CN113429410B - Polyheterocyclic substituted pyrimidine or pyridylamine derivatives, compositions and medical uses thereof - Google Patents

Polyheterocyclic substituted pyrimidine or pyridylamine derivatives, compositions and medical uses thereof Download PDF

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CN113429410B
CN113429410B CN202110205515.5A CN202110205515A CN113429410B CN 113429410 B CN113429410 B CN 113429410B CN 202110205515 A CN202110205515 A CN 202110205515A CN 113429410 B CN113429410 B CN 113429410B
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cancer
hydrogen
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CN113429410A (en
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赵志明
刘力锋
刘青雲
王海龙
关慧平
达晨啸
陈曦
徐贵良
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Abstract

The invention discloses a multi-heterocyclic ring substituted pyrimidine or pyridylamine derivative, which has a structure shown as a formula (I). In addition, the invention also discloses pharmaceutically acceptable salts of the derivatives, solvates, stereoisomers, prodrugs, pharmaceutical compositions and application thereof in medicines. The compounds of the invention have significant adenosine A 2A Receptor and/or adenosine A 2B The receptor antagonistic activity has very practical value.

Description

Polyheterocyclic substituted pyrimidine or pyridylamine derivatives, compositions and medical uses thereof
The present application claims priority from chinese patent application entitled "polyheterocyclic substituted pyrimidine or pyridylamine derivatives, compositions thereof, and pharmaceutical uses" filed at 23/03/2020, 2020102084384, which is hereby incorporated by reference in its entirety.
Technical Field
The invention relates to the technical field of medicines, in particular to a polyheterocycle substituted pyrimidine or pyridylamine derivative, and pharmaceutically acceptable salts, solvates, stereoisomers, prodrugs, a pharmaceutical composition and medical application thereof.
Background
Adenosine (Adenosine) is an endogenous nucleoside distributed throughout human cells, consisting of adenine and ribose, which are widely distributed both inside and outside the cell. Adenosine is involved in various physiological and biochemical functions in the body, for example, adenosine can directly enter cardiac muscle, and Adenosine Triphosphate (ATP) is generated through phosphorylation, and is involved in energy metabolism of cardiac muscle. In the Central Nervous System (CNS), adenosine controls neurotransmitter release and postsynaptic neuronal responses and serves to regulate important vital processes such as locomotion, neuronal protection, sleep and wakefulness. In pathological conditions, extracellular adenosine concentrations increase significantly in tumor or hypoxic conditions. Adenosine can play an important role in tumor immunosuppression by promoting tumor angiogenesis, proliferation, progression, and tumor migration.
Adenosine Receptors (ARs) belong to the family of G-Protein Coupled receptors (GPCRs), the endogenous ligand of which is Adenosine. The adenosine receptors known at present consist of four subtypes, A1, A2a, A2b and A3 receptors. Wherein adenosine binding to the A1 or A3 receptor inhibits cAMP production; and the binding with A2a or A2b receptor can activate adenosine activating enzyme, further up-regulate cAMP level and play a further role in physiological regulation.
The two receptors, A1 and A3, are mainly expressed in the central nervous system, and the two adenosine receptors, A2a and A2b, are expressed in both the central nervous system and the peripheral system. In the tumor microenvironment, two adenosine receptors, A2a and A2b, are widely expressed on immune cells and have strong immunosuppressive function. An increase in extracellular adenosine concentration is one of the important mechanisms of immune escape from tumor cells, and the concentration level is determined by the ATP level and the expression levels of CD39 and CD 73. The increase in extracellular adenosine concentrations is associated with cell death or hypoxia in the tumor microenvironment, releasing large amounts of ATP at concentrations that can be 10-20 times higher than normal tissues. Adenosine binds to adenosine receptors in the tumor microenvironment and can inhibit anti-tumor responses, such as inhibition of CD8+ T cell function, enhancement of immunosuppressive regulatory T cell function, inhibition of antigen presenting cell function via dendritic cells, and the like. Recent studies have shown that binding to A2a receptors can also inhibit tumor killing by natural killer cells. Further research shows that the A2a adenosine receptor antagonist can improve the activity and killing capacity of dendritic antigen presenting cells, T cells and natural killer cells, inhibit the functions of regulatory T cells (T-regs), MDSC and TAM, eliminate tumor immune tolerance, promote the generation of tumor immune response, further inhibit the growth of tumors and prolong the survival period of mice. In addition, A2b receptor has also been reported to promote tumor migration in murine models of melanoma and triple negative breast cancer, and therefore A2b receptor antagonists are also effective cancer therapeutic targets. Therefore, blocking the activation of adenosine signaling pathway to reduce or relieve immunosuppression and enhance the anti-tumor function of immune cells, especially T cells, is considered to be one of the effective means for cancer therapy. The A2a/A2b dual receptor antagonist is used for simultaneously blocking the activation of the two receptors, so that the A2a/A2b dual receptor antagonist is used for comprehensively blocking the immunosuppressive action brought by adenosine in a microenvironment by regulating and controlling different immune cell groups in terms of mechanism, and has profound clinical application value for tumor treatment.
Adenosine receptor antagonists are currently the focus of clinical research, either alone or in combination with other chemotherapeutic/immunomodulatory drugs.
Disclosure of Invention
The invention aims to provide a polyheterocycle substituted pyrimidine or pyridylamine derivative with higher activity. The invention provides a compound shown in a formula (I), or pharmaceutically acceptable salt thereof, or stereoisomer thereof, or solvate thereof, or prodrug thereof in a first aspect,
Figure BDA0002950355860000011
in the formula, ring B 1 Is a fused 5-to 8-membered monocyclic or fused 5-to 6-membered heteroaryl; 1-6 ring atoms of the fused 5-to 8-membered monocyclic ring are each independently optionally substituted by C (O), O, NR B1 (or N), S (O) or SO 2 Alternatively, the remaining ring atoms are carbon;
ring B 2 Is a fused phenyl, fused 5-to 6-membered heteroaryl or fused pyridin-2 (1H) -one group;
(R 01 ) u1 is a ring B 1 Is substituted by u 1R 01 Substituted, u1 is 0, 1,2,3,4, 5 or 6, each R 01 Identical or different, are each independently cyano, hydroxy, carboxy, halogen, preferably fluorine or chlorine, -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl and 8 to 10 membered heteroaryl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or two R 01 Linked to form a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated monocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R B1 is hydrogen, C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl group), C 3-8 Cycloalkyl (preferably C) 3-6 Cycloalkyl), 3-to 8-membered heterocycloalkyl, -C 1-4 Alkyl-3 to 8 membered heterocycloalkyl, -SO 2 C 1-8 Alkyl (preferably-SO) 2 C 1-6 Alkyl, more preferably-SO 2 C 1-3 Alkyl), -C (O) NR a0 R b0 、-C(O)C 1-8 Alkyl (preferably-C (O) C) 1-6 Alkyl, more preferably-C (O) C 1-3 Alkyl), -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), C (O) NR a1 R b1 (ii) a Wherein said C 1-8 Alkyl radical, C 3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl, -SO 2 C 1-8 Alkyl, -C (O) C 1-8 Alkyl and-C (O) OC 1-8 Alkyl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: cyano, hydroxy, carboxyl, halogen, acetyl, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl, -C (O) C 1-3 Alkyl, -C (O) NR a1 R b1 、NR a1 R b1 、-NR c1 C(O)C 1-3 Alkyl, -NR c1 C(O)C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl;
(R 02 ) u2 is a ring B 2 Hydrogen of (a) is substituted by u 2R 02 Substituted, u2 is 0, 1,2,3,4 or 5, each R 02 The same or different, each independently hydrogen, halogen (preferably fluorine or chlorine), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl group), C 3-8 Cycloalkyl (preferably C) 3-6 Cycloalkyl), 3-to 8-membered heterocycloalkyl, -C 1-4 Alkyl-3 to 8 membered heterocycloalkyl, -SO 2 C 1-8 Alkyl (preferably-SO) 2 C 1-6 Alkyl, more preferably-SO 2 C 1-3 Alkyl), -C (O) NR a0 R b0 、-C(O)C 1-8 Alkyl (preferably-C (O) C) 1-6 Alkyl, more preferably-C (O) C 1-3 Alkyl), -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), C (O) NR a1 R b1 (ii) a Wherein said C 1-8 Alkyl radical, C 3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl, -SO 2 C 1-8 Alkyl, -C (O) C 1-8 Alkyl and-C (O) OC 1-8 Alkyl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: cyano, hydroxy, carboxyl, halogen, acetyl, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl, -C (O) C 1-3 Alkyl, -C (O) NR a1 R b1 、NR a1 R b1 、-NR c1 C(O)C 1-3 Alkyl, -NR c1 C(O)C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl;
Z 0 、Z 0 ' represents a ring atom, each independently C or N;
ring a is phenyl or 5 to 10 membered heteroaryl;
(R 0 ) u is a hydrogen on the ring A by u R 0 Substituted, u is 0, 1,2,3,4 or 5, each R 0 The same or different, each independently hydrogen, cyano, acetyl, hydroxy, carboxy, halogen (preferably fluorine or chlorine), NR a0 R b0 、C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy group), C 3-8 Cycloalkyl (preferably C) 3-6 Cycloalkyl), 3-to 6-membered heterocycloalkyl, 5-to 6-membered heteroaryl or C 6-10 An aryl group; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 6-membered heteroaryl and C 6-10 Aryl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
q is 5-to 6-membered heteroaryl, phenyl, C 3-6 Cycloalkyl, 4-to 8-membered heterocycloalkyl, 6-to 12-membered fused heterocycloalkyl, 7-to 11-membered phenyl-heterocycloalkyl, 7-to 11-membered heteroaryl-heterocycloalkyi, 7-to 11-membered spirocyclic group, or 7-to 11-membered heterospirocyclic group; wherein said 5-to 6-membered heteroaryl, phenyl, C 3-6 Cycloalkyl, 4-to 8-membered heterocycloalkyl, 6-to 12-membered fused heterocycloalkyl, 7-to 11-membered phenyl-heterocycloalkyl, 7-to 11-membered heteroaryl-heterocycloalkyi, 7-to 11-membered spirocyclic, and 7-to 11-membered heterospirocyclic are unsubstituted or substituted with 1,2, or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, oxo, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 An alkyl group,Halogen substituted C 1-3 Alkoxy, NR a0 R b0 、-C(O)C 1-3 Alkyl, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
L 1 、L 2 each independently of the other is a bond, NR 1 '、CR 2 'R 3 ', O, S or C (O); and L is 1 、L 2 Is not O or S at the same time;
R 1 '、R 2 '、R 3 ' are each independently hydrogen, deuterium, cyano, hydroxy, halogen (preferably fluoro or chloro) or C 1-6 An alkyl group; or R 1 ' and R 2 ' join to form a 3-to 8-membered heterocycloalkyl ring; or R 2 ' and R 3 ' join to form a 3-to 8-membered heterocycloalkyl ring; wherein said 3 to 8 membered heterocycloalkyl ring is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
U 1 is N or CR U1 ；U 2 Is N or CR U2 ；
R U1 、R a And R b Is defined by the following group (i) or (ii):
(i)R U1 is hydrogen, cyano, hydroxy, halogen (preferably fluorine or chlorine), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl), halo C 1-8 Alkyl (preferably halogenated C) 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl radical)Halogen substituted C 1-8 Alkoxy (preferably halo C) 1-6 Alkoxy, more preferably halo C 1-3 Alkoxy) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups);
R a 、R b each independently of the others is hydrogen, deuterium, C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl), -C (O) C 1-8 Alkyl (preferably-C (O) C) 1-6 Alkyl, more preferably-C (O) C 1-3 Alkyl), - (CH) 2 ) t C 3-8 Cycloalkyl (preferably- (CH) 2 ) t C 3-6 Cycloalkyl), - (CH) 2 ) t -3 to 8 membered heterocycloalkyl or is a structure of formula (a); wherein said C 1-8 Alkyl, -C (O) C 1-8 Alkyl and- (CH) 2 ) t -3 to 8 membered heterocycloalkyl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
or R a 、R b Together with the nitrogen atom to which they are attached form a 5-or 6-membered saturated or partially unsaturated mono-heterocyclic ring; wherein the 5 or 6 membered saturated or partially unsaturated mono-heterocyclic ring is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
Figure BDA0002950355860000031
wherein R is 1a Is hydrogen or C 1-3 An alkyl group; r 2a 、R 3a Each independently is hydrogen or C 1-3 An alkyl group; or R 2a And R 3a Joined to form a 5-to 8-membered heterocycloalkenyl ring or a 5-to 6-membered heteroaryl ring; the 5-to 8-membered heterocycloalkenyl ring contains 2,3, or 4 nitrogen atoms and 0, 1, or 2 oxygen atoms; the 5-to 6-membered heteroaryl ring contains 2,3, or 4 nitrogen atoms and 0 or 1 oxygen atom; the 5-to 8-membered heterocycloalkenyl ring and the 5-to 6-membered heteroaryl ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: halogen, cyano, hydroxy, C 1-3 Alkyl radical, C 1-3 Alkoxy, halo C 1-3 Alkyl, halo C 1-3 An alkoxy group;
(ii)R U1 and R a Linked to form a fused 5-or 6-membered saturated or partially unsaturated mono-heterocyclic ring, or a fused 5-to 6-membered heteroaryl ring; the fused 5 or 6 membered saturated or partially unsaturated mono-heterocyclic ring and the 5 to 6 membered heteroaryl ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, oxo, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R b is hydrogen, deuterium, C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl), -C (O) C 1-8 Alkyl (preferably-C (O) C) 1-6 Alkyl, more preferably-C (O) C 1-3 Alkyl radical)、-(CH 2 ) t C 3-8 Cycloalkyl (preferably- (CH) 2 ) t C 3-6 Cycloalkyl), - (CH) 2 ) t -3 to 8 membered heterocycloalkyl or is a structure of formula (a); wherein said C 1-8 Alkyl, -C (O) C 1-8 Alkyl and- (CH) 2 ) t -3 to 8 membered heterocycloalkyl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R U2 is hydrogen, cyano, hydroxy, halogen (preferably fluorine or chlorine), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl), halo C 1-8 Alkyl (preferably halogenated C) 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), halo C 1-8 Alkoxy (preferably halo C) 1-6 Alkoxy, more preferably halo C 1-3 Alkoxy) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups);
t is 0, 1,2 or 3;
R a0 、R b0 each independently is hydrogen or C 1-3 An alkyl group; or R a0 、R b0 Taken together with the nitrogen atom to which they are attached to form a 4-to 6-membered saturated monocyclic heterocycle; said 4 to 6 membered saturated mono-heterocyclic ring is optionally substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl;
R a1 、R b1 each independently is hydrogen, C 1-3 Alkyl or C 3-6 A cycloalkyl group; r is c1 Is hydrogen or C 1-3 An alkyl group.
A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof:
Figure BDA0002950355860000041
in the formula (I), the compound is shown in the specification,
ring B 1 Is a fused 5-to 8-membered monocyclic ring, a fused 5-to 6-membered heteroaryl, or a fused phenyl; the fused 5-to 8-membered monocyclic ring atoms are carbon;
other definitions are as described above and will not be described herein.
More preferably, the first and second liquid crystal display panels are,
Figure BDA0002950355860000042
is a structure represented by formula (A), formula (B), formula (C), formula (D), formula (E), formula (F), formula (G) or formula (H), or is an 8-to 10-membered heteroaryl;
Figure BDA0002950355860000043
in the formula, W 3 、W 8 、W 10 Each independently is NR 03 O or S;
W 1 、W 2 、W 4 、W 5 、W 6 、W 7 、W 9 、W 11 、W 12 、Y 1 、Y 2 、Y 3 、Y 4 each independently is N or CR 02 ；
R 03 Is hydrogen, C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl), C 3-8 Cycloalkyl (preferably C) 3-6 Cycloalkyl), 3-to 8-membered heterocycloalkyl, -C 1-4 Alkyl-3 to 8 membered heterocycloalkyl, -SO 2 C 1-8 Alkyl (preferably-SO) 2 C 1-6 Alkyl, more preferably-SO 2 C 1-3 Alkyl), -C (O) NR a0 R b0 、-C(O)C 1-8 Alkyl (preferably-C (O) C) 1-6 Alkyl, more preferably-C (O) C 1-3 Alkyl), -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), C (O) NR a1 R b1 (ii) a Wherein said C 1-8 Alkyl radical, C 3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl, -SO 2 C 1-8 Alkyl, -C (O) C 1-8 Alkyl and-C (O) OC 1-8 Alkyl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: cyano, hydroxy, carboxyl, halogen, acetyl, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl, -C (O) C 1-3 Alkyl, -C (O) NR a1 R b1 、NR a1 R b1 、-NR c1 C(O)C 1-3 Alkyl, -NR c1 C(O)C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl;
Z 1 is a bond, C (O), CR Z1a R Z1b 、O、NR Z1c S, S (O) or SO 2 ；
Z 2 Is O, CR Z2a R Z2b 、NR Z2c C (O), S (O) or SO 2 ；
Z 3 Is CR Z3a R Z3b 、C(O)、O、NR Z3c S, S (O) or SO 2 ；
Z 4 Is CR Z4a R Z4b C (O) or SO 2 ；
E 1 Is O, CR E1a R E1b 、NR E1c C (O) or SO 2 ；
E 2 Is a bond, CR E2a R E2b 、O、NR E2c C (O) or SO 2 ；
E 3 Is C (O), CR E3a R E3b 、O、NR E3c Or SO 2 ；
E 4 Is O, CR E4a R E4b 、NR E4c C (O) or SO 2 ；
R Z1a 、R Z1b Each independently hydrogen, cyano, hydroxy, carboxy, halogen (preferably fluorine or chlorine), -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl and 8 to 10 membered heteroaryl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R Z1a 、R Z1b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated monocyclic heterocycle or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R Z2a 、R Z2b each independently hydrogen, cyano, hydroxy, carboxy, halogen (preferably fluorine or chlorine))、-C(O)OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl and 8 to 10 membered heteroaryl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R Z2a 、R Z2b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R Z1c 、R Z2c 、R Z3c 、R E1c 、R E2c 、R E3c each independently is hydrogen, C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl group), C 3-8 Cycloalkyl (preferably C) 3-6 Cycloalkyl), 3-to 8-membered heterocycloalkyl, -C 1-4 Alkyl-3 to 8 membered heterocycloalkyl, -SO 2 C 1-8 Alkyl (preferably-SO) 2 C 1-6 Alkyl, more preferably-SO 2 C 1-3 Alkyl), -C (O) NR a0 R b0 、-C(O)C 1-8 Alkyl (preferably-C (O) C) 1-6 Alkyl, more preferably-C (O) C 1-3 Alkyl), -C (O) OC 1-8 Alkyl (a)preferably-C (O) OC 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), C (O) NR a1 R b1 (ii) a Wherein said C 1-8 Alkyl radical, C 3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl, -SO 2 C 1-8 Alkyl, -C (O) C 1-8 Alkyl and-C (O) OC 1-8 Alkyl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: cyano, hydroxy, carboxyl, halogen, acetyl, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl, -C (O) C 1-3 Alkyl, -C (O) NR a1 R b1 、NR a1 R b1 、-NR c1 C(O)C 1-3 Alkyl, -NR c1 C(O)C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl;
R Z3a 、R Z3b each independently hydrogen, cyano, hydroxy, carboxy, halogen (preferably fluorine or chlorine), -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl and 8 to 10 membered heteroaryl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R Z3a 、R Z3b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated monocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl radicalHalogen substituted C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R Z4a 、R Z4b each independently of the others, hydrogen, cyano, hydroxy, carboxy, halogen, preferably fluorine or chlorine, -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl and 8 to 10 membered heteroaryl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R Z4a 、R Z4b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated monocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
or R Z1a And R Z2a Linked to form a fused 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a fused 3-to 7-membered saturated or partially unsaturated monocyclic ring; or R Z2a And R Z3a Linked to form a fused 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a fused 3-to 7-membered saturated or partially unsaturated monocyclic ring; or R Z3a And R Z4a Linked to form a fused 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a fused 3-to 7-membered saturated or partially unsaturated monocyclic ring;
wherein the fused 3 to 7 membered saturated or partially unsaturated mono-heterocyclic ring and the fused 3 to 7 membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R E1a 、R E1b each independently of the others, hydrogen, cyano, hydroxy, carboxy, halogen, preferably fluorine or chlorine, -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl group), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R E1a 、R E1b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated monocyclic heterocycle or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R E2a 、R E2b each independently hydrogen, cyano, hydroxy, carboxy, halogen (preferably fluorine or chlorine), -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R E2a 、R E2b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated monocyclic heterocycle or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated monocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R E3a 、R E3b each independently of the others, hydrogen, cyano, hydroxy, carboxy, halogen, preferably fluorine or chlorine, -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R E3a 、R E3b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R E4a 、R E4b each independently hydrogen, cyano, hydroxy, carboxy, halogen (preferably fluorine or chlorine), -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl group), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R E4a 、R E4b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated monocyclic heterocycle or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring and 3-to 7-membered saturated or partially unsaturated monocyclic ringIs unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R E4c is hydrogen or C 1-3 An alkyl group;
or R E1a And R E2a Linked to form a fused 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a fused 3-to 7-membered saturated or partially unsaturated monocyclic ring; or R E2a And R E3a Linked to form a fused 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a fused 3-to 7-membered saturated or partially unsaturated monocyclic ring; or R E3a And R E4a Linked to form a fused 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a fused 3-to 7-membered saturated or partially unsaturated monocyclic ring;
wherein the fused 3-to 7-membered saturated or partially unsaturated monocyclic ring and the fused 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl.
In some embodiments of the present invention, the,
Figure BDA0002950355860000071
is composed of
Figure BDA0002950355860000072
W 13 、W 14 、W 15 、W 16 Each independently is N or CR 01 ；R 01 As defined above.
In some embodiments of the present invention, the,
Figure BDA0002950355860000073
is composed of
Figure BDA0002950355860000074
Wherein two Z are 4 Identical to or different from each other, Z 1 -Z 4 As described above;
in some embodiments of the present invention, the,
Figure BDA0002950355860000075
is composed of
Figure BDA0002950355860000076
Wherein each Z is 2 Identical to or different from each other, Z 1 -Z 2 As described above.
More preferably, the compound is represented by formula (I-1):
Figure BDA0002950355860000077
wherein Ar is a structure shown in formula (I-a), formula (I-b) or formula (I-c):
Figure BDA0002950355860000078
wherein G is 1 Is a bond, C (O), CR G1a R G1b 、O、NR G1c S, S (O) or SO 2 ；
G 2 Is O, CR G2a R G2b 、NR G2c C (O), S (O) or SO 2 ；
G 3 Is CR G3a R G3b 、C(O)、O、NR G3c S, S (O) or SO 2 ；
G 4 Is CR G4a R G4b C (O) or SO 2 ；
R G1a 、R G1b Each independently of the others, hydrogen, cyano, hydroxy, carboxy, halogen, preferably fluorine or chlorine, -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl and 8 to 10 membered heteroaryl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R G1a 、R G1b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated monocyclic heterocycle or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R G2a 、R G2b each independently of the others, hydrogen, cyano, hydroxy, carboxy, halogen, preferably fluorine or chlorine, -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl and 8 to 10 membered heteroaryl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R G2a 、R G2b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated monocyclic heterocycle or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R G1c 、R G2c 、R G3c each independently is hydrogen, C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl), C 3-8 Cycloalkyl (preferably C) 3-6 Cycloalkyl), 3-to 8-membered heterocycloalkyl, -C 1-4 Alkyl-3 to 8 membered heterocycloalkyl, -SO 2 C 1-8 Alkyl (preferably-SO) 2 C 1-6 Alkyl, more preferably-SO 2 C 1-3 Alkyl), -C (O) NR a0 R b0 、-C(O)C 1-8 Alkyl (preferably-C (O) C) 1-6 Alkyl, more preferably-C (O) C 1-3 Alkyl), -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), C (O) NR a1 R b1 (ii) a Wherein said C 1-8 Alkyl radical, C 3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl, -SO 2 C 1-8 Alkyl, -C (O) C 1-8 Alkyl radicals and-C(O)OC 1-8 alkyl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: cyano, hydroxy, carboxyl, halogen, acetyl, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl, -C (O) C 1-3 Alkyl, -C (O) NR a1 R b1 、NR a1 R b1 、-NR c1 C(O)C 1-3 Alkyl, -NR c1 C(O)C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl;
R G3a 、R G3b each independently of the others, hydrogen, cyano, hydroxy, carboxy, halogen, preferably fluorine or chlorine, -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl and 8 to 10 membered heteroaryl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R G3a 、R G3b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R G4a 、R G4b each independently of the others, hydrogen, cyano, hydroxy, carboxy, halogen, preferably fluorine or chlorine, -C (O) OC 1-8 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -OC (O) C 1-8 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl and 8 to 10 membered heteroaryl), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl) or C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups); or R G4a 、R G4b Taken together with the attached carbon atom to form a 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a 3-to 7-membered saturated or partially unsaturated monocyclic ring; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy, a 3-to 7-membered saturated or partially unsaturated monocyclic ring and a 3-to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
or R G1a And R G2a Linked to form a fused 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a fused 3-to 7-membered saturated or partially unsaturated monocyclic ring; or R G2a And R G3a Linked to form a fused 3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring or a fused 3-to 7-membered saturated or partially unsaturated monocyclic ring; or R G3a And R G4a Are linked to form a fused 3-to 7-membered saturated or partially unsaturated monoheterocycle or a fused 3-to 7-membered saturated or partially non-saturatedA saturated monocyclic ring;
wherein the fused 3 to 7 membered saturated or partially unsaturated mono-heterocyclic ring and the fused 3 to 7 membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl.
More preferably, the first and second liquid crystal display panels are,
Figure BDA0002950355860000081
selected from the following structures:
Figure BDA0002950355860000091
Figure BDA0002950355860000092
wherein in each of the above structures Z 1 、Z 2 、Z 3 、Z 4 、R 02 、R 03 、R B1 As defined in the specification.
More preferably, ring a is phenyl, 5-to 6-membered heteroaryl or 8-to 10-membered heteroaryl.
More preferably, U 1 Is N; u shape 2 Is CR U2 . More preferably, R U1 、R U2 Each independently hydrogen, cyano, hydroxy, fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy. More preferably, U 1 Is CR U1 ；U 2 Is N. More preferably, R U1 Is fluorine or chlorine.
More preferably, said 5-to 6-membered heteroaryl in Q is selected from the following structures:
Figure BDA0002950355860000093
more preferably, said 4 to 8 membered heterocycloalkyl in Q is selected from the following structures:
Figure BDA0002950355860000094
more preferably, the compound has a structure shown in formula (II), formula (III) or formula (IV):
Figure BDA0002950355860000095
wherein R in the formula (II) U1 、R a And R b As defined in group (i); r in the formula (III) a And R b As defined in group (i); r in the formula (IV) b As defined in group (ii);
X 1 is O, NR 11 Or CR 12 R 13 ；
X 2 Is C (O) or CR 21 R 22 ；
R 11 Is hydrogen or C 1-3 An alkyl group;
R 12 、R 13 、R 21 、R 22 each independently of the others is hydrogen, halogen, C 1-3 Alkyl or C 1-3 An alkoxy group;
U 0 is N or CR U0 ；R U0 Is hydrogen, deuterium or C 1-3 An alkyl group;
R 1 、R 2 、R 3 、R 4 、R 5 each independently hydrogen, cyano, acetyl, hydroxy, carboxy, halogen (preferably fluorine or chlorine), NR a0 R b0 、C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl group), C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy group), C 3-8 Cycloalkyl (preferably C) 3-6 Cycloalkyl), 3-to 6-membered heterocycloalkyl, 5-to 6-membered heteroaryl or C 6-10 An aryl group; wherein said C 1-8 Alkyl radical, C 1-8 Alkoxy radical, C 3-8 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 6-membered heteroaryl and C 6-10 Aryl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 3-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl;
R 6 、R 7 each independently hydrogen, deuterium, cyano, hydroxy, halogen (preferably fluoro or chloro) or C 1-6 An alkyl group.
In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 At least one of them is C 1-3 Alkyl, one is cyano; in some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 One of them is C 1-3 Alkyl, one is cyano and the remainder are H; in some embodiments, R 1 Is methyl, R 2 Cyano and the rest are H.
More preferably, U 0 Is N.
More preferably, R a 、R b Each independently of the others is hydrogen, deuterium, C 1-3 Alkyl, -C (O) C 1-3 Alkyl, - (CH) 2 ) t C 3-6 Cycloalkyl, - (CH) 2 ) t -a 4 to 6 membered heterocycloalkyl group or is of formula (a); or R a 、R b Together with the nitrogen atom to which they are attached form a 5-or 6-membered saturated mono-heterocyclic ring; wherein said C 1-3 Alkyl, -C (O) C 1-3 Alkyl, - (CH) 2 ) t -4 to 6 membered heterocycloalkyl and 5 or 6 membered saturated mono-heterocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radicalBase, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 4-to 6-membered heterocycloalkyl; the 4-to 6-membered heterocycloalkyl is selected from: azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl-1, 1-dioxide, tetrahydropyranyl; said C is 3-6 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 5 or 6 membered saturated mono-heterocyclic ring is selected from: tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, dioxolane, dioxane, morpholine ring, thiomorpholine ring, tetrahydropyran ring.
More preferably, R a 、R b Is hydrogen or deuterium. More preferably, R a Is hydrogen or deuterium, R b Is C 1-3 An alkyl group. More preferably, R a Is hydrogen; r b Is a structure of formula (a).
More preferably, R 2a And R 3a Joined to form a 5-to 8-membered heterocycloalkenyl ring or a 5-to 6-membered heteroaryl ring; wherein the 5-to 8-membered heterocycloalkenyl ring is selected from: :4, 5-dihydro-1H-imidazole ring, 1,4,5, 6-tetrahydropyrimidine ring, 3,4,7, 8-tetrahydro-2H-1, 4, 6-oxadiazolazine ring, 1, 6-dihydropyrimidine ring, 4,5,6, 7-tetrahydro-1H-1, 3-diazepine ring, 2,5,6, 7-tetrahydro-1, 3, 5-oxadiazepine ring; the 5-to 6-membered heteroaryl ring is selected from: 1H-imidazole ring, 4H-1,2, 4-triazole ring, 1H-1,2, 4-triazole ring, pyrimidine ring, 1,2, 4-triazine ring, 1,3, 5-triazine ring, 1,2, 4-triazine ring.
More preferably, the structure of formula (a) is selected from:
Figure BDA0002950355860000101
more preferably, R U1 Is halogen.
More preferably, R U1 And R a Linked to form a fused 5 or 6 membered saturated mono-heterocyclic ring, or a fused 5 to 6 membered heteroaryl ring; the fused 5 or 6 membered saturated mono-heterocyclic ring and 5 to 6 membered heteroaryl ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, oxo, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 4-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl; the fused 5 or 6 membered saturated mono-heterocyclic ring is selected from: tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, morpholine-3-one ring, piperazine-2-one ring, piperidine-2-one ring; the fused 5-to 6-membered heteroaryl ring is selected from: thiophene ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2, 3-triazole ring, 1,2, 4-triazole ring, 1,2, 5-triazole ring, 1,3, 4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2, 4-oxadiazole ring, 1,2, 5-oxadiazole ring, 1,3, 4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring.
More preferably, W 4 Is N; w 6 Is CR 02 . More preferably, W 4 Is CR 02 ；W 6 Is N. More preferably, W 4 Is N; w 5 Is CR 02 。
More preferably, Z 1 Is a bond, C (O), CR Z1a R Z1b Or NR Z1c ；Z 2 Is O, CR Z2a R Z2b Or NR Z2c (ii) a And Z is 1 、Z 2 Does not contain N at the same time. More preferably, Z 1 Is a bond or CR Z1a R Z1b ；Z 2 Is CR Z2a R Z2b . More preferably, Z 1 Is a bond; z 2 Is O, C (O) or NR Z2c 。
More preferably, Z 1 Is C (O) or CR Z1a R Z1b ；Z 2 Is O, CR Z2a R Z2b Or NR Z2c . More preferably, Z 1 Is NR Z1c ；Z 2 Is CR Z2a R Z2b 。
More preferably, G 1 Is a bond, C (O), CR G1a R G1b Or NR G1c ；G 2 Is O, CR G2a R G2b Or NR G2c (ii) a And G 1 、G 2 Does not contain N at the same time. More preferably, G 1 Is a bond or CR G1a R G1b ；G 2 Is CR G2a R G2b . More preferably, G 1 Is a bond; g 2 Is O, C (O) or NR G2c . More preferably, G 1 Is C (O) or CR G1a R G1b ；G 2 Is O, CR G2a R G2b Or NR G2c . More preferably, G 1 Is NR G1c ；G 2 Is CR G2a R G2b 。
More preferably, the 4-to 6-membered saturated monocyclic heterocycle is selected from the group consisting of azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, dioxolane, dioxane ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring, morpholin-3-one ring, piperazin-2-one ring, piperidin-2-one ring.
More preferably, said 3-to 6-membered saturated monocyclic ring is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ring.
More preferably, the 5-to 6-membered heteroaryl group is selected from thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl.
More preferably, the 4-to 6-membered heterocycloalkyl is selected from azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl-1, 1-dioxide, tetrahydropyranyl, morpholin-3-onyl, piperazin-2-onyl, piperidin-2-onyl.
More preferably, the 5 to 8 membered heterocycloalkenyl ring is selected from: 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1, 4, 6-oxadiazolazine ring, 1, 6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1, 3-diazepine ring, 2,5,6,7-tetrahydro-1,3, 5-oxadiazepine ring.
More preferably, R Z1a 、R Z1b Each independently of the others being hydrogen, hydroxy, fluorine, chlorine or C 1-6 An alkyl group; or R Z1a 、R Z1b Taken together with the attached carbon atom to form a 4-to 6-membered saturated monocyclic heterocycle or a 3-to 6-membered saturated monocyclic ring; wherein said C 1-6 The alkyl, 4-to 6-membered saturated monocyclic ring and 3-to 6-membered saturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 4-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl; wherein the 4-to 6-membered heterocycloalkyl is selected from: azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl-1, 1-dioxide, tetrahydropyranyl; said C is 3-6 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 5-to 6-membered heteroaryl is selected from: thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, tetrazolyl, isoxazolylOxazolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl; the 4-to 6-membered saturated mono-heterocyclic ring is selected from: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, dioxolane, dioxane ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring; the 3-to 6-membered saturated monocyclic ring is selected from: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl rings.
More preferably, R Z1a 、R Z1b Each independently hydrogen, hydroxy, fluoro, chloro, methyl, ethyl, n-propyl or isopropyl; or R Z1a 、R Z1b Taken together with the attached carbon atom to form a cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, or a 4-to 6-membered saturated monocyclic heterocycle selected from: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, dioxolane, dioxane ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring; wherein the 4-to 6-membered saturated mono-heterocyclic ring is optionally substituted with 1,2 or 3 substituents each independently selected from: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl.
More preferably, R Z2a 、R Z2b Each independently of the others is hydrogen, hydroxy, fluorine, chlorine or C 1-6 An alkyl group; or R Z2a 、R Z2b Taken together with the attached carbon atom to form a 4-to 6-membered saturated monocyclic heterocycle or a 3-to 6-membered saturated monocyclic ring; wherein said C 1-6 The alkyl, 4-to 6-membered saturated monocyclic ring and 3-to 6-membered saturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy,Carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 4-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl; wherein the 4-to 6-membered heterocycloalkyl is selected from: azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl-1, 1-dioxide, tetrahydropyranyl; said C is 3-6 Cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 5-to 6-membered heteroaryl is selected from: thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl; the 4-to 6-membered saturated mono-heterocyclic ring is selected from: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, dioxolane, dioxane ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring; the 3-to 6-membered saturated monocyclic ring is selected from: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl rings.
More preferably, R Z2a 、R Z2b Each independently hydrogen, hydroxy, fluoro, chloro, methyl, ethyl, n-propyl or isopropyl; or R Z2a 、R Z2b Taken together with the carbon atom to which they are attached to form a cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, or a 4-to 6-membered saturated monocyclic heterocycle selected from: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, dioxolane, dioxaneMorpholine ring, thiomorpholine ring, tetrahydropyran ring; wherein the 4-to 6-membered saturated mono-heterocyclic ring is optionally substituted with 1,2 or 3 substituents each independently selected from: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl.
More preferably, R Z3a 、R Z3b Each independently of the others is hydrogen, hydroxy, fluorine, chlorine or C 1-6 An alkyl group; or R Z3a 、R Z3b Taken together with the attached carbon atom to form a 4-to 6-membered saturated monocyclic heterocycle or a 3-to 6-membered saturated monocyclic ring; wherein said C 1-6 Alkyl, 4 to 6 membered saturated monocyclic heterocycle and 3 to 6 membered saturated monocyclic ring are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 4-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl; wherein the 4-to 6-membered heterocycloalkyl is selected from: azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholine-1, 1-dioxide, tetrahydropyranyl; said C is 3-6 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 5-to 6-membered heteroaryl is selected from: thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl1,3, 4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl; the 4-to 6-membered saturated mono-heterocyclic ring is selected from: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, dioxolane, dioxane ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring; the 3-to 6-membered saturated monocyclic ring is selected from: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl rings.
More preferably, R Z3a 、R Z3b Each independently hydrogen, hydroxy, fluoro, chloro, methyl, ethyl, n-propyl or isopropyl; or R Z3a 、R Z3b Taken together with the carbon atom to which they are attached to form a cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, or a 4-to 6-membered saturated monocyclic heterocycle selected from: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, dioxolane, dioxane ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring; wherein the 4-to 6-membered saturated mono-heterocyclic ring is optionally substituted with 1,2 or 3 substituents each independently selected from: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl.
More preferably, R Z4a 、R Z4b Each independently of the others is hydrogen, hydroxy, fluorine, chlorine or C 1-6 An alkyl group; or R Z4a 、R Z4b Taken together with the attached carbon atom to form a 4-to 6-membered saturated monocyclic heterocycle or a 3-to 6-membered saturated monocyclic ring; wherein said C 1-6 The alkyl, 4-to 6-membered saturated monocyclic ring and 3-to 6-membered saturated monocyclic ring are unsubstituted or substituted by 1,2 or 3 substituents each independently selected from the group consisting ofGeneration: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyloxy, 4-to 6-membered heterocycloalkyl, phenyl, 5-to 6-membered heteroaryl; wherein the 4-to 6-membered heterocycloalkyl is selected from: azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl-1, 1-dioxide, tetrahydropyranyl; said C is 3-6 The cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 5-to 6-membered heteroaryl is selected from: thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl; the 4-to 6-membered saturated mono-heterocyclic ring is selected from: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, piperazine ring, dioxolane, dioxane ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring; the 3-to 6-membered saturated monocyclic ring is selected from: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl rings.
More preferably, R Z4a 、R Z4b Each independently hydrogen, hydroxy, fluoro, chloro, methyl, ethyl, n-propyl or isopropyl; or R Z4a 、R Z4b Taken together with the carbon atom to which they are attached to form a cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, or a 4-to 6-membered saturated monocyclic heterocycle selected from: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine,Piperazine ring, dioxolane, dioxane, morpholine ring, thiomorpholine ring, tetrahydropyran ring; wherein the 4-to 6-membered saturated mono-heterocyclic ring is optionally substituted with 1,2 or 3 substituents each independently selected from: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo C 1-3 Alkyl, halo C 1-3 Alkoxy, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl radical, C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl.
More preferably, R Z1c 、R Z2c 、R G1c 、R G2c Each independently of the other is hydrogen, C 1-3 Alkyl radical, C 3-6 Cycloalkyl, - (CR) 1a R 1b ) s1 -SO 2 C 1-3 Alkyl, - (CR) 2a R 2b ) s2 -C(O)NR a0 R b0 、-(CR 3a R 3b ) s3 -C(O)C 1-3 Alkyl, - (CR) 4a R 4b ) s4 -C(O)OC 1-3 Alkyl, - (CR) 5a R 5b ) s5 -NR a1 R b1 、-(CR 6a R 6b ) s6 -carboxy, - (CR) 7a R 7b ) s7 -C 1-3 Alkoxy, - (CR) 8a R 8b ) s8 -C(O)NR a1 R b1 、-(CR 9a R 9b ) s9 -NR c1 C(O)C 1-3 Alkyl, - (CR) 10a R 10b ) s10 -NR c1 C(O)C 3-6 Cycloalkyl, - (CR) 11a R 11b ) s11 -a 4 to 6 membered heterocycloalkyl; wherein said C 1-3 Alkyl radical, C 3-6 Cycloalkyl, 4-to 6-membered heterocycloalkyl, -SO 2 C 1-3 Alkyl, -C (O) C 1-3 Alkyl and-C (O) OC 1-3 Alkyl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: cyano, hydroxy, carboxyl, halogen, acetyl, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, -SO 2 C 1-3 Alkyl, -S (O) C 1-3 Alkyl, -C (O) NR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl, -C (O) C 1-3 Alkyl, -C (O) NR a1 R b1 、NR a1 R b1 、-NR c1 C(O)C 1-3 Alkyl, -NR c1 C(O)C 3-6 A cycloalkyl group; s1, s2, s3, s4, s8, s11 are each independently 0, 1,2,3 or 4; s5, s6, s7, s9, s10 are each independently 1,2,3 or 4; r 1a 、R 1b 、R 2a 、R 2b 、R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b 、R 6a 、R 6b 、R 7a 、R 7b 、R 8a 、R 8b 、R 9a 、R 9b 、R 10a 、R 10b 、R 11a 、R 11b Each independently is hydrogen, hydroxy or C 1-3 An alkyl group.
More preferably, said 4 to 6 membered heterocycloalkyl is selected from: azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholin-1, 1-dioxide, tetrahydropyranyl.
More preferably, formula (I-a) is selected from the following structures of formula (I-a-1), formula (I-a-2), and formula (I-a-3):
Figure BDA0002950355860000131
wherein Z 21 Is O, CR Z2a R Z2b Or NR Z2c ；Z 11 Is C (O) or CR Z1a R Z1b ；Z 22 Is O, CR Z2a R Z2b Or NR Z2c ；Z 12 Is O or NR Z1c 。
More preferably, formula (I-a) is selected from the following structures:
Figure BDA0002950355860000132
Figure BDA0002950355860000141
more preferably, formula (I-b) is selected from the following structures of formula (I-b-1), formula (I-b-2), and formula (I-b-3):
Figure BDA0002950355860000142
wherein G 21 Is O, CR G2a R G2b Or NR G2c ；G 11 Is C (O) or CR G1a R G1b ；G 22 Is O, CR G2a R G2b Or NR G2c ；G 12 Is O or NR G1c 。
More preferably, formula (I-b) is selected from the following structures:
Figure BDA0002950355860000143
more preferably, E 1 Is O or CR E1a R E1b ；E 2 Is a bond or CR E2a R E2b ；E 3 Is C (O); e 4 Is NR E4c 。
More preferably, E 1 Is O or CR E1a R E1b ；E 2 Is a bond or CR E2a R E2b ；E 3 Is CR E3a R E3b ；E 4 Is O or CR E4a R E4b 。
More preferably, formula (I-c) is
Figure BDA0002950355860000151
More preferably, formula (I-c) is selected from the following structures:
Figure BDA0002950355860000152
more preferably, the compound has a structure shown in a formula (II-a), a formula (III-a) or a formula (IV-a):
Figure BDA0002950355860000153
more preferably, the compound of formula (I) is any one of the following compounds:
Figure BDA0002950355860000154
Figure BDA0002950355860000161
Figure BDA0002950355860000171
more preferably, the compound of formula (I) is selected from the following group of structures:
Figure BDA0002950355860000172
Figure BDA0002950355860000181
more preferably, the compound of formula (I) is any one of the example compounds.
In a second aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier.
In a third aspect, the present invention provides a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, and the present inventionUse of a pharmaceutical composition according to the second aspect of the invention for the preparation of a medicament for the treatment of a disease caused by adenosine A 2A Receptor and/or adenosine A 2B Use in the manufacture of a medicament for the treatment of a receptor mediated disease.
In a fourth aspect, the invention provides a method of preventing and/or treating a disease caused by adenosine A 2A Receptor and/or adenosine A 2B A method of treating a receptor mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition according to the second aspect of the invention.
More preferably, the disease is caused by adenosine A 2A Receptor mediation. More preferably, the disease is caused by adenosine A 2B Receptor mediation. More preferably, the disease is caused by adenosine A 2A Receptor and A 2B The receptors mediate together. More preferably, the disease is cancer.
More preferably, the cancer is selected from the group consisting of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, stomach cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, cervical cancer, melanoma, basal cancer, mesothelial lining cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer, non-small cell lung cancer, adrenal cancer, thyroid cancer, kidney cancer, or bone cancer; or glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, basal cell carcinoma of the skin or seminoma of the testes.
More preferably, the cancer is selected from the group consisting of melanoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, leukemia, brain tumors, lymphoma, ovarian cancer, kaposi's sarcoma, renal cell carcinoma, head and neck cancer, and esophageal cancer.
More preferably, the disease is an immune-related disease.
More preferably, the immune-related disorder is selected from the group consisting of rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infection, crohn's disease, ulcerative colitis, allergic contact dermatitis, and other eczemas, systemic sclerosis, and multiple sclerosis.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be repeated herein, depending on the space.
Detailed Description
The present inventors have made extensive and intensive studies and have unexpectedly found that such polyheterocycle substituted pyrimidine or pyridylamine derivatives have a significant adenosine a 2A Receptor and/or adenosine A 2B Receptor activity. Therefore, the series of compounds are expected to be developed into compounds for treating and preventing adenosine A 2A Receptor and/or adenosine A 2B A medicament for treating a related disease mediated by a receptor. On this basis, the inventors have completed the present invention.
Definition of terms
The term "optionally" as used herein means that the defined group may or may not be selected from a range of candidate groups, for example "the 1-6 ring atoms of the fused 5-to 8-membered monocyclic ring are each independently optionally substituted by C (O), O, NR B1 S, S (O) or SO 2 Alternatively, the remaining ring atoms are carbon ", the expression fused 5-to 8-membered monocyclic 1-6 ring atoms can be derived from" C (O), O, NR B1 S, S (O) or SO 2 "optionally, 1-6 of the carbon atoms are replaced, i.e., all of the ring atoms of the fused 5-to 8-membered monocyclic ring may be carbon atoms.
In order to make the technical contents of the present invention more clearly understood, the terms of the present invention are further described below.
"alkyl" refers to straight and branched chain saturated aliphatic hydrocarbon groups. "C 1-8 Alkyl "refers to an alkyl group having 1 to 8 carbon atoms, preferably C 1-6 Alkyl, more preferably C 1-3 An alkyl group; non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, <xnotran> 3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- ,2,2- , ,3,3- ,2,2- , . </xnotran>
"alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having one or more carbon-carbon double bonds (C = C), "C 2-8 Alkenyl "means an alkenyl group having 2 to 8 carbon atoms, preferably C 2-6 Alkenyl, more preferably C 2-4 Alkenyl, defined analogously; non-limiting examples include ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl, and the like.
"alkynyl" refers to straight and branched chain unsaturated aliphatic hydrocarbon radicals having one or more carbon-carbon triple bonds, "C 2-8 Alkynyl "means an alkynyl group having 2 to 8 carbon atoms, preferably C 2-6 Alkynyl, more preferably C 2-4 Alkynyl, defined similarly; non-limiting examples include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like.
"cycloalkyl" and "cycloalkyl ring" are used interchangeably and refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon radical which may be substituted with one or more substituents selected from the group consisting ofAryl or heteroaryl fused. The cycloalkyl ring may be optionally substituted. In certain embodiments, the cycloalkyl ring contains one or more carbonyl groups, such as oxo groups. ' C 3-8 Cycloalkyl "refers to monocyclic cycloalkyl groups having 3 to 8 carbon atoms, and non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1, 3-dione, and the like. Preferably C 3-6 Cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "C 8-10 Cycloalkyl "refers to a fused bicyclic cyclic hydrocarbon radical having 8 to 10 ring atoms, C 8-10 Non-limiting examples of cycloalkyl radicals include
Figure BDA0002950355860000191
"Spirocyclic" and "spirocyclic" are used interchangeably and refer to polycyclic cyclic hydrocarbon groups that share a common carbon atom (referred to as a spiro atom) between the individual rings. "7-to 11-membered spirocyclic" refers to spirocyclic rings having 7 to 11 ring atoms. The spiro rings are divided into double spiro rings or multi spiro rings according to the number of rings, and the double spiro rings are preferred. More preferably a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered double helix. For example:
Figure BDA0002950355860000192
"cycloalkenyl" and "cycloalkenyl ring" are used interchangeably and refer to a monocyclic, bicyclic, or polycyclic cyclic hydrocarbon group within the ring containing one or more carbon-carbon double bonds, which group may be fused to an aryl or heteroaryl group. The cycloalkenyl ring may be optionally substituted. In certain embodiments, the cycloalkenyl ring contains one or more carbonyl groups, such as oxo. "C 3-8 Cycloalkenyl "refers to monocyclic cycloalkenyl groups having 3 to 8 carbon atoms. Preferably C 3-6 A cycloalkenyl group. Non-limiting examples of cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, cyclopentyl-2-en-1-one, cyclohexyl-2, 5-dien-1-one, cyclohexyl-2-en-1-Ketones, cyclohex-2-ene-1, 4-diones, and the like.
"heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably and refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, which may be fused to an aryl or heteroaryl group. The heterocycloalkyl ring may be optionally substituted. In certain embodiments, the heterocycloalkyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thioxo. "3-to 8-membered heterocycloalkyl" refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1,2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, preferably 4 to 8-membered heterocycloalkyl. More preferably a3 to 6 membered heterocycloalkyl group having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. More preferably a 4 to 6 membered heterocycloalkyl group having 4 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include aziridinyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl-1, 1-dioxide, tetrahydropyranyl, azetidin-2-onyl, oxetan-2-onyl, dihydrofuran-2 (3H) -onyl, pyrrolidin-2, 5-dione, dihydrofuran-2, 5-dione, piperidin-2-onyl, tetrahydro-2H-pyran-2-onyl, piperazin-2-onyl, morpholin-3-onyl and the like. "6 to 12 membered heterocycloalkyl" and "6 to 12 membered fused heterocycloalkyl" are used interchangeably and refer to a fused bicyclic cyclic hydrocarbon radical having 6 to 12 ring atoms wherein 1,2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. "8-to 10-membered heterocycloalkyl" and "8-to 10-membered fused heterocycloalkyl" are used interchangeably and refer to a fused bicyclic cyclic hydrocarbon radical having 8 to 10 ring atoms, wherein 1,2, or 3 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples include hexahydro-1H-furo [3,4-c ] pyrrole, octahydro-1H-cyclopenta [ c ] pyridine, hexahydro-1H-pyrrolo [2,1-c ] [1,4] oxazine, octahydropyrrolo [1,2-a ] pyrazine, hexahydropyrrolo [1,2-a ] pyrazin-4 (1H) -one, octahydrocyclopenta [ c ] pyrrole, and the like. In fused bicyclic heterocycloalkyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Bicyclic heterocycloalkyl systems may include one or more heteroatoms in one or both rings.
"Heterospirocyclic" and "heterospirocyclic" are used interchangeably to refer to a monovalent non-aromatic ring system having two monocyclic rings that share a carbon atom, are composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, do not contain unsaturation, and are linked to the parent nucleus by a single bond. The heterospirocycles may be optionally substituted. In certain embodiments, the heterospirocyclic ring contains one or more carbonyl or thiocarbonyl groups, for example, groups containing oxo and thioxo. "7-to 11-membered heterospirocyclic group" refers to a heterospirocyclic group having 7 to 11 ring atoms, wherein 1,2, or 3 ring atoms are heteroatoms. Non-limiting examples of heterospirocyclic groups include 2, 6-diazaspiro [3.4] octane-5-keto, 2-oxo-6-azaspiro [3.3] heptanyl, 6-oxaspiro [3.3] heptan-2-yl, 7-methyl-7-azaspiro [3.5] nonan-2-yl, 7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl, 9-methyl-9-phosphaspiro [5.5] undecan-3-yl, and the like.
"heterocycloalkenyl" and "heterocycloalkenyl ring" are used interchangeably to refer to a heterocycloalkyl group containing one or more carbon-carbon or carbon-nitrogen double bonds within the ring, but are not intended to include heteroaryl moieties as defined herein. The group may be fused to an aryl or heteroaryl group. The heterocycloalkenyl ring may be optionally substituted. In certain embodiments, the heterocycloalkenyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thioxo. "5 to 8 membered heterocycloalkenyl ring" means a heterocycloalkenyl ring having 5 to 8 ring atoms, wherein 1,2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Preferably a 5 to 6 membered heterocycloalkenyl ring. Non-limiting examples of the heterocycloalkenyl ring include a 4,5-dihydro-1H-imidazole ring, a1,4,5,6-tetrahydropyrimidine ring, a3,4,7,8-tetrahydro-2H-1,4,6-oxadiazolazine ring, a1,6-dihydropyrimidine ring, a 4,5,6,7-tetrahydro-1H-1, 3-diazepine ring, and a2,5,6,7-tetrahydro-1,3, 5-oxadiazepine ring.
"aryl" and "aromatic ring" are used interchangeably and both refer to a conjugated pi-electron systemAn all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group which can be fused to a cycloalkyl ring, heterocycloalkyl ring, cycloalkenyl ring, heterocycloalkenyl ring or heteroaryl group. ' C 6-10 The aryl group "means a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, and non-limiting examples of the aryl group include phenyl, naphthyl and the like.
"heteroaryl" and "heteroaryl ring" are used interchangeably and each refers to a monocyclic, bicyclic or polycyclic 4n +2 aromatic ring system having ring carbon atoms and ring heteroatoms (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In the context of the present invention, heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl or aromatic rings. The heteroaryl ring may be optionally substituted. "5-to 10-membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, wherein 1,2,3, or 4 ring atoms are heteroatoms. "5-to 6-membered heteroaryl" refers to monocyclic heteroaryl having 5 to 6 ring atoms in which 1,2,3, or 4 ring atoms are heteroatoms, non-limiting examples of which include thienyl, furyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl. "8-to 10-membered heteroaryl" refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1,2,3 or 4 ring atoms are heteroatoms, non-limiting examples of which include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothienyl, benzofuranyl, benzoisoturanyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenylyl, purinyl, pyrido [3,2-d ] pyrimidinyl, pyrido [2,3-d ] pyrimidinyl, pyrido [3,4-d ] pyrimidinyl, pyrido [4,3-d ] pyrimidinyl, 1, 8-naphthyridinyl, 1, 7-naphthyridinyl, 1, 6-naphthyridinyl, 1, 5-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl and quinazolinyl. "heteroatom" means nitrogen, oxygen or 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.
"fused" refers to a structure in which two or more rings share one or more bonds.
"Phenylheterocycloalkyi" refers to a group in which a benzene ring is fused to a heterocycloalkyl ring to form a bicyclic, tricyclic, or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above. "7-to 11-membered phenylalkylheterocycloalkyl" refers to a bicyclic cyclic group having 7 to 11 ring atoms, wherein 1,2,3, or 4 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Preferably 8 to 10-membered phenyl-and-heterocycloalkyl having 8 to 10 ring atoms, of which 1,2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include indolines, benzo [ d ] [1,3] bisoxazoles, 1,2,3, 4-tetrahydroisoquinolines, 3, 4-dihydro-2H-benzo [ b ] [1,4] oxazines, and the like.
"Heteroarylheterocycloalkyi" refers to a group in which a heteroaryl ring is fused to a heterocycloalkyl ring to form a bicyclic, tricyclic, or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above. "7-to 11-membered heteroaryland heterocycloalkyl" refers to bicyclic cyclic groups having 7 to 11 ring atoms, wherein 1,2,3, or 4 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Preferably an 8-to 10-membered heteroaryland heterocycloalkyl group having 8 to 10 ring atoms, wherein 1,2,3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include 2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine, [1,3] dioxolan [4,5-b ] pyridine, 2, 3-dihydro-1H-pyrido [3,4-b ] [1,4] oxazine, 2,3,4, 6-tetrahydropyrrolo [3,4-b ] [1,4] oxazine, 2,4,5, 6-tetrahydropyrano [2,3-c ] pyrazole, 5,6,7, 8-tetrahydropyrrolo [3,4-d ] pyrimidine, and the like.
"alkoxy" refers to-O-alkyl, wherein alkyl is as defined above. Preferably C 1-8 Alkoxy, more preferably C 1-6 Alkoxy, most preferably C 1-3 An alkoxy group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.
"cycloalkyloxy" means-O-cycloalkyl, wherein cycloalkyl is as defined above. Preferably C 3-8 Cycloalkyloxy, more preferably C 3-6 A cycloalkyloxy group. Non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
"bond" means that the two groups connected by it are linked by a covalent bond.
"halogen" means fluorine, chlorine, bromine or iodine.
"halo" means that one or more (e.g., 1,2,3,4, or 5) hydrogens in a group are replaced with a halogen.
For example, "haloalkyl" refers to an alkyl group substituted with one or more (e.g., 1,2,3,4, or 5) halogens, wherein the alkyl group is as defined above. Preferably a halogen atom C 1-8 Alkyl, more preferably halo C 1-6 Alkyl, more preferably halogenated C 1-3 An alkyl group. Examples of haloalkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
As another example, "haloalkoxy" refers to an alkoxy group substituted with one or more (e.g., 1,2,3,4, or 5) halogens, wherein the alkoxy group is as defined above. Preferably a halogen atom 1-8 Alkoxy, more preferably halo C 1-6 Alkoxy, more preferably halo C 1-3 An alkoxy group. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
Also for example, "halo C 3-8 Cycloalkyl "means a cycloalkyl group substituted with one or more (e.g., 1,2,3,4, or 5) halogens wherein the cycloalkyl group is as defined above. Preferably a halogen atom 3-6 A cycloalkyl group. Including (but not limited to)Trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl and the like.
"deuterated alkyl" refers to an alkyl group substituted with one or more (e.g., 1,2,3,4, or 5) deuterium atoms, wherein alkyl is as defined above. Preferably deuterated C 1-8 Alkyl, more preferably deuterated C 1-6 Alkyl, more preferably deuterated C 1-3 An alkyl group. Examples of deuterated alkyl include, but are not limited to, mono-deuterated methyl, mono-deuterated ethyl, di-deuterated methyl, di-deuterated ethyl, tri-deuterated methyl, tri-deuterated ethyl, and the like.
"amino" means NH 2 "cyano" means CN, "nitro" means NO 2 And "benzyl" means-CH 2 -phenyl, "oxo" means = O, "carboxy" means-C (O) OH, "acetyl" means-C (O) CH 3 And "hydroxymethyl" means-CH 2 OH, "hydroxyethyl" means-CH 2 CH 2 OH or-CHOHCH 3 "hydroxy" means-OH, "thiol" means SH, and "cyclopropylene" has the structure:
Figure BDA0002950355860000211
"saturated or partially unsaturated monocyclic ring" refers to a saturated or partially unsaturated all-carbon monocyclic ring system, wherein "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond, and "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein. In certain embodiments, a saturated or partially unsaturated monocyclic ring contains one or more carbonyl groups, such as oxo. A "3-to 7-membered saturated or partially unsaturated monocyclic ring" has 3 to 7 ring carbon atoms, preferably a saturated or partially unsaturated monocyclic ring having 3 to 6 ring carbon atoms, more preferably a saturated monocyclic ring having 3 to 6 ring carbon atoms. Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl rings, cycloheptatrienyl rings, cyclopentanone rings, cyclopentane-1, 3-dione rings, and the like.
"saturation ofOr partially unsaturated monocyclic ring "means that 1,2 or 3 ring carbon atoms in the saturated or partially unsaturated monocyclic ring are replaced by a carbon atom selected from nitrogen, oxygen or S (O) t (wherein t is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. A "3-to 7-membered saturated or partially unsaturated mono-heterocyclic ring" has 3 to 7 ring atoms, of which 1,2 or 3 ring atoms are the above heteroatoms. Preferably a3 to 6 membered saturated or partially unsaturated mono-heterocyclic ring having 3 to 6 ring atoms, of which 1 or 2 ring atoms are the above heteroatoms, more preferably a 5 to 6 membered saturated or partially unsaturated mono-heterocyclic ring having 5 to 6 ring atoms, of which 1 or 2 ring atoms are the above heteroatoms, most preferably a 5 or 6 membered saturated mono-heterocyclic ring. Non-limiting examples of saturated monoheterocycles include propylene oxide rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings, oxazolidine rings, piperazine rings, dioxolane rings, dioxane rings, morpholine rings, thiomorpholine-1, 1-dioxide rings, tetrahydropyran rings, azetidin-2-one rings, oxetan-2-one rings, pyrrolidin-2-one rings, pyrrolidine-2, 5-dione rings, piperidin-2-one rings, dihydrofuran-2 (3H) -one rings, dihydrofuran-2, 5-dione rings, tetrahydro-2H-pyran-2-one rings, piperazine-2-one rings, morpholine-3-one rings. Non-limiting examples of partially unsaturated mono-heterocycles include 1, 2-dihydroazetidine ring, 1, 2-dihydrooxetane ring, 2, 5-dihydro-1H-pyrrole ring, 2, 5-dihydrofuran ring, 2, 3-dihydro-1H-pyrrole ring, 3, 4-dihydro-2H-pyran ring, 1,2,3, 4-tetrahydropyridine ring, 3, 6-dihydro-2H-pyran ring, 1,2,3, 6-tetrahydropyridine ring, 4, 5-dihydro-1H-imidazole ring, 1,4,5, 6-tetrahydropyrimidine ring, 3,4,7, 8-tetrahydro-2H-1, 4, 6-oxadiazolazine ring, 1, 6-dihydropyrimidine ring, 4,5,6, 7-tetrahydro-1H-1, 3-diazepine ring, 2,5,6, 7-tetrahydro-1, 3, 5-diazepine ring, and the like.
"substituted" means that one or more hydrogen atoms, preferably 1 to 5 hydrogen atoms, in the group are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
The substituent group of the formula \8230 \ 8230; "is defined as the same or different substituent groups when more than one hydrogen atom is substituted by a substituent group, and the substituent groups are independently selected.
The term "\\8230; \8230; which may be the same or different and are each independently of the other, \8230;" refers to the case where more than one of the same substituent groups is present in the formula, the groups may be the same or different and are each independently of the other, unless otherwise defined. For example L is (CR) 01 R 02 ) s When s is 2, i.e. L is (CR) 01 R 02 )-(CR 01 R 02 ) Two of R 01 Or R 02 May be the same or different and are each independently of the other, e.g., L may be C (CH) 3 )(CN)-C(CH 2 CH 3 )(OH)，C(CH 3 )(CN)-C(CH 3 ) (OH) or C (CN) (CH) 2 CH 3 )-C(OH)(CH 2 CH 3 )。
Any group herein may be substituted or unsubstituted, unless otherwise defined. When the above groups are substituted, the substituents are preferably 1 to 5 or less groups independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halo C 1-8 Alkyl (preferably halogenated C) 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), C 3-8 Cycloalkyl (preferably C) 3-6 Cycloalkyl), halo C 1-8 Alkoxy (preferably halo C) 1-6 Alkoxy, more preferably halo C 1-3 Alkoxy group), C 1-8 Alkyl-substituted amino, halo C 1-8 Alkyl substituted amino, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, nitro, C 6-10 Aryl (preferably phenyl), C 3-8 Cycloalkyloxy (preferably C) 3-6 Cycloalkyloxy), C 2-8 Alkenyl (preferably C) 2-6 Alkenyl, more preferably C 2-4 Alkenyl group), C 2-8 Alkynyl (preferably C) 2-6 Alkynyl, more preferably C 2-4 Alkynyl), -CONR a0 R b0 、-C(O)OC 1-10 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -CHO, -OC (O) C 1-10 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), -SO 2 C 1-10 Alkyl (preferably-SO) 2 C 1-6 Alkyl, more preferably-SO 2 C 1-3 Alkyl), -SO 2 C 6-10 Aryl (preferably-SO) 2 C 6 Aryl radicals, e.g. SO 2 -phenyl), -COC 6-10 Aryl (preferably-COC) 6 Aryl, such as-CO-phenyl), 4-to 6-membered saturated or unsaturated monocyclic ring, 5-to 6-membered monocyclic heteroaryl ring, 8-to 10-membered bicyclic heteroaryl ring, spiro ring, bridged ring or bridged heterocyclic ring, wherein R is a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
The various substituent groups described herein above may themselves be substituted by groups described herein.
When the 4-to 6-membered saturated mono-heterocyclic ring described herein is substituted, the positions of the substituents may be at their possible chemical positions, and representative substitution of exemplary mono-heterocyclic rings are as follows:
Figure BDA0002950355860000221
Figure BDA0002950355860000222
wherein "Sub" represents the various types of substituents described herein;
Figure BDA0002950355860000223
express and itThe attachment of other atoms.
All atoms of the present invention satisfy their intended valence, for example, one ring atom in ring B1 is NR, and the presence or absence of R is determined by the number of bonds to N, which is understood to be within the scope of the present invention, for example: when N is attached to two single bonds, the corresponding R substituent is present, and when N is attached to one single bond, one double bond, R is absent.
Pharmaceutical composition
Generally, the compounds of the present invention or pharmaceutically acceptable salts thereof, or solvates thereof, or stereoisomers, or prodrugs thereof, may be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, oral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, syrups, and the like. The compounds of the invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like. The above-mentioned dosage forms can be prepared from the active compounds and one or more carriers or adjuvants by customary pharmaceutical methods. The above-mentioned carriers need to be compatible with the active compound or other adjuvants. For solid formulations, non-toxic carriers that are commonly used include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, polyethylene glycol and the like. The active compound may be in solution or suspension with the carrier as described above.
By "pharmaceutically acceptable carrier" is meant a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary agent or any type of excipient compatible with the patient, preferably a mammal, more preferably a human, that is suitable for delivering the active agent to the target site without terminating the activity of the agent.
"active substance according to the invention" or "active compound according to the invention" means a compound according to the invention of formula (I), or a pharmaceutical thereofThe above acceptable salt, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, which has adenosine A 2A Receptor and/or adenosine A 2B Receptor activity.
The compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice guidelines. The "therapeutically effective amount" of a compound to be administered will depend on, among other factors, the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
"therapeutically effective amount" refers to that amount of a compound of the invention that will elicit the biological or medical response of an individual, e.g., decrease or inhibit enzyme or protein activity or ameliorate symptoms, alleviate a condition, slow or delay disease progression or prevent disease, etc.
The therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof contained in the pharmaceutical composition of the present invention or the pharmaceutical composition is preferably 0.1mg to 5g/kg (body weight).
By "patient" is meant an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.
"treating" or "treatment" refers to alleviating, slowing progression, attenuating, preventing, or maintaining an existing disease or disorder (e.g., cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent one or more symptoms of the disease or disorder.
The "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, propionates, glycolates, gluconates, lactates, oxalates, maleates, succinates, fumarates, tartrates, citrates, glutamates, aspartates, benzoates, methanesulfonates, p-toluenesulfonate, salicylates, and the like. These salts can be prepared by methods known in the art.
"pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases such as sodium, potassium, calcium, and magnesium salts, and the like. Including but not limited to salts with organic bases such as ammonium, triethylamine, lysine, arginine, and the like. These salts can be prepared by methods known in the art.
Reference to a "solvate" in the present invention refers to a complex formed between a compound of the present invention and a solvent. They either react in a solvent or precipitate out of a solvent or crystallize out. For example, a complex with water is called a "hydrate". Solvates of the compounds of formula (I) are within the scope of the invention.
The compounds of formula (I) according to the invention may contain one or more chiral centres and exist in different optically active forms. When the compound contains one chiral center, the compound comprises enantiomers. The present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compounds of formula (I) contain more than one chiral center, diastereoisomers may be present. The invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography.
The present invention includes prodrugs of the above compounds. Prodrugs include known amino protecting groups and carboxy protecting groups, which are hydrolyzed under physiological conditions or released via enzymatic reactions to give the parent compound. Specific prodrug preparation methods are referenced (Saulnier, M.G.; frannesson, D.B.; deshpande, M.S.; hansel, S.B and Vysa, D.M.Bioorg.Med.chem Lett.1994,4, 1985-1990; and Greenwald, R.B.; choe, Y.H.; conover, C.D.; shum, K.; wu D.; royzen M.J.Med.chem.2000, 43, 475.).
Preparation method
The present invention provides methods for the preparation of compounds of formula (I) which can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. The solvents, temperatures, and other reaction conditions set forth herein may vary according to the skill in the art. The reactions may be used sequentially to provide the compounds of the invention, or they may be used to synthesize fragments that are subsequently added by the methods described herein and/or known in the art.
The compounds described herein may be synthesized using methods analogous to those described below or the exemplary methods described in the examples, or the relevant publications used by those skilled in the art, by using appropriate alternative starting materials. The starting materials for synthesizing the compounds described herein may be synthesized or may be obtained from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods of making the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to incorporate various moieties in the molecules provided herein.
Compared with the prior art, the invention has the main advantages that:
provides a series of polyheterocycle substituted pyrimidine or pyridylamine derivatives with novel structure, namely, para-adenosine A 2A Receptor and/or adenosine A 2B The receptor has high inhibitory activity, IC 50 Values of less than 100nM, preferably less than 50nM, more preferably less than 10nM, and are therefore useful as agents for the treatment of cancer or other immune-related diseases.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight. Unless otherwise defined, terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present invention.
Reagent and apparatus
1 HNMR: bruker AVANCE-400 NMR instrument with internal standard of Tetramethylsilane (TMS). LC-MS: agilent 1290HPLC System/6130/6150MS liquid Mass Spectrometry (manufacturer: agilent), column Waters BEH/CHS, 50X 2.1mm,1.7 μm. Preparative high performance liquid chromatography (pre-HPLC): waters PHW007 column XBridge C18,4.6 x 150mm,3.5um. ISCO Combiflash-Rf75 or Rf200 type automatic column-passing instrument, agela 4g,12 g,20 g, 40g, 80g, 120g disposable silica gel column is adopted.
Known starting materials can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shaoyuan Chemical technology (Accela ChemBio Inc) and Darri Chemicals.
Unless otherwise specified, the reactions in the examples were carried out under a nitrogen atmosphere or an argon atmosphere.
DMF: dimethylformamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran, DIEA: n, N-diisopropylethylamine, EA: ethyl acetate, PE: petroleum ether, BINAP: (2R, 3S) -2,2 '-bis-diphenylphosphino-1, 1' -binaphthyl, NBS: n-bromosuccinimide, NCS: n-chlorosuccinimide, pd 2 (dba) 3 : tris (dibenzylideneacetone) dipalladium, pd (dppf) Cl 2 : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, DPPA: diphenylphosphoryl azide, DBU:1, 8-diazabicycloundecen-7-ene, TBAF: tetrabutylammonium fluoride, na ascolate: sodium ascorbate. Y: the yield was found. P: and (4) purity. As used herein, room temperature means about 20-30 ℃.
Preparation of intermediate M1
Figure BDA0002950355860000241
Step 1: starting material M1-1 (600mg, 3.95mmol) was dissolved in 15mL of tetrahydrofuran under ice-bath conditions. Under the protection of argon, adding LiAlH in batches 4 (300mg, 7.9 mmol), then warmed to room temperature overnight and the reaction was detected by LC-MS to be complete. 4.0g of Na was added to the reaction mixture 2 SO 4 .10H 2 O, then stirred for 1 hour at room temperature, filtered, and concentrated to dryness under reduced pressure to obtain the product M1-2 (430 mg, purity: 78%, yield: 78.90%) MS (ESI) 139.1[ M ] +H ]] + 。
Step 2: DPPA (869mg, 3.16mmol) and DBU (480mg, 3.1 6mmol) were added to 10mL of dichloromethane of the compound M1-2 (430mg, 2.43mmol), and the reaction mixture was stirred at room temperature for 4 hours. The LC-MS detection reaction is complete. The reaction mixture was added to 100mL of water, extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product M1 (580mg, P32%, Y: 100%). MS (ESI) 164.2[ 2 ], [ M ] +H] + 。
Example 1: preparation of 3- (2-amino-6- (1- ((5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl ] methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-1)
Figure BDA0002950355860000242
Step 1: 2-methyl-3-bromoxynil (15g, 76.51mmol), bis (pinacolato) borate (23.32g, 91.82mmol), potassium acetate (15.02g, 153.03mmol), pd (dppf) Cl 2 (2.80g, 3.8 mmol) and DMSO (20 mL) were dissolved in dioxane (100 mL) and stirred at 100 ℃ for 3.5h under nitrogen. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a solid product, which was separated by column chromatography (EA: PE 15% to 40%) to obtain 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzonitrile (21.05 g, purity: 78.0%, yield: 100%). MS (ESI) 244.1[ deg. ] M + H ]] + 。
Step 2: 2-amino-4, 6-dichloropyrimidine (14.17g, 86.38mmol), 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxanBoroaentan-2-yl) benzonitrile (10.50g, 43.19mmol), potassium bicarbonate (12.97g, 129.57mmol), pdCl 2 (PPh 3 ) 2 (606 mg) and H 2 O (50 mL) was dissolved in ethanol (250 mL) and stirred at 80 ℃ for 5h under nitrogen. The reaction was completed, and the solvent was evaporated under reduced pressure to obtain a solid product, which was isolated by column chromatography (DCM: EA =4: 1) to obtain the product 3- (2-amino-6-chloropyrimidin-4-yl) -2-methylbenzonitrile (8.5 g, purity: 84.8%, yield: 80.4%). MS (ESI) 245.1[ deg. ] M + H ]] + 。
And 3, step 3: the product obtained in the above step, 3- (2-amino-6-chloropyrimidin-4-yl) -2-methylbenzonitrile (8.4 g, 34.33mmol), triisopropylsilylacetylene (9.39g, 51.50mmol), triethylamine (10.42g, 102.99mmol), pdCl 2 (PPh 3 ) 2 (2.41g, 3.43mmol) and cuprous iodide (1.31g, 6.87mmol) were dissolved in dry tetrahydrofuran (100 mL) and stirred overnight at 50 ℃ under nitrogen. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a solid product, and the product, 3- (2-amino-6- ((triisopropylsilyl) ethynyl) pyrimidin-4-yl) -2-methylbenzonitrile (7.53 g, purity: 79.94%, yield: 56.1%) was obtained by column chromatography (EA: PE 60% -80%). MS (ESI) 391.1[ deg. ] M + H ]] + 。
And 4, step 4: the product 3- (2-amino-6- ((triisopropylsilyl) ethynyl) pyrimidin-4-yl) -2-methylbenzonitrile (7.5g, 19.20mmol) obtained in the above step was dissolved in tetrahydrofuran (50 mL), and the reaction solution was cooled to 0 ℃. TBAF (1 mol/L) (25ml, 25.00mmol) was slowly added at 0 ℃, the reaction solution was stirred at room temperature for 2h, the reaction was completed, the solvent was evaporated under reduced pressure to obtain a solid product, and the product, 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (3.07 g, purity: 97.0%, yield: 68.0%) was obtained by column chromatography (EA: PE = 1. MS (ESI) 235.1[ deg. ] M + H ]] + 。
And 5: adding the intermediate M1 (98mg, 0.6 mmol) and the product 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (117mg, 0.5 mmol) into a mixed solvent of 2mL of tert-butyl alcohol and 3mL of water, and adding Cu under the protection of argon 2 SO 4 .5H 2 O (125mg, 0.5mmol), sodium ascorbate (95mg, 0.5mmol), heating to 50 deg.C for 1 hr, detecting by LC-MSIt should be complete. The reaction mixture was poured into water, extracted with dichloromethane (50ml × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to give compound L-1 (19.84mg, p. 1 H NMR(400MHz,dmso)δ8.49(s,1H),7.85(d,J＝7.6Hz,1H),7.71(d,J＝6.9Hz,1H),7.47(t,J＝7.8Hz,1H),7.21(s,1H),6.83(s,1H),6.02(s,1H),5.55(s,1H),3.99(t,J＝7.2Hz,1H),2.76(t,J＝7.4Hz,1H),2.50(s,1H),2.41-2.43(m,1H).MS(ESI)398.2[M+H] + 。
Example 2: preparation of 3- (2-amino-6- (1- ((5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl ] methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-2)
Figure BDA0002950355860000251
Step 1 starting material 4,5,6, 7-tetrahydropyrazolo [1,5-a ] under ice-bath conditions]Pyridine-2-carboxylic acid (500mg, 3.0 mmol) was dissolved in tetrahydrofuran 10 mL. Under the protection of argon, adding LiAlH in batches 4 (228mg, 6.0mmol), and then the reaction was warmed to room temperature for 5 hours, and the reaction was detected to be complete by LC-MS. 4.0g of Na was added to the reaction mixture 2 SO 4 .10H 2 O, then stirred at room temperature for 1 hour, filtered, and concentrated under reduced pressure to dryness to give the product (4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-2-yl) methanol (420mg, P88%, Y: 92%) MS (ESI) 153[ 2 ], [ M + H ]] + 。
Step 2 Compound (4, 5,6, 7-Tetrahydropyrazolo [1,5-a ]]Pyridin-2-yl) methanol (420mg, 2.43mmol) was added to 10mL of dichloromethane, DPPA (869mg, 3.16mmol) and DBU (480mg, 3.16mmol) and the reaction solution was stirred at room temperature for 18 hours. The LC-MS detection reaction is complete. Adding the above reaction solution into 100mL of water, extracting with dichloromethane (20mL. Multidot.3), drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain crude product 2- (azidomethyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrido is dissolved in tert-butanol (23mL, 0.12M). MS (ESI) 178[ 2 ] M + H] + 。
Step 3 crude product 2- (azidomethyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] obtained in the above step]Pyridine (4mL, 0.12M, 0.48mmol), 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylBenzonitrile (112mg, 0.48mmol) was added to a mixed solvent of 2mL t-butanol and 3mL water, cu was added under argon shield 2 SO 4 .5H 2 O (120mg, 0.48mmol) and sodium ascorbate (95mg, 0.48mmol) were heated to 50 ℃ for 1 hour and the reaction was complete by LC-MS detection. Pouring the reaction solution into water, extracting with dichloromethane (50mL × 2), drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying with high performance liquid phase to obtain white solid product L-2 (30 mg, total yield of three steps is 15%) MS (ESI) 412.2[ M ] +H ]] + .1H NMR(400MHz,dmso)δ8.50(s,1H),7.85(d,J＝7.6Hz,1H),7.71(d,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,1H),7.21(s,1H),6.84(s,2H),5.98(s,1H),5.54(s,2H),3.97(t,J＝6.0Hz,2H),2.66(t,J＝6.3Hz,2H),2.50(s,3H),1.95–1.84(m,2H),1.71(dd,J＝11.8,5.9Hz,2H).
Example 3: preparation of 3- (4-amino-6- (1- ((5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl ] methyl) -1H-1,2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) -2-methylbenzonitrile (L-3)
Figure BDA0002950355860000261
Step 1: dissolving 2,4, 6-trichloro-5-fluoropyrimidine (2.0g, 9.93mmol), triisopropylsilylacetylene (1.8g, 9.93mmol) and triethylamine (3.01g, 3.00mmol) in 25mL tetrahydrofuran, cooling to 0 ℃ under the protection of argon, and adding CuI (378mg, 1.99mmol) and Pd (PPh) 3 ) 2 Cl 2 (697 mg, 0.99mmol), then heating to room temperature for 3 hours, and detecting the reaction completion by LC-MS. The reaction solution was used directly in the next step without any treatment to give the product 2, 4-dichloro-5-fluoro-6- ((triisopropylsilyl) ethynyl) pyrimidine (3.44g, P86.78%, Y: 100%) MS (ESI) 347[ M ] +H ]] + 。
Step 2: to 25mL of the tetrahydrofuran reaction solution containing the compound 2, 4-dichloro-5-fluoro-6- ((triisopropylsilyl) ethynyl) pyrimidine (3.44g, 9.93mmol), 10mL of an aqueous solution of aqueous ammonia (concentration: 80%) was added, and the mixture was stirred at room temperature over the weekend. The LC-MS detection reaction is complete. Adding the above reaction solution into 300mL of water, extracting with dichloromethane (100mL. Multidot.2), drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and passing throughThe product 2-chloro-5-fluoro-6- ((triisopropylsilyl) ethynyl) pyrimidine-4-amine (2.30g, P88.54%, Y70.77%) MS (ESI) 328.1[ M ] +H ]] + 。
And step 3: the compound 2-chloro-5-fluoro-6- ((triisopropylsilyl) ethynyl) pyrimidin-4-amine (500mg, 1.52mmol), 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzonitrile (408mg, 1.68mmol) were dissolved in a mixed solvent of acetonitrile 15mL and water 4mL, and Pd (PPh) was added 3 ) 2 Cl 2 (107mg,0.152mmol),KHCO 3 (611mg, 6.10mmol), raising the temperature to 95 ℃ under the protection of reaction liquid nitrogen, stirring overnight, and detecting the completion of the reaction by LC-MS. The reaction solution was poured into water, extracted with dichloromethane (50mL. Multidot.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and subjected to separation and purification on a silica gel column to obtain the product 3- (4-amino-5-fluoro-6- (((triisopropylsilyl) ethynyl) pyrimidin-2-yl) -2-methylbenzonitrile (300mg, P] + 。
And 4, step 4: the compound 3- (4-amino-5-fluoro-6- (((triisopropylsilyl) ethynyl) pyrimidin-2-yl) -2-methylbenzonitrile (70mg, 0.171mmol) was added to 2mL of tetrahydrofuran, the temperature was reduced to 0 ℃,0.2 mL of TBAF tetrahydrofuran solution (1.0 mol/L) was slowly added, the reaction solution was stirred at room temperature for 30 minutes, LC-MS detected that the reaction completed the reaction solution was directly used in the next step without any treatment to give the product 3- (4-amino-6-ethynyl-5-fluoropyrimidin-2-yl) -2-methylbenzonitrile (43mg, 93.75%, Y: 100%) MS (ESI) 253.1M + H] +
And 5:3- (4-amino-6-ethynyl-5-fluoropyrimidin-2-yl) -2-methylbenzonitrile (50mg, 0.198mmol), 2- (azidomethyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] methyl]Pyrazole (32mg, 0.198mmol) was added to a mixed solvent of 5mL t-butanol, 4mL tetrahydrofuran and 1.5mL water, and Cu was added under argon 2 SO 4 .5H 2 O (14mg, 0.059mmol) and sodium ascorbate (23mg, 0.119mmol), raising the temperature to 40 ℃ for reaction for 40 minutes, and detecting the reaction completion by LC-MS. The reaction solution was poured into water, extracted with dichloromethane (50ml. X.2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to preparative separation and purification by thick high performance liquid chromatography to obtain a white solid product L-3 (11.88mg, P97.15%, Y: 14.43%). 1 H NMR(400MHz,dmso)δ8.62(s,1H),7.90(d,J＝7.9Hz,1H),7.83(d,J＝7.7Hz,1H),7.51(s,2H),7.44(t,J＝7.9Hz,1H),6.01(s,1H),5.55(s,2H),3.98(t,J＝7.2Hz,2H),2.78(t,J＝6.8Hz,2H),2.61(s,3H),2.43-2.45(m,2H).MS(ESI)416.2[M+H] + 。
Example 4: preparation of 3- (2-amino-6- (1- (dihydro-benzopyran-8-ylmethyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-4)
Figure BDA0002950355860000262
Step 1: 1-chroman-8-carboxylic acid (200mg, 1.12mmol) was dissolved in tetrahydrofuran (30 mL) at-50 ℃. Under the protection of argon, adding LiAlH in batches 4 (171mg, 4.49mmol), heating to room temperature for 18 hours, and detecting the reaction completion by LC-MS. Adding Na to the reaction solution 2 SO 4 .10H 2 O (4.0 g), then stirred at room temperature for 1 hour, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the product 1-chroman-8-methanol (184mg, P92%, Y: 100%) MS (ESI) 165[ M ] +H ]] + 。
Step 2: the compound 1-chroman-8-methanol (184mg, 1.12mmol) was dissolved in dichloromethane (10 mL) and DPPA (463mg, 1.68mmol) and DBU (256mg, 1.68mmol) were added and the reaction solution was stirred at room temperature for 18 hours. And the LC-MS detection reaction is complete. The reaction mixture was added to methylene chloride (50 mL) and washed with water (20 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 1-chroman-8-methylazido (367 mg).
And step 3: the crude product 1-chroman-8-methyl azide (300 mg) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (149mg, 0.63mmol) were added to a mixed solvent of t-butanol (6 mL) and water (3 mL), and Cu was added under argon protection 2 SO 4 .5H 2 O (1695g, 0.06mmol) and sodium ascorbate (50mg, 0.25mmol), heating to 65 deg.C, reacting for 2 hr, and LC-MS detecting reaction completion. Pouring the reaction solution into water, extracting with dichloromethane (50 mL multiplied by 2), drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying by high performance liquid chromatography to obtain white solid productL-4 (21mg, P100%, three-step reaction yield total Y: 7%). MS (ESI) 424.2[ deg. ] M + H ]] + . 1 H NMR(400MHz,dmso)δ8.37(s,1H),7.85(d,J＝7.7Hz,1H),7.71(d,J＝7.8Hz,1H),7.47(t,J＝7.7Hz,1H),7.21(s,1H),7.05(d,J＝7.5Hz,1H),6.94(d,J＝7.3Hz,1H),6.84(s,2H),6.79(t,J＝7.4Hz,1H),5.54(s,2H),4.21–4.10(m,2H),2.72(t,J＝6.4Hz,2H),2.50(s,3H),1.93–1.82(m,2H)。
Example 5: preparation of 3- (2-amino-6- (1- ((2-oxo-2, 3-dihydrobenzo [ d ] oxazol-4-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-5)
Figure BDA0002950355860000271
Step 1: the starting material, methyl 3-hydroxy-2-nitrobenzoate (4.5g, 22.84mmol) was dissolved in a mixed solvent of methanol (30 mL) and ethanol (30 mL) at room temperature, pd/C (10%, 800 mg) was added, and then the reaction solution was reacted in hydrogen for 48 hours, and the completion of the reaction was detected by LC-MS. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to be dried to obtain a crude product of methyl 2-amino-3-hydroxybenzoate (3.6 g, P100%, Y: 94%). MS (ESI) 168[ 2[ M ] +H ]] + 。
Step 2: the crude methyl 2-amino-3-hydroxybenzoate (835mg, 5.0 mmol) obtained in the above step was dissolved in dichloromethane (25 mL) under ice-bath conditions. Et is added under the protection of argon 3 N (1.52g, 15.0 mmol), 4-nitrophenylcarbonyl chloride (1.21g, 6.0 mmol) was added dropwise, the reaction was warmed to room temperature and reacted for 18 hours, and LC-MS checked that the reaction was complete. Water (10 mL) was added to the reaction solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to dryness and purified by Combi-Flash (EA: PE = 0-30%) to give a solid product of 2-oxo-2, 3-dihydrobenzo [ d ] b]Oxazole-4-carboxylic acid methyl ester (642mg, P95%, Y: 67%). MS (ESI) 194, [ m + H ]] + 。
And step 3: at-50 deg.C, mixing the above product 2-oxo-2, 3-dihydrobenzo [ d]Methyl oxazole-4-carboxylate (193mg, 1.0 mmol) was dissolved in tetrahydrofuran (15 mL). Under the protection of argon, adding LiAlH in batches 4 (76mg, 2.0 mmol), and then warmed to room temperature to react for 4 hoursAnd the LC-MS detection reaction is complete. Adding Na to the reaction solution 2 SO 4 .10H 2 O (2.0 g), then stirred at room temperature for 1 hour, filtered, and concentrated to dryness under reduced pressure to give a crude product of 4- (hydroxymethyl) benzo [ d]Oxazole-2 (3H) -one (165mg, P87%, Y: 100%). MS (ESI) 166[ 2 ], [ M + H ]] + 。
And 4, step 4: at room temperature, the crude compound 4- (hydroxymethyl) benzo [ d ] in the above step]Oxazol-2 (3H) -one (165mg, 1.0mmol) was dissolved in methylene chloride (7 mL), DPPA (413mg, 1.5mmol) and DBU (228mg, 1.5mmol) were added, and the reaction solution was stirred at room temperature for 18 hours. And the LC-MS detection reaction is complete. The reaction mixture was added with methylene chloride (50 mL) and washed with water (20 mL. Times.4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 4- (azidomethyl) benzo [ d ]]Oxazol-2 (3H) -one (283mg>100％).MS(ESI)191[M+H] + 。
And 5: the crude product obtained in the previous step, 4- (azidomethyl) benzo [ d ]]Oxazol-2 (3H) -one (249mg, 1.31mmol) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (153mg, 0.66mmol) were added to a mixed solvent of t-butanol (6 mL) and water (3 mL), and Cu was added under argon 2 SO 4 .5H 2 O (1695g, 0.06mmol) and sodium ascorbate (50mg, 0.25mmol) are heated to 65 deg.C for 1 hr, and LC-MS detects the reaction is complete. The reaction solution was poured into water, extracted with dichloromethane (50 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to obtain a white solid product L-5 (5 mg, p 100%, total Y:2% in three-step reaction yield). MS (ESI) 425.1[ deg. ] M + H ]] + . 1 H NMR(400MHz,dmso)δ12.11(s,1H),8.61(s,1H),7.85(d,J＝7.6Hz,1H),7.70(d,J＝8.0Hz,1H),7.47(t,J＝7.7Hz,1H),7.29–7.24(m,1H),7.20(s,1H),7.06(d,J＝4.7Hz,2H),6.84(s,2H),5.72(s,2H),2.49(s,3H).
Example 6: preparation of 3- (2-amino-6- (1- (chroman-5-ylmethyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-6)
Figure BDA0002950355860000272
Step 1: the compound chroman-5-carboxylic acid (240mg, 1.35mmol) is added to tetrahydrofuran (15 mL), the reaction is cooled to 0 deg.C, then lithium aluminium hydride (153mg, 4.04mmol) is added in portions, allowed to rise to 50 deg.C naturally and stirred for 3 hours. After the reaction of the starting materials was completed, the reaction was quenched by adding sodium sulfate decahydrate in portions, insoluble materials were removed by filtration, and the filtrate was concentrated to give a crude product of 3, 4-dihydro-2H-chroman-2-ylmethanol (217mg, y 98%) as an oil.
Step 2:3, 4-dihydro-2H-chroman-2-ylmethanol (217mg, 1.32mmol) was added to methylene chloride (2 mL), followed by the addition of 1, 8-diazabicycloundec-7-ene (183mg, 1.59mmol) and diphenyl azidophosphate 438mg, 1.59mmol), respectively. The reaction mixture was stirred at room temperature for 16 hours. After the starting material had reacted to completion, additional dichloromethane (30 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL), and the organic phase was concentrated to give the crude 5- (azidomethyl) chroman salt as an oil (430 mg).
And step 3: the crude product, 5- (azidomethyl) chromane salt (97mg, 0.51mmol) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (80mg, 0.34mmol) were added to a mixed solvent of t-butanol (10 mL) and water (5 mL), copper sulfate pentahydrate (43mg, 0.17mmol) and sodium ascorbate (20mg, 0.10mmol) were added under argon protection, and the mixture was heated to 70 ℃ for reaction for 3 hours. The reaction was checked by LC-MS to be complete, and the reaction solution was poured into water, extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to give a white solid product L-6 (39mg, P100%, Y: 26.9%). MS (ESI) 424.1[ deg. ] M + H ]]+. 1 H NMR(400MHz,dmso)δ8.49(s,1H),7.90(dd,J＝7.6,1.2Hz,1H),7.75(d,J＝6.8Hz,1H),7.51(s,1H),7.25(s,1H),7.09(d,J＝7.6Hz,1H),6.88(s,2H),6.75(dd,J＝14.6,8.0Hz,2H),5.66(s,2H),4.14–4.01(m,2H),2.70(d,J＝6.6Hz,2H),2.54(s,3H),1.93(s,2H).
Example 7: preparation of 3- (6- (1- ((5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -2- ((2-methoxyethyl) amino) pyrimidin-4-yl) -2-methylbenzonitrile (L-7)
Figure BDA0002950355860000281
Step 1: 2-methyl-3- (2- (methylsulfonyl) -6- ((triisopropylsilyl) ethynyl) pyrimidin-4-yl) benzonitrile (200mg, 0.44mmol), N-diisopropylethylamine (171mg, 1.32mmol) and 2-methoxyethan-1-amine (99mg, 1.32mmol) were added to a solvent of N, N-dimethylformamide (5 mL), and the reaction was stirred at room temperature for 2 hours. LC-MS checked that the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 0-30%) to give the product 3- (2- ((2-methoxyethyl) amino) -6- ((triisopropylsilyl) ethynyl) pyrimidin-4-yl) -2-methylbenzonitrile (113mg, y 57.1%) as a white solid. MS (ESI) 449 (+H) +] + 。
And 2, step: 3- (2- ((2-methoxyethyl) amino) -6- ((triisopropylsilyl) ethynyl) pyrimidin-4-yl) -2-methylbenzonitrile (103mg, 0.23mmol) was added to a solvent of N, N-dimethylformamide (5 mL), TBAF (0.5mL, 0.5mmol) was slowly added at room temperature, and the mixture was further stirred for reaction for 3 hours. LC-MS checked that the reaction was complete, the reaction was poured into water, extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 30-50%) to give the product 3- (6-ethynyl-2- ((2-methoxyethyl) amino) pyrimidin-4-yl) -2-methylbenzonitrile (52mg, p 92.38%, Y: 77.2%) as a white solid. MS (ESI) 293[ m ] +H] + 。
And step 3: reacting 2- (azidomethyl) -5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazole (49mg, 0.30mmol) and 3- (6-ethynyl-2- ((2-methoxyethyl) amino) pyrimidin-4-yl) -2-methylbenzonitrile (52mg, 0.18mmol) were added to a mixed solvent of t-butanol (5 mL) and water (2 mL), copper sulfate pentahydrate (23mg, 0.09mmol) and sodium ascorbate (11mg, 0.054mmol) were added, and the temperature was raised to 70 ℃ to react for 2 hours. The reaction was detected to be complete by LC-MS, and the reaction solution was poured into water, extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to give L-7 (16.52mg, P, 97.73%, Y: 23.4%) as a yellow solid product. MS (ESI) 456.2[ deg. ] M + H ]] + . 1 H NMR(400MHz,dmso)δ8.55(s,1H),7.90(d,J＝7.6Hz,1H),7.77(s,1H),7.52(t,J＝7.6Hz,1H),7.37(t,J＝5.2Hz,1H),7.26(s,1H),6.05(s,1H),5.60(s,2H),4.07–3.97(m,2H),3.50(s,4H),3.27(s,3H),2.80(t,J＝7.6Hz,2H),2.65–2.51(m,3H),2.47(s,2H).
Example 8: preparation of 3- (2-amino-6- (1- ((3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-5-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-8)
Figure BDA0002950355860000291
Step 1: methyl 3-hydroxy-2-nitrobenzoate (2g, 10.1mmol), ethyl bromoacetate (1.71g, 10.1mmol) and potassium carbonate (2.7g, 20.2mmol) were mixed in 30ml of DMF. Stir at room temperature overnight. The reaction solution was filtered, the solid was washed with ethyl acetate, and the obtained filtrate was spin-dried under reduced pressure. The crude product was purified by combiflash (EA: PE = 40%) to give the product (2.86g, 100%) as a white solid.
Step 2: methyl 3- (2-ethoxy-2-oxoethoxy) -2-nitrobenzoate (2.86g, 10.1mmol) was dissolved in acetic acid (30 mL). Iron powder (5.66g, 101mmol) was added thereto. The reaction solution was stirred at 90 ℃ for 4 hours. The solvent was spin-dried under reduced pressure, and then ethyl acetate and saturated NaHCO were added thereto 3 And (3) solution. Extraction with ethyl acetate (50ml × 2), drying over anhydrous sodium sulfate, concentration to dryness under reduced pressure, and purification of the crude product by combiflash (EA/PE = 60%) gave the product (2g, 96.6%) as a yellow solid. MS (ESI) 208.1[ deg. ] M + H ]] + 。
And step 3: reacting 3-oxo-3, 4-dihydro-2H-benzo [ b ]][1,4]Methyl oxazine-5-carboxylate (555mg, 2.68mmol) and tetrahydrofuran (12 mL) were combined. The temperature is reduced to 0 ℃, and lithium aluminum hydride (107mg, 2.82mmol) is added under the protection of nitrogen. Stirring was continued at this temperature for 4 hours. At 0 ℃, the reaction was quenched by the addition of decawater and sodium sulfate. The solid was filtered and washed, and the filtrate was rotary dried under reduced pressure. The crude product was purified by combiflash (MeOH/DCM = 10%) to give the product (53mg, 11%) as a white solid. MS (ESI) 180.1[ deg. ] M + H ]] + 。
And 4, step 4: reacting 5- (hydroxymethyl) -2H benzo [ b ]][1,4]Oxazin-3 (4H) -one (53mg, 0.3 mmol) was dissolved in DCM (3 mL) and DPPA (122mg, 0.44mmol) and DBU (68mg, 0.44mmol) were added. Stir at room temperature overnight. Concentrating the solvent under reduced pressureAnd (4) drying, and directly using the obtained crude product for the next reaction. MS (ESI) 205.1[ deg. ] M + H ]] + 。
And 5: reacting 5- (azidomethyl) -2H benzo [ b ]][1,4]Oxazin-3 (4H) -one (61mg, 0.30mmol), 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (69mg, 0.30mmol) were added to a mixed solvent of t-butanol (4 mL) and water (2 mL), and Cu was added under argon protection 2 SO 4 .5H 2 O (38mg, 0.15mmol) and sodium ascorbate (18mg, 0.09mmol) were stirred at 65 ℃ for 20 hours. The reaction mixture was poured into water, extracted with dichloromethane (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by preparative high performance liquid chromatography to give the product L-8 (40mg, 30.5%) as a white solid. MS (ESI) 439.1[ deg. ] M + H ]] + 。 1 H NMR(400MHz,dmso)δ10.51(br s,1H),8.57(s,1H),7.89(d,J＝8Hz,1H),7.74(d,J＝8Hz,1H),7.53-7.49(m,1H),7.25(s,1H),7.02-6.95(m,2H),6.89-6.85(m,3H),5.80(s,2H),4.59(s,2H),2.54(s,3H).
Example 9: preparation of 3- (2-amino-6- (1- ((5, 5-difluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-9)
Figure BDA0002950355860000292
Step 1: the compound (S) -1- (tert-butoxycarbonyl) -4, 4-difluoropyrrolidine-2-carboxylic acid (4.5g, 17.93mmol) was dissolved in dioxane hydrochloride solution (4M, 30mL, 120mmol). The reaction mixture was reacted at room temperature under argon for 3 hours. The reaction was checked by LC-MS to be complete, and then the reaction solution was concentrated under reduced pressure to give a brown solid crude product (S) -4, 4-difluoropyrrolidine-2-carboxylate (3.35g, Y. MS (ESI) 152[ 2 ], [ M ] +H] + 。
Step 2: the compound (S) -4, 4-difluoropyrrolidine-2-carboxylic acid hydrochloride (3.35g, 17.91mmol) was dissolved in water (35 mL), the reaction solution was cooled to 0 ℃, concentrated hydrochloric acid (12M, 1.79mL, 21.50mmol) was added first, then sodium nitrite (1.85g, 26.87mmol) was added slowly, and finally the reaction solution was slowly warmed to room temperature and stirred at room temperature for 1 hour. After the reaction of the starting materials was complete, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3)Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product of (S) -4, 4-difluoro-1-nitrosopyrrolidine-2-carboxylic acid (3.12g, y 97%). MS (ESI) 181[ deg. ] M ] +H] + 。
And step 3: the compound (S) -4, 4-difluoro-1-nitrosopyrrolidine-2-carboxylic acid (3.12g, 17.33mmol) was added to toluene (35 mL), the reaction solution was cooled to 0 ℃ and trifluoroacetic anhydride (5.46g, 26.00mmol) was added dropwise, after which the reaction solution was allowed to warm to room temperature naturally and stirred at room temperature for 2 hours. After the starting material had reacted completely, the reaction was concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 0-60%) to give the solid product 9a (2.53g, y 81%). MS (ESI) 163[ deg. ] M ] +H] + 。
And 4, step 4: compound 9a (2.18g, 13.46mmol) and ethyl propargyl acetate (2.64g, 26.91mmol) were added to xylene (25 mL), and the reaction mixture was heated to 130 ℃ and reacted for 16 hours. After the reaction of the raw materials is completed, the reaction solution is concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 0-30%) to obtain a solid product of 5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazole-2-carboxylic acid ethyl ester (1.63g, y. MS (ESI) 217[ m ] +H] + 。 1 H NMR(400MHz,cdcl 3 )δ6.64(s,1H),4.55(t,J＝12.4Hz,2H),4.37(q,J＝7.2Hz,2H),3.48(td,J＝13.6,0.8Hz,2H),1.37(t,J＝7.2Hz,3H).
And 5: the compound 5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b]Ethyl pyrazole-2-carboxylate (432mg, 2.0 mmol) was added to tetrahydrofuran (25 mL), the reaction solution was cooled to 0 ℃ and then lithium aluminum hydride (152mg, 4.0 mmol) was added in portions, allowed to naturally warm to room temperature and stirred for 1 hour. After the reaction of the starting materials was completed, the reaction was quenched by adding sodium sulfate decahydrate in portions and stirred at room temperature for 30 minutes, insoluble matters were removed by filtration, and the filtrate was concentrated to give an oily crude product (5, 5-difluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] -pyrrole]Pyrazol-2-yl) methanol (321mg, y. MS (ESI) 175 (+H) +] + 。
Step 6: the compound (5, 5-difluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] is reacted with]Pyrazol-2-yl) methanol (321mg, 1.84mmol) was added to dichloromethane (15 mL), followed by 1, 8-diazabicycloundec-7-ene (421mg, 2.77mmol) and diphenylphosphorylazide (761mg, 2.77mmol), respectively. Reaction mixThe mixture was stirred at room temperature for 18 hours. After the starting material had reacted completely, dichloromethane (50 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL. Times.4), and the organic phase was concentrated to give the crude 2- (azidomethyl) -5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b ] as an oily product]Pyrazole (430 mg). MS (ESI) 200[ 2 ], [ M ] +H] + 。
And 7: the crude product 2- (azidomethyl) -5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b]Pyrazole (430 mg) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (253mg, 1.08mmol) were added to a mixed solvent of t-butanol (6 mL) and water (3 mL), copper sulfate pentahydrate (27mg, 0.11mmol) and sodium ascorbate (86mg, 0.43mmol) were added under argon, and the mixture was heated to 70 ℃ for reaction for 2 hours. The reaction was detected to be complete by LC-MS, and the reaction solution was poured into water, extracted with dichloromethane (50 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to give a white solid product L-9 (46mg, P100%, total Y:10% in the two-step reaction yield). MS (ESI) 434.1[ deg. ] M + H ]] + .1H NMR(400MHz,dmso)δ8.55(s,1H),7.86(dd,J＝7.6,1.2Hz,1H),7.72(dd,J＝7.8,1.2Hz,1H),7.48(t,J＝7.6Hz,1H),7.22(s,1H),6.85(s,2H),6.22(s,1H),5.64(s,2H),4.62(t,J＝13.2Hz,2H),3.52(t,J＝14.2Hz,2H),2.50(d,J＝12.8Hz,3H).
Example 10: preparation of 3- (2-amino-6- (1- ((5, 5-difluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-10)
Figure BDA0002950355860000301
Step 1: compound 9a (2.18g, 13.46mmol) and ethyl propargyl acetate (2.64g, 26.91mmol) were added to xylene (25 mL) and heated to 130 ℃ for reaction for 16 hours. After the reaction of the raw materials is completed, the reaction solution is concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 0-30%) to obtain an oily product 5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazole-3-carboxylic acid ethyl ester (0.87g, Y30%) MS (ESI) 217[ 2 ], [ M + H ]] + 。 1 H NMR(400MHz,cdcl 3 )δ7.92(s,1H),4.51(t,J＝12.6Hz,2H),4.24(q,J＝7.2Hz,2H),3.61(t,J＝13.6Hz,2H),1.30(t,J＝7.2Hz,3H).
Step 2: the compound 5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b]Pyrazole-3-carboxylic acid ethyl ester (432mg, 2.0 mmol) was added to tetrahydrofuran (25 mL), the reaction was cooled to 0 deg.C, followed by addition of aluminum lithium hydride (152mg, 4.0 mmol) in portions, natural warming to room temperature and stirring for 1 hour, after completion of the reaction of the starting materials, the reaction was quenched by addition of sodium sulfate decahydrate in portions, and stirring for 30 minutes at room temperature, insoluble materials were removed by filtration, and the filtrate was concentrated to give a crude product (5, 5-difluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] as an oil (5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b ] in the form of an oil]Pyrazol-3-yl) methanol (317mg, y. MS (ESI) 175.2[ 2 ], [ M ] +H] + 。
And step 3: the compound (5, 5-difluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] is reacted with]Pyrazol-3-yl) methanol (317mg, 1.82mmol) was added to dichloromethane (15 mL), followed by the addition of 1, 8-diazabicycloundec-7-ene (415mg, 2.73mmol) and azido diphenyl phosphate (752mg, 2.73mmol), respectively. The reaction mixture was stirred at room temperature for 18 hours. After the starting material had reacted completely, dichloromethane (50 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL. Times.4), and the organic phase was concentrated to give the crude product 3- (azidomethyl) -5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b ] as an oil]Pyrazole (407 mg). MS (ESI) 200[ deg. ] M ] +H] + 。
And 4, step 4: the crude product, 3- (azidomethyl) -5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b]Pyrazole (407 mg) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (239mg, 1.02mmol) were added to a mixed solvent of t-butanol (6 mL) and water (3 mL), copper sulfate pentahydrate (26mg, 0.10mmol) and sodium ascorbate (81mg, 0.40mmol) were added under argon atmosphere, and the mixture was heated to 70 ℃ for reaction for 2 hours. The LC-MS detection reaction is complete. The reaction solution was poured into water, extracted with dichloromethane (50 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to obtain a white solid product L-10 (23mg, p 100%, total Y:5% in the two-step reaction yield. MS (ESI) 434.1[ deg. ] M + H ]] + .1H NMR(400MHz,dmso)δ8.54(s,1H),7.84(d,J＝7.6Hz,1H),7.70(d,J＝7.4Hz,1H),7.62(s,1H),7.47(t,J＝7.8Hz,1H),7.21(s,1H),6.80(s,2H),5.52(s,2H),4.61(t,J＝13.2Hz,2H),3.53(d,J＝14.0Hz,2H),2.58–2.47(m,3H).
Example 11: preparation of 3- (2-amino-6- (1- ((2, 3-dihydropyrazolo [5,1-b ] oxazol-6-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-11)
Figure BDA0002950355860000311
Step 1: ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (400mg, 2.56mmol) and 1, 2-dichloroethane (1267mg, 12.80mmol) were added to acetonitrile (15 mL) solvent and the reaction was stirred at 100 ℃ for 8 hours. LC-MS (liquid chromatography-Mass Spectrometry) detection shows that the reaction is complete, the reaction solution is poured into water, extracted by ethyl acetate (100 mL), dried by anhydrous sodium sulfate and concentrated to obtain a colorless oily crude product of 2, 3-dihydropyrazolo [5, 1-b)]Oxazole-6-carboxylic acid ethyl ester (338 mg) and the crude product was used directly in the next reaction. MS (ESI) 183[ m ] +H] + 。
And 2, step: crude 2, 3-dihydropyrazolo [5,1-b ] is prepared]Ethyl oxazole-6-carboxylate (328mg, 1.80mmol) was added to tetrahydrofuran (20 mL), and the reaction liquid was cooled to 0 ℃ and then lithium aluminum hydride (102mg, 2.70mmol) was added in portions, allowed to naturally warm to room temperature, and stirred for 2 hours. After the reaction of the starting materials was completed, sodium sulfate decahydrate was added in portions to quench the reaction, insoluble materials were removed by filtration, and the filtrate was concentrated to give a crude product (2, 3-dihydropyrazolo [5,1-b ] -a colorless oil]Oxazol-6-yl) methanol (256mg, Y: 100%). MS (ESI) 141[ m ] +H] + 。
And step 3:2, 3-dihydropyrazolo [5, 1-b)]Oxazol-6-yl) methanol (254mg, 1.81mmol) was added to dichloromethane (2 mL), followed by 1, 8-diazabicycloundec-7-ene (414mg, 2.72mmol) and diphenylphosphoryl azide (748mg, 2.72mmol), respectively. The reaction mixture was stirred at room temperature for 16 hours. After the starting materials reacted completely, dichloromethane (30 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL), and the organic phase was concentrated to give crude 6- (azidomethyl) -2, 3-dihydropyrazolo [5,1-b ] as a colorless oil]Oxazole (182mg, Y. MS (ESI) 166[ 2 ], [ M ] +H] + 。
And 4, step 4: the crude product 6- (azidomethyl) -2, 3-dihydropyrazolo [5,1-b]Oxazole (62mg, 0.38mmol) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (80 mg)0.34 mmol) was added to a mixed solvent of t-butanol (10 mL) and water (5 mL), copper sulfate pentahydrate (42mg, 0.17mmol) and sodium ascorbate (20mg, 0.10mmol) were added, and the temperature was raised to 70 ℃ to react for 3 hours. The reaction was detected by LC-MS to be complete, and the reaction solution was poured into water, extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to give L-11 (11.2mg, P96.59%, Y: 8.2%) as a pale yellow solid product. MS (ESI) 400.1[ deg. ] M + H ], [ solution of calcium ] C] + 。 1 H NMR(400MHz,dmso)δ8.54(s,1H),7.89(d,J＝7.6Hz,1H),7.75(d,J＝6.8Hz,1H),7.51(t,J＝7.6Hz,1H),7.25(s,1H),6.87(s,2H),5.52(d,J＝5.6Hz,3H),5.07–5.00(m,2H),4.28–4.19(m,2H),2.54(s,3H).
Example 12: preparation of 3- (2-amino-6- (1- ((2-oxo-1, 2,3, 4-tetrahydroquinolin-8-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-12)
Figure BDA0002950355860000312
Step 1: methyl 3-methyl-2-nitrobenzoate (5 g,25.6 mmol) and N-bromosuccinimide (5.01g, 28.2mmol) were combined in carbon tetrachloride (60 mL). The temperature was raised to 85 ℃ and benzoyl peroxide (372mg, 1.54mmol) was added under nitrogen protection. Stir at this temperature overnight. The reaction was poured into water, extracted with dichloromethane (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by combiflash (EA/PE, 0-30%) to give the product (3.69g, 52.8%) as a yellow solid.
Step 2: methyl 3- (bromomethyl) -2-nitrobenzoate (3g, 11mmol), diethyl malonate (1.94g, 12mmol) and potassium carbonate (2.28g, 16.5mmol) were mixed in DMF (20 mL). Stir at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, extracted with ethyl acetate (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by combiflash (EA/PE, 0-50%) to give the product (2.5 g, 64.4%) as a yellow oily liquid. MS (ESI) 354.2[ deg. ] M + H ]] + 。
And step 3: diethyl 2- (3- (methoxycarbonyl) -2-nitrobenzyl) malonate (1.35g, 3.82mmol) and water (0.3 mL) were dissolved in DMF (10 mL). Micro-meterThe wave was heated to 160 ℃ for 45 minutes. The solvent was concentrated to dryness under reduced pressure and purified by combiflash (EA/PE, 0-80%) to give the product (747mg, 69.5%) as a yellow oily liquid. MS (ESI) 282.1[ deg. ] M + H ]] + 。
And 4, step 4: methyl 3- (3-ethoxy-3-oxopropyl) -2-nitrobenzoate (1.3g, 4.63mmol) was dissolved in acetic acid (20 mL). Iron powder (2.6g, 46.3mmol) was added thereto. The reaction solution was stirred at 90 ℃ for 3 hours. The solvent was spin-dried under reduced pressure, and then ethyl acetate and saturated NaHCO were added thereto 3 And (3) solution. Extraction with ethyl acetate (50ml × 2), drying over anhydrous sodium sulfate, concentration to dryness under reduced pressure, purification of the crude product by combiflash (EA/PE = 60%) yielded the product (807mg, 85%) as a yellow solid. MS (ESI) 206.1[ 2 ], [ M ] +H] + 。
And 5: methyl 2-oxo-1, 2,3, 4-tetrahydroquinoline-8-carboxylate (100mg, 0.49mmol) was dissolved in tetrahydrofuran (10 mL). The temperature was reduced to-40 ℃ and DIBAL-H (1.95mL, 1.95mmol, 1M) was added under nitrogen. Stirring was carried out at this temperature for 2 hours. Quenched with saturated ammonium chloride solution, extracted with ethyl acetate (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by combiflash (EA/PE, 0-90%) to give the product (17mg, 21.2%) as a yellow solid. MS (ESI) 178.1[ 2 ], [ M ] +H] + 。
And 6:8- (hydroxymethyl) -3, 4-dihydroquinolin-2 (1H) -one (17mg, 0.1mmol) was dissolved in DCM (3 mL) and DPPA (41mg, 0.15mmol) and DBU (24mg, 0.15mmol) were added. Stir at room temperature overnight. The solvent was concentrated to dryness under reduced pressure, and the crude product was used directly in the next reaction. MS (ESI) 203.1[ deg. ] M + H ]] + 。
And 7:8- (Azidomethyl) -3, 4-dihydroquinolin-2 (1H) -one (20mg, 0.1mmol) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (24mg, 0.1mmol) were added to a mixed solvent of t-butanol (4 mL) and water (2 mL), and Cu was added under argon protection 2 SO 4 .5H 2 O (13mg, 0.05mmol) and sodium ascorbate (6mg, 0.03mmol) were heated to 65 ℃ and stirred for 20 hours. The reaction mixture was poured into water, extracted with dichloromethane (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by preparative separation in high performance liquid chromatography to give the product L-12 (25mg, 57%) as a white solid. MS (ESI) 437.1[ deg. ] M + H ]] + 。 1 H NMR(400MHz,dmso)δ9.91(s,1H)，8.55(s,1H)，7.89(d,J＝8Hz,1H),7.74(d,J＝8Hz,1H),7.53-7.51(m,1H),7.24-7.21(m,2H),7.05(d,J＝8Hz,1H),6.98-6.94(m,1H),6.87(s,2H),5.79(s,2H),2.93-2.89(m,2H),2.54(s,3H),2.47-2.45(m,2H).
Example 13: preparation of 3- (2-amino-6- (1- ((6, 7-dihydro-5H-pyrazolo [5,1-b ] [1,3] oxazin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-13)
Figure BDA0002950355860000321
Step 1: the compound ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (1.0 g, 6.40mmol), 1, 3-dibromopropane (0.72mL, 7.04mmol) and potassium carbonate (3.54g, 25.65mmol) were added to acetonitrile (40 mL) and heated to reflux for 16 hours. Cooling the reaction liquid to room temperature after the raw materials completely react, filtering to remove insoluble substances, and concentrating the filtrate to obtain an oily crude product 6, 7-dihydro-5H-pyrazolo [5, 1-b)][1,3]Oxazine-2-carboxylic acid ethyl ester (1.81g, y. MS (ESI) 197[ deg. ] M ] +H] + 。
Step 2: reacting the compound 6, 7-dihydro-5H-pyrazolo [5, 1-b)][1,3]Ethyl oxazine-2-carboxylate (500mg, 2.55mmol) was added to tetrahydrofuran (25 mL), the reaction was cooled to 0 deg.C, then lithium aluminum hydride (194mg, 5.10 mmol) was added in portions, allowed to warm to room temperature naturally, and stirred for 1 hour. After the reaction of the starting materials was completed, the reaction was quenched by adding sodium sulfate decahydrate in portions, and stirred at room temperature for 30 minutes, insoluble matters were removed by filtration, and the filtrate was concentrated to give an oily crude product (6, 7-dihydro-5H-pyrazole [5,1-b ]][1,3]Oxazin-2-yl) methanol (380mg, y 97%). MS (ESI) 155 (+H) +] + 。
And step 3: the compound (6, 7-dihydro-5H-pyrazolo [5, 1-b)][1,3]Oxazin-2-yl) methanol (380mg, 2.47mmol) was added to dichloromethane (15 mL), followed by 1, 8-diazabicycloundec-7-ene (5632 mg, 3.70mmol) and diphenylphosphoryl azide (1.02g, 3.70mmol), respectively. The reaction mixture was at room temperature for 16 hours. After the starting material had reacted completely, dichloromethane (50 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL. Times.4), and the organic phase was concentrated to give the crude 2- (azido) as an oilMethyl) -6, 7-dihydro-5H-pyrazolo [5,1-b][1,3]Oxazine (467 mg). MS (ESI) 200[ 2 ], [ M ] +H] + 。
And 4, step 4: the crude product 2- (azidomethyl) -6, 7-dihydro-5H-pyrazolo [5, 1-b)][1,3]Oxazine (344 mg) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (150mg, 0.64mmol) were added to a mixed solvent of t-butanol (6 mL) and water (3 mL), copper sulfate pentahydrate (1695g, 0.06mmol) and sodium ascorbate (51mg, 0.26mmol) were added under argon, and the mixture was heated to 70 ℃ for 2 hours. LC-MS detects that the reaction is complete, the reaction liquid is poured into water, dichloromethane is used for extraction (50 mL multiplied by 2), anhydrous sodium sulfate is used for drying, and after decompression and concentration, the white solid product L-13 (27mg, P100%, and the total yield of two steps is Y: 10%) is obtained through high performance liquid phase preparation, separation and purification. MS (ESI) 414.2[ deg. ] M + H ]] + .1H NMR(400MHz,dmso)δ8.51(s,1H),7.86(dd,J＝7.7,1.1Hz,1H),7.72(dd,J＝7.6,1.1Hz,1H),7.48(t,J＝7.6Hz,1H),7.22(s,1H),6.85(s,2H),5.52(s,1H),5.47(s,2H),4.24–4.19(m,2H),4.01(t,J＝6.0Hz,2H),2.51(s,3H),2.16–2.07(m,2H).
Example 14: preparation of 3- (4-amino-6- (1- ((6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) -2-methylbenzonitrile (L-14)
Figure BDA0002950355860000331
Step 1: dissolving morpholine-3-carboxylate 1.0g, 5.97mmol) in 2.5ml water, cooling to 0 deg.C, adding sodium nitrite (577mg, 8.35mmol), stirring at 0 deg.C for 3 hr, and LC-MS detecting reaction completion. The reaction solution was concentrated under reduced pressure to dryness, 20ml of acetone was added, filtration was carried out, the filtrate was concentrated under reduced pressure to dryness, 50ml of tetrahydrofuran was added, and concentration to dryness was continued to obtain crude green foamy solid 4-nitrosomorpholine-3-carboxylic acid (2.5 g, P100%, Y: 100%). MS (ESI) 161[ M ] +H ]] + 。
Step 2: dissolving 4-nitrosomorpholine-3-carboxylic acid (956 mg, 5.97mmol) in anhydrous tetrahydrofuran (20 mL), cooling to 0 ℃ under the protection of argon, adding dry trifluoroacetic acid (1.63g, 7.76mmol), stirring for 5 hours in ice bath, then heating to room temperature and continuing stirring for 16 hours. LCMS monitor reaction complete. The reaction solution was directly evaporated to dryness under reduced pressure to give crude 14a (2.0 g, P, 90%, Y: 100%), which was used in the next reaction without further purification. MS (ESI) 143[ m ] +H ]] + 。
And step 3: the compound 14a (600mg, 4.16mmol) and ethyl propiolate (1.23g, 12.49mmol) are dissolved in xylene 50ml, heated to 150 ℃ and stirred for 5 hours, and the LC-MS detects that the reaction is complete and the target product is generated. Concentrating the reaction solution under reduced pressure, separating and purifying by silica gel column to obtain white solid 6, 7-dihydro-4H-pyrazolo [5,1-c][1,4]Oxazine-2-carboxylic acid ethyl ester (380mg, p. MS (ESI) 197[ deg. ] M ] +H] + 。
And 4, step 4: reacting 6, 7-dihydro-4H-pyrazolo [5, 1-c)][1,4]Dissolving oxazine-2-carboxylic acid ethyl ester (330mg, 1.68mmol) in tetrahydrofuran 15ml, cooling to 0 ℃ under the protection of argon, adding lithium aluminum hydride (128mg, 3.36mmol) in batches, continuing stirring at 0 ℃ for 30 minutes, and detecting by LC-MS that the reaction is complete and the target product is generated. Sodium sulfate decahydrate (1.0 g) was added to the reaction solution in portions, slowly warmed to room temperature and stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to dryness to give a colorless oil (6, 7-dihydro-4H-pyrazolo [5, 1-c)][1,4]Oxazin-2-yl) methanol (220mg, p 100%, Y: 84%) MS (ESI) 155[ 2[ M ] +H ]] + 。
And 5: reacting (6, 7-dihydro-4H-pyrazolo [5, 1-c)][1,4]Oxazin-2-yl methanol (220mg, 1.43mmol) was dissolved in 5ml of methylene chloride, and diphenyl phosphorazidate (589mg, 2.14mmol) and 1, 8-diazabicycloundecen-7-ene (326mg, 2.14mmol) were added in this order, and the mixture was stirred overnight at 40 ℃. And (4) detecting the complete reaction by LC-MS, and generating a target product. Directly decompressing, concentrating and drying the reaction liquid, separating and purifying by a silica gel column to obtain a colorless oily substance 2- (azidomethyl) -6, 7-dihydro-4H-pyrazolo [5,1-c][1,4]Oxazine (140mg, P] + 。
Step 6:3- (4-amino-6-ethynyl-5-fluoropyrimidin-2-yl) -2-methylbenzonitrile (100mg, 0.396mmol) and 2- (azidomethyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c)][1,4]Oxazine (71mg, 0.396mmol) was dissolved in a mixed solvent of t-butanol (10 ml) and water (2 ml), copper sulfate pentahydrate (191mg, 0.793mmol) and sodium ascorbate (158mg, 0.793mmol) were added successively under stirring and argon protection at room temperature, and the mixture was stirred at 40 ℃ for 1 hourAnd the LC-MS detection reaction is complete, and the target product is generated. The reaction mixture was poured into water, extracted with dichloromethane (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to HPLC separation and purification to give L-14 (21.50mg, p 99.28%, Y: 12%) as a white solid. 1 H NMR(400MHz,dmso)δ8.67(s,1H),7.99–7.72(m,2H),7.48(d,J＝26.8Hz,3H),6.07(s,1H),5.60(s,2H),4.72(s,2H),4.02(d,J＝9.4Hz,4H),2.61(s,3H).MS(ESI)432[M+H] + 。
Example 15: preparation of 3- (2-amino-6- (1- ((5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-15)
Figure BDA0002950355860000341
Step 1: the compound 4, 4-dimethylpyrrolidine-2-carboxylic acid (850mg, 5.94mmol) was dissolved in water (10 mL), the reaction solution was cooled to 0 ℃ and then concentrated hydrochloric acid (12M, 1.19mL, 14.27mmol) was added first, then sodium nitrite (615mg, 8.92mmol) was added slowly, and finally the reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16 hours. After the reaction of the starting materials was completed, the aqueous phase was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product of 4, 4-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid (1.02g, y 83%). MS (ESI) 173[ deg. ] M +H] + 。
Step 2: the compound 4, 4-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid (1.02g, 5.93mmol) was added to toluene (12 mL), the reaction solution was cooled to 0 deg.C, and then 1.87g,8.90mmol of trifluoroacetic anhydride was added dropwise, and after the addition, the temperature was naturally raised to room temperature and stirred at room temperature for 2 hours. After the starting material had reacted completely, the reaction was concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 0-60%) to give the solid product 15a (0.87g, y. MS (ESI) 155 (+H) +] + 。
And 3, step 3: compound 15a (0.87g, 5.65mmol) and ethyl propargyl propionate (1.11g, 11.30mmol) were added to xylene (25 mL) and heated to 130 ℃ for 16 hours. After the reaction of the raw materials is completed, the reaction solution is concentrated and column chromatography is carried out (ethyl acetate: petroleum ether =0-60%) Purifying to obtain oily product 5, 5-dimethyl-5, 6-dihydro-4H-pyrrole [1,2-b]Pyrazole-2-carboxylic acid ethyl ester (620mg, y. MS (ESI) 209[ deg. ] M ] +H] + 。
And 4, step 4: the compound 5, 5-dimethyl-5, 6-dihydro-4H-pyrrole [1, 2-b)]Pyrazole-2-carboxylic acid ethyl ester (380mg, 1.83mmol) was added to tetrahydrofuran (20 mL), the reaction was cooled to 0 deg.C, and then lithium aluminum hydride (139mg, 3.65mmol) was added in portions, allowed to naturally warm to room temperature, and stirred for 1 hour. After the reaction of the starting materials was completed, the reaction was quenched by adding sodium sulfate decahydrate in portions, and stirred at room temperature for 30 minutes, insoluble matters were removed by filtration, and the filtrate was concentrated to give an oily crude product (5, 5-dimethyl-5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazol-2-yl) methanol (285mg, y. MS (ESI) 167M + H] + 。
And 5: the compound (5, 5-dimethyl-5, 6-dihydro-4H-pyrrole [1, 2-b)]Pyrazol-2-yl) methanol (285mg, 1.72mmol) was added to methylene chloride (12 mL), followed by addition of 1, 8-diazabicycloundec-7-ene (391mg, 2.58mmol) and diphenyl azidophosphate (708mg, 2.58mmol), respectively. The reaction mixture was stirred at room temperature for 18 hours. After the starting materials had reacted completely, additional dichloromethane (50 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL. Times.4), and the organic phase was concentrated to give the crude 2- (azidomethyl) -5, 5-dimethyl-5, 6-dihydro-4H-pyrrole [1,2-b ] as an oil]Pyrazole (373 mg). MS (ESI) 192[ deg. ] M ] +H] + 。
Step 6: the crude product 2- (azidomethyl) -5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] is isolated]Pyrazole (373 mg) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (152mg, 0.65mmol) were added to a mixed solvent of t-butanol (6 mL) and water (3 mL), copper sulfate pentahydrate (1695g, 0.07mmol) and sodium ascorbate (52mg, 0.26mmol) were added under argon, and the temperature was raised to 70 ℃ for reaction for 2 hours. The completion of the reaction was checked by LC-MS, and the reaction solution was poured into water, extracted with dichloromethane (50 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to obtain a white solid product L-15 (25mg, P100%, total Y:9% in the two-step reaction yield. MS (ESI) 426.2[ deg. ] M + H ]] + .1H NMR(400MHz,dmso)δ8.51(s,1H),7.86(dd,J＝6.8,0.8Hz,1H),7.72(dd,J＝7.6,0.8Hz,1H),7.48(t,J＝7.6Hz,1H),7.21(s,1H),6.84(s,2H),6.02(s,1H),5.56(s,2H),3.78(s,2H),2.60(s,2H),2.51(s,3H),1.16(s,6H).
Example 16: preparation of 3- (4-amino-5-fluoro-6- (1- ((4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile (L-16)
Figure BDA0002950355860000342
Step 1: the compound 4,5,6, 7-tetrahydropyrazolo [1,5-a]Pyridine-2-carboxylic acid (630mg, 3.80mmol) was added to tetrahydrofuran (20 mL), the reaction solution was cooled to 0 ℃ and then lithium aluminum hydride (577mg, 15.18mmol) was added in portions, allowed to naturally warm to room temperature, and stirred for 3 hours. After the reaction of the starting materials was completed, the reaction was quenched by adding sodium sulfate decahydrate in portions and stirring at room temperature for 30 minutes, insoluble materials were removed by filtration, and the filtrate was concentrated to give an oily crude product (4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-2-yl) methanol (480mg, Y. MS (ESI) 153[ deg. ] M ] +H] + 。
Step 2: reacting the compound (4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-2-yl) methanol (480mg, 3.16mmol) was added to methylene chloride (15 mL), followed by 1, 8-diazabicycloundecen-7-ene (720mg, 4.74mmol) and diphenylphosphoryl azide (1.30g, 4.74mmol), respectively. The reaction mixture was stirred at room temperature for 16 hours. After the starting materials reacted completely, methylene chloride (50 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL. Times.4), and then the organic phase was concentrated to give the crude product 2- (azidomethyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] as an oil]Pyridine (640 mg). MS (ESI) 178 (+H)] + 。
And 3, step 3: the crude product 2- (azidomethyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a]Pyridine (211 mg) and 3- (4-amino-6-ethynyl-5-fluoropyrimidin-2-yl) -2-methylbenzonitrile (100mg, 0.40mmol) were added to a mixed solvent of t-butanol (6 mL) and water (3 mL), copper sulfate pentahydrate (10mg, 0.04mmol) and sodium ascorbate (31mg, 0.16mmol) were added under argon protection, and the mixture was heated to 70 ℃ to react for 2 hours. LC-MS detects that the reaction is complete, and the white solid product L-1 is obtained by directly decompressing and concentrating the reaction liquid and then separating and purifying the reaction liquid through high performance liquid phase preparation6 (17mg, P. MS (ESI) 430.3[ deg. ] M + H ]] + . 1 H NMR(400MHz,dmso)δ8.64(s,1H),7.91(dd,J＝7.6,1.2Hz,1H),7.83(dd,J＝7.6,1.2Hz,1H),7.51(s,2H),7.45(t,J＝7.6Hz,1H),5.98(s,1H),5.54(s,2H),3.97(t,J＝6.0Hz,2H),2.66(t,J＝6.4Hz,2H),2.61(s,3H),1.88(ddd,J＝8.4,7.6,4.3Hz,2H),1.70(ddd,J＝15.6,7.6,4.4Hz,2H).
Example 17: preparation of 3- (4-amino-6- (1- ((4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile (L-17)
Figure BDA0002950355860000351
Step 1: 4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine-2-carboxylic acid ethyl ester (930mg, 4.45mmol) is dissolved in tetrahydrofuran 20ml, the temperature is reduced to 0 ℃ under the protection of argon, lithium aluminum hydride (337mg, 8.89mmol) is added in batches, stirring is continued at 0 ℃ for 2 hours, lc-ms detects that the reaction is complete, and the target product is generated. Sodium sulfate decahydrate (2.0 g) was added to the reaction solution in portions, the mixture was slowly warmed to room temperature and stirred for 1 hour, and then filtered, and the filtrate was concentrated under reduced pressure to dryness to give 2- (hydroxymethyl) -6, 7-dihydropyrazolo [1,5-a as a colorless oil]Pyrazine-4 (5H) -one (700mg, p 90%, Y: 94%) MS (ESI) 168[ 2 ], [ M + H ]] + 。
Step 2: 2- (hydroxymethyl) -6, 7-dihydropyrazolo [1,5-a]Pyrazin-4 (5H) -one (700mg, 4.19mmol) was dissolved in 5ml of methylene chloride, diphenyl phosphorazidate (1.73g, 6.28mmol) and 1, 8-diazabicycloundecen-7-ene (0.96g, 6.28mmol) were added in this order, and the mixture was stirred at 40 ℃ overnight. And (4) detecting the complete reaction by LC-MS, and generating a target product. The reaction solution is directly decompressed, concentrated and dried, and is separated and purified by a silica gel column to obtain colorless oily substance 2- (azidomethyl) -6, 7-dihydropyrazolo [1,5-a]Pyrazin-4 (5H) -one (700g, p 97.38%, Y: 87%). MS (ESI) 193 (++ M)] + 。
And step 3:3- (4-amino-6-ethynylpyrimidin-2-yl) -2-methylbenzonitrile (50mg, 0.213mmol) and 2- (azidomethyl) -6, 7-dihydropyrazolo [1,5-a ]]Pyrazin-4 (5H) -one (62mg, 0.320mmol) was dissolved in a mixture of tert-butanol (10 ml) and water (3 ml)Adding copper sulfate pentahydrate (51mg, 0.213mmol) and sodium ascorbate (43mg, 0.213mmol) into the solvent in turn at room temperature under stirring and argon protection, heating to 40 ℃, stirring for 1 hour, and detecting complete reaction by lc-ms to obtain the target product. The reaction mixture was poured into water, extracted with dichloromethane (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to HPLC separation and purification to give L-17 (11.02mg, p 100%, Y: 12%) as a white solid. 1 H NMR(400MHz,dmso)δ8.59(s,1H),8.21(s,1H),7.86(d,J＝7.6Hz,1H),7.72(d,J＝7.8Hz,1H),7.48(t,J＝7.7Hz,1H),7.22(s,1H),6.85(s,2H),6.78(s,1H),5.68(s,2H),4.26(t,J＝6.0Hz,2H),3.56(s,2H),2.51(s,3H).MS(ESI)427[M+H] + 。
Example 18: preparation of 3- (6- (1- ((1H-benzo [ d ] imidazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -2-aminopyrimidin-4-yl) -2-methylbenzonitrile (L-18)
Figure BDA0002950355860000352
Step 1: benzene-1, 2-diamine (3.5g, 32.4 mmol) and methyl 2-glycolate (11.7g, 130mmol) were mixed in 4M HCl (60 mL). The temperature is raised to 100 ℃ and the mixture is stirred overnight. Cool to room temperature, add 2M NaOH solution to adjust pH =8, extract with dichloromethane (50ml × 2), dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, purify with combiflash (MeOH/DCM = 15%) to obtain the product (2.5g, 52.1%) as a yellow solid. MS (ESI) 149.1[ deg. ] M + H ]] + 。
Step 2: (1H-benzo [ d ]]Imidazol-2-yl) methanol (148mg, 1mmol) was dissolved in DCM (5 mL) and DPPA (410mg, 1.5 mmol) and DBU (240mg, 1.5 mmol) were added. Stir at room temperature overnight. The solvent was concentrated to dryness under reduced pressure, and the crude product was used directly in the next reaction. MS (ESI) 174.1[ 2 ] M + H] + 。
And step 3:2- (azidomethyl) -1H-benzo [ d]Imidazole (34mg, 0.19mmol), 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (35mg, 0.15mmol) were added to a mixed solvent of tert-butanol (4 mL) and water (2 mL), and Cu was added under argon protection 2 SO 4 .5H 2 O (19mg, 0.08mmol) and sodium ascorbate (9mg, 0.05mmol), heating to 65 deg.C, and stirring for 20 hr. Pouring the reaction solution into water, andextraction with dichloromethane (50ml × 2), drying over anhydrous sodium sulfate, concentration under reduced pressure to dryness, and preparative separation and purification by high performance liquid chromatography gave the product L-18 (13mg, 16.9%) as a white solid. MS (ESI) 408.1[ deg. ] M + H ]] + 。
1 H NMR(400MHz,dmso)δ8.74(s,1H),7.90-7.88(m,1H),7.76(d,J＝8Hz,1H),7.60-7.49(m,3H),7.28(s,1H),7.21-7.19(m,2H),6.90(s,2H),6.00(s,2H),2.55(s,3H).
Example 19: preparation of 3- (4-amino-5-chloro-6- (1- ((5, 5-difluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile (L-19)
Figure BDA0002950355860000361
Step 1: the crude product 2- (azidomethyl) -5, 5-difluoro-5, 6-dihydro-4H-pyrrole [1,2-b]Pyrazole (301 mg) and 3- (4-amino-5-chloro-6-ethynylpyrimidin-2-yl) -2-methylbenzonitrile (80mg, 0.30mmol) were added to a mixed solvent of tert-butanol (6 mL) and water (3 mL), copper sulfate pentahydrate (10mg, 0.04mmol) and sodium ascorbate (31mg, 0.16mmol) were added under the protection of argon, the temperature was raised to 70 ℃ and the reaction was allowed to react for 2 hours, and the reaction was detected to be complete by LC-MS. The reaction solution was directly concentrated under reduced pressure and then subjected to preparative separation and purification by high performance liquid chromatography to obtain a white solid product L-19 (4.4mg, P100%, Y: 3%). MS (ESI) 468.1[ deg. ] M + H ]] + 。 1 H NMR(400MHz,dmso)δ8.77(s,1H),7.94(d,J＝7.6Hz,1H),7.85(d,J＝6.8Hz,1H),7.46(t,J＝7.6Hz,1H),6.21(s,1H),5.63(s,2H),4.60(t,J＝13.2Hz,2H),3.51(t,J＝14.4Hz,2H),2.63(s,3H).
Example 20: preparation of 3- (4-amino-5-chloro-6- (1- ((5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile (L-20)
Figure BDA0002950355860000362
Step 1, reacting 5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazole-2-carboxylic acid (152mg, 1.0 mmol) was added to tetrahydrofuran (10 mL), and the reaction solution was cooled toLithium aluminum hydride (152mg, 4.0 mmol) was added to the reaction solution at 0 ℃ and then slowly warmed to room temperature and stirred for 3 hours. Adding sodium sulfate decahydrate in batches when the raw materials react completely until no bubbles are generated in the reaction solution, stirring the reaction solution for 10 minutes, filtering, and directly concentrating the filtrate to obtain an oily crude product (5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazol-2-yl) methanol (127mg, P77%, Y: 92%). MS (ESI) 139[ deg. ] M +H] + 。
And 2, step: reacting (5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazol-2-yl) methanol (127mg, 0.92mmol) was dissolved in DCM (6 mL), followed by the addition of diphenyl azidophosphate (380mg, 1.38mmol) and 1, 8-diazabicycloundec-7-ene ((210mg, 1.38mmol), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction of the starting materials was completed, dichloromethane (50 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL. Times.4), and the filtrate was concentrated to give a crude product, 2- (azidomethyl) -5, 6-dihydro-4H-pyrrole [1,2-b ] as an oily oil]Pyrazole (324 mg). MS (ESI) 164[ deg. ] M ] +H] + 。
And step 3:2- (azidomethyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole (324mg, 2.0mmol) and 3- (4-amino-5-chloro-6-ethynylpyrimidin-2-yl) -2-methylbenzonitrile (80mg, 0.30mmol), sodium ascorbate (24mg, 0.12mmol) and copper sulfate pentahydrate (7.5mg, 0.03mmol) were added to t-butanol/water (v/v =2/1,6 mL) and stirred at 70 ℃ for 2 hours, when the starting materials were reacted completely, the reaction was filtered and concentrated, and isolated by high performance liquid phase preparative isolation to give the product L-20 as a white solid (4.5mg, P100%, Y: 3.5%). MS (ESI)
432.1[M+H] + 。 1 H NMR(400MHz,dmso)δ8.71(s,1H),7.94(d,J＝6.8Hz,1H),7.85(dd,J＝7.6,1.2Hz,1H),7.46(t,J＝7.8Hz,1H),6.01(s,1H),5.56(s,2H),4.04–3.93(m,2H),2.75(t,J＝7.2Hz,2H),2.63(s,3H),2.44(m,2H).
Example 21: preparation of 3- (4-amino-5-chloro-6- (1- ((4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile (L-21)
Figure BDA0002950355860000371
Step 1: 2- (azidomethyl) -4,5,6, 7-tetrahydropyrazoline [1,5-a ]]Pyridine (213mg, 1.20mmol) and 3- (4-amino-5-chloro-6-ethynylpyrimidin-2-yl) -2-methylbenzonitrile (80mg, 0.30mmol), sodium ascorbate (24mg, 0.12mmol) and copper sulfate pentahydrate (7.5mg, 0.03mmol) were added to t-butanol/water (v/v =2/1,6 ml) and stirred at 70 ℃ for 2 hours, and when the starting material was reacted completely, the reaction solution was filtered and concentrated, and isolated and purified by high performance liquid phase preparative isolation to give a white solid product L-21 (17.42mg, y 13%). MS (ESI) 446.2[ deg. ] M + H ]] + 。 1 H NMR(400MHz,dmso)8.72(1H,s),7.95(1H,dd,J＝7.6,1.2),7.84(1H,dd,J＝7.6,1.2),7.46(1H,t,J＝7.6),5.98(1H,s),5.54(2H,s),3.96(2H,t,J＝6.0),2.66(2H,d,J＝6.4),2.63(3H,s),1.94–1.82(2H,m),1.70(2H,ddd,J＝15.6,7.6,4.4).
Example 22: preparation of 3- (2-amino-6- (1- ((5-methyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-22)
Figure BDA0002950355860000372
Step 1: the compound methyl triphenyl phosphine bromide (11.6 g,32.5 mmol) is dissolved in anhydrous tetrahydrofuran (200 mL), the internal temperature is lowered to 0 deg.C, then a solution of potassium tert-butoxide in tetrahydrofuran (1M, 32.5mL,32.5 mmol) is added dropwise, the reaction mixture is stirred at 0 deg.C for 30 minutes after the addition of the solution is completed, then a solution of 1- (tert-butyl) 2-methyl 4-oxypyrrolidine-1, 2-dicarboxylate (7.19g, 29.6 mmol) in tetrahydrofuran (20 mL) is added dropwise again, the reaction mixture is stirred at 0 deg.C for 30 minutes, then allowed to rise to the chamber and stirred for 18 hours. The reaction was quenched by adding saturated ammonium chloride, the aqueous phase was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 0-25%) to give 1- (tert-butyl) 2-methyl 4-methylenepyrrolidine-1, 2-dicarboxylate (3.5g, y. MS (ESI) 242[ sic ], [ M ] +H] + 。
And 2, step: the compound 1- (tert-butyl) 2-methyl-4-methylenepyrrolidine-1, 2-dicarboxylate (6.6 g, 27)39 mmol) and palladium on carbon (10%, 660 mg) were added to methanol (50 mL), the reaction solution was stirred under hydrogen at room temperature for 16 hours, and then the reaction solution was filtered and concentrated to give a crude product 1- (tert-butyl) 2-methyl 4-methylpyrrolidine-1, 2-dicarboxylate (6.42g, y 97%) as an oil. MS (ESI) 244[ m ] +H] + 。
And step 3: compound 1- (tert-butyl) 2-methyl-4-methylpyrrolidine-1, 2-dicarboxylate (6.42g, 26.42mmol) was added to dioxane hydrochloride (4M, 40mL, 160mmol), and the reaction solution was stirred at room temperature for 16 hours. After the reaction of the starting materials was completed, the reaction mixture was concentrated to give 4-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (4.91 g) as an oily crude product. MS (ESI) 144[ deg. ] M ] +H] + 。
And 4, step 4: the compound methyl 4-methylpyrrolidine-2-carboxylate hydrochloride (4.91g, 27.28mmol) was added to 1, 4-dioxane (60 mL), concentrated hydrochloric acid (12M, 25mL) was further added, the reaction mixture was heated to 90 ℃ and stirred for 8 hours, and then the reaction liquid was concentrated to give an oily crude 4-methylpyrrolidine-2-carboxylate (6.3 g). MS (ESI) 130 (+H) +] + 。
And 5: the compound 4-methylpyrrolidine-2-carboxylate (6.3 g, 37.95mmol) was dissolved in water (40 mL), the reaction was cooled to 0 deg.C, then concentrated hydrochloric acid (12M, 6.33mL, 175.90mmol) was added first, then sodium nitrite (5.24g, 75.90mmol) was added slowly, and finally the reaction mixture was allowed to warm to room temperature slowly and stirred at room temperature for 16 hours. After the reaction of the starting materials was completed, the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product of 4-methyl-1-nitrosopyrrolidine-2-carboxylic acid (3.1 g, total Y:52% in the three-step reaction yield). MS (ESI) 159, M +H] + 。
And 6: the compound 4-methyl-1-nitrosopyrrolidine-2-carboxylic acid (3.1g, 19.62mmol) was added to toluene (50 mL), the reaction liquid was cooled to 0 ℃ and then 6.18g,29.43mmol of trifluoroacetic anhydride was added dropwise, followed by natural warming to room temperature after the addition and stirring at room temperature for 2 hours. When the starting material was completely reacted, the reaction was concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 0-50%) to give the oily product 22a (2.1g, y. MS (ESI) 141[ m ] +H] + 。
And 7: will be provided withCompound 22a (2.1g, 15.0 mmol) and ethyl propargyl acetate (2.94g, 30.0 mmol) were added to xylene (30 mL) and heated to 130 ℃ to react for 16 hours. After the reaction of the raw materials is completed, the reaction solution is concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 0-70%) to obtain an oily product 5-methyl-5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazole-2-carboxylic acid ethyl ester (1.1g, y. MS (ESI) 195[ m ] +H] + 。 1 H NMR(400MHz,cdcl 3 )δ6.48(s,1H),4.34(qd,J＝7.2,0.4Hz,2H),4.31–4.23(m,1H),3.78–3.67(m,1H),3.05(dt,J＝13.2,6.4Hz,2H),2.52–2.41(m,1H),1.35(td,J＝7.2,0.4Hz,3H),1.27–1.20(m,3H).
And 8: the compound 5-methyl-5, 6-dihydro-4H-pyrrole [1,2-b]Pyrazole-2-carboxylic acid ethyl ester (194mg, 1.0 mmol) was added to tetrahydrofuran (15 mL), the reaction solution was cooled to 0 deg.C, then lithium aluminum hydride (152mg, 4.0 mmol) was added in portions, allowed to naturally rise to room temperature and stirred for 1 hour, after completion of the reaction of the raw materials, the reaction was quenched by adding sodium sulfate decahydrate in portions, and stirred at room temperature for 30 minutes, insoluble materials were removed by filtration, and the filtrate was concentrated to give a crude product (5-methyl-5, 6-dihydro-4H-pyrrole [1,2-b ] as an oily oil]Pyrazol-2-yl) methanol (132mg, y. MS (ESI) 153.2[ deg. ] M + H ]] + 。
And step 9: the compound (5-methyl-5, 6-dihydro-4H-pyrrole [1, 2-b)]Pyrazol-2-yl) methanol (132mg, 0.87mmol) was added to dichloromethane (5 mL), followed by addition of 1, 8-diazabicycloundec-7-ene (198mg, 1.30mmol) and diphenylphosphorylazide (358mg, 1.30mmol), respectively. After the starting material had reacted completely, dichloromethane (50 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL. Times.4), and the organic phase was concentrated to give the crude 2- (azidomethyl) -5-methyl-5, 6-dihydro-4H-pyrrole [1,2-b ] as an oil]Pyrazole (321 mg). MS (ESI) 178.2[ deg. ] M + H ]] + 。
Step 10: the crude product 2- (azidomethyl) -5-methyl-5, 6-dihydro-4H-pyrrole [1,2-b]Pyrazole (321 mg) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (100mg, 0.43mmol) were added to a mixed solvent of tert-butanol (6 mL) and water (3 mL), copper sulfate pentahydrate (11mg, 0.04mmol) and sodium ascorbate (34mg, 0.17mmol) were added under argon, and the mixture was heated to 70 ℃ to react for 2 hoursThen (c) is performed. The reaction was detected to be complete by LC-MS, and the reaction solution was poured into water, extracted with dichloromethane (50 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to give a white solid product L-22 (29mg, P100%, total Y:16% in the two-step reaction yield). MS (ESI) 412.1[ deg. ] M + H ]] + 。 1 H NMR(400MHz,dmso)δ8.50(s,1H),7.85(d,J＝7.6Hz,1H),7.71(d,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.22(s,1H),6.85(s,2H),6.01(s,1H),5.56(s,2H),4.16(dd,J＝10.4,7.6Hz,1H),3.58(dd,J＝10.4,6.4Hz,1H),3.03–2.90(m,2H),2.51(s,3H),2.36(dd,J＝18.8,9.6Hz,1H),1.13(d,J＝6.4Hz,3H).
Example 23: preparation of 3- (2-amino-6- (1- ((3a, 4,5,6,7, 7a-hexahydro-1H-benzo [ d ] imidazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-23)
Figure BDA0002950355860000381
Step 1: cyclohexane-1, 2-dione (4.2g, 37.5 mmol), ethyl glyoxylate (3.82g, 37.5 mmol) and ammonium acetate (5.78g, 75mmol) were dissolved in ethanol (60 mL). Heat to 90 ℃ and stir overnight. The solvent was dried under reduced pressure and the crude product was purified by combiflash (EA/PE, 0-90%) to give the product (2.5g, 34.4%) as a yellow solid. MS (ESI) 195.1[ deg. ] M + H ]] + 。
And 2, step: 3a,4,5,6,7,7a-hexahydro-1H-benzo [ d]Imidazole-2-carboxylic acid ethyl ester (200mg, 1.03mmol) and tetrahydrofuran (12 mL) were combined. The temperature is reduced to 0 ℃, and lithium aluminum hydride (118mg, 3.06mmol) is added under the protection of nitrogen. The temperature was slowly raised to room temperature and stirring was continued for 2 hours. Then the temperature is reduced to 0 ℃, and decahydrate and sodium sulfate are added to quench the reaction. The solid was filtered and washed, and the filtrate was rotary dried under reduced pressure. The crude product was used directly in the next reaction. MS (ESI) 153.1[ deg. ] M + H ]] + 。
And step 3: (3a, 4,5,6,7, 7a-hexahydro-1H-benzo [ d)]Imidazol-2-yl) methanol (156mg, 1.03mmol) was dissolved in DCM (5 mL) and DPPA (426mg, 1.55mmol) and DBU (235mg, 1.55mmol) were added. Stir at room temperature overnight. The solvent was concentrated to dryness under reduced pressure, and the crude product was used directly in the next reaction. MS (ESI) 178.1[ deg. ] M + H ]] + 。
And 4, step 4:2- (Azidomethyl) -3a,4,5,6,7, 7a-hexahydro-1H-benzo [ d]Imidazole (36mg, 0.21mmol), 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (40mg, 0.17mmol) was added to a mixed solvent of t-butanol (4 mL) and water (2 mL), and Cu was added under argon protection 2 SO 4 .5H 2 O (21mg, 0.09mmol), and sodium ascorbate (10mg, 0.05mmol), were stirred for 20 hours after the temperature was raised to 65 ℃. The reaction solution was poured into water, extracted with dichloromethane (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by preparative separation in high performance liquid chromatography to give the product L-23 (13mg, 18.6%) as a white solid. MS (ESI) 412.2[ 2 ] M + H] + 。 1 H NMR(400MHz,dmso)δ8.54(s,1H),7.89(d,J＝8Hz,1H)，7.75(d,J＝8Hz,1H)，7.53-7.49(m,1H)，7.25(s,1H)，6.90(s,2H)，5.61(s,2H)，2.54(s,3H)，2.42-2.38(m,4H),1.70(s,4H).
Example 24: preparation of 3- (4-amino-6- (1- ((5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile (L-24)
Figure BDA0002950355860000391
Reacting 2- (azidomethyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazole, 3- (4-amino-6-ethynylpyrimidin-2-yl) -2-methylbenzonitrile (60mg, 0.26mmol), sodium ascorbate (26mg, 0.13mmol) and copper sulfate pentahydrate (33mg, 0.13mmol) were added to t-butanol/water (v/v =2/1,6 ml) and stirred at 70 ℃ for 2 hours, and when the starting material was reacted completely, the reaction was filtered and concentrated to obtain a product L-24 (26.75mg, p, 95.01%, Y: 25.92%) as a white solid through preparative isolation and purification by high performance liquid chromatography. MS (ESI) 398.1[ deg. ] M + H ]] + 。
Example 25: preparation of 3- (2-amino-6- (1- ((4-hydroxy-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-25)
Figure BDA0002950355860000392
Step 1: diethyl 1H-pyrazole-3, 5-dicarboxylate (10g, 47.17mmol), ethyl 4-bromobutyrate (9.1g, 47.17mmol), potassium carbonate (6.5g, 47.17mmol) and acetonitrile (100 mL) were heated to 85 ℃ under nitrogen protection to react for 16 hours. The reaction solution was filtered and concentrated to dryness to give diethyl 1- (4-ethoxy-4-oxybutyl) -1H-pyrazole-3, 5-dicarboxylate (15.2 g, yield 89.9%) as a white solid. MS m/z (ESI) 327.1[ 2 ], [ M ] +H] + 。
Step 2: adding sodium hydrogen (1.47g, 36.81mmol) into a solution of (1- (4-ethoxy-4-oxybutyl) -1H-pyrazole-3, 5-dicarboxylic acid diethyl ester (10g, 30.67mmol) and tetrahydrofuran (100 mL) at 0 ℃ under the protection of nitrogen, reacting at room temperature for 16 hours after the addition, quenching the reaction solution by using 1N hydrochloric acid, adjusting the pH to 3-4, extracting by using ethyl acetate (150mL-2), washing an organic layer by using saturated saline solution, drying anhydrous sodium sulfate, evaporating to obtain a crude product, and purifying by column chromatography (petroleum ether: ethyl acetate =90%: 10-80%: 20%) to obtain 4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Diethyl pyridine-2, 5-dicarboxylate (7.2 g, 81.5% yield) was obtained as a white solid. MS m/z (ESI) 281.1[ 2 ] M + H] + 。
And step 3: 4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Diethyl pyridine-2, 5-dicarboxylate (7g, 25mmol), concentrated hydrochloric acid (100 mL) and water (200 mL) were heated to 100 ℃ and reacted for 3 hours. Evaporating the reaction solution to dryness, and concentrating with toluene and water to obtain 4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine-2-carboxylic acid (4 g,88.9% yield), white solid. MS m/z (ESI) 181.1[ 2 ] M + H] + 。
And 4, step 4: lithium aluminum hydride (190mg, 5 mmol) was added to 4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] under nitrogen at 0 deg.C]Pyridine-2-carboxylic acid (300mg, 1.67mmol) and tetrahydrofuran (10 mL) were added and heated at 70 ℃ for 16 hours. Water (300 mg), a 15% aqueous solution of sodium hydroxide (300 mg) and water (900 mg) were added to the reaction mixture at-10 ℃ to quench the reaction, and after stirring at room temperature for 0.5 hour, anhydrous magnesium sulfate was added thereto and stirred for 0.5 hour, followed by filtration and concentration to give 2- (hydroxymethyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] s]Pyridin-4-ol (270mg, 96.4% yield), a colorless oil. MS m/z (ESI) 169.1[ 2 ] M + H] + 。
And 5: will 2- (hydroxymethyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a]Pyridin-4-ol (220mg, 1.31mmol), diphenylphosphorylazide (360mg, 1.31mmol), 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (298mg, 1.96mmol) and methylene chloride (3 mL) were mixed and reacted at room temperature for 16 hours. Adding water into the reaction solution, extracting with dichloromethane (5 mL. Multidot.2), washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, and evaporating to dryness to obtain crude product of 2- (azidomethyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-4-ol (260 mg, 100% yield) as a yellow oil. The crude product is directly put into the next step. MS m/z (ESI) 194.1[ 2 ], [ M ] +H] + 。
Step 6:3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (75mg, 0.32mmol), 2- (azidomethyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-4-ol (123mg, 0.64mmol), L-ascorbic acid sodium salt (25mg, 0.13mmol), copper sulfate pentahydrate (8mg, 630.91. Mu. Mol), t-butanol (4 mL) and water (2 mL) were mixed and reacted at 60 ℃ for 1 hour. After adding water to the reaction mixture, dichloromethane was used for extraction (5 ml. X2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to HPLC preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH) 4 HCO 3 H 2 O; wavelength: 254/214 nm) to obtain the title compound L-25 (50.51 mg, 36.9% yield) as a white solid. MS m/z (ESI) 428.2[ 2 ] M + H] + 。 1 H NMR(400MHz,dmso)δ8.52(s,1H),7.86(d,J＝7.6Hz,1H),7.71(d,J＝8.0Hz,1H),7.48(t,J＝7.6Hz,1H),7.21(s,1H),6.85(s,2H),6.18(s,1H),5.57(s,2H),5.40(d,J＝5.6Hz,1H),4.63(dd,J＝11.2,5.6Hz,1H),3.95(t,J＝6.0Hz,2H),2.51(s,3H),2.10–2.01(m,1H),1.95–1.87(m,1H),1.85–1.76(m,1H),1.66–1.57(m,1H).
Example 26: preparation of 3- (2-amino-6- (1- ((4-hydroxy-5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-26)
Figure BDA0002950355860000401
Step 1: sodium hydride (444mg, 11.11mmol) was added at 0 ℃ under nitrogen blanket(4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine-2-carboxylic acid (500mg, 2.78mmol) and N, N-dimethylformamide (20 mL) were added, followed by reaction at 0 to 10 ℃ for 0.5 hour. Methyl iodide (1.97g, 13.9 mmol) was added to the above reaction mixture, and the reaction was completed at room temperature for 2 hours. Quenching the reaction solution with 1N hydrochloric acid at 0 deg.C, extracting with ethyl acetate (30mL × 2), washing the organic layer with water (15mL × 3), washing with saturated sodium chloride (20 mL), drying with anhydrous sodium sulfate, evaporating to obtain crude product, and purifying by column chromatography (petroleum ether: ethyl acetate =90%:10% -75%: 25%) to obtain 5, 5-dimethyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ])]Pyridine-2-carboxylic acid methyl ester (480 mg, yield 77.8%). MS m/z (ESI) 223.1[ 2 ], [ M ] +1] + 。
Step 2: 1M diisobutylaluminum hydride (2mL, 2.01mmol) was added to 5, 5-dimethyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] at 0 ℃ under nitrogen]A solution of methyl pyridine-2-carboxylate (150mg, 0.67mmol) and tetrahydrofuran (10 mL) was mixed and reacted at room temperature for 16 hours. The reaction mixture was quenched with water at 0 deg.C, washed with ethyl acetate (10 mL. About.2), and the aqueous phase was concentrated to dryness to give 2- (hydroxymethyl) -5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-4-ol (66 mg, 50.2% yield), white solid. The crude product is directly put into the next step. MS m/z ESI) 197.2[ mu ] M +1] + 。
And step 3:2- (hydroxymethyl) -5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a]Pyridin-4-ol (66mg, 0.34mmol), diphenylphosphorylazide (102mg, 0.37mmol), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (78mg, 0.51mmol) and dichloromethane (1 mL) were combined and reacted at room temperature under nitrogen for 16 hours. Adding water into the reaction solution, extracting with dichloromethane (3 mL. About.2), washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, and evaporating to dryness to obtain crude product of 2- (azidomethyl) -5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-4-ol (76 mg, 100% yield) as a yellow oil. The crude product is directly put into the next step. MS m/z (ESI) 222.1[ 2 ], [ M ] +1] + 。
And 4, step 4:3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (40mg, 0.17mmol), 2- (azidomethyl) -5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] -methyl-amide]Pyridin-4-ol (76mg, 0.34mmol), L-ascorbic acid sodium salt (13.4 mg, 0.068mmol), pentahydrateCopper sulfate (4.2mg, 0.017mmol), tert-butanol (4 mL) and water (2 mL) were mixed and reacted at 60 ℃ for 1 hour. After adding water to the reaction mixture, dichloromethane was used for extraction (5 ml × 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to HPLC preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH) 4 HCO 3 H 2 O; wavelength: 254/214 nm) to obtain the objective compound L-26 as a white solid (31.15 mg, 40.3% yield). MS m/z (ESI) 456.2[ deg. ] M +1 ]] + 。 1 H NMR(400MHz,dmso)δ8.53(s,1H),7.86(d,J＝7.6Hz,1H),7.71(d,J＝7.6Hz,1H),7.48(t,J＝7.6Hz,1H),7.22(s,1H),6.85(s,2H),6.13(s,1H),5.57(s,2H),5.43(d,J＝6.0Hz,1H),4.19(d,J＝6.0Hz,1H),3.94(m,2H),2.51(s,3H),1.85(m,1H),1.75–1.66(m,1H),0.92(s,3H),0.78(s,3H).
Example 27: preparation of 3- (2-amino-6- (1- ((5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-27)
Figure BDA0002950355860000402
Step 1: reacting 5, 5-dimethyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine-2-carboxylic acid methyl ester (430mg, 1.94mmol), triethylsilane (3 mL) and trifluoroacetic acid (5 mL) were heated to 70 ℃ and reacted for 16 hours. The reaction was extracted with dichloromethane (10 mL. Multidot.2) by adding water, and the organic layer was concentrated to give a crude product. Purifying the crude product by column chromatography (reversed phase) to obtain 5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine-2-carboxylate (150mg, 37.2% yield), white solid. MS m/z (ESI) 209.1[ 2 ] M +1] + 。
Step 2: lithium tetrahydroaluminium (31.5 mg, 0.83mmol) was added to a solution of 5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridine-2-carboxylate (145mg, 0.69mmol) and tetrahydrofuran (10 mL) under nitrogen at 0 ℃ and reacted at 0.5 h. Water (31 mg), a 15% aqueous solution of sodium hydroxide (31 mg) and water (93 mg) were added to the reaction mixture at-10 ℃ to quench the reaction, and after stirring at room temperature for 0.5 hour, anhydrous magnesium sulfate was added thereto and stirred for 0.5 hour, followed by filtration and concentration to give (5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) methanol (130 mg, yield 100%) as a yellow oil. The crude product is directly put into the next step.
And 3, step 3: reacting (5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-2-yl) methanol (130mg, 0.72mmol), diphenylphosphorylazide (238mg, 0.86mmol), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (164mg, 1.08mmol) and dichloromethane (2 mL) were mixed and reacted at room temperature under nitrogen for 3 hours. Adding water into the reaction solution, extracting with dichloromethane (5 mL), washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, and evaporating to obtain crude product of 2- (azidomethyl) -5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine (150 mg, 100% yield) as a yellow oil. The crude product is directly put into the next step. MS m/z (ESI) 206.2[ 2 ] M +1] + 。
And 4, step 4:3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (114mg, 0.49mmol), 2- (azidomethyl) -5, 5-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] -was reacted]Pyridine (150mg, 0.73mmol), L-sodium ascorbate (39mg, 0.19mmol), copper sulfate pentahydrate (12mg, 0.049mmol), tert-butanol (4 mL) and water (2 mL) were mixed and reacted at 60 ℃ for 1 hour. After adding water to the reaction mixture, dichloromethane was used for extraction (5 ml. X2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to HPLC preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH) 4 HCO 3 H 2 O; wavelength: 254/214 nm) to give L-27 (119.49 mg, 55.8% yield) as a yellow solid. MS m/z (ESI) 440.2[ 2 ] M +1] + 。 1 H NMR(400MHz,dmso)δ8.51(s,1H),7.86(d,J＝8.0Hz,1H),7.71(d,J＝7.2Hz,1H),7.48(t,J＝8.0Hz,1H),7.21(s,1H),6.85(s,2H),5.96(s,1H),5.55(s,2H),3.99(t,J＝6.4Hz,2H),2.51(s,3H),2.47(s,2H),1.73(t,J＝6.4Hz,2H),0.93(s,6H).
Example 28: preparation of 3- (2-amino-6- (1- ((2, 3-dihydro-1H-imidazo [1,2-b ] pyrazol-6-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-28)
Figure BDA0002950355860000411
Step 1: diethyl 3, 5-pyrazolecarboxylate (5g, 23.56mmol), benzyl-2-bromoethyl ether (5.58g, 25.92mmol) and potassium carbonate (6.51g, 47.12mmol) were added to acetonitrile (100 mL) solvent, and the reaction was stirred at 85 ℃ for 2 hours. The reaction was checked by LC-MS to be complete and the reaction was poured into water, extracted with ethyl acetate (500 mL), dried over anhydrous sodium sulfate and concentrated to give crude 1- (2- (benzyloxy) ethyl) -1H-pyrazole-3, 5-dicarboxylic acid diethyl ester as a colorless oil (8.04g, y 98.7%) which was used directly in the next reaction. MS (ESI) 347[ 2 ], [ M ] +H] + 。
Step 2: diethyl 1- (2- (benzyloxy) ethyl) -1H-pyrazole-3, 5-dicarboxylate (7.84g, 22.63mmol) was dissolved in ethanol (100 ml), 70ml of an aqueous solution of sodium hydroxide (0.5 mol/L) was added, and the mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, as determined by LC-MS, most of the ethanol solvent was concentrated under reduced pressure, water (200 mL) was added, extracted with ethyl acetate (500 mL), dried over anhydrous sodium sulfate, and concentrated to give crude 1- (2- (benzyloxy) ethyl) -3- (ethoxycarbonyl) -1H-pyrazole-5-carboxylic acid as a colorless oil (7.05g, Y97.8%), which was used directly in the next reaction. MS (ESI) 319 (++ M)] + 。
And 3, step 3: 1- (2- (benzyloxy) ethyl) -3- (ethoxycarbonyl) -1H-pyrazole-5-carboxylic acid (6.85g, 32.28mmol) and triethylamine (4.90g, 48.42mmol) were dissolved in t-butanol (50 ml), diphenyl phosphorazidate (9.77g, 35.51mmol) was added, and the mixture was stirred at room temperature for 1 hour, then heated to 80 ℃ and stirred for 4 hours. The reaction was complete by LC-MS detection, most of the ethanol solvent was concentrated under reduced pressure, water (100 mL) was added, extracted with ethyl acetate (200 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 50-100%) to give the product 1- (2- (benzyloxy) ethyl) -5- ((tert-butoxycarbonyl) amino) -1H-pyrazole-3-carboxylic acid ethyl ester (3.69g, p 76.17%, Y: 29.4%) as a colorless oil. MS (ESI) 390[ m ] +H] + 。
And 4, step 4: 1- (2- (benzyloxy) ethyl) -5- ((tert-butoxycarbonyl) amino) -1H-pyrazole-3-carboxylic acid ethyl ester (3.28g, 8.42mmol) was dissolved in methanol (50 ml) solvent, 10% palladium hydroxide on charcoal (55% water) (3.0 g) was added, and the mixture was hydrogenatedThe reaction was stirred at room temperature for 5 days with air displacement, LCMS monitored for completion, the reaction was filtered, the filtrate was concentrated and purified by column chromatography (methanol: dichloromethane = 20-40%) to give the product 5- ((tert-butoxycarbonyl) amino) -1- (2-hydroxyethyl) -1H-pyrazole-3-carboxylic acid ethyl ester (613mg, p 78.04%, Y: 24.3%) as a colorless oil. MS (ESI) 300[ deg. ] M ] +H] + 。
And 5: ethyl 5- ((tert-butoxycarbonyl) amino) -1- (2-hydroxyethyl) -1H-pyrazole-3-carboxylate (603mg, 2.01mmol) and azobisformyldipiperidine (610mg, 2.42mmol) were dissolved in tetrahydrofuran (20 ml), tri-n-butylamine (490mg, 2.42mmol) was added, the mixture was subjected to nitrogen substitution, the reaction was stirred at 80 ℃ for 1.5 hours, the reaction was monitored by LCMS for completion, the reaction mixture was concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 40-80%) to give 1- (tert-butyl) 2, 3-dihydro-1H-imidazo [1,2-b ] as a colorless oil]Pyrazole-6-carboxylic acid ethyl ester (508mg, P83.72%, Y: 89.6%). MS (ESI) 282 (+H) +] + 。
Step 6:1- (tert-butyl) 2, 3-dihydro-1H-imidazo [1,2-b ]]Pyrazole-6-carboxylic acid ethyl ester (250mg, 0.89mmol) was dissolved in dichloromethane (5 ml) solvent, trifluoroacetic acid (2 ml) was added, the mixture was stirred at room temperature for 3 hours, LCMS was used to monitor completion of the reaction, dichloromethane (50 ml) was added to the reaction, washed twice with saturated sodium bicarbonate solution (30ml × 2), the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to give crude yellow oil (143mg, y. MS (ESI) 182[ m ] +H ]] + 。
And 7:2, 3-dihydro-1H-imidazo [1,2-b ]]Dissolving pyrazole-6-carboxylic acid ethyl ester (133mg, 0.73mmol) in tetrahydrofuran (10 ml), adding lithium aluminum hydride (139mg, 3.67mmol) in portions at room temperature, stirring the mixture at room temperature for 1 hour, monitoring the reaction completion by LCMS, adding methanol (10 ml) into the reaction solution, filtering, concentrating the filtrate to dryness to obtain crude product (2, 3-dihydro-1H-imidazo [1,2-b ] as yellow oily substance]Pyrazol-6-yl) methanol (112 mg) was used directly in the next step. MS (ESI) 140[ m ] +H] + 。
And 8: reacting (2, 3-dihydro-1H-imidazo [1,2-b ]]Pyrazol-6-yl) methanol (112mg, 0.80mmol) was added to dichloromethane (2 mL), followed by the addition of 1, 8-diazabicycloundec-7-ene (182mg, 1), respectively.20 mmol) and diphenylphosphoryl azide (332mg, 1.20mmol). The reaction mixture was stirred at room temperature for 3 hours. After the starting materials reacted completely, additional dichloromethane (30 mL) was added to the reaction mixture, the organic phase was washed with water (20 mL), and the organic phase was concentrated to give the crude 6- (azidomethyl) -2, 3-dihydro-1H-imidazo [1,2-b ] product as a colorless oil]Pyrazole 133.6mg (theoretical amount). MS (ESI) 167[ deg. ] M +H] + 。
And step 9: the crude product 6- (azidomethyl) -2, 3-dihydro-1H-imidazo [1,2-b]Pyrazole (85mg, 0.51mmol) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (100mg, 0.43mmol) were added to a mixed solvent of t-butanol (5 mL) and water (2 mL), copper sulfate pentahydrate (52mg, 0.21mmol) and sodium ascorbate (25mg, 0.13mmol) were added, and the mixture was heated to 70 ℃ for reaction for 3 hours. The reaction was detected to be complete by LC-MS, and the reaction solution was poured into water, extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to give a pale yellow solid product L-28 (1.87mg, P100%, Y: 1.1%). MS (ESI) 399.1[ 2 ] M + H] + 。 1 H NMR(400MHz,dmso)δ8.49(s,1H),7.88(s,1H),7.74(s,1H),7.51(s,1H),7.24(s,1H),6.87(s,2H),5.73(s,1H),5.47(s,2H),5.31(s,1H),4.03(dd,J＝9.0,7.2Hz,2H),3.79(d,J＝2.4Hz,2H),2.54(s,3H).
Example 29: preparation of 3- (2-amino-6- (1- ((4-fluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-29)
Figure BDA0002950355860000421
Step 1: sodium borohydride (88mg, 2.32mmol) was added to 4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] at 0 deg.C under nitrogen]To a solution of methyl pyridine-2-carboxylate (300mg, 1.55mmol) and methanol (10 mL) was added 0 ℃ for 0.5 hour and then reacted at room temperature for 1 hour. The reaction was quenched with 1N hydrochloric acid, concentrated to dryness, and the residue was dissolved with water (5 mL) and dichloromethane: methanol =10 (1: 10ml × 5), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 4-hydroxy-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] s]Pyridine-2-carboxylic acidAcid methyl ester (300mg, 98.7% yield), white solid. MS m/z (ESI) 197.1[ 2 ] M +1] + 。
And 2, step: diethylamine sulfur trifluoride (476mg, 2.96mmol) was added to 4-hydroxy-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] at 0 ℃ under nitrogen protection]To a solution of methyl pyridine-2-carboxylate (290mg, 1.48mmol) and methylene chloride (15 mL) was added 0 ℃ for 0.5 hour and then 1 hour at room temperature. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (10mL. Multidot.2), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 4-fluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] s]Pyridine-2-carboxylic acid methyl ester (280 mg, 95.5% yield) as a yellow oil. The crude product is directly put into the next step. MS m/z (ESI) 199.1[ 2 ] M +1] + 。
And 3, step 3: lithium aluminum hydride (20mg, 0.52mmol) was added to 4-fluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] at 0 ℃ under nitrogen atmosphere]To a solution of methyl pyridine-2-carboxylate (80mg, 0.40mmol) and tetrahydrofuran (5 mL) was added 0 ℃ for 0.5 hour and then reacted at room temperature for 0.5 hour. Adding sodium sulfate decahydrate into the reaction solution at-0 deg.C, stirring at room temperature for 0.5 hr, filtering, and concentrating to obtain (4-fluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-2-yl) methanol (65 mg, 95.6% yield) as a yellow oil. The crude product is directly put into the next step. MS m/z (ESI) 171.1[ deg. ] M +1 ]] + 。
And 4, step 4: reacting (4-fluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-2-yl) methanol (65mg, 0.38mmol), diphenylphosphorylazide (126mg, 0.46mmol), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (87mg, 0.57mmol) and dichloromethane (2 mL) were mixed and reacted at room temperature under nitrogen for 16 hours. Adding water into the reaction solution, extracting with dichloromethane (5 mL), washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, and evaporating to obtain crude product of 2- (azidomethyl) -4-fluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine (80 mg, 100% yield) as a yellow oil. The crude product is directly put into the next step. MS m/z (ESI) 196.1[ 2 ] M +1] + 。
And 5:3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (68mg, 0.29mmol), 2- (azidomethyl) -4-fluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine (80mg, 0.38mmol), sodium L-ascorbate (30mg, 0.15mmol), sulfuric acid pentahydrateCopper (9.5mg, 0.038mmol), tert-butanol (4 mL) and water (2 mL) were mixed and reacted at 60 ℃ for 1 hour. After adding water to the reaction mixture, dichloromethane was used for extraction (5 ml. X2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to HPLC preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH) 4 HCO 3 H 2 O; wavelength: 254/214 nm) to obtain the objective compound L-29 as a white solid (37.45 mg, 30% yield). MS m/z (ESI) 430.1[ 2 ], [ M ] +1] + 。 1 H NMR(400MHz,dmso)δ8.55(s,1H),7.86(dd,J＝8.0,1.2Hz,1H),7.72(dd,J＝8.0,1.2Hz,1H),7.48(t,J＝8.0Hz,1H),7.22(s,1H),6.84(s,2H),6.45(d,J＝2.8Hz,1H),5.72(dt,J＝51.6,3.6Hz,1H),5.63(s,2H),4.19(dt,J＝12.8,4.o Hz,1H),3.94(m,,1H),2.51(s,3H),2.08(m,2H),2.03–1.89(m,2H).
Example 30: preparation of 3- (2-amino-6- (1- (pyrazolo [1,5-a ] pyrimidin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-30)
Figure BDA0002950355860000431
Step 1: lithium aluminum hydride (0.98g, 25.8mmol) was charged into a nitrogen-blanketed three-necked flask, cooled to 0 ℃ and tetrahydrofuran (15 mL) was slowly added. Then a solution of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester (1g, 6.5 mmol) in tetrahydrofuran (10 mL) was slowly added thereto. The reaction was slowly warmed to room temperature and stirred overnight. The reaction solution was cooled to 0 ℃ and quenched with sodium sulfate decahydrate. Filtering, washing the solid, decompressing and spin-drying the filtrate, and directly using the obtained crude product for the next reaction. MS (ESI) 114.1[ 2 ] M + H] + 。
Step 2: (5-amino-1H-pyrazol-3-yl) methanol (725mg, 6.42mmol) and 1, 3-tetramethoxypropane (1.05g, 6.42mmol) were dissolved in acetic acid (15 mL). The reaction solution was stirred at 100 ℃ for 4 hours. The solvent was spin dried under reduced pressure, to which was added saturated sodium bicarbonate to pH =8. Dichloromethane extraction (50ml × 2), drying over anhydrous sodium sulfate, concentration to dryness under reduced pressure, purification by combiflash (MeOH/DCM = 10%) yielded the product (159mg, 16.6%) as a yellow solid. MS (ESI) 150.1[ deg. ] M + H ]] + 。
And step 3: pyrazole [1,5-a ]]Pyrimidin-2-yl-methanol (159mg, 1.07mmol) was dissolved in DCM (5 mL) and DPPA (243mg, 1.60mmol) and DBU (440mg, 1.60mmol) were added. Stir at room temperature overnight. The solvent was concentrated to dryness under reduced pressure, and the crude product was used directly in the next reaction. MS (ESI) 175.1[ 2 ], [ M ] +H] + 。
And 4, step 4:2- (Azidomethyl) pyrazole [1,5-a ]]Pyrimidine (44mg, 0.26mmol), 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (40mg, 0.17mmol) were added to a mixed solvent of t-butanol (4 mL) and water (2 mL), and Cu was added under argon protection 2 SO 4 .5H 2 O (21mg, 0.09mmol) and sodium ascorbate (10mg, 0.05mmol), and the mixture was stirred at 65 ℃ for 20 hours. The reaction solution was poured into water, extracted with dichloromethane (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to give the product L-30 (22mg, 31.9%) as a white solid. MS (ESI) 409.2[ 2 ], [ M ] +H] + 。 1 H NMR(400MHz,dmso)δ9.11(d,J＝8Hz,1H)，8.69(s,1H)，8.58-8.56(m,1H)，7.89(d,J＝8Hz,1H)，7.75(d,J＝8Hz,1H)，7.53-7.49(m,1H)，7.26(s,1H)，7.09-7.06(m,1H)，6.88(s,2H)，6.77(s,1H)，5.96(s,2H)，2.54(s,3H)。
Example 31: preparation of 3- (2-amino-6- (1- ((6, 6-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-31)
Figure BDA0002950355860000432
Step 1: (1H-pyrazol-3-yl) methanol (2.44g, 24.9 mmol) and imidazole (2.88g, 42.3 mmol) were dissolved in DMF (30 mL). After cooling to 0 deg.C, t-butyldimethylsilyl chloride (6 g, 37.3mmol) was slowly added. Stir at room temperature overnight. To the reaction solution were added ethyl acetate and water, extracted with ethyl acetate (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by combiflash (EA/PE = 50%) to obtain a product (5.28g, 100%) as a colorless liquid. MS (ESI) 213.1[ deg. ] M + H ]] + 。
Step 2:3- (((tert-butyldimethylsilyl) oxy) methyl) -1HPyrazole (2.65g, 12.5 mmol), ethyl 3-methyl-2-butenoate (2.41g, 18.8 mmol) and cesium carbonate (6.11g, 18.8 mmol) were mixed in DMF (40 mL). Stir at room temperature overnight. To the reaction solution were added ethyl acetate and water, extracted with ethyl acetate (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by combiflash (EA/PE = 80%) to obtain a product (3.13g, 73.6%) as a colorless liquid. MS (ESI) 341.1[ 2 ], [ M ] +H] + 。
And step 3: ethyl 3- (3- (((tert-butyldimethylsilyl) oxy) methyl) -1H-pyrazol-1-yl) -3-methylbutyrate (3.13g, 9.2mmol) and lithium hydroxide (773mg, 18.4 mmol) were dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL). Stirred at room temperature for 2 hours. pH =6 was adjusted by adding 1N hydrochloric acid, dichloromethane extracted (30ml × 5), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the crude product was used directly in the next reaction. MS (ESI) 313.1[ deg. ] M + H ]] + 。
And 4, step 4:3- (3- (((tert-butyldimethylsilyl) oxy) methyl) -1H-pyrazol-1-yl) -3-methylbutanoic acid (1g, 3.2mmol) was dissolved in dry tetrahydrofuran (10 mL). The temperature is reduced to-78 ℃, and n-butyllithium (3.2mL, 8mmol, 2.5M) is added under the protection of nitrogen. The reaction solution was slowly warmed to room temperature and stirred for 4 hours. The reaction was cooled to 0 ℃, saturated ammonium chloride solution was added, dichloromethane extracted (50ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by combiflash (EA/PE = 70%) to give the product (80mg, 8.5%) as a white solid. MS (ESI) 295.1[ deg. ] M + H ], [ solution of ] M +H] + 。
And 5:2- (((tert-butyldimethylsilyl) oxy) methyl) -6, 6-dimethyl-5, 6-dihydro-4H-pyrrolo [1, 2-b)]Pyrazol-4-one (150mg, 0.5mmol) was dissolved in methanol (6 mL). Sodium borohydride (116mg, 3.1mmol) was added. Stirred at room temperature for 2 hours. The temperature was reduced to 0 ℃, water was added, dichloromethane was extracted (20ml × 3), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the crude product was used directly in the next reaction. MS (ESI) 297.1[ 2 ], [ M ] +H] + 。
And 6:2- (((tert-butyldimethylsilyl) oxy) methyl) -6, 6-dimethyl-5, 6-dihydro-4H-pyrrolo [1, 2-b)]Pyrazol-4-ol (150mg, 0.51mmol) was dissolved in triethylsilane (4 mL) and trifluoroacetic acid (8 mL). The temperature was raised to 75 ℃ and stirred overnight. The solvent was spin dried under reduced pressure. Adding saturated carbon theretoSodium hydrogen carbonate solution, dichloromethane extraction (20ml × 3), drying over anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and the crude product was used directly in the next reaction. MS (ESI) 167.1[ 2 ] M + H] + 。
And 7: (6, 6-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazol-2-yl) methanol (83mg, 0.5 mmol) was dissolved in DCM (3 mL) and DPPA (206mg, 0.75mmol) and DBU (114mg, 0.75mmol) were added. Stir at room temperature overnight. The solvent was concentrated to dryness under reduced pressure, and the crude product was used directly in the next reaction. MS (ESI) 192.1[ deg. ] M + H ], [ solution of calcium ] C] + 。
And 8:2- (Azidomethyl) -6, 6-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazole (72mg, 0.37mmol), 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (80mg, 0.34mmol) was added to a mixed solvent of t-butanol (4 mL) and water (2 mL), and Cu was added under argon protection 2 SO 4 .5H 2 O (43mg, 0.17mmol) and sodium ascorbate (20mg, 0.1mmol), and the mixture was stirred at 65 ℃ for 20 hours. The reaction solution was poured into water, extracted with dichloromethane (30ml × 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to preparative separation and purification by high performance liquid chromatography to give the product L-31 (33mg, 22.9%) as a white solid. MS (ESI) 426.2[ deg. ] M + H ]] + 。 1 H NMR(400MHz,dmso)δ8.53(s,1H)，7.89(d,J＝8Hz,1H)，7.75(d,J＝8Hz,1H)，7.53-7.49(m,1H)，7.25(s,1H)，6.87(s,2H)，5.97(s,1H)，5.60(s,2H)，2.80-2.77(m,2H)，2.54(s,3H)，2.38-2.34(m,2H)，1.39(s,6H)。
Example 32: preparation of 3- (2-amino-6- (1- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-32)
Figure BDA0002950355860000441
Step 1: 4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] is reacted under nitrogen protection]To a solution of methyl pyridine-2-carboxylate (100mg, 0.51mmol), diethylaminosulfur trifluoride (2 mL) and methylene chloride (1 mL) was added a closed tube and the reaction was carried out at 60 ℃ for 36 hours. The reaction mixture was added with ice water, extracted with dichloromethane (3 mL. About.2), and the organic phase was washed with saturated brine and anhydrous sulfuric acidDrying sodium, concentrating, and purifying by column chromatography (petroleum ether: ethyl acetate =95%:5% -80%: 20%) to obtain 4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine-2-carboxylic acid methyl ester (75 mg, 68% yield) as a yellow oil. MS m/z (ESI) 217.1[ 2 ] M + H] + 。
And 2, step: lithium aluminum hydride (15mg, 0.38mmol) was added to 4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] at 0 ℃ under nitrogen protection]To a solution of methyl pyridine-2-carboxylate (70mg, 0.32mmol) and tetrahydrofuran (3 mL) was added at 0 ℃ for 1 hour. Adding sodium sulfate decahydrate into the reaction solution at-0 deg.C, stirring at room temperature for 0.5 hr, filtering, and concentrating to obtain (4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-2-yl) methanol (61 mg, 100% yield) as a yellow oil. The crude product is directly put into the next step. MS m/z (ESI) 189.1[ deg. ] M + H ]] + 。
And step 3: reacting (4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-2-yl) methanol (61mg, 0.32mmol), diphenylphosphorylazide (106mg, 0.38mmol), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (73mg, 0.48mmol) and dichloromethane (2 mL) were mixed and reacted at room temperature under nitrogen for 16 hours. Adding water into the reaction solution, extracting with dichloromethane (5 mL), washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, and evaporating to obtain crude product of 2- (azidomethyl) -4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine (70 mg, 100% yield) as a yellow oil. The crude product is directly put into the next step. MS m/z (ESI) 214.1[ deg. ] M + H] + 。
And 4, step 4:3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (50mg, 0.21mmol), 2- (azidomethyl) -4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine (70mg, 0.32mmol), L-sodium ascorbate (17mg, 0.084 mmol), copper sulfate pentahydrate (5mg, 0.021mmol), tert-butanol (4 mL) and water (2 mL) were mixed and reacted at 60 ℃ for 1 hour. After adding water to the reaction mixture, dichloromethane was used for extraction (3 ml × 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was subjected to HPLC preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH) 4 HCO 3 H 2 O; wavelength: 254/214 nm) to give the objective compound L-32 (57.32 mg, yield 61%) as a yellow solid. MS m/z (ESI) 448.2[ 2 ], [ M + H ]] + 。 1 H NMR(400MHz,dmso)δ8.59(s,1H),7.86(d,J＝8.0Hz,1H),7.72(d,J＝7.6Hz,1H),7.48(t,J＝7.6Hz,1H),7.22(s,1H),6.84(s,2H),6.67(s,1H),5.67(s,2H),4.14(m,2H),2.51(s,3H),2.37(m,2H),2.14–2.08(m,2H).
Example 33: preparation of (S) -3- (4-amino-5-chloro-6- (1- ((5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile (L-33)
Figure BDA0002950355860000451
Step 1: (2S, 4S) -1- (tert-butoxycarbonyl) -4-fluoropyrrolidine-2-carboxylic acid (5.0g, 21.46mmol) was added to a dioxane solution (3M, 30mL), followed by addition of concentrated hydrochloric acid (12M, 6 mL) and heating to 75 ℃ for 4 hours with stirring. The reaction mixture was concentrated to give an oily crude product (2S, 4S) -4-fluoropyrrolidine-2-carboxylic acid hydrochloride (6.1 g). MS (ESI) 134[ m ] +H] + 。
Step 2 the crude product (2S, 4S) -4-fluoropyrrolidine-2-carboxylic acid hydrochloride (6.1 g) obtained in the above step was added to water (40 mL), the reaction solution was cooled to 0 ℃ and then sodium nitrite (2.22g, 32.19mmol) was added in portions, followed by addition of concentrated hydrochloric acid (12M, 2.68mL, 32.19mmol) dropwise, and the reaction solution was stirred at room temperature for 4 hours after the addition. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a solid crude product (2s, 4s) -4-fluoro-1-nitrosopyrrolidine-2-carboxylic acid (3.0 g, y 86%). MS (ESI) 163[ 2 ], [ M ] +H] + 。
And step 3: the crude product (2S, 4S) -4-fluoro-1-nitrosopyrrolidine-2-carboxylic acid (3.0g, 18.52mmol) obtained in the above step was added to toluene (40 mL), and the temperature of the reaction mixture was lowered to 0 ℃ followed by slowly dropping trifluoroacetic anhydride (5.83g, 27.78mmol) and stirring at room temperature for 2 hours. The starting materials reacted completely, the reaction liquid was concentrated and the solid product 33a was obtained by silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%) (2.2g, Y. MS (ESI) 145[ m ] +H] + 。
And 4, step 4: compound 33a (2.2g, 15.28mmol) and ethyl propiolate (3.0 g, 30.56mmol) were addedXylene (40 mL) and heated to 125 ℃ with stirring for 16 hours. The starting materials reacted completely, the reaction solution was concentrated and subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-70%) to obtain a solid product (S) -5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] as a solid product]Pyrazole-2-carboxylic acid ethyl ester (1.3g, Y. MS (ESI) 199[ m ] +H] + 。
And 5: reacting (S) -5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Ethyl pyrazole-2-carboxylate (198mg, 1.0 mmol) was added to tetrahydrofuran (10 mL), the reaction solution was cooled to 0 ℃ and lithium aluminum hydride (76mg, 2.0 mmol) was added to the reaction solution, which was then stirred at 0 ℃ for 1 hour, then warmed to room temperature and stirred for 2 hours. Adding sodium sulfate decahydrate in batches when the raw materials completely react until no bubbles are generated in the reaction liquid, stirring the reaction liquid for 10 minutes, filtering, and directly concentrating the filtrate to obtain an oily crude product (S) - (5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazol-2-yl) methanol (152mg, P85%, Y: 97%). MS (ESI) 157[ 2 ], [ M ] +H] + 。
Step 6: reacting (S) - (5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazol-2-yl) methanol (152mg, 0.97mmol) was dissolved in DCM (5 mL), then DPPA (402mg, 1.46mmol) and DBU (231mg, 1.46mmol) were added successively, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction of the raw materials is finished, the reaction solution is diluted by dichloromethane, then washed twice by water, the organic phase is dried by anhydrous sodium sulfate, filtered, and the oily crude product (S) -2- (azidomethyl) -5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] is obtained after the filtrate is concentrated]Pyrazole (367mg, p 39%). MS (ESI) 182[ m ] +H ]] + 。
And 7: reacting (S) -2- (azidomethyl) -5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazole (367 mg) and 3- (4-amino-5-chloro-6-ethynylpyrimidin-2-yl) -2-methylbenzonitrile (100mg, 0.37mmol), sodium ascorbate (30mg, 0.15mmol) and copper sulfate pentahydrate (10mg, 0.04mmol) were added to t-butanol/water (v/v =2/1, 9ml) and stirred at 70 ℃ for 6 hours, and when the reaction of the starting materials was completed, the reaction solution was filtered and concentrated, and isolated and purified by high performance liquid phase preparative isolation to give the product L-33 (20.14mg, y. MS (ESI) 450.1[ 2 ], [ M ] +H] + 。 1 H NMR(400MHz,dmso)δ8.75(s,1H),7.95(d,J＝7.6Hz,1H),7.85(d,J＝6.8Hz,1H),7.46(t,J＝7.6Hz,1H),6.12(s,1H),5.85(t,J＝4.8Hz,0.5H),5.71(t,J＝4.6Hz,0.5H),5.60(s,2H),4.34(ddd,J＝33.8,13.2,4.4Hz,1H),4.22(dd,J＝26.2,13.2Hz,1H),3.27–3.16(m,1H),2.99(dd,J＝26.8,17.6Hz,1H),2.64(s,3H).
Example 34 preparation of 3- (2-amino-6- (1- ((6-methyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-34)
Figure BDA0002950355860000452
Step 1: 1- (tert-Butoxycarbonyl) -5-methylpyrrolidine-2-carboxylic acid (1.0 g, 4.36mmol) was dissolved in 5ml of methylene chloride, and a dioxane solution (4.0M, 6 ml) of hydrochloric acid was added thereto with stirring at room temperature, followed by stirring at room temperature for 6 hours, whereupon the reaction was detected by LC-MS to be complete. The reaction solution was concentrated under reduced pressure to dryness to give a white solid 5-methylpyrrolidine-2-carboxylate (720mg, P90%, Y: 100%). MS (ESI) 130[ 2 ], [ M + H ]] + 。
And 2, step: 5-methylpyrrolidine-2-carboxylate (720mg, 4.35mmol) is dissolved in 3ml of water, 0.5ml of concentrated hydrochloric acid is added, the temperature is reduced to 0 ℃, sodium nitrite (450mg, 6.52mmol) is added, stirring is continued at 0 ℃ for 16 hours, and the LC-MS detects that the reaction is complete. The reaction solution was extracted with ethyl acetate (50ml. About.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to give 5-methyl-1-nitrosopyrrolidine-2-carboxylic acid (700mg, P96.48%, Y: 79%) as a colorless oil, MS (ESI) 159[ M + [ H ]] + 。
And step 3: 5-methyl-1-nitrosopyrrolidine-2-carboxylic acid (700mg, 4.43mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0 ℃ under argon protection, added with dry trifluoroacetic acid (1.39g, 6.64mmol), stirred for 5 hours under ice bath, then warmed to room temperature and stirred for 16 hours. LCMS monitored reaction completion. The reaction mixture was directly evaporated to dryness under reduced pressure to give crude 34a (720mg, P80%, Y: 100%), which was used in the next reaction without further purification. MS (ESI) 141[ m ] +H] + 。
Step 4, dissolving the compound 34a (700mg, 4.99mmol) and ethyl propiolate (2.0 g, 19.98mmol) in 50ml of xylene, heating to 150 ℃, stirring for 5 hours, detecting by LC-MS that the reaction is complete and the target product isAnd (4) generating. Concentrating the reaction solution under reduced pressure, separating and purifying by silica gel column to obtain colorless oily substance 6-methyl-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazole-2-carboxylic acid ethyl ester (70mg, p 66.58%, Y: 7%). MS (ESI) 195[ m ] +H] + .
And 5: reacting 6-methyl-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Dissolving pyrazole-2-carboxylic acid ethyl ester (60mg, 0.309mmol) in tetrahydrofuran 5ml, cooling to 0 ℃ under the protection of argon, adding lithium aluminum hydride (23.45mg, 0.618mmol) in batches, continuing stirring at 0 ℃ for 30 minutes, and detecting by LC-MS that the reaction is complete and the target product is generated. Sodium sulfate decahydrate (0.5 g) was added to the reaction solution in portions, the mixture was slowly warmed to room temperature and stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to dryness to give a colorless oil (6-methyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] -pyrrole]Pyrazol-2-yl) methanol (47mg, p 37%, Y: 37%). MS (ESI) 153[ deg. ] M ] +H] + 。
Step 6: reacting (6-methyl-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazol-2-yl) methanol (47mg, 308.82. Mu. Mol) was dissolved in methylene chloride (5 mL), diphenyl azidophosphate (127.48mg, 463.23. Mu. Mol) and 8-diazabicycloundecen-7-ene (70.52mg, 463.23. Mu. Mol) were added to the solution under stirring, and the reaction solution was heated to 40 ℃ under argon atmosphere and stirred overnight. And (4) detecting the complete reaction by LC-MS, and generating a target product. Pouring the reaction solution into water, extracting with dichloromethane (40ml × 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying with silica gel column to obtain colorless oily substance 2- (azidomethyl) -6-methyl-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazole (7 mg,7.67% yield, 60% purity), MS (ESI) 178[ 2 ], [ M + H ]] + 。
And 7:3- (4-amino-6-ethynyl-5-fluoropyrimidin-2-yl) -2-methylbenzonitrile (10mg, 42.69. Mu. Mol) and 2- (azidomethyl) -6-methyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] were reacted]Pyrazole (7.56mg, 42.69. Mu. Mol) is dissolved in a mixed solvent of tert-butyl alcohol (10 ml) and water (5 ml), copper sulfate pentahydrate (10.66mg, 42.69. Mu. Mol) and sodium ascorbate (8.46mg, 42.69. Mu. Mol) are added in sequence under stirring argon protection at room temperature, the temperature is raised to 40 ℃, stirring is carried out for 1 hour, LC-MS detection shows that the reaction is complete, and the target product is generated. The reaction mixture was poured into water, extracted with dichloromethane (30ml x 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by HPLC to give L-34 (1.3mg, 7.40% yield, 100% purity) as a white solid。 1 H NMR(400MHz,dmso)δ8.50(s,1H),7.86(d,J＝7.8Hz,1H),7.72(d,J＝6.8Hz,1H),7.48(t,J＝7.8Hz,1H),7.22(s,1H),6.84(s,2H),5.99(s,1H),5.57(s,2H),4.29(dd,J＝13.4,6.4Hz,1H),2.82–2.61(m,3H),2.51(s,3H),2.10–1.97(m,1H),1.35(d,J＝6.4Hz,3H)。MS(ESI)412[M+H] + 。
Example 35: preparation of (S) -3- (2-amino-6- (1- ((5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-35)
Figure BDA0002950355860000461
Reacting (S) -2- (azidomethyl) -5-fluoro-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazole (139mg, 0.77mmol) and 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (180mg, 0.77mmol), sodium ascorbate (61mg, 0.31mmol) and copper sulfate pentahydrate (38mg, 0.15mmol) were added to t-butanol/water (v/v =2/1,9 ml) and stirred for an additional 2 hours at 70 ℃, when the starting material was reacted completely, the reaction was filtered and concentrated, and purified by preparative separation in a high performance liquid phase to give the product L-35 as a white solid (36mg, y. MS (ESI) 416.1[ 2 ], [ M ] +H] + 。 1 H NMR(400MHz,dmso)δ8.53(s,1H),7.86(dd,J＝7.6,1.2Hz,1H),7.72(dd,J＝7.6,1.1Hz,1H),7.48(t,J＝7.6Hz,1H),7.22(s,1H),6.86(s,2H),6.13(s,1H),5.86(t,J＝4.7Hz,0.5H),5.73(t,J＝4.7Hz,0.5H),5.60(s,2H),4.36(ddd,J＝32.0,12.2,3.2Hz,1H),4.24(dd,J＝26.4,13.6Hz,1H),3.29–3.16(m,1H),3.01(dd,J＝26.6,17.8Hz,1H),2.51(s,3H).
Example 36: preparation of 3- (6- (1- ((5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -2- (methylamino) pyrimidin-4-yl) -2-methylbenzonitrile (L-36)
Figure BDA0002950355860000462
Figure BDA0002950355860000471
Step 1: reacting 5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazole-2-carboxylic acid (120mg, 0.79mmol) was dissolved in THF (5 mL), and lithium aluminum hydride (44.90mg, 1.18mmol) was added thereto while cooling on ice. The reaction was stirred at 0 ℃ for 0.5 h, then at room temperature (24 ℃) for 1h and monitored by LCMS for completion of the starting material reaction. Sodium sulfate decahydrate (1 g) was added to the reaction solution in an ice bath, and the mixture was stirred for 10 minutes, filtered, and the filtrate was dried by spinning under reduced pressure to give a crude colorless oily substance (5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazol-2-yl) methanol (60 mg) was used directly in the next reaction. MS (ESI) 139.1[ deg. ] M + H ]] + 。
Step 2: reacting (5, 6-dihydro-4H-pyrrole [1,2-b ]]Pyrazol-2-yl) methanol (60mg, 0.43mmol) was added to dichloromethane (2 mL), followed by the addition of 1, 8-diazabicycloundec-7-ene (79mg, 0.52mmol) and diphenylphosphoryl azide (143mg, 0.52mmol), respectively. The reaction mixture was stirred at room temperature for 18 hours. After the starting materials reacted completely, additional dichloromethane (20 mL) was added to the reaction mixture, the organic phase was washed with water (10 mL), and the organic phase was concentrated to give the crude product 2- (azidomethyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] as a colorless oil]Pyrazole 71mg (theoretical amount). MS (ESI) 164.1[ deg. ] M + H ]] + 。
And step 3: 2-methyl-3- (2- (methylsulfonyl) -6- ((triisopropylsilyl) ethynyl) pyrimidin-4-yl) benzonitrile (300mg, 0.66mmol), N-diisopropylethylamine (855mg, 6.61mmol) and methylamine hydrochloride (446mg, 6.61mmol) were added to a solvent of N, N-dimethylformamide (15 mL), and the reaction was stirred at room temperature for 3 hours. The reaction was completed by LC-MS detection, and after completion of the reaction, the reaction solution was concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 0-60%) to give 2-methyl-3- (2- (methylamino) -6- ((triisopropylsilyl) ethynyl) pyrimidin-4-yl) benzonitrile (185mg, p 97.19%, Y: 67.2%) as a pale yellow solid. MS (ESI) 405.2[ deg. ] M + H ]] + 。
And 4, step 4: 2-methyl-3- (2- (methylamino) -6- ((triisopropylsilyl) ethynyl) pyrimidin-4-yl) benzonitrile (185mg, 0.46mmol) and ammonium fluoride (339mg, 9.14mmol) were added to a methanol (20 mL) solvent, and the mixture was stirred for a reaction time of 8 hours at 75 ℃. LC-MS detection reaction is complete, and after the reaction is finished, the reaction solution is concentratedAnd purified by column chromatography (ethyl acetate: petroleum ether = 0-70%) to give 3- (6-ethynyl-2- (methylamino) pyrimidin-4-yl) -2-methylbenzonitrile (99mg, p 92.57%, Y: 80.7%) as a pale yellow solid. MS (ESI) 4249.1[ 2 ] M + H] + 。
And 5:3- (6-ethynyl-2- (methylamino) pyrimidin-4-yl) -2-methylbenzonitrile (50mg, 0.20mmol) and 2- (azidomethyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazole (49mg, 0.30mmol) was added to a mixed solvent of t-butanol (10 mL) and water (5 mL), copper sulfate pentahydrate (25mg, 0.10mmol) and sodium ascorbate (12mg, 0.06mmol) were added, and the mixture was reacted at room temperature for 18 hours. LC-MS detects that the reaction is complete, the reaction liquid is poured into water, extracted by ethyl acetate (30 mL), dried by anhydrous sodium sulfate, and separated and purified by high performance liquid phase preparation after being concentrated under reduced pressure to obtain a white solid product L-36 (19.60mg, P99.69%, Y: 22.0%). MS (ESI) 412.1[ deg. ] M + H ]] + 。 1 H NMR(400MHz,dmso)δ8.58(s,1H),7.94–7.86(m,1H),7.77(s,1H),7.52(t,J＝7.6Hz,1H),7.31(d,J＝4.8Hz,1H),7.25(s,1H),6.05(s,1H),5.60(s,2H),4.07–3.98(m,2H),2.88(s,3H),2.84–2.77(m,2H),2.56(s,3H),2.50–2.44(m,2H).
Example 37: preparation of 3- (2-amino-6- (1- ((4-fluoro-6, 6-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile (L-37)
Figure BDA0002950355860000472
Step 1: reacting 2- (((tert-butyldimethylsilyl) oxy) methyl) -6, 6-dimethyl-5, 6-dihydro-4H-pyrrolo [1, 2-b)]Pyrazol-4-ol (300mg, 1.01mmol) was dissolved in dichloromethane (4 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (448mg, 2.02mmol) was added thereto. The reaction was stirred at room temperature for 2 hours. The reaction mixture was added with saturated brine, extracted with DCM, dried and the solvent was dried under reduced pressure. The crude product was used directly in the next reaction. MS (ESI) 299.2[ deg. ] M + H ]] + 。
Step 2: reacting 2- (((tert-butyldimethylsilyl) oxy) methyl) -4-fluoro-6, 6-dimethyl-5, 6-dihydro-4H-pyrroleAnd [1,2-b ]]Pyrazole (300mg, 1.01mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (6mL, 6mmol, 1M) was added thereto. The reaction was stirred at room temperature for 20 hours. The reaction mixture was added with saturated brine, extracted with ethyl acetate (20mL: 3), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the crude product was used in the next reaction. MS (ESI) 185.1[ deg. ] M + H ]] + 。
And step 3: (4-fluoro-6, 6-dimethyl-5, 6-dihydro-4H-pyrrole [1, 2-b)]Pyrazol-2-yl) methanol (100mg, 0.54mmol) was dissolved in DCM (3 mL), and DPPA (149mg, 0.54mmol) and DBU (83mg, 0.54mmol) were added. Stir at room temperature overnight. The solvent was concentrated to dryness under reduced pressure, and the crude product was used directly in the next reaction. MS (ESI) 210.1[ deg. ] M + H ]] + 。
And 4, step 4:2- (Azidomethyl) -4-fluoro-6, 6-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ]]Pyrazole (71mg, 0.34mmol), 3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile (80mg, 0.34mmol) was added to a mixed solvent of t-butanol (4 mL) and water (2 mL), and Cu was added under argon protection 2 SO 4 .5H 2 O (43mg, 0.17mmol) and sodium ascorbate (20mg, 0.1mmol), and the mixture was stirred at 65 ℃ for 20 hours. The reaction was poured into water, extracted with dichloromethane (30ml x 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by preparative separation in high performance liquid to give the product L-37 (14.3 mg, 9.42%) as a white solid. MS (ESI) 444.2[ deg. ] M + H ]] + 。 1 H NMR(400MHz,dmso)δ8.59(s,1H)，7.89(d,J＝8Hz,1H)。7.75(d,J＝8Hz,1H)，7.53-7.49(m,1H)，7.25(s,1H)，6.88(s,2H)，6.40(s,1H)，6.06-5.90(m,1H)，5.69(s,2H),2.89-2.75(m,1H)，2.66-2.55(m,1H)，2.54(s,3H)，1.47(s,6H)。
Example 38: preparation of 3- (4-amino-5-fluoro-6- (1- ((1- (1- (2, 2-trifluoroethyl) -1H-benzo [ d ] imidazol-7-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile (L-38)
Figure BDA0002950355860000481
Step 1: methyl 1H-benzimidazole-4-carboxylate (1.0 g, 5.68mmol) was dissolved in N, N-dimethylformamide (20 mL),1, 1-trifluoro-2-iodoethane (3.57g, 17.03mmol) and potassium carbonate (1.57g, 11.35mmol) were added sequentially with stirring at room temperature, and then the reaction was allowed to warm to 120 ℃ under argon for 4 hours. And (4) detecting the complete reaction by LC-MS, and generating a target product. The reaction mixture was poured into water, extracted with ethyl acetate (50ml. X.2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column separation and purification to give methyl 3- (2, 2-trifluoroethyl) benzimidazole-4-carboxylate (330mg, y 21.30%, P: 94.61%) as a white solid. MS (ESI) 259[ M ] +H] + 。
And 2, step: methyl 3- (2, 2-trifluoroethyl) benzimidazole-4-carboxylate (330mg, 1.28mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ℃ under argon, lithium aluminum hydride (97.01mg, 2.56mmol) was added in portions, and stirring was continued at 0 ℃ for 30 minutes. And (4) detecting the reaction is complete by LC-MS, and generating a target product. 0.5g of sodium sulfate decahydrate was added to the reaction mixture at 0 ℃ and the mixture was stirred for 1 hour while slowly raising the temperature to room temperature. Filtration and concentration of the filtrate under reduced pressure to dryness gave a colorless oil (3- (2, 2-trifluoroethyl) benzimidazol-4-yl) methanol (294mg, Y99.93%) MS (ESI) 231.1[ M + H ]] + 。
And 3, step 3: (3- (2, 2-trifluoroethyl) benzimidazol-4-yl) methanol (294 mg, 1.28mmol) was dissolved in dichloromethane (5 mL), to which was added, diphenyl azidophosphate (465.93mg, 1.92mmol), 8-diazabicycloundecene (291.67mg, 1.92mmol, 285.95. Mu.L) under argon, followed by warming to 45 ℃ and stirring overnight. And (4) detecting the reaction is complete by LC-MS, and generating a target product. The reaction mixture was directly concentrated to dryness under reduced pressure, and purified by silica gel column separation to give 7- (azidomethyl) -1- (2, 2-trifluoroethyl) benzimidazole as a colorless oily substance (140mg, 42.95% yield). MS (ESI) 255.1[ deg. ] M + H ]] + 。
And 4, step 4:7- (azidomethyl) -1- (2, 2-trifluoroethyl) benzimidazole (40mg, 156.74. Mu. Mol) and 3- (4-amino-6-ethynyl-5-fluoro-pyrimidin-2-yl) -2-methyl-benzonitrile (39.54mg, 156.74. Mu. Mol) were dissolved in a mixed solvent of t-butanol (10 mL) and water (5 mL), and copper sulfate pentahydrate (39.13mg, 156.74. Mu. Mol), sodium ascorbate (31.05mg, 156.74. Mu. Mol) were added in this order under stirring argon atmosphere at room temperature, followed by warming to 45 ℃ and stirring for 1 hour. And (5) completing LC-MS detection reaction and producing a target product. The reaction mixture was poured into water and dichloromethane (30 m)L2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and isolated and purified by HPLC to give L-38 (5.11mg, 6.42% yield, 100% purity) as a white solid. 1 H NMR(400MHz,dmso)δ8.81(s,1H),8.32(s,1H),7.90(dd,J＝7.8,1.2Hz,1H),7.82(dd,J＝7.7,1.3Hz,1H),7.70(dd,J＝8.0,0.9Hz,1H),7.52(s,2H),7.44(t,J＝7.8Hz,1H),7.24(t,J＝7.8Hz,1H),7.09(d,J＝7.0Hz,1H),6.08(s,2H),5.62(q,J＝8.9Hz,2H),2.60(s,3H)。MS(ESI)508.2[M+H] + 。
Example 39: preparation of 3- (4-amino-5-fluoro-6- (1- ((1- (2, 2-trifluoroethyl) -1H-benzo [ d ] imidazol-4-yl) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile (L-39)
Figure BDA0002950355860000482
Step 1: methyl 1H-benzimidazole-4-carboxylate (1.0 g, 5.68mmol) was dissolved in N, N-dimethylformamide (20 mL), and 1, 1-trifluoro-2-iodoethane (3.57g, 17.03mmol), potassium carbonate (1.57g, 11.35mmol) and then heated to 120 ℃ under argon atmosphere were added sequentially with stirring at room temperature for 4 hours. LC-MS detects that the raw material does not completely react and a plurality of target products are generated. The reaction mixture was poured into water, extracted with ethyl acetate (50ml. Times.2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column separation and purification to give methyl 1- (2, 2-trifluoroethyl) benzimidazole-4-carboxylate (220mg, 828.29. Mu. Mol,14.59% yield, 97.21% purity) as a white solid.
Step 2: methyl 1- (2, 2-trifluoroethyl) benzimidazole-4-carboxylate (220mg, 852.07. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ℃ under argon, lithium aluminum hydride (64.67mg, 1.70mmol) was added in portions, and then stirring was continued at 0 ℃ for 1 hour. And (4) detecting the complete reaction by LC-MS, and generating a target product. 0.5g of sodium sulfate decahydrate was added to the reaction mixture at 0 ℃ and the mixture was stirred for 1 hour while slowly raising the temperature to room temperature. Filtration and concentration of the filtrate under reduced pressure gave a colorless oil (1- (2, 2-trifluoroethyl) benzimidazol-4-yl) methanol (196mg, 851.48. Mu. Mol,99.93% yield). MS (ESI) 231.1[ deg. ] M + H ]] + 。
And step 3: (1- (2, 2-trifluoroethyl) benzimidazol-4-yl)) Methanol (196mg, 851.48. Mu. Mol) was dissolved in dichloromethane (5 mL), diphenyl phosphorazidate (310.62mg, 1.28mmol) and 8-diazabicycloundec-7-ene (194.45mg, 1.28mmol) were added sequentially under argon, and the mixture was stirred overnight at 45 ℃. And (4) detecting the complete reaction by LC-MS, and generating a target product. The reaction solution was directly concentrated to dryness under reduced pressure, and separated and purified by silica gel column to give colorless oily substance 4- (azidomethyl) -1- (2, 2-trifluoroethyl) benzimidazole (70mg, 274.30. Mu. Mol,32.21% yield) MS (ESI) 255.1[ M ] +H ]] + 。
And 4, step 4:4- (Azidomethyl) -1- (2, 2-trifluoroethyl) benzimidazole (70mg, 274.30. Mu. Mol) and 3- (4-amino-6-ethynyl-5-fluoro-pyrimidin-2-yl) -2-methylbenzonitrile (69.19mg, 274.30. Mu. Mol) were dissolved in a mixed solvent of t-butanol (10 mL) and water (5 mL), and copper sulfate pentahydrate (68.49mg, 274.30. Mu. Mol), sodium ascorbate (54.34mg, 274.30. Mu. Mol) were added successively under stirring at room temperature under argon atmosphere, and then, the temperature was raised to 45 ℃ to continue stirring for 1 hour. And (4) detecting complete reaction by LC-MS, and producing a target product. The reaction was poured into water, extracted with dichloromethane (30ml x 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by HPLC to give L-39 (64.48mg, 45.16% yield, 97.48% purity) as a white solid. 1 H NMR(400MHz,dmso)δ8.75(s,1H),8.35(s,1H),7.90(d,J＝7.6Hz,1H),7.85–7.79(m,1H),7.70(d,J＝8.2Hz,1H),7.50(s,2H),7.44(t,J＝7.6Hz,1H),7.30(t,J＝7.6Hz,1H),7.14(d,J＝7.2Hz,1H),6.03(s,2H),5.35(q,J＝9.2Hz,2H),2.60(s,3H).MS(ESI)508.2[M+H] + 。
Test example 1: inhibitory Activity against A2A receptor and A2B receptor
CHO-K1/ADORA2A/G α 15 (GenScript, M00246) and CHO-K1/ADORA2B/G α 15 (GenScript, M00329) cells were cultured in Ham's F-12 (Gibco, 31765092) medium under conditions comprising 10% FBS, 200 μ G/ml Zeocin and 100 μ G/ml Hygromycin B or 10% FBS, 400 μ G/ml G418 and 100ug/ml Hygromycin B, the specific culture conditions being specified in the corresponding manual. The screening steps are as follows:
1. cell density was adjusted to 6X10 with serum-free medium 5 One per ml.
Mu.l of cell fluid, 2.5. Mu.l of NECA (Sigma, 119140-10 MG) and 2.5. Mu.l of compound solution were added sequentially to each well of a 2.384 well plate (Greiner Bio-One, 784075) at a final NECA concentration of 10nM and 3. Mu.M initial 3-fold dilutions of compound.
3. Placing in an incubator at 37 deg.C, and standing for 30min.
4.5 μ l of cAMP-d was added sequentially 2 And 5. Mu.l cAMP-ab (Cisbio, 62AM4 PEB).
The 5.384 well plates were left for 1h at room temperature in the dark.
6. Reading plates (Victor X5, perkinElmer), XLfit nonlinear regression analysis data, and calculating IC50 of compound.
TABLE 1 Compound Pair A 2A Receptor and A 2B Inhibitory Activity of receptor
Figure BDA0002950355860000491
As can be seen from Table 1, the compounds of the examples of the present invention are represented by the formula A 2A Receptor and A 2B The receptors all have higher inhibitory activity.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (21)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
Figure FDA0003754782340000011
in the formula (I), the compound is shown in the specification,
ring B 1 Is a fused 5-to 6-membered monocyclic or fused 5-to 6-membered heteroaryl; 1-3 ring atoms of the fused 5-to 6-membered monocyclic ring are each independently optionally substituted with C (O), O, N or NR B1 Alternatively, the remaining ring atoms are carbon;
Z 0 、Z 0 ' represents a ring atom, each independently C or N;
ring B 2 Being a fused phenyl group, or ring B 2 Is a fused pyrazolyl radical and Z 0 Or Z 0 ' is N;
(R 01 ) u1 is a ring B 1 Is substituted by u 1R 01 Substituted, u1 is 0, 1,2 or 3, each R 01 Identical or different, each independently cyano, hydroxy, halogen or C 1-8 An alkyl group; wherein said C 1-8 Alkyl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano and hydroxy;
R B1 is hydrogen;
(R 02 ) u2 is absent;
ring A is phenyl;
(R 0 ) u is a hydrogen on the ring A by u R 0 Substituted, u is 0, 1,2,3,4 or 5, each R 0 Identical or different, each independently cyano, hydroxy, halogen, or C 1-8 An alkyl group; wherein said C 1-8 Alkyl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: deuterium, halogen, cyano and hydroxy;
q is 5 to 6 membered heteroaryl; wherein said 5-to 6-membered heteroaryl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen and cyano;
L 1 is CR 2 'R 3 '；L 2 Is a bond;
R 2 '、R 3 ' are each independently hydrogen;
U 1 is N or CR U1 ；U 2 Is N or CR U2 ；
R U1 Is hydrogen, cyano, hydroxy, halogen or C 1 An alkyl group;
R a 、R b each independently of the other is hydrogen, deuterium or C 1-8 An alkyl group;
R U2 is hydrogen.
2. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein the 5-to 6-membered heteroaryl in Q is selected from the following structures:
Figure FDA0003754782340000012
3. the compound of claim 1, or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the compound is according to formula (I-1),
Figure FDA0003754782340000013
wherein Ar is a structure shown in formula (I-a), formula (I-b) or formula (I-c):
Figure FDA0003754782340000021
wherein formula (I-a) is selected from the following structures:
Figure FDA0003754782340000022
formula (I-b) is selected from the following structures:
Figure FDA0003754782340000023
in the formula (I-c),
E 1 is O or CR E1a R E1b ；E 2 Is a bond or CR E2a R E2b ；E 3 Is C (O); e 4 Is NR E4c (ii) a Wherein R is E1a 、R E1b Each independently is hydrogen, halogen or C 1-3 An alkyl group; r E2a 、R E2b Each is independent of othersThe site is hydrogen; r is E4c Is hydrogen;
or, E 1 Is O or CR E1a R E1b ；E 2 Is a bond or CR E2a R E2b ；E 3 Is CR E3a R E3b ；E 4 Is O or CR E4a R E4b (ii) a Wherein R is E1a 、R E1b Each independently is hydrogen; r is E2a 、R E2b Each independently of the other is hydrogen, halogen or C 1-3 An alkyl group; r is E3a 、R 3b Each independently is hydrogen, halogen or C 1-3 An alkyl group; r E4a 、R E4b Each independently hydrogen.
4. The compound of claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein in formula (I-c), E is in formula (I-c) 1 Is O or CR E1a R E1b ；E 2 Is a bond or CR E2a R E2b ；E 3 Is C (O); e 4 Is NR E4c (ii) a Wherein R is E1a 、R E1b Each independently is hydrogen; r is E2a 、R E2b Each independently is hydrogen; r E4c Is hydrogen;
or, E 1 Is O or CR E1a R E1b ；E 2 Is a bond or CR E2a R E2b ；E 3 Is CR E3a R E3b ；E 4 Is O or CR E4a R E4b (ii) a Wherein R is E1a 、R E1b Each independently is hydrogen; r is E2a 、R E2b Each independently hydrogen or halogen; r E3a 、R 3b Each independently hydrogen or halogen; r E4a 、R E4b Each independently hydrogen.
5. The compound of claim 3, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein formula (I-c) is
Figure FDA0003754782340000031
6. The compound of claim 5, or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein formula (I-c) is selected from the following structures:
Figure FDA0003754782340000032
7. the compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, (R) 01 ) u1 Is a ring B 1 By u 1R on a ring carbon atom of (2) 01 Substituted, u1 is 0, 1 or 2, each R 01 Identical or different, each independently of the others, is hydroxy, halogen or C 1-3 An alkyl group; wherein said C 1-3 Alkyl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of: deuterium or halogen.
8. The compound of claim 7, or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein each R 01 Identical or different, each independently is hydroxy, halogen or C 1-3 An alkyl group.
9. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, (R) 0 ) u Is a hydrogen on the ring A by u R 0 Substituted, u is 2, each R 0 Different from each independently cyano, hydroxy, halogen or C 1-3 An alkyl group.
10. The compound of claim 9, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein two R are 0 Is cyano and C 1-3 An alkyl group.
11. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, having the structure of formula (II) or formula (III) formula (IV):
Figure FDA0003754782340000033
wherein R is U1 Is hydrogen, halogen or C 1-3 An alkyl group; r is a 、R b Each independently is hydrogen or C 1-3 An alkyl group;
U 0 is N;
R 1 、R 2 、R 3 、R 4 、R 5 each independently hydrogen, cyano, or C 1-3 An alkyl group;
R 6 、R 7 each independently hydrogen.
12. The compound, or a pharmaceutically acceptable salt, or a stereoisomer thereof, of claim 11, wherein R is R 1 Is C 1-3 Alkyl radical, R 2 Is cyano, R 3 、R 4 、R 5 Each independently hydrogen.
13. The compound of claim 12, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R is U1 Is hydrogen, halogen or C 1-3 An alkyl group; r is a 、R b Each independently hydrogen.
14. The compound of claim 13, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R is U1 Is hydrogen, halogen or C 1 An alkyl group.
15. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is any one of the following compounds:
Figure FDA0003754782340000041
Figure FDA0003754782340000051
16. a pharmaceutical composition, comprising:
a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and
a pharmaceutically acceptable carrier.
17. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutical composition according to claim 16 for the preparation of a medicament for the treatment of a disease caused by adenosine a 2A Receptor and/or adenosine A 2B Use in the manufacture of a medicament for the treatment of a receptor mediated disease.
18. The use according to claim 17, wherein said composition consists of adenosine a 2A Receptor and/or adenosine A 2B The receptor-mediated disease is cancer or an immune-related disease.
19. The use of claim 18, wherein the cancer is selected from the group consisting of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, melanoma, basal cancer, mesothelial lining cancer, white blood cell cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer, non-small cell lung cancer, adrenal cancer, thyroid cancer, renal or bone cancer, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma, choriocarcinoma, and basal cell carcinoma of the skin.
20. The use according to claim 18, wherein the cancer is selected from testicular seminoma.
21. The use according to claim 18, wherein the immune-related disease is selected from rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, parkinson's disease, infections, crohn's disease, ulcerative colitis, allergic contact dermatitis, and other eczemas, systemic sclerosis, or multiple sclerosis.
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