CN111393447B

CN111393447B - Pyrimidopyrazole compound, and preparation method and application thereof

Info

Publication number: CN111393447B
Application number: CN202010407722.4A
Authority: CN
Inventors: 胡永韩; 吴冬冬; 彭薇; 张秀春; 吴予川
Original assignee: Suzhou Sinovent Pharmaceuticals Co Ltd
Current assignee: Suzhou Sinoway Pharmaceutical Technology Co ltd
Priority date: 2020-05-14
Filing date: 2020-05-14
Publication date: 2021-01-15
Anticipated expiration: 2040-05-14
Also published as: CN111393447A

Abstract

The invention discloses a pyrimido pyrazole compound, and a preparation method and application thereof. The application provides a pyrimido pyrazole compound shown as a formula I or a pharmaceutically acceptable salt thereof; the compound has better inhibiting effect on CDK 7.

Description

Pyrimidopyrazole compound, and preparation method and application thereof

Technical Field

The invention relates to a pyrimido pyrazole compound, a preparation method and application thereof.

Background

Cyclin-dependent kinases (CDKs) belong to the serine/threonine kinase family, whose monomers are not active themselves and must bind to corresponding Cyclins (Cyclins) to form active heterodimer complexes to exert a regulatory action, which can catalyze phosphorylation of corresponding substrates, directly or indirectly regulate the cells to complete the cell cycle, leading to growth and proliferation of the cells. It has now been found that the human genome encodes 21 CDKs and more than 15 Cyclins. CDKs can be divided into two major categories according to their function: CDKs that control the cell cycle and CDKs that control transcription by the cell. CDK 1/2/4/6 is mainly related to the cell cycle, while CDK7/8/9/10 is mainly related to the transcription mechanism of intracellular genetic information (Asghar U, Witkiewicz A K, Turner N C, et al. the history and future of targeting cycle-dependent kinases in cancer therapy. Nat Rev Drug Discov, 2015 (2): 130-) -146).

CDK7 is an important member of the CDKs family, regulating the cell cycle mainly in two indirect ways: CDK7 together with cyclin H and Mat1 constitute CAK (CDKs activating kinase), which further phosphorylates CDK1/2, thereby activating their function in the cell cycle (Yee A, Nichols MA, Wu L, Hall FL, Kobayashi R, Xiong Y. molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) activating factor. cancer Res 1995; 55: 6058-. Another way is CDK7 as a subunit component of the universal transcription factor TFIIH, phosphorylating the large subunit carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII), regulating the gene transcription process in cells (Kelso TW, Baumgart K, Eickhoff J, Albert T, Antrecht C, Lemcke S et al. cycle-dependent kinase 7control mRNA synthesis by feedback stability of initiation complexes, lead to altered gene expression, Cell cycle progression, and summary of Cell cells mol 2014; 34:3675 3688.). Because CDK7 has the dual functions of CAK and CTD phosphorylation, it plays important roles in cell proliferation, cell cycle and transcription.

In recent years, inhibition of CDK7 has become a potential therapeutic strategy in a variety of cancers. Inhibition of CDK7 inhibits the expression of key oncogenes such as c-Myc and the like (Chipurro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, et al, CDK7 inhibition supressors super-enhancer-linked oncogenenic transcription in MYCN-drive cancer. Cell 2014; 159: 1126-39.). Data from preclinical studies show that small molecule inhibitors that inhibit CDK7 have good anti-cancer effects in hormone receptor positive and triple negative breast cancers (Wang Y, Zhang T, Kwiatkowski N, Abraham BJ, Lee TI, Xie S, et al.cdk7dependent transcriptional introduction in triple-negative breast cancer. Cell 2015; 163: 174-86), as well as in transcription factor driven cancers such as Small Cell Lung Cancer (SCLC) (Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, et al.targeting transcriptional introduction in small Cell lung cancer. Cell 7 inhibitor. Cell 909; 201422: 201422). These cancers currently lack effective therapeutic means and have significant unmet medical needs. Also, because of their different mechanisms of action, CDK7 inhibitors may be effective against cancers that are resistant to current therapeutic approaches. Therefore, the development of specific inhibitors of CDK7 would likely be an effective means of treating these malignancies.

Among the reported CDK7 inhibitors are the covalent irreversible inhibitor SY1365, THZ1 of Syros. THZ1 has the structure:

disclosure of Invention

The technical problem to be solved by the invention is the defect that the existing CDK7 inhibitor has an excessively single structure, so that the application provides a pyrimido pyrazole compound, a preparation method and application thereof, and the compound has a good effect of inhibiting CDK 7.

The present invention solves the above-mentioned problems by the following technical means.

The invention provides a pyrimido pyrazole compound shown as a formula I or a pharmaceutically acceptable salt thereof;

wherein ring B is

L is-C ═ O- (NR)^c1)_n1-(CR^c2R^c3)_n2-; (including-C-O-attached to ring B or to ring D)

n1 and n2 are independently 0 or 1; (when 0, it is represented by a bond)

R^c1、R^c2And R^c3Independently is H or C₁-C₄An alkyl group;

ring D is 5-10 membered heteroaryl, or substituted with one or more substituents R^d1Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by one or more substituents R^d1In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1-3; when the substituents are plural, the same or different;

R^d1independently is C₁-C₆Alkyl, N (R)^d11R^d12)-、C₃-C₇Cycloalkyl or 4-7 membered heterocycloalkyl; in said 4-7 membered heterocycloalkyl, the heteroatom or heteroatom group is selected from the group consisting of N, O, S, S (═ O) and S (═ O)₂1-2 in number;

R^d11and R^d12Independently is H or C₁-C₄An alkyl group;

the band "-" carbon atom means, when a chiral carbon atom, an R configuration, an S configuration, or a mixture thereof.

In certain preferred embodiments of the present invention, certain groups of the pyrimido pyrazole compounds of formula I are defined as follows (non-referenced groups are as described in any embodiment herein)

Ring B represents

Ring B represents

L is-C ═ O-, -C ═ O- (NR)^c1)-(CR^c2R^c3) -or-C ═ O- (NR)^c1)_n1-. (including-C ═ O-flanked by ring B, or ring D).

When ring B represents

When L is- (NR)^c1)-(CR^c2R^c3) -C ═ O-or-C ═ O- (NR)^c1)_n1-. (L right side connected to Ring B).

When ring B represents

When L is — C ═ O-. (N-side is bonded to-C ═ O-).

In certain preferred embodiments of the present invention, certain groups of the heteroaromatic nitrile compounds of formula I are defined as follows (the groups not mentioned are as described in any of the embodiments of the present application),

in the ring B, when the carbon atom bonded to NH is a chiral carbon atom, it is

Configuration. (terminal a is connected to L)

in the ring B, when the carbon atom bonded to L is a chiral carbon atom, it is

Configuration. (terminal a is connected to L)

in ring B, when the carbon atom to which L, NH is bonded is simultaneously a chiral carbon atom, it is

Configuration. (terminal a is connected to L)

R^c1Is H.

R^c2And R^c3Independently is H.

Ring D is pyridazine, pyrimidine, pyrazine, and thiazole;

for example, the ring B group is

When, ring D is pyrimidine, pyrazine, or thiazole;

the ring B group being

When ring D is pyridazine, pyrimidine or pyrazine.

R^d1Independently is C₁-C₆Alkyl, N (R)^d11R^d12) -or 4-7 membered heterocycloalkyl; e.g. C₁-C₆Alkyl or 4-7 membered heterocycloalkyl; and also e.g. C₁-C₆An alkyl group.

R^d11And R^d12Independently is C₁-C₄An alkyl group.

The L group is located meta or para to-CN.

When R is^c1、R^c2And R^c3Independently is C₁-C₄When alkyl, said C₁-C₄Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

When ring D represents a 5-to 10-membered heteroaryl group, or substituted by one or more substituents R^d1Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by a substituent R^d1The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is 5-6 membered heteroaryl; such as pyridazine (a.k.a., for example)

) Pyrimidines (also e.g.

Also for example

d-terminal denotes a connection to CN), pyrazine (again, for example

) And thiazoles (e.g. thiazole)

Also for example

End d indicates attachment to CN).

When R is^d1Is C₁-C₆When alkyl, said C₁-C₆Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; such as methyl.

When R is^d1Is C₃-C₇When there is a cycloalkyl group, said C₃-C₇Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

When R is^d1In the case of 4-7 membered heterocycloalkyl, said 4-7 membered heterocycloalkyl is a morphinyl group, e.g.

When R is^d11And R^d12Independently is C₁-C₄When alkyl, said C₁-C₄Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; such as methyl.

L is-C ═ O-, -NH-C ═ O-, or-C ═ O- (NH) - (CH)₂)-。

Ring B is

Ring B is

R^d1Independently is-CH₃、—CH₂CH₃、—NH₃、—NH(CH₃)、—N(CH₃)₂、

For example R^d1Independently is-CH₃、—N(CH₃)₂Or

Ring D is

(e.g. in

)、

(e.g. in

)、

(e.g. in

)、

(e.g. in

(e.g. in

)、

(e.g. in

) Or

(e.g. in

(e.g. in

). The d-terminal indicates attachment to the CN ring.

Is composed of

Is composed of

Ring B is

L is-C ═ O-, -C ═ O- (NR)^c1)-(CR^c2R^c3) -or-C ═ O- (NR)^c1)_n1-; (including-C ═ O-flanked by ring B, or ring D); for example: when L is-C ═ O- (NR)^c1)-(CR^c2R^c3) -C ═ O-is attached to ring B;

R^c1、R^c2and R^c3Independently is H;

ring D is 5-10 membered heteroaryl, or substituted with one or more substituents R^d1Substituted 5-10 membered heteroaryl; for example, said 5-to 10-membered heteroaryl group is substituted by a substituent R^d1The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is 5-6 membered heteroaryl;

R^d1is independently C₁-C₆Alkyl, N (R)^d11R^d12) -or 4-7 membered heterocycloalkyl; e.g. C₁-C₆Alkyl or N (R)^d11R^d12) -; and also e.g. C₁-C₆An alkyl group;

preferably, when the carbon atoms connected with NH and L in the ring B are chiral carbon atoms, the ring B is

And/or, when ring B represents cyclohexyl, L is-C ═ O- (NR)^c1)-(CR^c2R^c3)-、-(NR^c1) -C ═ O-or-C ═ O- (NR)^c1)_n1-；

And/or, when ring B represents piperidine, L is-C ═ O-;

and/or, R^d11And R^d12Independently is C₁-C₄An alkyl group;

and/or the L group is positioned meta or para to the-CN.

When the ring B group is

The L groups are independently-C ═ O- (NR)^c1)-(CR^c2R^c3) -or-C ═ O- (NR)^c1)_n1-; for example-NH-C ═ O-or-C ═ O- (NH) - (CH)₂) (ii) a -NH-side to ring B or ring D;

ring D represents a 5-to 10-membered heteroaryl group, or substituted by one or more substituents R^d1Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by a substituent R^d15-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is pyrimidine, pyrazine and thiazole;

preferably, ring D is

(e.g. in

)、

(e.g. in

)、

(e.g. in

(e.g. in

)、

(e.g. in

)、

(e.g. in

)

(e.g. in

). The d-terminal indicates attachment to the CN ring.

When the ring B group is

The L groups are independently-C ═ O-;

ring D represents a 5-to 10-membered heteroaryl group, or substituted by one or more substituents R^d1Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by a substituent R^d15-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is pyridazine, pyrimidine and pyrazine;

ring D is

(e.g. in

)、

(e.g. in

)、

(e.g. in

)、

(e.g. in

). The d-terminal indicates attachment to the CN ring.

In certain preferred embodiments of the present invention, the heteroaromatic nitrile compound of formula I has any one of the following structures:

in the invention, the heteroaromatic nitrile compound shown as the formula I or the pharmaceutically acceptable salt thereof has one or more chiral carbon atoms, so that optical purity isomers, such as pure enantiomers, racemes or mixed isomers, can be obtained by separation. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization to form salts, or by chiral preparative column separation.

In the invention, the heteroaromatic nitrile compound shown in the formula I or the pharmaceutically acceptable salt thereof can exist in the form of a single stereoisomer or a mixture (such as racemate) of the stereoisomer if the stereoisomer exists. The term "stereoisomer" refers to either a cis-trans isomer or an optical isomer. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound according to the invention is not less than 95% relative to all stereoisomers of the compound.

In the present invention, the heteroaromatic nitrile compounds represented by formula I or pharmaceutically acceptable salts thereof can be synthesized by methods similar to those known in the chemical art, and the steps and conditions thereof can be synthesized by referring to the steps and conditions of similar reactions in the art, particularly according to the description herein. The starting materials are generally from commercial sources, such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SciFinder, Reaxys online databases).

The invention also provides a preparation method of the heteroaromatic nitrile compound shown in the formula I, which comprises the following steps: in a solvent, in the presence of a condensing agent and alkali, carrying out a condensation reaction shown as the following on a compound shown as a formula II or a compound shown as a formula IV and a compound shown as a formula V, or carrying out a condensation reaction shown as the following on a compound shown as a formula III and a compound shown as a formula VI to obtain the pyrimido pyrazole compound shown as the formula I;

wherein, the definition of the ring D is as described above.

The conditions and operation of the condensation reaction described in the present invention are as conventional in such condensation reactions in the art. In the present invention, the solvent may be an amide-based solvent, such as DMF. The condensing agent may be HATU. The base may be DIEA. The temperature of the condensation reaction may be room temperature (e.g., 10 ℃ to 30 ℃).

In the invention, the heteroaromatic nitrile compound shown in the formula I or the pharmaceutically acceptable salt thereof can also be prepared by peripheral modification of the prepared heteroaromatic nitrile compound shown in the formula I or the pharmaceutically acceptable salt thereof by adopting a conventional method in the field to obtain other heteroaromatic nitrile compounds shown in the formula I or the pharmaceutically acceptable salt thereof.

The necessary starting materials or reagents for the preparation of the heteroaromatic nitrile compounds of formula I or pharmaceutically acceptable salts thereof are commercially available or are prepared by synthetic methods known in the art. The compounds of the invention can be prepared as free bases or as salts with acids by the methods described in the experimental section below. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and has all the effects of the parent compound. Pharmaceutically acceptable salts can be prepared by treating according to conventional methods with the corresponding acid in a suitable organic solvent which is an organic base.

Examples of salt formation include: for base addition salts, it is possible to prepare salts of alkali metals (such as sodium, potassium or lithium) or alkaline earth metals (such as aluminum, magnesium, calcium, zinc or bismuth) by treating the compounds of the invention having suitably acidic protons in an aqueous medium with alkali metal or alkaline earth metal hydroxides or alkoxides (such as ethoxide or methoxide) or with suitably basic organic amines (such as diethanolamine, choline or meglumine).

Alternatively, for acid addition salts, salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, Eurya japonica acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid, mandelic acid, methanesulfonic acid, myfuroic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid or trimethylacetic acid.

The "compound of the invention" or "compound of the invention" includes any heteroaromatic nitrile compound shown in formula I or pharmaceutically acceptable salt thereof. The compounds of the invention may also exist in the form of hydrates or solvates.

The invention also provides a pharmaceutical composition, which comprises the heteroaromatic nitrile compound shown as the formula I or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. In the pharmaceutical composition, the dosage of the heteroaromatic nitrile compound shown in the formula I or the pharmaceutically acceptable salt thereof can be therapeutically effective amount.

The invention also provides a kit, which comprises the heteroaromatic nitrile compound shown as the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition.

The pharmaceutically acceptable carrier (pharmaceutic adjuvant) can be those widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

The invention also provides an application of the heteroaromatic nitrile compound shown in the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of CDK kinase inhibitors. The CDK kinase is preferably CDK7 kinase.

In said use, said CDK7 kinase inhibitor is useful in a mammalian organism; also useful in vitro, primarily for experimental purposes, for example: the comparison is provided as a standard or control, or a kit is prepared according to methods conventional in the art, to provide a rapid test for the inhibitory effect of CDK7 kinase.

The invention also provides application of the heteroaromatic nitrile compound shown in the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of medicines for treating and/or preventing diseases related to CDK kinase interaction. The CDK kinase may be CDK7 kinase; the medicament can be used for treating and/or preventing proliferative diseases or infectious diseases.

The invention also provides an application of the heteroaromatic nitrile compound shown as the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicines; the medicament can be used for treating and/or preventing proliferative diseases or infectious diseases.

The invention also provides a method for treating and/or preventing proliferative diseases, which adopts the heteroaromatic nitrile compound shown as the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition.

Exemplary proliferative diseases for the above applications include cancer (e.g., leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, or lung cancer), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases. The leukemia (blood cancer) is selected from Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), lymphoma, and multiple myeloma.

The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal tissue mass in which the growth of the tissue mass exceeds and is not coordinated with the growth of normal tissue. A neoplasm or tumor can be "benign" or "malignant," depending on the following characteristics: the degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. A "benign neoplasm" is generally well differentiated, grows characteristically slower than a malignant neoplasm, and remains localized to the site of origin. In addition, benign neoplasms do not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenoma, acrochordon, senile hemangioma, seborrheic keratosis, freckles, and sebaceous hyperplasia. In some cases, certain "benign" tumors may subsequently develop malignant neoplasms, which may be caused by additional genetic changes occurring in a subpopulation of the tumor's neoplastic cells, and these tumors are referred to as "pre-malignant neoplasms". An exemplary pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplasia) and have characteristically rapid growth with progressive infiltration, invasion, and damage to surrounding tissues. In addition, malignant neoplasms generally have the ability to metastasize to distant sites.

The term "metastasis," "metastatic," or "metastasizing" refers to the expansion of cancer cells or metastasis from a primary or primary tumor to another organ or tissue, and is generally identified by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary or primary tumor and not of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is referred to as metastatic prostate cancer and includes cancerous prostate cancer cells that grow in bone tissue.

The term "cancer" refers to malignant tumors (Stedman's Medical Dictionary, 25th edition (25th ed), Hensyl edition; Williams and Wilkins (Williams & Wilkins: Philadelphia): Philadelphia (Philadelphia), 1990). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland tumors; anal cancer; angiosarcomas (e.g., lymphangiosarcoma, lymphangial endotheliosarcoma, angiosarcoma); appendiceal carcinoma; benign monoclonal gammopathy; biliary tumors (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, papillary breast cancer, medullary breast cancer); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumors; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colon adenocarcinoma); connective tissue tumors; epithelial cancer; ependymoma; ependymoma (e.g., kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, barrett's adenocarcinoma); ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiarity with hypereosinophilia; gallbladder cancer; stomach cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumors (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemias such as Acute Lymphocytic Leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), Acute Myelogenous Leukemia (AML) (e.g., B-cell AML, T-cell, AML), Chronic Myelogenous Leukemia (CML) (e.g., B-cell CML, T-cell CML), and Chronic Lymphocytic Leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomas such as Hodgkin's Lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL such as Diffuse Large Cell Lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Mantle Cell Lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), Hairy Cell Leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary Central Nervous System (CNS) lymphoma, and T-cell non-Hodgkin's lymphoma, such as precursor T-lymphocyte lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large-cell lymphoma); one or more leukemia/lymphoma mixtures as described above; and Multiple Myeloma (MM)), heavy chain disorders (e.g., alpha chain disorders, gamma chain disorders, mu chain disorders); hemangioblastoma; cancer of the pharynx; inflammatory myofibroma tumors; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer); lung cancer (e.g., bronchial cancer, Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., Polycythemia (PV), Essential Thrombocythemia (ET), agnogenic myelodysplasia (AMM), also known as Myelofibrosis (MF), chronic idiopathic myelofibrosis, Chronic Myelogenous Leukemia (CML), Chronic Neutrophilic Leukemia (CNL), hyperkinetic syndrome (HES)); neuroblastoma; neurofibromas (e.g., Neurofibromatosis (NF) type 1 or type 2, schwannoma); neuroendocrine tumors (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid)); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonic carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic carcinoma, Intraductal Papillomatosis (IPMN), islet cell tumor of pancreas); penile cancer (e.g., paget's disease of the penis and scrotum); pineal tumor; primitive Neuroectodermal Tumors (PNT); a plasmacytoma; a paraneoplastic syndrome; intraepithelial tumors; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; tumors of salivary glands; skin cancer (e.g., Squamous Cell Carcinoma (SCC), Keratoacanthoma (KA), melanoma, Basal Cell Carcinoma (BCC)); small bowel cancer (e.g., appendiceal cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma, liposarcoma, malignant schwannoma (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small bowel cancer; sweat gland cancer; a synovial tumor; testicular cancer (e.g., seminoma, testicular embryonic carcinoma); thyroid cancer (e.g., thyroid cancer, Papillary Thyroid Cancer (PTC), medullary thyroid cancer, papillary thyroid cancer); cancer of the urethra; vaginal cancer; and vulvar cancer (e.g., vulvar paget's disease).

The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in the healthy body of a subject for healing wounds after injury and for restoring blood flow to tissues. The healthy body controls angiogenesis by many means, for example, angiogenesis-stimulating growth factors and angiogenesis inhibitors. Many disease states, such as cancer, blindness to diabetes, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by aberrant (i.e., increased or excessive) angiogenesis. Abnormal or pathological angiogenesis refers to angiogenesis greater than that in the normal body, particularly in adults not associated with normal angiogenesis (e.g., menstruation or wound healing). Aberrant angiogenesis can provide new blood vessels that feed diseased tissues and/or destroy normal tissues, and in the case of cancer, the new vessels can allow cancer cells to escape into the circulation and lodge in other organs (tumor metastases). In certain embodiments, the angiogenesis is pathological angiogenesis.

The term "inflammatory disease" refers to a disease caused, derived or caused by inflammation. The term "inflammatory disease" may also refer to an inflammatory response that is aberrant through the regulation of macrophage, granulocyte and/or T-lymphocyte evoked amplification responses leading to aberrant tissue damage and/or cell death. Inflammatory diseases may be acute or chronic inflammatory conditions and may be caused by infectious or non-infectious causes. Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune diseases, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type I), myasthenia gravis, hashimoto's thyroiditis, Graves 'disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, interstitial pneumonia of common type (UIP), asbestosis, Crohn's disease, Graves's disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, progressive systemic sclerosis, degenerative arthritis, rheumatoid arthritis, sclerosing disease, sclerosing's, Silicosis, bronchiectasis, berylliosis, talcpsis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphatic interstitial pneumonia, giant cell interstitial pneumonia, intercellular pneumonia, exogenous allergic alveolitis, wegener's granulomatosis and the relevant forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, hepatitis, delayed hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, airway inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hay fever, allergy, acute hypersensitivity reactions, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, transplant rejection, host versus graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, Bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.

The term "autoimmune disease" refers to a disease resulting from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some parts of the body as pathogens and attacks its own cells. This may be limited to certain organs (e.g., in autoimmune thyroiditis) or contain specific tissues in different places (e.g., Goodpasture's disease which may affect basement membrane in both the lung and kidney). Autoimmune diseases are typically treated with immunosuppression (e.g., drugs that reduce the immune response). Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarticular inflammatory polyarteritis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-related vasculitis (e.g., wegener's granulomatosis, microscopic polyangiitis), uveitis, sjogren's syndrome, crohn's disease, reiter's syndrome, ankylosing spondylitis, lyme arthritis, guillain-barre syndrome, hashimoto's thyroiditis, and cardiomyopathy.

The term "autoinflammatory disease" refers to a similar but different disease classification than autoimmune disease. Both autoinflammatory and autoimmune diseases share the same feature, i.e. both groups of disorders result from the immune system attacking the subject's own tissues and leading to increased inflammation. In idiopathic inflammatory diseases, the innate immune system of a subject causes inflammation of unknown origin. The innate immune system reacts, although in subjects it never encounters autoantibodies or antigens. Spontaneous inflammatory disorders are characterized by a strong onset of inflammation that leads to such symptoms as fever, rash, or joint swelling. These diseases can also carry the risk of amyloidosis, a potentially fatal accumulation of blood proteins in vital organs. Autoinflammatory diseases include, but are not limited to, Familial Mediterranean Fever (FMF), neonatal onset multiple system inflammatory disease (NOMID), Tumor Necrosis Factor (TNF) receptor-associated periodic syndrome (TRAPS), interleukin 1 receptor antagonist (DIRA) deficiency, and behcet's disease.

The term "kinase" refers to any enzyme that catalyzes the addition of phosphate groups to amino acid residues of proteins. For example, serine kinases catalyze the addition of phosphate groups to serine residues in proteins. In certain embodiments, the kinase is a protein kinase. Examples of kinases include, but are not limited to, CMGC kinases (e.g., cyclin-dependent kinases (CDKs, e.g., CDK1, CDK2, CDK2, CDK4, CDK5, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, CDK14, CDK16, CDK20), mitogen protein kinases (MAPKs, e.g., MAPK1, MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK15), glycogen synthase kinase 3(GSK3, e.g., GSK 3a, GSK3 β), or CDC-like kinases (CLK, e.g., CLK1, pkc 2, CLK3, 4), pka protein kinases (e.g., pka protein kinases a) AGC), CDC protein kinases (e.g., pkc protein kinases c), CDC protein kinases c protein kinase c), CDC protein kinase c kinase (pkc) kinases, CDC protein kinase c), cdpk), CDK11, CDK 3²⁺Calmodulin-dependent protein kinases (CaM kinases, e.g., specialized CaM kinases, multifunctional CaMKinases), casein kinase 1(CK1, e.g., CK1 α, CK1 β 1, CK1 γ 1, CK1 γ 2, CK1 γ 3, CK1 δ, CK1 ∈), stekinase (e.g., sterilized yeast homolog 7, sterilized yeast homolog 11, or sterilized yeast homolog 20 kinase), tyrosine kinase (TK, e.g., Receptor Tyrosine Kinase (RTK), non-receptor tyrosine kinase (nRTK)), and tyrosine kinase-like kinase (TKL, e.g., Mixed Lineage Kinase (MLK), RAF, Serine Threonine Kinase Receptor (STKR), leucine-rich repeat kinase (rk), LIM domain kinase (LIMK), testis-expressing serine kinase (TESK), IL1 receptor-associated kinase (iRAK), Receptor Interacting Protein Kinase (RIPK)).

The term "CDK" refers to a cyclin-dependent kinase. The CDK binds to cyclin (e.g., cyclin H), which is a regulatory protein. CDKs phosphorylate serine and threonine on substrates. The consensus sequence for the phosphorylation site in the amino acid sequence of the CDK substrate is [ S/T ] PX [ K/R ], wherein S/T is phosphorylated serine or threonine, P is proline, X is any amino acid, K is lysine, and R is arginine. CDKs include CDK1, CDK2, CDK2, CDK4, CDK5, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK14, CDK16, and CDK 20. CDK7 is a CDK in which the substrate is cyclin H, MAT1 (e.g., MNAT1), or cyclin H and MAT 1.

The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for use by the patient. The "patient" is preferably a mammal, more preferably a human.

The term "pharmaceutically acceptable salts" refers to salts prepared from the compounds of the present invention with relatively non-toxic, pharmaceutically acceptable acids. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, phosphorous acid, sulfuric acid, hydrogen sulfate, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively basic functional groups, they may be converted to acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).

By "treatment" is meant any treatment of a disease in a mammal, including: (1) preventing disease, i.e., the symptoms that cause clinical disease do not develop; (2) inhibiting disease, i.e., arresting the development of clinical symptoms; (3) alleviating the disease, i.e., causing regression of clinical symptoms.

By "effective amount" is meant an amount of a compound, when administered to a patient in need of treatment, that is sufficient to (i) treat the associated disease, (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease or condition, or (iii) delay the onset of one or more symptoms of a particular disease or condition described herein. The amount of the heteroaromatic nitrile compound of formula I or a pharmaceutically acceptable salt thereof or pharmaceutical composition as described above that corresponds to this amount will vary depending on factors such as the particular compound, the disease condition and its severity, the characteristics of the patient in need of treatment (e.g., body weight), etc., but can nevertheless be routinely determined by one skilled in the art.

"prevention" as used herein refers to a reduction in the risk of acquiring or developing a disease or disorder.

"pharmaceutical composition" as used herein, refers to a formulation of one or more compounds of the present invention or salts thereof with a carrier generally accepted in the art for delivery of biologically active compounds to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate delivery of the drug to an organism.

The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with, and facilitates the administration of, an active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is acceptable for use in humans or animals (e.g., livestock) as permitted by the national food and drug administration. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

The pharmaceutical composition can be prepared into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powder, granules, paste, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.

The route of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof includes, but is not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral.

For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient. For example, for pharmaceutical compositions intended for oral administration, tablets may be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and processed into a mixture or granules, if necessary with the addition of small amounts of excipients, to form tablets or tablet cores. The core may be combined with an optional enteric coating material and processed into a coated dosage form more readily absorbed by an organism (e.g., a human).

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds. When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left.

Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. E.g. C₁-C₆Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5, or 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.

Numerical ranges defined in the substituents herein, such as 0 to 4, 1-4, 1 to 3, etc., indicate integers within the range, such as 1-6 being 1, 2, 3, 4, 5, 6.

In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.

The term "comprising" is open-ended, i.e. comprising what is specified in the invention, but does not exclude other aspects.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including deuterium and hydrogen variants, so long as the valency of the particular atom is normal and the substituted compound is stable.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.

The term "one or more" or "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more; such as 1, 2, 3, 4 or 5.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁～C₆Alkyl "or" C₁～C₆Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group; "C_1-4Alkyl refers specifically to independently disclosed methyl, ethyl, C₃Alkyl (i.e. propyl, including n-propyl and isopropyl), C₄Alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms. E.g. C₁-C₂₀Alkyl, preferably C₁-C₆Alkyl groups such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl and the like.

The term "heterocycloalkyl" refers to a saturated cyclic group having a heteroatom containing 1 or more independently selected from N, O, S, S (═ O) and S (═ O)₂And the remainder are groups of a stable 3-to 10-membered saturated heterocyclic ring system composed of carbon. Unless otherwise specifically indicated herein, a heterocycloalkyl group can be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic, or higher ring system, which can include fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocycloalkyl"). heterocycloalkyl bicyclic ring systems can include one or more heteroatoms in one or both rings; and are saturated exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, and thietanyl, or stereoisomers thereof; exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, oxiranyl, thietanyl, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiafuranyl, dithiofuranyl, or isomers and stereoisomers thereof. Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, sulfocyclopentanyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof; exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepinyl, thiepanyl, and diazepanyl, or isomers and stereoisomers thereof. In one embodiment, a typical 5-6 membered monocyclic heterocyclyl containing 1 or more heteroatoms independently selected from N, O and S, for example

In a certain embodiment, "heterocycloalkyl" is a 4-6 membered heterocycloalkyl in which the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, or 3.

The term "heteroaryl" refers to an aromatic group containing a heteroatom, which may be a single ring or a fused ring, preferably a 5-12 membered heteroaryl group containing 1-4 heteroatoms independently selected from N, O and S, including but not limited to pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrahydropyrrolyl. In one embodiment, a 5-6 membered monocyclic heteroaryl group typically containing 1 or more heteroatoms independently selected from N, O and S, e.g.

(e.g. in

)、

(e.g. in

)、

(e.g. in

)、

(e.g. in

)、

(e.g. in

)、

(e.g. in

)、

(e.g. in

)、

(e.g. in

)、

(e.g. in

) Or

(e.g. in

). In a certain embodiment, a "heteroaryl" is a 5-6 membered heteroaryl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, or 3.

The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.

When no atom is indicated in the listed substituents for connecting to a compound included in the general chemical structure but not specifically mentioned, such substituent may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When no substituent is specifically indicated in the listed group, such group is simply referred to as unsubstituted. For example when "C₁～C₄When an alkyl group is "without the limitation of" substituted or unsubstituted ", it means only" C₁～C₄Alkyl "by itself or unsubstituted C₁～C₄Alkyl groups ".

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

In some specific structures, when an alkyl group is explicitly indicated as a linking group, then the alkyl group represents a linked alkylene group.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is standard in the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.

It should be understood that as used herein, singular forms, such as "a", "an", include plural references unless the context clearly dictates otherwise. Furthermore, the term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects.

The present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions can be referred to those conventional in the art unless otherwise indicated.

Unless otherwise indicated, the present invention employs standard nomenclature for analytical chemistry, organic synthetic chemistry, and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, light emitting device performance detection.

In addition, it should be noted that, unless otherwise explicitly indicated, the description of "… independently" as used herein is to be understood in a broad sense to mean that each individual entity so described is independent of the other and may be independently the same or different specific groups. In more detail, the description "… is independently" can mean that the specific options expressed between the same symbols do not affect each other in different groups; it can also be said that in the same group, the specific options expressed between the same symbols do not affect each other.

It will be understood by those skilled in the art that, in accordance with the convention used in the art, the structural formulae used in the radicals described herein

Means that the corresponding group is linked to other fragments, groups in the compound through this site.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the CDK7 kinase inhibitor has high inhibitory activity and can be used for treating various malignant tumors.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1 synthesis of SZ-015249:

step 1:

015249A1 (ref US2019144456A1) (500mg,2.39mmol), 015249A2(600mg, 2.87mmol), DIEA (1.0mL) were mixed in isopropanol (5mL) and stirred at room temperature for 1 h. The organic phase was dried over sodium sulfate, dried and purified by flash silica gel column chromatography (PE: EA: 5: 1; Rf: 0.3) to give 015249A3(600mg), LCMS: [ M + H ]: silica gel column chromatography]⁺374.2。

Step 2:

015249A3(600mg) was dissolved in 4mL of DCM, and TFA (2mL) was added slowly and stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was directly spin-dried, adjusted to pH 8 with saturated sodium bicarbonate, extracted with DCM (20mL), and the organic phase was spin-dried to give 400mg of a white solid, LCMS: [ M + H ]]⁺274.5。

And 3, step 3:

015249A4(91mg,0.33mmol), 2-cyanopyrimidine-5-carboxylic acid (50mg, 0.33mmol), HATU (153mg,0.39mmol) and DIEA (0.3mL) were mixed in DMF (2mL) and stirred at room temperature for 1 h. The organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% aqueous ammonium carbonate) and lyophilized to give 54mg of SZ-015249. LCMS: [ M + H]⁺405.3。

¹H NMR(400MHz,DMSO-d₆)9.69(s,1H),9.13(s,2H),8.33(s,1H),6.74(s,1H),4.60-4.63(m,1H),4.21-4.23(m,1H),3.69-3.72(m,1H),3.21-3.22(m,2H),2.96-3.02(m,1H),2.60(s,3H),2.03-2.05(m,1H),1.79-1.91(m,3H),1.30(d,J＝6.8Hz,6H)。

Example 2 synthesis of SZ-015248:

SZ-015248A1(77mg,0.51mmol), SZ-015248A2(200mg, 0.51mmol), HATU (240mg,0.62mmol) and DIEA (0.4mL) were mixed in DMF (2mL) and stirred at room temperature for 1 h. The organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% aqueous ammonium carbonate) and lyophilized to give 54mg of SZ-015248. LCMS: [ M + H]⁺419.3。

¹H NMR(400MHz,DMSO-d₆)9.32(d,J＝1.2Hz,2H),9.11(d,J＝8.4Hz,1H),7.88(d,J＝1.2Hz,1H),7.42(d,J＝8.8Hz,1H),6.17(s,1H),4.08-4.10(m,1H),3.76-3.78(m,1H),3.11-3.16(m,1H),2.42(s,3H),2.09-2.12(m,1H),1.74-1.92(m,4H),1.46-1.52(m,3H),1.30(d,J＝7.2Hz,6H)。

Example 3 synthesis of SZ-015247:

SZ-015266A3(100mg,0.67mmol), SZ-015248A2(250mg, 0.67mmol), HATU (321mg,0.81mmol) and DIEA (0.5mL) were mixed in DMF (2mL) and stirred at room temperature for 1 h. The organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% aqueous ammonium carbonate) and lyophilized to give 54mg of SZ-015247. LCMS: [ M + H]⁺419.3。

¹H NMR(400MHz,DMSO-d₆)9.55(d,J＝1.2Hz,1H),9.14(d,J＝8.4Hz,1H),8.54(d,J＝1.2Hz,1H),7.88(s,1H),7.42(d,J＝8.8Hz,1H),6.17(s,1H),4.06-4.08(m,1H),3.75-3.77(m,1H),3.11-3.16(m,1H),2.41(s,3H),2.08-2.11(m,1H),1.74-1.92(m,4H),1.46-1.51(m,3H),1.30(d,J＝7.2Hz,6H)。

Example 4 synthesis of SZ-015262:

step 1:

ethyl 2, 4-dichloro-5-pyrimidinecarboxylate (8.84g, 40mmol) and tetrahydrofuran (120mL) were added to the reaction flask, the system was cooled to-78 deg.C, a solution of dimethylamine in tetrahydrofuran (0.5mmol/mL,80mL) was added dropwise, and stirring was continued for two hours after the end of the addition. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column separation to obtain SZ-015262A1(2.46 g). LCMS: [ M + H]⁺230.0

Step 2:

adding SZ-015262A1(1g) and tetrahydrofuran (15mL) into a reaction bottle, cooling the system to-78 ℃, and dropwise adding DIBAL-H tetrahydrofuranAfter the completion of dropwise addition of the pyran solution (1mmol/mL,13mL), the temperature was returned to normal temperature, and stirring was continued for two hours. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column separation to obtain SZ-015262A2(565mg, 87%). LCMS: [ M + H]⁺188.1

And 3, step 3:

SZ-015262A2(565mg), DBU (456mg), DPPA (825mg), dichloromethane (15mL), and toluene (12mL) were added to a reaction flask, and stirred at room temperature for 24 hours until the reaction was completed, after which the reaction solution was concentrated and separated and purified by a silica gel column to obtain SZ-015262A3(267 mg). LCMS: [ M + H]⁺213.1

And 4, step 4:

the reaction flask was charged with SZ-015262A3(267mg), triphenylphosphine (655mg), H₂O (2mL) and THF (20mL) are stirred at room temperature for 20h, after the reaction is finished, the solvent is removed by rotary evaporation, dichloromethane and water are used for extraction, the pH value of an aqueous phase is adjusted to 2, the aqueous phase is collected and lyophilized, and the solvent is removed, so that crude SZ-015262A4 hydrochloride lyophilized powder is obtained. LCMS: [ M + H]⁺187.1

And 5, step 5:

adding SZ-015262A4 hydrochloric acid freeze-dried powder into a reaction bottle, dissolving in tetrahydrofuran (10mL), adding sodium bicarbonate to adjust to neutrality, adding Boc anhydride (2mL), and stirring at room temperature for 2h until the reaction is finished. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column separation to obtain SZ-015262A5(261 mg). LCMS: [ M + H]⁺287.1

And 6, step 6:

further, SZ-015262A5(261mg), zinc cyanide (351mg), dppf (338mg), Pd were added to the reaction flask₂(dba)₃(558mg), DMF (10mL) and nitrogen were purged three times, and the reaction mixture was concentrated after completion of the reaction at 110 ℃ for 12 hours, and then separated and purified by a silica gel column to obtain SZ-015262A6(210 mg). LCMS: [ M + H]⁺278.1

And 7, step 7:

SZ-015262A6(80mg), dichloromethane (5mL), trifluoroacetic acid (1mL) was added to the flask, stirred at room temperature for 1h, and the solvent was removed by rotary evaporation to give crude SZ-015262A7, which was used in the next step without purification. LCMS: [ M + H]⁺178.2

And 8, step 8:

the reaction flask was charged with SZ-015262A7 (crude), SZ-015262A8(80mg), HATU (133mg), DIEA (90mL), and DMF (10mL), stirred at room temperature for 1h, the reaction was concentrated, separated by reverse phase column (acetonitrile/0.1% aqueous formic acid), and lyophilized to give SZ-015262(21 mg). LCMS: [ M + H]⁺530.2。

¹H NMR(400MHz,DMSO)δ13.53(s,1H),9.79(d,J＝8.6Hz,1H),8.31(d,J＝10.5Hz,2H),6.66(s,1H),4.34(d,J＝4.8Hz,2H),3.31-3.16(m,1H),3.11(s,6H),2.56(s,3H),2.40(t,J＝11.8Hz,1H),1.97-1.72(m,5H),1.70-1.53(m,1H),1.53-1.36(m,1H),1.34–1.17(m,8H).

Example 5 synthesis of SZ-015222:

triethylamine (9.3mL, 65mmol) was added portionwise at 26 deg.C to a solution of compound 015248A2(3.3g, 8.3mmol) and compound 2-cyanopyrimidine-5-carboxylic acid (1g,6.69mmol) in acetonitrile (39 mL). Then put T₃A solution of P (26.6mL, 41.6mmol, 50 Wt% in EA) was added dropwise to the above reaction solution. The resulting reaction mixture was stirred at 6 ℃ for an additional 1.6 hours. After the reaction solution was quenched with water, solid sodium carbonate was additionally added to saturate the system, and the suspension was extracted with ethyl acetate. After the organic phases are combined, anhydrous magnesium sulfate is added for drying, filtering and spin-drying the organic solvent. The residue was purified by HPLC to give SZ-015222(969mg) as a pale yellow solid. LCMS: [ M + H]⁺419.2。

¹HNMR(CD₃OD,400MHz):δ9.31(s,2H),8.93-8.91(m,1H),7.85(s,1H),7.47(d,J＝9.2Hz,1H),6.15(s,1H),4.19-4.03(m,1H),3.79-3.71(m,1H),3.29-3.23(m,1H),2.39(s,3H),2.15-2.12(m,1H),21.92-1.81(m,3H),1.64-1.61(m,1H),1.53-1.51(m,2H),1.30-1.25(m,7H).

Example 6 synthesis of SZ-015243:

step 1:

compound 015243A1(12.1g, 60.1mmol), zinc cyanide (21.36g, 180mmol), Pd₂(dba)₃A suspension of (330mg,0.36mmol), N, N dimethylformamide (130mL) and the compound dppf (180mg, 0.33mmol) was stirred at 29 deg.C and replaced three times with nitrogen. Then heated to 110 degrees celsius under nitrogen and stirring was continued for 16 hours. The resulting dark brown suspension was spin-dried, the residue was partitioned with ethyl acetate and water, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, the organic solvent was dried by rotary chromatography to give 015243A2(8g) as a yellow oily product. LCMS: [ M + H]⁺192.1。

Step 2:

compound 015243A2(3.99g, 21mmol) was dissolved in tetrahydrofuran (18mL), the reaction was cooled to 1-3 deg.C, and then aqueous lithium hydroxide (18mL,1M) was added dropwise. The resulting reaction mixture was stirred at 1-3 deg.C for an additional half hour. The reaction mixture was slowly added dropwise with dilute hydrochloric acid (1M) until the system pH became 1-3. The reaction solution was extracted with ethyl acetate. After the extracts were combined, anhydrous magnesium sulfate was added, and the mixture was dried, filtered, and the organic solvent was dried by spin-drying. Oil pump then took nine minutes to give 015243A3(3.9g) as a red viscous semi-solid, which was used directly in the next reaction. LCMS (liquid Crystal display Module) [ M-H ]]^-190.1。

And 3, step 3:

triethylamine (1.39mL,9mmol) was added portionwise at 26 deg.C to a solution of compound 015248A2(360mg, 0.9mmol) and compound 015243A3(360mg,1.76mmol, 80 Wt%) in acetonitrile (6 mL). Then put T₃A solution of P (3.9mL,6mmol,50 Wt%) was added dropwise to the above reaction solution. The resulting reaction mixture was stirred at 23-26 ℃ for an additional 16 hours. After quenching the reaction mixture with water, solid sodium carbonate was additionally added to saturate the system, and the suspension was extracted with ethyl acetate. Combining organic phases, adding anhydrous magnesium sulfate, drying, filtering, and spin-drying organic solvent. The residue was purified by HPLC to give SZ-015243(97mg) as a white solid. LCMS: [ M + H]⁺433.2。

¹HNMR(CD₃OD,400MHz):δ8.81(s,1H),8.49(s,1H),7.91(s,1H),6.22(s,1H),4.11(s,1H),3.84(s,1H),3.29-3.13(m,1H),2.66(s,3H),2.63-2.33(m,5H),2.23-1.91(m,3H),1.73-1.51(m,3H),1.33(s,6H).

Example 7 synthesis of SZ-015246:

step 1:

compound 015246A1(1.36g, 5mmol), zinc cyanide (1.6g, 13mmol), Pd₂(dba)₃A suspension of (110mg,0.13mmol), N, N dimethylformamide (16mL) and the compound dppf (60mg, 0.13mmol) was stirred at 26 deg.C and replaced three times with nitrogen. Then heated to 110 degrees celsius under nitrogen and stirring was continued for 16 hours. The resulting dark brown suspension was spin-dried, the residue was partitioned with ethyl acetate and water, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, the organic solvent was dried by rotary chromatography to give 015246A2(900mg) as a yellow oily product. LCMS: [ M + H]⁺263.1。

Step 2:

compound 015246A2(900mg,3.39mmol) was dissolved in tetrahydrofuran (9mL), the reaction was cooled to 1-3 deg.C, and then aqueous lithium hydroxide (9mL,1M) was added dropwise. The resulting reaction mixture was stirred at 1-3 deg.C for an additional hour. The reaction mixture was diluted with water, and then diluted hydrochloric acid (1M) was slowly added dropwise until the system pH became 1-3. The reaction solution was extracted with ethyl acetate. After the organic phases were combined, anhydrous magnesium sulfate was added to dry, filter and spin-dry the organic solvent. The product was obtained as a pale yellow oil 015246A3(900mg), which was used directly in the next reaction. LCMS (liquid Crystal display Module) [ M-H ]]^-233.1。

And 3, step 3:

triethylamine (1.39mL,9mmol) was added portionwise at 26 deg.CTo a solution of compound 015248a2(210mg, 0.6mmol) and compound 015246A3(310mg) in acetonitrile (9 mL). Then put T₃A solution of P (3.9mL,6mmol,50 Wt%) was added dropwise to the above reaction solution. The resulting reaction mixture was stirred at 23-26 ℃ for an additional 16 hours. After the reaction solution was quenched with water, solid sodium carbonate was additionally added to saturate the system, and the suspension was extracted with ethyl acetate. After the organic phases are combined, anhydrous magnesium sulfate is added for drying, filtering and spin-drying the organic solvent. The residue was purified by HPLC preparative to give SZ-015246(146mg) as a white solid. LCMS: [ M + H]⁺504.3。

¹HNMR(CD₃OD,400MHz):δ8.32(s,1H),7.92(s,1H),6.18(s,1H),4.13-4.01(m,1H),3.91-3.79(m,1H),3.79-3.73(m,4H),3.73-3.69(m,4H),3.36-3.28(m,1H),2.55(s,3H),2.53-2.43(m,1H),2.23-2.16(m,1H),2.16-2.06(m,1H),2.06-1.96(m,1H),1.73-1.61(m,1H),1.58-1.39(m,3H),1.36(d,J＝4.0Hz,6H).

Example 8 synthesis of SZ-015260:

step 1:

compound 015260A1(760mg, 4.3mmol), zinc cyanide (1.6g, 13mmol), Pd₂(dba)₃A suspension of (110mg,0.13mmol), N, N dimethylformamide (9mL) and the compound dppf (60mg, 0.13mmol) was stirred at 23 deg.C and replaced three times with nitrogen. Then heated to 110 degrees celsius under nitrogen and stirring was continued for 16 hours. The resulting dark brown suspension was spin-dried, the residue was partitioned with ethyl acetate and water, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, the organic solvent was dried by rotary chromatography to give 015260A2(210mg) as a yellow oily product. LCMS: [ M + H]⁺178.1。

Step 2:

compound 015260A2(210mg, 1.29mmol) was dissolved in tetrahydrofuran (3mL), the reaction was cooled to 1-3 deg.C, and then aqueous lithium hydroxide (3mL, 1M) was added dropwise. What is needed isThe reaction mixture was allowed to continue stirring at 1-3 deg.C for half an hour. The reaction mixture was diluted with water, and then diluted hydrochloric acid (1M) was slowly added dropwise until the system pH became 1-3. The reaction solution was extracted with ethyl acetate. After the extracts were combined, anhydrous magnesium sulfate was added, and the mixture was dried, filtered, and the organic solvent was dried by spin-drying. The product was obtained as a pale yellow oil 015260A3(210mg), which was used directly in the next reaction. LCMS (liquid Crystal display Module) [ M-H ]]^-148.1。

And 3, step 3:

compound 015260A3(210mg) was dissolved in anhydrous dichloromethane (6mL) and oxalyl chloride (0.9mL) was added. The resulting reaction mixture was stirred at 26 ℃ followed by the addition of a drop of anhydrous N, N dimethylformamide (a rapid evolution of gas, a gradual change in the reaction solution to dark brown). The reaction mixture was stirred at 26 ℃ for an additional hour, then the solvent was spun off and the residue was pumped through an oil pump for three minutes to give the crude acid chloride.

A white suspension of compound 015248A2(260mg,0.6mmol), sodium carbonate solid (330mg,3mmol), water (6mL) and tetrahydrofuran (6mL) was cooled to 1-3 deg.C. The crude acid chloride was dissolved in anhydrous tetrahydrofuran (6mL) and half of the amount (3mL) was added slowly by syringe dropwise to the white suspension. The resulting reaction mixture was stirred at 26 ℃ for an additional 1 hour. The reaction solution was quenched with water and extracted with ethyl acetate. After the organic phases are combined, anhydrous magnesium sulfate is added for drying, filtering and spin-drying the organic solvent. The residue was purified by HPLC to give SZ-015260(23mg) as a white solid. LCMS: [ M + H]⁺419.2。

¹HNMR(DMSO-d6,400MHz):δ9.43(d,J＝8.0Hz,1H),8.56(d,J＝8.0Hz,1H),8.44(d,J＝8.0Hz,1H),7.89(s,1H),7.44(d,J＝8.0Hz,1H),6.18(s,1H),4.19-4.09(m,1H),3.91-3.69(br,1H),3.21-3.11(m,1H),2.42(s,3H),2.19-2.09(m,1H),2.39(s,3H),1.98-1.78(m,4H),1.58-1.39(m,3H),1.30(d,J＝8.0Hz,6H).

Example 9 synthesis of SZ-015270:

A white suspension of compound 015249A4(210mg, 0.6mmol), sodium carbonate solid (330mg,3mmol), water (6mL) and tetrahydrofuran (6mL) was cooled to 1-3 deg.C. The crude acid chloride was dissolved in anhydrous tetrahydrofuran (6mL) and half of the amount (3mL) was added slowly by syringe dropwise to the white suspension. The resulting reaction mixture was stirred at 26 ℃ for an additional 1 hour. The reaction solution was quenched with water and extracted with ethyl acetate. After the organic phases are combined, anhydrous magnesium sulfate is added for drying, filtering and spin-drying the organic solvent. The residue was purified by HPLC to give SZ-015270(32.1mg) as a white solid. LCMS: [ M + H]⁺405.2。

¹HNMR(DMSO-d6,400MHz):δ8.52(d,1H,J＝8.0Hz),8.17(d,1H,J＝8.0Hz),7.87(s,1H),7.51(s,1H),6.17(s,1H),4.63-4.49(m,1H),3.93(br,1H),3.68-3.58(m,1H),3.29-3.21(m,1H),3.19-3.01(m,2H),2.39(s,3H),2.11-2.01(m,1H),1.93-1.81(m,1H),1.81-1.69(m,2H),1.28(d,6H,J＝4.0Hz).

Example 10 synthesis of SZ-015267:

step 1:

015267A1(5g,21.3mmol) and cuprous cyanide (3.8g,42.7mmol) were suspended in N, N dimethylformamide (50mL) under argon and stirred at 150 ℃ for 2 h. After the reaction was completed, the reaction mixture was spin-dried and purified by column chromatography to obtain 015267A2(2 g).

Step 2:

015267A2(1.0g,5.5mmol) was dissolved in tetrahydrofuran (10mL) and water (5mL), and lithium hydroxide monohydrate (460mg) was added under ice water bath and stirred at room temperature for 10 min. After the reaction was completed, the reaction mixture was exchanged with Amberlite IR120 hydrogen type resin, and an appropriate amount of water and ethyl acetate were added to the filtrate, followed by drying over sodium sulfate for the organic phase and then spin-drying to obtain 015267A3(0.5 g).

And 3, step 3:

015267A3(400mg,2.3mmol) was dissolved in dichloromethane (8mL) and triethylamine (1.6mL) was added and TFAA (1.2g,5.7mmol) was stirred at this temperature for 30 minutes under an ice-water bath. After the reaction was complete, water (10mL) was added and the aqueous phase was lyophilized at low temperature to yield 150mg of product.

And 4, step 4:

015267A4(50mg,0.29mmol), 015249A4(100mg, 0.36mmol), HATU (153mg,0.39mmol) and DIEA (0.3mL) were mixed in DMF (2mL) and stirred at room temperature for 1 h. The organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% ammonium carbonate in water) and lyophilized to give 28mg of SZ-015267. LCMS: [ M + H]⁺410.2。

SZ-015267:¹H NMR(400MHz,DMSO-d₆)：8.62(s,1H),8.31(s,1H),6.73(s,1H),4.63-4.59(m,1H),4.26-4.19(m,1H),4.13-4.09(m,1H),3.27-3.26(m,2H),3.00-2.90(m,1H),2.60(s,3H),2.04-1.86(m,4H),1.30(d,J＝6.8Hz,6H)。

Example 11 synthesis of SZ-015281:

015267A4(50mg,0.29mmol), 015248A2(80mg, 0.29mmol), HATU (134mg,0.35mmol) and DIEA (0.2mL) were mixed in DMF (2mL) and stirred at room temperature for 1 h. The organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% ammonium carbonate in water) and lyophilized to give 12mg of SZ-015281. LCMS: [ M + H]⁺424.2。

SZ-015281:¹H NMR(400MHz,DMSO-d₆)：8.77-8.75(m,2H),7.89(s,1H),7.47-7.44(m,1H),6.16(s,1H),4.09-3.98(m,1H),3.77-3.70(m,1H),3.16-3.13(m,1H),2.41(s,3H),2.08-2.05(m,1H),1.90-1.70(m,4H),1.49-1.39(m,3H),1.30(d,J＝6.8Hz,6H)。

Example 12 synthesis of SZ-015266:

step 1:

015266A1(2g,10.7mmol), zinc cyanide (600mg,5.2mmol), DPPF (1g) and Pd under argon₂(dba)₃(1g) Mix in anhydrous DMF (30mL) and stir at 100 degrees for 2 hours. After the reaction, a proper amount of water and ethyl acetate are added, and the organic phase is directly dried by spinning and subjected to column chromatography to obtain 015266A2(1.0 g).

Step 2:

015266A2(700mg,3.9mmol) was dissolved in tetrahydrofuran (7mL) and water (3mL), potassium carbonate (1.1g,7.9mmol) was added and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was exchanged with Amberlite IR120 hydrogen type resin, and an appropriate amount of water and ethyl acetate were added to the filtrate to dry the organic phase by spin-drying to obtain 015266A3(300 mg).

And 3, step 3:

015266A3(50mg,0.29mmol), 015249A4(100mg, 0.29mmol), HATU (153mg,0.35mmol) and DIEA (0.2mL) were mixed in DMF (2mL) and stirred at room temperature for 1 h. The organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% ammonium carbonate in water) and lyophilized to give 12mg of SZ-015266. LCMS: [ M + H]⁺405.1。

¹H NMR(400MHz,DMSO-d₆)：9.77(s,1H),9.50(s,1H),8.37-8.33(m,2H),6.73(s,1H),4.62-4.59(m,1H),4.24-4.21(m,1H),3.75-3.72(m,1H),3.28-3.20(m,2H),3.03-2.97(m,1H),2.60(s,3H),2.06-2.03(m,1H),1.87-1.85(m,3H),1.30(d,J＝6.8Hz,6H)。

Example 13 synthesis of SZ-015265:

step 1:

015265A1(3g,17.4mmol), zinc cyanide (1.2g,10.2mmol), DPPF (1.1g) and Pd under argon₂(dba)₃(1.5g) was mixed in anhydrous DMF (30mL) and stirred at 100 ℃ for 1 hour. After the reaction, a proper amount of water and ethyl acetate are added, and the organic phase is directly dried by spinning and subjected to column chromatography to obtain 015265A2(1.5 g).

Step 2:

015265A2(1.4g,8.5mmol) was dissolved in tetrahydrofuran (20mL) and water (10mL), potassium carbonate (2.3g,17.1mmol) was added and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was exchanged with Amberlite IR120 hydrogen type resin, and an appropriate amount of water and ethyl acetate were added to the filtrate to dry the organic phase by spin-drying to obtain 015265A3(800 mg).

And 3, step 3:

015265A3(50mg,0.29mmol), 015249A4(100mg, 0.29mmol), HATU (153mg,0.35mmol) and DIEA (0.2mL) were mixed in DMF (2mL) and stirred at room temperature for 1 h. The organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% ammonium carbonate in water) and lyophilized to give 12mg of SZ-015265. LCMS: [ M + H]⁺405.3。

¹H NMR(400MHz,DMSO-d₆)：9.77(s,1H),9.80(s,1H),9.30(d,J＝1.6Hz,1H),9.06(d,J＝1.6Hz,1H),8.34(s,1H),6.74(s,1H),4.64-4.62(m,1H),4.24-4.21(m,1H),3.83-3.79(m,1H),3.29-3.21(m,2H),3.04-2.98(m,1H),2.60(s,3H),2.07-2.04(m,1H),1.92-1.88(m,3H),1.31(d,J＝5.6Hz,6H)。

Synthesis of intermediate 015248a 2:

step 1:

compound 015249A1(6g,28.7mmol) and the compound tert-butyl (1S,3R) -3-aminocyclohexylcarbamate (9g, 29mmol) were dissolved in 1, 4-dioxane (69mL) and triethylamine (39mL, 280mmol) was added. The resulting reaction mixture was heated to 110 degrees and the reaction was continued with stirring for 16 hours. Cooling the reaction mixture to room temperature, adding water for quenching, extracting with ethyl acetate, combining organic phases, and MgSO₄Drying and passing throughFiltering and spin-drying the organic solvent. The residue was purified by column separation on silica gel to give 015249A1-1(6g) as a pale yellow solid. LCMS: [ M + H]⁺388.3。

Step 2:

trifluoroacetic acid (29mL) was added portionwise to a solution of compound 015249a1-1(6g, 16mmol) in dichloromethane (29mL) at 29 ℃ and the resulting reaction mixture was stirred at 29 ℃ for 1 hour. The resulting reaction mixture was drained of the solvent and then pumped with an oil pump for 11 minutes to give a red-yellow viscous paste of compound 015248A2(6 g). LCMS: [ M + H]⁺288.2.

Synthesis of intermediate 015262a 8:

step 1:

to a reaction flask were added (1S,3R) -3- ((tert-butoxycarbonyl) amino) cyclohexane-1-carboxylic acid (1.216g), methyl iodide (1.4g), potassium carbonate (1.4g), and DMF (16mL), and after completion of the reaction, the reaction mixture was stirred at room temperature for 2d, concentrated, and separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 0 to 20%) to obtain 015262a8-1(1.1 g).

Step 2:

015262A8-1(1.1g), dichloromethane (5mL), trifluoroacetic acid (1mL) was added to the flask, stirred at room temperature for 1h, and the solvent was removed by rotary evaporation to give 015262A8-2 crude, which was used in the next step without purification.

And 3, step 3:

015262A8-2 (crude product), 7-chloro-3-isopropyl-5-methylpyrazolo [1,5-a ] was added to the reaction flask]Pyrimidine (851mg), DIEA (1.0g), and isopropanol (10mL) were stirred at 90 ℃ for 5 hours, and after completion of the reaction, the reaction was concentrated and purified by silica gel column chromatography to give 015262A8-3(1.17 g). LCMS: [ M + H]⁺331.2

And 4, step 4:

015262A8-3(1.17g) and 1, 4-dioxane (10mL) were added to a reaction flask, an aqueous solution (10mL) containing NaOH (2g) was added dropwise to the reaction mixture, the mixture was stirred at 70 ℃ for 5 hours, and the reaction mixture was neutralized with dilute hydrochloric acidThe reaction solution was concentrated, and extracted with ethyl acetate to give 015262A8(530 mg). LCMS: [ M + H]⁺317.1。

Comparative example 1 SZ-015055

The first step is as follows: 015055A1 Synthesis

Tert-butyl ((1S,3R) -3-aminocyclohexyl) carbamate (1.6g, 4.0mmol) and 015039A1(2.1g, 10mmol) were dissolved in DMF/EtOH (10mL/10mL) and DIEA (1.5g, 12mmol) was added. The reaction mixture was heated to 120 ℃ under nitrogen and stirred at this temperature overnight, after cooling the solvent was removed by rotary drying and the residue was concentrated and purified by silica gel column chromatography (PE/EA-10/1) to give crude 015055a1 as a yellow solid (1.9g, yield 79%).

LCMS(M+H)⁺m/z calculated 608.2，found 608.2。

The second step is that: 015055A2 Synthesis

Compound 015055A1(1.9g,3.125mmol) was dissolved in 20mL of dichloromethane, and 20mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 1 hour. The solvent was removed by rotation, the residue was dissolved in a mixed solution of dichloromethane and methanol, and ammonia was added thereto, followed by stirring at room temperature for half an hour. Extraction with dichloromethane, drying and concentration, ethyl acetate petroleum ether fermented soybean paste, and filtration gave compound 015055A2(400mg, yield 30%) as a white solid. LCMS (M + H)⁺m/z calculated 378.2，found 378.2。

The third step: 015055 Synthesis

Compound 015055A2(75.6mg, 0.2mmol), compound 6-cyanonicotinic acid (30mg, 0.2mmol), DIEA (78mg,0.6mmol) and HATU (91.2mg, 0.24mmol) were added to DMF (5mL) and stirred at room temperature overnight. Water (40mL) was added, extraction was performed with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give SZ-015055(10.4mg, yield 10%) as a pale yellow solid.

Liquid phase mass spectrometry [ mobile phase: at 40 degrees CelsiusElution was carried out in a gradient from 55% water (containing 0.02% ammonium acetate) and 45% acetonitrile to 45% water (containing 0.02% ammonium acetate) and 55% acetonitrile at a flow rate of 1.5 ml/min for 6 minutes at column temperature. Column: waters XBridge C183.5um, 50 x 4.6mm]The purity is more than 95 percent, and Rt is 2.514 min; LCMS (M + H)⁺m/z calculated 508.1.2，found 508.1。

¹H NMR(DMSO-d₆，400MHz)：δ12.54(s，1H)，9.10(d，J＝1.6Hz，1H)，8.78(d，J＝3.6Hz，1H))，8.47(s，1H)，8.41-8.30(m，3H)，8.15(d，J＝8.0Hz，1H),7.40(d，J＝8.0Hz，1H)，7.30-7.20(m，1H)，3.91-3.85(m，2H)，2.33-2.24(m，1H)，2.08-1.82(m，3H)，1.47-1.23(m，4H)。

Effect example 1 Activity test (test in Biortus)

Detection of IC on CDK7 kinase for test Compounds₅₀The value is obtained. Screening of Staurosporine as a positive control compound was performed on CDK7 kinase using the method of Mobility shift assay at an initial concentration of 0.5mM, 3-fold dilution, 10 concentrations, duplicate wells for 0min, 10 min and 60min preincubation time for compound and enzyme, respectively.

1 preparation of the Compound

Compound powders were dissolved in 100% DMSO to make 10mM stock solutions, diluted to 0.5mM as the starting concentration, and further diluted 3-fold to obtain 10 concentrations of compound solutions.

2 kinase reaction Process

(1) Compound solution and ddH for positive control₂O diluted 8.3 times and added to 384 well plates at 2 uL/well each.

(2) 6nM kinase solution was added to each of the compound wells and positive control wells.

(3) Incubate at room temperature for 0, 10 and 60 minutes.

(4) ATP (2mM) and peptide substrate solution (2uM) were added.

(5) The 384 well plates were incubated for 30 min at 25 ℃.

(6) The kinase reaction was stopped by adding 4uL of 120mM EDTA.

(7) Conversion was read using Caliper EZ readei.

3 the results are as follows

Remarking: 1 pre-incubation time; 2IC₅₀Ratio (0min/60 min). "/" indicates not measured.

The Staurosporine (antibiotic AM-2282 or STS) has the structure

Claims

1. A pyrimido pyrazole compound shown as a formula I or a pharmaceutically acceptable salt thereof;

wherein ring B is

L is- (C ═ O) - (NR)^c1)_n1-(CR^c2R^c3)_n2-；

n1 and n2 are independently 0 or 1;

R^c1、R^c2and R^c3Independently is H or C₁-C₄An alkyl group;

ring D is 5-10 membered heteroaryl, or substituted with one or more substituents R^d1Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by a substituent R^d15-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is pyridazine, pyrimidine, pyrazine and thiazole; r^d1Independently is C₁-C₆Alkyl, N (R)^d11R^d12) -, or 4-7 membered heteroA cycloalkyl group; in the 4-7 membered heterocycloalkyl, the heteroatom or heteroatom group is selected from one or more of N, O and S, and the number of the heteroatoms or heteroatom groups is 1-2;

R^d11and R^d12Independently is H or C₁-C₄An alkyl group;

2. The pyrimido pyrazole compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1,

l is- (C ═ O) -, - (C ═ O) - (NR)^c1)-(CR^c2R^c3) -or- (NR)^c1)_n1-(C＝O)-；

And/or, in ring B, when the carbon atom to which NH is attached is a chiral carbon atom, is

Configuration;

and/or, in ring B, when the carbon atom to which L is attached is a chiral carbon atom, is

Configuration;

and/or, R^c1Is H;

and/or, R^c2And R^c3Independently is H;

and/or, R^d11And R^d12Independently is C₁-C₄An alkyl group;

and/or the L group is positioned meta or para to the-CN.

3. The pyrimido pyrazole compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1,

Configuration;

and/or, when ring B represents

When L is- (C ═ O) - (NR)^c1)-(CR^c2R^c3) -or- (NR)^c1)_n1-(C＝O)-；

And/or, when ring B represents

When L is- (C ═ O) -;

and/or when R^c1、R^c2And R^c3Independently is C₁-C₄When alkyl, said C₁-C₄Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R^d1Is C₁-C₆When alkyl, said C₁-C₆Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R^d1When the substituted heterocyclic group is 4-7 membered heterocyclic alkyl, the 4-7 membered heterocyclic alkyl is morpholinyl;

and/or when R^d11And R^d12Independently is C₁-C₄When alkyl, said C₁-C₄Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

4. The pyrimido pyrazole compound of formula I or the pharmaceutically acceptable salt thereof according to claim 3 wherein R is^d1Is C₁-C₆When alkyl, said C₁-C₆Alkyl is methyl;

and/or when R^d1In the case of 4-7 membered heterocycloalkyl, said 4-7 membered heterocycloalkyl is

And/or when R^d11And R^d12Independently is C₁-C₄When alkyl, said C₁-C₄The alkyl group is a methyl group.

5. A pyrimido pyrazole compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3,

when ring D represents a 5-to 10-membered heteroaryl group, or substituted by one or more substituents R^d1Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by a substituent R^d1The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is

And the end d represents the connection with CN.

6. The pyrimido pyrazole compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1,

l is- (C ═ O) -, -NH- (C ═ O) -, or- (C ═ O) - (NH) - (CH)₂)-；

And/or, ring B is

And/or, R^d1Independently is-CH₃、—CH₂CH₃、—NH₂、—NH(CH₃)、—N(CH₃)₂、

7. The pyrimidopyrazole compound of formula I or the pharmaceutically acceptable salt thereof according to claim 6, whereinCharacterized in that the preparation method is characterized in that,

is composed of

And/or the presence of a gas in the gas,

is composed of

8. The pyrimido pyrazole compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1, which is according to scheme 1, scheme 2 or scheme 3;

scheme 1: the ring B group being

The L groups are independently- (C ═ O) - (NR)^c1)-(CR^c2R^c3) -or- (C ═ O) - (NR)^c1)_n1-；

scheme 2 Ring B groups are

The L groups are independently- (C ═ O) -;

ring D represents a 5-to 10-membered heteroaryl group, or substituted by one or more substituents R^d1Substituted by5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by a substituent R^d15-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is pyridazine, pyrimidine and pyrazine;

scheme 3: ring B is

L is- (C ═ O) -, - (C ═ O) - (NR)^c1)-(CR^c2R^c3) -or- (C ═ O) - (NR)^c1)_n1-; - (C ═ O) -side to ring B, or to ring D;

R^c1、R^c2and R^c3Independently is H;

ring D is 5-10 membered heteroaryl, or substituted with one or more substituents R^d1Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by a substituent R^d15-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is pyridazine, pyrimidine, pyrazine and thiazole;

R^d1is independently C₁-C₆Alkyl, N (R)^d11R^d12) -or 4-7 membered heterocycloalkyl.

9. The pyrimido pyrazole compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1,

the pyrimido pyrazole compound shown in the formula I is shown in any structure as follows:

10. a process for the preparation of pyrimidinopyrazoles of formula I as claimed in any of claims 1 to 9,

which comprises the following steps:

in a solvent, in the presence of a condensing agent and alkali, carrying out a condensation reaction shown as the following on a compound shown as a formula II or a compound shown as a formula IV and a compound shown as a formula V, or carrying out a condensation reaction shown as the following on a compound shown as a formula III and a compound shown as a formula VI to obtain the pyrimido pyrazole compound shown as the formula I;

wherein ring D is as defined in any one of claims 1 to 9.

11. A pharmaceutical composition, comprising a pyrimidopyrazole compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, and one or more pharmaceutically acceptable carriers.

12. Use of a pyrimido pyrazole compound of formula I or a pharmaceutically acceptable salt thereof according to any of claims 1 to 9, or a pharmaceutical composition according to claim 11 for the preparation of a medicament or a CDK kinase inhibitor; wherein said medicament is a medicament for the treatment and/or prevention of a disease associated with a CDK kinase interaction.

13. Use according to claim 12 wherein the CDK kinase is CDK7 kinase.

14. Use of a pyrimido pyrazole compound of formula I according to any of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for the manufacture of a medicament; the medicament is used for treating and/or preventing proliferative diseases or infectious diseases; said proliferative disease is cancer, benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases; the cancer is leukemia, melanoma, multiple myeloma, breast cancer, brain cancer or lung cancer.

15. The use according to claim 14, wherein the proliferative disease is an autoinflammatory disease.