CN111393415A

CN111393415A - Heteroaromatic nitrile compound and application thereof

Info

Publication number: CN111393415A
Application number: CN202010361000.XA
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: 2020-04-30
Filing date: 2020-04-30
Publication date: 2020-07-10
Anticipated expiration: 2040-04-30
Also published as: CN111393415B

Abstract

The invention discloses a heteroaromatic nitrile compound and application thereof. The application provides a heteroaromatic nitrile compound shown as a formula I or pharmaceutically acceptable salt thereof; the compound has better inhibiting effect on CDK 7.

Description

Heteroaromatic nitrile compound and application thereof

Technical Field

The invention relates to a heteroaromatic nitrile compound 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 (Ashhar U, Witkiewicz A K, Turner N C, et al. the history and future of obtaining cycle-dependent kinases in cancer therapy. Nat Rev Drug Discov, 2015 (2): 130-). 146).

CDK7 is an important member of the CDKs family, and regulates the Cell cycle mainly through two indirect ways, namely CDK7 together with cycle H and Mat1 constitutes CAK (CDKs activating kinase), CDKs activating kinase, further phosphorylating CDK1/2, thereby activating their function in the Cell cycle (Yee A, Nichols MA, Wu L, Hall F L, Xiong Y.molecular cloning of CDK7-associated human MAT1, a cycle-dependent kinase-activating kinase (CAK) activating factor. cancer Res 1995; 55: 6058-6062. Another way is that CDK2 constitutes a subunit of the general transcription factor TFIIH, phosphorylating polymerase (apoptosis II, AP II) large subunit carboxyl end domain (CTK) plays a role in Cell cycle growth process, CD 34, Cell activating kinase, CD 75, Cell growth process, and Cell growth process of Cell III.

In recent years, inhibition of CDK7 has become a promising therapeutic strategy in many cancers, inhibition of CDK7 can inhibit expression of key oncogenes such as C-Myc and the like (Chipumuro E, Marco E, Christensen C L, Kwiatkowski N, Zhang T, Hatheway CM, et Al. CDK7 inhibition of cancer patients super-enhance-malignant transcription in MYCN-drive cancer. Cell 2014; 159: 1126-39.). preclinical studies data show that small molecule inhibitors that inhibit 7 are effective in hormone receptor positive and triple negative breast cancers (Wang Y, Zhang T, Kwiatkowski N, Abraham BJ, &TtltTtlttranslation L "= Ttgttg L/& gt/T/& gt, Ttgertner L & gt/& gt, Ttgrain J/& gt, Tjtt translation J/& gt, Tjtt 5. these approaches are likely to be effective as anticancer drugs for cancer therapy for cancer patients with different cancer resistance mechanisms such as Kpusilvictory factors and the anticancer drug resistance of cancer cells marked as Kpudendar J22. the current.

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 CDK7inhibitor has an excessively single structure, and therefore, the application provides a heteroaromatic nitrile compound and application thereof, wherein the heteroaromatic nitrile compound has a good CDK7 inhibition effect.

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

The invention provides a heteroaromatic nitrile compound shown as a formula I or pharmaceutically acceptable salt thereof;

wherein R is¹Is halogen, C₁-C₄Alkyl or C substituted by one or more halogens₁-C₄An alkyl group; when the substituents are plural, the same or different;

is an indole ring;

R^1a、R^1b、R^1cand R^1dIndependently is H or halogen;

ring B being cyclohexyl, substituted by one or more substituents R^b1Substituted cyclohexyl, piperidinyl or by one or more substituents R^b2A substituted piperidinyl group; when the substituents are plural, the same or different;

R^b1and R^b2Independently of one another, halogen, C₁-C₄Alkyl or C substituted by one or more halogens₁-C₄An alkyl group; when the substituents are plural, the same or different;

l is- (CR)^c2R^c1)_n1-N(R^c3)-(C(＝O))_n2-; (including- (C (═ O))_n2Lateral to ring B or to ring D)

n1 and n2 are independently 0 or 1; and n1 and n2 are not 0 at the same time; (when 0, it is represented by a bond)

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

alternatively, in L, R^c1And/or R^c2Linked to ring D, together with the linked C, form: 5-6 membered heteroaryl; the heteroatom in the 5-6 membered heteroaryl is selected from one or more of N, O and S, and the number of the heteroatoms is 1-3;

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 number of heteroatoms is 2-3, and the heteroatoms are selected from one or more of N, O and S; when the substituents are plural, the same or different;

R^d1independently halogen, N (R)^d11R^d12)-、C₁-C₄Alkyl, C substituted by one or more halogens₁-C₄Alkyl radical, C₁-C₄alkyl-O-, C substituted by one or more halogens₁-C₄alkyl-O-or 4-6 membered heterocycloalkyl; in said 4-6 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; when the substituents are plural, the same or different;

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

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

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),

R¹independently is halogen or C₁-C₄Alkyl groups, such as halogen.

R^1aand R^1bIndependently is H; r^1cAnd R^1dIndependently H or halogen.

ring B being cyclohexyl, piperidinyl or substituted by one or more substituents R^b2A substituted piperidinyl group;

for example piperidinyl or by one or more substituents R^b2Substituted piperidinyl, in turn, for example, by one or more substituents R^b2A substituted piperidinyl group.

l on Ring B is located meta to the-NH-shown.

in ring B, when the carbon atom to which NH is attached is a chiral carbon atom, it is in S or R configuration, again for example

(end a is connected with L)

in ring B, when the carbon atom to which L is attached is a chiral carbon atom, it is in S or R configuration, again for example

(end a is connected with L)

in the ring B, when the carbon atom connected with NH, L is a chiral carbon atom, the configuration is S configuration, R configuration or the mixture of the S configuration and the R configuration;

for example

R^b1and R^b2Independently is halogen or C₁-C₄An alkyl group; e.g. C₁-C₄An alkyl group.

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

l is- (CR)^c2R^c1)-N(R^c3)-C(＝O)-、-N(R^c3)-C(＝O)-、-C(＝O)-N(R^c3) -or- (CR)^c2R^c1)-N(R^c3)-。

l is- (CR)^c2R^c1)-N(R^c3)-C(＝O)-、-N(R^c3)-C(＝O)-、-C(＝O)-N(R^c3) -or- (CR)^c2R^c1)-N(R^c3) -; for example- (CR)^c2R^c1)-N(R^c3)-C(＝O)-、-C(＝O)-N(R^c3) -or- (CR)^c2R^c1)-N(R^c3) -; and for example-C (═ O) -N (R)^c3) -. (wherein the right side is connected to Ring B)

R^c1and R^c2Independently is H;

or, R^c1And/or R^c2Linked to ring D, together with the linked C, form: 5-6 membered heteroaryl; the heteroatom in the 5-6 membered heteroaryl is selected from one or more of N, O and S, and the number of the heteroatoms is 1-3;

and also for example R^c1And R^c2Independently is H.

R^c3independently is H.

l in which R is^c1And/or R^c2Linked to ring D, together with the linked C, form: 5-6 membered heteroaryl; the heteroatom in the 5-6 membered heteroaryl is selected from one or more of N, O and S, and the number of the heteroatoms is 1-3.

R^d1independently is N (R)^d11R^d12)-、C₁-C₄Alkyl radical, C₁-C₄alkyl-O-or 4-6 membered heterocycloalkyl; for example N (R)^d11R^d12)-、C₁-C₄Alkyl or C₁-C₄alkyl-O-; and also e.g. C₁-C₄Alkyl or C₁-C₄alkyl-O-.

when ring D is substituted by one or more substituents R^d1When substituted 5-to 10-membered heteroaryl, R^d1Located at the position ortho to the link of ring D at L.

R¹independently is halogen or C₁-C₄Alkyl, such as halogen;

is an indole ring;

R^1a、R^1b、R^1cand R^1dIndependently is H or halogen;

ring B being cyclohexyl, piperidinyl or substituted by one or more substituents R^b2A substituted piperidinyl group; for example piperidinyl or by one or more substituents R^b2Substituted piperidinyl, in turn, for example, by one or more substituents R^b2A substituted piperidinyl group;

R^b2independently is C₁-C₄An alkyl group;

l is- (CR)^c2R^c1)-N(R^c3)-C(＝O)-、-N(R^c3)-C(＝O)-、-C(＝O)-N(R^c3) -or- (CR)^c2R^c1)-N(R^c3) -; for example- (CR)^c2R^c1)-N(R^c3)-C(＝O)-、-C(＝O)-N(R^c3) -or- (CR)^c2R^c1)-N(R^c3) -; and for example-C (═ O) -N (R)^c3) -; (wherein the right side is connected to Ring B)

R^c1And R^c2Independently is H;

R^c3independently is H;

R^d1independently is N (R)^d11R^d12)-、C₁-C₄Alkyl radical, C₁-C₄alkyl-O-or 4-6 membered heterocycloalkyl; for example N (R)^d11R^d12)-、C₁-C₄Alkyl or C₁-C₄alkyl-O-; and also e.g. C₁-C₄Alkyl or C₁-C₄alkyl-O-;

preferably, L on ring B is located meta to the indicated-NH-;

and/or, ring B is configured as

R¹independently is halogen or C₁-C₄Alkyl, such as halogen;

is an indole ring;

R^1a、R^1b、R^1cand R^1dIndependently is H or halogen;

ring B being cyclohexyl, piperidinyl or substituted by one or more substituents R^b2A substituted piperidinyl group; for example piperidinyl or by one or moreA substituent R^b2Substituted piperidinyl, in turn, for example, by one or more substituents R^b2A substituted piperidinyl group;

R^b2independently is C₁-C₄An alkyl group;

R^c1And R^c2Independently is H;

R^c3independently is H;

R^d1independently is C₁-C₄Alkyl radical, C₁-C₄alkyl-O-or 4-6 membered heterocycloalkyl; e.g. C₁-C₄Alkyl or C₁-C₄alkyl-O-;

preferably, L on ring B is located meta to the indicated-NH-;

and/or, ring B is configured as

R¹is halogen or C₁-C₄Alkyl, such as halogen;

is an indole ring;

R^1a、R^1b、R^1cand R^1dIndependently is H or halogen;

ring B is cyclohexyl, piperidinyl or substituted by oneOr a plurality of substituents R^b2A substituted piperidinyl group; for example piperidinyl or by one or more substituents R^b2Substituted piperidinyl, in turn, for example, by one or more substituents R^b2A substituted piperidinyl group;

R^b2independently is C₁-C₄An alkyl group;

l is- (CR)^c2R^c1)-N(R^c3)-C(＝O)-、-C(＝O)-N(R^c3) -or- (CR)^c2R^c1)-N(R^c3) -; for example-C (═ O) -N (R)^c3) -; (wherein the right side is connected to Ring B)

R^c1And R^c2Independently is H;

R^c3independently is H;

preferably, L on ring B is located meta to the indicated-NH-;

and/or, ring B is configured as

when R is¹Independently halogen or C substituted by one or more halogens₁-C₄When alkyl, said halogen and C substituted by one or more halogens₁-C₄Halogen in the alkyl group is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine, and also for example chlorine.

when R is¹Independently is C₁-C₄Alkyl radicals or by oneOr C substituted by more than one halogen₁-C₄When alkyl, said C₁-C₄Alkyl and C substituted by one or more halogens₁-C₄C in alkyl₁-C₄Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; such as methyl or ethyl, and further such as ethyl.

is composed of

For example

when R is^1a、R^1b、R^1cAnd R^1dIndependently halogen, the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine, and further for example fluorine.

when ring B is cyclohexyl, or substituted by one or more substituents R^b1When the cyclohexyl is substituted, the cyclohexyl is independently

(end a is connected with L)

when ring B is piperidinyl or substituted by one or more substituents R^b2When substituted piperidinyl, said piperidinyl and said substituents R are substituted by one or more substituents R^b2Piperidinyl in substituted piperidinyl is

(also e.g.

) (end a is connected with L)

when R is^b1And R^b2Independently halogen, or C substituted by one or more halogens₁-C₄When alkyl, said halogen and C substituted by one or more halogens₁-C₄Halogen in the alkyl group is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

when R is^b1And R^b2Independently is C₁-C₄Alkyl or C substituted by one or more halogens₁-C₄When alkyl, said C₁-C₄Alkyl and C substituted by one or more halogens₁-C₄C in alkyl₁-C₄Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; such as methyl or ethyl.

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

when in L, R is^c1And/or R^c2Linked to ring D, together with the linked C, form: 5-6 membered heteroaryl, wherein the heteroatom is selected from N, the number of heteroatoms is 1-3; for example

(b terminal is connected to ring D in parallel)

when ring D is a 5-to 10-membered heteroaryl, or substituted with one or more substituents R^d1When substituted with 5-10 membered heteroaryl, said 5-10 membered heteroaryl is substituted with one or more substituents R^d1The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is independently a 5-6 membered heteroaryl in which the heteroatom is one or more selected from N, O and S, and contains at least one N, and the number of heteroatoms is 2-3; such as pyrazinyl (e.g. as

) Or thiazolyl (e.g.

)。

when R is^d1Independently isHalogen, C substituted by one or more halogens₁-C₄Alkyl or C substituted by one or more halogens₁-C₄alkyl-O-, said halogen, C substituted by one or more halogens₁-C₄Alkyl and C substituted by one or more halogens₁-C₄Halogen in alkyl-O-is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

when R is^d1Independently is C₁-C₄Alkyl, C substituted by one or more halogens₁-C₄Alkyl radical, C₁-C₄alkyl-O-, or C substituted by one or more halogens₁-C₄alkyl-O-said C₁-C₄Alkyl, C substituted by one or more halogens₁-C₄Alkyl radical, C₁-C₄alkyl-O-and C substituted by one or more halogens₁-C₄C in alkyl-O-radicals₁-C₄Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; such as methyl.

when R is^d1When independently a 4-6 membered heterocycloalkyl group, the 4-6 membered heterocycloalkyl group is morpholino (e.g., methyl-amino

)。

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

R¹is chlorine or ethyl.

is composed of

For example

ring B is

(e.g. in

)、

(e.g. in

)、

(e.g. in

) Or

(e.g. in

) (end a is shown attached to L)

l is

(e.g. in

)、

(e.g. in

) Or

(e.g. in

)；

For example

End c indicates attachment to ring B.

ring D is

(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

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

is composed of

is composed of

For example

is composed of

In certain preferred embodiments of the present invention, the heteroaromatic nitrile compounds of formula I are represented by 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).

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 (C LL), acute lymphoblastic leukemia (a LL), T-cell acute lymphoblastic leukemia (T-a LL), chronic myelogenous leukemia (CM L), acute myelogenous leukemia (AM L), 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 a malignant tumor (Stedman 'S medical dictionary (Stedman' S medicinal Dictionary), 25th edition (25th ed), Hensyl edition; Williams and Wilkins (Williams & Wilkins: Philadelphia): Philadelphia (Philadelphia), an exemplary cancer includes but is not limited to auditory neuroma, adenocarcinoma, adrenal gland, anal carcinoma, angiosarcoma (e.g., lymphatic sarcoma, lymphatic endothelioma, angiosarcoma), benign monoclonal gammaglobular globulin disease, biliary tract tumor (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma, papillary carcinoma, breast cancer, medullary carcinoma), brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), cervical cancer (e.g., adenocarcinoma), cervical cancer (e.g., adenocarcinoma), meningiocarcinoma, adenocarcinoma, etc.), neuroblastoma, bronchogenic carcinoma, as a bronchogenic carcinoma of the gastrointestinal tract, e, as a neuroblastoma, lung cancer (LL), as a gastrointestinal neuroblastoma, as a lymphoblastic lymphoma, as a splendid not a neuroblastoma, as a gastrointestinal neuroblastoma (LL, as a), as a neuroblastoma (epithelial carcinoma of the gastrointestinal neuroblastoma, as a), as a neuroblastoma, as a gastrointestinal neuroblastoma (LL, as a neuroblastoma, as a), as a (epithelial carcinoma of a), as a gastrointestinal neuroblastoma, as a (epithelial carcinoma of a, as a gastrointestinal neuroblastoma, as a gastrointestinal tract, as a (as a gastrointestinal neuroblastoma, as a), as a (as a), as a gastrointestinal neuroblastoma, as a, as.

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.

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., CDKs, CDK, mitogen protein kinases (MAPKs, e.g., MAPK, glycogen synthase kinase 3(GSK, e.g., GSK), or CDC-like kinases (C0K, e.g., C1K, C2K, C3K, C4K)), kinases (e.g., protein kinase a (a), protein kinase C), tyrosine kinase C1 kinase (K), tyrosine kinase-dependent kinase (e.g., kinase), tyrosine kinase-like kinase (kinase-like kinase), tyrosine kinase-like kinase (tack-kinase-expressing protein kinase-gamma kinase-like kinase (tack-kinase-gamma-expressing protein-kinase-.

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 dCaminolle 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 found in the descriptions of "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 "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

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 in the specification, a heterocycloalkyl group can be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic, or higher ring system, which can include a fused (fused), bridged (bridged) or spiro ring system (e.g., a bicyclic ring system ("bicyclic heterocycloalkyl"). A heterocycloalkyl bicyclic ring system can include one in one or both ringsOr a plurality of heteroatoms; and is 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, oxetanyl, 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, oxathiolanyl, 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 "aryl" refers to an all-carbon aromatic group having a fully conjugated pi-electron system, which may be a single ring or a fused ring, generally having 6 to 14 carbon atoms, preferably having 6 to 12 carbon atoms, and most preferably having 6 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "heteroaryl" refers to an aromatic group containing a heteroatom, which may be a single ring or a fused ring, preferably containing 1-4 5-12 membered heteroatoms independently selected from N, O and SAryl groups 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 expressly indicated as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "halo-C₁-C₆C in alkyl₁-C₆Alkyl is understood to mean C₁-C₆An 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.

In the following examples, abbreviations are explained:

DCM: dichloromethane; boc₂O: di-tert-butyl dicarbonate; PE: petroleum ether; EA: ethyl acetate; r_fThe specific migration value, Dess-Martin, DMF, N-dimethylformamide, DIEA, N-diisopropylethylamine, ACN, acetonitrile, L iHMDS, lithium bistrimethylsilyl amide, THF, tetrahydrofuran, dioxane, TFA, trifluoroacetic acid, MeOH, methanol, prep-T L C, thin layer chromatography, DCE, 1, 2-dichloroethane, room temperature, 10-30 ℃, rt, room temperature, HATU, 2- (7-benzotriazole oxide)N, N, N ', N' -tetramethyluronium hexafluorophosphate, prep-HP L C, preparation of high performance liquid phase, B₂Pin₂: pinacol ester diborate; SEM: (trimethylsilyl) ethoxymethyl; boc: tert-butoxycarbonyl group.

In the following examples, room temperature means 10-30 ℃; overnight means 8-15 hours, e.g., 12 hours; eq means equivalent; solvent ratio such as PE/EA refers to the volume ratio.

Example 1 synthesis of SZ-015056:

the first step is as follows: SZ-015056 Synthesis

Compound 015056A7(436mg, 1.28mmol), 2-cyanopyrimidine-5-carboxylic acid (190mg, 1.28mmol), HATU (730mg, 1.92mmol) and N, N-diisopropylethylamine (495mg, 3.84mmol) were added to tetrahydrofuran (30M L), the reaction was stirred at room temperature for 2 hours, tetrahydrofuran was removed under reduced pressure, the concentrated residue was purified by thin layer chromatography to give a yellow product, and slurried with dichloromethane (50M L) to give a pale yellow solid compound SZ-015056(170mg), L CMS: [ M + H L ]]⁺473.2。

¹H NMR(DMSO-d₆,400MHz)：11.84(s，1H)，9.32(s，2H)，8.93(d，J＝8.0Hz，1H)，8.62-8.60(m，1H)，8.48(s，1H)，8.27(s，1H)，7.51-7.48(m，1H)，7.33(d，J＝8.0Hz，1H)，7.22(s，2H)，3.97-3.90(m，2H)，2.32-2.26(m，1H)，2.09-1.85(m，3H)，1.46-1.23(m，4H)。

Example 2 synthesis of SZ-015088:

step 1:

compound 015081a1(1.0g, 1.748mmol), potassium vinyltrifluoroborate (1.17g, 8.741mmol), palladium acetate (196mg, 0.874mmol), 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl (833mg, 1.748mmol) and cesium carbonate (1.14g, 3.496mmol) were added to a toluene/water (30m L/6 m L) mixed solvent, stirred at 120 degrees celsius under nitrogen protection overnight, the reaction mixture was concentrated in vacuo after cooling and purified by column chromatography to give 015088a2(460mg) as a pale yellow solid.

¹HNMR(DMSO-d₆,400MHz):8.52(s,1H),8.42(d,J＝6.4Hz,1H),7.95(s,1H),7.70(d,J＝8.4Hz,1H),7.36-7.24(m,3H),6.94-6.88(m,2H),5.74-5.70(m,3H),5.25(d,J＝11.6Hz,1H),4.12-4.09(m,1H),3.59(t,J＝7.6Hz,2H),2.25-2.09(m,1H),2.00-1.98(m,1H),1.85-1.83(m,2H),1.46-1.16(m,14H),0.92(t,J＝7.6Hz,2H),-0.001(s,9H).

Step 2:

compound 015088A2(460mg, 0.816mmol) was dissolved in a mixed solvent of ethyl acetate/methanol (20M L/10M L), palladium/carbon (92mg) was added, the reaction mixture was stirred overnight at room temperature under hydrogen (1 atm), and after filtration, the mixture was concentrated to give crude yellow oily compound 015088A3(400mg) L CMS [ M + H ]]⁺566.4。

And 3, step 3:

dissolving compound 015088A3(400mg, 0.707mmol) in dichloromethane (20M L), slowly adding trifluoroacetic acid (10M L) dropwise under ice bath, stirring the reaction solution at room temperature for 2 hours, removing the solvent by rotary drying, dissolving the concentrated residue in 20ml of methanol, adding ammonia (5M L), stirring the reaction mixture at room temperature overnight, then rotary drying, purifying the concentrated residue by preparative high performance liquid chromatography to obtain a light yellow solid 015088A4(75mg), L CMS [ M + H ] L CMS]⁺336.2。

And 4, step 4:

adding compound 015088A4(75mg, 0.223mmol), compound 2-cyanopyrimidine-5-carboxylic acid (33.3mg, 0.223mmol), triethylamine (48.6mg, 0.446mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (126.9mg, 0.335mmol) into N, N-dimethylformamide (5M L), stirring at room temperature for 2 hours, vacuum concentrating and purifying by preparative high performance liquid chromatography to obtain light yellow solid compound SZ-015088(39.4mg), L CMS [ M + H ] 015088]⁺467.3；¹HNMR(DMSO-d₆,400MHz):11.57(s,1H),9.31(s,2H),8.89(d,J＝6.8Hz,1H),8.41(d,J＝8.8Hz,1H),8.13(s,1H),7.83(d,J＝2.8Hz,1H),7.46(t,J＝1.6Hz,1H),7.18-7.13(m,2H),6.79(d,J＝8.4Hz,1H),3.96-3.94(m,2H),2.74-2.68(m,2H),2.27-2.25(m,1H),1.99-1.82(m,3H),1.46-1.26(m,4H),1.18-1.14(m,3H).

Example 3 synthesis of SZ-015221:

step 1:

SZ-015221A1(5.0g,31.6mmol) was dissolved in dichloromethane (250M L) and di-tert-butyl dicarbonate (7.0g, 32.1mmol) and triethylamine (5M L, 32.1mmol) were added successively and stirred at room temperature overnight, the solvent was removed by rotary evaporation and purified by flash column chromatography on silica gel (MeOH: EA ═ 10: 1; Rf ═ 0.3) to give SZ-015221A2(1.7g), L CMS: [ M + H: [ 10:1 ]; [ 0.3 ] as a colorless oil]⁺259.1。

Step 2:

SZ-015221A2(0.9g,3.4mmol) and 9150A5(1.5g,3.4mmol) are dissolved in DMA (30M L), DIEA (1.3M L, 6.8mmol) is added to the system and stirred at 120 ℃ for 48 hours, after the reaction is completed, 50M L of water and 100M L of ethyl acetate are added, the organic phase is dried over sodium sulfate and dried, and purified by flash silica gel column to obtain SZ-015221A4(900mg) L CMS as a foamy solid]⁺652.4。

And 3, step 3:

SZ-015221A4(0.8g, 1.2mmol) is dissolved in 1, 4-dioxane (8M L) and water (4M L), sodium hydroxide (240mg, 6.1mmol) is added into the system, the temperature is raised to 40 ℃, the mixture is stirred for 2 hours, after the reaction is finished, 1N hydrochloric acid aqueous solution is used for adjusting the pH of the system to about 6, the mixture is extracted by ethyl acetate of 20M L, and the organic phase is dried in a spinning mode to obtain a foamy solid 900mg, L CMS [ M + H ] CMS]⁺638.5。

And 4, step 4:

SZ-015221A5(800mg,1.25mmol), DPPA (520mg, 1.88mmol) and triethylamine (0.5m L, 3.75mmol) were dissolved in anhydrous toluene (20m L), the system was stirred at 100 ℃ for 2 hours, sodium trimethylsiloxy (560mg,5.0mmol) was added in one portion and stirring was continued at this temperature for 2 hours, and 280mg of sodium trimethylsiloxy was added againAfter 2 hours, the reaction was stopped, insoluble matter in the system was filtered off, the filtrate was spun dry and purified with a flash silica gel column to obtain SZ-015221A6(530mg) as a foamy solid, L CMS, [ M + H ]]⁺609.3。

And 5, step 5:

SZ-015221A5(250mg,0.41mmol), HATU (187mg,0.49mmol) and 2-cyanopyrimidine-5-carboxylic acid (61mg,0.41mmol) were dissolved in DMF (5M L), DIEA (0.6M L, 3.25mmol) was added and stirred at room temperature for 1 hour, after the reaction was complete, spin-dried to obtain the next step, L CMS: [ M + H]⁺740.4。

And 6, step 6:

dissolving the crude product obtained in the previous step in dichloromethane (5M L), slowly dropping trifluoroacetic acid (3M L), stirring at room temperature for about 2 hours, pouring the obtained intermediate into 5M L cold water, adjusting pH to about 11 with 28% ammonia water (aq), adding acetonitrile (5M L) to make the system uniform, stirring rapidly for 2 minutes, adding 10M L ethyl acetate, spin-drying the organic phase, purifying by high pressure reverse phase column chromatography (ACN-0.1% ammonium carbonate aqueous solution), and freeze-drying to obtain SZ-015221(75mg) L CMS: [ M + H L ]]⁺510.1。

SZ-015221：¹H NMR(400MHz,DMSO-d₆)9.33(s,2H),8.87(d,J＝8.0Hz,1H),8.50(s,1H),8.33(s,1H),7.38(d,J＝8.4Hz,1H),3.07-3.14(m,2H),2.34-2.52(m,2H),1.51-1.60(m,1H).

Example 4 synthesis of SZ-015086:

step 1:

the compound methyl 5-aminopyridine-3-carboxylate (30g, 197mmol), rhodium/alumina (16g, 5%), methanol (140M L) and hydrochloric acid (140M L, 2N) were added to a high pressure reactor, the reaction solution was reacted at 70 ℃ under hydrogen pressure of 3MPa for 8 hours, cooled and filtered, and the filtrate was concentrated to give 015086A1(31g) [ M + H ] L CMS as a yellow solid]⁺159.1。

Step 2:

compound 015086A1(31g,197mmol), potassium carbonate (59g, 197mmol) were added to methanol (300M L) and the reaction was stirred at reflux overnight, cooled and filtered, and the filtrate was concentrated to give a white solid compound 015086A2(21g) [ M + H ] L CMS: [ M + H ] M]⁺127.1。

And 3, step 3:

compound 015086A2(30g, 236mmol) was dissolved in tetrahydrofuran (150M) and water (200M L) and then sodium carbonate (37.5g, 354mmol) and benzyl chloroformate (44g, 259mmol) were added and the reaction mixture was stirred at room temperature overnight, filtered and concentrated to give compound 015086A3(25g) as a white solid, [ M + H ] L CMS: [ M + H + CMS ]]⁺261.1；¹HNMR(DMSO-d₆,400MHz):7.74-7.70(m,1H),7.39-7.28(m,5H),5.10-5.06(m,2H),3.92-3.85(m,1H),3.73-3.65(m，2H),3.17-2.96(m,2H),2.26-2.22(m，1H),2.17-2.12(m,1H),1.76-1.73(m,1H)。

And 4, step 4:

compound 015086A4(5.4g,20.6mmol) was dissolved in tetrahydrofuran (45M L), followed by addition of sodium hydride (1.24g,31.0mmol), di-tert-butyl carbonate (6.8g,31.0mmol) and 4-dimethylaminopyridine (1.2g,0.5mmol), reaction with stirring at room temperature for 1 hour, addition of methanol (10M L), stirring at room temperature for 2 hours, addition of sodium hydroxide (2N,12M L), stirring at room temperature for 2 hours, pH adjustment with hydrochloric acid (1N) to 3-4, and filtration to give white solid 015086A4(6.5g), L CMS: [ M + H L: (M + H)]⁺379.2。

And 5, step 5:

compound 015086A4(3.0g,7.94mmol) was dissolved in t-butanol (60M L), followed by addition of diphenylphosphorylazide (2.4g,8.72mmol), N, N-diisopropylethylamine (2.04g,15.8mmol), stirring at 100 ℃ for 8 hours, cooling to room temperature, concentration, and purification of the concentrated residue by column chromatography to give 015086A5(1.8g) as a yellow solid L CMS [ M + H ] M]⁺450.2。

And 6, step 6:

compound 015086A5(1.4g,3.12mmol) was dissolved in methanol (15M L), followed by addition of palladium on carbon (500mg, 10% l), stirring under hydrogen at room temperature for 5 hours, filtration, and concentration of the filtrate to give 015086A6(825mg) as a white solid L CMS [ M + H ] M]⁺316.2。

And 7, step 7:

compound 015086A6(725mg, 2.3mmol) is dissolved in methanol (5M L), 37% aqueous formaldehyde (1M L), sodium cyanoborohydride (214mg,3.45mmol) are added, the reaction is stirred at room temperature for 12 hours, and the concentrated residue is purified by column chromatography to obtain 015086A7(695mg) as a yellow solid, L CMS [ M + H ] M]⁺330.2

And 8, step 8:

compound 015086A7(695mg,2.1mmol) is dissolved in 1, 4-dioxane (5M L), dioxane/hydrochloric acid gas (5M,5M L) is added, the reaction is stirred at room temperature for 2 hours, and the white solid salt 015086A8(435mg, crude product) is obtained after concentration, L CMS [ M + H L ]]⁺130.2

Step 9:

the compound 015086A8 (crude product, 200mg), the compound 015056A4(606mg,1.5mmol) are dissolved in dimethyl sulfoxide (5M L), then triethylamine (454mg,4.5mmol) is added, the mixture is stirred and reacted for 5 hours at 80 ℃, after cooling, the mixture is concentrated in vacuum and purified by column chromatography to obtain a yellow solid compound 015086A9(143mg), L CMS: [ M + H]⁺497.2

Step 10:

dissolving compound 015086A9(143mg,0.281mmol) in dioxane (6M L), adding 2N sodium hydroxide aqueous solution (4M L), reacting at 70 deg.C under stirring for 5 hr, cooling, extracting with ethyl acetate, washing with saturated saline, drying the separated organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain light yellow solid compound 015086A10(95mg), L CMS: [ M + H): (M + H))]⁺357.2

And 11, step 11:

compound 015086a10(95mg,0.286mmol), compound 2-cyanopyrimidine-5-carboxylic acid (43mg,0.286mmol), triethylamine (115mg,1.14mmol) and HATU (130mg,0.343mmol) were added to tetrahydrofuran (5m L), the reaction was stirred at room temperature for 2 hours, the reaction mixture was poured into 50 ml of water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the concentrated residue was purified by preparative high performance liquid chromatography to give SZ-015086(45mg) as a pale yellow solid compound, which was resolved by chiral column to give SZ-015086a (16.5mg) and SZ-015086B (15.4 mg).

SZ-015086A：LCMS：[M+H]⁺489.9。HNMR:(DMSO-d₆,400MHz):11..87(s,1H),9.33(s,2H),9.10(s,1H),8.59(s,1H),8.48-8.47(m,1H),8.30(s,1H),7.50-7.44(m,2H),7.41-7.20(m,2H),4.24-4.16(m,2H),2.42-2.21(m,3H),2.00-1.98(m,1H)，1.61-1.56(m,1H),1.23(s,3H)。

SZ-015086B:LCMS：[M+H]⁺489.9。¹HNMR:(DMSO-d₆,400MHz):11.85(s,1H),9.31(s,2H),8.98-8.96(m,1H),8.58(s,1H),8.48-8.46(m,1H)，8.28(s,1H),7.50-7.48(m,1H),7.39-7.31(m,1H),7.23-7.16(m,2H),4.15(s，2H),3.1-2.99(m,2H),2.31-2.21(m,4H),2.01-1.82(m，2H),1.53-1.44(m，1H)。

Example 5 SZ-015093 synthesis:

step 1:

compound 015086a5(1.6g, 4.65mmol) was dissolved in methanol (15M L) and then palladium on carbon (500mg, 10%), acetaldehyde tetrahydrofuran solution (5M, 2.0M L) was added and the reaction was stirred under hydrogen (1 atm) at room temperature for 5 hours, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:5) to give 015093a1(623mg) as a yellow solid L CMS: [ M + H: [ CMS + CMS: [ 1:5 ]: M + H ]: L:]⁺344.2.

step 2:

compound 015093A1(623mg, 1.81mmol) is dissolved in 1, 4-dioxane (5M L), dioxane/hydrochloric acid gas (5M,5M L) is added, the reaction is stirred at room temperature for 2 hours, and the mixture is concentrated to obtain white solid 015093A2(351mg) L CMS: [ M + H ] CMS]⁺144.2.

And 3, step 3:

compound 015093A3(200mg, crude), compound 015056A4(564mg, 1.39mmol) were dissolved in dimethyl sulfoxide (5M L), triethylamine (671mg,4.5mmol) was added thereto and the reaction was stirred at 80 ℃ for 5 hours, concentrated in vacuo and purified by column chromatography to give 015093A3(215mg) as a yellow solid, [ M + H ] L CMS: [ M + H ] was obtained]⁺511.2.

And 4, step 4:

compound 015093A3(194mg, 0.379mmol) was dissolved in dioxane (6m L) and 2 was addedStirring N sodium hydroxide solution (4M L) at 70 deg.C for 5 hr, cooling, extracting with ethyl acetate, washing the combined extractive solutions with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain light yellow solid compound 015093A4(135mg) L CMS]⁺371.2.

And 5, step 5:

compound 015093a4(145mg, 0.391mmol), compound 2-cyanopyrimidine-5-carboxylic acid (58.2mg, 0.391mmol), triethylamine (118mg, 1.17mmol) and 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (178mg, 0.469mmol) were added to tetrahydrofuran (5m L), stirred at room temperature for 2 hours, the reaction was poured into 50 ml of water, ethyl acetate was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the concentrated residue was purified by preparative high performance liquid chromatography to give a pale yellow solid compound SZ-015093(65mg, yield 33%), followed by chiral column resolution to give SZ-015093a (18.8mg) and SZ-015093B (14.6mg)

SZ-015093A：LCMS:[M+H]⁺502.2.¹HNMR(DMSO-d₆,400MHz):11.84(s,1H),9.32(s,2H),8.94(d,J＝8Hz,1H),8.58-8.47(m,2H),8.27(s,1H),7.49(d,J＝8Hz,1H),7.37(d,J＝8Hz 1H),7.23-7.15(m,2H),4.12-4.11(m,2H),3.19-3.05(m,2H),2.50-2.45(m,2H),2.25-2.23(m,1H),1.88-1.83(m,2H),1.55-1.46(m,1H),1.03(t,J＝8Hz,3H).

SZ-015093B：LCMS:[M+H]⁺502.2.¹HNMR(DMSO-d₆,400MHz):11.84(s,1H),9.32(s,2H),8.94(d,J＝8Hz,1H),8.58-8.47(m,2H),8.28(s,1H),7.49(d,J＝8Hz,1H),7.37(d,J＝8Hz 1H),7.23-7.15(m,2H),4.12(s,2H),3.26-3.07(m,2H),2.51-2.49(m,2H),2.25-2.23(m,1H),2.01-1.97(m,2H),1.52-1.47(m,1H),1.03(t,J＝8.0Hz,3H).

Example 6 SZ-015091 synthesis:

step 1:

compound 015091A1(400mg, 0.847mmol), compound 2-chloropyrimidine-5-carbaldehyde (483mg, 3.39mmol), formic acid (117mg, 2.54mmol) and sodium cyanoborohydride (153mg, 2.54mmol) were added to methanol (15M L), and after stirring at room temperature for 12 hours, the reaction was concentrated in vacuo and purified by silica gel column chromatography to give 015091A2(250mg) & L CMS: [ M + H ] as a yellow solid]⁺598.2

Step 2:

compound 015091A2(220mg, 0.368mmol), zinc cyanide (86.3mg, 0.736mmol), 1' -bis (diphenylphosphino) ferrocene (10.2mg, 0.018mmol) and tris (dibenzylidene-BASE acetone) dipalladium (16.5mg, 0.018mmol) were added to DMF (10M L), stirred at 100 deg.C under nitrogen for 12 hours, the reaction mixture was cooled, concentrated in vacuo and purified by silica gel column chromatography to give 015091A3(120mg), L CMS [ M + H ] as a yellow solid]⁺589.2.

And 3, step 3:

compound 015091A3(120mg, 0.187mmol) and trifluoroacetic acid (3M L) were added to dichloromethane (5M L), the reaction mixture was stirred at room temperature for 2 hours, and then concentrated in vacuo, and to the remaining residue was added aqueous ammonia (6M L), the mixture was stirred at room temperature for 2 hours, concentrated in vacuo, and purified by preparative high performance liquid chromatography to give SZ-015091(15mg) as a white solid, [ M + H ] L CMS: [ M + H L ]]⁺459.2.

¹HNMR(DMSO-d₆,400MHz):11.82(s,1H),8.94(s,2H),8.52-8.46(m,2H),8.23(s,1H),7.49-7.47(m,1H),7.23-6.97(m,3H),3.88-3.79(m,3H),2.32-2.21(m,1H),2.03-1.97(m,2H),1.95-1.77(m,1H),1.38-0.98(m,5H).

Example 7 Synthesis of SZ-015092 and SZ-015094:

step 1:

2-chloro-4, 5-diaminopyrimidine (2.0g, 13.83mmol), (1S,3R) -3- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid (3.4mg, 13.83mmol), triethylamine (4.2g, 41.49mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylureaHexafluorophosphate (5.3g, 13.83mmol) was added to N, N-dimethylformamide (40M L), the reaction mixture was stirred at room temperature overnight, 80M L water was added to the reaction mixture, ethyl acetate (30M L X3) was extracted, the organic phases were combined, washed with saturated brine, filtered and concentrated, and the concentrated residue was isolated and purified by silica gel column to give a brown paste 015092A1(2.4g) L CMS: [ M + H + M3]⁺370.2.

Step 2:

compound 015092A1(2.4g,6.49mmol) was dissolved in dichloromethane solution (30M L), trifluoroacetic acid (8M L) was added thereto, the reaction mixture was stirred at room temperature for 1 hour, and after stirring the reaction mixture, the solvent was removed by rotary drying to give 015092A2 (crude 5.8g, quantitative yield) as a brown oil which was used in the next reaction without purification [ M + H ] L CMS: [ M + H ] as a solid]⁺270.1

And 3, step 3:

compound 015092a2 (crude 5.8g, 6.49mmol) and compound 015056a4(2.62g, 6.49mmol) were dissolved in N-methylpyrrolidone/ethanol (20M L/20M L), diisopropylethylamine (4.2g, 32.45mmol) was added, the reaction was heated to 120 ℃ and stirred overnight, L CMS found little product, diisopropylethylamine (5M L) was added to the reaction, stirring was continued overnight at 120 ℃ L CMS found product, the reaction was cooled to room temperature, concentrated to remove solvent, 30M L water was added to the residue, ethyl acetate (30M L x 3) was extracted, the combined organic phases were concentrated to remove solvent, and the residue was purified by silica gel column separation to give a brown oil 015092A3(1.7g), L CMS [ M + H) as an oil]⁺637.1.

¹HNMR(DMSO-d₆,400MHz):9.11-9.02(m,1H),8.61(s,1H),8.45-8.43(m,2H),8.16(s,1H),8.12-8.07(m,2H),8.02-7.98(m,1H),7.75-7.72(m,1H),7.65-7.61(m,2H),7.56(d,J＝8.4Hz,1H),7.47-7.43(m,1H),7.38-7.35(m,1H),7.32-7.16(m,1H),3.84(s,1H),2.20-2.12(m,1H),2.03-1.85(m,4H),1.53-1.44(m,1H),1.40-1.18(m,4H).

And 4, step 4:

compound 015092A3(150mg, 0.235mmol) was dissolved in methanol/tetrahydrofuran/water (4m L/2 m L/2 m L) followed by the addition of lithium hydroxide monohydrate (49mg, 1.177mmol), the reaction solution was stirred at room temperature overnight, L CMS checked to find the product 015094a1 content 60% and 015092a4 content 40%, the reaction was complete, the reaction was concentrated to remove the solvent, the residue was added 10m L water, extracted with ethyl acetate (15m L x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent to give a yellow oil solid mixture 015094a1 and 015092a4(58 mg).

015094A1：LCMS:[M+H]⁺497.1。

015092A4：LCMS:[M+H]⁺479.1。

And 5, step 5:

at room temperature, mixtures 015094A1 and 015092A4(58mg, 0.117mmol) are dissolved in N-methylpyrrolidone (4m L), zinc cyanide (27mg, 0.233mmol) and tetratriphenylphosphine palladium (135mg, 0.117mmol) are added, the reaction solution is stirred overnight at 100 ℃ under the protection of nitrogen, products 015094 and 015092 are detected by L CMS, 10m L water is added after the reaction solution is cooled to room temperature, ethyl acetate (8m L x 3) is extracted, the organic phases are combined, the solvent is removed by concentration, and the residue is purified by preparative high performance liquid chromatography to obtain two compounds 015094 and 015092 of trifluoroacetate salt, the two compounds are respectively neutralized by aqueous sodium bicarbonate solution, extracted by ethyl acetate, the organic phases are separated, the organic phases are washed by distilled water, the aqueous layers are separated for multiple times, the organic phases are respectively concentrated, and freeze-dried at low temperature to respectively obtain white solid SZ-015094(4mg) and white solid SZ-015092(8 mg).

SZ-015094:LCMS:[M+H[⁺488.2.¹HNMR(DMSO-d₆,400MHz):11.82(s,1H),9.28(s,1H),8.69-8.58(m,2H),8.47-8.43(m,1H),8.25(d,J＝5.2Hz,1H),7.59-7.44(m,2H),7.37-7.06(m,4H),4.00-3.78(m,1H),2.67-2.54(m,1H),2.21-2.14(m,2H),2.02-1.83(m,6H).

SZ-015092:LCMS:[M+H]⁺470.2.¹HNMR(DMSO-d₆,400MHz):13.77(s,1H),11.82(s,1H),9.12(s,1H),8.63(br s,1H),8.47(d,J＝2.8Hz,1H),8.26(s,1H),7.49(d,J＝7.6Hz,1H),7.36(d,J＝8.0Hz,1H),7.23-7.17(m,2H),4.05-3.93(m,1H),3.25-3.17(m,1H),2.49-2.43(m,1H),2.21-2.07(m,1H),2.03-1.90(m,2H),1.75-1.20(m,4H).

Example 8 synthesis of SZ-015218:

step 1:

the compound 1(3g, 14.9mmol), zinc cyanide (3g, 78.8mmol), Pd₂(dba)₃(0.11g,0.12mmol), DMF (33m L) and dppf (69mg,0.12mmol) were stirred at 26 ℃ and replaced three times with nitrogen, heated to 110 ℃ under nitrogen and stirred for a further 16 hours, the resulting black suspension was dried over solvent, the residue was stirred thoroughly with ethyl acetate (60m L) and water (60m L) and filtered under reduced pressure, the filtrates were combined and extracted with ethyl acetate (60m L x 3), the organic phases were combined and anhydrous MgSO 3 was added₄Drying, filtration, spin-drying of the organic solvent the residue was purified by column chromatography to give 15218A0(1.8g) as a yellow oily product L CMS: [ M + H ]]⁺192.1

Step 2:

an aqueous solution of lithium hydroxide (1.6M L, 1M) was added dropwise to a solution of 15218a0(0.33g,1.73mmol) in tetrahydrofuran at 1-3 ℃ and the resulting reaction mixture was stirred at 1-3 ℃ for 16 minutes, the resulting reaction mixture was stirred at 1-3 ℃ and diluted hydrochloric acid (1N) was added dropwise to adjust the pH to 1-3, the resulting reaction mixture was extracted with ethyl acetate (30M L x 3), the organic phases were combined and anhydrous MgSO was added₄Drying, filtration, spin-drying of the organic solvent followed by oil pumping for three minutes gave 15218A1 as a pale yellow oil (330mg, crude 80 Wt%) which was used directly in the next reaction L CMS: [ M + H ]]⁺162.1

And 3, step 3:

oxalyl chloride (1.5g, 11.8mmol) was added portionwise to a solution of compound 15218a1(330mg, crude 80 Wt%, 1.6mmol) in dichloromethane (9m L) at 29 ℃ and then catalyzed by the addition of a drop of anhydrous DMF the resulting reaction mixture was stirred for an additional 1.6 h at 29 ℃ then the resulting reaction mixture was spun dry of organic solvent and then pumped using an oil pump for three minutes to give crude 15218a1(330mg, crude 80 Wt%, 1.6mmol) which was used directly in the next reaction.

And 4, step 4:

crude 15218A1(330mg, crude 80 Wt%, 1.6mmol) obtained above was dissolved in anhydrous tetrahydrofuran (6m L), this solution was added dropwise at 1-3 ℃ to a mixed solvent of 015056A7 and sodium carbonate (1.1g,10mmol) in tetrahydrofuran (6m L)/water (6m L). The resulting reaction mixture was stirred at 1-3 ℃ for one hour, then diluted with water (30m L), followed by ethyl acetate extraction (30m L x 3). the combined organic phases were dried over anhydrous magnesium sulfate, filtered, concentrated to remove the solvent, and the residue was purified by preparative high pressure chromatography to give a pale yellow solid compound SZ-015218(63 mg).

LCMS:[M+H]⁺487.2；¹H NMR(400MHz,CD₃OD)11.92(s,1H),8.89(s,2H),8.63(br,1H),8.48(s,1H),8.26(s,1H),7.50(s,1H),7.28(s,1H),7.22(s,2H),3.95(s,2H),2.58(s,3H),2.33(s,1H),1.98(s,2H),1.86(s,1H),1.41(m,2H),1.26(m,2H)

Example 9 synthesis of SZ-015216:

step 1:

aqueous potassium carbonate (19.1g in 50 ml water) was added dropwise at 1-3 ℃ to a solution of compound 1(13g,30mmol) and methylamine hydrochloride (4.9g,73mmol) in acetone (500m L) the reaction mixture was stirred at 1-3 ℃ for an additional hour to give a white suspension, the reaction mixture was spun dry of organic solvent, the residue was stirred thoroughly with ethyl acetate and water and then extracted with ethyl acetate (0.3L. sup.3). the organic phases were combined and anhydrous MgSO was added₄Drying, filtering and spin-drying the organic solvent. Oil pump was then used to pump for three minutes to give crude 15216A0(12.9g, crude) as a white solid. A portion of the crude product (3g) was purified by column to afford pure compound 15216A0(1.6 g).

¹H NMR(400MHz,DMSO-d₆)8.55(s,1H),8.43(br,1H),3.83(s,3H),2.94(d,J＝4.0Hz,3H)。

Step 2:

compound 15216A0(930g,4.6mmol), zinc cyanide (1.16g,9.8mmol), Pd₂(dba)₃(0.11g,0.12mmol),After stirring a mixture of DMF (16m L) and dppf (69mg,0.12mmol) at 26 ℃ and displacing with nitrogen three times, heating to 110 ℃ under nitrogen and stirring for a further 16 hours, the resulting black suspension is drained of solvent, the residue is stirred thoroughly with ethyl acetate (30m L) and water (30m L) and filtered under reduced pressure, the filtrates obtained are combined and extracted with ethyl acetate (30m L. multidot.3). the organic phases are combined and anhydrous MgSO (MgSO) is added₄Drying, filtration and spin-drying of the organic solvent the residue was purified by column chromatography to give the product 15216A1(630 mg). L CMS: [ M + H ]]⁺193.09。

And 3, step 3:

adding dropwise lithium hydroxide solution (6M L, 1M) into 15216A1(630mg,3.26mmol) tetrahydrofuran (6M L) solution at 1-3 deg.C, stirring the obtained reaction mixture at 1-3 deg.C for half an hour, stirring the obtained reaction solution at 1-3 deg.C, adding diluted hydrochloric acid (1M) to adjust pH to 1-3, extracting the obtained reaction solution with ethyl acetate (30M L × 3), combining organic phases, and adding anhydrous MgSO (MgSO)₄Drying, filtration, spin-drying of the organic solvent followed by pumping for three minutes using an oil pump gave product 15216A2(530mg) as a white solid which was used directly in the next reaction L CMS: [ M + H ]]⁺179.08。

And 4, step 4:

oxalyl chloride (1.5g, 11.8mmol) was added portionwise to a solution of compound 15216a2(260mg, 1.39mmol) in dichloromethane (9m L) at 29 degrees celsius and then catalyzed by the addition of a drop of anhydrous DMF the resulting reaction mixture was stirred for an additional 1 hour at 29 degrees celsius then the resulting reaction mixture was spun dry of organic solvent and then pumped using an oil pump for three minutes to give crude 15216A3(260mg) which was used directly in the next reaction.

And 5, step 5:

crude 15216A3(260mg) obtained above was dissolved in anhydrous tetrahydrofuran (6m L), this solution was added dropwise at 1-3 ℃ to a mixed solvent of 015056A7(180mg, 0.5mmol) and sodium carbonate (1.1g,10mmol) in tetrahydrofuran (6m L)/water (6m L), the reaction mixture obtained was stirred at 1-3 ℃ for one hour, then diluted with water (30m L), followed by ethyl acetate extraction (30m L x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated to remove the solvent, and the residue was purified by preparative high pressure chromatography to givePale yellow solid compound SZ-015216(60mg), L CMS [ M + H ]]⁺502.1。

¹H NMR(400MHz,CD₃OD)11.92(s,1H),8.79(s,1H),8.75(s,1H),8.59(s,2H),8.46(s,1H),8.26(s,1H),7.50(d,J＝8.0Hz,1H),7.30(d,J＝8.0Hz,1H),7.20(s,2H),3.93(br,2H),2.92(s,3H),2.23(s,1H),2.01(s,1H),1.91-1.86(m,2H),1.63-1.39(m,2H),1.36-1.21(m,2H)。

Example 10 synthesis of SZ-015217:

step 1:

the sodium metal salt was added in the form of sodium chloride (0.39g,16.3mmol) and stirred until dissolved in anhydrous methanol (6m L). The resulting methanolic sodium methoxide solution was added dropwise to a solution of compound 1(2.69g,15mmol) in THF (33m L) at 1-3 deg.C, the resulting reaction mixture was stirred for an additional hour at 1-3 deg.C, the resulting reaction mixture was spun dry of organic solvent, the residue was partitioned between ethyl acetate (30m L) and water (30m L), the suspension was extracted with ethyl acetate (30m L. sup.3), the organic phases were combined and anhydrous MgSO 25 was added₄Drying, filtering, spin-drying the organic solvent, and separating the residue by column chromatography to obtain 15217A0(1.3g) as a white solid compound L CMS: [ M + H ]]⁺203.1。

Step 2:

the compound 15217A0(1.1g, 5mmol), zinc cyanide (1.3g, 11mmol) and Pd₂(dba)₃(0.11g,0.12mmol), DMF (16m L) and dppf (69mg,0.12mmol) were stirred at 26 ℃ and replaced three times with nitrogen, heated to 110 ℃ under nitrogen and stirred for a further 16 hours, the resulting black suspension was dried to remove solvent, the residue was stirred thoroughly with ethyl acetate (30m L) and water (30m L) and filtered under reduced pressure, the filtrates were combined and extracted with ethyl acetate (30m L x 3), the organic phases were combined and anhydrous MgSO 3 was added₄Drying, filtering and spin-drying the organic solvent. The residue was purified by column chromatography to give compound 15217A1(410mg) as a pale yellow solid.

LCMS:[M+H]⁺194.1；¹H NMR(400MHz,DMSO-d₆)9.03(s,1H),4.08(s,3H),3.87(s,3H)。

And 3, step 3:

aqueous lithium hydroxide (1.6M L, 1M) was added dropwise to a solution of 15217a1(360mg,1.86mmol) in tetrahydrofuran at 1-3 ℃ and the resulting reaction mixture was stirred at 1-3 ℃ for 16 minutes, the reaction mixture was stirred at 1-3 ℃ and diluted hydrochloric acid (1M) was added dropwise to adjust the pH to 1-3, the reaction was extracted with ethyl acetate (30M L x 3), the organic phases were combined and anhydrous MgSO added₄Drying, filtration, spin-drying of the organic solvent followed by oil pumping for three minutes gave 15217A2 as a pale yellow oil (330mg, crude 33 Wt%) which was used directly in the next reaction L CMS: [ M + H ]]⁺178.12。

And 4, step 4:

EDCI (1.3g, 6.8mmol) was added to a solution of crude compound 15217a2(330mg, 33 Wt%, 0.6mmol) and 015056a7(170mg, 0.5mmol) in DMF (9m L) at 31 ℃, then HOAt (0.93g, 6.8mmol) was added and the resulting reaction mixture was stirred at 26-31 ℃ for a further 16 hours, the resulting reaction mixture was spun dry of organic solvent then pumped using an oil pump for three minutes, ethyl acetate (30m L) and water (30m L) were added to the residue, after stirring well, ethyl acetate was extracted (30m L × 3) and the organic phase was combined and dried over anhydrous magnesium sulfate, filtered, concentrated to remove solvent and the residue was purified by preparative chromatography to give light yellow solid compound SZ-015217(23 mg).

LCMS:[M+H⁺]503.1；¹H NMR(400MHz,DMSO-d₆)11.85(s,1H),8.81(s,1H),8.62(br,1H),8.46(s,2H),8.27(s,1H),7.50(s,1H),7.23(br,3H),4.03(s,3H),3.90(br,2H),2.28(s,1H),2.16-1.63(m,3H),1.58-1.21(m,4H)。

Example 11 synthesis of SZ-015220:

step 1:

in a reaction bottleAdding compound SZ-015220A1(1.00g,6.94mmol), adding dichloromethane (20ml) and toluene (15ml), stirring at room temperature, adding DBU (1.16g,7.63mmol) and DPPA (2.10g,7.63mmol), stirring at room temperature for 16 h.T L C, monitoring reaction, removing solvent by reduced pressure rotary evaporation, and purifying with silica gel column to obtain SZ-015220A2(747mg, white solid) [ M + H ] L CMS: [ M + H-015220A 2(]⁺170.1

Step 2:

compound SZ-015220A2(524mg, 3mmol) was dissolved in tetrahydrofuran (10m L) in a reaction flask, triphenylphosphine (1.50g, 6mmol) was slowly added, stirring at room temperature for 1 hour, and H was added₂O (3m L), stirring at room temperature under 16 h.T L C, monitoring reaction, removing solvent under reduced pressure, adding dichloromethane (10m L) to dissolve the residue, and adding H₂O (10M L), adjusting the pH of the aqueous phase to 2 with 1N hydrochloric acid, washing the aqueous phase with dichloromethane (10M L), lyophilizing the aqueous phase to give crude SZ-015220A3(548mg, pale yellow solid), which is reacted in the next step without purification L CMS: [ M + H]⁺144.0

And 3, step 3:

in a reaction flask, the crude compound SZ-015220A3(548mg) was neutralized and dissolved with saturated aqueous sodium bicarbonate (3M L), tetrahydrofuran (10M L) and Boc anhydride (1.96g,9mmol) were added, the reaction was monitored at room temperature for 1 h.T L C, the solvent was removed by rotary evaporation under reduced pressure after completion of the reaction, and the reaction was purified by a silica gel column to give SZ-015220A4(490mg, white solid) L CMS: [ M + H8983 (white solid) ]]⁺244.1

And 4, step 4:

the reaction flask was charged with SZ-015220A4(490mg, 2.01mmol), Pd₂(dba)₃(183mg,0.2mmol), dppf (110mg,0.2mmol) and zinc cyanide (351mg,3mmol) were replaced three times with nitrogen, DMF (5M L) was added to the reaction flask with syringe, the reaction was monitored for completion by stirring at 110 ℃ at 12 h.T L C and filtered through celite (EA), and purified by silica gel column to give SZ-015220A5(305mg, light brown solid) L CMS: [ M + H-8925]⁺235.12(weak)，[M-H]⁺233.21。

And 5, step 5:

SZ-015220A5(290mg,1.24mmol) was dissolved in dichloromethane (5m L) in a reaction flask, stirred at 0 ℃ and trifluoroacetic acid (f: (1)1M L) was added dropwise to a reaction flask, and after completion of the reaction was monitored by stirring at 0 ℃ under 1 h.T L C, the solvent and trifluoroacetic acid were removed by rotary evaporation under reduced pressure to give crude product of SZ-015220A6(241mg, light brown oily substance) which was reacted without purification in the next step L CMS: [ M + H ] reaction]⁺135.0。

And 6, step 6:

adding SZ-015220A6 (crude product in the previous step), SZ-015220A7(370mg,1mmol), DMF (10M L) and DIEA (258mg,2mmol) into a reaction flask, stirring at normal temperature, slowly adding HATU (494mg,1.3mmol), stirring at normal temperature for 1H, performing decompression rotary evaporation to remove the solvent after the monitoring reaction of L CMS to obtain crude product, performing reversed-phase column chromatography with acetonitrile/0.1% formic acid water, and freeze-drying to obtain SZ-015220(151mg, light yellow solid) L CMS: [ M + H015220, light yellow solid) ]]⁺487.09。

¹H NMR(400MHz,DMSO-d₆)11.83(s,1H),8.86(s,2H),8.57(brs,1H),8.51(t,J＝5.8Hz,1H),8.47(d,J＝2.7Hz,1H),8.24(s,1H),7.49(d,J＝7.9Hz,1H),7.25(d,J＝7.2Hz,1H),7.23–7.11(m,2H),4.38(d,J＝5.7Hz,2H),3.87(brs,1H),2.39(m,1H),2.04(m,2H),1.81(m,2H),1.37(m,4H).

Example 12 synthesis of SZ-015227:

step 1:

adding compound SZ-015227A1(4.91g, 22mmol) into a reaction bottle, adding tetrahydrofuran (40M L), stirring at-78 deg.C, slowly dropping morpholine (22mmol) solution in tetrahydrofuran (10M L) into the reaction bottle by using a syringe, stirring at-78 deg.C for 2 h.T L C, monitoring reaction, removing solvent by rotary evaporation under reduced pressure, and purifying by using silica gel column to obtain SZ-015227A2(2.79g, white solid) L CMS: [ M + H8A 2(2.79g, white solid) ]]⁺272.1。

Step 2:

the compound SZ-015227A2(2.79g, 10mmol) was added to a reaction flask, followed by addition of tetrahydrofuran (10m L), and the mixture was stirred at-78 deg.CDIBA L-H (40mmol) in toluene solution (26M L) was slowly dropped into the reaction flask with a syringe, stirred at-78 deg.C for 2H, L C-MS monitored after the reaction was completed, potassium sodium tartrate saturated aqueous solution (50M L) was added to quench the reaction, stirred at room temperature overnight, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the solvent was removed by evaporation under reduced pressure, and purified by silica gel column chromatography (EA) to give SZ-015227A3(290mg), L CMS: [ M + H3 (290mg) ]]⁺230.1。

And 3, step 3:

the compound SZ-015227A3(161.4mg,0.7mmol), dichloromethane (5ml) and toluene (4ml) were added to a reaction flask, and stirred at room temperature, DBU (117.2mg,0.77mmol) and DPPA (211.9mg,0.77mmol) were added, stirring at room temperature 16 h.T L C was carried out, after completion of the reaction, the solvent was removed by reduced pressure rotary evaporation, and purification was carried out by a silica gel column to obtain SZ-015227A4(133.2mg, colorless oily substance) [ M + H015227A 4 ]. L CMS: [ M + H ] was obtained]⁺255.1。

And 4, step 4:

compound SZ-015227A4(133.2mg, 0.5mmol) was dissolved in tetrahydrofuran (5m L) in a reaction flask, triphenylphosphine (262mg, 1mmol) was slowly added, stirring at room temperature for 1 hour, and H was added₂O (0.5m L), stirring at room temperature under 16 h.T L C, monitoring reaction, removing solvent by rotary evaporation under reduced pressure, adding dichloromethane (10m L) to dissolve the residue, and adding H₂O (10M L), adjusting the pH of the aqueous phase to 2 with 1N hydrochloric acid, washing the aqueous phase with dichloromethane (10M L), lyophilizing the aqueous phase to give crude SZ-015227A5 (pale yellow solid), which is reacted in the next step without purification L CMS: [ M + H ], []⁺229.0。

And 5, step 5:

in a reaction flask, the crude product of compound SZ-015227A5 was neutralized and dissolved with saturated aqueous sodium bicarbonate (3M L), tetrahydrofuran (10M L) and Boc anhydride (1g,4.5mmol) were added, the reaction was monitored at room temperature under stirring at1 h.T L C, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by silica gel column to give SZ-015227A6(120.8mg, white solid) [ M + H84 CMS ]: L CMS: [ M + H + C]⁺329.1。

And 6, step 6:

the reaction flask was charged with SZ-015227A6(120mg,0.36mmol), Pd₂(dba)₃(167.3mg,0.18mmol), dppf (101.3mg,0.18mmol) and zinc cyanide (85.6 mmol)mg,0.7mmol) was replaced with nitrogen three times, DMF (5M L) was added to the reaction flask with syringe, the reaction was monitored at 110 ℃ under stirring at 12 h.T L C and after completion of the reaction was filtered through celite (EA), which was purified by silica gel column to give SZ-015227A7(96.1mg, light brown solid): L CMS: [ M + H ] was]⁺278.1(weak)。

And 7, step 7:

SZ-015227A7(90mg,0.28mmol) was dissolved in dichloromethane (5m L) in a reaction flask, stirred at 0 ℃, trifluoroacetic acid (1m L) was added dropwise to the reaction flask, and after completion of the reaction was monitored by stirring at 0 ℃ at1 h.T L C, the solvent and trifluoroacetic acid were removed by rotary evaporation under reduced pressure to give crude product of SZ-015227A8 (light brown oily substance), which was reacted in the next step without purification.

And 8, step 8:

adding SZ-015227A8 (crude product in the previous step), SZ-015220A7(103.8mg,0.28mmol), DMF (5m L), DIEA (77.54mg,0.6mmol) into a reaction bottle, stirring at normal temperature, slowly adding HATU (159.6mg,0.42mmol), stirring at normal temperature for 1h, monitoring the reaction of L CMS, performing reduced pressure rotary evaporation to remove the solvent to obtain a crude product, performing reversed phase column chromatography with acetonitrile/0.1% formic acid water, and performing freeze drying to obtain SZ-015227(55mg, light yellow solid).

LCMS：[M+H]⁺572.2。¹H NMR(400MHz,DMSO-d₆)11.86(s,1H),8.61(br,1H),8.50(d,J＝2.6Hz,1H),8.39(t,J＝4.9Hz,1H),8.27(d,J＝5.7Hz,2H),7.52(d,J＝7.8Hz,1H),7.28(d,J＝8.0Hz,1H),7.26-7.12(m,2H),4.30(d,J＝4.9Hz,2H),3.90(br,1H),3.68(d,J＝3.8Hz,4H),3.53(d,J＝4.3Hz,4H),2.48-2.35(m,1H),2.17-1.96(d,J＝11.6Hz,2H),1.94-1.69(m,2H),1.60-1.16(m,4H).

Example 13 synthesis of SZ-015224:

step 1:

the compound SZ-015224A1(8.84g, 40mmol) was added to the reaction flask, and thenTetrahydrofuran (120M L), stirring at-78 deg.C, slowly dropping dimethylamine (40mmol) in tetrahydrofuran (20M L) into the reaction flask by syringe, stirring at-78 deg.C for 2 h.T L C, monitoring reaction, removing solvent by rotary evaporation under reduced pressure, and purifying with silica gel column to obtain SZ-015224A2(2.46g, yellow liquid) [ M + H ] L CMS: [ M + H ] S]⁺230.0

Step 2:

adding a compound SZ-015224A2(2.22g, 9.7mmol) into a reaction bottle, adding tetrahydrofuran (30M L), stirring at-78 ℃, slowly dropping a toluene solution (40M L) of DIBA L-H (60mmol) into the reaction bottle by using a syringe, stirring at-78 ℃ for 2H, monitoring the reaction by L C-MS, adding a saturated aqueous solution (50M L) of potassium sodium tartrate to quench the reaction, stirring at room temperature overnight, extracting an aqueous phase by using ethyl acetate, combining the organic phases, carrying out reduced pressure rotary evaporation to remove the solvent, and purifying by using a silica gel column chromatography (EA) to obtain SZ-015224A3(565.2mg), L: [ M + H CMS 24 ]]⁺188.1

And 3, step 3:

the compound SZ-015224A3(565.2mg,3mmol), dichloromethane (15ml) and toluene (12ml) were added to a reaction flask, and stirred at room temperature, DBU (456.7mg,3mmol) and DPPA (825.6mg,3mmol) were added, stirring at room temperature for 16 h.T L C was carried out, after completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and purification was carried out by a silica gel column to obtain SZ-015224A4(267mg, colorless oily substance) [ M + H ] L CMS: [ M + H ] was obtained]⁺213.01

And 4, step 4:

compound SZ-015224A4(267mg, 1.25mmol) was dissolved in tetrahydrofuran (10m L) in a reaction flask, triphenylphosphine (655mg, 2.5mmol) was slowly added, stirring at room temperature for 1 hour, and H was added₂O (2m L), stirring at room temperature under 16 h.T L C, monitoring reaction, removing solvent by rotary evaporation under reduced pressure, adding dichloromethane (10m L) to dissolve the residue, and adding H₂O (10M L), adjusting the pH of the aqueous phase to 2 with 1N hydrochloric acid, washing the aqueous phase with dichloromethane (10M L), lyophilizing the aqueous phase to give crude SZ-015224A5 (white solid), which is reacted in the next step without purification L CMS: [ M + H ], []⁺187.1。

And 5, step 5:

in a reaction flask, the compound was dissolved with saturated aqueous sodium bicarbonate (3m L)The crude product of SZ-015224A5 was neutralized and dissolved, tetrahydrofuran (10M L) and Boc anhydride (1g,4.5mmol) were added, the reaction was monitored by stirring at room temperature at1 h.T L C, the solvent was removed by rotary evaporation under reduced pressure, and then purified by silica gel column chromatography (EA/PE 0-40%) to obtain SZ-015224A6(261.3mg, colorless oily substance) [ M + H ] CMS: [ M + H ] L CMS: []⁺287.1。

And 6, step 6:

the reaction flask was charged with SZ-015224A6(261.3mg,0.91mmol), Pd₂(dba)₃(558.15mg,0.61mmol), dppf (337.94mg,0.61mmol) and zinc cyanide (351mg,3mmol) were replaced three times with nitrogen, DMF (10M L) was added to the reaction flask with a syringe, the reaction was monitored at 110 ℃ under stirring at 12 h.T L C and then filtered (EA) with celite, and purified by silica gel column chromatography (EA/PE 0-40%) to give SZ-015224A7(210mg, light brown solid) L CMS: [ M + H-015224A 7(210mg, light brown solid) ]]⁺278.1(weak)。

And 7, step 7:

SZ-015220A7(80mg,0.3mmol) is dissolved in dichloromethane (5M L) in a reaction bottle, stirred at 0 ℃, trifluoroacetic acid (1M L) is dripped into the reaction bottle, stirred at 0 ℃ for 1 h.T L C, after the reaction is monitored, the solvent and the trifluoroacetic acid are removed by reduced pressure rotary evaporation to obtain a crude product of SZ-015220A8 (light brown oily substance), and the crude product is directly reacted in the next step without purification L CMS: [ M + H ]]⁺178.2。

And 8, step 8:

adding SZ-015220A8 (crude product in the previous step), SZ-015220A7(80mg,0.25mmol), DMF (10M L) and DIEA (90mg,0.7mmol) into a reaction bottle, stirring at normal temperature, slowly adding HATU (133mg,0.35mmol), stirring at normal temperature for 1H, monitoring at L CMS, removing the solvent by reduced pressure rotary evaporation after the reaction is finished to obtain a crude product, performing reversed phase column chromatography with acetonitrile/0.1% formic acid water, and freeze-drying to obtain SZ-015224(37mg, light yellow solid) L CMS: [ M + H, light yellow solid ]]⁺530.2。

¹H NMR(400MHz,DMSO-d₆)11.87(s,1H),8.60(br,1H),8.51(d,J＝2.7Hz,1H),8.30(t,J＝5.0Hz,1H),8.27(s,1H),8.16(s,1H),7.52(d,J＝7.9Hz,1H),7.30(br,1H),7.21(dt,J＝19.9,6.9Hz,2H),4.35(d,J＝5.1Hz,2H),3.89(br,1H),3.12(s,6H),2.47-2.31(m,1H),2.19-1.94(m,2H),1.92-1.74(m,2H),1.60-1.21(m,4H).

Example 14 synthesis of SZ-015240:

step 1:

SZ-015240A1(1.0g,4.8mmol) was dissolved in DMF (5m L), CDI (1.0g,6.0mmol), tert-butanol (1.4m L) and DBU (0.8m L, 5.5mmol) were added in this order in an ice-water bath, after the addition was complete, stirring was carried out at room temperature for 2 hours, 20m L water and 50m L ethyl acetate were added to the system, the organic phase was dried over sodium sulfate, dried and flash purified with a silica gel column to give SZ-015240A2 as a foamy solid (0.9 g).

Step 2:

SZ-015240a2(3.5g,16.6mmol) copper cyanide (2.9g,33.3mmol) was added to pyridine (15m L) and stirred at 150 ℃ for 30 minutes after the system was cooled, 100m L water and 100m L ethyl acetate were added, the organic phase was dried over sodium sulfate and then spun dry and purified by flash column chromatography on silica gel (PE: EA ═ 6: 1; Rf ═ 0.3) to give SZ-015240A3(0.3g) as a beige solid.

And 3, step 3:

SZ-015240A3(0.3g) was dissolved in dichloromethane (5m L), TFA (2m L) was added to the system and stirred at room temperature overnight, and the solvent was directly removed to give crude SZ-015240A4(0.4 g).

And 4, step 4:

015056A7(100mg,0.29mmol), SZ-015240A4(120mg, 40% content), HATU (133mg,0.35mmol) and DIEA (0.2M L) were mixed in DMF (2M L) and stirred at room temperature for 1 hour the organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% aqueous ammonium carbonate), freeze dried to give 4.5mg of SZ-015240. L CMS [ M + H: []⁺478.1。

SZ-015240：¹H NMR(400MHz,DMSO-d₆)11.85(s,1H),8.97(d,J＝7.6Hz,1H),8.71(s,1H),8.62(s,1H),8.49(d,J＝1.2Hz,1H),8.28(s,1H),7.49-7.52(m,1H),7.34-7.35(m,1H),7.21-7.25(m,2H),3.95(s,2H),2.26-2.27(m,1H),1.78-2.03(m,3H),1.20-1.51(m,4H)。

Example 15 synthesis of SZ-015241:

015056A7(100mg,0.29mmol), SZ-015241A1(50mg), HATU (133mg,0.35mmol) and DIEA (0.3M L) were mixed in DMF (2M L) and stirred at room temperature for 1 hour the organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% aqueous ammonium carbonate), freeze dried to give 20mg of SZ-015241. L CMS: [ M + H]⁺478.11。

SZ-015241：¹H NMR(400MHz,DMSO-d₆)11.85(s,1H),8.75(s,2H),8.73(d,J＝8.2Hz,1H),8.60(s,1H),8.49(s,1H),8.27(s,1H),7.50-7.52(m,1H),7.31-7.33(m,1H),7.23-7.25(m,1H),4.04(s,2H),2.19-2.24(m,1H),1.99-2.03(m,1H),1.84-1.89(m,2H),1.26-1.48(m,4H)。

Example 16 synthesis of SZ-015235:

step 1:

under the protection of nitrogen, SZ-015235A1(2.0g,10.75mmol), zinc cyanide (600mg,5.12mmol) and Pd₂(dba)₃(1g, 10%) and dppf (1g, 10%) were mixed in DMF (20m L), warmed to 100 ℃ and stirred for 2 hours after completion of the reaction 50m L of water and 50m L of ethyl acetate were added, dried over sodium sulfate in the organic phase and purified by flash silica gel column to give SZ-015235A2(1.0g) as a foamy solid.

Step 2:

SZ-015235A2(700mg,3.9mmol) is dissolved in tetrahydrofuran (7m L) and water (3m L), potassium carbonate (1.1g,7.9mmol) is added to the system at one time and stirred at room temperature for 1 hour, after the reaction is finished, the pH is adjusted to about 6 by using ambolaite IR120 hydrogen type resin, the resin is filtered off, 20m L water and 20m L ethyl acetate are added to the filtrate, and the organic phase is dried by spinning to obtain SZ-015235A3(300 mg).

And 3, step 3:

SZ-015235A3(43mg,0.29mmol), 015056A7(100mg,0.29mmol), HATU (133mg,0.34mmol) and DIEA (0.2M L, 1.16mmol) were mixed in DMF (2M L), the system was stirred at room temperature for 1 hour, the organic phase was spin-dried and purified by high pressure reverse phase column chromatography (ACN-0.1% aqueous ammonium carbonate), freeze-dried to give 26mg of SZ-015235. L CMS [ M + H ] S]⁺473.1。

SZ-015235：¹H NMR(400MHz,CD₃OD)9.34(d,J＝1.2Hz,1H),8.65-8.67(m,1H),8.50(s,1H),8.46(d,J＝1.2Hz,1H),8.2(s,1H),8.16(s,2H),7.48-7.50(m,1H),7.24-7.31(m,2H),4.19-4.20(m,0.5H),2.47-2.49(m,1H),2.10-2.07(m,1H),1.97-2.40(m,2H),1.33-1.68(m,4H)。

Example 17 synthesis of SZ-015236:

step 1:

under the protection of nitrogen, SZ-015236A1(3.0g,17.41mmol), zinc cyanide (1.2mg,10.25 mmol) and Pd₂(dba)₃(1.5g, 10%) and dppf (1.1g, 10%) were mixed in DMF (30m L), warmed to 100 ℃ and stirred for 1 hour after the reaction was complete 50m L of water and 50m L of ethyl acetate were added, the organic phase was dried over sodium sulphate and dried and purified with flash silica gel column to give SZ-015236A2 as a foamy solid (1.5 g).

Step 2:

SZ-015236A2(1.4g,8.5mmol) is dissolved in tetrahydrofuran (20m L) and water (10m L), potassium carbonate (2.3g,17.1mmol) is added to the system at one time and stirred at room temperature for 1 hour, after the reaction is finished, the pH is adjusted to about 6 by using ambolaite IR120 hydrogen type resin, the resin is filtered, 20m L water and 20m L ethyl acetate are added to the filtrate, and the organic phase is dried by spinning to obtain SZ-015235A3(800 mg).

And 3, step 3:

SZ-015236A3(43mg,0.29mmol), 015056A7(100mg,0.29mmol), HATU (133mg,0.34mmol) and DIEA (0.2m L, 1.16mmol) were mixed in DMF (2m L),the system was stirred at room temperature for 1 hour, the organic phase was spin dried and purified by high pressure reverse phase column chromatography (ACN-0.1% ammonium carbonate in water) and freeze dried to give 30mg of SZ-015236, L CMS [ M + H ]: M + H]⁺473.1。

SZ-015236：¹H NMR(400MHz,CD₃OD)9.38(d,J＝1.2Hz,1H),9.07(s,1H),8.92(d,J＝8.0Hz,1H),8.65-8.67(m,1H),8.55(s,1H),8.2(s,1H),8.16(s,1H),7.49-7.51(m,1H),7.25-7.34(m,2H), 4.13-4.21(m,2H),2.47-2.49(m,1H),2.10-2.23(m,1H),1.98-2.07(m,2H),1.38-1.68(m,4H)。

Synthesis of intermediate 9150a 5:

step 1:

adding chloral (13.7g, 93.03mmol), hydroxylamine hydrochloride (15.4g,223.27mmol) and anhydrous sodium sulfate (70.5g,496.16mmol) to an aqueous solution (420M L) of 2, 3-difluoroaniline (8.0g, 62.02mmol) at room temperature respectively, stirring at 50 ℃ overnight, cooling to room temperature, adding an aqueous solution of 2N HCl (22M L), stirring for 30 minutes, filtering, collecting the filter cake, drying to obtain a solid 11.3g, adding concentrated sulfuric acid (60M L) to the solid obtained, stirring at 80 ℃ for 3 hours, cooling to room temperature, pouring the reaction solution into 400M L ice water, filtering, collecting the filter cake, and drying to obtain a dark green solid 9150A2(6.3g), L CMS [ M-H8938 (6.3 g): [ M-H-CMS ]]^-182.1.

The second step is that:

under the protection of nitrogen at a temperature of-20 ℃, boron trifluoride diethyl etherate (891mg,6.28mmol) is added dropwise to 9150A2(500mg,2.73mmol) and sodium borohydride (415mg,10.93mmol) in tetrahydrofuran (10m L), the dropwise addition process is controlled at a temperature not higher than-5 ℃, the mixture is stirred at the temperature of-10 ℃ for 4 hours, then potassium hydrogen sulfate (825mg) in water (10m L) is added dropwise, the mixture is extracted by ethyl acetate (10m L x 3), organic phases are combined, the solvent is removed by concentration, and the residue is separated and purified by silica gel column chromatography (EA/PE 1/20-1/10) to obtain a red oily substance 9150A3(260 mg).¹HNMR(CDCl₃,400MHz):8.37(br s,1H),7.30-7.27(m,1H),7.23-7.21(m,1H),6.98-6.92(m,1H),6.56-6.54(m,1H).

The third step:

adding aluminum trichloride (240mg,1.80mmol) into a mixture of 9150A3(230mg,1.5mmol) and 2,4, 5-trichloropyrimidine (825mg,4.50mmol) at room temperature, stirring at room temperature for 30 minutes, heating to 80 ℃, continuing stirring for 1 hour, cooling to room temperature, adding ice water (8M L) and ethyl acetate (10M L) into the reaction solution, separating out a solid, filtering, washing the filter cake with water, and drying in vacuum to obtain a yellow solid 9150A4(260mg), L CMS [ M + H L ] (M + H)]⁺300.1。

¹HNMR(DMSO-d₆,400MHz):12.96(s,1H),8.79(s,1H),8.70(s,1H),8.26-8.22(m,1H),7.33-7.26(m,1H).

The fourth step:

intermediate 9150A4(2.0g,6.7mmol) was suspended in 20mL DMF, sodium hydride (402mg,10.05 mmol) was slowly added, stirring was carried out in an ice bath for 15 minutes, 2- (trimethylsilyl) ethoxymethyl chloride (1.67g,10.05mmol) was added, stirring was carried out at room temperature for 30 minutes, the reaction solution was poured into water, filtered, washed with methanol, filtered, and dried to give 9150A5 as a white solid compound (2.2g), L CMS: [ M + H ], (M + H) ]]⁺430.1。

Synthesis of intermediate 015056a 7:

step 1:

dissolving the compound (1S,3R) -3- ((Boc-amino) cyclohexanecarboxylic acid (20.0g, 82mmol) in anhydrous toluene (200m L), adding triethylamine (9.1g, 90mmol) and diphenylphosphorylazide (22.6g, 82mmol), stirring at 110 ℃ under nitrogen for 2 hours, cooling to 80 ℃, adding benzyl alcohol (11.6g, 107mmol) and triethylamine (9.1g, 90mmol), stirring at 80 ℃ for overnight reaction, cooling to room temperature after reaction, adding water (200m L), extracting with ethyl acetate (3 × 200m L), combining the organic phases, MgSO (MgSO) and ethyl acetate₄Drying, filtering and concentrating. The concentrated residue was purified by column separation on silica gel to give 015056A2(22.0g) as a white solid.¹HNMR(CDCl₃，400MHz)：7.38-7.26(m，5H)，5.08(s，2H)，4.60-4.59(m，1H)，4.38-4.37(m，1H)，3.54-3.47(m，2H)，2.31-2.28(m，1H)，2.02-1.96(m，2H)，1.80-1.75(m，1H)，1.44(s，9H)，1.40-1.33(m，1H)，1.04-0.90(m，3H)。

Step 2:

compound 015056a2(500mg, 1.44mmol) was dissolved in dichloromethane (4M L), followed by dropwise addition of hydrochloric acid/dioxane (4.5M, 2M L) at 0 deg.c, reaction with stirring at room temperature for 2 hours, and concentration under reduced pressure to give compound 015056A3(410mg) as a white solid.¹HNMR(DMSO-d₆，400MHz)：8.20(br，3H)，7.40-7.29(m，5H)，5.10(m，2H)，3.43-3.32(m，1H)，3.03-2.97(m，1H)，2.11(d，J＝11.6Hz，1H)，1.89(d，J＝11.6Hz，1H)，1.74-1.71(m，2H)，1.35-1.01(m，4H)。

And 3, step 3:

compound 015056a4(5.0g, 12.4mmol) and compound 015056A3(2.84g, 10mmol) were dissolved in N, N-dimethylformamide/ethanol (40m L/40 m L), diisopropylethylamine (4.7g, 37.2mmol) was added, the reaction was heated to 120 ℃ and stirred at this temperature overnight, the solvent was removed by concentration, and the residue was isolated and purified by silica gel column chromatography (PE: EA ═ 2: 1) to give compound 015056a5(4.0g) as a yellow solid.¹HNMR(DMSO-d₆，400MHz)：8.62(s，1H)，8.43-8.39(m，2H)，8.11-7.99(m，3H)，7.75–7.72(m，1H)，7.65-7.61(m，2H)，7.54-7.52(m，1H)，7.46-7.30(m，8H)，5.01(s，2H)，3.78-3.76(m，1H)，3.35(s，1H)，2.13(brs，1H)，1.87-1.73(m，3H)，1.34-1.09(m，4H)。

And 4, step 4:

compound 015056A5(4.0g, 6.49mmol) was dissolved in dichloromethane (40M L) and boron tribromide (8.44M L, 8.44mmol, 1M dichloromethane solution) was added, the reaction was stirred at room temperature for 4 hours, after completion of L CMS detection, quenched with methanol and quenched with saturated NaHCO₃The reaction solution was adjusted to neutral, extracted with dichloromethane, and the organic phases were combined and concentrated. The concentrated residue was purified by silica gel column chromatography (DCM/MeOH ═ 20: 1) to give 015056a6(1.4g, yield 45%) as a pale yellow oil.¹HNMR(DMSO-d₆，400MHz)：8.61(s，1H)，8.42-8.39(m，2H)，8.11-8.09(m，2H)，8.02-7.99(m，1H)，7.75–7.74(m，1H)，7.65-7.61(m，2H)，7.52-7.33(m，3H)，3.76-3.72(m，1H)，3.31-3.18(m，2H)，2.66-2.60(m，1H)，2.05-1.99(m，1H)，1.89-1.87(m，1H)，1.74-1.69(m，2H)，1.30-0.92(m，4H)。

And 5, step 5:

compound 015056a6(1.2g, 2.4mmol) was dissolved in a mixture of dioxane (5m L) and water (5m L), followed by the addition of sodium hydroxide (390mg, 9.9 mmol). after stirring at 70 ℃ for 4 hours, concentration to dryness, addition of 20m L water to the residue, extraction with ethyl acetate (10m L x 2), drying of the organic phase over magnesium sulfate, and spin-drying of the solvent gave 015056a7(500mg) as a yellow solid.

Synthesis of intermediate SZ-015220A 7:

step 1:

compound 015056a4(2.0g, 5.0mmol) and compound (1S,3R) -3-aminocyclohexylcyclohexylcarboxylic acid methyl ester (1.0g, 5.0mmol) were dissolved in N, N-dimethylformamide/ethanol (8M L/8M L), diisopropylethylamine (1.29g, 10.0mmol) was added, the reaction mixture was heated to 120 degrees under nitrogen protection and stirred at this temperature overnight, the solvent was removed by spin-drying, the residue was concentrated and purified by silica gel column chromatography (PE/EA ═ 4/1) to give compound SZ-015220A7a (1.0g) as a yellow oily compound, L CMS: [ M + H ] cm]⁺525.1。

Step 2:

the compound SZ-015220A7a (1.0g, 1.905mmol) is dissolved in a mixed solution of dioxane (10M L) and water (10M L), NaOH (762mg, 19.05mmol) is added, reaction is carried out for 4 hours under stirring at 70 ℃, then concentration is carried out until the mixture is dry, the concentrated residue is dissolved in water (20M L), 1M hydrochloric acid aqueous solution is added to adjust the pH to be 5-6, filtration is carried out, a filter cake is dried in vacuum to obtain yellow solid SZ-015220A7(580mg), and the solid compound is directly used for next reaction without purification. L CMS: [ M + H + M L ]]⁺370.9。

Synthesis of intermediate 015091a 1:

the first step is as follows:

intermediate 9104A5(16.0g,60.6mmol) was suspended in 150 mL DMF, sodium hydride (3.6g,90.9mmol) was slowly added and stirred in ice bath for 15 min, 2- (trimethylsilyl) ethoxymethyl chloride (5.2g,90.9mmol) was added and stirred at room temperature for 30 min, the reaction was poured into water, filtered, washed with methanol, filtered and dried to give 015091B1 as a white solid compound (15..8g, yield 66%). L CMS: [ M + H ] CMS: [ M + H]⁺394.2

The second step is that:

dissolving intermediate 015091B1(6.12g,15.5mmol), ((1S,3R) -3-aminocyclohexyl) benzyl carbamate (5.4g,21.8mmol), DIEA (6.01g,46.6mmol) in dimethylformamide (80M L) and ethanol (80M L), stirring overnight at 120 ℃, pouring the reaction solution into water, extracting with ethyl acetate, spin-drying to remove the solvent, and separating and purifying the concentrated residue with silica gel column to obtain yellow solid compound 015091B2(1.1 g). L CMS: [ M + H ], [⁺606.2

The third step:

dissolving compound 01509B2(1.1g,1.82mmol) in ethyl acetate/methanol (20M L/20M L), adding palladium on carbon (400mg), stirring at room temperature for 4 hr, filtering the reaction phase, concentrating the filtrate, and removing solvent to obtain compound 015091A1(650M g) L CMS [ M + H ] as yellow oil]⁺472.2

Synthesis of intermediate 015081a 1:

intermediate 015091B1(5.53g,13.99mmol), ((1S,3R) -3-aminocyclohexyl) carbamic acid tert-butyl ester (3.0g,13.99mmol), DIEA (3.61g,27.99mmol) were dissolved in N-methylpyrrolidone (20m L) and ethanol (10m L), stirred overnight at 120 ℃, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was dried over sodium sulfate, the filtrate was filtered off and the residue was concentrated and purified by separation on a silica gel column to give compound 015081A1(2.6g) as a yellow solid.

LCMS:[M+H[⁺572.2

¹H NMR(DMSO-d₆,400MHz)：8.74-8.72(m，2H),8.28(s,1H),7.63(d,J＝8.8Hz，1H)，7.34-7.26(m,3H),6.84(d,J＝7.2Hz,1H),5.69(s,2H),3.80-3.68(m,1H),3.51(t,J＝8.4Hz,2H),3.38-3.35(m,1H),2.15-2.05(m,1H),2.00-1.88(m，1H),1.77-1.65(m,2H),1.33(s，9H),1.29-1.05(m,4H),0.83(t,J＝8.4Hz,2H),0.01(s,9H)。

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 (10m L/10 m L) and DIEA (1.5g, 12mmol) was added, the reaction was heated to 120 ℃ under nitrogen and stirred at this temperature overnight, the solvent was removed by rotary drying after cooling, and the concentrated residue was isolated and purified by silica gel column chromatography (PE/EA 10/1) to give crude yellow solid compound 015055a1(1.9g, yield 79%).

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

The second step is that: 015055A2 Synthesis

Dissolving compound 015055A1(1.9g,3.125mmol) in dichloromethane 20M L, adding trifluoroacetic acid 20M L, stirring at room temperature for 1 hour, removing the solvent by rotation, dissolving the residue in a mixed solution of dichloromethane and methanol, adding ammonia, stirring at room temperature for half an hour, extracting with dichloromethane, drying, concentrating, adding ethyl acetate, petroleum ether, and filtering to obtain a white solid compound 015055A2(400mg, yield 30%). L CMS (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 (5m L), stirred at room temperature overnight, water (40m L) was added, ethyl acetate was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, the residue was concentratedIsolation and purification by preparative high performance liquid chromatography gave compound SZ-015055 as a pale yellow solid (10.4mg, yield 10%). Liquid phase mass spectrometry [ mobile phase: elution 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 40 degrees celsius column temperature. Column: waters XBridge C183.5um, 50 x 4.6mm]Purity greater than 95%, Rt 2.514min, L CMS (M + H)⁺m/zcalculated 508.1.2，found 508.1。

¹H NMR(DMSO-d₆，400MHz)：12.54(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 2u L/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 4u L120 mM 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

Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative and that various changes or modifications may be made without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.

Claims

1. A heteroaromatic nitrile compound shown as a formula I or a pharmaceutically acceptable salt thereof;

is an indole ring;

R^1a、R^1b、R^1cand R^1dIndependently is H or halogen;

l is- (CR)^c2R^c1)_n1-N(R^c3)-(C(＝O))_n2-；

n1 and n2 are independently 0 or 1; and n1 and n2 are not 0 at the same time;

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

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

2. The heteroaromatic nitrile compounds of formula I or pharmaceutically acceptable salts thereof according to claim 1,

R¹is halogen or C₁-C₄An alkyl group;

and/or ring B is cyclohexyl, piperidinyl or substituted by one or more substituents R^b2A substituted piperidinyl group;

and/or L on ring B is meta to the indicated-NH-;

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^b1And R^b2Independently is halogen or C₁-C₄An alkyl group;

and/or, L is- (CR)^c2R^c1)-N(R^c3)-C(＝O)-、-N(R^c3)-C(＝O)-、-C(＝O)-N(R^c3) -or- (CR)^c2R^c1)-N(R^c3)-；

And/or, R^c1And R^c2Independently is H; or, R^c1And/or R^c2Linked to ring D, together with the linked C, form: 5-6 membered heteroaryl;

and/or, R^c3Independently is H;

and/or, R^d1Independently is N (R)^d11R^d12)-、C₁-C₄Alkyl radical, C₁-C₄alkyl-O-or 4-6 membered heteroA cycloalkyl group;

and/or, when ring D is substituted by one or more substituents R^d1When substituted 5-to 10-membered heteroaryl, R^d1Located at the position ortho to the link of ring D at L.

3. The heteroaromatic nitrile compounds of formula I or pharmaceutically acceptable salts thereof as claimed in claim 1 or 2,

when R is¹Independently is C₁-C₄Alkyl or C substituted by one or more halogens₁-C₄When alkyl, said C₁-C₄Alkyl and C substituted by one or more halogens₁-C₄C in alkyl₁-C₄Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; such as methyl or ethyl;

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

is composed of

For example

And/or when R^1a、R^1b、R^1cAnd R^1dWhen independently halogen, said halogen is independently fluorine, chlorine, bromine or iodine; such as fluorine or chlorine;

and/or, when ring B is cyclohexyl, or substituted by one or more substituents R^b1When the cyclohexyl is substituted, the cyclohexyl is independently

And/or, when ring B is piperidinyl or substituted by one or more substituents R^b2When substituted piperidinyl, said piperidinyl and are substituted by one or moreSubstituent R^b2Piperidinyl in substituted piperidinyl is

Also for example

And/or when R^b1And R^b2Independently halogen, or C substituted by one or more halogens₁-C₄When alkyl, said halogen and C substituted by one or more halogens₁-C₄Halogen in the alkyl group is independently fluorine, chlorine, bromine or iodine; such as fluorine or chlorine;

and/or when R^b1And R^b2Independently is C₁-C₄Alkyl or C substituted by one or more halogens₁-C₄When alkyl, said C₁-C₄Alkyl and C substituted by one or more halogens₁-C₄C in alkyl₁-C₄Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; such as methyl;

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; such as methyl;

and/or, when L, R^c1And/or R^c2Linked to ring D, together with the linked C, form: 5-6 membered heteroaryl, wherein the heteroatom is selected from N, the number of heteroatoms is 1-3; for example

And/or, when ring D is a 5-10 membered heteroaryl, or substituted with one or more substituents R^d1When substituted with 5-10 membered heteroaryl, said 5-10 membered heteroaryl is substituted with one or more substituents R^d1SubstitutionThe 5-to 10-membered heteroaryl group in the 5-to 10-membered heteroaryl group of (a) is independently a 5-to 6-membered heteroaryl group in which the heteroatom is one or more selected from N, O and S, and contains at least one N, and the number of heteroatoms is 2 to 3; such as pyrazinyl or thiazolyl; the pyrazinyl group may be

The thiazolyl may be

And/or when R^d1Independently halogen, C substituted by one or more halogens₁-C₄Alkyl or C substituted by one or more halogens₁-C₄alkyl-O-, said halogen, C substituted by one or more halogens₁-C₄Alkyl and C substituted by one or more halogens₁-C₄Halogen in alkyl-O-is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine;

and/or when R^d1Independently is C₁-C₄Alkyl, C substituted by one or more halogens₁-C₄Alkyl radical, C₁-C₄alkyl-O-, or C substituted by one or more halogens₁-C₄alkyl-O-said C₁-C₄Alkyl, C substituted by one or more halogens₁-C₄Alkyl radical, C₁-C₄alkyl-O-and C substituted by one or more halogens₁-C₄C in alkyl-O-radicals₁-C₄Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; such as methyl;

and/or when R^d1When independently is a 4-6 membered heterocycloalkyl, said 4-6 membered heterocycloalkyl is morpholino; for example

And/or when R^d11And R^d12Independent of each otherGround is C₁-C₄When alkyl, said C₁-C₄Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; such as methyl.

4. The heteroaromatic nitrile compounds of formula I or pharmaceutically acceptable salts thereof of claim 3,

R¹is chlorine or ethyl;

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

is composed of

And/or, ring B is

For example

End a is shown connected to L;

and/or, L is

For example

End c represents the link to ring B;

and/or ring D is

For example

The d-terminal indicates attachment to the CN ring.

5. The heteroaromatic nitrile compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the heteroaromatic nitrile compound of formula I is according to scheme 1, scheme 2 or scheme 3;

scheme 1,

Wherein R is¹Independently is halogen or C₁-C₄An alkyl group;

is an indole ring;

R^1a、R^1b、R^1cand R^1dIndependently is H or halogen;

R^b2independently is C₁-C₄An alkyl group;

l is- (CR)^c2R^c1)-N(R^c3)-C(＝O)-、-N(R^c3)-C(＝O)-、-C(＝O)-N(R^c3) -or- (CR)^c2R^c1)-N(R^c3)-；

R^c1And R^c2Independently is H;

R^c3independently is H;

alternatively, in L, R^c1And/or R^c2Linked to ring D, together with the linked C, form: 5-6 membered heteroaryl; the heteroatom in the 5-6 membered heteroaryl is selected from one or more of N, O and SThe number is 1-3;

R^d1independently is N (R)^d11R^d12)-、C₁-C₄Alkyl radical, C₁-C₄alkyl-O-or 4-6 membered heterocycloalkyl;

scheme 2,

Wherein R is¹Independently is halogen or C₁-C₄An alkyl group;

is an indole ring;

R^1a、R^1b、R^1cand R^1dIndependently is H or halogen;

R^b2independently is C₁-C₄An alkyl group;

R^c1And R^c2Independently is H;

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 one or more substituents R^d1In the 5-to 10-membered heteroaryl group in the substituted 5-to 10-membered heteroaryl group, the heteroatom is selected fromN, O and S, the number is 2-3; when the substituents are plural, the same or different;

scheme 3,

Wherein R is¹Independently is halogen or C₁-C₄Alkyl, such as halogen;

is an indole ring;

R^1a、R^1b、R^1cand R^1dIndependently is H or halogen;

R^b2independently is C₁-C₄An alkyl group;

R^c1And R^c2Independently is H;

R^c3independently is H;

R^d1independently is C₁-C₄Alkyl, aryl, heteroaryl, and heteroaryl,C₁-C₄alkyl-O-or 4-6 membered heterocycloalkyl; e.g. C₁-C₄Alkyl or C₁-C₄alkyl-O-.

6. The heteroaromatic nitrile compounds of formula I or pharmaceutically acceptable salts thereof according to claim 1,

the heteroaromatic nitrile compound shown in the formula I is shown in any structure as follows:

7. a pharmaceutical composition comprising a heteroaromatic nitrile of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers.

8. Use of a heteroaromatic nitrile of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament or CDK kinase inhibitor.

9. The use according to claim 8, wherein,

the CDK kinase is CDK7 kinase;

and/or, said medicament is a medicament for the treatment and/or prevention of a disease associated with a CDK kinase interaction,

and/or the medicament is used for treating and/or preventing proliferative diseases or infectious diseases.

10. The use of claim 9, wherein the proliferative disease is cancer, benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases; such as leukemia, melanoma, multiple myeloma, breast, brain or lung cancer.