CN108191857B

CN108191857B - 6-substituted pyrido [2,3-D ] pyrimidines as protein kinase inhibitors

Info

Publication number: CN108191857B
Application number: CN201810053736.3A
Authority: CN
Inventors: 徐亮; 蒋昌盛; 何皓; 程航
Original assignee: Shengke Pharmaceutical Jiangsu Co ltd
Current assignee: Shengke Pharmaceutical (Jiangsu) Co., Ltd.
Priority date: 2017-01-24
Filing date: 2018-01-19
Publication date: 2020-10-23
Anticipated expiration: 2038-01-19
Also published as: HK1257799A1; CN108191857A

Abstract

The present invention provides 6-substituted pyrido [2,3-d ] of the general formula (I)]Pyrimidines which are useful in the treatment of cell proliferative disorders. The novel compounds of the present invention are potent inhibitors of cyclin-dependent kinases 4 and 6(CDK 4/6).

Description

6-substituted pyrido [2,3-D ] pyrimidines as protein kinase inhibitors

Technical Field

The invention provides a 6-substituted pyrido [2,3-d ] pyrimidine compound as a cyclin dependent kinase inhibitor, in particular cyclin dependent kinases 4 and 6. The compounds of the invention are useful for the treatment of cancer, inflammation, and also for the treatment of neurodegenerative diseases such as parkinson's syndrome.

Background

Cancer is the second leading disease of death worldwide, and global cancer report 2014 issued by the world health organization states that global cancer patients and death cases are all increasing disturbingly, and nearly half of newly added cancer cases appear in asia, most of which are in china. It is also reported that global cancer cases are predicted to present a rapidly growing situation, increasing from 1400 million people in 2012 to 1900 million people in 2025 year by year to 2400 million people in 2035 year, where china will account for 21.9% of the global population. Organic structural data show that the cancer mortality rate of China is increased by 80 percent in the last 30 years, the number of cancer diseases is about 260 thousands every year, and the number of deaths is about 180 thousands.

The cell cycle is an important part of the vital activity of a cell. Research shows that the occurrence and development of various malignant tumors are closely related to disorder of cell cycle regulatory mechanism, so that the tumors are also considered as a cell cycle disease. Three scientists in the united states and the united kingdom discovered, after the 70's of the 20 th century, the important roles of cyclin-dependent kinases (CDKs) and cyclins in cell regulation. Thus, the 2001 nobel physiological/medical prize was won. With the progress of cell cycle regulation mechanism research, especially the core role of CDK in cell cycle regulation, cyclin dependent kinase has become the hot spot for current anticancer drugs in recent years.

Cyclin-dependent kinases are a class of serine (Ser)/threonine (Thr) kinases. As important signal transduction molecules within the cell, and the CDK-cyclin complex formed by cyclins, are involved in the growth, reproduction, dormancy or apoptosis of cells (Morgan d.o., annu. rev. cell. dev.biol.1997; 13261-. Unlike other kinases, CDKs must form a corresponding dimeric complex with cyclins in order to function. Cyclins are continuously expressed and degraded periodically and are respectively combined with CDKs which are activated by the cyclins instantaneously, and the phosphorylation of different substrates is catalyzed through the activity of the CDKs, so that the promotion and conversion effects on different phases of the cell cycle are realized. In addition, CDKs may bind to CDK inhibitors, blocking cell division. In humans, 13 CDK members (CDK 1-13) have been identified, corresponding to which 12 cyclins (A-L) are present. It is currently believed that CDK1, 2,4, 6 and 7 are primarily responsible for regulation in the cell cycle.

It has been shown that increased activity or transient abnormalities in activation of cyclin-dependent kinases lead to the formation of human tumors (Sherr C.J., Science 1996; 274: 1672-. Indeed, the formation of human tumors is commonly associated with alterations in the CDK protein itself or its regulators (Cordon-Cardo C., am. J. Pathol. 1995; 147, 545. 560; Karp J. E. and Broder S., nat. Med. 1995; 1: 309. 320; Hall. M. et al., adv. cancer Res. 1996; 68: 67-108). Protein inhibitors of naturally occurring CDKs such as p16 and p27 result in growth inhibition of lung cancer cell lines in vitro (Kamb A., Curr. Top. Microbiol. Immunol. 1998; 227: 139-148). Small molecule CDK inhibitors may also be useful in the treatment of cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders caused by abnormal cell proliferation. Vascular smooth muscle proliferation and intimal hyperplasia secondary to balloon angioplasty are inhibited by overexpression of the cyclin-dependent kinase inhibitor p21 protein (Chang M.W.et al, J.Clin.Invest., 1995; 96: 2260; Yang Z-Y.et al, Proc.Natl.Acad.Sci.1996; 93: 9905). Furthermore, CVT-313(Ki ═ 95nM), a purine CDK2 inhibitor, resulted in greater than 80% inhibition of neointimal formation in rats (Brooks e.e.et al, j.biol.chem.1997: 29207-. CDK inhibitors can be used to treat diseases caused by a variety of infectious agents, including fungi, protozoan parasites (e.g., plasmodium falciparum), and DNA and RNA viruses. For example, cyclin-dependent kinases are essential for viral replication secondary to Herpes Simplex Virus (HSV) infection (Schang L.M.et al, J.Virol.1998; 72:5626), a homologue of CDKs known to play a key role in yeast. Selective CDK inhibitors can be used to ameliorate the consequences of various autoimmune disorders. Chronic inflammatory disease rheumatoid arthritis is characterized by synovial tissue hyperplasia; inhibition of synovial tissue proliferation minimizes inflammation and prevents joint destruction. Expression of the CDK inhibitor p16 protein in synovial fibroblasts causes growth inhibition (Taniguchi K.et al, nat. Med.1999; 5: 760-767). Similarly, joint swelling was substantially inhibited by treatment with p 16-expressing adenovirus in a rat model of arthritis. CDK inhibitors may be effective against other cell proliferative disorders including psoriasis (characterized by keratinocyte hyperproliferation), glomerulonephritis and lupus. Certain CDK inhibitors may be used as chemoprotectants by their ability to inhibit cell cycle progression in normal untransformed cells (Chen et al, j. nat. cancer institute, 2000; 92: 1999-2008). Pretreatment of cancer patients with CDK inhibitors prior to the use of cytotoxic agents can reduce the side effects commonly associated with chemotherapy. Normally proliferating tissues are protected from cytotoxic effects by the action of selective CDK inhibitors. Review articles on small molecule inhibitors of cyclin-dependent kinases have noted the difficulty of identifying compounds that inhibit specific CDK proteins without inhibiting other enzymes.

A selective targeted therapeutic against CDK4 and/or CDK6 may play a role in (1) CDK4 gene amplification or high expression of proteins, such changes often occurring in well-differentiated and de-differentiated liposarcomas, and also in some other solid and hematologic malignancies; (2) the expansion or high expression of cyclin Dl, which is observed in mantle cell lymphomas, as well as in a variety of solid tumors; (3) loss of the p16INK4A gene (CDKN2A), also a common event in many cancers. In cells, the p16INK4A protein is a natural inhibitor of CDK4, and cancers with p16 loss are generally sensitive to inhibition by CDK 4. In ovarian cancer, for example, these cancer cell lines have low p16 protein levels and high Rb expression and would be sensitive to inhibitors of CDK 4. Because of the high similarity of the proteins of CDK6 and CDK4, current CDK4 inhibitors also have similar inhibitory effects on CDK6 protein kinases. Three CDK4/CDK6 inhibitors, Palbociclib (Palbociclib, PD0332991), LEE011 and LY2835219, which fail CDK4/6 to form a complex with cyclin D, effectively block the progression of the cell cycle from the G1 phase to the S phase, thereby achieving the purpose of inhibiting tumor cell proliferation, and exhibit antitumor activity in breast cancer, neuroblastoma, malignant rhabdomyoma, lymphoma, sarcoma and other tumors, either as a single agent or in combination with other targeted therapeutic drugs, have been clinically tested.

Disclosure of Invention

The present invention provides 6-substituted pyrido [2,3-d ] pyrimidines as inhibitors of cyclin dependent kinases, particularly cyclin dependent kinases 4 and 6(CDK 4/6). The compounds of the present invention are useful in the treatment of cell proliferative disorders such as restenosis, cancer and inflammation. The compounds of the invention further improve the pharmacokinetic properties, including metabolic stability and clearance, over existing drugs. Meanwhile, the compound has stronger activity in more specifically inhibiting cyclin-dependent kinase 4 or 6 and better selectivity for other kinases. In addition, the compounds of the present invention are readily synthesized and can be administered to a patient by a variety of methods.

In one aspect, the present invention provides a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof:

wherein:

A₁selected from the group consisting of CR₃Or N;

A₂selected from the group consisting of CR₃Or N;

A₃selected from the group consisting of CR₃Or N;

b is selected from C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl, wherein said C_3-7Cycloalkyl or 3-7 membered heterocyclyl is optionally substituted by oxo or thioxo;

z is selected from O or S;

R₁selected from H, halogen, -CN, -NO₂、-OR₅、-S-R₅、-NR₆R₇、-C(O)OR₅、-C(O)NR₆R₇、C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R₂selected from H, -C (O) OR₅、-C(O)NR₆R₇、C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl, wherein said C is_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl is optionally substituted with 1,2 or 3R_aSubstituted by groups;

R₃selected from H, halogen, -CN, -NO₂、-L-OR₅、-L-S-R₅、-L-NR₆R₇、-L-C(O)OR₅、-L-C(O)NR₆R₇、-L-S(O)_mR₅、-L-S(O)_mOR₅、-L-S(O)_mNR₆R₇、-O-C_1-6alkylene-R₄、C_1-6Alkyl radical, C_1-6Haloalkyl, -L-C_3-7Cycloalkyl, -L-3-11 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl, said groups optionally substituted with 1,2 or 3R₄Substituted by groups;

R₄selected from H, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Haloalkyl, -C_1-6alkylene-OH, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl;

R₅independently selected from H, C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-6Haloalkyl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl;

R₆and R₇Independently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl; or, R₆、R₇Together with the N atom, form a 3-7 membered heterocyclyl;

R₈independently selected from H, C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-6Haloalkyl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl;

R_aindependently selected from H, halogen, -CN, -NO₂、-OR₅、-S-R₅、-NR₆R₇、-C(O)OR₅、-C(O)NR₆R₇、C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R₃and R₅-R₈Optionally substituted by 1,2 or 3R_bIs substituted by radicals in which R_bIndependently selected from H, halogen, -NO₂Carbonyl, -L-CN, -L-OR₅、-L-S-R₅、-L-NR₆R₇、-L-C(O)R₅、-L-C(S)R₅、-L-C(O)OR₅、-L-C(S)OR₅、-L-C(O)-NR₆R₇、-L-C(S)-NR₆R₇、-L-O-C(O)R₅、-L-O-C(S)R₅、-L-N(R₆)-C(O)-R₅、-L-N(R₆)-C(S)-R₅、-L-S(O)_mR₅、-L-S(O)_mOR₅、-L-S(O)_mNR₆R₇、-L-N(R₆)-S(O)_m-R₅、-L-N(R₆)-S(O)_m-NR₆R₇、-L-N(R₆)-C(O)OR₅、-L-N(R₆)-C(S)OR₅、-L-O-C_1-6alkylene-OR₅、-L-C(O)-C_1-6alkylene-NR₆R₇、-L-N(R₆)-C(O)-NR₆R₇、-L-N(R₆)-C(S)-NR₆R₇、-L-O-C(O)-NR₆R₇、-L-O-C(S)-NR₆R₇、C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl; wherein said C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl optionally further substituted with one or more of the following groups:

-L-CN、-NO₂carbonyl, -L-OR₅、-L-S-R₅、-L-NR₆R₇、-L-C(O)R₅、-L-C(S)R₅、-L-C(O)OR₅、-L-C(S)OR₅、-L-C(O)-NR₆R₇、-L-C(S)-NR₆R₇、-L-O-C(O)R₅、-L-O-C(S)R₅、-L-N(R₆)-C(O)-R₅、-L-N(R₆)-C(S)-R₅、-L-S(O)_mR₅、-L-S(O)_mOR₅、-L-S(O)_mNR₆R₇、-L-N(R₆)-S(O)_m-R₅、-L-N(R₆)-S(O)_m-R₆R₇、-L-N(R₆)-C(O)OR₅、-L-N(R₆)-C(S)OR₅、-L-O-C_1-6alkylene-OR₅、-L-C(O)-C_1-6alkylene-NR₆R₇、-L-N(R₆)-C(O)-NR₆R₇、-L-N(R₆)-C(S)-NR₆R₇、-L-O-C(O)-NR₆R₇、-L-O-C(S)-NR₆R₇；

L is selected from the group consisting of a bond, -C_1-6Alkylene-, -C_2-6alkenylene-or-C_2-6Alkynylene-;

m represents 0, 1 or 2;

n represents 0, 1,2,3,4, 5 or 6.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.

In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient, which also contain an additional therapeutic agent.

In another aspect, the invention provides kits comprising a compound of the invention, and other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

In another aspect, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prevention of a CDK (particularly CDK4 and/or CDK6) mediated disorder.

In another aspect, the invention provides a method of treating and/or preventing a CDK (particularly CDK4 and/or CDK6) mediated disorder in a subject, comprising administering to said subject a compound of the invention or a composition of the invention.

In another aspect, the present invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of a CDK (particularly CDK4 and/or CDK6) mediated disorder.

In particular embodiments, the disease includes a cell proliferative disorder, including but not limited to cancer, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders, and other cell proliferative disorders. More specifically, the cancers include, but are not limited to, solid tumors and hematologic malignancies, such as breast cancer, neuroblastoma, malignant rhabdomyoma, well-differentiated and de-differentiated liposarcoma, glioma, lung cancer, colorectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, prostate tumor, sarcoma, ovarian cancer, cervical cancer, pancreatic cancer, melanoma, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, mesothelioma, lymphoma, leukemia, non-hodgkin's lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma, Acute Myeloid Leukemia (AML), multiple myeloma. Such as restenosis, atherosclerosis, vascular smooth muscle proliferation and intimal hyperplasia following balloon angioplasty, and other vascular disorders caused by abnormal cell proliferation. Such infectious diseases include fungal, protozoan parasites (e.g., plasmodium falciparum), and DNA and RNA viral infections, such as Herpes Simplex Virus (HSV) infections. Such as rheumatoid arthritis. Such other cell proliferative disorders include psoriasis (characterized by keratinocyte hyperproliferation), glomerulonephritis, lupus, and the like.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

Definition of

Chemical definition

The definitions of specific functional groups and chemical terms are described in more detail below.

When a range of values is recited, it is intended to include each value and every subrange within the range. E.g. "C_1-6Alkyl "includes C₁、C₂、C₃、C₄、C₅、C₆、C_1-6、C_1-5、C_1-4、C_1-3、C_1-2、C_2-6、C_2-5、C_2-4、C_2-3、C_3-6、C_3-5、C_3-4、C_4-6、C_4-5And C_5-6An alkyl group.

It is to be understood that any of the moieties defined below may be substituted with a number of substituents when described herein, and that the corresponding definitions are within their scope as set forth below, including such substituted moieties. Unless otherwise specified, the term "substituted" is as defined below.

“C_1-12Alkyl "means a straight or branched chain saturated monovalent alk (en) yl group containing 1 to 12 carbon atoms. In some embodiments, C_1-6Alkyl groups are preferred. In some embodiments, C_1-4Alkyl groups are particularly preferred. Typical C_1-12Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. The alkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C_2-8Alkenyl "represents a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-buten-1-yl, 2-vinylbutyl, 3-hexen-1-yl, and the like. In some embodiments, C_2-6Alkenyl groups are preferred. In some embodiments, C_2-4Alkenyl groups are particularly preferred. The term "C_2-8Alkenyl "includes cycloalkenyl and heteroalkenyl, wherein from 1 to 3 nitrogen atoms selected from O, S, N or substituted may be substituted for a carbon atom. The alkenyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C_2-8Alkynyl "refers to a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms with one or more unsaturated carbon-carbon double bonds, with at least one carbon-carbon triple bond. In some embodiments, C_2-6Alkynyl groups are preferred. In some embodiments, C_2-4Alkynyl groups are particularly preferred. Typical alkynyl groups include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and hexenyl. The alkynyl group may be substituted at any available point of attachment,for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“-C_1-6Alkylene-, -C_2-6alkenylene-or-C_2-6Alkynylene- "means" C "as defined above_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl "is a divalent radical.

“C_1-6Alkylene "means removal of C_1-6One hydrogen of the alkyl group forms a divalent alkylene group and may be a substituted or unsubstituted alkylene group. In some embodiments, C_1-4Alkylene groups are particularly preferred. Unsubstituted said alkylene groups include, but are not limited to: methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH₂-) butylene (-CH)₂CH₂CH₂CH₂-) pentylene (-CH)₂CH₂CH₂CH₂CH₂-) and hexylene (-CH₂CH₂CH₂CH₂CH₂CH₂-) and the like. Exemplary substituted said alkylene groups, for example, said alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH (CH)₃)-、-C(CH₃)₂-) substituted ethylene (-CH (CH)₃)CH₂-、-CH₂CH(CH₃)-、-C(CH₃)₂CH₂-、-CH₂C(CH₃)_2-) Substituted propylene (-CH (CH)₃)CH₂CH₂-、-CH₂CH(CH₃)CH₂-、-CH₂CH₂CH(CH₃)-、-C(CH₃)₂CH₂CH₂-、-CH₂C(CH₃)₂CH₂-、-CH₂CH₂C(CH₃)₂-) and the like.

“C_2-6Alkenylene "means the removal of C_2-6One hydrogen of an alkenyl group forms a divalent alkenylene group, and may be a substituted or unsubstituted alkenylene group. In some embodiments, C_2-4Alkenylene is particularly preferred. Exemplary embodiments of the inventionThe unsubstituted alkenylene group of (a) includes, but is not limited to: vinylidene (-CH-) and propenylene (e.g., -CH-) CHCH₂-、-CH₂-CH ═ CH —). Exemplary substituted alkenylene groups, for example, alkenylene substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted ethylene (-C (CH)₃)＝CH-、-CH＝C(CH₃) -) substituted propenylene (-C (CH)₃)＝CHCH₂-、-CH＝C(CH₃)CH₂-、-CH＝CHCH(CH₃)-、-CH＝CHC(CH₃)₂-、-CH(CH₃)-CH＝CH-、-C(CH₃)₂-CH＝CH-、-CH₂-C(CH₃)＝CH-、-CH₂-CH＝C(CH₃) -) and the like.

“C_2-6Alkynylene "means removal of C_2-6One hydrogen of the alkynyl group forms a divalent alkynylene group, and may be a substituted or unsubstituted alkynylene group. In some embodiments, C_2-4Alkynylene groups are particularly preferred. Exemplary such alkynylene groups include, but are not limited to: ethynylene (-C [ identical to ] C-), substituted or unsubstituted propynyl (-C [ identical to ] CCH)₂-) and the like.

“C_1-6Alkoxy "refers to the group-OR, where R is substituted OR unsubstituted C_1-6An alkyl group. In some embodiments, C_1-4Alkoxy groups are particularly preferred. Specific said alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexoxy, cyclohexoxy, n-heptoxy, n-octoxy and 2-ethylhexoxy. The alkoxy group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

“C_1-12Haloalkyl "represents the above-mentioned" C_1-12Alkyl "substituted with one or more halo groups. Examples include monohalogen substituted, dihalogen substituted and polyhaloalkyl including perhalo. A single halogenThe substituents may have an iodine, bromine, chlorine or fluorine atom in the radical; two halogen substituents and multiple halogen substituents may have two or more of the same halogen atom or a combination of different halogens. The "lower haloalkyl" group contains 1 to 6 carbon atoms, i.e. C_1-6A haloalkyl group. Examples of preferred haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The haloalkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C_3-7Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C_3-6Cycloalkyl is particularly preferred, more preferably C_5-6A cycloalkyl group. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C)₃) Cyclopropenyl group (C)₃) Cyclobutyl (C)₄) Cyclobutenyl radical (C)₄) Cyclopentyl (C)₅) Cyclopentenyl group (C)₅) Cyclohexyl (C)₆) Cyclohexenyl (C)₆) Cyclohexyldienyl (C)₆) Cycloheptyl (C)₇) Cycloheptenyl (C)₇) Cycloheptadienyl (C)₇) Cycloheptatrienyl (C)₇) And so on.

"3-11 membered heterocyclyl" refers to a radical of a 3 to 11 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be carbon or a nitrogen atom, as valency permits. In some embodiments, a 3-9 membered heterocyclic group is preferred which is a 3 to 9 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, the composition has advantagesA 3-7 membered heterocyclic group which is a 3-to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably a 3-6 membered heterocyclic group which is a 3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4-6 membered heterocyclic group which is a 4 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferred are 5-6 membered heterocyclic groups which are 5 to 6 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or ring systems wherein the aforementioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxacyclopropaneyl, thienylyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulphuryl), and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thiacyclohexyl (thianyl). Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiinyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepane, oxepanyl and thiepane.Exemplary with C₆Aryl ring fused 5-membered heterocyclyl (also referred to herein as 5, 6-bicyclic heterocyclyl) includes, but is not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolonyl, and the like. Exemplary with C₆Aryl ring fused 6-membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) includes, but is not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

3-11 membered heterocyclyl also includes spiroheterocyclyl, i.e., groups in which two rings (e.g., heterocycle and carbone) share a carbon atom, at least one of which is heterocyclyl as defined above. More specifically, the spiroheterocyclyl is a spirocyclic ring formed of two 4-membered rings, two 5-membered rings, two 6-membered rings, one 4-membered ring and one 5-membered ring, one 4-membered ring and one 6-membered ring, or one 5-membered ring and one 6-membered ring, wherein at least one ring is a 4-6-membered heterocyclyl group as defined above, preferably a 4-6-membered heterocyclyl group containing 1,2 or 3O, N or S heteroatoms, more preferably a 4-6-membered heterocyclyl group containing 1N heteroatom.

Specific examples of preferred heterocyclic groups include: pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, dihydropyranyl, dihydrofuranyl, thiazolidinyl, dihydrothiazolyl, 2, 3-dihydro-benzo [ l,4] dioxanyl, indolinyl, isoindolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, isochromanyl, chromanyl, 1, 2-dihydroisoquinoline, 1,2,3, 4-tetrahydroisoquinoline, 1,2,3, 4-tetrahydroquinoline, 2,3,4,4a,9,9 a-hexahydro-lH-3-azafluorene, 5,6, 7-trihydro-1, 2, 4-triazolo [3,4-a ] isoquinolinyl, 3, 4-dihydro-2H-benzo [ l,4] oxazinyl, benzo [ l,4] dioxanyl, 2, 3-dihydro-lH-lk' -benzo [ d ] isothiazol-6-yl, 2, 3-di-benzo [ l,4] dioxinyl, dihydrobenzofuran, 2-oxoaziridin-1-yl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxoazacyclohex-1-yl, 2-oxoazepin-1-yl, 2-oxoazocin-1-yl, 2-oxoazepin-1-yl, 2-oxoazacyclodec-1-yl, aziridine, azetidine, pyrrolidinyl, azacyclohexane, azepane, azooctane, azocane, Azacyclononane, azacyclodecane, piperidinyl, piperazinyl, morpholinyl, diazaspiro [3.3] heptane, diazaspiro [3.4] octane, diazaspiro [3.5] nonane, diazaspiro [4.4] nonane, diazaspiro [4.5] decane, and diazaspiro [5.5] undecane.

“C_6-10Aryl "refers to a group having a monocyclic or polycyclic (e.g., bicyclic) 4n +2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) of 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C)₆Aryl "; for example, phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C)₁₀Aryl "; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.

"5-10 membered heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) with ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n +2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: a tetrazolyl group. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: a pyridyl group. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxacycloheptyl, and thiacycloheptyl trienyl groups. Exemplary 5, 6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisothiafuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indezinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryls include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.

Specific examples of preferred heteroaryl groups include: pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-l,2, 4-triazolyl, 1H-1,2, 3-triazolyl, 2H-l,2, 3-triazolyl, pyranyl, 2-furyl, 3-furan, etc., 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2, 4-oxazolyl, 1,3, 4-oxazolyl, 1,2, 5-oxazolyl, thiazolyl, thiadiazolyl (1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl).

"carbonyl", whether used alone or in combination with other terms (e.g., aminocarbonyl), is designated as-C (O) -.

"oxo" represents ═ O.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, and the like, as defined herein, are optionally substituted groups. Generally, the term "substituted," whether preceded by the term "optionally" or not, refers to the substitution of at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) with an allowable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent at each position is the same or different. The term "substituted" includes substitution with all permissible substituents of organic compounds (any of the substituents described herein that result in the formation of stable compounds). For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any suitable substituent described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety.

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OR^aa、-ON(R^bb)₂、-N(R^bb)₂、-N(R^bb)₃ ⁺X^-、-N(OR^cc)R^bb、-SH、-SR^aa、-SSR^cc、-C(＝O)R^aa、-CO₂H、-CHO、-C(OR^cc)₂、-CO₂R^aa、-OC(＝O)R^aa、-OCO₂R^aa、-C(＝O)N(R^bb)₂、-OC(＝O)N(R^bb)₂、-NR^bbC(＝O)R^aa、-NR^bbCO₂R^aa、-NR^bbC(＝O)N(R^bb)₂、-C(＝NR^bb)R^aa、-C(＝NR^bb)OR^aa、-OC(＝NR^bb)R^aa、-OC(＝NR^bb)OR^aa、-C(＝NR^bb)N(R^bb)₂、-OC(＝NR^bb)N(R^bb)₂、-NR^bbC(＝NR^bb)N(R^bb)₂、-C(＝O)NR^bbSO₂R^aa、-NR^bbSO₂R^aa、-SO₂N(R^bb)₂、-SO₂R^aa、-SO₂OR^aa、-OSO₂R^aa、-S(＝O)R^aa、-OS(＝O)R^aa、-Si(R^aa)₃、-OSi(R^aa)₃、-C(＝S)N(R^bb)₂、-C(＝O)SR^aa、-C(＝S)SR^aa、-SC(＝S)SR^aa、-SC(＝O)SR^aa、-OC(＝O)SR^aa、-SC(＝O)OR^aa、-SC(＝O)R^aa、-P(＝O)₂R^aa、-OP(＝O)₂R^aa、-P(＝O)(R^aa)₂、-OP(＝O)(R^aa)₂、-OP(＝O)(OR^cc)₂、-P(＝O)₂N(R^bb)₂、-OP(＝O)₂N(R^bb)₂、-P(＝O)(NR^bb)₂、-OP(＝O)(NR^bb)₂、-NR^bbP(＝O)(OR^cc)₂、-NR^bbP(＝O)(NR^bb)₂、-P(R^cc)₂、-P(R^cc)₃、-OP(R^cc)₂、-OP(R^cc)₃、-B(R^aa)₂、-B(OR^cc)₂、-BR^aa(OR^cc) Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2,3,4 or 5R^ddSubstituted by groups;

or two geminal hydrogens on a carbon atom are replaced by groups ═ O, ═ S, ═ NN (R)^bb)₂、＝NNR^bbC(＝O)R^aa、＝NNR^bbC(＝O)OR^aa、＝NNR^bbS(＝O)₂R^aa、＝NR^bbOr as NOR^ccSubstitution;

R^aaeach is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R^aaThe radicals combining to form a heterocyclic or heteroaromatic radicalRing wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2,3,4 or 5R^ddSubstituted by groups;

R^bbeach independently selected from: hydrogen, -OH, -OR^aa、-N(R^cc)₂、-CN、-C(＝O)R^aa、-C(＝O)N(R^cc)₂、-CO₂R^aa、-SO₂R^aa、-C(＝NR^cc)OR^aa、-C(＝NR^cc)N(R^cc)₂、-SO₂N(R^cc)₂、-SO₂R^cc、-SO₂OR^cc、-SOR^aa、-C(＝S)N(R^cc)₂、-C(＝O)SR^cc、-C(＝S)SR^cc、-P(＝O)₂R^aa、-P(＝O)(R^aa)₂、-P(＝O)₂N(R^cc)₂、-P(＝O)(NR^cc)₂Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R^bbThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2,3,4 or 5R^ddSubstituted by groups;

R^cceach is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R^ccThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2,3,4 or 5R^ddSubstituted by groups;

R^ddeach independently selected from: halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OR^ee、-ON(R^ff)₂、-N(R^ff)₂,、-N(R^ff)₃ ⁺X^-、-N(OR^ee)R^ff、-SH、-SR^ee、-SSR^ee、-C(＝O)R^ee、-CO₂H、-CO₂R^ee、-OC(＝O)R^ee、-OCO₂R^ee、-C(＝O)N(R^ff)₂、-OC(＝O)N(R^ff)₂、-NR^ffC(＝O)R^ee、-NR^ffCO₂R^ee、-NR^ffC(＝O)N(R^ff)₂、-C(＝NR^ff)OR^ee、-OC(＝NR^ff)R^ee、-OC(＝NR^ff)OR^ee、-C(＝NR^ff)N(R^ff)₂、-OC(＝NR^ff)N(R^ff)₂、-NR^ffC(＝NR^ff)N(R^ff)₂、-NR^ffSO₂R^ee、-SO₂N(R^ff)₂、-SO₂R^ee、-SO₂OR^ee、-OSO₂R^ee、-S(＝O)R^ee、-Si(R^ee)₃、-OSi(R^ee)₃、-C(＝S)N(R^ff)₂、-C(＝O)SR^ee、-C(＝S)SR^ee、-SC(＝S)SR^ee、-P(＝O)₂R^ee、-P(＝O)(R^ee)₂、-OP(＝O)(R^ee)₂、-OP(＝O)(OR^ee)₂Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2,3,4 or 5R^ggSubstituted by radicals, or two geminal R^ddSubstituents may combine to form ═ O or ═ S;

R^eeis independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2,3,4 or 5R^ggSubstituted by groups;

R^ffeach is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R^ffThe groups combine to form a heterocyclyl or heteroaryl ring, wherein,each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2,3,4 or 5R^ggSubstituted by groups;

R^ggis independently from each other: halogen, -CN, -NO₂、-N₃、-SO₂H、-SO₃H、-OH、-OC_1-6Alkyl, -ON (C)_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₂、-N(C_1-6Alkyl radical)₃ ⁺X^-、-NH(C_1-6Alkyl radical)₂ ⁺X^-、-NH₂(C_1-6Alkyl radical)⁺X^-、-NH₃ ⁺X^-、-N(OC_1-6Alkyl) (C_1-6Alkyl), -N (OH) (C)_1-6Alkyl), -NH (OH), -SH, -SC_1-6Alkyl, -SS (C)_1-6Alkyl), -C (═ O) (C)_1-6Alkyl), -CO₂H、-CO₂(C_1-6Alkyl), -OC (═ O) (C)_1-6Alkyl), -OCO₂(C_1-6Alkyl), -C (═ O) NH₂、-C(＝O)N(C_1-6Alkyl radical)₂、-OC(＝O)NH(C_1-6Alkyl), -NHC (═ O) (C)_1-6Alkyl), -N (C)_1-6Alkyl) C (═ O) (C)_1-6Alkyl), -NHCO₂(C_1-6Alkyl), -NHC (═ O) N (C)_1-6Alkyl radical)₂、-NHC(＝O)NH(C_1-6Alkyl), -NHC (═ O) NH₂、-C(＝NH)O(C_1-6Alkyl), -OC (═ NH) (C)_1-6Alkyl), -OC (═ NH) OC_1-6Alkyl, -C (═ NH) N (C)_1-6Alkyl radical)₂、-C(＝NH)NH(C_1-6Alkyl), -C (═ NH) NH₂、-OC(＝NH)N(C_1-6Alkyl radical)₂、-OC(NH)NH(C_1-6Alkyl), -OC (NH) NH₂、-NHC(NH)N(C_1-6Alkyl radical)₂、-NHC(＝NH)NH₂、-NHSO₂(C_1-6Alkyl), -SO₂N(C_1-6Alkyl radical)₂、-SO₂NH(C_1-6Alkyl), -SO₂NH₂、-SO₂C_1-6Alkyl, -SO₂OC_1-6Alkyl, -OSO₂C_1-6Alkyl, -SOC_1-6Alkyl, -Si (C)_1-6Alkyl radical)₃、-OSi(C_1-6Alkyl radical)₃、-C(＝S)N(C_1-6Alkyl radical)₂、C(＝S)NH(C_1-6Alkyl), C (═ S) NH₂、-C(＝O)S(C_1-6Alkyl), -C (═ S) SC_1-6Alkyl, -SC (═ S) SC_1-6Alkyl, -P (═ O)₂(C_1-6Alkyl), -P (═ O) (C)_1-6Alkyl radical)₂、-OP(＝O)(C_1-6Alkyl radical)₂、-OP(＝O)(OC_1-6Alkyl radical)₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Carbocyclyl, C₆-C₁₀Aryl radical, C₃-C₇Heterocyclic group, C₅-C₁₀A heteroaryl group; or two geminal R^ggSubstituents may combine to form ═ O or ═ S; wherein, X^-Are counter ions.

Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR^aa、-N(R^cc)₂、-CN、-C(＝O)R^aa、-C(＝O)N(R^cc)₂、-CO₂R^aa、-SO₂R^aa、-C(＝NR^bb)R^aa、-C(＝NR^cc)OR^aa、-C(＝NR^cc)N(R^cc)₂、-SO₂N(R^cc)₂、-SO₂R^cc、-SO₂OR^cc、-SOR^aa、-C(＝S)N(R^cc)₂、-C(＝O)SR^cc、-C(＝S)SR^cc、-P(＝O)₂R^aa、-P(＝O)(R^aa)₂、-P(＝O)₂N(R^cc)₂、-P(＝O)(NR^cc)₂Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R's attached to a nitrogen atom^ccThe groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1,2,3,4 or 5R^ddIs substituted by radicals, and wherein R^aa、R^bb、R^ccAnd R^ddAs described above.

Other definitions

The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal and pharyngeal (oral), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, hodgkin's disease, hairy cell carcinoma, and leukemia.

The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein relates to the act of verb treatment, the latter being as just defined.

The term "pharmaceutically acceptable salts, esters, amides and prodrugs" as used herein means those carboxylic acid salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, including, where possible, the zwitterionic forms of the compounds of the present invention.

The term "salts" denotes the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or separately by reacting the purified free base form of the compound with a suitable organic or inorganic acid and isolating the resulting salt. As long as the compounds of the present invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is often necessary to first isolate a pharmaceutically unacceptable salt of the base compound from the reaction mixture and then simply convert it to the free base compound by treatment with a basic agent, after which the free base is converted to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base may be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salts are also equivalent to their respective free bases.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and separating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the salts are also equivalent to their respective free acids for the purposes of the present invention.

The salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate, isethionate and the like. Salts may also be prepared from organic acids such as aliphatic mono-and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoic acid basin, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, mesylate, and the like. Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are salts of amino acids such as arginate, gluconate, galacturonate, and the like (see, e.g., "pharmaceutical salts," J.pharm.Sci., 1977; 66:1-19, incorporated herein by reference).

Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include those derived from C_l-C₆Alkyl esters, wherein the alkyl group is linear or branched. Acceptable esters also include C₅-C₇Cycloalkyl esters and arylalkyl esters, such as but not limited to benzyl esters. C₁-C₄Alkyl esters are preferred. Esters of the compounds of the invention may be prepared according to conventional methods, for example: march's advanced organic Chemistry,5Edition "m.b. smith&J.March,John Wiley&Sons，2001。

Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include those derived from ammonia, primary C₁-C₆Alkylamine and secondary C₁-C₆Dialkylamine derived amides in which the alkyl group is linear or branched. In the case of secondary amines, the amines may also beIn the form of a 5-or 6-membered heterocyclic ring containing one nitrogen atom. From ammonia, C₁-C₃Alkyl primary amines and C₁-C₂Secondary dialkylamine derived amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods, for example: march's Advanced organic chemistry,5Edition ", m.b. smith&J.March,John Wiley&Sons，2001。

The term "prodrug" means a compound that is rapidly converted in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. For a thorough discussion see T.Higuchi and V.Ste11a, "Pro-drugs as Novel delivery systems," Vol.14of the A.C.S.Sympossium Series and Bioversiblecommunications in drug delivery, ed.Edward B.Roche, American Pharmaceutical Association and PergammonPress, 1987, both of which are incorporated by reference.

The "subject" to which the drug is administered includes, but is not limited to: a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and/or a dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

"disease," "disorder," and "condition" are used interchangeably herein.

As used herein, unless otherwise specified, the term "treatment" includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also includes the effect that occurs before the subject begins to have the particular disease, disorder or condition ("prophylactic treatment").

Generally, an "effective amount" of a compound is an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present invention may vary depending on the following factors: for example, biological goals, pharmacokinetics of the compound, the disease being treated, mode of administration, and the age, health, and condition of the subject. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.

As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.

"combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the present invention may be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosage forms, or simultaneously with the other therapeutic agent in a single unit dosage form.

Detailed description of the preferred embodiments

Herein, "compound of the present invention" refers to the following compounds of formula (I) -formula (VIII), pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variations thereof, and mixtures thereof.

Compounds are generally described herein using standard nomenclature. Compounds having asymmetric centers, it is understood (unless otherwise indicated) that all optical isomers and mixtures thereof are included. Furthermore, all isomeric compounds and carbon-carbon double bonds encompassed by the present invention may occur as Z and E unless otherwise specified. Compounds that exist in different tautomeric forms, one such compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms. The general formula used for some compounds includes description, variables. Unless otherwise specified, each variable in such a formula is defined as a plurality of variables that are independent of any other variable and that independently define any one variable in a formula at each occurrence.

In one embodiment, the present invention relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof:

wherein:

A₁selected from the group consisting of CR₃Or N;

A₂selected from the group consisting of CR₃Or N;

A₃selected from the group consisting of CR₃Or N;

z is selected from O or S;

R₁selected from H, halogen, -CN, -NO₂、-OR₅、-S-R₅、-NR₆R₇、-C(O)OR₅、-C(O)NR₆R₇、C_1-6Alkyl radical、C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R₆and R₇Independently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -L-C_3-7Cycloalkyl, -L-3-7 membered heterocyclyl, -L-C_6-10Aryl or-L-5-10 membered heteroaryl; or, R₆、R₇Together with the N atomTo form a 3-7 membered heterocyclic group;

m represents 0, 1 or 2;

n represents 0, 1,2,3,4, 5 or 6.

In another embodiment, the present invention relates to the above compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variations thereof, and mixtures thereof, having the general formula (II):

wherein the content of the first and second substances,

A₁selected from the group consisting of CR₃Or N;

A₂selected from the group consisting of CR₃Or N;

A₃selected from the group consisting of CR₃Or N;

b is selected from 5-6 membered heteroaryl and 3-7 membered heterocyclyl optionally substituted with oxo or thioxo;

R₃is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, -O-C_1-6alkylene-R₄Or 3-11 membered heterocyclyl, said group optionally substituted with 1,2 or 3R₄Substituted by groups;

R₄selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, -NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂；

R₅、R₆、R₇And R₈Independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group;

n is 0, 1 or 2.

In another embodiment, the present invention relates to the above compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variations thereof, and mixtures thereof, having the general formula (III):

wherein the content of the first and second substances,

b is selected from:

is the point of attachment to the parent nucleus;

R₁selected from H, halogen, -CN, -NO₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl, 3-7 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R₃is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, -O-C_1-6alkylene-R₄Or the following groups:

R₅、R₆、R₇、R₈Independently selected from H, C_1-6Alkyl or C_1-6A haloalkyl group;

n is 0, 1 or 2.

In another embodiment, the present invention relates to the above compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variations thereof, and mixtures thereof, having the general formula (IV):

wherein:

b is selected from:

is the point of attachment to the parent nucleus;

R₁selected from H or Me;

R₄selected from H or Me;

R₈selected from H or Me;

n is 0 or 1.

In another embodiment, the present invention relates to the above compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variations thereof, and mixtures thereof, having the general formulae (V) - (VIII):

wherein A is₁-A₃、R₁-R₃、R₈And n is as defined in any one of claims 1 to 4.

In another embodiment, the present invention relates to a compound of formula (V), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof:

wherein the content of the first and second substances,

A₁selected from N, CH, C (halogen), C (C)_1-6Alkyl group), C (C)_1-6Haloalkyl) Or C (OC)_1-6Alkyl groups); preferably, A₁Selected from N, CH Or C (OC)_1-6Alkyl groups); preferably, A₁Selected from N, CH Or C (OCH)₃)；

A₂Selected from N, CH, C (halogen), C (C)_1-6Alkyl group), C (C)_1-6Haloalkyl) Or C (OC)_1-6Alkyl groups); preferably, A₂Selected from N, CH, C (halogen), C (C)_1-6Alkyl) Or C (OC)_1-6Alkyl groups); preferably，A₂Selected from N, CH, CF, CCH₃Or C (OCH)₃)；

A₃Selected from N, CH, C (C)_1-6Alkyl) or C (C)_1-6Haloalkyl); preferably, A₃Selected from N, CH or C (C)_1-6Alkyl groups); preferably, A₃Selected from N, CH or CCH₃；

R₁Selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₁Is selected from H or C_1-6An alkyl group; preferably, R₁Selected from H or Me;

R₂is selected from C_3-7Cycloalkyl or 3-7 membered heterocyclyl; preferably, R₂Is C_3-7A cycloalkyl group; preferably, R₂Is cyclopentyl;

R₃is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, -O-C_1-6alkylene-R₄Or optionally substituted with 1,2 or 3R₄The following groups substituted with groups:

preferably, R₃Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, -O-C_1-6alkylene-R₄Or the following groups:

R₄selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂or-C_1-6alkylene-OH; preferably, R₄Selected from H, C_1-6Alkyl, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂or-C_1-6alkylene-OH; preferably, R₄Selected from H, Me, Et, iPr, NH₂、NMe₂、CH₂CH₂OH or CH₂CH₂CH₂OH；

R₈Selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl; preferably, R₈Selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-7A cycloalkyl group; preferably, R₈Selected from H, Me, CF₃Et, cyclopropyl or cyclobutyl.

wherein the content of the first and second substances,

A₂Selected from N, CH, C (halogen), C (C)_1-6Alkyl group), C (C)_1-6Haloalkyl) Or C (OC)_1-6Alkyl groups); preferably, A₂Selected from N, CH, C (halogen), C (C)_1-6Alkyl) Or C (OC)_1-6Alkyl groups); preferably, A₂Selected from N, CH, CF, CCH₃Or C (OCH)₃)；

A₃Selected from CH and C (C)_1-6Alkyl) or C (C)_1-6Haloalkyl); preferably, A₃Selected from CH or C (C)_1-6Alkyl groups); preferably, A₃Selected from CH or CCH₃；

R₁Is selected from C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₁Is C_1-6An alkyl group; preferably, R₁Is Me;

R₃is selected from

wherein the content of the first and second substances,

A₁is N;

A₂selected from CH and C (C)_1-6Alkyl) or C (C)_1-6Haloalkyl); preferably, A₂Selected from CH or C (C)_1-6Alkyl groups); preferably, A₂Selected from CH or CCH₃；

R₃is piperazinyl, optionally substituted with 1,2 or 3R₄Substituted by groups; preferably, R₃Is composed of

R₄Selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₄Is selected from H or C_1-6An alkyl group; preferably, R₄Selected from H, Me or Et;

R₈selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl; preferably, R₈Selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-7A cycloalkyl group; preferably, R₈Selected from H, Me, CF₃Et or cyclopropyl.

In another embodiment, the present invention relates to a compound of formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variation thereof, and mixtures thereof:

wherein the content of the first and second substances,

A₁is N;

A₂selected from CH or C (C)_1-6Alkyl groups); preferably, A₂Is CH;

A₃selected from CH or C (C)_1-6Alkyl groups); preferably, A₃Is CH;

R₃is a 3-7 membered heterocyclyl optionally substituted with 1,2 or 3R₄Substituted by groups; preferably, R₃Is composed of

R₄Selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₄Is selected from H or C_1-6An alkyl group; preferably, R₄Selected from H or Me;

R₈is selected from C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₈Is C_1-6An alkyl group; preferably, R₈Is Me.

In another embodiment, the present invention relates to compounds of general formula (VII) or (VIII), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variations thereof, and mixtures thereof:

wherein the content of the first and second substances,

A₁is selected from N;

A₂selected from CH and C (C)_1-6Alkyl) or C (C)_1-6Haloalkyl); preferably, A₂Is CH;

A₃selected from CH and C (C)_1-6Alkyl) or C (C)_1-6Haloalkyl); preferably, A₃Selected from CH and C (C)_1-6Alkyl) or C (C)_1-6Haloalkyl); preferably, A₃Selected from CH or C (C)_1-6Alkyl groups); preferably, A₃Selected from CH and C (CH)₃)；

R₁Selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₁Selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₁Is selected from H or C_1-6An alkyl group; preferably, R₁Selected from H or Me;

R₂is selected from C_3-7Cycloalkyl or 3-7 membered heterocyclyl; preferably, R₂Is selected from C_3-7Cycloalkyl or 3-7 membered heterocyclyl; preferably, R₂Is C_3-7A cycloalkyl group; preferably, R₂Is cyclopentyl;

R₄Selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₄Selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₄Is selected from H or C_1-6An alkyl group; preferably, R₄Is Me;

R₈selected from H, C_1-6Alkyl or C_1-6A haloalkyl group; preferably, R₈Is selected from H or C_1-6An alkyl group; preferably, R₈Is H;

n is 0, 1 or 2; preferably, n is 0.

A₁、A₂And A₃

In a particular embodiment, A₁Is CR₃(ii) a In another specific embodiment, A₁Is CH; in another specific embodiment, A₁Is N.

In a particular embodiment, A₂Is CR₃(ii) a In another specific embodiment, A₂Is CH; in another specific embodiment, A₂Is N.

In a particular embodiment, A₃Is CR₃(ii) a In another specific embodiment, A₃Is CH; in another specific embodiment, A₃Is N.

B

In one embodiment, B is C_3-7A cycloalkyl group; in a particular embodiment, B is C substituted by oxo_3-7A cycloalkyl group; in one embodiment, B is C substituted with thio_3-7A cycloalkyl group; in another embodiment, B is C_3-7A heterocycloalkyl group; in another embodiment, B is C substituted with oxo_3-7A heterocycloalkyl group; in another embodiment, B is C substituted with thio_3-7A heterocycloalkyl group; in another embodiment, B is C_6-10An aryl group; in another embodiment, B is a 5-10 membered heteroaryl.

In a more specific embodiment, B is selected from

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

At another placeIn a more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

In another more particular embodiment, B is

Wherein x is the point of attachment to the parent nucleus.

Z

In a specific embodiment, Z is O; in another specific embodiment, Z is S.

R₁

In one embodiment, R₁Is H; in another embodiment, R₁Is halogen; in another embodiment, R₁is-CN; in another embodiment, R₁is-NO₂(ii) a In another embodiment, R₁is-OR₅(ii) a In addition toIn one embodiment, R₁is-S-R₅(ii) a In another embodiment, R₁is-NR₆R₇(ii) a In another embodiment, R₁is-C (O) OR₅(ii) a In another embodiment, R₁is-C (O) NR₆R₇(ii) a In another embodiment, R₁Is C_1-6An alkyl group; in another embodiment, R₁Is C_1-6A haloalkyl group; in another embodiment, R₁Is C_3-7A cycloalkyl group; in another embodiment, R₁Is a 3-7 membered heterocyclic group; in another embodiment, R₁Is C_6-10An aryl group; in another embodiment, R₁Is a 5-10 membered heteroaryl.

R₂

In one embodiment, R₂Is H; in another embodiment, R₂is-C (O) OR₅(ii) a In another embodiment, R₂is-C (O) NR₆R₇(ii) a In another embodiment, R₂Is C_1-6An alkyl group; in another embodiment, R₂Is C_1-6A haloalkyl group; in another embodiment, R₂Is C_3-7A cycloalkyl group; in another embodiment, R₂Is a 3-7 membered heterocyclic group.

At R₂In the above specific embodiment, the C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-7Cycloalkyl or 3-7 membered heterocyclyl is optionally substituted with 1,2 or 3R_aAnd (4) substituting the group. In one embodiment, the group is substituted with 1R_aSubstituted by groups; in another embodiment, the group is substituted with 2R_aSubstituted by groups; in another embodiment, the group is substituted with 3R_aAnd (4) substituting the group.

R₃

In one embodiment, R₃Is H; in another embodiment, R₃Is halogenA peptide; in another embodiment, R₃is-CN; in another embodiment, R₃is-NO₂(ii) a In another embodiment, R₃is-L-OR₅(ii) a In another embodiment, R₃is-L-S-R₅(ii) a In another embodiment, R₃is-L-NR₆R₇(ii) a In another embodiment, R₃is-L-C (O) OR₅(ii) a In another embodiment, R₃is-L-C (O) NR₆R₇(ii) a In another embodiment, R₃is-L-S (O)_mR₅(ii) a In another embodiment, R₃is-L-S (O)_mOR₅(ii) a In another embodiment, R₃is-L-S (O)_mNR₆R₇(ii) a In another embodiment, R₃is-O-C_1-6alkylene-R₄(ii) a In another embodiment, R₃Is C_1-6An alkyl group; in another embodiment, R₃Is C_1-6A haloalkyl group; in another embodiment, R₃is-L-C_3-7A cycloalkyl group; in another embodiment, R₃is-L-3-11 membered heterocyclyl; in another embodiment, R₃is-L-3-9 membered heterocyclyl; in another embodiment, R₃is-L-C_6-10An aryl group; in another embodiment, R₃is-L-5-10 membered heteroaryl.

At R₃In the above specific embodiments, the group is optionally substituted with 1,2 or 3R₄And (4) substituting the group. In one embodiment, the group is substituted with 1R₄Substituted by groups; in another embodiment, the group is substituted with 2R₄Substituted by groups; in another embodiment, the group is substituted with 3R₄And (4) substituting the group.

In more specific embodiments, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

In another more particular embodiment, R₃Is composed of

R₄

In one embodiment, R₄Is H; in another embodiment, R₄is-NH₂(ii) a In another embodiment, R₄is-NHC_1-6An alkyl group; in another embodiment, R₄is-N (C)_1-6Alkyl radical)₂(ii) a In another embodiment, R₄Is C_1-6An alkyl group; in another embodiment, R₄Is C_1-6A haloalkyl group; in another embodiment, R₄is-C_1-6alkylene-OH; in another embodiment, R₄is-L-C_3-7A cycloalkyl group; in another embodiment, R₄is-L-3-7 membered heterocyclyl; in another embodiment, R₄is-L-C_6-10An aryl group; in another embodiment, R₄is-L-5-10 membered heteroaryl.

R₅

In one embodiment, R₅Is H; in another embodiment, R₅Is C_1-6An alkyl group; in another embodiment, R₅Is C_2-8An alkenyl group; in another embodiment, R₅Is C_2-8An alkynyl group; in another embodiment, R₅Is C_1-6A haloalkyl group; in another embodiment, R₅is-L-C_3-7A cycloalkyl group; in another embodiment, R₅is-L-3-7 membered heterocyclyl; in another embodiment, R₅is-L-C_6-10An aryl group; in another embodiment, R₅is-L-5-10 membered heteroaryl.

R₆And R₇

In one embodiment, R₆And R₇Independently is H; in another embodiment, R₆And R₇Independently is C_1-6An alkyl group; in another embodiment, R₆And R₇Independently is C_2-6An alkenyl group; in another embodiment, R₆And R₇Independently is C_2-6An alkynyl group; in another embodiment, R₆And R₇Independently is C_1-6A haloalkyl group; in another embodiment, R₆And R₇Independently is-L-C_3-7A cycloalkyl group; in another embodiment, R₆And R₇independently-L-3-7 membered heterocyclyl; in another embodiment, R₆And R₇Independently is-L-C_6-10An aryl group; in another embodiment, R₆And R₇independently-L-5-10 membered heteroaryl; or, R₆、R₇Together with the N atom, form a 3-7 membered heterocyclic group.

R₈

In one embodiment, R₈Is H; in another embodiment, R₈Is C_1-6An alkyl group; in another embodiment, R₈Is C_2-8An alkenyl group; in another embodiment, R₈Is C_2-8An alkynyl group; in another embodiment, R₈Is C_1-6A haloalkyl group; in another embodiment, R₈is-L-C_3-7A cycloalkyl group; in another embodiment, R₈is-L-3-7 membered heterocyclyl; in another embodiment, R₈is-L-C_6-10An aryl group; in another embodiment, R₈is-L-5-10 membered heteroaryl.

L

In a specific embodiment, L is a bond; in another embodiment, L is-C_1-6Alkylene-; in another embodiment, L is-C_2-6Alkenylene-; in another embodiment, L is-C_2-6Alkynylene-.

m

In a specific embodiment, m is 0; in another embodiment, m is 1; in another embodiment, m is 2.

n

In a specific embodiment, n is 0; in another embodiment, n is 1; in another embodiment, n is 2; in another embodiment, n is 3; in another embodiment, n is 4; in another embodiment, n is 5; in another embodiment, n is 6.

Any of the above embodiments, or any combination thereof, may be combined with any of the other embodiments, or any combination thereof. For example, A₁Any one or any combination of the above technical means, can be combined with A₂、A₃、B、Z、R₁-R₈L, m and n, or any combination thereof. The present invention is intended to include all combinations of these solutions, limited to space, not listed one by one.

The compounds of the invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.

One skilled in the art will appreciate that the organic compound may form a complex with a solvent in which it reacts or from which it precipitates or crystallizes. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

The term "solvate" refers to a form of a compound or salt thereof that is combined with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term "hydrate" refers to a compound that is associated with an aqueous phase. In general, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, hydrates of the compounds can be used, for example, with the formula R.xH₂O represents, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrates (x is a number greater than 0 and less than 1), e.g., hemihydrate (R0.5H)₂O)) and polyhydrates (x is a number greater than 1, e.g. dihydrate (R.2H)₂O) and hexahydrate (R.6H)₂O))。

The compounds of the invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause a crystalline form to dominate. Various polymorphs of a compound may be prepared by crystallization under different conditions.

The invention also includes isotopically-labeled compounds, which are identical to those recited in formulas I-VIII, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the invention, e.g. by incorporation of radioactive isotopes (e.g. by introducing³H and¹⁴C) can be used in drug and/or substrate tissue distribution assays. Tritium, i.e.³H and carbon-14, i.e.¹⁴The C isotopes are particularly preferred because of their ease of preparation and detection. Further, by heavier isotopes, e.g. deuterium, i.e.²H, may be preferred in some cases because of the higher metabolic stability that may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of formulae I-VIII of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent in carrying out the procedures disclosed in the schemes and/or in the examples and preparations below.

In addition, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo by hydrolysis, for example in the blood, to its active form with a medicinal effect. Pharmaceutically acceptable Prodrugs are described in t.higuchi and v.stella, Prodrugs as Novel Delivery Systems, vol.14of a.c.s.symposium series, Edward b.roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press,1987, and d.fleisher, s.ramon and h.bara "Improved oral Drug Delivery: the solubility limits over company the use of drivers, Advanced Drug Delivery Reviews (1996)19(2)115-130, each of which is incorporated herein by reference.

A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a manner such that the modification is effected by routine manipulation or in vivo cleavage to produce the parent compound. Prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, cleaves to form a hydroxy, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of hydroxy, mercapto, and amino functional groups of the compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like may be used. The ester itself may be active and/or may hydrolyze under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which readily break down in the human body to release the parent acid or salt thereof.

The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formulae I-VIII, or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are within the scope of the present invention.

Pharmaceutical compositions, formulations and kits

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

The invention also includes kits (e.g., pharmaceutical packages). The provided kits can include a compound of the invention, an additional therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispensable packages or other suitable containers) containing the compound of the invention, the additional therapeutic agent. In some embodiments, provided kits may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent. In some embodiments, the compound of the present invention and the additional therapeutic agent provided in the first container and the second container are combined to form one unit dosage form.

Administration of drugs

The pharmaceutical compositions provided by the present invention may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implant or other modes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intracerebrospinal administration, intralesional administration, and intracranial injection or infusion techniques.

Typically, an effective amount of a compound provided herein is administered. The amount of compound actually administered can be determined by a physician, as the case may be, including the condition to be treated, the chosen route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

When used to prevent a condition according to the invention, a subject at risk of developing the condition is administered a compound provided herein, typically based on physician's advice and under the supervision of a physician, at a dosage level as described above. Subjects at risk of developing a particular disorder, typically include subjects with a family history of the disorder, or those determined to be particularly susceptible to developing the disorder by genetic testing or screening.

The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). By long-term administration is meant administration of the compound or pharmaceutical composition thereof over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue for an indefinite period of time, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within the therapeutic window.

Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the targeted systemic level of the active ingredient through the body, e.g., intramuscular or subcutaneous bolus doses result in slow release of the active ingredient, while a bolus delivered directly to the vein (e.g., by IV intravenous drip) can be delivered more rapidly, resulting in a rapid rise in the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV intravenous drip, to provide a steady state concentration of the active ingredient in the body of the subject. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.

Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the compositions are provided in unit dosage form for convenient administration of the precise dosage. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for the purpose of producing the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful in forming the desired form of administration.

For oral dosages, a representative regimen is one to five oral dosages, particularly two to four oral dosages, typically three oral dosages per day. Using these dosing modes, each dose provides about 0.01 to about 20mg/kg of a compound of the invention, with preferred doses each providing about 0.1 to about 10mg/kg, especially about 1 to about 5 mg/kg.

In order to provide a blood level similar to, or lower than, the use of the injected dose, a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

From about 1 to about 120 hours, especially 24 to 96 hours, the injection dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To obtain sufficient steady state levels, a preload bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, as well as buffers, suspending and dispersing agents, coloring and flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds with similar properties: a binder, for example, microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example, starch or lactose, disintegrants, for example, alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, e.g., colloidal silicon dioxide; sweetening agents, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with a cream base, for example of the oil-in-water type. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.

The compounds of the present invention may also be administered by transdermal means. Thus, transdermal administration can be achieved using a reservoir (reservoir) or porous membrane type, or a patch of various solid matrices.

The above components of the compositions for oral, injectable or topical administration are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences,17th edition,1985, Mack Publishing Company, Easton, Pennsylvania, section 8, which is incorporated herein by reference.

The compounds of the present invention may also be administered in sustained release form, or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α -, β -and γ -cyclodextrins consisting of 6,7 and 8 α -1, 4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, e.g., U.S.5,376,645. In some embodiments, the formulation includes hexapropyl- β -cyclodextrin (e.g., 10-50% in water).

Treatment of

The present invention provides methods of treating a mammal (including a human) for a disorder or condition selected from the group consisting of: cell proliferation disorders such as cancer, vascular smooth muscle proliferation associated with atherosclerosis, post-operative vascular stenosis, restenosis and endometriosis; infections, including viral infections, e.g., DNA viruses, such as herpes, and RNA viruses, such as HIV, and fungal infections; autoimmune diseases, such as psoriasis, inflammation, such as rheumatoid arthritis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis and glomerulonephritis; organ transplant rejection, including host versus graft disease, comprising administering to said mammal a therapeutically effective amount of a compound of the present invention or a composition thereof.

The invention further provides compounds of the invention useful for treating abnormal cell proliferation, such as cancer. The invention further provides a method of treating abnormal cell proliferation, such as a cancer selected from: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal and pharyngeal (oral), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, hodgkin's disease, hairy cell carcinoma, and leukemia comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention or a composition thereof.

Further, the present invention relates to a method of treating a subject suffering from a disease caused by vascular smooth muscle cell proliferation. The compounds of the present invention effectively inhibit the proliferation and migration of vascular smooth muscle cells. The method comprises administering to a subject in need thereof an amount of a compound of the invention or composition thereof sufficient to inhibit vascular smooth muscle proliferation and/or migration.

The present invention further provides a method of treating a subject suffering from gout comprising administering to said subject in need of treatment a compound of the present invention or a composition thereof in an amount sufficient to treat the condition.

The invention further provides a method of treating a subject having a renal disease, e.g., polycystic kidney disease, comprising administering to said subject in need thereof a compound of the invention or composition thereof in an amount sufficient to treat the condition.

Due to their inhibitory activity against CDKs and other kinases, the compounds of the present invention are also useful research tools for studying the mechanism of action of these kinases in vitro and in vivo.

The above treatment method is preferably carried out as follows: administering to a subject in need thereof a therapeutically effective amount of a compound of the invention (as described below). The compounds of the invention are potent inhibitors of cyclin dependent kinase 4(CDK 4). These compounds are readily synthesized, can be administered by a variety of routes, including oral and parenteral, with little or no toxicity.

The compounds of the present invention are selective inhibitors of the cyclin dependent kinase CDK4, that is, they inhibit CDK4 more efficiently than they inhibit tyrosine kinases and other serine-threonine kinases, including other cyclin dependent kinases, such as CDK 2. Although they are selective for CDK4 inhibition, the compounds of the invention may also inhibit other kinases, although at concentrations above those at which they inhibit CDK 4. However, the compounds of the invention may also inhibit CDK6 at concentrations similar to those necessary to inhibit CDK4, since CDK6 is structurally similar to CDK4 and performs similar functions.

The compounds of the invention are useful in the treatment of cancer (e.g., leukemia and cancers of the lung, breast, prostate and skin, such as melanoma) and other proliferative diseases, including but not limited to psoriasis, HSV, HIV, restenosis and atherosclerosis. To treat cancer with a compound of the present invention, a therapeutically effective amount of a pharmaceutically acceptable composition comprising at least one compound of the present invention is administered to a patient in need of such treatment, e.g., a patient suffering from cancer or another proliferative disease.

An effective amount of a compound of the invention is generally in a mean daily dose of from 0.01mg to 50mg of compound per kilogram of body weight of the patient, preferably from 0.1mg to 25mg of compound per kilogram of body weight of the patient, in single or multiple administrations. Generally, the compounds of the present invention may be administered to such patients in need of such treatment in a daily dosage range of from about 1mg to about 3500mg, preferably from 10mg to 1000mg per patient. For example, the daily dose per patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000 mg. Administration may be once or more daily, weekly (or at intervals of several days), or on an intermittent schedule. For example, the compound may be administered one or more times per day on a weekly basis (e.g., monday), indefinitely or for several weeks, e.g., 4-10 weeks. Alternatively, the administration may be continued daily for several days (e.g., 2-10 days), followed by several days (e.g., 1-30 days) without administration of the compound, with the cycle repeated indefinitely or for a given number of times, e.g., 4-10 cycles. For example, the compounds of the invention may be administered daily for 5 days, followed by 9 days, followed by 5 days, followed by 9 days, and so on, with the cycle repeated indefinitely or 4-10 times in total.

Combination therapy

The compounds or compositions of the present invention may be administered concurrently with, before, or after one or more additional agents, for use as a combination therapy. The medicament includes a therapeutically active agent. The medicament also includes a prophylactically active agent. Agents include small organic molecules, such as pharmaceutical compounds (e.g., human or veterinary compounds approved by the U.S. food and drug administration as provided in the federal regulations Compilation (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. In some embodiments, the additional agent is an agent for treating and/or preventing a disease described herein. Each additional agent may be administered at a dose and/or on a schedule determined by the agent. The additional agents may also be administered together with each other and/or with the compounds or compositions described herein, in a single dose or separately in different doses. The particular combination employed in this regimen will take into account the compatibility of the compounds of the present invention with additional agents and/or the desired therapeutic and/or prophylactic effect that will be achieved. Typically, the additional agents are used in combination at a level that is no greater than the level at which they are used individually. In some embodiments, the levels used in combination will be lower than they are used individually.

Such additional agents include, but are not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressive agents, antibacterial agents, antiviral agents, cardiovascular agents, lipid-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, and analgesics. In particular embodiments, the additional agent is an antiproliferative agent. In a specific embodiment, the additional agent is an anti-cancer agent. In particular embodiments, the additional agent is an anti-leukemic agent. In particular embodiments, the additional agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin HCl), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (Oxaliumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin HCl), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOFARAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINE (Alopecuroidea), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (methotrexate), GAZUTYVA (Involumab), GLEEVEC (imatinib mesylate), Hydrab-SIG (CVB), vincristine hydrochloride (Nitrogen mustard), Neosincalix (Nitrogen mustard), Neobrevicine hydrochloride (Nitrogen mustard), Neobrevicine (IV), Neobrevudine hydrochloride (N B), Neobrevicine (N-L), Neobrevicine (N-B), Neoprene (N-L), Neoprene, Neobrene, Neobrevudine hydrochloride (N-L, Neoprene, METHOTREXATE LPF (METHOTREXATE), MEXATE-AQ (METHOTREXATE), mitoxantrone hydrochloride, mustagen (nitrogen mustard hydrochloride), myreran (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (peimepirnase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), triribo (cephalotaxine), TARABINE PFS (cytarabine), TASIGNA (nilotinib), trenda (bendamustine hydrochloride), senox (arsenic trioxide), VINCASAR PFS (vincristine sulfate), zydelig (idelalisib), or combinations thereof. In a specific embodiment, the additional agent is an anti-lymphoma drug. In particular embodiments, the additional agent is ABITREXATE (methotrexate), ABVD, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and I131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP-ABV, CVP, CYXAN (cyclophosphamide), DECYPOT (cytarabine), DTIC-DOME (EPOCAPIN), FOPHOSPHOLIFA (FOURACH), FOUREA-2, FOURACEAX (FOURACEAX), FORCONITAX-2, FORCONITAX (FOURACAT), FORCONITON (FORCONITON), FORCONITAX-2, FORCONITON (FORCONITX), FORCONITON (FORCAT), BENCA, BENC, Isotaxx (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (METHOTREXATE), MEXATE-AQ (METHOTREXATE), MOPP, MOZOBIL (plerixafof), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (dinil 2), OPPA, R-CHOP, revalid (lenalidomide), rituximab (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), velsa (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), zetimumab), zovovaciz (vinelalin), linidizein (zuelidlyigin), or combinations thereof. In specific embodiments, the additional agent is revalimid (lenalidomide), DACOGEN (decitabine), vidaka (azacitidine), cytar-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In particular embodiments, the additional agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticulate formulation), AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (disodium pemetrexed), AREDIA (disodium pamidronate), ARANIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BECEP, BICNU (carmustine), BLENOXANOX (bleomycin), CAF, CAMPAR (irinotecan hydrochloride), CAPRELA (vandetanib), BOPLATIN-TAXOL, CARBRMUMUIS (carmustine), CASOX (DEMOX), BILUX (CLARITUIX (HPV), HOMORPE-HCL (CINOX), HOMORPE (CINOX), HALCOME (CIT-C), HALCOME (CIE), HALON (CIT-C (CIE), HALOX (CALCOME), HALOX (CALCO-C), HALOX), HALON (CALCO-C (CALCO, COSMEGEN (Actinomycin D), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), doxorubicin hydrochloride, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITIX (CETUXIMAB), ERIVEGEL (VIVAGID), ERIVEGE (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPELEX (fluorouracil), FOLEX (methotrexate), FOLELFPFS (FOLFIRI), FOBEI-BEFU, FOXIFU, FOIREFI, FOXIDOXIFU-like vaccine (FOIREFI), FOLIX (FOIRIFLOX, FOIRIF, GEMCITABINE-CISPLATIN, GEMCITABINE-OXALLATIN, GEMZAR (GEMCITABINE hydrochloride), GILOTRIF (Afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (acitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emsine), KEYTRUDA (KYrolizumab), PROLIS (Carbamizumab), EPOLIPY (Liposome), Lipolax (Lipolax), Lipolamin (Dellulupulin hydrochloride), Leuprolin (Pro-4-acetate), Leuprolin (Pro-4-L, LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol), MEKINIST (trimetatinib), METHAZOLASTONE (temozolomide), METHOTREE LPF (METHOTREXATE), MEXATE-AQ (METHOTREXATE), mitoxantrone hydrochloride, MITOTZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacitidine), ELBINAVIREBIN (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), NOVALAPSE (tamoxifen citrate), PAD, PARLATAPIN (carboplatin), cisplatin (carboplatin), PEG-interferon-2 b), pemetrexen (polyethylene glycol), dipotassium citrate), prednisone (prednisone), cisplatin (prednisone), prednisone (prednisone), cisplatin), prednisone (prednisone, cisplatin), cisplatin, prednisone (prednisone, cisplatin, prednisone, and cisplatin, and, PROLIA (dinolizumab), PROVENGE (sipuleucel-t), revalimid (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), sylaron (peginterferon alfa-2b), sylvatan (cetuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dalafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), tasiua (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), topveveveveveveovar (etoposide), ristol (sirolimus), tresx (trisafen), tykerabenzene (tyxol), vinpocetine (perimidin), vinpocetine (peril), perimidin (peril), vinpocetine), perimidin (vinpocetine), perimidin (valbutrin), perimidin (valacil), perimidin (valbutrin), vinpocetine), tremulin (valacil), tremulin (valbutrin), tremulin (valacil), tremulin (val, Vidazane (azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (calcium folinate), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (dinomab), xolago (radium dichloride 223), xtanid (enzalutamide), yeloy (ipilimumab), ZALTRAP (aflibercept), zelborafenib (william), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), or combinations thereof.

In a specific embodiment, the additional agent is an antiviral agent. In particular embodiments, the additional agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other differentiation promoting drugs. In particular embodiments, the compounds or pharmaceutical compositions of the present invention may be administered in combination with anti-cancer therapies, including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

Examples

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are carried out, prepared, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what is claimed herein.

The preparation schemes of the compounds of the present invention are shown in, for example, schemes 1 to 4.

Reaction scheme 1

The compounds of formula V may be prepared according to the general reaction scheme above. First, 6-bromo-2-methylthio-8H-pyrido [2,3-d ] is prepared according to the reported literature (J.Med.chem.2005,48, 2371-2387)]Pyrimidin-7-one (1). Then converting the bromide (1) into 2-methylthio-7-oxo-7, 8-dihydropyrido [2,3-d ] under the action of cuprous cyanide]Intermediate 2 of pyrimidine-6-carbonitrile. When it is desired to synthesize a compound having no substituent at the 5-position (R)¹H), intermediate 2 can also be obtained by direct ring closure using (4-amino-2- (methylthio) pyrimidin-5-yl) carbaldehyde and cyanoacetic acid using the method of reference (j.med.chem.2014,57, 578-599). The cyano group at the 6-position of the intermediate 2 is then further modified with hydroxylamine to give an amidoxime compound 3 which can be cyclized with triethyl orthoformate or the corresponding anhydride to give a compound 4, thus forming a five-membered heterocycle of 1,2, 4-oxadiazole at the 6-position of the mother ring. After the compound 4 has oxidized the methylthio group at the 2-position to methylsulfinyl group with m-chloroperoxybenzoic acid or oxaziridine, this group is substituted under heating with a different amino compound (6) to give the corresponding compound having the structure of formula V.

Reaction formula 2

The compounds of formula VI may be prepared according to the general reaction scheme above. Hydrolyzing an intermediate 2 prepared by the same reaction formula as the compound shown in the general formula V by using a sodium hydroxide solution, converting 6-cyano into carboxyl to obtain a compound 7, condensing the carboxyl and different hydrazides to obtain a compound 8 from the compound 7, and then obtaining a compound 9 of which the 6-position forms a 1,3, 4-oxadiazole five-membered heterocyclic ring under the action of phosphorus oxychloride. Oxidizing the compound 9 with m-chloroperoxybenzoic acid to obtain a methanesulfinyl compound 10, and finally substituting with different amino compounds (6) under heating to obtain the corresponding compound with the structure of the general formula VI.

Reaction formula 3

The compounds of formula VII may be prepared according to the general reaction scheme above. 6-bromo-2-methylthio-8H-pyrido [2,3-d ] prepared by the literature method (J.Med.chem.2005,48, 2371-2387)]Pyrimidine-7-one (1) with various substitutions (R) under the catalytic condition of cuprous iodide⁸) Or coupling unsubstituted 2-azetidinone to obtain a compound 11, oxidizing by m-chloroperoxybenzoic acid to obtain a methanesulfinyl compound 12, and finally substituting by different amino compounds (6) under heating to obtain the corresponding compound with the structure of a general formula VII.

Reaction formula 4

The compound of formula VIII can be prepared according to the same reaction scheme as the compound of formula VII except that the coupling with bromide 1 is catalyzed by copper powder for various substitutions (R)⁸) Or the reaction of non-substituted 2-pyrrolidone can obtain a coupling product 13 with the catalytic yield equivalent to that of cuprous iodide, then the coupling product is oxidized by m-chloroperoxybenzoic acid to obtain a methanesulfinyl compound 14, and finally the coupling product is substituted by different amino compounds (6) under the heating condition to obtain the corresponding compound with the structure of the general formula VIII.

Example 1

(8-cyclopentyl-2-methylsulfanyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-6-yl) -N' -hydroxyformamidine (3a)

2a (5g,17.46mmol), hydroxylamine hydrochloride (2.67g,38.41mmol) and sodium bicarbonate (3.23g,38.41mmol) were placed in a reaction flask, t-butanol (60mL) was added, and the reaction was heated to 70 ℃ with stirring overnight. After bringing to room temperature, the reaction was diluted with methanol (80mL) and filtered, the filtrate was concentrated and the resulting crude product was filtered again and washed with solvent (methyl tert-butyl ether/petroleum ether ═ 3:1, ca. 15mL) to give 3a (5.2g, 93.4%) as a yellow solid.

¹H NMR(400MHz,DMSO-d₆,ppm):9.70(s,1H),8.99(s,1H),8.19(s,1H),5.94(br,2H),5.94–5.82(m,1H),2.59(s,3H),2.31–2.17(m,2H),2.07–1.93(m,2H),1.90–1.77(m,2H),1.71–1.58(m,2H).

8-cyclopentyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (4a)

3a (3.9g,12.21mmol) and acetic anhydride (6.23g,61.05mmol) were dissolved in pyridine (30mL), heated to 120 ℃ with stirring for 3 hours, and then allowed to cool to room temperature naturally and stirred overnight. Most of pyridine was removed by rotary evaporation, and the reaction mixture was diluted with ethyl acetate (about 40mL), washed with saturated aqueous copper sulfate solution 2 times, washed with saturated brine 1 time, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatographed (5: 1 to 1:1 petroleum ether/ethyl acetate) to give 4a (2.1g, 45.8%) as a white solid.

¹H NMR(400MHz,CDCl₃,ppm):8.71(s,1H),8.44(s,1H),6.12–6.03(m,1H),2.66(s,3H),2.64(s,3H),2.42–2.33(m,2H),2.18–2.09(m,2H),1.95–1.87(m,2H),1.73–1.66(m,2H).

8-cyclopentyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (5a)

4a (2.1g,6.11mmol) was dissolved in dichloromethane (20mL) and then m-chloroperoxybenzoic acid (85%, 0.993g,4.89mmol) was added and stirred at room temperature for 12 hours. Saturated aqueous sodium sulfite (20mL) was added to extract the reaction out, followed by three extractions with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatographed (1: 1 to 0:1 petroleum ether/ethyl acetate) to give 5a (1.49g, 67.6%) as a white solid.

¹H NMR(400MHz,CDCl₃,ppm):9.05(s,1H),8.59(s,1H),6.16–6.07(m,1H),3.02(s,3H),2.70(s,3H),2.37–2.28(m,2H),2.22–2.14(m,2H),2.02–1.93(m,2H),1.76–1.67(m,2H).

8-cyclopentyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one (V-1)

5a (100mg,0.278mmol) and 6a (107mg,0.556mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and replaced with argon 3 times, toluene (3mL) was added, and the mixture was heated to 100 ℃ under stirring with an argon balloon overnight for reaction. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 2 hours. The precipitated solid was filtered and washed with ethyl acetate to give V-1(40mg, 29.5%) as a yellow solid.

¹H NMR(400MHz,CDCl₃,ppm):9.15(br,1H),8.78(s,1H),8.41(s,1H),8.19(d,J＝9.2Hz,1H),8.13(d,J＝2.8Hz,1H),7.34(dd,J＝9.0,3.0Hz,1H),6.05–5.96(m,1H),3.24(t,J＝5.0Hz,4H),2.66(s,3H),2.61(t,J＝4.8Hz,4H),2.49–2.34(m,2H),2.37(s,3H),2.20–2.10(m,2H),1.95–1.87(m,2H),1.74–1.64(m,2H).

HRMS (ESI) for C₂₅H₂₉N₉O₂[M+H]⁺488.2517 for the calculated value m/z; measured value m/z is 488.2515.

Table 1 examples 2-7

Example 2

4- (6- (8-cyclopentyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (V-2a)

5a (200mg,0.556mmol) and 6b (170.4mg,0.612mmol) were placed in a dry 15mL reaction tube, sealed with a rubber stopper and replaced with argon for 3 times, toluene (5mL) was added, and the mixture was heated to 100 ℃ under stirring with an argon balloon for 6 hours. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 2 hours. The precipitated solid was filtered, and washed with ethyl acetate to give a yellow solid, i.e., V-2a (102mg, 32%).

¹H NMR(400MHz,CDCl₃,ppm):9.15(br,1H),8.79(s,1H),8.41(s,1H),8.21(d,J＝9.2Hz,1H),8.13(d,J＝2.8Hz,1H),7.34(dd,J＝9.2,2.8Hz,1H),6.05–5.96(m,1H),3.62(t,J＝5.0Hz,4H),3.15(t,J＝5.0Hz,4H),2.66(s,3H),2.47–2.39(m,2H),2.20–2.11(m,2H),1.95–1.87(m,2H),1.74–1.65(m,2H),1.49(s,9H).

8-cyclopentyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -2- (5- (piperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (V-2)

Placing V-2a (90mg,0.157mmol) in a reaction bottle, adding 1, 4-dioxane solution of hydrogen chloride (4N,4mL) and methanol (4mL), stirring at room temperature for 4 hours, removing the solvent by rotary evaporation under reduced pressure, and washing the obtained crude product with ethyl acetate and ether sequentially to obtain yellow powder, namely V-2(76mg, 95%).

¹H NMR(400MHz,DMSO-d₆,ppm):11.41(br,1H),9.57(br,2H),9.13(s,1H),8.71(s,1H),8.07(s,1H),8.01(d,J＝9.2Hz,1H),7.84(d,J＝9.2Hz,1H),5.95–5.87(m,1H),3.51–3.43(m,4H),3.29–3.20(m,4H),2.66(s,3H),2.30–2.21(m,2H),2.05–1.95(m,2H),1.87–1.79(m,2H),1.66–1.57(m,2H).

HRMS (ESI) for C₂₄H₂₇N₉O₂[M+H]⁺474.2360 for the calculated value m/z; measured value m/z is 474.2359.

Example 3

Referring to the method for the synthesis of V-2a in example 2, compound V-3a (36.9mg, 27%) was obtained by reacting compound 5a (80mg,0.223mmol) with 6c (74.4mg,0.234 mmol).

HRMS (ESI) for C₃₂H₃₉N₉O₄[M+H]⁺614.3198 for the calculated value m/z; measured value m/z is 614.3206.

With reference to the method for synthesizing V-2 in example 2, the title compound V-3(28mg, 96%) was prepared from compound V-3a (32.5mg,0.053 mmol).

HRMS (ESI) for C₂₇H₃₁N₉O₂[M+H]⁺514.2673 for the calculated value m/z; measured value m/z is 514.2679.

Example 4

Referring to the method for the synthesis of V-2a in example 2, compound 5a (63.4mg,0.176mmol) and 6d (59mg,0.185mmol) were reacted to give compound V-4a (26mg, 24%).

HRMS (ESI) for C₃₂H₃₉N₉O₄[M+H]⁺614.3198 for the calculated value m/z; measured value m/z is 614.3203.

With reference to the method for synthesizing V-2 in example 2, the title compound V-4(19mg, 97%) was prepared from compound V-4a (21.9mg,0.036 mmol).

HRMS (ESI) for C₂₇H₃₁N₉O₂[M+H]⁺514.2674 for the calculated value m/z; measured value m/z is 514.2677.

Example 5

Referring to the method for synthesizing V-1 in example 1, compound 5a (90mg,0.25mmol) and 6e (58.2mg,0.263mmol) were reacted to give the title compound V-5(29.2mg, 22.6%).

HRMS (ESI) for C₂₇H₃₄N₉O₂[M+H]⁺516.2830 for the calculated value m/z; measured value m/z is 516.2837.

Example 6

Referring to the method for synthesizing V-1 in example 1, compound 5a (90mg,0.25mmol) and 6f (55.3mg,0.263mmol) were reacted to give the title compound V-6(36mg, 28.5%).

HRMS (ESI) for C₂₆H₃₁N₇O₄[M+H]⁺506.2510 for the calculated value m/z; measured value m/z is 506.2514.

Example 7

Referring to the method for synthesizing V-2a in example 2, compound V-7a (45.2mg, 30.7%) was obtained by reacting compound 5a (90mg,0.25mmol) with 6g (76.9mg,0.263 mmol).

HRMS (ESI) for C₃₀H₃₇N₉O₄[M+H]⁺588.3041 for the calculated value m/z; measured value m/z is 588.3047.

With reference to the method for synthesizing V-2 in example 2, the title compound V-7(35mg, 98%) was prepared from compound V-7a (40mg,0.068 mmol).

HRMS (ESI) for C₂₅H₂₉N₉O₂[M+H]⁺488.2517 for the calculated value m/z; measured value m/z is 488.2523.

Example 8

8-cyclopentyl-2-methylsulfanyl-6- (1,2, 4-oxadiazol-3-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (4b)

3a (2g,6.26mmol) was placed in a reaction flask, triethyl orthoformate (30mL) was added, and the mixture was heated to 130 ℃ with stirring for 12 hours. The excess triethyl orthoformate was removed by rotary evaporation under reduced pressure and the crude product obtained was purified by column chromatography (3: 1 to 1:1 petroleum ether/ethyl acetate) to give 4b (1g, 44.2%) as a white solid.

¹H NMR(400MHz,CDCl₃,ppm):8.79(s,1H),8.74(s,1H),8.53(s,1H),6.14–6.05(m,1H),2.65(s,3H),2.43–2.34(m,2H),2.20–2.10(m,2H),1.97–1.88(m,2H),1.75–1.65(m,2H).

8-cyclopentyl-2-methanesulfinyl-6- (1,2, 4-oxadiazol-3-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (5b)

4b (1g,3.04mmol) was dissolved in dichloromethane (20mL) and then m-chloroperoxybenzoic acid (85%, 0.506g,2.49mmol) was added and stirred at room temperature for 3 hours. Saturated aqueous sodium sulfite (20mL) was added to extract the reaction out, followed by three extractions with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatographed (petroleum ether/ethyl acetate 2:1 to 0:1) to give 5b (0.73g, 69.7%) as a pale yellow solid.

¹H NMR(400MHz,CDCl₃,ppm):9.09(s,1H),8.84(s,1H),8.67(s,1H),6.18–6.09(m,1H),3.03(s,3H),2.37–2.29(m,2H),2.24–2.14(m,2H),2.04–1.94(m,2H),1.77–1.67(m,2H).

8-cyclopentyl-2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -6- (1,2, 4-oxadiazol-3-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (V-8)

With reference to the synthesis of V-1 in example 1, the title compound V-8(88mg, 32%) was prepared from 5b (200mg,0.579mmol) and 6a (122.5mg,0.637 mmol).

¹H NMR(400MHz,CDCl₃,ppm):8.78(s,1H),8.76(s,1H),8.49(s,1H),8.19(d,J＝9.2Hz,1H),8.11(d,J＝2.8Hz,1H),7.35(dd,J＝9.2,2.8Hz,1H),6.06–5.97(m,1H),3.24(t,J＝5.0Hz,4H),2.62(t,J＝5.0Hz,4H),2.47–2.37(m,2H),2.38(s,3H),2.21–2.11(m,2H),1.97–1.88(m,2H),1.75–1.69(m,2H).

HRMS (ESI) for C₂₄H₂₇N₉O₂[M+H]⁺474.2360 for the calculated value m/z; measured value m/z is 474.2368.

TABLE 2 examples 9-14

Example 9

Referring to the procedure for the synthesis of V-2a in example 2, compound V-9a (55.7mg, 17.2%) was obtained by reacting compound 5b (200mg,0.579mmol) and 6c (177.3mg,0.637 mmol).

¹H NMR(400MHz,CDCl₃,ppm):8.77(s,1H),8.76(s,1H),8.61(br,1H),8.50(s,1H),8.21(d,J＝8.8Hz,1H),8.09(d,J＝2.8Hz,1H),7.35(dd,J＝9.2,3.2Hz,1H),6.06–5.97(m,1H),3.62(t,J＝5.0Hz,4H),3.15(t,J＝5.0Hz,4H),2.48–2.38(m,2H),2.22–2.12(m,2H),1.97–1.89(m,2H),1.75–1.67(m,2H),1.49(s,9H).

Referring to the method for synthesizing V-2 in example 2, the title compound V-9(49mg, 99%)

¹H NMR(400MHz,DMSO-d₆,ppm):11.24(br,1H),9.72(s,1H),9.48(br,2H),9.13(s,1H),8.74(s,1H),8.08(s,1H),7.94(d,J＝8.4Hz,1H),7.85(d,J＝9.2Hz,1H),5.96–5.87(m,1H),3.48–3.45(m,4H),3.29–3.21(m,4H),2.33–2.22(m,2H),2.03–1.94(m,2H),1.87–1.80(m,2H),1.67–1.58(m,2H).

HRMS (ESI) for C₂₃H₂₅N₉O₂[M+H]⁺460.2204 for the calculated value m/z; measured value m/z is 460.2207.

Example 10

Referring to the method for the synthesis of V-2a in example 2, compound 5b (100mg,0.29mmol) and 6c (96.8mg,0.3mmol) were reacted to give compound V-10a (50.4mg, 29%).

HRMS (ESI) for C₃₁H₃₇N₉O₄[M+H]⁺600.3041 for the calculated value m/z; measured value m/z is 600.3048.

Referring to the synthesis of V-2 in example 2, the title compound V-10(39.8mg, 99%) was prepared from compound V-10a (45mg,0.075 mmol).

HRMS (ESI) for C₂₆H₂₉N₉O₂[M+H]⁺500.2517 for the calculated value m/z; measured value m/z is 500.2510.

Example 11

Referring to the method for the synthesis of V-2a in example 2, compound 5b (100mg,0.29mmol) and 6d (96.8mg,0.3mmol) were reacted to give compound V-11a (48.7mg, 28%).

HRMS (ESI) for C₃₁H₃₇N₉O₄[M+H]⁺600.3041 for the calculated value m/z; measured value m/z is 600.3037.

Referring to the synthesis of V-2 in example 2, the title compound V-11(38mg, 99%) was prepared from compound V-11a (43mg,0.072 mmol).

HRMS (ESI) for C₂₆H₂₉N₉O₂[M+H]⁺500.2517 for the calculated value m/z; measured value m/z is 500.2505.

Example 12

Referring to the method for synthesizing V-1 in example 1, compound 5b (100mg,0.29mmol) and 6e (67.3mg,0.3mmol) were reacted to give the title compound V-12(33.5mg, 23%).

HRMS (ESI) for C₂₆H₃₂N₉O₂[M+H]⁺502.2673 for the calculated value m/z; measured value m/z is 502.2684.

Example 13

Referring to the method for synthesizing V-1 in example 1, compound 5b (100mg,0.29mmol) and 6f (63.9mg,0.3mmol) were reacted to give the title compound V-13(41.8mg, 29.3%).

HRMS (ESI) for C₂₅H₂₉N₇O₄[M+H]⁺492.2354 for the calculated value m/z; measured value m/z is 492.2356.

Example 14

Referring to the method for synthesizing V-2a in example 2, compound V-14a (47.7mg, 28.7%) was obtained by reacting compound 5b (100mg,0.29mmol) with 6g (88.9mg,0.3 mmol).

HRMS (ESI) for C₂₉H₃₅N₉O₄[M+H]⁺574.2885 for the calculated value m/z; measured value m/z is 574.2879.

Referring to the method for synthesizing V-2 in example 2, the title compound V-14(37mg, 99%) was prepared from compound V-14a (42mg,0.073 mmol).

HRMS (ESI) for C₂₄H₂₇N₉O₂[M+H]⁺474.2360 for the calculated value m/z; measured value m/z is 474.2366.

Example 15

8-cyclopentyl-N' - ((cyclopropanecarbonyl) oxy) -2- (methylthio) -7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carboxamidine (3ac)

Cyclopropanecarboxylic acid (568mg,6.6mmol) was dissolved in dichloromethane (25mL) under argon and 1-hydroxybenzotriazole (892mg,6.6mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.27g,6.6mmol) were added. The resulting solution was stirred at room temperature for 20 minutes, then crude 3c (1.89g,6mmol) was added and stirring continued for 2 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane. After the organic phases are combined, the organic phases are washed by sodium hydroxide aqueous solution (1N) and saturated saline solution in sequence, dried by anhydrous sodium sulfate, filtered and dried in a spinning way to obtain yellow foamy solid, namely a crude product of 3ac, which can be directly used for the next reaction.

8-cyclopentyl-6- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (4c)

Under the protection of argon, crude 3ac (6mmol) was dissolved in a mixed solvent of ethanol and water (4:1,30mL), sodium acetate trihydrate (2.04g,15mmol) was added, and the resulting reaction solution was sealed and heated to 90 ℃ for reaction for 14 hours. After the reaction solution was cooled, it was diluted with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (petroleum ether: dichloromethane: acetone: 7:1:1) to give 4c as a yellow foamy solid (1.01g, 45.3% overall yield in three steps).

HRMS (ESI) for C₁₈H₂₀N₅O₂S[M+H]⁺370.1332 for the calculated value m/z; measured value m/z is 370.1323.

8-cyclopentyl-6- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (5c)

After 4c (922mg,2.5mmol) was dissolved in chloroform (30mL), 2-benzenesulfonyl-3-phenylazepino propane (718mg,2.75mmol) was added, and the mixture was stirred at room temperature for 15 hours. After evaporation of the solvent to dryness, the crude product was purified by column chromatography (dichloromethane: methanol 50:1) to yield 5c (876mg, 91%) as a yellow solid.

HRMS (ESI) for C₁₈H₂₀N₅O₃S[M+H]⁺386.1281 for the calculated value m/z; measured value m/z is 386.1293.

(6- ((8-cyclopentyl-6- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (V-15a)

5c (193mg,0.5mmol) and 6b (139mg,0.5mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and replaced with argon for 3 times, and then benzotrifluoride (1mL) was added and heated to 80 ℃ under stirring with an argon balloon for 16 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the obtained reaction residue was subjected to column chromatography (petroleum ether: dichloromethane: acetone ═ 5:2:1) to obtain a crude product, which was then washed with a mixed solvent of methyl tert-butyl ether and ethyl acetate (4:3) to obtain a yellow solid, i.e., V-15a (72.2mg, 24.1%).

HRMS (ESI) for C₃₁H₃₈N₉O₄[M+H]⁺600.3041 for the calculated value m/z; measured value m/z is 600.3023.

8-cyclopentyl-6- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one hydrochloride (V-15)

With reference to the synthesis of V-2 in example 2, the title compound V-15(26mg, 97%) was prepared from V-15a (30mg, 50. mu. mol).

HRMS (ESI) for C₂₆H₃₀N₉O₂[M+H]⁺500.2517 for the calculated value m/z; measured value m/z is 500.2539.

Table 3 examples 16 to 19

Example 16

Referring to the method for synthesizing V-1 in example 1, compound 5c (115.5mg,0.3mmol) and 6h (53.7mg,0.3mmol) were reacted to give the title compound V-16(40.5mg, 27%).

HRMS (ESI) for C₂₆H₂₉N₈O₃[M+H]⁺501.2357 for the calculated value m/z; measured value m/z is 501.2359.

Example 17

Referring to the method for synthesizing V-1 in example 1, compound 5c (115.5mg,0.3mmol) and 6a (57.6mg,0.3mmol) were reacted to give the title compound V-17(47.7mg, 31%).

HRMS (ESI) for C₂₇H₃₂N₉O₂[M+H]⁺514.2673 for the calculated value m/z; measured value m/z is 514.2689.

Example 18

Referring to the method for synthesizing V-2a in example 2, compound V-18a (31.3mg, 21%) was obtained by reacting compound 5c (115.5mg,0.3mmol) with 6i (88mg,0.3 mmol).

HRMS (ESI) for C₃₂H₄₀N₉O₄[M+H]⁺614.3198 for the calculated value m/z; measured value m/z is 614.3203.

The title compound V-18(31.3mg, 99%) was prepared from compound V-18a (35.0mg, 57. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₇H₃₂N₉O₂[M+H]⁺514.2673 for the calculated value m/z; measured value m/z is 514.2688.

Example 19

Referring to the method for synthesizing V-2a in example 2, compound V-19a (60.7mg, 33%) was obtained by reacting compound 5c (115.5mg,0.3mmol) with 6g (88mg,0.3 mmol).

HRMS (ESI) for C₃₂H₄₀N₉O₄[M+H]⁺614.3198 for the calculated value m/z; measured value m/z is 614.3183.

The title compound V-19(35.7mg, 99%) was prepared from compound V-19a (40mg, 65. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₇H₃₂N₉O₂[M+H]⁺514.2673 for the calculated value m/z; measured value m/z is 514.2679.

Example 20

8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (2b)

After sealing 10mL under argon atmosphere, 1b (100mg,0.28mmol), cuprous cyanide (112mg,1.25mmol) and 1-methyl-2-pyrrolidone (1mL) were added, and the mixture was heated and stirred at 150 ℃ for 3 hours. After cooling to room temperature, the tube was opened, the reaction solution was diluted with ethyl acetate and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and column chromatographed to give 2b (29mg, 34.2%) as an off-white solid.

¹H NMR(400MHz,CDCl₃,ppm):8.81(s,1H),5.98–5.89(m,1H),2.72(s,3H),2.63(s,3H),2.31–2.23(m,2H),2.12–2.05(m,2H),1.92–1.84(m,2H),1.73–1.66(m,2H).

(8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-6-yl) -N' -hydroxyformamidine (3b)

2b (750mg,2.5mmol), hydroxylamine hydrochloride (433mg,6.24mmol) and sodium bicarbonate (524mg,6.24mmol) were placed in a reaction flask, tert-butanol (30mL) was added and the reaction was heated to 70 ℃ with stirring overnight. After bringing to room temperature, the reaction was diluted with methanol (10mL) and filtered, the filtrate was concentrated and the resulting crude product was filtered again and washed with solvent (methyl tert-butyl ether/petroleum ether ═ 3:1, ca. 5mL) to give 3b (378mg, 45.4%) as a yellow solid.

¹H NMR(400MHz,DMSO-d₆,ppm):8.79(s,1H),6.00–5.91(m,1H),4.99(br,2H),2.62(s,3H),2.52(s,3H),2.35–2.25(m,2H),2.09–2.01(m,2H),1.90–1.82(m,2H),1.71–1.61(m,2H).

8-cyclopentyl-5-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (4d)

3b (378mg,1.13mmol) and acetic anhydride (289mg,2.83mmol) were dissolved in pyridine (3mL) and heated to 120 ℃ with stirring for 2 hours. Most of pyridine was removed by rotary evaporation, and the reaction mixture was diluted with ethyl acetate (about 30mL), washed with saturated aqueous copper sulfate solution 2 times, washed with saturated brine 1 time, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatographed (petroleum ether/ethyl acetate 10:1) to give 4d (243mg, 60%) as a yellow oil.

¹H NMR(400MHz,CDCl₃,ppm):8.82(s,1H),6.05–5.96(m,1H),2.70(s,3H),2.64(s,3H),2.40(s,3H),2.37–2.28(m,2H),2.11–2.01(m,2H),1.92–1.84(m,2H),1.71–1.62(m,2H).

8-cyclopentyl-5-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (5d)

After 4d (247mg,0.69mmol) was dissolved in chloroform (2mL), 2-benzenesulfonyl-3-phenyloxaziridine (239.7mg,0.91mmol) was added, and the mixture was stirred at room temperature for 3 hours. After evaporation of the solvent to dryness, the crude product was purified by column chromatography (petroleum ether/ethyl acetate 1:1 to 0:1) to give 5d (170mg, 65.9%) as a yellow oil.

¹H NMR(400MHz,CDCl₃,ppm):9.14(s,1H),6.06–5.97(m,1H),3.00(s,3H),2.71(s,3H),2.49(s,3H),2.29–2.21(m,2H),2.13–2.05(m,2H),1.98–1.88(m,2H),1.71–1.63(m,2H).

4- (6- (8-cyclopentyl-5-methyl-6- (5-methyl-1, 2, 4-oxadiazol-3-yl) -7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (V-20a)

Referring to the synthesis of V-15a in example 15, V-20a (23.9mg, 14.7%) was prepared from 5d (103mg,0.276mmol) and 6b (80.6mg,0.29 mmol).

HRMS (ESI) for C₃₀H₃₇N₉O₄[M+H]⁺588.3041 for the calculated value m/z; measured value m/z is 588.3037.

With reference to the synthesis of V-15 in example 15, the title compound V-20(21mg, 99%) was prepared from V-20a (23.9mg,0.04 mmol).

¹H NMR(400MHz,D₂O,ppm):9.07(s,1H),8.06(d,J＝7.6Hz,1H),7.86(s,1H),7.51(d,J＝9.6Hz,1H),5.88–5.79(m,1H),3.54–3.52(m,4H),3.46–3.44(m,4H),2.72(s,3H),2.41(s,3H),2.14–2.07(m,2H),2.02–1.89(m,4H),1.71–1.65(m,2H).

TABLE 4 examples 21 to 25

Example 21

Referring to the method for synthesizing V-15a in example 15, compound V-21a (31.4mg, 18.7%) was obtained by reacting compound 5d (100mg,0.268mmol) and 6c (89.5mg,0.281 mmol).

HRMS (ESI) for C₃₃H₄₁N₉O₄[M+H]⁺628.3354 for the calculated value m/z; measured value m/z is 628.3361.

Referring to the method for synthesizing V-2 in example 2, the title compound V-21(23.6mg, 99%) was prepared from compound V-21a (26.5mg,0.042 mmol).

HRMS (ESI) for C₂₈H₃₃N₉O₂[M+H]⁺528.2830 for the calculated value m/z; measured value m/z is 528.2833.

Example 22

Referring to the method for synthesizing V-15a in example 15, compound V-22a (28.9mg, 17.2%) was obtained by reacting compound 5d (100mg,0.268mmol) and 6d (89.5mg,0.281 mmol).

HRMS (ESI) for C₃₃H₄₁N₉O₄[M+H]⁺628.3354 for the calculated value m/z; measured value m/z is 628.3357.

Referring to the method for synthesizing V-2 in example 2, the title compound V-22(22mg, 98%) was prepared from compound V-22a (25mg,0.04 mmol).

HRMS (ESI) for C₂₈H₃₃N₉O₂[M+H]⁺528.2830 for the calculated value m/z; measured value m/z is 528.2826.

Example 23

Referring to the method for synthesizing V-1 in example 1, compound 5d (100mg,0.268mmol) and 6e (62.2mg,0.281mmol) were reacted to give the title compound V-23(22.5mg, 15.8%).

HRMS (ESI) for C₂₈H₃₆N₉O₂[M+H]⁺530.2986 for the calculated value m/z; measured value m/z is 530.3001.

Example 24

Referring to the method for synthesizing V-1 in example 1, compound 5d (100mg,0.268mmol) and 6f (59.1mg,0.281mmol) were reacted to give the title compound V-24(19.3mg, 13.9%).

HRMS (ESI) for C₂₇H₃₃N₇O₄[M+H]⁺520.2667 for the calculated value m/z; measured value m/z is 520.2678.

Example 25

Referring to the method for synthesizing V-15a in example 15, compound V-25a (21.9mg, 13.6%) was obtained by reacting compound 5d (100mg,0.268mmol) with 6g (82.2mg,0.281 mmol).

Referring to the method for synthesizing V-2 in example 2, the title compound V-25(15.8mg, 98%) was prepared from compound V-25a (18mg,0.03 mmol).

HRMS (ESI) for C₂₆H₃₁N₉O₂[M+H]⁺502.2673 for the calculated value m/z; measured value m/z is 502.2670.

Example 26

8-cyclopentyl-5-methyl-2-methylsulfanyl-6- (1,2, 4-oxadiazol-3-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (4e)

3b (300mg,0.9mmol) was placed in a reaction flask, triethyl orthoformate (3mL) was added, and the mixture was heated to 130 ℃ with stirring for reaction for 3 hours. The excess triethyl orthoformate was removed by rotary evaporation under reduced pressure and the crude product was purified by column chromatography to give 4e (110mg, 35.6%) as a yellow oil.

¹H NMR(400MHz,CDCl₃,ppm):8.91(s,1H),8.84(s,1H),6.06–5.97(m,1H),2.65(s,3H),2.40(s,3H),2.36–2.28(m,2H),2.11–2.01(m,2H),1.93–1.85(m,2H),1.71–1.64(m,2H).

8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (1,2, 4-oxadiazol-3-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (5e)

4e (110mg,0.32mmol) was dissolved in dichloromethane (2mL), cooled to 0 ℃ in an ice water bath, and then m-chloroperoxybenzoic acid (44.2mg,0.256mmol) was added in portions and stirred at room temperature for 3 hours. Saturated aqueous sodium sulfite (2mL) was added to extract the reaction out, followed by three extractions with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatographed (1: 1 to 0:1 petroleum ether/ethyl acetate) to give 5e (80mg, 69.5%) as a yellow solid.

¹H NMR(400MHz,CDCl₃,ppm):9.16(s,1H),8.95(s,1H),6.08–6.00(m,1H),3.02(s,3H),2.50(s,3H),2.30–2.21(m,2H),2.15–2.06(m,2H),2.00–1.90(m,2H),1.75–1.65(m,2H).

4- (6- (8-cyclopentyl-5-methyl-6- (1,2, 4-oxadiazol-3-yl) -7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (V-26a)

Referring to the procedure for the synthesis of V-15a in example 15, compound V-26a (17.7mg, 12.3%) was reacted from compound 5e (90mg,0.25mmol) and 6b (73.2mg,0.263 mmol).

¹H NMR(400MHz,CDCl₃,ppm):8.90(s,1H),8.87(s,1H),8.46(br,1H),8.21(d,J＝9.2Hz,1H),8.06(d,J＝3.2Hz,1H),7.35(dd,J＝9.2,2.8Hz,1H),6.00–5.91(m,1H),3.62(t,J＝5.0Hz,4H),3.14(t,J＝5.0Hz,4H),2.39(s,3H),2.39–2.31(m,2H),2.10–2.02(m,2H),1.93–1.85(m,2H),1.70–1.63(m,2H),1.49(s,9H).

8-cyclopentyl-5-methyl-6- (1,2, 4-oxadiazol-3-yl) -2- (5- (piperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (V-26)

Referring to the method for synthesizing V-2 in example 2, the title compound V-26(15mg, 98%) was prepared from compound V-26a (17.2mg,0.03 mmol).

¹H NMR(400MHz,D₂O,ppm):9.44(s,1H),9.05(s,1H),8.02(d,J＝4.0Hz,1H),7.85(s,1H),7.49(d,J＝6.4Hz,1H),5.83–5.79(m,1H),3.53–3.52(m,4H),3.46–3.45(m,4H),2.38(s,3H),2.11–2.07(m,2H),1.99–1.91(m,4H),1.70–1.66(m,2H).

TABLE 5 examples 27 to 31

Example 27

Referring to the method for synthesizing V-15a in example 15, compound V-27a (18.1mg, 11.8%) was obtained by reacting compound 5e (90mg,0.25mmol) with 6c (83.7mg,0.263 mmol).

Referring to the synthesis of V-2 in example 2, the title compound V-27(13.2mg, 98%) was prepared from compound V-27a (15mg,0.024 mmol).

HRMS (ESI) for C₂₇H₃₁N₉O₂[M+H]⁺514.2673 for the calculated value m/z; measured value m/z is 514.2667.

Example 28

Referring to the procedure for the synthesis of V-15a in example 15, compound 5e (90mg,0.25mmol) and 6d (83.7mg,0.263mmol) were reacted to give compound V-28a (19.6mg, 12.8%).

HRMS (ESI) for C₃₂H₃₉N₉O₄[M+H]⁺614.3198 for the calculated value m/z; measured value m/z is 614.3194.

Referring to the synthesis of V-2 in example 2, the title compound V-28(13mg, 97%) was prepared from compound V-28a (15mg,0.024 mmol).

HRMS (ESI) for C₂₇H₃₁N₉O₂[M+H]⁺514.2673 for the calculated value m/z; measured value m/z is 514.2677.

Example 29

Referring to the method for synthesizing V-1 in example 1, compound 5e (90mg,0.25mmol) and 6e (58.2mg,0.263mmol) were reacted to give the title compound V-29(17.2mg, 13.3%).

HRMS (ESI) for C₂₇H₃₄N₉O₂[M+H]⁺516.2830 for the calculated value m/z; measured value m/z is 516.2844.

Example 30

Referring to the method for synthesizing V-1 in example 1, compound 5e (90mg,0.25mmol) and 6f (55.3mg,0.263mmol) were reacted to give the title compound V-30(22.4mg, 17.7%).

HRMS (ESI) for C₂₆H₃₁N₇O₄[M+H]⁺506.2510 for the calculated value m/z; measured value m/z is 506.2512.

Example 31

Referring to the method for synthesizing V-15a in example 15, compound V-31a (15.6mg, 10.6%) was obtained by reacting compound 5e (90mg,0.25mmol) with 6g (76.9mg,0.263 mmol).

HRMS (ESI) for C₃₀H₃₇N₉O₄[M+H]⁺588.3041 for the calculated value m/z; measured value m/z is 588.3038.

With reference to the method for synthesizing V-2 in example 2, the title compound V-31(11.9mg, 99%) was prepared from compound V-31a (13.5mg,0.023 mmol).

HRMS (ESI) for C₂₅H₂₉N₉O₂[M+H]⁺488.2517 for the calculated value m/z; measured value m/z is 488.2520.

Example 32

8-cyclopentyl-6- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one hydrochloride (V-32)

8-cyclopentyl-N' - ((cyclopropanecarbonyl) oxy) -5-methyl-2- (methylthio) -7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carboxamidine (3bf)

Cyclopropanecarboxylic acid (1.33g,15.5mmol) was dissolved in dichloromethane (150mL) under argon and 1-hydroxybenzotriazole (2.09g,15.5mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.97g,15.5mmol) were added. The resulting solution was stirred at room temperature for 20 minutes, then crude 3b (14.1mmol) was added and stirring continued for 2 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane. The organic phases are combined and washed by sodium hydroxide aqueous solution (1N) and saturated saline solution in sequence, dried by anhydrous sodium sulfate, filtered and dried in a spinning way to obtain yellow foamy solid, namely a crude product of 3bf, which can be directly used for the next reaction.

8-cyclopentyl-6- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (4f)

Under the protection of argon, crude 3bf (15mmol) is dissolved in a mixed solvent of ethanol and water (4:1,75mL), sodium acetate trihydrate (4.80g,35.3mmol) is added, and the obtained reaction solution is heated to 90 ℃ for reaction for 14 hours after being sealed. After the reaction solution was cooled, it was diluted with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (petroleum ether: dichloromethane: acetone: 7:1:1) to give 4f (2.47g, 45.7% overall yield in three steps) as a yellow foamy solid.

¹H NMR(400MHz,CDCl₃,ppm):8.81(s,1H),6.03–5.94(m,1H),2.64(s,3H),2.37(s,3H),2.35–2.27(m,3H),2.09–2.01(m,2H),1.91–1.83(m,2H),1.71–1.64(m,2H),1.34–1.32(m,2H),1.30–1.27(m,2H).

8-cyclopentyl-6- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -5-methyl-2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (5f)

After 4f (2.43g,6.33mmol) was dissolved in chloroform (110mL), 2-benzenesulfonyl-3-phenyloxaziridine (776.9mg,2.973mmol) was added and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated to dryness and the crude product was purified by column chromatography (dichloromethane: methanol ═ 50:1) to yield 5f (2.5g, 99%) as a yellow solid.

¹H NMR(400MHz,CDCl₃,ppm):9.12(s,1H),6.05–5.96(m,1H),3.01(s,3H),2.46(s,3H),2.38–2.23(m,3H),2.13–2.07(m,2H),1.98–1.88(m,2H),1.71–1.65(m,2H),1.37–1.27(m,4H).

(6- ((8-cyclopentyl-6- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -5-methyl-7-oxo-7, 8-dihydropyrido [2,3-3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (V-32a)

Referring to the synthesis of V-2a in example 2, compound V-32a (18.4mg, 20.8%) was prepared from 5f (57.5mg,0.144mmol) and 6b (42mg,0.151 mmol).

¹H NMR(400MHz,CDCl₃,ppm):8.84(s,1H),8.38(br,1H),8.20(d,J＝9.2Hz,1H),8.06(d,J＝2.4Hz,1H),7.34(dd,J＝9.2,2.8Hz,1H),5.97–5.88(m,1H),3.62(t,J＝4.8Hz,4H),3.13(t,J＝4.4Hz,4H),2.36(s,3H),2.33–2.27(m,3H),2.07–2.02(m,2H),1.90–1.85(m,2H),1.72–1.66(m,2H),1.49(s,9H),1.34–1.31(m,2H),1.29–1.27(m,2H).

With reference to the synthesis of V-2 in example 2, the title compound V-32(16mg, 97%) was prepared from V-32a (18.4mg,0.03 mmol).

¹H NMR(400MHz,D₂O,ppm):9.07(s,1H),8.06(d,J＝9.2Hz,1H),7.87(s,1H),7.52(d,J＝9.2Hz,1H),5.87–5.78(m,1H),3.55–3.47(m,8H),2.45–2.39(m,1H),2.41(s,3H),2.15–2.08(m,2H),2.01–1.90(m,4H),1.73–1.66(m,2H),1.43–1.38(m,2H),1.31–1.27(m,2H).

TABLE 6 examples 34 to 36

Example 33

Referring to the method for synthesizing V-1 in example 1, the title compound V-33(20.5mg, 26%) was obtained by reacting compound 5f (60mg,0.15mmol) and 6a (29mg,0.15 mmol).

HRMS (ESI) for C₂₈H₃₄N₉O₂[M+H]⁺528.2830 for the calculated value m/z; measured value m/z is 528.2833.

Example 34

Referring to the method for the synthesis of V-2a in example 2, compound V-34a (26.5mg, 27%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6c (47.7mg,0.15 mmol).

HRMS (ESI) for C₃₅H₄₄N₉O₄[M+H]⁺654.3511 for the calculated value m/z; measured value m/z is 654.3519.

The title compound V-34(18mg, 99%) was prepared from compound V-34a (20mg, 30.6. mu. mol) by following the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₃₀H₃₆N₉O₂[M+H]⁺554.2986 for the calculated value m/z; measured value m/z is 554.2991.

Example 35

Referring to the method for the synthesis of V-2a in example 2, compound V-35a (20.5mg, 21%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6d (47.7mg,0.15 mmol).

The title compound V-35(13.5mg, 99%) was prepared from compound V-35a (15mg,23. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₃₀H₃₆N₉O₂[M+H]⁺554.2986 for the calculated value m/z; measured value m/z is 554.2977.

Example 36

Referring to the method for synthesizing V-1 in example 1, compound 5f (60mg,0.15mmol) and 6e (33mg,0.15mmol) were reacted to give the title compound V-36(15mg, 18%).

HRMS (ESI) for C₃₀H₃₈N₉O₂[M+H]⁺556.3143 for the calculated value m/z; measured value m/z is 556.3153.

Example 37

Referring to the method for synthesizing V-1 in example 1, the title compound V-37(9mg, 11%) was obtained by reacting compound 5f (60mg,0.15mmol) and 6f (31.5mg,0.15 mmol).

HRMS (ESI) for C₂₉H₃₆N₇O₄[M+H]⁺546.2823 for the calculated value m/z; measured value m/z is 546.2836.

Example 38

Referring to the method for the synthesis of V-2a in example 2, compound V-38a (27.3mg, 29%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6i (44mg,0.15 mmol).

HRMS (ESI), forIn C₃₃H₄₁N₉O₄[M]⁺627.3276 for the calculated value m/z; measured value m/z is 627.3271.

The title compound V-38(21.3mg, 95%) was prepared from compound V-38a (25mg, 40.0. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₈H₃₄N₉O₂[M+H]⁺528.2830 for the calculated value m/z; measured value m/z is 528.2839.

Example 39

Referring to the method for synthesizing V-2a in example 2, compound V-39a (21.6mg, 23%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6g (44mg,0.15 mmol).

HRMS (ESI) for C₃₃H₄₁N₉O₄[M]⁺627.3276 for the calculated value m/z; measured value m/z is 627.3276.

The title compound V-39(16.1mg, 93%) was prepared from compound V-39a (18mg, 28.7. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₈H₃₄N₉O₂[M+H]⁺528.2830 for the calculated value m/z; measured value m/z is 528.2841.

Example 40

Referring to the method for synthesizing V-1 in example 1, compound 5f (60mg,0.15mmol) and 6h (26.9mg,0.15mmol) were reacted to give the title compound V-40(23.9mg, 31%).

HRMS (ESI) for C₂₇H₃₁N₈O₃[M+H]⁺515.2514 for the calculated value m/z; measured value m/z is 515.2519.

EXAMPLE 41

Referring to the method for synthesizing V-1 in example 1, compound 5f (60mg,0.15mmol) and 6j (30.9mg,0.15mmol) were reacted to give the title compound V-41(28.4mg, 35%).

HRMS (ESI) for C₂₉H₃₆N₉O₂[M+H]⁺542.2986 for the calculated value m/z; measured value m/z is 542.3001.

Example 42

Referring to the method for synthesizing V-1 in example 1, compound 5f (60mg,0.15mmol) and 6k (33.2mg,0.15mmol) were reacted to give the title compound V-42(19.2mg, 23%).

HRMS (ESI) for C₃₀H₃₆N₈O₃[M]⁺557.2905 for the calculated value m/z; measured value m/z is 556.2906.

Example 43

Referring to the method for synthesizing V-1 in example 1, compound 5f (60mg,0.15mmol) and 6l (35.3mg,0.15mmol) were reacted to give the title compound V-43(7.7mg, 9%).

HRMS (ESI) for C₃₁H₃₈N₇O₄[M+H]⁺572.2980 for the calculated value m/z; measured value m/z is 572.2983.

Example 44

Referring to the method for synthesizing V-1 in example 1, compound 5f (60mg,0.15mmol) and 6m (39.5mg,0.15mmol) were reacted to give the title compound V-44(11.7mg, 13%).

HRMS (ESI) for C₃₂H₃₉N₈O₄[M+H]⁺599.3089 for the calculated value m/z; measured value m/z is 599.3106.

Example 45

Referring to the method for synthesizing V-1 in example 1, compound 5f (60mg,0.15mmol) and 6n (35.1mg,0.15mmol) were reacted to give the title compound V-45(16.2mg, 19%).

HRMS (ESI) for C₃₂H₄₀N₇O₃[M+H]⁺570.3187 for the calculated value m/z; measured value m/z is 570.3187.

Example 46

Referring to the method for synthesizing V-1 in example 1, compound 5f (60mg,0.15mmol) and 6o (26.6mg,0.15mmol) were reacted to give the title compound V-46(21.5mg, 28%).

HRMS (ESI) for C₂₈H₃₃N₈O₂[M+H]⁺513.2721 for the calculated value m/z; measured value m/z is 513.2739.

Example 47

Referring to the method for the synthesis of V-2a in example 2, compound V-47a (25.8mg, 28%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6p (41.7mg,0.15 mmol).

HRMS (ESI) for C₃₂H₄₀N₉O₄[M+H]⁺614.3198 for the calculated value m/z; measured value m/z is 614.3200.

The title compound V-47(17.4mg, 97%) was prepared from compound V-47a (20mg, 32.6. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₇H₃₂N₉O₂[M+H]⁺514.2673 for the calculated value m/z; measured value m/z is 514.2686.

Example 48

Referring to the method for the synthesis of V-2a in example 2, compound V-48a (29.2mg, 31%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6q (43.8mg,0.15 mmol).

HRMS (ESI) for C₃₃H₄₂N₉O₄[M+H]⁺628.3354 for the calculated value m/z; measured value m/z is 628.3355.

The title compound V-48(22.4mg, 99%) was prepared from compound V-48a (25mg, 40.0. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

Example 49

Referring to the method for the synthesis of V-2a in example 2, compound V-49a (26.0mg, 27%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6r (45.9mg,0.15 mmol).

HRMS (ESI) for C₃₄H₄₄N₉O₄[M+H]⁺642.3511 for the calculated value m/z; measured value m/z is 642.3511.

The title compound V-49(18.3mg, 96%) was prepared from compound V-49a (21mg, 32.7. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₆H₃₆N₉O₂[M+H]⁺542.2986 for the calculated value m/z; measured value m/z is 542.2991.

Example 50

Referring to the method for synthesizing V-1 in example 1, the reaction of compound 5f (60mg,0.15mmol) and 6s (33.3mg,0.15mmol) gave the title compound V-50(23.4mg, 28%).

HRMS (ESI) for C₂₉H₃₆N₉O₃[M+H]⁺558.2936 for the calculated value m/z; measured value m/z is 558.2942.

Example 51

Referring to the method for synthesizing V-2a in example 2, compound V-51a (23.1mg, 24%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6t (45.9mg,0.15 mmol).

HRMS (ESI) for C₃₄H₄₄N₉O₄[M+H]⁺642.3511 for the calculated value m/z; measured value m/z is 642.3523.

With reference to the method for synthesizing V-2 in example 2, the title compound V-51(17.8mg, 99%) was prepared from compound V-51a (20mg, 31.2. mu. mol).

HRMS (ESI) for C₂₉H₃₆N₉O₂[M+H]⁺542.2986 for the calculated value m/z; measured value m/z is 542.2989.

Example 52

Referring to the method for synthesizing V-1 in example 1, compound 5f (60mg,0.15mmol) and 6u (35.3mg,0.15mmol) were reacted to give the title compound V-52(18.0mg, 21%).

HRMS (ESI) for C₃₁H₃₉N₈O₃[M+H]⁺571.3140 for the calculated value m/z; measured value m/z is 571.3149.

Example 53

Referring to the method for the synthesis of V-2a in example 2, compound V-53a (17.8mg, 19%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6V (43.5mg,0.15 mmol).

HRMS (ESI) for C₃₃H₄₀N₉O₄[M+H]⁺626.3198 for the calculated value m/z; measured value m/z is 626.3203.

The title compound V-53(12.5mg, 93%) was prepared from compound V-53a (15mg, 24.0. mu. mol) by following the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₈H₃₂N₉O₂[M+H]⁺526.2673 for the calculated value m/z; measured value m/z is 526.2685.

Example 54

Referring to the method for the synthesis of V-2a in example 2, compound V-54a (17.6mg, 18%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6w (47.7mg,0.15 mmol).

The title compound V-54(10.7mg, 91%) was prepared from compound V-54a (13mg, 19.9. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₃₀H₃₆N₉O₂[M+H]⁺554.2986 for the calculated value m/z; measured value m/z is 554.2993.

Example 55

Referring to the method for the synthesis of V-2a in example 2, compound V-55a (12.7mg, 13%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6X (47.7mg,0.15 mmol).

HRMS (ESI) for C₃₅H₄₄N₉O₄[M+H]⁺654.3511 for the calculated value m/z; measured value m/z is 654.3513.

The title compound V-55(9.0mg, 99%) was prepared from compound V-55a (10mg, 15.3. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

Example 56

Referring to the method for the synthesis of V-2a in example 2, compound V-56a (22mg, 22%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6y (49.8mg,0.15 mmol).

HRMS (ESI) for C₃₆H₄₆N₉O₄[M+H]⁺668.3667 for the calculated value m/z; measured value m/z is 668.3671.

The title compound V-56(12.7mg, 94%) was prepared from compound V-56a (15mg, 22.5. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₃₁H₃₈N₉O₂[M+H]⁺568.3143 for the calculated value m/z; measured value m/z is 568.3161.

Example 57

Referring to the method for the synthesis of V-2a in example 2, compound V-57a (18.2mg, 19%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6z (45.6mg,0.15 mmol).

HRMS (ESI) for C₃₄H₄₂N₉O₄[M+H]⁺640.3354 for the calculated value m/z; measured value m/z is 640.3355.

The title compound V-57(13.4mg, 99%) was prepared from compound V-57a (15mg, 23.5. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₉H₃₄N₉O₂[M+H]⁺540.2830 for the calculated value m/z; measured value m/z is 540.2839.

Example 58

Referring to the method for the synthesis of V-1 in example 1, compound 5f (60mg,0.15mmol) and 6za (39.0mg,0.15mmol) were reacted to give the title compound V-58(24.1mg, 27%).

HRMS (ESI) for C₃₂H₃₈N₉O₃[M+H]⁺596.3092 for the calculated value m/z; measured value m/z is 596.3091.

Example 59

Referring to the method for the synthesis of V-1 in example 1, compound 5f (60mg,0.15mmol) and 6zb (36.9mg,0.15mmol) were reacted to give the title compound V-59(22.7mg, 26%).

HRMS (ESI) for C₃₁H₃₆N₉O₃[M+H]⁺582.2936 for the calculated value m/z; measured value m/z is 582.2941.

Example 60

Referring to the method for the synthesis of V-1 in example 1, compound 5f (60mg,0.15mmol) and 6zc (41.4mg,0.15mmol) were reacted to give the title compound V-60(21.1mg, 23%).

HRMS (ESI) for C₃₂H₃₈N₉O₄[M+H]⁺612.3041 for the calculated value m/z; measured value m/z is 612.3058.

Example 61

Referring to the method for the synthesis of V-2a in example 2, compound V-61a (23.5mg, 25%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6zd (43.8mg,0.15 mmol).

The title compound V-61(13.3mg, 99%) was prepared from compound V-61a (15mg, 23.9. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₈H₃₄N₉O₂[M+H]⁺528.2830 for the calculated value m/z; measured value m/z is 528.2821.

Example 62

Referring to the procedure for the synthesis of V-2a in example 2, reaction of compound 5f (60mg,0.15mmol) and 6ze (41.9mg,0.15mmol) gave compound V-62a (12.0mg, 13%).

HRMS (ESI) for C₃₁H₃₉N₁₀O₄[M+H]⁺615.3150 for the calculated value m/z; measured value m/z is 615.3157.

The title compound V-62(8.9mg, 99%) was prepared from compound V-62a (10mg, 16.3. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₆H₃₁N₁₀O₂[M+H]⁺515.2626 for the calculated value m/z; measured value m/z is 515.2633.

Example 63

Referring to the method for the synthesis of V-1 in example 1, compound 5f (60mg,0.15mmol) and 6zf (33mg,0.15mmol) were reacted to give the title compound V-63(25.8mg, 31%).

HRMS (ESI) for C₃₀H₃₈N₉O₂[M+H]⁺556.3143 for the calculated value m/z; measured value m/z ═556.3133.

Example 64

Referring to the method for the synthesis of V-1 in example 1, compound 5f (60mg,0.15mmol) and 6zg (35.7mg,0.15mmol) were reacted to give the title compound V-64(22.4mg, 26%).

HRMS (ESI) for C₃₀H₃₇FN₉O₂[M+H]⁺574.3049 for the calculated value m/z; measured value m/z is 574.3044.

Example 65

Referring to the method for the synthesis of V-1 in example 1, compound 5f (60mg,0.15mmol) and 6zh (37.5mg,0.15mmol) were reacted to give the title compound V-65(19.3mg, 22%).

HRMS (ESI) for C₃₁H₄₀N₉O₃[M+H]⁺586.3249 for the calculated value m/z; measured value m/z is 586.3253.

Example 66

Referring to the method for synthesizing V-2a in example 2, compound V-66a (21.2mg, 23%) was obtained by reacting compound 5f (60mg,0.15mmol) with 6zi (41.7mg,0.15 mmol).

The title compound V-66(13.1mg, 97%) was prepared from compound V-66a (15mg, 24.5. mu. mol) by reference to the procedure for the synthesis of V-2a in example 2.

HRMS (ESI) for C₂₇H₃₂N₉O₂[M+H]⁺514.2673 for the calculated value m/z; measured value m/z is 514.2673.

Example 67

8-cyclopentyl-6- (5-ethyl-1, 2, 4-oxadiazol-3-yl) -5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one hydrochloride (V-67)

8-cyclopentyl-5-methyl-2- (methylthio) -7-oxo-N' - (propionyloxy) -7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carboxamidine (3bg)

Propionic acid (408mg,5.5mmol) was dissolved in dichloromethane (20mL) under argon and 1-hydroxybenzotriazole (743mg,5.5mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.05g,5.5mmol) were added. The resulting solution was stirred at room temperature for 20 minutes, then crude 3b (1.67,5mmol) was added and stirring continued for 2 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane. The organic phases are combined and washed by sodium hydroxide aqueous solution (1N) and saturated saline solution in sequence, dried by anhydrous sodium sulfate, filtered and dried in a spinning way to obtain yellow foamy solid which is a crude product of 3bg and can be directly used for the next reaction.

8-cyclopentyl-6- (5-ethyl-1, 2, 4-oxadiazol-3-yl) -5-methyl-2- (methylthio) pyrido [2,3-d ] pyrimidin-7 (8H) -one (4g)

Under the protection of argon, 3bg (5mmol) of the crude product is dissolved in a mixed solvent of ethanol and water (4:1,30mL), sodium acetate trihydrate (1.7g,12.5mmol) is added, and the obtained reaction solution is heated to 90 ℃ for reaction for 14 hours after being sealed. After the reaction solution was cooled, it was diluted with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (petroleum ether: dichloromethane: acetone: 7:1:1) to give 4g (835mg, 45% overall yield in three steps) of a yellow foamy solid.

HRMS (ESI) for C₁₈H₂₂N₅O₂[M+H]⁺372.1489 for the calculated value m/z; measured value m/z is 372.1490.

8-cyclopentyl-6- (5-ethyl-1, 2, 4-oxadiazol-3-yl) -5-methyl-2- (methylsulfinyl) pyrido [2,3-d ] pyrimidin-7 (8H) -one (5g)

After 4g (800mg,2.16mmol) was dissolved in chloroform (12mL), 2-benzenesulfonyl-3-phenylazepin (679mg,2.6mmol) was added, and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated to dryness and the crude product was purified by column chromatography (dichloromethane: methanol 50:1) to give 5g (936mg, 93%) of a yellow solid.

HRMS (ESI) for C₁₈H₂₂N₅O₃S[M+H]⁺388.1438 for the calculated value m/z; measured value m/z is 388.1441.

(6- ((8-cyclopentyl-6- (5-ethyl-1, 2, 4-oxadiazol-3-yl) -5-methyl-7-oxo-7, 8-dihydropyrido [2,3-3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (V-67a)

5g (116mg,0.3mmol) and 6b (83.5mg,0.3mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and replaced with argon for 3 times, and then benzotrifluoride (0.6mL) was added and heated to 80 ℃ under stirring with an argon balloon for 16 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the obtained reaction residue was subjected to column chromatography (petroleum ether: dichloromethane: acetone ═ 5:2:1) to obtain a crude product, which was then washed with a mixed solvent of methyl tert-butyl ether and ethyl acetate (4:3) to obtain a yellow solid, i.e., V-67a (48.7mg, 27%).

HRMS (ESI) for C₃₁H₄₀N₉O₄[M+H]⁺602.3198 for the calculated value m/z; measured value m/z is 602.3205.

8-cyclopentyl-6- (5-ethyl-1, 2, 4-oxadiazol-3-yl) -5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidine-7 (8H) -hydrochloride (V-67)

V67a (30mg, 50. mu. mol) was dissolved in dichloromethane (2mL), the resulting solution was cooled to 0 ℃ with an ice water bath, and then a 1, 4-dioxane solution of hydrogen chloride (4N,0.25mL) was added dropwise, followed by warming to room temperature and stirring for 16 hours. The resulting suspension was filtered and washed with dichloromethane to give the title compound V-67(26.5mg, 99%) as a yellow powder.

HRMS (ESI) for C₂₆H₃₂N₉O₂[M+H]⁺502.2673 for the calculated value m/z; measured value m/z is 502.2681.

TABLE 7 examples 68-71

Example 68

Referring to the method for synthesizing V-1 in example 1, the reaction of compound 5g (116mg,0.3mmol) and 6h (53.7mg,0.3mmol) gave the title compound V-68(31.6mg, 21%).

HRMS (ESI) for C₂₆H₃₁N₈O₃[M+H]⁺503.2514 for the calculated value m/z; measured value m/z is 503.2515.

Example 69

Referring to the method for synthesizing V-1 in example 1, the reaction of compound 5g (116mg,0.3mmol) and 6a (57.6mg,0.3mmol) gave the title compound V-69(27.8mg, 18%).

HRMS (ESI) for C₂₇H₃₄N₉O₂[M+H]⁺516.2830 for the calculated value m/z; measured value m/z is 516.2839.

Example 70

Referring to the method for synthesizing V-2 in example 2, compound V-70a (42.5mg, 23%) was obtained by reacting 5g (116mg,0.3mmol) of compound with 6i (87.7mg,0.3 mmol).

HRMS (ESI) for C₃₂H₄₂N₉O₄[M+H]⁺616.3354 for the calculated value m/z; measured value m/z is 616.3359.

The title compound V-70(25.6mg, 95%) was prepared from compound V-70a (30mg, 48.8. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₇H₃₄N₉O₂[M+H]⁺516.2830 for the calculated value m/z; measured value m/z is 516.2822.

Example 71

Referring to the method for synthesizing V-2a in example 2, 5g (116mg,0.3mmol) and 6g (87.7mg,0.3mmol) of the compound were reacted to obtain compound V-71a (38.8mg, 21%).

HRMS (ESI) for C₃₂H₄₂N₉O₄[M+H]⁺616.3354 for the calculated value m/z; measured value m/z is 616.3361.

The title compound V-71(26.9mg, 99%) was prepared from compound V-71a (30mg, 48.8. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₇H₃₄N₉O₂[M+H]⁺516.2830 for the calculated value m/z; measured value m/z is 516.2826.

Example 72

N' - ((cyclobutanecarbonyl) oxy) -8-cyclopentyl-5-methyl-2- (methylthio) -7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carboxamidine (3bh)

Cyclobutylcarboxylic acid (550mg,5.5mmol) was dissolved in dichloromethane (20mL) under argon and 1-hydroxybenzotriazole (743mg,5.5mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.05g,5.5mmol) were added. The resulting solution was stirred at room temperature for 20 minutes, then crude 3b (5mmol) was added and stirring continued for 2 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane. After the organic phases are combined, the organic phases are washed by sodium hydroxide aqueous solution (1N) and saturated saline solution in sequence, dried by anhydrous sodium sulfate, filtered and dried in a spinning way to obtain yellow foamy solid, namely a crude product of 3bh, which can be directly used for the next reaction.

6- (5-cyclobutyl-1, 2, 4-oxadiazol-3-yl) -8-cyclopentyl-5-methyl-2- (methylthio) pyrido [2,3-d ] pyrimidin-7 (8H) -one (4H)

Under the protection of argon, the crude product 3bh (5mmol) was dissolved in a mixed solvent of ethanol and water (4:1,30mL), sodium acetate trihydrate (1.7g,12.5mmol) was added, and the resulting reaction solution was sealed and heated to 90 ℃ for reaction for 14 hours. After the reaction solution was cooled, it was diluted with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and column chromatographed (petroleum ether: dichloromethane: acetone: 7:1:1) to give a yellow foamy solid of 4h (774.5mg, 39% overall yield over three steps).

HRMS (ESI) for C₂₀H₂₄N₅O₂S[M+H]⁺398.1645 for the calculated value m/z; measured value m/z is 398.1641.

6- (5-cyclobutyl-1, 2, 4-oxadiazol-3-yl) -8-cyclopentyl-5-methyl-2- (methylsulfinyl) pyrido [2,3-d ] pyrimidin-7 (8H) -one (5H)

After 4h (700mg,1.76mmol) was dissolved in chloroform (12mL), 2-benzenesulfonyl-3-phenylazepine (506mg,1.94mmol) was added, and the mixture was stirred at room temperature for 15 hours. After evaporation of the solvent to dryness, the crude product was purified by column chromatography (dichloromethane: methanol 50:1) to give a yellow solid, i.e. 5h (690mg, 95%).

HRMS (ESI) for C₂₀H₂₄N₅O₃S[M+H]⁺414.1594 for the calculated value m/z; measured value m/z is 414.1590.

(6- ((6- (5-cyclobutyl-1, 2, 4-oxadiazol-3-yl) -8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (V-72a)

5h (124mg,0.3mmol) and 6b (83.4mg,0.3mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and replaced with argon for 3 times, benzotrifluoride (0.6mL) was added, and the mixture was heated to 80 ℃ under stirring with an argon balloon for 16 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the obtained reaction residue was subjected to column chromatography (petroleum ether: dichloromethane: acetone ═ 5:2:1) to obtain a crude product, which was then washed with a mixed solvent of methyl tert-butyl ether and ethyl acetate (4:3) to obtain a yellow solid, i.e., V-72a (35.8mg, 19%).

HRMS (ESI) for C₃₃H₄₂N₉O₄[M+H]⁺628.3354 for the calculated value m/z; measured value m/z is 628.3361.

6- (5-cyclobutyl-1, 2, 4-oxadiazol-3-yl) -8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one hydrochloride (V-72)

V-72a (25mg, 39.9. mu. mol) was dissolved in methylene chloride (2mL), and the resulting solution was cooled to 0 ℃ with an ice water bath, then a 1, 4-dioxane solution of hydrogen chloride (4N,0.2mL) was added dropwise, and then warmed to room temperature and stirred for 16 hours. The resulting suspension was filtered and washed with dichloromethane to give a yellow powder as the title compound V-72(21.0mg, 93%).

TABLE 8 examples 73-76

Example 73

Referring to the method for synthesizing V-1 in example 1, the title compound V-73(36.4mg, 23%) was obtained by reacting compound 5h (124mg,0.3mmol) and 6h (53.7mg,0.3 mmol).

HRMS (ESI) for C₂₈H₃₃N₈O₃[M+H]⁺529.2670 for the calculated value m/z; measured value m/z is 529.2659.

Example 74

Referring to the method for synthesizing V-1 in example 1, the title compound V-74(34.1mg, 21%) was obtained by reacting compound 5h (124mg,0.3mmol) and 6a (57.7mg,0.3 mmol).

HRMS (ESI) for C₂₉H₃₆N₉O₂[M+H]⁺542.2986 for the calculated value m/z; measured value m/z is 542.2971.

Example 75

Referring to the method for the synthesis of V-2a in example 2, compound V-75a (42.3mg, 22%) was obtained by reacting compound 5h (124mg,0.3mmol) with 6i (87.7mg,0.3 mmol).

HRMS (ESI) for C₃₄H₄₄N₉O₄[M+H]⁺642.3511 for the calculated value m/z; measured value m/z is 642.3522.

The title compound V-75(17.5mg, 97%) was prepared from compound V-75a (20mg, 31.2. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₉H₃₆N₉O₂[M+H]⁺542.2986 for the calculated value m/z; measured value m/z is 542.2993.

Example 76

Referring to the method for synthesizing V-2a in example 2, compound V-76a (46.2mg, 24%) was obtained by reacting compound xx (124mg,0.3mmol) with 6g (87.7mg,0.3 mmol).

HRMS (ESI) for C₃₄H₄₄N₉O₄[M+H]⁺642.3511 for the calculated value m/z; measured value m/z is 642.3519.

The title compound V-76(16.4mg, 91%) was prepared from compound V-76a (20mg, 31.2. mu. mol) by reference to the procedure for the synthesis of V-2 in example 2.

HRMS (ESI) for C₂₉H₃₆N₉O₂[M+H]⁺542.2986 for the calculated value m/z; measured value m/z is 542.2991.

Example 77

8-cyclopentyl-5-methyl-2-methylsulfanyl-6- (5-trifluoromethyl-1, 2, 4-oxadiazol-3-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (4i)

Crude 3b (0.5mmol) was dissolved in trifluoroacetic anhydride (1mL) and heated to 110 ℃ with stirring for 2 h. The reaction solution was cooled, then washed with saturated aqueous sodium bicarbonate solution in an ice-water bath to pH 8, followed by extraction with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatography (petroleum ether: ethyl acetate: 10:1) gave 4i (131mg, 63.7%) as a yellow viscous solid.

¹H NMR(400MHz,CDCl₃,ppm):8.86(s,1H),6.04–5.95(m,1H),2.65(s,3H),2.43(s,3H),2.37–2.28(m,2H),2.11–2.01(m,2H),1.94–1.86(m,2H),1.73–1.65(m,2H).

¹⁹F NMR(376MHz,CDCl₃,ppm):–65.01(s,3F).

8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (5-trifluoromethyl-1, 2, 4-oxadiazol-3-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (5i)

After 4i (114.5mg,0.278mmol) was dissolved in chloroform (2.8mL), 2-benzenesulfonyl-3-phenyloxaziridine (123.6mg,0.473mmol) was added and the mixture was stirred at room temperature for 40 hours. After evaporation of the solvent to dryness, the crude product was purified by column chromatography (dichloromethane: methanol 50:1) to yield 5i (77mg, 64.7%) as a white powder.

¹H NMR(400MHz,CDCl₃,ppm):9.18(s,1H),6.07–5.98(m,1H),3.02(s,3H),2.53(s,3H),2.30–2.22(m,2H),2.13–2.07(m,2H),2.01–1.91(m,2H),1.72–1.67(m,2H).

¹⁹F NMR(376MHz,CDCl₃,ppm):–64.97(s,3F).

(6- ((8-cyclopentyl-5-methyl-7-oxo-6- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (V-77a)

5i (72mg,0.168mmol) and tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (6b,49.2mg,0.177mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and replaced with argon 3 times, benzotrifluoride (0.7mL) was added, and the mixture was heated to 80 ℃ under stirring with an argon balloon for 16 hours. After cooling to room temperature, the solvent was evaporated to dryness under reduced pressure, and the obtained reaction residue was subjected to column chromatography (petroleum ether: dichloromethane: acetone ═ 5:1:1) to obtain a crude product, which was then washed with methyl tert-butyl ether to obtain a yellow powder, i.e., V-77a (17mg, 15.7%).

¹H NMR(400MHz,CDCl₃,ppm):8.89(s,1H),8.43(br,1H),8.20(d,J＝8.8Hz,1H),8.07(s,1H),7.35(dd,J＝9.0,2.2Hz,1H),5.98–5.89(m,1H),3.62(t,J＝5.0Hz,4H),3.14(t,J＝4.8Hz,4H),2.42(s,3H),2.38–2.31(m,2H),2.11–2.01(m,2H),1.94–1.86(m,2H),1.73–1.67(m,2H),1.49(s,9H).

¹⁹F NMR(376MHz,CDCl₃,ppm):–65.06(s,3F).

8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -6- (5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) pyrido [2,3-d ] pyrimidin-7 (8H) -one hydrochloride (V-77)

V-77a (16.5mg,0.0257mmol) was dissolved in dichloromethane (1mL), the resulting solution was cooled to 0 ℃ with an ice water bath, and then a solution of hydrogen chloride in 1, 4-dioxane (4N,0.48mL) was added dropwise, followed by warming to room temperature and stirring for 21 hours. The resulting suspension was filtered and washed with dichloromethane to give a yellow powder as the title compound V-77(13mg, 87.5%).

¹H NMR(400MHz,D₂O,ppm):9.10(s,1H),8.08(s,1H),7.87(s,1H),7.51(s,1H),5.86–5.79(m,1H),3.59–3.42(m,8H),2.45(s,3H),2.17–2.07(m,2H),2.02–1.90(m,4H),1.73–1.64(m,2H).

Example 78

8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carboxylic acid (7a)

8-cyclopentyl-5-methyl-2-methylthio-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (2b,60mg,0.2mmol) was suspended in a mixed solvent of 5% aqueous sodium hydroxide (1mL) and ethanol (0.5mL), and the mixture was heated to 60 ℃ with stirring for 18 hours to react, whereby the solution gradually became clear. After cooling to room temperature, hydrochloric acid (6N) was added dropwise until the solution became weakly acidic (pH 4-5), and the precipitated solid was filtered and washed with ethyl acetate to remove a small amount of organic impurities from the solid. Then the filtrate was removed, the remaining crude solid was washed with ethanol, and the resulting filtrate was evaporated to dryness to give a pale solid, 8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carboxylic acid (7a,31.4mg, 49.2%).

¹H NMR(400MHz,CDCl₃,ppm):9.35(s,1H),5.27–5.19(m,1H),2.68(s,3H),2.64(s,3H),2.45–2.37(m,2H),2.12–1.98(m,4H),1.73–1.64(m,2H).

N' -acetyl-8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carboxylic acid hydrazide (8a)

8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carboxylic acid (7a,280mg,0.88mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (433.4mg,1.14mmol) were placed in a reaction flask, N, N-dimethylformamide (5mL) and N, N-diisopropylethylamine (339.9mg,2.63mmol) were added, and after stirring at room temperature for 5 minutes, acetyl hydrazine (71.7mg,0.97mmol) was added. Stirring is carried out for 15 hours at room temperature, ethyl acetate is added, the mixture is washed by saturated salt water for 3 times, an organic phase is dried by anhydrous sodium sulfate, the mixture is filtered, a filtrate is decompressed and evaporated to dryness, and a crude product is subjected to column chromatography to obtain a light brown solid, namely N' -acetyl-8-cyclopentyl-5-methyl-2-methylthio-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-formylhydrazine (8a,203mg, 61.7%).

¹H NMR(300MHz,CDCl₃,ppm):10.34(br,1H),8.92(s,1H),8.33(br,1H),6.04–5.92(m,1H),2.75(s,3H),2.64(s,3H),2.34–2.21(m,2H),2.13(s,3H),2.13–2.02(m,2H),1.89–1.82(m,2H),1.75–1.67(m,2H).

8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (9a)

N' -acetyl-8-cyclopentyl-5-methyl-2-methylthio-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidine-6-carbohydrazide (8a,200mg,0.53mmol) was placed in a dry reaction flask under argon protection, dried toluene (2mL) and phosphorus oxychloride (89.4mg,0.58mmol) were added, and the mixture was stirred and heated at reflux for 4 hours. The reaction solution was cooled to room temperature, poured into ice water, adjusted to neutral (pH 7) with aqueous sodium hydroxide (1N), extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure and subjected to column chromatography to obtain a yellow solid, i.e., 8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (9a,42mg, 22%).

¹H NMR(300MHz,CDCl₃,ppm):8.89(s,1H),6.07–5.95(m,1H),2.69(s,3H),2.67(s,3H),2.56(s,3H),2.40–2.29(m,2H),2.09–1.98(m,2H),1.94–1.87(m,2H),1.78–1.70(m,2H).

8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (10a)

8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (9a,112mg,0.31mmol) was dissolved in dichloromethane (2mL), cooled to 0 ℃ in a ice water bath, and then m-chloroperoxybenzoic acid (85%, 50.9mg,0.25mmol) was added in portions and stirred at room temperature for 3 hours. Saturated aqueous sodium sulfite (2mL) was added to extract the reaction out, followed by three extractions with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and subjected to column chromatography to give a yellow solid, 8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (10a,86mg, 73.5%).

HRMS (ESI) for C₁₇H₁₉N₅O₃S[M+H]⁺374.1281 for the calculated value m/z; measured value m/z is 374.1276.

8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one (VI-1)

8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -2-methanesulfinyl-8H-pyrido [2,3-d ] pyrimidin-7-one (10a,82mg,0.22mmol) and 2-amino-5- (4-methylpiperazin-1-yl) pyridine (6a,44.3mg,0.23mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and replaced with argon 3 times, benzotrifluoride (1mL) was added, and the mixture was heated to 80 ℃ under argon balloon protection with stirring for 16 hours. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 2 hours. The precipitated solid was filtered, and washed with ethyl acetate to give a yellow solid, i.e., 8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one (VI-1,20.8mg, 18.9%).

HRMS (ESI) for C₂₆H₃₁N₉O₂[M+H]⁺502.2674 for the calculated value m/z; measured value m/z is 502.2680.

Example 79

4- (6- (8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) -4-methylpyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (VI-2a)

Referring to the procedure for the synthesis of V-15a in example 15, compound VI-2a (18.7mg, 14.5%) was reacted from compound 10a (80mg,0.214mmol) and 6g (65.8mg,0.225 mmol).

HRMS (ESI) for C₃₁H₃₉N₉O₄[M+H]⁺602.3198 for the calculated value m/z; measured value m/z is 602.3193.

8-cyclopentyl-5-methyl-6- (5-methyl-1, 3, 4-oxadiazol-2-yl) -2- (4-methyl-5- (piperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (VI-2)

Referring to the synthesis of V-15 in example 15, the title compound VI-2(14mg, 99%) was prepared from compound VI-2a (16mg,0.027 mmol).

HRMS (ESI) for C₂₆H₃₁N₉O₂[M+H]⁺502.2673 for the calculated value m/z; measured value m/z is 502.2682.

Example 80

8-cyclopentyl-2-methylsulfanyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (11a)

Under argon, cuprous iodide (56mg,0.294mmol), 6-bromo-8-cyclopentyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1a,1g,2.94mmol), 2-azetidinone (418mg,5.88mmol) and potassium carbonate (609mg,4.41mmol) were added to a 25mL stopcock. The reaction tube was sealed with a rubber stopper, evacuated and returned to argon 3 times, and then N, N' -dimethylethylenediamine (52mg,0.588mmol) and toluene (4mL) were injected. After replacing the rubber stopper with a teflon stopper, the reaction mixture was stirred and heated to 100 ℃ for overnight reaction. After the reaction is cooled to room temperature, the cover is opened, the reaction solution is filtered, the filtrate is evaporated to dryness under reduced pressure, and a white solid obtained by column chromatography (petroleum ether/ethyl acetate ═ 2:1 to 0:1) is 8-cyclopentyl-2-methylthio-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (11a,890mg, 91.6%).

¹H NMR(400MHz,CDCl₃,ppm):8.59(s,1H),8.18(s,1H),5.98–5.89(m,1H),4.20(t,J＝4.8Hz,2H),3.15(t,J＝4.6Hz,2H),2.60(s,3H),2.36–2.27(m,2H),2.12–2.02(m,2H),1.92–1.84(m,2H),1.74–1.66(m,2H).

8-cyclopentyl-2-methanesulfinyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (12a)

8-cyclopentyl-2-methylsulfanyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (11a,820mg,2.48mmol) was dissolved in chloroform (10mL), and m-chloroperoxybenzoic acid (85%, 453mg,2.23mmol) was added and stirred at room temperature for 3 hours. Saturated aqueous sodium sulfite (10mL) was added to extract the reaction out, followed by three extractions with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatographed (petrol ether/ethyl acetate 2:1 to 0:1) to give 8-cyclopentyl-2-methanesulfinyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (12a,700mg, 81.4%) as a white solid.

¹H NMR(400MHz,CDCl₃,ppm):8.88(s,1H),8.30(s,1H),6.02–5.93(m,1H),4.26(t,J＝4.8Hz,2H),3.19(t,J＝4.8Hz,2H),2.96(s,3H),2.29–2.19(m,2H),2.15–2.08(m,2H),1.98–1.89(m,2H),1.73–1.63(m,2H).

8-cyclopentyl-2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (VII-1)

8-cyclopentyl-2-methanesulfinyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (12a,120mg,0.346mmol) and 2-amino-5- (4-methylpiperazin-1-yl) pyridine (6a,69.9mg,0.364mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and then replaced with argon 3 times, benzotrifluoride (1.7mL) was added, and the mixture was heated to 95 ℃ under argon balloon protection with stirring for 24 hours. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 2 hours. The precipitated solid was filtered and washed with ethyl acetate to give a yellow solid, 8-cyclopentyl-2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (VII-1,26mg, 15.8%).

¹H NMR(400MHz,CDCl₃,ppm):8.59(s,1H),8.22(br,1H),8.16–8.14(m,2H),8.05(d,J＝2.0Hz,1H),7.32(dd,J＝9.2,2.4Hz,1H),5.94–5.85(m,1H),4.17(t,J＝4.2Hz,2H),3.22(t,J＝4.4Hz,4H),3.13(t,J＝4.2Hz,2H),2.63(t,J＝4.2Hz,4H),2.38(s,3H),2.38–2.30(m,2H),2.11–2.02(m,2H),1.92–1.87(m,2H),1.74–1.66(m,2H).

HRMS (ESI) for C₂₅H₃₀N₈O₂[M+H]⁺475.2564 for the calculated value m/z; measured value m/z is 475.2561.

Example 81

4- (6- (8-cyclopentyl-7-oxo-6- (2-oxoazetidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (VII-2a)

8-cyclopentyl-2-methanesulfinyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (12a,173.2mg,0.5mmol) and tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (6b,146mg,0.525mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and then replaced with argon 3 times, benzotrifluoride (2mL) was added, and the mixture was heated to 90 ℃ under stirring with an argon balloon for 48 hours. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 2 hours. The precipitated solid was filtered and washed with ethyl acetate to give a yellow solid, i.e., tert-butyl 4- (6- (8-cyclopentyl-7-oxo-6- (2-oxoazetidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylate (VII-2a,62mg, 22%).

¹H NMR(400MHz,CDCl₃,ppm):8.61(s,1H),8.35(br,1H),8.19–8.16(m,2H),8.06(d,J＝2.4Hz,1H),7.33(dd,J＝9.0,2.6Hz,1H),5.94–5.85(m,1H),4.17(t,J＝4.6Hz,2H),3.61(t,J＝4.8Hz,4H),3.15–3.10(m,6H),2.39–2.31(m,2H),2.11–2.02(m,2H),1.92–1.85(m,2H),1.75–1.69(m,2H),1.49(s,9H).

8-cyclopentyl-6- (2-oxoazetidin-1-yl) -2- (5- (piperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (VII-2)

Tert-butyl 4- (6- (8-cyclopentyl-7-oxo-6- (2-oxoazetidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylate (VII-2a,45mg,0.08mmol) was placed in a reaction flask, and a solution of hydrogen chloride in 1, 4-dioxane (4N,2mL) and methanol (2mL) were added. After stirring at room temperature for 2 hours, the solvent was removed by rotary evaporation under reduced pressure, and the resulting crude product was stirred in ethyl acetate for half an hour and then filtered to give a yellow powder, 8-cyclopentyl-6- (2-oxoazetidin-1-yl) -2- (5- (piperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (VII-2,39mg, 98%).

¹H NMR(400MHz,D₂O,ppm):8.42(s,1H),7.98(dd,J＝9.6,2.4Hz,1H),7.59(d,J＝2.8Hz,1H),7.30(d,J＝9.6Hz,1H),6.33(s,1H),5.82–5.74(m,1H),3.48(s,8H),3.34(t,J＝6.6Hz,2H),2.71(t,J＝6.6Hz,2H),2.21–2.13(m,2H),2.09–1.93(m,4H),1.78–1.71(m,2H).

Example 82

8-cyclopentyl-5-methyl-2-methylsulfanyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (11b)

Under argon, cuprous iodide (53mg,0.282mmol), 6-bromo-8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1b,1g,2.82mmol), 2-azetidinone (0.4g,5.64mmol) and potassium carbonate (584.6mg,4.23mmol) were added to a 25mL block. The reaction tube was sealed with a rubber stopper, evacuated and returned to argon 3 times, and then N, N' -dimethylethylenediamine (50mg,0.564mmol) and toluene (5mL) were injected. After replacing the rubber stopper with a teflon stopper, the reaction mixture was stirred and heated to 100 ℃ for overnight reaction. After the reaction is cooled to room temperature, the reaction solution is uncapped, the reaction solution is filtered, the filtrate is evaporated to dryness under reduced pressure, and a white solid obtained by column chromatography (petroleum ether/ethyl acetate ═ 2:1 to 0:1) is 8-cyclopentyl-5-methyl-2-methylthio-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (11b,500mg, 51.5%).

¹H NMR(400MHz,CDCl₃,ppm):8.77(s,1H),5.97–5.88(m,1H),3.95(t,J＝4.6Hz,2H),3.19(t,J＝4.6Hz,2H),2.61(s,3H),2.42(s,3H),2.34–2.25(m,2H),2.11–2.01(m,2H),1.91–1.83(m,2H),1.73–1.67(m,2H).

8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (12b)

8-cyclopentyl-5-methyl-2-methylsulfanyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (11b,550mg,1.6mmol) was dissolved in chloroform (8mL), and m-chloroperoxybenzoic acid (85%, 292mg,1.44mmol) was added and stirred at room temperature for 3 hours. Saturated aqueous sodium sulfite (10mL) was added to extract the reaction out, followed by three extractions with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatographed (petrol ether/ethyl acetate 2:1 to 0:1) to give 8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (12b,435mg, 75.6%) as a white solid.

¹H NMR(400MHz,CDCl₃,ppm):9.08(s,1H),6.01–5.92(m,1H),4.09–4.02(m,2H),3.23(t,J＝4.6Hz,2H),2.97(s,3H),2.50(s,3H),2.27–2.19(m,2H),2.14–2.08(m,2H),1.98–1.89(m,2H),1.74–1.67(m,2H).

8-cyclopentyl-5-methyl-2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (VII-3)

8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (12b,120mg,0.333mmol) and 2-amino-5- (4-methylpiperazin-1-yl) pyridine (6a,67.2mg,0.35mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and then replaced with argon 3 times, benzotrifluoride (1.7mL) was added, and the mixture was heated to 90 ℃ under stirring with an argon balloon for 18 hours. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 2 hours. The precipitated solid was filtered and washed with ethyl acetate to give a yellow solid, 8-cyclopentyl-5-methyl-2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (VII-3,46mg, 28%).

¹H NMR(400MHz,CDCl₃,ppm):8.79(s,1H),8.25(br,1H),8.15(d,J＝9.2Hz,1H),8.05(d,J＝2.4Hz,1H),7.33(dd,J＝9.2,2.8Hz,1H),5.93–5.84(m,1H),3.91(t,J＝4.2Hz,2H),3.23–3.17(m,6H),2.61(t,J＝4.8Hz,4H),2.41(s,3H),2.37(s,3H),2.37–2.29(m,2H),2.10–2.01(m,2H),1.91–1.83(m,2H),1.71–1.63(m,2H).

HRMS (ESI) for C₂₆H₃₂N₈O₂[M+H]⁺489.2721 for the calculated value m/z; measured value m/z is 489.2715.

Example 83

4- (6- (8-cyclopentyl-5-methyl-7-oxo-6- (2-oxoazetidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (VII-4a)

8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (12b,120mg,0.333mmol) and tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (6b,94.4mg,0.34mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and replaced with argon 3 times, benzotrifluoride (1.3mL) was added, and the mixture was heated to 85 ℃ under argon balloon protection for 17 hours. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 3 hours. The precipitated solid was filtered and washed with ethyl acetate to give a bright yellow solid, i.e., tert-butyl 4- (6- (8-cyclopentyl-5-methyl-7-oxo-6- (2-oxoazetidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylate (VII-4a,53.3mg, 27.9%).

¹H NMR(400MHz,CDCl₃,ppm):8.82(s,1H),8.44(br,1H),8.18(d,J＝9.2Hz,1H),8.06(d,J＝2.8Hz,1H),7.33(dd,J＝9.0,3.0Hz,1H),5.93–5.84(m,1H),3.92(t,J＝4.4Hz,2H),3.61(t,J＝5.0Hz,4H),3.18(t,J＝4.4Hz,2H),3.12(t,J＝4.8Hz,4H),2.42(s,3H),2.37–2.29(m,2H),2.11–2.01(m,2H),1.91–1.83(m,2H),1.74–1.64(m,2H),1.49(s,9H).

8-cyclopentyl-5-methyl-6- (2-oxoazetidin-1-yl) -2- (5- (piperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (VII-4)

Tert-butyl 4- (6- (8-cyclopentyl-5-methyl-7-oxo-6- (2-oxoazetidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylate (VII-4a,43.4mg,0.0755mmol) was placed in a reaction flask and a solution of hydrogen chloride in 1, 4-dioxane (4N,2mL) and methanol (2mL) were added. After stirring at room temperature for 2 hours, the solvent was removed by rotary evaporation under reduced pressure, and the resulting crude product was stirred in ethyl acetate for half an hour and then filtered to give a yellow powder, 8-cyclopentyl-5-methyl-6- (2-oxoazetidin-1-yl) -2- (5- (piperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (VII-4,35mg, 90.7%).

¹H NMR(400MHz,D₂O,ppm):9.05(s,1H),8.14(dd,J＝9.6,2.8Hz,1H),7.87(d,J＝2.8Hz,1H),7.53(d,J＝9.6Hz,1H),5.91–5.82(m,1H),3.61(t,J＝6.0Hz,2H),3.57–3.54(m,4H),3.49–3.47(m,4H),2.81(t,J＝6.0Hz,2H),2.60(s,3H),2.23–2.15(m,2H),2.07–1.91(m,4H),1.76–1.66(m,2H).

Example 84

4- (6- (8-cyclopentyl-5-methyl-7-oxo-6- (2-oxoazetidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) -4-methylpyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (VII-5a)

Referring to the procedure for the synthesis of VII-4a in example 32, compound 12b (100mg,0.277mmol) and 6g (84.8mg,0.29mmol) were reacted to give compound VII-5a (43.3mg, 26.5%).

HRMS (ESI) for C₃₁H₄₀N₈O₄[M+H]⁺589.3245 for the calculated value m/z; measured value m/z is 589.3253.

8-cyclopentyl-5-methyl-2- (4-methyl-5- (piperazin-1-yl) pyridin-2-ylamino) -6- (2-oxoazetidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (VII-5)

The title compound VII-5(34.3mg, 96%) was prepared from compound VII-5a (40mg,0.068mmol) by referring to the procedure for the synthesis of VII-4 in example 32.

HRMS (ESI) for C₂₆H₃₂N₈O₂[M+H]⁺489.2721 for the calculated value m/z; measured value m/z is 489.2724.

Example 85

8-cyclopentyl-2-methylsulfanyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (13a)

Copper powder (13mg,0.206mmol), 6-bromo-8-cyclopentyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1a,700mg,2.06mmol), 2-pyrrolidone (350mg,4.11mmol) and potassium carbonate (426mg,3.09mmol) were added to a 25mL sealed tube under argon. The reaction tube was sealed with a rubber stopper, evacuated and returned to argon 3 times, and then N, N' -dimethylethylenediamine (36mg,0.411mmol) and toluene (4mL) were injected. After replacing the rubber stopper with a teflon stopper, the reaction mixture was stirred and heated to 135 ℃ for overnight reaction. After the reaction was cooled to room temperature, the reaction solution was uncapped, the reaction solution was filtered, the filtrate was evaporated to dryness under reduced pressure, and a white solid obtained by column chromatography (petroleum ether/ethyl acetate ═ 2:1 to 0:1) was 8-cyclopentyl-2-methylthio-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (13a,490mg, 69%).

¹H NMR(400MHz,CDCl₃,ppm):8.61(s,1H),7.77(s,1H),6.01–5.92(m,1H),3.96(t,J＝7.0Hz,2H),2.62(s,3H),2.57(t,J＝8.0Hz,2H),2.37–2.28(m,2H),2.22–2.14(m,2H),2.12–2.03(m,2H),1.93–1.85(m,2H),1.74–1.64(m,2H).

8-cyclopentyl-2-methanesulfinyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (14a)

8-cyclopentyl-2-methylsulfanyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (13a,490mg,1.42mmol) was dissolved in dichloromethane (10mL), m-chloroperoxybenzoic acid (85%, 260mg,1.28mmol) was added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium sulfite (10mL) was added to extract the reaction out, followed by three extractions with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatographed (petrol ether/ethyl acetate 2:1 to 0:1) to give 8-cyclopentyl-2-methanesulfinyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (14a,320mg, 62.4%) as a white solid.

¹H NMR(400MHz,CDCl₃,ppm):8.93(s,1H),7.97(s,1H),6.04–5.95(m,1H),4.05–4.01(m,2H),2.97(s,3H),2.58(t,J＝8.0Hz,2H),2.29–2.07(m,6H),1.99–1.89(m,2H),1.74–1.65(m,2H).

8-cyclopentyl-2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (VIII-1)

8-cyclopentyl-2-methanesulfinyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (14a,120mg,0.333mmol) and 2-amino-5- (4-methylpiperazin-1-yl) pyridine (6a,67.2mg,0.35mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and replaced with argon 3 times, benzotrifluoride (1.7mL) was added, and the mixture was heated to 95 ℃ under stirring with an argon balloon for 24 hours. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 2 hours. The precipitated solid was filtered and washed with ethyl acetate to give a yellow solid, i.e., 8-cyclopentyl-2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (VIII-1,46mg, 28.3%).

¹H NMR(400MHz,CDCl₃,ppm):8.62(s,1H),8.44(br,1H),8.16(d,J＝9.2Hz,1H),8.07(d,J＝2.4Hz,1H),7.70(s,1H),7.33(dd,J＝9.0,3.0Hz,1H),5.96–5.87(m,1H),3.93(t,J＝7.0Hz,2H),3.22(t,J＝4.8Hz,4H),2.61(t,J＝4.6Hz,4H),2.56(t,J＝8.0Hz,2H),2.39–2.30(m,2H),2.37(s,3H),2.22–2.14(m,2H),2.10–2.02(m,2H),1.93–1.85(m,2H),1.71–1.64(m,2H).

HRMS (ESI) for C₂₆H₃₂N₈O₂[M+H]⁺489.2721 for the calculated value m/z; measured value m/z is 489.2718.

Example 86

8-cyclopentyl-5-methyl-2-methylsulfanyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (13b)

Under argon, cuprous iodide (268mg,1.41mmol), 6-bromo-8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido [2,3-d ] pyrimidin-7-one (1b,5g,14.1mmol), 2-pyrrolidone (2.4g,28.2mmol) and potassium carbonate (2.92g,21.15mmol) were added to a 100mL block. The reaction tube was sealed with a rubber stopper, evacuated and returned to argon 3 times, and then N, N' -dimethylethylenediamine (248mg,2.82mmol) and toluene (25mL) were injected. After replacing the rubber stopper with a teflon stopper, the reaction mixture was stirred and heated to 100 ℃ for overnight reaction. After the reaction is cooled to room temperature, the cover is opened, the reaction solution is filtered, the filtrate is evaporated to dryness under reduced pressure, and a white solid obtained by column chromatography (petroleum ether/ethyl acetate is 2:1 to 0:1) is 8-cyclopentyl-5-methyl-2-methylthio-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (13b,420mg, 8.3%).

¹H NMR(400MHz,CDCl₃,ppm):8.76(s,1H),5.98–5.89(m,1H),4.14–4.08(m,1H),3.42–3.36(m,1H),2.67–2.50(m,2H),2.61(s,3H),2.34(s,3H),2.34–2.15(m,4H),2.09–2.01(m,2H),1.90–1.82(m,2H),1.70–1.65(m,2H).

8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (14b)

8-cyclopentyl-5-methyl-2-methylsulfanyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (13b,420mg,1.17mmol) was dissolved in chloroform (6mL), and m-chloroperoxybenzoic acid (85%, 214mg,1.05mmol) was added and the mixture was stirred at room temperature for 40 minutes. Saturated aqueous sodium sulfite (8mL) was added to extract the reaction out, followed by three extractions with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and column chromatographed (petrol ether/ethyl acetate 2:1 to 0:1) to give 8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (14b,120mg, 27.3%) as a white solid.

¹H NMR(400MHz,CDCl₃,ppm):9.07(d,J＝8.0Hz,1H),6.01–5.89(m,1H),4.18–4.12(m,1H),3.44–3.38(m,1H),2.95(s,3H),2.67–2.51(m,2H),2.41(s,3H),2.35–2.18(m,4H),2.12–2.04(m,2H),1.94–1.88(m,2H),1.71–1.64(m,2H).

8-cyclopentyl-5-methyl-2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (VIII-2)

8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (14b,92mg,0.246mmol) and 2-amino-5- (4-methylpiperazin-1-yl) pyridine (6a,49.6mg,0.258mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and then replaced with argon 3 times, benzotrifluoride (1.2mL) was added, and the mixture was heated to 90 ℃ under stirring with an argon balloon for 18 hours. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 2 hours. The precipitated solid was filtered and subjected to column chromatography to obtain a yellow solid, i.e., 8-cyclopentyl-5-methyl-2- (5- (4-methylpiperazin-1-yl) pyridin-2-ylamino) -6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (VIII-2,18mg, 14.6%).

¹H NMR(400MHz,CDCl₃,ppm):8.78(s,1H),8.34(br,1H),8.16(d,J＝9.2Hz,1H),8.05(d,J＝2.0Hz,1H),7.33(dd,J＝8.8,2.4Hz,1H),5.93–5.84(m,1H),4.13–4.07(m,1H),3.40–3.37(m,1H),3.21(t,J＝4.4Hz,4H),2.67–2.50(m,6H),2.37(s,3H),2.33(s,3H),2.29–2.16(m,2H),2.06–1.82(m,6H),1.70–1.63(m,2H).

HRMS (ESI) for C₂₇H₃₄N₈O₂[M+H]⁺503.2877 for the calculated value m/z; measured value m/z is 503.2878.

Example 87

4- (6- (8-cyclopentyl-5-methyl-7-oxo-6- (2-oxopyrrolidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (VIII-3a)

8-cyclopentyl-5-methyl-2-methanesulfinyl-6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one (14b,120mg,0.32mmol) and tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (98mg,0.35mmol) were placed in a dry 10mL reaction tube, sealed with a rubber stopper and then replaced with argon 3 times, benzotrifluoride (1.3mL) was added, and the mixture was heated to 80 ℃ under argon balloon protection for 24 hours. After cooling to room temperature, a small amount of ethyl acetate was added and stirring was continued for about 6 hours. The precipitated solid was filtered and washed with ethyl acetate to give a yellow solid, i.e., tert-butyl 4- (6- (8-cyclopentyl-5-methyl-7-oxo-6- (2-oxopyrrolidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylate (VIII-3a,33.6mg, 17.8%).

¹H NMR(400MHz,CDCl₃,ppm):8.79(s,1H),8.28(br,1H),8.19(d,J＝9.2Hz,1H),8.05(d,J＝2.8Hz,1H),7.33(dd,J＝8.8,2.8Hz,1H),5.93–5.84(m,1H),4.13–4.07(m,1H),3.61(t,J＝5.0Hz,4H),3.42–3.36(m,1H),3.12(t,J＝4.6Hz,4H),2.68–2.50(m,2H),2.38–2.18(m,4H),2.33(s,3H),2.09–2.01(m,2H),1.90–1.82(m,2H),1.67–1.62(m,2H),1.49(s,9H).

8-cyclopentyl-5-methyl-6- (2-oxopyrrolidin-1-yl) -2- (5- (piperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (VIII-3)

Tert-butyl 4- (6- (8-cyclopentyl-5-methyl-7-oxo-6- (2-oxopyrrolidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) pyridin-3-yl) piperazine-1-carboxylate (VIII-3a,25mg,0.0425mmol) was placed in a reaction flask and a solution of hydrogen chloride in 1, 4-dioxane (4N,1.1mL) and methanol (1.1mL) were added. After stirring at room temperature for 2 hours, the solvent was removed by rotary evaporation under reduced pressure, and the resulting crude product was stirred in ethyl acetate for half an hour and then filtered to give a yellow powder, 8-cyclopentyl-5-methyl-6- (2-oxopyrrolidin-1-yl) -2- (5- (piperazin-1-yl) pyridin-2-ylamino) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (VIII-3,22mg, 99%).

¹H NMR(400MHz,D₂O,ppm):9.08(s,1H),8.11(dd,J＝9.6,2.4Hz,1H),7.90(d,J＝2.8Hz,1H),7.54(d,J＝9.6Hz,1H),5.92–5.83(m,1H),3.83–3.77(m,1H),3.65–3.63(m,1H),3.56–3.54(m,4H),3.49–3.46(m,4H),2.69–2.65(m,2H),2.43(s,3H),2.36–2.29(m,2H),2.16–2.07(m,2H),2.00–1.88(m,4H),1.72–1.66(m,2H).

Example 88

4- (6- (8-cyclopentyl-5-methyl-7-oxo-6- (2-oxopyrrolidin-1-yl) -7, 8-dihydropyrido [2,3-d ] pyrimidin-2-ylamino) -4-methylpyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (VIII-4a)

Referring to the procedure for the synthesis of VIII-3a in example 36, compound 14b (100mg,0.267mmol) and 6g (82mg,0.28mmol) were reacted to give compound VIII-4a (24.6mg, 15.3%).

HRMS (ESI) for C₃₂H₄₂N₈O₄[M+H]⁺603.3402 for the calculated value m/z; measured value m/z is 603.3996.

8-cyclopentyl-5-methyl-2- (4-methyl-5- (piperazin-1-yl) pyridin-2-ylamino) -6- (2-oxopyrrolidin-1-yl) -8H-pyrido [2,3-d ] pyrimidin-7-one hydrochloride (VIII-4)

The title compound VIII-4(19mg, 97%) was prepared from compound VIII-4a (22mg,0.037mmol) by referring to the procedure for the synthesis of VIII-3 in example 36.

HRMS (ESI) for C₂₇H₃₄N₈O₂[M+H]⁺503.2877 for the calculated value m/z; measured value m/z is 503.2883.

Example 89

And (3) measuring the potency of the biochemical kinase inhibition test. Kinase activity assay and IC50 assay. First, 10ng of recombinant CDK 4/cyclin D1 or recombinant CDK 6/cyclin D3(Life Technologies PV4204) was diluted in kinase buffer (20mM Tris pH7.5,10mM MgCl. RTM₂0.01% NP-40,2mM DTT), at the indicated concentration of inhibitor for 30 minutes at room temperature. The kinase reaction was initiated by the addition of 1. mu.g (1.5. mu.M) of recombinant retinoblastoma (Rb) protein, 5. mu.M ATP and 10. mu. Ci of γ -32P-ATP. The reaction was incubated at 30 ℃ for 20 minutes, quenched by the addition of 2 × Laemmli sample buffer, heated at 95 ℃ for three minutes, solubilized by 12% acrylamide SDS-PAGE, and autoradiographed. The autoradiogram was scanned and the corresponding phosphorylated substrate protein bands were quantified using a densitometer (Bio-Rad). The resulting optical density values were plotted as a function of log drug concentration using Prism 4 Graphpad software, and IC50 values were determined by plotting a sigmoidal nonlinear regression curve with variable slope.

The results of the enzyme inhibitory activity of the compounds of the present invention are shown in the following table. Compounds were tested in a 10-fold amount of IC50 in a 10 μ M initial concentration three-fold serial dilution mode. Control compound: staurosporine, tested in a 10-fold-amount IC50, 20 μ M starting concentration four-fold serial dilution mode. The reaction was run under 10. mu.M ATP.

The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.

Claims

1. A compound of formula (V), or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

A₁is selected from N;

A₂selected from CH, C (halogen), C (C)_1-6Alkyl) Or C (OC)_1-6Alkyl groups);

A₃selected from CH or C (C)_1-6Alkyl groups);

R₁is selected from H or C_1-6An alkyl group;

R₂is C_3-7A cycloalkyl group;

R₄selected from H, C_1-6Alkyl, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂or-C_1-6alkylene-OH;

R₈selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-7A cycloalkyl group.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,

A₁is selected from N;

A₂selected from CH, CF, CCH₃Or C (OCH)₃)；

A₃Selected from CH or CCH₃；

R₁Selected from H or Me;

R₂is cyclopentyl;

R₄selected from H, Me, Et, iPr, NH₂、NMe₂、CH₂CH₂OH or CH₂CH₂CH₂OH；

R₈Selected from H, Me, CF₃Et, cyclopropyl or cyclobutyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,

A₁is selected from N;

A₂selected from CH, C (halogen), C (C)_1-6Alkyl) Or C (OC)_1-6Alkyl groups);

A₃selected from CH or C (C)_1-6Alkyl groups);

R₁is C_1-6An alkyl group;

R₂is C_3-7A cycloalkyl group;

R₃is selected from

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof,

A₁is selected from N;

A₂selected from CH, CF, CCH₃Or C (OCH)₃)；

A₃Selected from CH or CCH₃；

R₁Is Me;

R₂is cyclopentyl;

R₃is selected from

R₈Selected from H, Me, CF₃Et, cyclopropyl or cyclobutyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,

A₁is N;

A₂selected from CH or C (C)_1-6Alkyl groups);

A₃selected from CH or C (C)_1-6Alkyl groups);

R₁is C_1-6An alkyl group;

R₂is C_3-7A cycloalkyl group;

R₃is composed of

R₄Is selected from H or C_1-6An alkyl group;

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof,

A₁is N;

A₂selected from CH or CCH₃；

A₃Selected from CH or CCH₃；

R₁Is Me;

R₂is cyclopentyl;

R₃is composed of

R₄Selected from H, Me or Et;

R₈selected from H, Me, CF₃Et or cyclopropyl.

7. A compound of formula (VI), or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

A₁is N;

A₂is CH;

A₃is CH;

R₁is C_1-6An alkyl group;

R₂is C_3-7A cycloalkyl group;

R₃is composed of

R₄Is selected from H or C_1-6An alkyl group;

R₈is C_1-6An alkyl group.

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof,

A₁is N;

A₂is CH;

A₃is CH;

R₁is Me;

R₂is cyclopentyl;

R₃is composed of

R₄Selected from H or Me;

R₈is Me.

9. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:

10. a pharmaceutical composition comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. The pharmaceutical composition of claim 10, further comprising an additional therapeutic agent.

12. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prevention of a CDK mediated disorder.

13. Use according to claim 12 wherein the CDK mediated disorder is mediated by CDK4 and/or CDK 6.

14. Use according to claim 12 or 13, wherein the disease is selected from the group consisting of cell proliferative diseases, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders and other cell proliferative disorders.

15. The use of claim 14, wherein the cell proliferative disorder is cancer.

16. The use of claim 15, wherein the cancer is selected from the group consisting of a solid tumor and a hematologic malignancy.

17. The use of claim 16, wherein the solid and hematological malignancies are selected from the group consisting of breast cancer, neuroblastoma, malignant rhabdomyoma, glioma, lung cancer, colorectal cancer, gastric cancer, gastrointestinal stromal tumor, hepatocellular carcinoma, prostate cancer, sarcoma, ovarian cancer, cervical cancer, pancreatic cancer, melanoma, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, mesothelioma, lymphoma, leukemia and multiple myeloma.

18. The use of claim 16, wherein the solid and hematological malignancies are well-differentiated and de-differentiated liposarcomas, non-hodgkin's lymphomas, mantle cell lymphomas, anaplastic large cell lymphomas, or acute myeloid leukemia.

19. The use of claim 14, wherein the cardiovascular disorder is selected from the group consisting of restenosis, atherosclerosis, vascular smooth muscle proliferation and intimal hyperplasia following balloon angioplasty, and other vascular disorders caused by abnormal cell proliferation.

20. The use of claim 14, wherein the infectious disease is selected from the group consisting of fungal, protozoal parasite and DNA and RNA virus infections.

21. The use of claim 20, wherein the infectious disease is an infection by plasmodium falciparum.

22. The use of claim 20, wherein the infectious disease is selected from herpes simplex virus infection.

23. The use of claim 14, wherein the chronic inflammatory disease is rheumatoid arthritis.

24. The use of claim 14, wherein the other cell proliferative disorder is selected from psoriasis, glomerulonephritis and lupus.

25. The use of claim 24, wherein said psoriasis is characterized by keratinocyte hyperproliferation.