CDK inhibitor compound with lactam structure

Abstract

The invention relates to a compound as shown in a formula (I), a pharmaceutical composition containing the compound and application of the compound as shown in the formula (I) to prevention and / or treatment of cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

Technical Field

[0001] This invention relates to a compound, and more particularly to a highly active CDK inhibitor containing a lactam structure and its uses. Background Technology

[0002] Cyclin-dependent kinases (CDKs) are a class of serine / threonine kinases, which can be divided into two main categories: cell cycle-related (such as CDK1 / 2 / 4 / 6) and transcription-related (such as CDK7 / 9 / 12).

[0003] Currently, CDK4 and CDK6 are the most studied, playing crucial regulatory roles in the cell cycle. They can form CDK-cyclin complexes with cyclin D, participating in cell growth, proliferation, dormancy, or apoptosis. CDK4 / 6-cyclin D is a key pathway for the cell cycle to transition from G1 to S phase; overexpression of these compounds leads to uncontrolled cell cycle progression, potentially causing cancer. Represented by Palbociclib, the world's first selective CDK4 / 6 inhibitor launched by Pfizer, several other selective CDK4 / 6 inhibitors have been approved for marketing, primarily for the treatment of HR+ / HER2- breast cancer.

[0004] While CDK4 / 6 inhibitors have achieved great success, significant side effects, particularly myelosuppression, have been observed in clinical practice. Studies have demonstrated that CDK6 is a key factor in hematopoietic stem cell activation, while CDK4 has a relatively smaller impact on the hematopoietic system. Further research indicates that CDK4 is expressed at higher levels in tumors, while CDK6 is expressed at lower levels; in breast cancer, CDK4 may be a more significant oncogenic factor. Therefore, maintaining CDK4 activity while reducing CDK6 inhibition would be beneficial in reducing the clinical toxicity of CDK inhibitors.

[0005] CDK2 is another important cell cycle regulator that can bind to cyclin E or A, playing a role in the transition from G1 phase to S phase and maintaining S phase, respectively. When CDK4 / 6 is inhibited, CDK2-cyclin E is activated, compensating for the function of CDK4 / 6, which may be one of the main reasons for CDK4 / 6 inhibitor resistance.

[0006] In conclusion, optimizing selectivity to further improve the efficacy and safety of existing CDK4 / 6 inhibitor-based treatments has significant social implications. Summary of the Invention

[0007] This invention provides a novel class of CDK inhibitors. Unlike existing CDK4 / 6 dual-target inhibitors, these structures exhibit optimized activity and selectivity, thereby enhancing anti-tumor efficacy and reducing toxic side effects. This represents a significant improvement over existing technologies.

[0008] In one aspect, the present invention provides a compound of formula I, an isotopic derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] R 1 It represents D, halogen, CN, C1-C3 alkyl, halo-C1-C3 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy or 3-6 membered heterocyclic alkyl;

[0012] Ar 1 Indicates a 5-membered heteroaryl group;

[0013] Cy 1 It represents a 4-8 membered heterocyclic alkyl group, a 4-8 membered heterocyclic alkenyl group, or a 5-8 membered heteroaryl group;

[0014] X 1 and X 2 It is Ar 1 and Cy 1 Shared bridgehead atom, X 1 and X 2 Each can be represented independently as C or N, X 1 and X 2 The covalent bonds between them can be single or double bonds;

[0015] R 2 Each can be independently represented by H, D, halogen, CN, and OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl may optionally be represented by 0, 1, 2, 3, or 4 R groups. 22 replace;

[0016] R 3 Each can be independently represented by H, D, oxo, halogen, CN, OR.a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl may optionally be represented by 0, 1, 2, 3, or 4 R groups. 23 replace;

[0017] Two R connected on the same C 3 Or two R atoms connected on different atoms 3 It can form 3-8 membered rings with the atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0018] Y 1 and Y 2 Each represents CR independently. 4 Or N;

[0019] R 4 Each of these elements independently represents H, D, halogen, CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy may optionally be represented by 0, 1, 2, 3, or 4 Rs. 24 replace;

[0020] V represents C(O), S(O), S(O)2 or S(O)(NR) 6 );

[0021] W represents CR independently. 5 R 5 '、C(O),NR 6 ,O,S,S(O),S(O)2 or S(O)(NR 6 ); R 5 R 5 Each can be represented independently as H, D, halogen, CN, OR a SR a NR a R a '、N(R a COR a '、CON(Ra )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 25 replace;

[0022] R connected on the same C 5 R 5 It can also form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0023] R attached to different C atoms 5 With R 5 It can form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0024] R 6 Each of H, D, and -S(O)2R can be represented independently. a -S(O)R a -C(O)R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 26 replace;

[0025] R 5 With R 6 It can form 3-8 membered rings together with the ring atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0026] R 22 R 23 R 24 R 25R 26 R 30 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 22 Two R atoms on the same atom or different atoms 23 Two R atoms on the same atom or different atoms 24 Two R atoms on the same atom or different atoms 25 Two R atoms on the same atom or different atoms 26 Or R 25 With R 26 It can form a 3-6 membered ring with the C atom and / or N atom it is connected to, and the ring may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0027] R a and R a Each can independently represent H, D, C1-C3 alkyl, or C3-C6 cycloalkyl;

[0028] m represents 0, 1, or 2;

[0029] n represents 0, 1, 2, 3, or 4;

[0030] o can be 2, 3, 4, 5 or 6.

[0031] In one aspect, the present invention provides a compound of formula II, an isotopic derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0032]

[0033] in:

[0034] R 1It represents D, halogen, CN, C1-C3 alkyl, halo-C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C2 alkoxy;

[0035] Cy 1 It represents a 4-8 membered heterocyclic alkyl group, a 4-8 membered heterocyclic alkenyl group, or a 5-8 membered heteroaryl group;

[0036] R 2 Each can be independently represented by H, D, halogen, CN, and OR. a NR a R a ', C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl may optionally be 0, 1, 2 or 3 R 22 replace;

[0037] R 3 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3 or 4 R 23 replace;

[0038] Two R connected on the same C 3 Or two R atoms attached to different C atoms 3 It can form 3-8 membered rings with the atoms it is attached to, wherein the rings may optionally contain 0, 1, or 2 heteroatoms selected from N, O, or S, and the rings may be further divided by 0, 1, or 2 R atoms. 30 replace;

[0039] R 4 Each of these elements independently represents H, D, halogen, CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy may optionally be represented by 0, 1, 2, 3, or 4 Rs. 24 replace;

[0040] W represents CR independently. 5 R 5 '、C(O),NR 6 O or S(O)2;

[0041] R 5 R 5 Each can be represented independently as H, D, halogen, CN, OR a SR a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 25 replace;

[0042] R connected on the same C 5 R 5 It can also form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0043] R attached to different C atoms 5 With R 5 It can form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0044] R 6 Each of H, D, and -S(O)2R can be represented independently. a -S(O)R a -C(O)R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 26 replace;

[0045] R 5 With R 6It can form 3-8 membered rings together with the ring atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0046] R 22 R 23 R 24 R 25 R 26 R 30 Each can be independently represented as D, oxo, halogen, CN, OR a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 22 Two R atoms on the same atom or different atoms 23 Two R atoms on the same atom or different atoms 24 Two R atoms on the same atom or different atoms 25 Two R atoms on the same atom or different atoms 26 Or R 25 With R 26 It can form a 3-6 membered ring with the C atom and / or N atom it is connected to, and the ring may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0047] R a and R a Each can independently represent H, D, C1-C3 alkyl, or C3-C6 cycloalkyl;

[0048] m represents 0, 1, or 2;

[0049] n represents 0, 1, 2, 3, or 4;

[0050] o can be 2, 3, 4, 5 or 6.

[0051] In one aspect, the present invention also provides a pharmaceutical composition comprising the compound described herein or thereof, as well as a pharmaceutically acceptable salt, isotope derivative or stereoisomer, and a pharmaceutically acceptable carrier.

[0052] In one aspect, the present invention also provides the use of the compounds described herein, or pharmaceutically acceptable salts, isotope derivatives, stereoisomers, or pharmaceutical compositions described herein, in the preparation of medicaments for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

[0053] In one aspect, the present invention provides a method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases, comprising administering the compounds of the present invention to mammals in need of such treatment.

[0054] It is particularly noteworthy that, in this article, when referring to a “compound” of a structure, the term generally also includes its stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives.

[0055] As is known to those skilled in the art, the salts, solvates, and hydrates of a compound are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noteworthy that when referring to a compound with a certain structure herein, its pharmaceutically acceptable salts are generally also included, and further include its solvates and hydrates.

[0056] Similarly, when referring to a compound in this article, its prodrug, metabolites, and nitrogen oxides are generally also included. Detailed Implementation

[0057] Terminology Definition

[0058] Chemical terminology

[0059] Unless otherwise stated, the terms used in this application, including those in the specification and claims, are defined as follows.

[0060] In this application, unless the context clearly indicates otherwise, the term "a (one)" means "one or more". As used herein, "another" means at least a second or more.

[0061] Although this disclosure supports the definition of "and / or" only, the term "or" is used to mean "and / or" unless it is explicitly stated that it refers only to an option or that the options are mutually exclusive.

[0062] Unless the context clearly indicates otherwise, the terms “comprising” or “including” should be understood to encompass the listed components or steps, whether the components or steps are presented alone or in combination with one or more additional components or steps.

[0063] As used herein, endpoints are included when providing a range.

[0064] As used herein, the term "about" is used to refer to a numerical value that includes the standard deviation of the error of the means or method used to determine that value. In some embodiments, the term "about" refers to a range of a numerical value along any direction (greater or less than) within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or a lower percentage of that value, unless otherwise specified or otherwise apparent from the context (e.g., when the number would exceed 100% of the possible value).

[0065] In this invention, when the connection direction of the listed linking groups is not specified, the connection direction is arbitrary, for example... In this case, L stands for -C(O)NH-. -C(O)NH- can be formed by connecting the phenyl group and the cyclohexyl group in a left-to-right reading order. Alternatively, the phenyl and cyclohexyl groups can be connected in the reverse reading order from left to right to form the structure. The combination of the linking group and the linked group is only permitted if it results in a stable compound. In some preferred embodiments of the invention, the order is read from left to right.

[0066] Unless otherwise defined, the substituents in this invention are independent of each other and not related to each other, for example (enumerating rather than exhaustively listing), in one aspect, for R in the substituents a (or R) a Regarding R, it is independent of the definitions of different substituents. Specifically, for R a (or R) a Choosing a meaning among substituents does not mean that R a (or R) a The same meaning applies to all other substituents. More specifically, for example (not exhaustive list only) for NR... a R a In 'middle, when R a (or R) a When the meaning of ') is taken from hydrogen, it does not mean that in -OR a or -C(O)-NR a R a R in 'a (or R) a ') must be hydrogen, and they can each independently represent those selected from R a (or R) a Other substituents in the definition of '). In another aspect, when a substituent contains more than one R... a (or R) a When '), these R a (or R) a ') are also independent. For example, in the substituent -(CR a R a’ ) m -O-(CR a R a’ ) n In the case where m+n is greater than or equal to 2, there are m+n R values. a (or R) a ') are independent of each other, they can express Selected from R a (or R) a The same or different in the definition of ') replace base .

[0067] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl group is optionally substituted”). It is not intended that the characteristic “X” (e.g., alkyl) itself is optional. As described herein, certain compounds may contain one or more “optionally substituted” moieties. Generally, the term “substituted”, whether preceded by the terms “optionally” or “arbitrarily”, means that one or more hydrogens of the specified moiety are replaced by suitable substituents, such as any of the substituents or groups described herein. Unless otherwise indicated, a “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. For example, in the term “optionally substituted C1-C6 alkyl-C5-C6 heteroaryl,” the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The combinations of substituents contemplated in this disclosure are preferably combinations that form stable or chemically viable compounds. As used herein, the term "stable" means that a compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and, in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein. In this document, "any substitution" has the same meaning as "optional substitution." Unless otherwise defined, "optional substitution" can refer to substitution by a monovalent substituent and / or a divalent substituent.For example, the monovalent substituent is selected from the following substituents, such as hydrogen, alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic, halogen, hydroxyl, alkoxy, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (where the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arylanoylamino, arylalkylanoylamino, substituted alkanoylamino, substituted arylamino, substituted arylalkylanoylamino, thio, alkylthio, arylthiothio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl (e.g., -SO2NH2), substituted sulfonylamino, nitro, cyano, carboxyl, ammonia The substituents may be alkyl, such as -CONH2; substituted carbamoyl, such as -CONHalkyl, -CONHaryl, -CONHarylalkyl; or have two substituents selected from alkyl, aryl, or arylalkyl on nitrogen; alkoxycarbonyl; aryl; substituted aryl; guanidine; heterocyclic, such as indolyl; imidazolyl; furanyl; thiophene; thiazolyl; pyrrolyl; pyridyl; pyrimidinyl; pyrrolyl; piperidinyl; morpholinyl; piperazinyl; homopiperazinyl; and substituted heterocyclic groups; for example, divalent substituents may be selected from the following substituents: =O, =S, =NNRr2, =NNHC(O)Rr, =NNHC(O)ORr, =NNHS(O)2Rr, =NRr, =NORr, and alkylene (e.g., -(C(Rr2)). 2-3 -、-(C(Rr2)) 2-3 O-、-O(C(Rr2)) 2-3 -、-O(C(Rr2)) 2-3 O-, -S(C(Rr2))2-3S-), etc., where Rr can represent hydrogen, alkyl, heteroalkyl, aromatic group, heteroaryl, etc.

[0068] Unless otherwise defined, the terms “single bond” or “bond” or “direct bond” as used herein refer to two atoms connected by a single saturated covalent bond. For example, when L represents a single bond, “ALB” means that A and B are connected by a single saturated covalent bond, i.e., “AB”; as another example, when L represents a single bond, “-CH2-L-NH-” means that -CH2- and -NH- are connected by a single saturated covalent bond, i.e., “-CH2-NH-”.

[0069] As used herein, the term "alkyl" or "alkylene" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). Alkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable link, preferably from one or more of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In this document, alkyl is an alkyl group having 1 to 12 carbon atoms, preferably having 1 to 10, 1 to 8, 1 to 6, 1 to 4, and more preferably having 1 to 4 carbon atoms.

[0070] As used herein, the term "alkylene" is intended to include branched, straight-chain, saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, comprising or not comprising cyclic alkyl groups, which are residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. For example, "C0-C6 alkylene" means an alkylene having 0 (i.e., bond), 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylene include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (e.g., -(CH2)3-, -(CHCH3)CH2-, -(CHCH2CH)-), butylene (e.g., -(CH2)4-, -CH2CH(CH2CH3)-, -CH2(CHCH2CH)-, etc.), and pentylene (e.g., -(CH2)5-, -CH2CH(CH(CH3)2)-, -CH2(CH... (e.g., CH2CH)CH2-), hexanediol (e.g., -(CH2)6-, -CH2CH2CH(CH(CH3)2)-, -CH2(CHCH(CH3)CH)CH2-, etc.). In this document, alkylene groups are preferably alkylene groups having 0-6, 0-4, 0-3, 0-2, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-3 carbon atoms. In this document, alkylene groups are preferably alkylene groups that do not contain cyclic alkyl groups.

[0071] Similarly, the term "X-subgroup" or "X-subgroup" as used herein is intended to include divalent residues derived by removing two hydrogen atoms from the same atom or two different atoms of the parent compound X. The parent compound X is defined as in other paragraphs herein. For example, X can be alkyl, cycloalkyl, heterocycloalkyl, or phenyl, and correspondingly, X-subgroup represents alkylene, cycloalkylene, heterocycloalkylene, or phenylene.

[0072] The term "cycloalkyl" refers to monocyclic, polycyclic, or branched cycloalkyl groups. For example, C3-C 12 Cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornel. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". In this invention, cycloalkyl groups are preferably saturated carbocyclic. Polycyclic cycloalkyl groups, such as bicyclic and tricyclic cycloalkyl groups, include bridged rings, spirocyclic, or fused ring cycloalkyl groups. In this invention, cycloalkyl groups are preferably C3-C6. 12 Cycloalkyl, C3-C8 cycloalkyl, C8-C 12 Cycloalkyl, C3-C7 cycloalkyl, C8-C 12 Cycloalkyl, C4-C8 cycloalkyl, C5-C 10 Cycloalkyl, C3-C6 cycloalkyl. For example, in some embodiments, the cycloalkyl group in monocyclic form is C3-C8, C3-C6, or C5-C6. In some embodiments, the cycloalkyl group in bicyclic form is C7-C6. 12 In some embodiments, the cycloalkyl group in spirocyclic form is C5-C6. 12 Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridging bicyclic cycloalkyl groups include, but are not limited to, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The cycloalkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0073] The term “heteroalkyl” refers to an alkyl group as defined herein, wherein one or more carbon atoms in the chain are replaced by heteroatoms selected from O, S and N.

[0074] Similarly, the term "heterocyclic alkyl" refers to a cyclic structure in which at least one carbon atom in the cycloalkyl ring is replaced by a heteroatom selected from N, O, S, and P. The N atom may optionally be quaternized, and the N and S atoms may optionally be oxidized (i.e., NO, SO, and SO2). It includes monocyclic, bicyclic, and tricyclic heterocyclic systems, wherein bicyclic and tricyclic heterocyclic systems include spirocyclic, fused, and bridged heterocyclic rings. Heterocyclic alkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable junction. The substituents are preferably one or more selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, alkyl groups, alkoxy groups, haloalkyl groups, cycloalkyl groups, heterocyclic alkyl groups, aryl groups, and heteroaryl groups. In this invention, the heterocyclic alkyl group is preferably a 4-12 membered heterocyclic alkyl group, more preferably a 4-8 membered heterocyclic alkyl group.

[0075] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more carbon-carbon double bonds and typically having a length of 2 to 20 carbon atoms, and includes groups having "cis" and "trans" orientations, or optionally "E" and "Z" orientations. For example, "C2-C6 alkenyl" is an alkenyl group containing two to six carbon atoms and having one, two, or three carbon-carbon double bonds. In some instances, the alkenyl group is C2-C... 18 alkenyl, C2-C 16 alkenyl, C2-C 14 alkenyl, C2-C 12 alkenyl, C2-C 10 The alkenyl group can be C2-C8, C2-C6, C2-C4, or C2-C3. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, and 1-methyl-2-buten-1-yl. In this invention, the alkenyl group is preferably C2-C6. In this invention, the alkenyl group preferably contains one or two double bonds, more preferably one double bond.

[0076] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more carbon-carbon triple bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "C2-C6 alkynyl" is an alkynyl group containing two to six carbon atoms and having one, two, or three carbon-carbon triple bonds. In some instances, the alkenyl group is C2-C... 18 alkynyl group, C2-C 16 alkynyl group, C2-C 14 alkynyl group, C2-C 12 alkynyl group, C2-C 10The alkynyl group can be C2-C8, C2-C6, C2-C4, or C2-C3. Representative alkynyl groups include, but are not limited to, ethynyl, propynyl-1-yl (-C≡C-CH2), propynyl-2-yl (propynyl, -CH2-C≡CH), butynyl-1-yl, butynyl-2-yl, and butynyl-3-yl. In this document, the alkynyl group is preferably C2-C6 alkynyl.

[0077] The term "cycloalkenyl" refers to a non-aromatic hydrocarbon cyclic group having at least one carbon-carbon double bond. Cycloalkenyl encompasses monocyclic, bicyclic, tricyclic, fused, spirocyclic, or bridged cyclic systems. Examples include C3-C8 cyclic alkenyl groups, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norcamphenyl. Examples of monocyclic cycloalkenyl groups include 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohexen-3-enyl, and cyclohexadienyl. Exemplary arrangements of bicyclic cycloalkenyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] cyclic systems. Exemplary bridging bicyclic cycloalkenyl groups include, but are not limited to, bicyclic [2.2.1]heptene, bicyclic [2.2.2]octene, and bicyclic [3.2.2]nonene. Examples of spirocycloalkyl groups include spiro[2.2]pentene, spiro[2.3]hexene, spiro[2.4]heptene, spiro[2.5]octene, and spiro[4.5]decene. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are also included in the definition of "cycloalkenyl". In some embodiments of the invention, the cycloalkenyl group is C3-C5 cycloalkenyl, C3-C6 cycloalkenyl, C3-C7 cycloalkenyl, C3-C8 cycloalkenyl, C3-C9 cycloalkenyl, C3-C10 cycloalkenyl, C3-C11 cycloalkenyl, and C3-C12 cycloalkenyl.

[0078] Similarly, "cycloalkynyl" refers to a non-aromatic hydrocarbon cyclic group having at least one carbon-carbon triple bond. Cycloalkynyl encompasses monocyclic, bicyclic, tricyclic, fused, spirocyclic, or bridged ring systems. In some embodiments of the present invention, the cycloalkynyl is C3-C5 cycloalkynyl, C3-C6 cycloalkynyl, C3-C7 cycloalkynyl, C3-C8 cycloalkynyl, C3-C9 cycloalkynyl, C3-C10 cycloalkynyl, C3-C11 cycloalkynyl, or C3-C12 cycloalkynyl.

[0079] Similarly, the term "heterocyclic alkenyl" refers to a non-aromatic heterocyclic group having at least one carbon-carbon double bond. Heterocyclic alkenyls encompass monocyclic, bicyclic, tricyclic, fused, spirocyclic, or bridged ring systems.

[0080] Similarly, the term "heterocyclic ynyl" refers to a non-aromatic heterocyclic group having at least one carbon-carbon triple bond. Heterocyclic ynyl encompasses monocyclic, bicyclic, tricyclic, fused, spirocyclic, or bridged ring systems.

[0081] The term "aryl" or "aromatic ring" refers to a carbocyclic aromatic group having a specified number of carbon atoms. If the number of carbon atoms is not specified, it is at most 14 carbon atoms. The aryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any usable junction. The substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some embodiments of the invention, the aryl group includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, 2-naphthyl, etc.

[0082] The term "heteroaryl" refers to an aromatic heterocycle having at least one monocyclic or fused polycyclic ring selected from oxygen, nitrogen, and sulfur. Suitable heteroaryl groups do not include ring systems such as pyranium that must be charged to be aromatic. Heteroaryl groups can be stable 5-, 6-, or 7-membered aromatic monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocycles. A suitable 5-membered heteroaryl ring (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) has one oxygen, sulfur, or nitrogen ring atom, or one nitrogen plus one oxygen or sulfur, or 2, 3, or 4 nitrogen ring atoms. A suitable 6-membered heteroaryl ring (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) has 1, 2, or 3 nitrogen ring atoms. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. The heteroaryl group can be unsubstituted or substituted, and if the resulting compound is stable, the heterocyclic group described herein can be substituted at any usable connection point, wherein the substituent is preferably one or more of halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indoleyl, benzimidazolyl, benzofuranyl, cenolinyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl, pteridinyl, purine, oxadiazolyl, triazolyl, thiazolyl, furazanyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, and furopyridyl. The term "heteroaryl" may also include biaryl structures formed by an "aryl" as defined above and a monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridinyl-", "-phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", and "-pyrimidinylbiphenyl-"; wherein the present invention also includes fused-ring and spirocyclic compounds containing, for example, the rings described above.

[0083] The term "heterocyclic" or "heterocyclic group" refers to any monocyclic, bicyclic, polycyclic, fused, spirocyclic, or bridged non-aromatic ring system that is fully saturated, partially unsaturated, or fully unsaturated, having, for example, 3 to 20 ring atoms, wherein the ring atoms are carbon, and at least one carbon atom is replaced by a heteroatom selected from nitrogen, sulfur, or oxygen. If any ring atom in the cyclic system is a heteroatom, the system is a heterocyclic system, regardless of the connection points between the cyclic system and the rest of the molecule. In one example, a heterocyclic group comprises 3-11 ring atoms ("members") and includes monocyclic, bicyclic, tricyclic, spirocyclic, and bridged ring systems, wherein the ring atoms are carbon, and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclic group comprises 4-10 or 5-10 ring atoms. In one example, a heterocyclic group comprises 1 to 4 heteroatoms. In one example, a heterocyclic group comprises 1 to 3 heteroatoms. In another example, the heterocyclic group comprises a 3- to 7-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, the heterocyclic group comprises a 4- to 6-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, the heterocyclic group comprises a 3-membered monocyclic ring. In another example, the heterocyclic group comprises a 4-membered monocyclic ring. In another example, the heterocyclic group comprises a 5- to 6-membered monocyclic ring. In some embodiments, the heterocyclic alkyl group comprises at least one nitrogen atom. In one example, the heterocyclic group comprises 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4+]Cl-, [NR4+]OH-).Examples of heterocycles include ethylene oxide, aziridinyl, thiohexacyclopropane, aziridinyl, oxetane, thiohexacyclobutane, 1,2-dithiohexacyclobutane, 1,3-dithiohexacyclobutane, pyrrolyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazoalkyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thioxanyl, homopiperazinyl, and homopiperidinyl. ridinyl), azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazaphene, triazaphene, thiazepanyl, tetrahydrothiaranyl, oxazolyl, thiazolyl, isothiazolyl, 1,1-dioxoisothiazolinyl, 1,1-dioxoisothiazolyl, oxazolidinyl, imidazolinone, 4,5,6,7-tetrahydro[2H]inzolyl, tetrahydrobenzo[2H]-benzyl Imidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxahiazinyl, thiatriazinyl, oxtriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, indololinyl, thiaranyl, 2H-pyranyl, 4H-pyranyl, dioxalyl, 1,3-dioxolanecycloyl, pyrazolinyl, pyrazolylalkyl, dithiopheneyl, dithiohexacyclopentyl, pyrimidinone, pyrimidinedione, pyrimidin-2,4-dicarboxyl, piperazinoneyl, piperazinedioneyl, pyrazolylalkyliminoimidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0] 1] Heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]dec-2-yl, azaspiro[5.5]undecane, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindolyl, 1,1-dioxahexahydrothiopyranyl.

[0084] Similarly, the terms "carbocyclic" or "carbocyclic group" or "cyclic hydrocarbon group" refer to any monocyclic, bicyclic, polycyclic, fused, spirocyclic, or bridged non-aromatic ring system that is fully saturated, partially unsaturated, or fully unsaturated, having, for example, 3 to 20 ring atoms, wherein said ring atoms are carbon.

[0085] In a specific embodiment, the heterocyclic group or the heteroaryl group is attached at a carbon atom of the heterocyclic group or the heteroaryl group. By way of example, carbon-bonded heterocyclic groups include the following bonding arrangements: at positions 2, 3, 4, 5, or 6 of the pyridine ring; at positions 3, 4, 5, or 6 of the pyridazine ring; at positions 2, 4, 5, or 6 of the pyrazine ring; at positions 2, 3, 5, or 6 of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole rings; at positions 2, 4, or 5 of the oxazole, imidazole, or thiazole rings; at positions 3, 4, or 5 of the isoxazole, pyrazole, or isothiazole rings; at positions 2 or 3 of the aziridine ring; at positions 2, 3, or 4 of the azacyclic butane ring; at positions 2, 3, 4, 5, 6, 7, or 8 of the quinoline ring; or at positions 1, 3, 4, 5, 6, 7, or 8 of the isoquinoline ring.

[0086] In some embodiments, the heterocyclic or heteroaryl group is N-linked. By way of example, nitrogen-bonded heterocyclic or heteroaryl groups include the following bonding arrangements: at the 1 position of aziridine, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrrololine, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, 1H-indazole, at the 2 position of isoindole or isodihydroindole, at the 4 position of morpholine, and at the 9 position of carbazole or β-carboline.

[0087] In this invention, the term "fused ring" or "fused ring" refers to a polycyclic group formed by two or more ring structures sharing two adjacent atoms.

[0088] In this invention, the term "bridged ring" refers to a polycyclic group in which two rings in the system share two or more ring atoms.

[0089] In this invention, the term "spirocyclic" refers to a polycyclic group in which single rings share a single carbon atom (called a spiro atom).

[0090] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. For example, "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. In this document, alkoxy groups are preferably alkoxy groups having 1 to 6, more preferably 1 to 4, carbon atoms. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above that is bridging a sulfur group and has a specified number of carbon atoms; for example, -S-methyl and -S-ethyl. Alkoxy groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable connection point, wherein the substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0091] In this invention, "halogenated" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" / "haloalkylene" is intended to include branched and straight-chain saturated alkyl / alkylene groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Similarly, "halocycloalkyl" / "haloheterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having a specified number of carbon atoms and substituted with one or more halogens. In this invention, the halogen atom is preferably fluorine or chlorine, more preferably fluorine. In this document, unless specifically stated that a certain alkyl, cycloalkyl, heterocycloalkyl, or alkylene group cannot be substituted with a halogen, or can be inferred from the context that the group cannot be halogenated, or is considered unsuitable for halogenation based on common knowledge in the art, then these groups are considered to be halogenated, for example, substituted with one, two, three, or four halogens; for example, substituted with one, two, or three halogens; for example, substituted with one or two halogens; for example, substituted with one halogen; in some other preferred embodiments of the invention, these groups are not halogenated.

[0092] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above that is oxygen-bridged and has a specified number of carbon atoms. For example, "haloC1-C6 alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above that is sulfur-bridged and has a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0093] In this text, "oxo" means that at least two hydrogen atoms or bonding electrons on at least one atom of a specified group are replaced by the =O atom. Oxidation can occur on carbon atoms and / or heteroatoms. For example, oxoation on a C atom can oxidize -CH2- to -C(=O)-; oxoation on a S atom can oxidize -S- to -S(=O)- or -S(=O)2-. A specified group can have 0, 1, 2, 3, 4, or even more atoms oxidized.

[0094] In this paper, the lines drawn from the ring system indicate that the bond can be attached to any suitable ring atom. If the ring is a bicyclic fused ring system, the substituent can be attached to any position on either ring in the bicyclic system.

[0095] In this document, wavy lines intersecting with bonds in a chemical structure represent the connection points between atoms or groups connected to wavy bonds in the chemical structure and the remainder of the molecule or molecular segment. When a chemical structure contains two wavy lines intersecting with bonds, the structure can be connected to the remainder of the molecule or molecular segment in either orientation.

[0096] As used herein, in the context of describing adjacent atoms, the term "adjacent" refers to two atoms directly connected by a covalent bond.

[0097] In some embodiments, the divalent group generally described does not have a specific bonding configuration. It should be understood that, unless otherwise stated, the general description is intended to include two bonding structures. For example, in the group R1-R2-R3, if group R2 is described as -CH2C(O)-, it should be understood that the group can be bonded as R1-CH2C(O)-R3 and R1-C(O)CH2-R3, unless otherwise stated.

[0098] As used herein, the term "substitution" means the replacement of at least one hydrogen atom with a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. The cyclic double bond used herein refers to a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0099] In this disclosure, C is used when referring to certain substituent groups. x1 -C x2The expression indicates that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C1-C8 indicates that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C2-C8 indicates that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C3-C8 indicates that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms; C4-C8 indicates that the group contains 4, 5, 6, 7, or 8 carbon atoms; C0-C6 indicates that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 indicates that the group contains 2, 3, 4, 5, or 6 carbon atoms; and C3-C6 indicates that the group contains 3, 4, 5, or 6 carbon atoms.

[0100] In this disclosure, when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), the expression "x1-x2 membered ring" is used, indicating that the number of ring atoms in the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; a 3-6 membered ring indicates that the cyclic group can be a 3, 4, 5, or 6 membered ring, and its number of ring atoms can be 3, 4, 5, or 6; a 3-8 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, or 8; a 3-9 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; 8 or 9; 4-7 membered ring indicates that the cyclic group can be a 4, 5, 6, or 7 membered ring, and its number of ring atoms can be 4, 5, 6, or 7; 5-8 membered ring indicates that the cyclic group can be a 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 5, 6, 7, or 8; 5-12 membered ring indicates that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 5, 6, 7, 8, 9, 10, 11, or 12; 6-12 membered ring indicates that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 6, 7, 8, 9, 10, 11, or 12. The ring atoms can be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cyclic heteroatoms, for example heteroatoms selected from N, O and S.

[0101] In cases where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxides to obtain derivatives of the present invention.

[0102] When any variable appears more than once in any composition or formula of a compound, its definition for each occurrence is independent of its definition for each other occurrence. Thus, for example, if a substituent group is shown to have 0-3 R groups, the substituent group may optionally be substituted with up to three R groups, and each occurrence of R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are only permitted if such combinations produce a stable compound.

[0103] Unless otherwise stated, the terms “compound(s) of the invention” and “compound(s) of the present invention” include compounds of general formula and compounds listed in the specific list, including their stereoisomers, tautomers, solvates, precursors, metabolites, isotope derivatives and salts (e.g., pharmaceutically acceptable salts).

[0104] The "stereoisomerism" described in this invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism (i.e., geometric isomerism) and optical isomerism (also called enantiomerism). Conformational isomerism refers to the phenomenon where organic molecules with a certain configuration exhibit different spatial arrangements of atoms or atomic groups due to the rotation or twisting of carbon atoms or carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations in cyclohexane. Cis-trans isomers are isomers caused by the presence of C=C double bonds, C=N double bonds, or ring systems, which make rotation difficult, and are usually represented by Z and E. Optical isomers, also called enantiomers, refer to two stereoisomers of a compound that are non-overlapping mirror images of each other. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the rotational sign of a compound with respect to plane-polarized light, where (-) or 1 indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Mixtures of enantiomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in a chemical reaction or process without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomer species. The compounds of the present invention may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist in the form of diastereomers, enantiomers, or mixtures thereof.

[0105] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that interconvert through low-barrier transformations. For example, proton tautomers (also known as proton-transformed tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions that occur through the recombination of some bonded electrons. The compounds described in this invention can exist in tautomer forms, having different hydrogen bonding sites through one or more double bond shifts.

[0106] The term "chirality" refers to a molecule that does not overlap with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0107] The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical procedures (such as electrophoresis) and chromatographic methods (such as HPLC).

[0108] The stereochemical definitions and conventions used in this article generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0109] All enantiomers, diastereomers, racemates, mesoomers, cis-trans isomers, trans-blocked isomers, tautomers, and mixtures thereof are included within the scope of this invention. All methods for preparing the compounds of this invention and the intermediates therein are considered part of this invention. When preparing enantiomers or diastereomers, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). The free forms and salts of these end products are within the scope of this invention. If desired, one form of the compound can be converted to another. Free bases or acids can be converted to salts; salts can be converted to free compounds or another salt; mixtures of isomers of this invention can be separated into individual isomers. The compounds of this invention, their free forms, and salts can exist in various tautomer forms, wherein hydrogen atoms are transposed to other parts of the molecule and chemical bonds between the atoms of the molecule are rearranged. It should be understood that all possible tautomer forms are included within this invention.

[0110] In the structures shown herein, where the stereochemistry of any specific chiral atom is not specified, all stereoisomers are considered as and included in the compound of the invention. When the stereochemistry is specified by a solid wedge or dashed line indicating a specific configuration, the stereoisomer is specified and defined. Unless otherwise stated, the use of a solid wedge or dashed line signifies relative stereochemistry.

[0111] In this invention, the term "pharmaceutical-acceptable salt" or "pharmaceutically acceptable salt" means that, within a reasonable medical judgment, it is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. The salt can be prepared in situ during the final separation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent, as outlined below. For example, the free base functional group can react with a suitable acid, which can be an organic or inorganic acid; the free acid functional group can react with a suitable base, which can be an organic or inorganic base. Examples of pharmaceutically acceptable inorganic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed using other methods in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enolate, glyceryl phosphate, gluconate, hernisulfate, heptaate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, bitter salts, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically usable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0112] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example by dissolving the compounds of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, and acetonitrile), adding an excess of an aqueous solution of an organic or inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid, and then separating the precipitated salt.

[0113] The precursors or metabolites described in this invention can be precursors or metabolites known in the art, as long as they are metabolized and transformed in vivo to form compounds. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism, or through N-demethylation of the compounds of this invention.

[0114] The term "solvate" as used in this invention refers to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0115] The term "isotope derivative" in this invention refers to molecules in which the compounds described herein are isotopically labeled. Commonly used isotopes for isotopic labeling are hydrogen isotopes. 2 H and 3 H; Carbon isotopes: 11 C, 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Tritium, in particular. 3 H and carbon 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2Substitution with H can enhance metabolic stability and prolong the half-life, thereby reducing the dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0116] As used herein, the terms "patient," "subject," or "patient" refer to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., rodents, apes, monkeys, horses, cattle, pigs, dogs, cats, etc.), and most preferably, humans.

[0117] As used herein, the term "effective amount" means the amount of a drug or agent (i.e., the compound of the present invention) that will elicit a biological or medical response in a tissue, system, animal, or human, as sought by, for example, a researcher or clinician. Furthermore, the term "therapeutic effective amount" means an amount that, compared to a corresponding subject who did not receive the aforementioned amount, results in improved treatment, cure, prevention, or reduction of disease, symptom, or side effects, or a slower rate of progression of disease or symptom. An effective amount may be administered, applied, or dosed in one or more ways and is not intended to be limited to a particular formulation or route of administration. The term also includes effective amounts that enhance normal physiological function within its scope. For cancer treatment, efficacy may be measured, for example, by assessing time to progression (TTP) or determining the response rate (RR).

[0118] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndrome; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; mitigating a disease or symptom; reducing complications arising from a disease or symptom, or preventing and / or treating signs arising from a disease or symptom.

[0119] The term "pharmaceutical" as used herein refers to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, and / or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0120] The term "pharmaceutically acceptable," as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for the general therapeutic goal, and does not produce adverse, allergic, or other adverse reactions.

[0121] The term "pharmaceutically acceptable carrier" or "pharmaceutical carrier" refers to media generally accepted in the art for the delivery of bioactive agents to animals (specifically mammals), including (i) adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on...

[0122] The term "pharmaceutical composition" means a composition comprising the compounds of the present invention and at least one other pharmaceutically acceptable carrier.

[0123] The term "combined administration" or similar terms, as used herein, refers to the administration of two or more selected therapeutic agents to a patient such that both formulations and / or their metabolites are present in the animal. Co-administration includes simultaneous administration of a single composition, administration of a single composition at different times, or administration of a composition in which both formulations are present.

[0124] The terms “enhancement” or “potential enhancement,” as used herein, refer to the expected increase or prolongation of either efficacy or duration of effect. Therefore, in the context of enhancing the therapeutic effect of a drug, the term “potential enhancement” refers to the ability of a drug in a system to increase or prolong its efficacy or duration. The term “synergistic value,” as used herein, refers to the ability of an ideal system to maximally enhance the efficacy of another therapeutic agent.

[0125] The terms “inhibition” or “reduction”, or any variations thereof, including any measurable reduction or complete inhibition, to achieve the desired result. For example, an activity may be reduced by about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range thereof, compared to normal.

[0126] The term "wildtype" refers to an entity that has the structure or activity seen in nature in a "normal" state or condition (as opposed to mutation, disease, alteration, etc.). Those skilled in the art will understand that wildtype genes and polypeptides often exist in many different forms (e.g., alleles).

[0127] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to compounds that have the biological function of inhibiting a target protein by inhibiting the activity or expression of proteins such as K-Ras, H-Ras, or N-Ras G12C. Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological function of the target protein. While the antagonists preferred herein interact specifically with the target (e.g., bind), compounds that inhibit the biological activity of a target protein by interacting with other members of the signal transduction pathway in which the target protein is a member are also specifically included within this definition. Preferred biological activities inhibited by antagonists are associated with tumor occurrence, growth, or spread.

[0128] As used herein, the term "agonist" refers to a compound that initiates or enhances the biological function of a target protein by inhibiting its activity or expression. Therefore, the term "agonist" is defined in the context of the biological action of the target peptide. While the preferred agonists herein interact specifically with the target (e.g., bind), compounds that initiate or enhance the biological activity of a target peptide by interacting with other members of the signal transduction pathway in which the target peptide is a member are also specifically included within this definition.

[0129] The term "immune disease" refers to a disease or symptom that results from an adverse or harmful reaction to endogenous or exogenous antigens. The result is often impaired cell function, or damage to cells leading to dysfunction, or damage to organs or tissues that may produce immune symptoms.

[0130] The terms “cancer” and “cancerous,” “vesicle” and “tumor,” along with related terms, describe a physiological condition in mammals characterized by the uncontrolled, abnormal growth of cells that can metastasize (spread) under certain conditions. A “tumor” contains one or more cancer cells, including, for example, solid tumors and hematologic malignancies. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer, including small cell lung cancer, non-small cell lung cancer (“NSCLC”), lung adenocarcinoma, and lung squamous cell carcinoma. Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral cavity), lips, tongue, mouth, salivary glands, esophagus, larynx, hepatocellular carcinoma, stomach, gastrointestinal tract, small intestine, large intestine, pancreas, cervix, ovary, liver, bladder, hepatocellular carcinoma, breast, colon, rectum, colorectal, genitourinary system, biliary tract, thyroid gland, mastoid process, hepatic, endometrium, uterus, salivary glands, kidneys or renal tract cancers, prostate, testes, vulva, peritoneum, anus, penis, bone, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system cancer, brain, head and neck cancer, Hodgkin's disease, and related metastases. Examples of myeloproliferative disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis such as primary myelofibrosis, and chronic myeloid leukemia (CML).

[0131] As used herein, the term "therapeutic effect" encompasses the therapeutic and / or preventative benefits described above. Preventative effects include delaying or eliminating the onset of a disease or symptom, delaying or eliminating the onset of symptoms of a disease or symptom, slowing, stopping, or reversing the progression of a disease or symptom, or any combination thereof.

[0132] "Chemotherapy agent" is a preparation that can be used to treat a pre-existing condition, such as cancer or an inflammatory condition. Examples of chemotherapeutic agents are well known in the art and include, for example, those disclosed in U.S. Publication No. 2010 / 0048557, which is incorporated herein by reference. Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any chemotherapeutic agent, and combinations of two or more of them.

[0133] The terms "reagent kit" and "product packaging" are synonyms.

[0134] In particular, it is considered that any limitations discussed with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention.

[0135] The titles used in this article are for compilation purposes only.

[0136] compound

[0137] In one aspect, the present invention provides compounds, isotope derivatives, stereoisomers, or pharmaceutically acceptable salts of Formula I:

[0138]

[0139] in:

[0140] R 1 It represents D, halogen, CN, C1-C3 alkyl, halo-C1-C3 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy or 3-6 membered heterocyclic alkyl;

[0141] Ar 1 Indicates a 5-membered heteroaryl group;

[0142] Cy 1 It represents a 4-8 membered heterocyclic alkyl group, a 4-8 membered heterocyclic alkenyl group, or a 5-8 membered heteroaryl group;

[0143] X 1 and X 2 It is Ar 1 and Cy 1 Shared bridgehead atom, X 1 and X 2 Each can be represented independently as C or N, X 1 and X 2 The covalent bonds between them can be single or double bonds;

[0144] R 2 Each can be independently represented by H, D, halogen, CN, and OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl may optionally be represented by 0, 1, 2, 3, or 4 R groups. 22 replace;

[0145] R 3 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a'、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl may optionally be represented by 0, 1, 2, 3, or 4 R groups. 23 replace;

[0146] Two R connected on the same C 3 Or two R atoms connected on different atoms 3 It can form 3-8 membered rings with the atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0147] Y 1 and Y 2 Each represents CR independently. 4 Or N;

[0148] R 4 Each of these elements independently represents H, D, halogen, CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy may optionally be represented by 0, 1, 2, 3, or 4 Rs. 24 replace;

[0149] V represents C(O), S(O), S(O)2 or S(O)(NR) 6 );

[0150] W represents CR independently. 5 R 5 '、C(O),NR 6 ,O,S,S(O),S(O)2 or S(O)(NR 6 );

[0151] R 5 R 5 Each can be represented independently as H, D, halogen, CN, OR a SR a NR a R a '、N(R a COR a '、CON(R a )Ra '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 25 replace;

[0152] R connected on the same C 5 R 5 It can also form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0153] R attached to different C atoms 5 With R 5 It can form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0154] R 6 Each of H, D, and -S(O)2R can be represented independently. a -S(O)R a -C(O)R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 26 replace;

[0155] R 5 With R 6 It can form 3-8 membered rings together with the ring atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0156] R 22 R 23 R 24 R 25 R 26R 30 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 22 Two R atoms on the same atom or different atoms 23 Two R atoms on the same atom or different atoms 24 Two R atoms on the same atom or different atoms 25 Two R atoms on the same atom or different atoms 26 Or R 25 With R 26 It can form a 3-6 membered ring with the C atom and / or N atom it is connected to, and the ring may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0157] R a and R a Each can independently represent H, D, C1-C3 alkyl, or C3-C6 cycloalkyl;

[0158] m represents 0, 1, or 2;

[0159] n represents 0, 1, 2, 3, or 4;

[0160] o can be 2, 3, 4, 5 or 6.

[0161] In some implementations, Ar 1 The groups represented are pyrazolyl, imidazolyl, thiophene, furanyl, pyrroleyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl; preferably, Ar. 1 It represents the pyrazol group.

[0162] In some embodiments, V represents C(O) or S(O)2; preferably, V represents C(O).

[0163] In some implementations, Y1 and Y 2 Each represents CR independently. 4 .

[0164] In some implementations, m represents 0 or 1;

[0165] In some embodiments, the compound represented by Formula I has the structure represented by Formula II:

[0166]

[0167] in:

[0168] R 1 It represents D, halogen, CN, C1-C3 alkyl, halo-C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C2 alkoxy;

[0169] Cy 1 It represents a 4-8 membered heterocyclic alkyl group, a 4-8 membered heterocyclic alkenyl group, or a 5-8 membered heteroaryl group;

[0170] R 2 Each can be independently represented by H, D, halogen, CN, and OR. a NR a R a ', C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl may optionally be 0, 1, 2 or 3 R 22 replace;

[0171] R 3 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3 or 4 R 23 replace;

[0172] Two R connected on the same C 3 Or two R atoms attached to different C atoms 3 It can form 3-8 membered rings with the atoms it is attached to, wherein the rings may optionally contain 0, 1, or 2 heteroatoms selected from N, O, or S, and the rings may be further divided by 0, 1, or 2 R atoms.30 replace;

[0173] R 4 Each of these elements independently represents H, D, halogen, CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy may optionally be represented by 0, 1, 2, 3, or 4 Rs. 24 replace;

[0174] W represents CR independently. 5 R 5 '、C(O),NR 6 O or S(O)2;

[0175] R 5 R 5 Each can be represented independently as H, D, halogen, CN, OR a SR a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 25 replace;

[0176] R connected on the same C 5 R 5 It can also form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0177] R attached to different C atoms 5 With R 5 It can form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0178] R 6Each of H, D, and -S(O)2R can be represented independently. a -S(O)R a -C(O)R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 26 replace;

[0179] R 5 With R 6 It can form 3-8 membered rings together with the ring atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace;

[0180] R 22 R 23 R 24 R 25 R 26 R 30 Each can be independently represented as D, oxo, halogen, CN, OR a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 22 Two R atoms on the same atom or different atoms 23 Two R atoms on the same atom or different atoms 24 Two R atoms on the same atom or different atoms 25 Two R atoms on the same atom or different atoms 26 Or R 25 With R 26It can form a 3-6 membered ring with the C atom and / or N atom it is connected to, and the ring may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0181] R a and R a Each can independently represent H, D, C1-C3 alkyl, or C3-C6 cycloalkyl;

[0182] n represents 0, 1, 2, 3, or 4;

[0183] o can be 2, 3, 4, 5 or 6.

[0184] In some implementations, R 1 This represents D, halogen, CN, C1-C2 alkyl, fluorinated C1-C2 alkyl; preferably, R 1 It represents F, Cl, CN, methyl, and trifluoromethyl.

[0185] In some implementations, Cy 1 It indicates a 4-8 membered heterocyclic alkyl group or a 5-8 membered heteroaryl group.

[0186] In some implementations, R 2 Each can be independently represented by H, D, halogen, CN, and OR. a NR a R a ', C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl may optionally be 0, 1, 2 or 3 R 22 Replacement; preferred, R 2 Each can be independently represented by H, D, halogen, CN, C1-C3 alkyl, or C1-C3 haloalkyl.

[0187] In some implementations, R 3 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3 or 4 R 23 Replacement; two R connected on the same C 3 Or two R atoms connected on different atoms3 It can form 3-8 membered rings with the atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace.

[0188] In some implementations, two Rs connected to the same C 3 Or two R atoms connected on different atoms 3 It can form 3-8 membered rings with the atoms it is attached to, wherein the rings may optionally contain 0, 1, or 2 heteroatoms selected from N, O, or S, and the rings may be further divided by 0, 1, or 2 R atoms. 30 replace.

[0189] In some implementations, R 4 It represents H, D, halogen, CN, C1-C6 alkyl, or R. 4 Represents H, D, halogen, CN, methyl, methoxy, hydroxymethyl, or methoxymethyl; preferably, R 4 It represents H, D, halogen, CN, and methyl.

[0190] In some implementations, W independently represents CR. 5 R 5 '、C(O),NR 6 O or S(O)2; preferably, W independently represents CR. 5 R 5 '、NR 6 、O.

[0191] In some implementations, R 5 R 5 Each can be represented independently as H, halogen, CN, OR a SR a NR a R a ', C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, or 3 R's. 25 Replace; R connected on the same C 5 R 5 It can also form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms.30 Substitution; R bonded to different C atoms 5 With R 5 It can form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 Replacement; preferred, R 25 Each can be used independently to represent either halogen or methyl.

[0192] In some implementations, R connected to the same C 5 R 5 It can form C3-C6 aliphatic rings or 4-8-membered heterocycles with the C atoms it is attached to, wherein the C3-C6 aliphatic rings or 4-8-membered heterocycles can be formed by 0, 1, 2 or 3 R atoms. 30 Replacement; preferred, R 30 Each can be used independently to represent either halogen or methyl.

[0193] In some implementations, R 6 Each can be represented independently as H, -S(O)2R a -C(O)R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, or 3 R 26 Replacement; preferred, R 26 Each can independently represent either a halogen or a methyl group; more preferably, R 6 Each can be independently represented by H or C1-C6 alkyl.

[0194] In some implementations, R connected to different atoms 5 With R 5 '、or R 5 With R 6 It can form C3-C6 aliphatic rings or 4-8-membered heterocycles together with atoms on the ring, wherein the C3-C6 aliphatic rings or 4-8-membered heterocycles can be formed by 0, 1, 2 or 3 R atoms. 30 replace;

[0195] In some implementations, R connected to different atoms 5 With R 5 '、or R 5 With R 6 It can form 3-8 membered rings together with atoms on the ring, the rings including unsaturated bonds, preferably 5-6 membered heteroaromatic rings, the 5-6 membered heteroaromatic rings being 0, 1, 2 or 3 R atoms.30 replace.

[0196] In some implementations, R 22 R 23 R 24 R 25 R 26 R 30 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substituted; preferably, R 22 R 23 R 24 R 25 R 26 R 30 Each can be independently represented by H, oxo, halogen, CN, OR. a NR a R a ', C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be substituted by 0, 1, 2, or 3 substituted from halogens, OH, or C1-C2 alkyl; more preferably, R 22 R 23 R 24 R 25 R 26 R 30 Each is independently selected from H, oxo, F, Cl, CN, OR a NR a R a '.

[0197] In some implementations, R a and R a Each can be independently represented by H, D, or C1-C3 alkyl.

[0198] This invention also provides compounds, isotope derivatives, stereoisomers, or pharmaceutically acceptable salts thereof having the following structures:

[0199]

[0200]

[0201] In some embodiments, compared to compounds known in the art, the compounds of the present invention exhibit significantly higher binding affinity to certain targets within the CDK family, such as CDK2 and CDK4, than to other targets within the same family. This results in a significant advantage for the compounds of the present invention in terms of improved antitumor efficacy and reduced toxicity compared to existing technologies in the art. Methods for measuring such efficacy are known in the art, such as kinase activity assays, FRET assays, etc., as provided in the following examples.

[0202] synthesis

[0203] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic methods.

[0204] The compounds of the present invention can be prepared by a variety of methods well known to those skilled in organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described in the following embodiments, as well as synthetic methods known in synthetic organic chemistry or modifications thereof as understood by those skilled in the art. These methods include, but are not limited to, those described in the following embodiments.

[0205] For illustrative purposes, the following reaction schemes provide pathways for the synthesis of the compounds of this invention and key intermediates. Detailed descriptions of each reaction step are provided in the following examples section. Those skilled in the art will understand that other synthetic routes can be used. Although certain specific starting materials and reagents are described in the process and discussed below, other starting materials and reagents can be substituted to provide various derivatives or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified using conventional chemical methods well known to those skilled in the art, based on this disclosure.

[0206] If necessary, starting materials and intermediates for the synthetic reaction can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. Conventional methods can be used to characterize these materials, including physical constants and spectral data.

[0207] Unless otherwise stated, the reactions described herein are preferably carried out under an inert atmosphere, at atmospheric pressure, in a temperature range of about -78°C to about 150°C, more preferably in a temperature range of about 0°C to about 125°C, and most preferably and conveniently at about room temperature (or ambient temperature) or about 20°C.

[0208] Some of the compounds in the following schemes contain broadly defined substituents; however, those skilled in the art will readily recognize that the nature of the substituents can be varied to provide the various compounds contemplated in this invention. Furthermore, the reaction conditions are exemplary and alternative conditions are well-known. The reaction sequences in the following examples are not intended to limit the scope of the invention as described in the claims.

[0209] Drug description

[0210] Drug composition and dosage

[0211] The compounds involved in this invention are CDK inhibitors and can be used to treat cancer. Therefore, one embodiment of this invention provides a pharmaceutical composition comprising the compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and a method for preparing such compositions using the compound of the invention.

[0212] For use as a treatment for subjects, the compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as pharmaceutical compositions. Depending on the subject to be treated, the mode of administration, and the desired type of treatment, such as prevention, treatment, or therapy, the compounds or pharmaceutically acceptable salts thereof are formulated in a manner consistent with the parameters described herein. An overview of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0213] The compositions can be prepared according to commonly used mixing, granulation, or coating methods, and the pharmaceutical compositions of the present invention may contain, by weight or volume, about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the compounds of the present invention or pharmaceutically acceptable salts thereof. In some embodiments, the amount of the compounds described herein or pharmaceutically acceptable salts thereof may be, by weight, 1-95% of the total amount of the pharmaceutical composition.

[0214] The composition may be provided in dosage forms suitable for administration such as intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intracystic, intraurethral, ​​intrathecal, epidural, ocular, or by injection, inhalation, or direct contact with the nasal, genitourinary, genital, or oral mucosa. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, solutions, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoresis delivery, or aerosols. The composition may be formulated according to common pharmaceutical practices.

[0215] As used herein, the term "administration" means administering a composition (e.g., a compound or a formulation comprising a compound as described herein) to a subject or system. Administration to animal subjects (e.g., to humans) can be performed via any suitable route. For example, in some embodiments, administration can be via bronchial (including bronchial infusion), buccal, intestinal, intradermal, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intrasacral, mucosal, nasal, oral, rectal, subcutaneous, sublingual, surface, tracheal (including intratracheal infusion), percutaneous, vaginal, or vitreous administration.

[0216] Formulations can be prepared for systemic or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous) or those prepared for transdermal, transmucosal, or oral administration. Formulations will generally include diluents and, in some cases, adjuvants, buffers, preservatives, etc. Compounds or pharmaceutically acceptable salts thereof may also be administered as liposome compositions or as microemulsions.

[0217] For injection, formulations can be prepared in commonly used forms, such as liquid solutions or suspensions, or in solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or in emulsion forms. Suitable excipients include, for example, water, saline, dextrose, glycerol, etc. These compositions may also contain a certain amount of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitol monolaurate, etc.

[0218] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or their pharmaceutically acceptable salts. It will be understood in the art that suitable forms include syrups, capsules, and tablets.

[0219] Each compound described herein, or its pharmaceutically acceptable salt, can be formulated in a variety of ways known in the art. For example, the first and second agents in a combination therapy can be formulated together or separately. Other modalities of combination therapy are also described herein.

[0220] Individually or separately formulated pharmaceutical preparations may be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and powder, suppositories, or liquids in vials, two topical creams, etc. The kit may include optional components to facilitate the administration of a unit dose to a subject, such as vials for reconstitution of the powder form, syringes, custom IV delivery systems, inhalers, etc. Additionally, the unit dose kit may contain instructions for the preparation and administration of the composition. The kit may be manufactured as a single-use unit dose for one subject, for multiple uses for a specific subject (constant dose, or in which the potency of individual compounds or their pharmaceutically acceptable salts may vary with treatment progression); or the kit may contain multiple doses suitable for administration to multiple subjects (“integral package”). The kit components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0221] Formulations for oral use include tablets containing a mixture of an active ingredient and a non-toxic, pharmaceutically acceptable excipient. The excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0222] Two or more compounds may be mixed together in tablets, capsules or other media, or they may be separated. In one example, the first compound is contained on the inside of the tablet, while the second compound is on the outside, thereby allowing the majority of the second compound to be released before the first compound is released.

[0223] Formulations for oral use may also be provided as chewable tablets or as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or as soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets may be prepared using the ingredients mentioned above for tablets and capsules, in a conventional manner, using, for example, a mixer, a fluid bed apparatus, or a spray dryer.

[0224] Controlled release through dissolution or diffusion can be achieved by appropriately coating the compound with tablets, capsules, pellets, or granules, or by incorporating the compound or a pharmaceutically acceptable salt thereof into a suitable matrix. Controlled release coatings may include one or more of the coating substances mentioned above, such as shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethacrylate, methacrylate hydrogels, 1,3-butanediol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene or halogenated fluorocarbons.

[0225] Liquid forms of compounds or pharmaceutically acceptable salts and compositions thereof that can be incorporated into the present invention for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical mediators.

[0226] Generally, when administered to humans, the oral dose of any compound of the present invention or a pharmaceutically acceptable salt thereof will depend on the nature of the compound and can be readily determined by those skilled in the art. The dose can be, for example, from about 0.001 mg to about 2000 mg daily, from about 1 mg to about 1000 mg daily, from about 5 mg to about 500 mg daily, from about 100 mg to about 1500 mg daily, from about 500 mg to about 1500 mg daily, from about 500 mg to about 2000 mg daily, or any range derived therefrom. In some embodiments, the daily dose for oral administration may, for example, be in the range of from about 0.001 mg to about 2000 mg per kilogram of human body weight, administered in a single dose or divided doses. On the other hand, in some cases, doses outside the stated limits may be necessary.

[0227] In some embodiments, the pharmaceutical composition may additionally contain an additional compound having antiproliferative activity. Depending on the administration regimen, the compound or a pharmaceutically acceptable salt thereof will be formulated to suit the composition for delivery. Each compound or a pharmaceutically acceptable salt thereof in the combination therapy may be formulated in a variety of ways known in the art. For example, the first and second agents in the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together for simultaneous or near-simultaneous administration of these agents.

[0228] It should be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated together with one or more other desired therapeutic agents or medical procedures, or administered concurrently with, before, or after the administration of such one or more other desired therapeutic agents or medical procedures. The specific combination of the therapies (therapeutic agents or procedures) used in the combination regimen should take into account the compatibility of the desired therapeutic agent or procedure with the desired therapeutic effect to be achieved. It should also be understood that the therapies used may achieve the desired effect for the same condition, or they may achieve different effects (e.g., controlling any adverse effects).

[0229] As described in this article, the individual drugs in the combination therapy can be administered independently, once to four times daily, for one day to one year, and even for the subject's lifetime. Chronic / long-term administration is also applicable.

[0230] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0231] How to use

[0232] In some embodiments, the present invention discloses a method for treating a disease or condition characterized by an abnormality caused by a CDK2 / 4 mutant.

[0233] In some implementations, the disease or condition is an inflammatory disease, an autoimmune disease, or an immune-mediated disease. Representative examples may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other inflammatory joint conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, and urticaria (rubella). Multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0234] In some implementations, the disease or condition is cancer or a tumor. Representative examples of cancer or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral thyroid cancer. Neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

[0235] When the compounds of the present invention or their pharmaceutically acceptable salts are administered in combination with other therapeutic agents for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compounds of the present invention or their pharmaceutically acceptable salts may provide enhanced therapeutic effects.

[0236] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein can be used to treat a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compounds of the present invention or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods include, but are not limited to, tumor types such as astrocytoma, breast, cervix, colorectal, endometrial, esophagus, stomach, head and neck, hepatocellular, larynx, lung, oral cavity, ovary, prostate and thyroid cancers and sarcomas.

[0237] Combination therapy

[0238] The methods of the present invention may include the compounds of the present invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). When administered alone, the dose of one or more of the additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced relative to a standard dose. For example, the dose may be determined empirically based on the combination and arrangement of drugs or inferred by isoradiometric analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).

[0239] The compounds of the present invention may be administered before, after, or simultaneously with one or more of the additional therapies. When combined, the dose of the compounds of the present invention provides a therapeutic effect (e.g., synergistic or additive therapeutic effect) in conjunction with the dose of the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). The compounds of the present invention and additional therapies, such as anticancer agents, may be administered together, for example, as a single pharmaceutical composition, or separately, and when administered separately, the administration may occur simultaneously or sequentially. Such sequential administration may be close in time or distant in time.

[0240] In some embodiments, the additional therapy is the administration of a side effect limiter (e.g., an agent intended to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of the present invention may also be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0241] In some implementations, the one or more additional therapies include Non-pharmacological treatment (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies include Therapeutic agents (e.g., compounds or biologics that act as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, the one or more additional therapies comprise non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics that act as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, the one or more additional therapies comprise two therapeutic agents. In still other embodiments, the one or more additional therapies comprise three therapeutic agents. In some embodiments, the one or more additional therapies comprise four or more therapeutic agents.

[0242] In this section on combination therapies, all references are incorporated by way of citation for the pharmaceutical agents described, or for their pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers, whether or not so explicitly stated.

[0243] Examples of non-pharmacological treatments include, but are not limited to, radiotherapy, cryotherapy, hyperthermia, surgery (e.g., surgical removal of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0244] In some embodiments, the compounds of the present invention can be used as postoperative adjuvant therapy. In some embodiments, the compounds of the present invention can be used as preoperative neoadjuvant therapy.

[0245] In some embodiments, the compounds of the present invention can sensitize abnormal cells to radiotherapy, thereby killing or inhibiting the growth of such cells. Therefore, the present invention further relates to a method for sensitizing abnormal cells in a mammal to radiotherapy, the method comprising administering to the mammal a quantity of the compounds of the present invention, the quantity of which effectively sensitizes the abnormal cells to radiotherapy. The amount of the compound in this method may be determined according to the manner used to determine the effective amount of such compounds described herein. In some embodiments, the compounds of the present invention can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0246] In some embodiments, the non-pharmacological treatment is adoptive T-cell transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The source of the T cells is obtained from the subject before the T cells are expanded and genetically modified. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of the invention, a variety of T cell lines available in the art may be used.

[0247] Therapeutic agents can be compounds used to treat cancer or its related symptoms.

[0248] For example, the therapeutic agent may be a steroid. Therefore, in some embodiments, the one or more additional therapies include steroids. Suitable steroids may include, but are not limited to, acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, and cortisol. sone, cortivazol, deflazacort, desonide, deoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortinbutyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasolPropionate, halometasone, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, 25-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone Triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0249] Therapeutic agents can be biological agents (e.g., cytokines such as interferon or leukocyte-stimulating factors such as IL-2) used to treat cancer or related symptoms. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that activates a target to stimulate an anticancer response or antagonizes an antigen important for cancer. Antibody-drug conjugates are also included.

[0250] The therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L2 inhibitor or antagonist (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor) (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or... Checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol. include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0251] Therapeutic agents can be anti-TIGIT antibodies, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0252] Therapeutic agents can be drugs used to treat cancer or related symptoms (e.g., cytotoxic agents, non-peptide small molecules, or other compounds that can be used to treat cancer or related symptoms, collectively referred to as "anticancer agents"). Anticancer agents can be, for example, chemotherapy agents or targeted therapy agents.

[0253] Anticancer agents include mitosis inhibitors, insertional antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted urea, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, the one or more additional therapies comprise two or more anticancer agents. The two or more anticancer agents can be used in a mixture for combined or separate administration.

[0254] Other non-limiting representative examples of anticancer agents may include cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dextrin, doxorubicin, epirubicin, doxorubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixaprone, and tamoxifen. Flutamide, Gonarelin analogues, Megestrol acetate, Prednisone, Dexamethasone, Methylprednisolone, Thalidomide, Interferon Alpha, Leucovorin, Sirolimus, Sirolimus esters, Everolimus, Afatinib, Alisertib, Amuvatinib, Apatinib, Axitinib, Bortezomib, Bosutinib, Brinib, Cabozantinib, Sildenafil, Crenolanib, Crizotinib, Dabrafenib, Dacomitinib, Danusertib, Dasatinib, Dovitinib, Erlotinib, Foretinib, Ganetespib, Gefitinib, Ibrutinib, Icotinib, Imatinib, i Niparib, Lapatinib, Lenvatinib, Linifanib, Linsitinib, Masatinib, Momelotinib, Motishanib, Lenatinib, Nilotinib, Niraparib, Oprozomib, Olaparib, Pazopanib, Pictilisib, Ponatinib, Quizartinib, Regorafenib, Rigosertib, Rucaparib, Ruxolitinib, Secatinib, Saridegib, Sorafenib, Sunitinib, Tilatinib, Vtivantinib, Tivolitinib Zanil, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vemodega, volasertib, alenumab, bevacizumab, belentoumab, vedotin, caputuzumab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, oflamumab, panitumab, rituximab, tosimomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, and anti-CTLA-4 antibodies, or any combination thereof.

[0255] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0256] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. They can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by variations thereof understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and suitable for the transformation achieved. Those skilled in the art of organic synthesis will understand that the functionalities present on the molecule are consistent with the proposed transformation. This sometimes necessitates determining whether to change the order of synthetic steps or the starting materials to obtain the desired compound of the present invention.

[0257] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0258] Example

[0259] General process

[0260] When the preparation method is not specified, all raw materials and reagents used in this invention are known products that can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents used require further purification.

[0261] Room temperature refers to 20-30℃.

[0262] Unless otherwise specified in the reaction examples, all reactions were carried out under a nitrogen atmosphere. A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon of approximately 1L.

[0263] Hydrogenation reactions are typically carried out under vacuum, filled with hydrogen gas, and repeated three times. A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon of approximately 1L.

[0264] Microwave reaction use Initiator + Microwave Reactor.

[0265] The structure of the compounds of this invention was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) were expressed in terms of 10⁻¹⁰. -6The measurements are given in units of (ppm). NMR determinations are performed using (Bruker Ascend) TM A Model 500 NMR spectrometer was used. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). The following abbreviations are used for NMR signal multiplicity: s = singlet, brs = broad peak, d = doublet, t = triplet, m = multiplet. Coupling constants are listed in J values ​​and measured in Hz.

[0266] Reversed-phase preparative chromatography was performed using a Thermo (UltiMate 3000) reversed-phase preparative chromatograph. Rapid column chromatography was performed using an Agilent (FS-9200T) automated column press, and pre-packed silica gel columns were obtained from Sante. Pre-packed column. Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The thickness used for thin-layer chromatography separation and purification of products is 0.4mm to 0.5mm.

[0267] The LC-MS analysis method is as follows:

[0268] 1) Mass spectrometry method: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameter settings: drying gas temperature 350℃; drying gas flow rate 10L / min; MS range: 120-1000.

[0269] 2) Liquid chromatography conditions: Column: Waters XBridge (3.5 μm, 50 mm × 4.6 mm); Mobile phase A is an aqueous solution containing 0.1% ammonium bicarbonate, and mobile phase B is an acetonitrile solution, with linear gradient elution according to Table 1; Flow rate: 2 mL / min; Column temperature: 30 ℃; UV detection wavelength: 214 nm, 254 nm, 280 nm; Injection volume: 2 μL.

[0270] Table 1. Gradient elution conditions

[0271]

[0272] The HPLC analysis method is as follows:

[0273] Chromatographic column: Waters XBridge phenyl (3.5 μm, 150 mm × 4.6 mm); mobile phase A was an aqueous solution containing 0.1% ammonium bicarbonate, and mobile phase B was an acetonitrile solution, with linear gradient elution performed according to Table 2; flow rate: 1 mL / min; column temperature: 30 ℃; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0274] Table 2. Gradient elution conditions

[0275]

[0276] The synthesis methods of some intermediates in the invention are as follows:

[0277] Intermediate 1

[0278]

[0279] Intermediate 1 is prepared by the following steps:

[0280]

[0281] Step 1: Dissolve INT-1a (1.0 g, 5.20 mmol) in 5 mL of formic acid and stir at 100 °C for 1 hour. After the reaction is complete, concentrate under reduced pressure to obtain an oily substance. Slurry the oily substance with petroleum ether / ethyl acetate (10 / 1), filter, and dry to obtain a white solid INT-1 (1.0 g, yield 87%). ESI-MS (m / z): 221.2 [M+H] + .

[0282] Example 1

[0283] 4-(4-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0284]

[0285] Example 1 was prepared by the following steps:

[0286]

[0287] Step 1: Dissolve 1b (250 mg, 1.01 mmol), 1a (235.85 mg, 1.21 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (73.32 mg, 0.10 mmol), and potassium carbonate (278.51 mg, 2.02 mmol) in a mixed solution of 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was stirred at 90°C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target product 1c (190 mg, yield 67.16%). ESI-MS (m / z): 280.8 [M+H] + .

[0288] Step 2: Dissolve 1c (190 mg, 0.68 mmol) in dichloromethane (10 mL). Add m-chloroperoxybenzoic acid (302.25 mg, 1.49 mmol, 85% purity) to the reaction solution at 0°C and in air. Stir the reaction solution at 0°C for 4 hours. After the reaction is complete, quench the reaction with saturated sodium thiosulfate aqueous solution (20 mL) and sodium bicarbonate aqueous solution (20 mL) at 0°C. Extract with dichloromethane (40 mL × 3). Dry and concentrate the organic phase to obtain the crude product. Perform column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the target product 1d (180 mg, yield 85.04%). ESI-MS (m / z): 312.9 [M+H] + .

[0289] Step 3: Dissolve INT-1 (42.25 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL). Under nitrogen protection and at 0°C, add sodium hydroxide (9.59 mg, 0.24 mmol, 60% purity) to the reaction solution. Stir the reaction solution at 0°C for 0.5 hours. Then, add 1d (50.00 mg, 0.16 mmol) to the reaction solution at 0°C. Stir the reaction solution at room temperature for 12 hours. After the reaction is complete, quench the reaction with saturated ammonium chloride aqueous solution (30 mL), extract with ethyl acetate (30 mL × 3), and dry and concentrate the organic phase to obtain the crude product. The crude product is subjected to reversed-phase column chromatography to obtain target product 1 (30.00 mg, yield 44.17%). ESI-MS (m / z): 424.8 [M+H] + .

[0290] 1 HNMR(500MHz,DMSO-d6)δ9.67(s,1H),8.48(s,1H),8.15(s,1H),7.70(d,J=10.0Hz,2H),7.30(d,J=10.0Hz,2H),4.19(s,2H ),4.14(t,J=6.1Hz,2H),3.98–3.95(m,2H),3.72–3.68(m,2H),3.09(t,J=6.4Hz,2H),2.02–1.98(m,2H),1.83-1.80(m,2H).

[0291] Example 2

[0292] 4-(4-((5-chloro-4-(6-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0293]

[0294] Example 2 was prepared by the following steps:

[0295]

[0296] Step 1: Compounds 2a (300 mg, 1.52 mmol) and 2b (5.18 g, 1.68 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (0.5 mL). Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (111 mg, 152 μmol) and sodium carbonate (1.49 g, 4.57 mmol) were added sequentially. The reaction mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 2c (435 mg, 95% yield). ESI-MS (m / z): 300.2 [M+H] + .

[0297] Step 2: Compound 2c (435 mg, 1.45 mmol) was dissolved in methanol (5 mL), followed by the addition of platinum dioxide (77 mg, 726 μmol). The reaction mixture was stirred at room temperature for 48 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 2d (435 mg, yield 98%). ESI-MS (m / z): 302.2 [M+H] + .

[0298] Step 3: Compound 2d (370 mg, 1.23 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-bromosuccinimide (229 mg, 1.29 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 2e (402 mg, yield 86%). ESI-MS (m / z): 381.9 [M+H] + .

[0299] Step 4: Compound 2e (260 mg, 683 μmol) and pinacol diborate (520 mg, 2.05 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL), followed by the sequential addition of palladium acetate (8 mg, 35 μmol), potassium carbonate (284 mg, 2.05 mmol), and tricyclohexylphosphine (20 mg, 69 μmol). The reaction mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to give compound 2f (438 mg, yield 81%). ESI-MS (m / z): 428.2 [M+H] + .

[0300] Step 5: Compound 2f (62 mg, 145 μmol) and 2,4,5-trichloropyrimidine (40 mg, 217 μmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (0.2 mL). Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (11 mg, 16 μmol) and sodium carbonate (47 mg, 435 μmol) were added sequentially. The reaction mixture was stirred at 90 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give 2 g (40 mg, yield 61%) of compound. ESI-MS (m / z): 450.0 [M+H] + .

[0301] Step 6: 2 g (40 mg, 89 μmol) of compound and INT-1a (30 mg, 151 μmol) were dissolved in 1,4-dioxane (5 mL). Tris(dibenzylacetone)dipalladium (8 mg, 9 μmol), potassium phosphate (56 mg, 267 μmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (11 mg, 18 μmol) were added sequentially. The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, filtered through diatomaceous earth, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 99) to give compound 2h (45 mg, yield 83%). ESI-MS (m / z): 603.9 [M+H] + .

[0302] Step 7: Compound 2h (45 mg, 75 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was added at room temperature. The reaction mixture was stirred for another 2 hours at room temperature. After the reaction was complete, triethylamine (0.3 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative chromatography to give compound 2 (8 mg, yield 14%). ESI-MS (m / z): 504.3 [M+H] + .

[0303] 1 H NMR(500MHz,DMSO-d6)δ9.79(s,1H),8.93(s,1H),8.67(s,1H),8.50(s,1H),7 .76–7.71(m,2H),7.51(dd,J=9.3,1.6Hz,1H),7.37–7.31(m,2H),4.21(s,2H), 3.98(dd,J=6.0,4.1Hz,2H),3.73(dd,J=5.9,4.2Hz,2H),3.08–3.02(m,2H),2. 77–2.70(m,1H),2.64–2.58(m,2H),1.79(d,J=12.3Hz,2H),1.63–1.55(m,2H).

[0304] Example 3

[0305] 4-(4-((4-(6-(aminomethyl)pyrazolo[1,5-a]pyridin-3-yl)-5-chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0306]

[0307] Example 3 was prepared by the following steps:

[0308]

[0309] Step 1: Compound 3a (1.0 g, 5.08 mmol) and compound 3b (1.8 g, 7.61 mmol) were dissolved in a mixed solvent of tert-butanol (10 mL) and water (1 mL). Palladium acetate (114 mg, 508 μmol), n-butyldi(1-adamantyl)phosphine (182 mg, 508 μmol), tetraethylammonium tetrafluoroborate (275 mg, 1.27 mmol), and cesium carbonate (3.3 g, 10.15 mmol) were then added. The reaction mixture was stirred at 110 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, it was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 3c (974 mg, yield 78%). ESI-MS (m / z): 248.4 [M+H] + .

[0310] Step 2: Compound 3c (174 mg, 704 μmol) was dissolved in N,N-dimethylformamide (3 mL), and N-bromosuccinimide (188 mg, 1.06 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 3d (220 mg, 95% yield). ESI-MS (m / z): 326.2 [M+H] + .

[0311] Step 3: Compound 3d (144 mg, 441 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and isopropanol pinacol borate (164 mg, 883 μmol) was added. The reaction mixture was stirred at -78 °C for 10 minutes under a nitrogen atmosphere. Then, n-butyllithium (265 μL, 2.5 mol / L hexanes) was slowly added dropwise to the reaction mixture, and the reaction mixture was stirred at -78 °C for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction, and the mixture was slowly brought to room temperature. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 3e (130 mg, 79% yield). ESI-MS (m / z): 374.1 [M+H] + .

[0312] Step 4: Dissolve compound 3e (130 mg, 348 μmol) and 2,4,5-trichloropyrimidine (96 mg, 523 μmol) in a mixed solvent of 1,4-dioxane (3 mL) and water (0.3 mL), then add sequentially

[0313] [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (25 mg, 35 μmol) and sodium carbonate (110 mg, 1.04 mmol) were reacted and stirred at 90 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give compound 3f (37 mg, 27% yield). ESI-MS (m / z): 394.2 [M+H] + .

[0314] Step 5: Compound 3f (30 mg, 76 μmol) and 4-(4-aminophenyl)morpholino-3-one (19 mg, 99 μmol) were dissolved in 1,4-dioxane (3 mL). Tris(dibenzylacetone)dipalladium (7 mg, 8 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (9 mg, 15 μmol), and potassium phosphate (33 mg, 152 μmol) were added sequentially. The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 3 g (8 mg, yield 19%) of compound. ESI-MS (m / z): 550.1 [M+H] + .

[0315] Step 6: Dissolve 3 g (8 mg, 15 μmol) of compound in dichloromethane (1 mL), and add trifluoroacetic acid (9 mg, 73 μmol). Stir the reaction mixture at 0 °C for 2 hours. After the reaction is complete, quench the reaction mixture with saturated sodium bicarbonate aqueous solution (10 mL), extract with dichloromethane (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by preparative chromatography to give compound 3 (3 mg, yield 46%) as a white solid. ESI-MS (m / z): 450.4 [M+H] + .

[0316] 1 H NMR(500MHz,DMSO-d6)δ9.84–9.77(m,1H),8.96(s,1H),8.81(s,1H),8.73–8.66(m,1H),8.52(s,1H),7.78–7.71(m,2H ),7.57(d,J=9.2Hz,1H),7.33(d,J=8.5Hz,2H),4.21(s,2H),3.98(t,J=5.0Hz,2H),3.89(s,2H),3.73(t,J=5.0Hz,2H).

[0317] Example 4

[0318] 4-(4-((4-(6-(aminomethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-chloropyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0319]

[0320] Example 4 was prepared by the following steps:

[0321]

[0322] Step 1: Compound 3c (500 mg, 2.02 mmol) was dissolved in methanol (10 mL), followed by the addition of a dioxane solution of hydrochloric acid (1.5 mL, 4 mol / L) and platinum dioxide (230 mg, 1.01 mmol). The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain crude compound 4a (305 mg, 99% yield). ESI-MS (m / z): 152.4 [M+H] + .

[0323] Step 2: Compound 4a (300 mg, 1.98 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of di-tert-butyl dicarbonate (650 mg, 2.98 mmol) and N,N-diisopropylethylamine (1.28 g, 9.92 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction. The mixture was slowly brought to room temperature and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a colorless oily compound 4b (397 mg, 80% yield). ESI-MS (m / z): 252.3 [M+H] + .

[0324] Step 3: Compound 4b (347 mg, 1.38 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N-bromosuccinimide (368 mg, 2.07 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / dichloromethane = 1 / 1) to obtain crude compound 4c (200 mg, yield 44%). ESI-MS (m / z): 330.2 [M+H] + .

[0325] Step 4: Compound 4c (150 mg, 454 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and isopropanol pinacol borate (169 mg, 908 μmol) was added. The reaction mixture was stirred at -78 °C for 10 minutes, followed by slow dropwise addition of n-butyllithium (454 μL, 2.5 mol / L hexanes). The reaction mixture was then stirred at -78 °C for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction, and the mixture was slowly brought to room temperature. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) to give compound 4d (90 mg, 53% yield). ESI-MS (m / z): 378.5 [M+H] + .

[0326] Step 5: Dissolve compound 4d (90 mg, 239 μmol) and 2,4,5-trichloropyrimidine (57 mg, 310 μmol) in a mixed solvent of 1,4-dioxane (3 mL) and water (0.3 mL), then add sequentially

[0327] [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (18 mg, 24 μmol) and sodium carbonate (51 mg, 477 μmol) were reacted and stirred at 90 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 4e (36 mg, yield 38%). ESI-MS (m / z): 398.4 [M+H] + .

[0328] Step 6: Compound 4e (22 mg, 55 μmol) and 4-(4-aminophenyl)morpholino-3-one (14 mg, 72 μmol) were dissolved in 1,4-dioxane (3 mL). Tris(dibenzylacetone)dipalladium (5 mg, 6 μmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (6 mg, 11 μmol), and potassium phosphate (24 mg, 110 μmol) were added sequentially. The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was purified by preparative thin-layer chromatography (ethyl acetate) to give compound 4f (15 mg, yield 49%). ESI-MS (m / z): 554.0 [M+H] + .

[0329] Step 7: Compound 4f (8 mg, 15 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (9 mg, 73 μmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative chromatography to give compound 4 (3 mg, 45% yield) as a white solid. ESI-MS (m / z): 453.9 [M+H] + .

[0330] 1 H NMR(500MHz,DMSO-d6)δ9.70–9.65(m,1H),8.51–8.45(m,1H),8.17(s,1H), 7.73–7.67(m,2H),7.33–7.27(m,2H),4.36–4.26(m,1H),4.19(s,2H),4.00 –3.95(m,2H),3.84–3.76(m,1H),3.70(t,J=5.1Hz,2H),3.12–2.91(m,3H), 2.76–2.68(m,1H),2.25–2.07(m,2H),2.04–1.88(m,2H),1.53–1.45(m,1H).

[0331] Example 5

[0332] 4-(4-((5-chloro-4-(6-(pyrrolidin-3-yl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one

[0333]

[0334] Example 5 was prepared by the following steps:

[0335]

[0336] Step 1: Compound 2a (500 mg, 2.54 mmol), 5a (973.79 mg, 3.30 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (185.68 mg, 253.77 μmol), and potassium carbonate (1.05 g, 7.61 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 5b (650 mg, yield 89%). ESI-MS (m / z): 286.2 [M+H] + .

[0337] Step 2: Compound 5b (650 mg, 2.28 mmol) was dissolved in methanol (10 mL), and palladium on carbon (65 mg, 10% purity) was added. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 5c (600 mg, 91% yield). ESI-MS (m / z): 288.3 [M+H] + .

[0338] Step 3: Compound 5c (600 mg, 2.09 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-bromosuccinimide (557.43 mg, 3.13 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 5d (600 mg, yield 78%). ESI-MS (m / z): 366.3 [M+H] + .

[0339] Step 4: Dissolve 5d (300 mg, 0.82 mmol) in anhydrous tetrahydrofuran (5 mL), cool to -78 °C, and slowly add n-butyllithium (0.39 mL, 0.98 mmol, 2.5 mol / L, n-heptane) dropwise under a nitrogen atmosphere. After half an hour, add tributyltin chloride (399.94 mg, 1.23 mmol) dropwise, and continue stirring at -78 °C for 2 hours. After the reaction is complete, quench the reaction with saturated sodium chloride aqueous solution (10 mL), slowly raise the temperature to room temperature, extract the reaction solution with ethyl acetate (50 mL × 3), combine the phases, dry through anhydrous sodium sulfate, filter and concentrate to obtain compound 5e (300 mg, yield 63%). ESI-MS (m / z): 578.2 [M+H] + .

[0340] Step 5: Dissolve 5e (300 mg, 0.52 mmol), 1a (121.83 mg, 0.62 mmol), and tetraphenylphosphine palladium (60.14 mg, 52.1 μmol) in 1,4-dioxane (5 mL). Stir the reaction mixture at 90 °C for 16 hours under a nitrogen atmosphere. After the reaction is complete, cool the reaction mixture to room temperature, dilute with ethyl acetate (50 mL), filter and concentrate to obtain the crude product. Perform column chromatography (petroleum ether / ethyl acetate = 2 / 1) on the crude product to obtain the target compound 5f (140 mg, 60% yield). ESI-MS (m / z): 445.8 [M+H] + .

[0341] Step 6: Dissolve 5f (140mg, 0.31mmol) in dichloromethane (2mL), cool to 0°C, add m-chloroperoxybenzoic acid (135.44mg, 0.78mmol) to the above reaction solution, slowly raise the reaction solution to room temperature, and stir at room temperature for 4 hours. After the reaction is complete, quench the reaction with saturated sodium bicarbonate aqueous solution (10mL). Extract the quenched reaction solution with dichloromethane (30mL×3), combine the phases, dry with anhydrous sodium sulfate, concentrate and evaporate to dryness to obtain 5g (130mg, yield 86%) of the target product. ESI-MS (m / z): 477.8 [M+H] + .

[0342] Step 7: Dissolve INT-1 (83.86 mg, 380.78 μmol) in anhydrous N,N-dimethylformamide (1 mL), cool to 0 °C, and add sodium hydroxide (16.32 mg, 407.98 μmol, 60% purity) to the above reaction solution under a nitrogen atmosphere. React at 0 °C for half an hour. Add 5 g (130 mg, 271.99 μmol) to anhydrous N,N-dimethylformamide (1 mL) to the above reaction solution. Maintain a nitrogen atmosphere and stir at room temperature for 12 hours. After the reaction is complete, quench the reaction with saturated ammonium chloride aqueous solution (10 mL), then extract with ethyl acetate (10 mL × 3). Combine the organic phases, wash with saturated brine (10 mL × 3), dry and concentrate to give compound 5h (100 mg, yield 62%). ESI-MS (m / z): 590.1 [M+H] + .

[0343] Step 8: Compound 5h (100 mg, 169.47 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added at room temperature. The reaction mixture was stirred for 3 hours at room temperature. After the reaction was complete, triethylamine (2 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative chromatography to give compound 5 formate (14.61 mg, yield 16%). ESI-MS (m / z): 490.1 [M+H] + .

[0344] 1 H NMR(500MHz,DMSO-d6)δ9.80(s,1H),8.95(s,1H),8.90–8.76(m,1H),8.72–8.6 3(m,1H),8.52(s,1H),8.31(s,1H),7.78–7.70(m,2H),7.65–7.52(m,1H),7.44– 7.29(m,2H),4.21(s,2H),4.04–3.96(m,2H),3.76–3.71(m,2H),3.55–3.50(m,2 H),3.37–3.29(m,2H),3.18–3.11(m,1H),2.40–2.24(m,1H),2.17–1.92(m,1H).

[0345] CDK2 / Cyclin E1 kinase activity inhibition assay

[0346] The purpose of this experiment was to evaluate the inhibitory effect (% inhibition and IC50) of small molecule compounds on CDK2 / Cyclin E1 kinase activity. 50First, the enzyme, ATP, substrate, and compound were diluted to the required concentrations using kinase buffer. The kinase buffer consisted of 40 mM Tris-HCl, pH 7.5; 20 mM MgCl2; 0.01% Triton X-100; and 1 mM MTT. The experiment was performed in 384-well plates. First, 2 μL of CDK2 / Cyclin E1 and 1 μL of the test compound (generally, the initial concentration of the compound is 10 μM, diluted 3-fold to create 9 concentration gradients) were added to each well. After centrifugation, the plates were incubated at room temperature for 10 minutes. Then, 2 μL of a mixture of Histone H1 and ATP was added, and after centrifugation, the plates were incubated at room temperature in the dark for 60 minutes. Finally, 5 μL of ADP-Glo ​​was added. TM The reaction was terminated by incubating the reagent (Promega, V9102) at room temperature for 120 minutes to consume all remaining ATP. Then, 10 μL of Kinase Detection Reagent (Promega, V9102) was added, and the mixture was incubated at room temperature for 30 minutes to convert ADP to ATP. The ATP was then measured using a multi-functional microplate reader. The i3x (Molecular Devices) read the fluorescence signal values, which were then standardized. A four-parameter regression equation was used to fit the curve, and the half-maximal inhibitory concentration (IC50) of the compound on the kinase activity was calculated. 50 ).

[0347] Time-resolved fluorescence resonance energy transfer (TR-FRET) detection of kinase inhibitory activity of compounds

[0348] This experiment utilizes time-resolved fluorescence resonance energy transfer (TR-FRET) technology to directly detect the phosphorylation of substrates in kinase reactions. By recognizing specific phosphorylation sites with antibodies, it achieves high specificity and significantly reduces background noise, resulting in good sensitivity and signal window. First, the kinase, analyte, and substrate are diluted to the required concentrations using kinase buffer. The kinase buffer composition is 200 mM Tris-HCl, pH 7.5; 100 mM MgCl2; 0.05% Triton X-100; and 5 mM DTT. First, add 1.5 μL of the 4X test compound to a 384-well plate (generally, the initial concentration of the compound is 10 μM, diluted 3-fold to create 9 concentration gradients), then add 2.5 μL of the 2X test kinase (e.g., 1 ng / μL LCDK4 / Cyclin D1), seal the plate with TopSeal-A, and incubate at room temperature for 15 minutes; then add 1.25 μL of the 4X reaction substrate (ULight-eIF4E-binding protein 1Thr37 / 46) and 200 μM ATP; seal the plate with TopSeal-A, and incubate at room temperature for 60 minutes. After incubation, transfer the sample to a multi-mode microplate reader (…). In the TR-FRET mode of i3x (Molecular devices), excitation with 320nm or 340nm excitation light was used, and the signal value at 665nm was detected. The signal value was then standardized, and a four-parameter regression equation was used for curve fitting to calculate the half-maximal inhibitory concentration (IC50) of the compound on kinase activity. 50 ).

[0349] The inhibitory activities of the compounds of this invention against CDK2, CDK4, and CDK6 are shown in Table 3.

[0350] Table 3

[0351]

[0352] *NT indicates that no detection was performed.

Claims

1. The compound represented by Formula I, or its preisotope derivative or stereoisomer, or its pharmaceutically acceptable salt: in: R 1 It represents D, halogen, CN, C1-C3 alkyl, halo-C1-C3 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy or 3-6 membered heterocyclic alkyl; Ar 1 Indicates a 5-membered heteroaryl group; Cy 1 It represents a 4-8 membered heterocyclic alkyl group, a 4-8 membered heterocyclic alkenyl group, or a 5-8 membered heteroaryl group; X 1 and X 2 It is Ar 1 and Cy 1 Shared bridgehead atom, X 1 and X 2 Each can be represented independently as C or N, X 1 and X 2 The covalent bonds between them can be single or double bonds; R 2 Each can be independently represented by H, D, halogen, CN, and OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl may optionally be represented by 0, 1, 2, 3, or 4 R groups. 22 replace; R 3 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, phenyl, or 5-6 heteroaryl may optionally be represented by 0, 1, 2, 3, or 4 R groups. 23 replace; Two R connected on the same C 3 Or two R atoms connected on different atoms 3 It can form 3-8 membered rings with the atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace; Y 1 and Y 2 Each represents CR independently. 4 Or N; R 4 Each of these elements independently represents H, D, halogen, CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy may optionally be represented by 0, 1, 2, 3, or 4 Rs. 24 Substitution; V represents C(O), S(O), S(O)2 or S(O)(NR) 6 ); W represents CR independently. 5 R 5 '、C(O),NR 6 ,O,S,S(O),S(O)2 or S(O)(NR 6 ); R 5 R 5 Each can be represented independently as H, D, halogen, CN, OR a SR a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 25 replace; R connected on the same C 5 R 5 It can also form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace; R attached to different C atoms 5 With R 5 It can form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace; R 6 Each of H, D, and -S(O)2R can be represented independently. a -S(O)R a -C(O)R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 26 replace; R 5 With R 6 It can form 3-8 membered rings together with the ring atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace; R 22 R 23 R 24 R 25 R 26 R 30 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 22 Two R atoms on the same atom or different atoms 23 Two R atoms on the same atom or different atoms 24 Two R atoms on the same atom or different atoms 25 Two R atoms on the same atom or different atoms 26 Or R 25 With R 26 It can form a 3-6 membered ring with the C atom and / or N atom it is connected to, and the ring may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; R a and R a Each can independently represent H, D, C1-C3 alkyl, or C3-C6 cycloalkyl; m represents 0, 1, or 2; n represents 0, 1, 2, 3, or 4; o can be 2, 3, 4, 5 or 6.

2. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Ar 1 The groups represented are pyrazolyl, imidazolyl, thiophene, furanyl, pyrroleyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl; preferably, Ar. 1 It represents the pyrazol group.

3. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, V represents C(O) or S(O)2; preferably, V represents C(O).

4. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Y 1 and Y 2 Each represents CR independently. 4 .

5. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, m represents 0 or 1.

6. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, having a structure as shown in Formula II: in: R 1 It represents D, halogen, CN, C1-C3 alkyl, halo-C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C2 alkoxy; Cy 1 It represents a 4-8 membered heterocyclic alkyl group, a 4-8 membered heterocyclic alkenyl group, or a 5-8 membered heteroaryl group; R 2 Each can be independently represented by H, D, halogen, CN, and OR. a NR a R a ', C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl may optionally be 0, 1, 2 or 3 R 22 replace; R 3 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3 or 4 R 23 Replacement; two R connected on the same C 3 Or two R atoms attached to different C atoms 3 It can form 3-8 membered rings with the atoms it is attached to, wherein the rings may optionally contain 0, 1, or 2 heteroatoms selected from N, O, or S, and the rings may be further divided by 0, 1, or 2 R atoms. 30 replace; R 4 Each of these elements independently represents H, D, halogen, CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy may optionally be represented by 0, 1, 2, 3, or 4 Rs. 24 Replacement; W represents CR independently. 5 R 5 '、C(O),NR 6 O or S(O)2; R 5 R 5 Each can be represented independently as H, D, halogen, CN, OR a SR a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 25 replace; R connected on the same C 5 R 5 It can also form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace; R attached to different C atoms 5 With R 5 It can form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace; R 6 Each of H, D, and -S(O)2R can be represented independently. a -S(O)R a -C(O)R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3, or 4 R 26 replace; R 5 With R 6 It can form 3-8 membered rings together with the ring atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace; R 22 R 23 R 24 R 25 R 26 R 30 Each can be independently represented as D, oxo, halogen, CN, OR a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substitution; two Rs on the same atom or different atoms 22 Two R atoms on the same atom or different atoms 23 Two R atoms on the same atom or different atoms 24 Two R atoms on the same atom or different atoms 25 Two R atoms on the same atom or different atoms 26 Or R 25 With R 26 It can form a 3-6 membered ring with the C atom and / or N atom it is connected to, and the ring may further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; R a and R a Each can independently represent H, D, C1-C3 alkyl, or C3-C6 cycloalkyl; n represents 0, 1, 2, 3, or 4; o can be 2, 3, 4, 5 or 6.

7. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 1 This represents D, halogen, CN, C1-C2 alkyl, fluorinated C1-C2 alkyl; preferably, R 1 It represents F, Cl, CN, methyl, and trifluoromethyl.

8. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Cy 1 It indicates a 4-8 membered heterocyclic alkyl group or a 5-8 membered heteroaryl group.

9. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 2 Each can be independently represented by H, D, halogen, CN, and OR. a NR a R a ', C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl, wherein the C1-C3 alkyl, C3-C6 cycloalkyl, 4-8 heterocyclic alkyl may optionally be 0, 1, 2 or 3 R 22 Replacement; preferred, R 2 Each can be independently represented by H, D, halogen, CN, C1-C3 alkyl, or C1-C3 haloalkyl.

10. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 3 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, 3 or 4 R 23 Replacement; two R connected on the same C 3 Or two R atoms connected on different atoms 3 It can form 3-8 membered rings with the atoms it is attached to, wherein the ring may optionally contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S, and the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 replace.

11. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Two R connected on the same C 3 Or two R atoms connected on different atoms 3 It can form 3-8 membered rings with the atoms it is attached to, wherein the rings may optionally contain 0, 1, or 2 heteroatoms selected from N, O, or S, and the rings may be further divided by 0, 1, or 2 R atoms. 30 replace.

12. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 4 It represents H, D, halogen, CN, C1-C6 alkyl, or R. 4 Represents H, D, halogen, CN, methyl, methoxy, hydroxymethyl, or methoxymethyl; preferably, R 4 It represents H, D, halogen, CN, and methyl.

13. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, W represents CR independently. 5 R 5 '、C(O),NR 6 O or S(O)2; preferably, W independently represents CR. 5 R 5 '、NR 6 、O.

14. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 5 R 5 Each can be represented independently as H, halogen, CN, OR a SR a NR a R a ', C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, or 3 R's. 25 Replace; R connected on the same C 5 R 5 It can also form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 Substitution; R bonded to different C atoms 5 With R 5 It can form a 3-8 membered ring with the C atom it is attached to, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S, the ring may further include 0, 1, 2, or 3 unsaturated bonds, and the ring may further be bounded by 0, 1, 2, 3, or 4 R atoms. 30 Replacement; preferred, R 25 Each can be used independently to represent either halogen or methyl.

15. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R connected on the same C 5 R 5 It can form C3-C6 aliphatic rings or 4-8-membered heterocycles with the C atoms it is attached to, wherein the C3-C6 aliphatic rings or 4-8-membered heterocycles can be formed by 0, 1, 2 or 3 R atoms. 30 Replacement; preferred, R 30 Each can be used independently to represent either halogen or methyl.

16. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 6 Each can be represented independently as H, -S(O)2R a -C(O)R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic alkyl may optionally be 0, 1, 2, or 3 R 26 Replacement; preferred, R 26 Each can independently represent either a halogen or a methyl group; more preferably, R 6 Each can be independently represented by H or C1-C6 alkyl.

17. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R connected to different atoms 5 With R 5 '、or R 5 With R 6 It can form C3-C6 aliphatic rings or 4-8-membered heterocycles together with atoms on the ring, wherein the C3-C6 aliphatic rings or 4-8-membered heterocycles can be formed by 0, 1, 2 or 3 R atoms. 30 replace.

18. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R connected to different atoms 5 With R 5 '、or R 5 With R 6 It can form 3-8 membered rings together with atoms on the ring, the rings including unsaturated bonds, preferably 5-6 membered heteroaromatic rings, the 5-6 membered heteroaromatic rings being 0, 1, 2 or 3 R atoms. 30 replace.

19. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 22 R 23 R 24 R 25 R 26 R 30 Each can be independently represented by H, D, oxo, halogen, CN, OR. a NR a R a '、N(R a COR a '、CON(R a )R a '、COR a -S(O)2R a C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be selected from 0, 1, 2, 3, or 4 halogens, OR a NR a R a ', C1-C2 alkyl or halo-C1-C2 alkyl substituted; preferably, R 22 R 23 R 24 R 25 R 26 R 30 Each can be independently represented by H, oxo, halogen, CN, OR. a NR a R a ', C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-8 heterocyclic alkyl may optionally be substituted by 0, 1, 2, or 3 substituted from halogens, OH, or C1-C2 alkyl; more preferably, R 22 R 23 R 24 R 25 R 26 R 30 Each is independently selected from H, oxo, F, Cl, CN, OR a NR a R a '.

20. The compound as claimed in any of the preceding claims, or a preisotope derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R a and R a Each can be independently represented by H, D, or C1-C3 alkyl.

21. Compounds, preisotope derivatives, stereoisomers, or pharmaceutically acceptable salts of the following structures:

22. A pharmaceutical composition comprising the compound of any of the preceding claims or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof.

23. Use of the compound of any one of claims 1-21, or a pharmaceutically acceptable salt, isotope derivative, stereoisomer thereof, or the pharmaceutical composition of claim 22, in the preparation of a medicament for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

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