc. C₁₄H₂₂ClN₃O₂ for 299.14, found: 300.14 (M+H) + ESI.

Step 3. N- (4- (5-cyano-4- ( (5- (4- (2-methoxyethyl) piperazin-1-yl) -6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol-1-yl) benzyl) -5-fluoro-2-methoxybenzamide

A mixture of Pd (OAc) ₂ (1.66g, 7.39 mmol) , XantPhos (5.70g, 9.85 mmol) , INT2 (18 g, 49.27 mmol) , B334-2 (14.77 g, 49.27 mmol) and Cs₂CO₃ (32.10 g, 98.53 mmol) in 1, 4-dioxane (450 mL) was de-gassed and stirred at 85 ℃ for 16 hours under N₂. LC-MS showed full conversion. The reaction mixture was filtered through diatomite and concentrated under reduced pressure to afford an oil residue, which was used to next step directly. Mass calc. C₃₃H₃₇FN₈O₄ for 628.29, found: 629.28 (M+H) + ESI.

Step 4. 1- (4- ( (5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- ( (5- (4- (2-methoxyethyl) pipe razin-1-yl) -6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazole-5-carboxamide

To a solution of B334-3 (23g, 36.58mmol) in EtOH (200 mL) was added NaOH dropwise (2.05 g NaOH in 25.6 mL water) . The mixture was heated to 70 ℃ and stirred for 1 h. LC-MS showed full conversion. The reaction mixture was cooled to room temperature and poured to water (500 mL) , and extracted with DCM (500 mL × 2) . The organic phase was combined and dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was triturated in a mixed solvent (EtOH: CH₂Cl₂: n-heptane = 50 mL: 10 mL: 10 mL) at room temperature for 3 h, and filtered to afford the crude product. The crude was triturated with a mixed solvent (EtOH: CH₂Cl₂: heptane = 20 mL: 5 mL: 5 mL) at r. t. for 30 minutes, and filtered to afford B334 after vacuum drying at 50 ℃ for 6 hours 36 g, 77.1%yield, 99.4%210 nm, 99.2%254 nm. Mass calc. C₃₃H₃₉FN₈O₅ for 646.30, found: 647.26 (M+H) + ESI.

¹H-NMR (DMSO-d⁶, 400Hz) : : δ 2.51 (s, 4H) , 2.73 (t, J=8.91, 4H) , 3.24 (s, 3H) , 3.34 (s, 3H) , 3.45 (t, J=5.88, 2H) , 3.83 (s, 3H) 4.37 (s, 2H) , 4.44 (s, 2H) , 6.29 (d, 8.77, 1H) , 6.98-7.17 (m, 2H) , 7.21-7.27 (m, 5H) , 7.39 (s, 1H) , 8.72 (s, 1H) .

The compounds in the table below (Table 4) were prepared by similarly following the procedures described above.

Table 4

BIOLOGICAL ASSAYS

Example 1. BTK^WT binding assay by LanthaScreen ^TM TR-FRET

Material and Reagents

1. BTK^WT recombinant human protein (Thermo fisher, Cat#PR5442A)

2. 5X LanthaScreen ^TM kinase buffer A (Thermo fisher, Cat#PV6135)

3. LanthaScreen ^TM Eu anti-His tag antibody (Thermo fisher, Cat#PV5596)

4. Kinase tracer 236 (Thermo fisher, Cat#PV5592)

5. DMSO (Thermo Fisher Scientific)

6. Compounds -20 mM stock in DMSO

7. Victor Nivo multimode plate reader (PerkinElmer)

8. OptiPlate-384, black opaque 384-well microplate (PerkinElmer)

Experimental procedure

BTK^WT binding affinity of each compound tested was determined using a time-resolved fluorescence resonance energy transfer (TR-FRET) techonology. 2 nM recombinant His-tagged BTK^WT kinase, varying concentrations of inhibitors, 2 nM LanthaScreen ^TM Eu anti-His Antibody and 25 nM Kinase Tracer 236 was incubated in 1X Kinase Buffer A for 1 h. Measurement was performed in a reaction volume of 15 μL by adding 5 μL of the test compound, 5 μL of kinase/antibody mixture and 5 μL of tracer into white opaque 384-well assay plates. The TR-FRET signal was read on a plate reader with an excitation wavelength of 340 nm and detection wavelengths of 615 and 665 nm. Binding affinity was determined for each compound by measuring TR-FRET signal at various concentrations of compound and plotting the relative fluorescence Emission Ratio (665 nm/615 nm) against the inhibitor concentration to estimate the IC₅₀ from [inhibitor] vs Emission Ratio using the sigmoidal dose-response curve with a variable slope model in GraphPad Prism.

Conclusion: The compounds of the present invention showed potent binding affinity to human BTK^WT kinase protein.

Example 2. Anti-Proliferative Activity

Cell line generation

Lentiviral vectors (pLV-Puro-EF1a-3X Flag) expressing Flag-tagged wild type or C481S human BTK have been generated by VectorBuilder (Chicago, IL) . BTK gene was cloned downstream of human EF1α promoter. The lentiviral vectors also express puromycin resistance gene under mouse PGK promoter. VSV-G pseudotyped lentiviral particles were produced by transient transfection of HEK293T cells using Transfection Reagent (Mirus, Madison, WI) . Viral particles were concentrated by PEG precipitation (Lenti-X concentrator, Takara Bio, San Jose, CA) . TMD8 activated B cell-like subtype of diffuse large B cell were infected with lentivirus using Retronectin-precoated plates (Takara Bio, San Jose, CA) . HEK293T cells were transduced by adding concentrated lentiviral particles. Lentivirus-infected cells were selected by culturing the cells with puromycin (Sigma) at 0.3 μg/ml (TMD8 cells) or 1 μg/ml (293T cells) .

Cellular Proliferation Assay

TMD8 cells were cultured in RPMI-1640 medium supplemented with 10%FBS, 100 U/ml penicillin, and 100 μg/ml streptomycin (Invitrogen, Carlsbad, CA, USA) . Cell were plated at 1X10⁴ cells per well in 96-well culture plates with various concentrations of compounds for 72 h at 37 ℃. Cell viability was measured using the CellTiter–Glo assay (Promega, WI, USA) . The IC₅₀ was then calculated as a percentage of the DMSO vehicle control and the percentages plotted against the inhibitor concentration to estimate the IC₅₀ from log [Inhibitor] vs response in Graphpad software (San Diego, CA, USA) .

Conclusion:

The compounds of the present invention showed similarly potent inhibitory activity against both wild type and C481S mutant TMD8 cell lines.

Example 3. PK

Pharmacokinetics of compounds were tested with C57BL/6 mice, 19-20 g, male, N=18, purchased from Jihui Laboratory Animal Co. LTD. IV and PO administration. IV: 0.2 mg/kg/cpd (5 mL/kg) via tail vein injection (N=9) ; PO: 1 mg/kg/cpd (10 mL/kg) via oral gavage (N=9) . Approximately 95 μL blood/time point was collected into K2EDTA tube via facial vein for bleeding. Plasma samples were put on ice and centrifuged to

obtain plasma sample (2000 g, 5 min under 4℃) within 15 minutes of collection. IV dosing solution in 5%DMAC+5%Solutol HS15+90%Saline at 0.04 mg/mL. PO dosing solution in 3%DMAC in (0.5%MC+0.5%Tween80 in water) at 0.1 mg/mL. PK parameters were estimated by non-compartmental model using WinNonlin 8.2.

The compounds of the present invention showed good exposure and bioavailability.

Example 4. Efficacy

The TMD-8 tumor cells were maintained as suspension cultured in RPMI 1640 medium supplemented with 10%fetal bovine serum, 100 U/mL penicillin and 100 μg/mL streptomycin at 37℃ in an atmosphere of 5%CO₂ in air. The tumor cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Each mouse was inoculated subcutaneously at the right flank with TMD-8 tumor cells (10 x 10⁶) in 0.1 mL of PBS supplemented with 50%matrigel (total 0.2 mL) for tumor development. The treatments were started on day 19 after tumor inoculation when the average tumor size reached approximately 215 mm³. Each group consisted of 9 tumor-bearing mice. The test articles were administrated to the mice according to the predetermined regimen. The major endpoint was to see if the tumor growth could be delayed or mice could be cured. Tumor size was measured three times weekly in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: V = 0.5 a x b² where a and b are the long and short diameters of the tumor, respectively. The tumor size was then used for calculations of TGI and T/C values. TGI was calculated for each group using the formula: TGI (%) = [1- (T_i-T₀) / (V_i-V₀) ] ×100; T_i is the average tumor volume of a treatment group on a given day, T₀ is the average tumor volume of the treatment group on the day of treatment start, V_i is the average tumor volume of the vehicle control group on the same day with T_i, and V₀ is the average tumor volume of the vehicle group on the day of treatment start.

The compounds of the present application have stronger efficacy. The range of TGI (%) is 80%to 120%. The TGI (%) of the preferred compound is greater than 100%.

Claims

A compound of formula (I-a) :

or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

A is 5-10 membered heterocyclyl or 5-10 membered heteroaryl;

L is bond, NH, O or S;

R₁ is independently selected from the group consisting of hydrogen, deuterium, oxo, halogen, amino, cyano, hydroxy, alkyl, alkylamino, alkoxy, haloalkyl, hydroxyalkyl, halohydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylamino, heterocyclylamino, arylamino, heteroarylamino, - (CHR_a) _nS (O) ₂R_b, - (CHR_a) _nC (O) R_b, - (CHR_a) _nNR_bR_c and - (CHR_a) _nC (O) NR_bR_c, wherein each of the alkyl, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylamino, heterocyclylamino, arylamino and heteroarylamino at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH₂) _mNR_dR_e, - (CH₂) _mOR_d, - (CH₂) _mC (O) R_d and - (CH₂) _mC (O) NR_dR_e;

R_a is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, halohydroxyalkyl, deuteroalkoxy and deuteroalkyl;

R_b and R_c are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein each of the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

or, R_b and R_c are together with the N atom to which they are bound form heterocyclyl, wherein the heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

R_d and R_e are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein each of the cycloalkyl and heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl and hydroxyalkyl;

R₂ is selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₃ is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₄ and R₅ are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and cycloalkyloxy;

x is 0, 1, 2 or 3;

y is 0, 1, 2 or 3;

z is 1, 2, 3 or 4,

each of m is independently selected from 0, 1, 2, 3 and 4; and

each of n is independently selected from 0, 1, 2, 3 and 4.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, A is

thesymbol indicates the point of attachment to L.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, being a compound of formula (I) :

wherein:

M₁ and M₂ are independently selected from the group consisting of–CR^a-and –N-;

R^a is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, halohydroxyalkyl, deuteroalkoxy and deuteroalkyl, wherein the hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkylamino, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, - (CHR_a) _nS (O) ₂R_b, - (CHR_a) _nC (O) R_b, - (CHR_a) _nNR_bR_c and - (CHR_a) _nC (O) NR_bR_c, wherein each of the alkyl, alkoxy, haloalkyl, hydroxyalkyl, deuteroalkoxy, deuteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH₂) _mNR_dR_e, - (CH₂) _mOR_d, - (CH₂) _mC (O) R_d and - (CH₂) _mC (O) NR_dR_e;

R_b and R_c are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein each of the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

or, R_b and R_c are together with the N atom to which they are bound form heterocyclyl, wherein the heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

R_d and R_e are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein each of the cycloalkyl and heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl and hydroxyalkyl;

R₂ is selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₃ is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₄ and R₅ are independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl;

x is 0, 1, 2 or 3;

y is 0, 1, 2 or 3;

z is 1, 2, 3 or 4,

each of m is independently selected from 0, 1, 2, 3 and 4; and

each of n is independently selected from 0, 1, 2, 3 and 4.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, being a compound of formula (II) :

wherein,

R₈ is selected from the group consisting of hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the C_3-8 cycloalkyl and 4-8 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

B is C_3-8 cycloalkyl or 4-9 membered heterocyclyl, optionally, unsubstituted or substituted with one or more substituents;

L₁ is bond, - (CH₂) _n-, -CHR_f-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

R_f is R_aa, –C (O) NR_aaR_bb, –NC (O) R_aa or NR_aaR_bb,

R_aa and R_bb are independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl;

or, R_aa and R_bb with the N atom to which they are bound form 4-8 membered heterocyclyl, optionally, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl and C_1-6 hydroxyalkyl;

A, R₂, R₃, R₄, R₅, R₆, n, y and z are defined as claim 1.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, being a compound of formula (II-a) :

wherein,

R₇ is independently selected from the group consisting of hydrogen, oxo, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl and C_1-6 alkoxy;

R₈ is selected from the group consisting of hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

X₁ is N or CH;

X₂ is O, S, S (O) ₂, N or CH, when X₂ is O, , S, or S (O) ₂, L₂ and R₈ are absent;

L₁ is bond, - (CH₂) _n-, -CHR_f-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

R_f is R_aa, –C (O) NR_aaR_bb, –NC (O) R_aa or NR_aaR_bb,

R_aa and R_bb are independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl;

or, R_aa and R_bb with the N atom to which they are bound form 4-6 membered heterocyclyl, optionally, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

M₁ and M₄ are independently selected from the group consisting of O, S, CR_a, C (O) , NR_a and N;

M₃ is C or N;

M₂ and M₅ are independently selected from the group consisting of absent, O, S, CR_a, C (O) , NR_a and N;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2;

R_a, R₂, R₃, R₄, R₅, R₆, n, y and z are defined as claim 4.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, being a compound of formula (II-a-1) :

wherein,

M₁, M₂, M₃, M₄ and M₅ are independently selected from the group consisting of N or CR^a;

R^a is independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, hydroxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_1-6 deuteroalkoxy and C_1-6 deuteroalkyl, wherein C_1-6 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl, C_4-7 heterocyclyl, C_6-12 aryl, and C_5-6 heteroaryl;

X₁ is N, C, or CH;

X₂ is N, C, or CH;

each of X₃ and X₄ is independently selected from the group consisting of bond, NR_a, CR_a or C (R_a) ₂;

R₃ is hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl;

R₄, and R₅ are selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₁-C₆ hydroxyalkyl;

R₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkoxy;

R₇ is independently selected from the group consisting of hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl and C_1-3 alkoxy;

or, two of R₇ are together with the atom to which they are bound form 3-6 cycloalkyl or 4-7 heterocyclyl, wherein 3-6 cycloalkyl or 4-7 heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

R₈ is hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of the C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_3-6 cycloalkyl and 4-6 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

p is 1, 2 or 3;

y is 1, 2 or 3;

z is 1, 2 or 3.
The compound of claim 3, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R^a is independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, hydroxy, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_1-3 hydroxyalkyl, C_1-3 deuteroalkoxy and C_1-3 deuteroalkyl, wherein the C_1-3 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-3 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl, and C_4-6 heterocyclyl;

preferably, R^a is independently selected from the group consisting of hydrogen, deuterium, halogen, and C_1-3 hydroxyalkyl, wherein the C_1-3 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-3 alkyl, C_2-4 alkenyl and C_3-6 cycloalkyl.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkylamino, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 deuteroalkoxy, C_1-6 deuteroalkyl, -C_0-6 alkyl (C_3-8 cycloalkyl) , -C_0-6 alkyl (4-10 membered heterocyclyl) , -C_0-6 alkyl (C_6-10 aryl) , -C_0-6 alkyl (5-10 membered heteroaryl) , -S (O) ₂R_b, -C (O) R_b, - (CH₂) _nNR_bR_c and -C (O) NR_bR_c, wherein each of the C_1-6 alkyl, C_1-6 alkylamino, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 deuteroalkoxy, C_1-6 deuteroalkyl, -C_0-6 alkyl (C_3-8 cycloalkyl) , -C_0-6 alkyl (4-10 membered heterocyclyl) , -C_0-6 alkyl (C_6-10 aryl) and –C_0-6 alkyl (5-10 membered heteroaryl) at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl, 4-10 membered heterocyclyl, - (CH₂) _nNR_dR_e, - (CH₂) _nOR_d, -C (O) R_d and -C (O) NR_dR_e;

R_b and R_c are independently selected from the group consisting of hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-10 membered heterocyclyl, wherein each of the C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-10 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-10 membered heterocyclyl;

or, R_b and R_c are together with the N atom to which they are bound form 4-10 heterocyclyl, wherein the 4-10 heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl and C_1-6 hydroxyalkyl;

R_d and R_e are independently selected from the group consisting of hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-10 membered heterocyclyl, wherein each of the C_3-8 cycloalkyl and 4-10 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl and C_1-6 hydroxyalkyl.
The compound of claim 8, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R₁ is independently selected from the group consisting of C_1-6 alkyl, -C_0-3 alkyl (C_3-6 cycloalkyl) , -C_0-3 alkyl (4-8 membered heterocyclyl) , -S (O) ₂R_b, - (CH₂) _nNR_bR_c and -C (O) NR_bR_c; wherein each of the -C_0-3 alkyl (C_3-6 cycloalkyl) and -C_0-3 alkyl (4-8 membered heterocyclyl) at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, - (CH₂) _nOR_d and -C (O) R_d;

or, R_b and R_c are together with the N atom to which they are bound form 4-6 membered heterocyclyl containing 1, 2 or 3 of heteroatoms selected from N or O, wherein the heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl and C_1-6 hydroxyalkyl;

R_d is independently selected from the group consisting of hydrogen, deuterium, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, wherein the cycloalkyl and heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl.
The compound of claim 9, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R₁ is:
optionally, R₁ is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, - (CH₂) _nOC_1-3 alkyl and -C (O) C_1-3 alkyl.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R₂ is selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy and C₁-C₃ hydroxyalkyl.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R₂ is hydrogen or deuterium.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R₃ is hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl or C₁-C₃ hydroxyalkyl.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R₄ and R₅ are independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl and C₁-C₃ hydroxyalkyl.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R₆ is independently selected from the group consisting of hydrogen, halogen, C₁-C₃ alkyl and C₁-C₃ alkoxy.
The compound of claim 1, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R₆ is independently selected from the group consisting of H, F, Cl, CH₃, OCH₃, OCD₃ and
The compound of claim 3, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, being a compound of formula (II-c) :

wherein,

L₁ is bond, - (CH₂) _n-, -C (O) -, -O-, -NHC (O) -or –C (O) NH-;

X₁ is N or CH;

X₂ is O, N or CH, when X₂ is O, L₂ and R₈ are absent;

R₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy and C₁-C₃ hydroxyalkyl;

R₇ is independently selected from the group consisting of hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl and C_1-6 alkoxy;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

R₈ is selected from the group consisting of hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_3-8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the C_3-8 cycloalkyl and 4-8 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

x is 0, 1 or 2;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2;

M₁, M₂, R₂, R₃, R₄, R₅, R₆, n, y and z are defined as claim 3.
The compound of claim 17, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, being a compound of formula (III-a) - (III-d) :
The compound of claim 3, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, being a compound of formula (IV) or (V) :

wheein,

R_e is independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, or 4-8 membered heterocyclyl;

L₁ is bond, - (CH₂) _n-, -CHR_f-, -C (O) -, O, -NHC (O) -or –C (O) NH-;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-;

R_f is R_aa, –C (O) NR_aaR_bb, –NC (O) R_aa or NR_aaR_bb,

R_aa and R_bb are independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl;

X₁ is N or CH;

X₂ is O, S, S (O) ₂, N or CH, when X₂ is O, S, or S (O) ₂, L₂ and R₈ are absent;

R₇ is independently selected from the group consisting of hydrogen, oxo, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl and C_1-6 alkoxy;

R₈ is selected from the group consisting of hydrogen, cyano, halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 hydroxyalkyl, C_3-8 cycloalkyl and 4-8 membered heterocyclyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

n is 0, 1, 2, 3 or 4;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2;

z is 0 or 1.
The compound of claim 19, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

R_e is independently selected from the group consisting of hydrogen, deuterium, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, or C₃-C₆ cycloalkyl;

M₁ is -CR^a-or –N-;

R^a is hydrogen, deuterium, halogen, C_1-3 alkyl or C_1-3 hydroxyalkyl, wherein the C_1-3 hydroxyalkyl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, C_1-3 hydroxyalkyl, and C_3-6 cycloalkyl;

L₁ is bond, - (CH₂) _n-, -C (O) -, -O-, -NHC (O) -or –C (O) NH-, preferable, L₁ is bond;

X₁ is N or CH;

X₂ is O, N or CH, when X₂ is O, L₂ and R₈ are absent;

R₇ is independently selected from the group consisting of hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl and C_1-3 alkoxy;

L₂ is bond, - (CH₂) _n-, -C (O) -, -NHC (O) -or –C (O) NH-, preferable, L₂ is bond or - (CH₂) _n-;

R₈ is selected from the group consisting of hydrogen, cyano, halogen, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_1-3 hydroxyalkyl, C_3-6cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, wherein each of the C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, C_1-3 hydroxyalkyl, C_3-6 cycloalkyl and 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl and C_1-3 hydroxyalkyl;

n is 1, 2 or 3;

p is 1, 2 or 3;

s is 0, 1 or 2;

t is 0, 1 or 2.
A compound selected from the group consisting of:

, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or
mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A pharmaceutical composition comprising a therapeutically effective amount of the compound of claims 1 to 21, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
A method of treatment of a condition which is modulated by BTK, wherein the method comprises administering a therapeutic amount of a compound of claims 1 to 21, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt solvate, or prodrug thereof, or the pharmaceutical composition of claim 22, to a patient in need thereof;

preferably, the condition modulated by BTK is solid cancer, lymphoma, leukemia, autoimmune diseases, inflammatory disorders, or fibrosis.
A method of treatment of a condition selected from solid cancer, lymphoma, leukemia, autoimmune diseases, inflammatory disorders, or fibrosis comprising administering a therapeutically effective amount of a compound of any of claims 1 to 21, or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt solvate, or prodrug thereof, or the pharmaceutical composition of claim 22;

preferably, the condition is selected from B-cell malignancy, B-cell lymphoma, chronic lymphocyte leukemia, small lymphocytic lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, Sjogren's syndrome and disorders associated with renal transplant.
A method for preparing a compound of formula (III-b) , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by comprising the following step:

reacting the compound of formula (b) with (a) to obtain the compound of formula (c) , and formula (III-b) is obtained by hydrolysis reaction;

wherein,

X is halogen,

M₁, M₂, X₁, X₂, L₁, L₂, R₇, R₈, s, t and x are defined as claim 18.