CN111793077B

CN111793077B - PD-1/PD-L1 small molecule inhibitor and application thereof in medicines

Info

Publication number: CN111793077B
Application number: CN202010236423.9A
Authority: CN
Inventors: 刘兵; 张英俊; 杨悌平; 喻性龙; 孙丹丹
Original assignee: Dongguan Dongyangguang New Drug R & D Co ltd; Sunshine Lake Pharma Co Ltd
Current assignee: Dongguan Dongyangguang New Drug R & D Co ltd; Guangdong HEC Pharmaceutical
Priority date: 2019-04-01
Filing date: 2020-03-30
Publication date: 2023-08-04
Anticipated expiration: 2040-03-30
Also published as: CN111793077A

Abstract

The invention belongs to the field of medicines, and relates to a PD-1/PD-L1 small molecule inhibitor and application thereof in medicines. In particular, the invention provides PD-1/PD-L1 small molecule inhibitors whichIs a compound shown as a formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug of the compound shown as the formula (I); the invention also provides a preparation method of the compound shown in the formula (I), a pharmaceutical composition containing the compound shown in the formula (I) and application of the compound and the pharmaceutical composition in preparation of medicines for preventing or treating diseases related to PD-1/PD-L1 signal paths.

Description

PD-1/PD-L1 small molecule inhibitor and application thereof in medicines

Technical Field

The invention belongs to the field of medicines, and discloses a compound serving as a PD-1/PD-L1 small molecule inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof.

Background

The immune system plays an increasingly important role in controlling or eradicating a number of refractory diseases, such as the treatment of cancer. However, cancer cells often escape or inhibit the immune system during proliferation, and immunotherapy can provide a sustained therapeutic effect compared to other types of tumor therapies, and has gradually shifted from an initial nonspecific immunotherapy to a specific immune-targeted therapy. One mechanism is to alter the expression of co-stimulatory and co-inhibitory molecules on immune cells (Poston et al, J.clinical Oncology 2015,1-9), and blocking signaling pathways of inhibitory immune checkpoints (e.g., PD-1) has proven to be a promising and effective therapeutic modality.

The programmed cell death receptor-1 (programmed death receptor-1, PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells and macrophages (Greenwald et, annu. Rev. Immunol 2005,23:515-548;Okazaki and Honjo,Trends Immunol 2006, (4): 195-201). It is a type I transmembrane protein composed of 268 amino acids, belonging to CD ₂₈ Family members. PD-1 is composed of three parts in structure, an extracellular immunoglobulin variable domain, a hydrophobic transmembrane region, and an intracellular domain (Parry et al, molCell Biol 2005, 9543-9553), which includes two phosphorylation sites located in the immunoreceptor tyrosine repression motif (ITIM) and immunoreceptor tyrosine transformation motif (ITSM), suggesting that PD-1 negatively regulates T-cell receptor-mediated signaling. As an intrinsic negative feedback system, PD-1 prevents activation of T cells, thereby reducing autoimmunity and promoting self-tolerance. In addition, PD-1 is also believed to play a key role in inhibiting antigen-specific T cell responses in diseases such as cancer and viral infections (Sharpe et al, nat Immunol 2007 8,239-245;Postowet al,J.Clinical Oncol 2015,1-9).

PD-1 has two ligands, PD-L1 and PD-L2, which differ in expression pattern (Parry et al, mol Cell Biol 2005,9543-9553;Latchman et al,Nat Immunol 2001,2,261-268). PD-L1 protein is up-regulated in macrophages and dendritic cells under the action of lipopolysaccharide and GM-CSF, and in T cells and B cells under the action of T cell receptor and B cell receptor signaling. PD-L1 is highly expressed on almost all tumor cells and expression is further increased after IFN-y treatment (Iwai et al, PNAS2002,99 (19): 12293-7;Blank et al,Cancer Res 2004,64 (3): 1140-5). In fact, the expression of PD-L1 in tumors has been shown to be predictive in a variety of tumor types (Wang et al, eur J Surg Oncol 2015;Huang et al,Oncol Rep 2015;Sabatier et al,Oncotarget 2015,6 (7): 5449-5464). In contrast, PD-L2 expression is more restricted, mainly by dendritic cells (Nakae et al, J Immunol 2006, 177:566-73). The linkage of PD-1 to its ligands PD-L1 and PD-L2 produces a signal on T cells that inhibits the production of IL-2 and IFN-y, while activation of the T cell receptor induces cell proliferation (Carter et al, eur J Immunol2002,32 (3): 634-43;Freeman et al,J Exp Med 2000,192 (7): 1027-34). The mechanism involves the use of SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling, such as Syk and Lck phosphorylation (Sharpe et al, nat Immunol 2007,8,239-245).

Some evidence from preclinical animal studies suggests that PD-1 and its ligands negatively regulate immune responses, PD-1 deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura et al, immunity 1999,11:141-151;Nishimura et al,Science 2001,291:319-322). Using the LCMV model of chronic infection, PD-1/PD-L1 interactions have been shown to inhibit activation and expansion of the effector region of virus-specific CD 8T cells (Barber et al, nature 2006,439,682-7). Together, these data support the development of a therapeutic approach to block PD-1-mediated inhibition signals to enhance or "rescue" T cell responses, and thus new compounds are needed to block PD-1/PD-L1 protein/protein interactions.

Monoclonal antibodies targeting PD-1/PD-L1 were first introduced in 2014, pembrolizumab from Merck (Merck) and Nivolumab from Bristol-Myers Squibb (Bristol-myquirb) were first marketed in the united states in 2014, 9, for the treatment of stage iv melanoma, followed by development of multiple indications. Atezolizumab developed by the Rogowski gene Talcet (Genntech) was approved by the FDA in the United states for the treatment of metastatic bladder cancer, and was obtained as a batch for the treatment of lung cancer at 10 months in the year 2016. Avelumab of Merck Serono SA and Pfizer Inc was marketed in the earliest 3 months 2017 for the treatment of Merck cell carcinoma. In 2018, 9, FDA approved Cemiplimab developed by the company Sainofil and Remoto pharmaceutical for the treatment of metastatic cutaneous squamous cell carcinoma. Durvalumab developed by the Sell Gene (Celgene Corp) and the Alston child (MedImmune LLC) was marketed in the earliest 5 th 2017 for the treatment of metastatic bladder cancer and metastatic non-small cell lung cancer. The latest market is the sintillimab developed by innovative biologicals (Innovent Biologics Inc) in cooperation with the company of gill, lilly & Co, toripalimab, the company of the bio-pharmaceutical sciences, jun-mari, 2019, was first marketed in china 2.

The development of molecular immune checkpoint blockers is relatively cool compared to the well-established market for antibody pharmaceuticals. The small molecule inhibitors reported to enter clinical stage are oral PD-L1 inhibitors (INCB-086550) of Saint Corp (Incyte Corp) approved to enter clinical stage I in 2018, 12, for the treatment of advanced solid tumors. Lazertinib from Yuhan Corp is currently in stage II of the research clinic for metastatic non-small cell lung cancer. Small molecule inhibitors (CA-170) developed cooperatively by Curis/Aurigene entered clinical phase II at 3 months 2018.

Compared with antibody medicines, the small molecular inhibitor has controllable pharmacokinetic behavior and relatively low cost, and well compensates for clinical defects of macromolecular medicines. Therefore, the design and synthesis of the small molecule inhibitor with blocking effect aiming at PD-1/PD-L1 has practical significance.

Summary of The Invention

The technical problem to be solved by the invention is to provide a small molecule inhibitor for inhibiting PD-1/PD-L1 interaction, which is a compound shown as a formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug of the compound shown as the formula (I), and a preparation method, a pharmaceutical composition and application of the compound in preparation of a medicament for preventing or treating diseases related to PD-1/PD-L1 signaling pathway.

Wherein,,

X ¹ selected from O, S, NH or CH ₂ ；

X ² Selected from CH or N;

R ¹ and R is ² Each independently selected from the group consisting of-H, -D, -F, -Cl, -Br, -I, -OH, -CN, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl can be independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^a ；

Or R is ¹ And R is ² Together with the carbon atoms to which they are attached form a 4-12 membered ring B which may optionally contain 1 or 2 heteroatoms selected from N, O or S, which may optionally be substituted with 1, 2, 3 or 4 substituents selected from R ^b ；

A is

R ⁴ And R is ⁵ Each independently selected from-H, -F, -Cl, -Br, -CN, methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, n-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy;

p and q are each independently 0, 1, 2, 3 or 4;

R ³ is that

R ⁶ And R is ⁷ Each independently selected from the group consisting of-H, -D, -F, -Cl-Br, -I, oxo, -OH, -CN, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl may be independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、C _1-6 An alkyl group;

or R is ⁶ And R is ⁷ Together with the nitrogen atom to which they are attached form a 5-12 membered heterocyclic C which may be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^c ；

m is 1, 2, 3 or 4;

R ^a each independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl can be independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^d ；

R ^b Each independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl can be independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^e ；

R ^c Each independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、-CONH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl can be independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^f ；

R ^d Each independently selected from the group consisting of-D, -OH, -CN, oxo, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _1-6 An alkoxy group;

R ^e each independently selected from the group consisting of-D, -OH, -CN, oxo, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _1-6 Alkoxy, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino and C _1-6 Alkoxy groups may independently be optionally substituted with 1, 2 or 3 substituents selected from-OH, -CN or-NH ₂ ；

R ^f Each independently selected from the group consisting of-D, -OH, -CN, oxo, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _1-6 An alkoxy group.

In some embodiments, ring B of the present invention is one of the groups formed by the following structural formulas:

wherein Z is ₁ And Z ₂ Each independently is CH ₂ NH, S or O; the ring B may be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^b 。

In other embodiments, R as described herein ^b Each independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy, ethoxy, or acetyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, methoxy, and ethoxy groups may be independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of R ^e The method comprises the steps of carrying out a first treatment on the surface of the The R is ^e Each independently selected from-D, -OH, -CN, -NH ₂ Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy and ethoxy groups may independently be optionally substituted with 1, 2 or 3 substituents selected from-OH, -CN or-NH ₂ 。

In other embodiments, R as described herein ^b Each independently is one of the groups formed by the following structural formulae:

in some embodiments, the heterocycle C of the present invention is one of the groups formed by the following structural formula:

wherein W is ₁ And W is ₂ Each independently is CH ₂ NH, S or O; the heterocyclic ring C may be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^c 。

In other embodiments, the heterocycle C of the present invention is one of the groups formed by the following structural formula:

wherein the heterocycle C may be optionally substituted with 1, 2, 3 or 4 substituents each independently selected from R ^c 。

In other embodiments, R as described herein ^c Each independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、-CONH ₂ Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy, ethoxy or acetyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy, ethoxy and acetyl groups may independently optionally be substituted with 1, 2, 3 or 4 substituents selected from R ^f The method comprises the steps of carrying out a first treatment on the surface of the The R is ^f Each independently selected from-OH, -CN, -NH ₂ Or methyl.

In some embodiments, the R of the present invention ⁶ And R is ⁷ Each independently selected from-H, -D, methyl, ethyl or acetyl.

In some embodiments, the R of the present invention ¹ And R is ² Each independently selected from the group consisting of-H, -D, methyl, ethyl, n-propyl, isopropylN-butyl, tert-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy and ethoxy groups may independently be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^a 。

In other embodiments, R as described herein ^a Each independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy, ethoxy, acetyl, N-methylamino, N-ethylamino, N, N-diethylamino, N-methyl-N-ethylamino, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl or dioxanyl, wherein the methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, isobutyl, methoxy, ethoxy, acetyl, N-methylamino, N-ethylamino, N-diethylamino, N-methyl-N-ethylamino, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl and dioxanyl groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^d The method comprises the steps of carrying out a first treatment on the surface of the The R is ^d Each independently selected from-D, -OH, -CN, -NH ₂ Methyl, ethyl or methoxy.

In other embodiments, R as described herein ^a Each independently is one of the groups formed by the following structural formulae:

in some embodiments, the invention provides a small molecule inhibitor having an effect of inhibiting PD-1/PD-L1 interactions, which is a compound of formula (II), or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof.

In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (II) of the present invention, or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, and pharmaceutically acceptable adjuvant or combination thereof.

In one aspect, the invention relates to the use of a compound of formula (I) or (II) or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment, prevention, amelioration, control or alleviation of a disease associated with the PD-1/PD-L1 signaling pathway in a patient.

In some embodiments, the disease associated with the PD-1/PD-L1 signaling pathway described herein is cancer, an infectious disease, or an autoimmune disease.

In other embodiments, the cancers of the present invention include bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, gastric cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, hodgkin's disease, non-hodgkin's lymphoma, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary tract cancer, penile cancer, chronic or acute leukemia, childhood solid tumors, lymphomas, bladder cancer, renal or ureteral cancer, renal pelvis cancer, central nervous system tumors, primary CNS lymphomas, tumor angiogenesis, spinal tumors, brain stem glioma, pituitary adenomas, kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, or environmentally induced cancers, and combinations thereof.

In other embodiments, the infectious disease described herein includes aids, hepatitis a, hepatitis b, hepatitis c, hepatitis d, a spore eruptive virus infection, papilloma virus infection, or influenza virus infection.

In other embodiments, the autoimmune diseases described herein include chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, syndrome of lung hemorrhagic nephritis, primary biliary cirrhosis, multiple cerebral spinal sclerosis, acute idiopathic polyneuritis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia

In another aspect, the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a patient comprising administering to a subject a therapeutically effective amount of a compound of the invention, thereby modulating the immune response in the patient.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds comprised by formula (I) or (II).

The foregoing merely outlines certain aspects of the invention and is not limited in this regard. Other aspects are described more fully below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

"stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.

"diastereomers" are stereoisomers of one or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994.

Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. One particular stereoisomer is an enantiomer, and a mixture of such isomers is referred to as an enantiomeric mixture. A50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.

Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racemates and Resolutions (Wiley Interscience, new York, 1981); principles ofAsymmetric Synthesis (2) ^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valance tautomers) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The terms "optional," "optionally," or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, i.e., that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted with 1, 2, 3, or 4 …" includes the case where the group is substituted with 1, or 2, or 3, or 4 substituents, as well as the case where the group is not substituted with the substituents. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same; or "optionally salified with a suitable acid" includes that the compound salifies with a suitable acid or does not salify with any acid, and may optionally salify in a ratio of 1:1, or 1:1.5, or 1:2, or 1:3, or 2:1, or 3:1.

As described in the present invention, the present inventionThe compounds of formula (I) may independently optionally be substituted with one or more substituents such as those of the general formula (I) above, or as exemplified in the examples, subclasses, and class of compounds encompassed by the invention. It will be appreciated that the terms "optionally substituted", "optionally substituted by … …" or "optionally containing" may be used interchangeably with the terms "substituted or unsubstituted". The term "independently optionally" is used interchangeably with the term "optionally independently" and generally, the term "independently optionally" whether or not prior to the term "substituted" means that one or more hydrogen atoms in a given structure may be substituted or unsubstituted with the particular substituent 1. An optional substituent group may be substituted by a substituent 1 at each substitutable rational position of the group, unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents 1 selected from a particular group, then the substituents may be the same or different at each reasonable position in the formula. Wherein the substituent 1 may be, but is not limited to: hydrogen, deuterium, oxo, fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl-S (=o) _t -haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde, aminoacyl, alkoxy, alkylamino, alkylthio, alkanoyl, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (c=o) -, benzyl, cycloalkyl, alkylamino-C (=o) -, CN-alkyl-C (=o) -, alkyl-O-C (=o) -alkyl, ester, hydroxyalkylacyl, alkoxyalkyl, or the like. Substituent 1 can further independently optionally be monosubstituted with substituent 2 or polysubstituted with multiple substituents 2, which may be the same or different, where appropriate. Wherein the substituent 2 may be, but is not limited to: hydrogen, oxo, fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl-S (=o) _t -, haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde, aminoacyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyAlkoxy, alkyl- (c=o) -, benzyl, alkylamino-C (=o) -, CN-alkyl-C (=o) -, alkyl-O-C (=o) -alkyl, ester, hydroxyalkylacyl, alkoxyalkyl, or the like. Wherein t is 0,1, or 2.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl and C ₆ An alkyl group.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon radicals of 1 to 20 carbon atoms, wherein the alkyl radicals may independently be optionally substituted by one or more substituents as described herein. Some of these are alkyl groups containing 1 to 10 carbon atoms; still other embodiments are alkyl groups containing 1 to 8 carbon atoms; still other embodiments are alkyl groups containing 1 to 6 carbon atoms, and still other embodiments are alkyl groups containing 1 to 4 carbon atoms; still other embodiments are alkyl groups containing 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH) ₃ ) Ethyl (Et, -CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl (i-Pr, -CH (CH) ₃ ) ₂ ) N-butyl (n-Bu, -CH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methylpropyl or isobutyl (i-Bu, -CH) ₂ CH(CH ₃ ) ₂ ) 1-methylpropyl or sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) Tert-butyl (t-Bu, -C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyl (-CH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butyl (-C (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) N-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ) 3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2, 3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3, 3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ ) N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" are used herein to encompass both straight and branched saturated carbon chains.

The term "haloalkyl" refers to the case where an alkyl group may be substituted with one or more halogen atoms, which may be the same or different. Wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, 2-difluoroethyl, 3-trifluoropropyl and the like. Haloalkyl groups may be substituted with substituents described herein.

Terminology"amino" means having the formula-NH ₂ Is a group of (2).

The term "carboxy", whether used alone or in combination with other terms, means-CO ₂ H is formed; the term "carbonyl", whether used alone or in combination with other terms, means- (c=o) -.

The term "amide" refers to a group having the formula R 'R "N-C (=o) -wherein R' and R" are each independently hydrogen, alkyl or haloalkyl.

The term "alkylamino" or "alkylamino" means that the hydrogens on the amino group are replaced with one or two alkyl groups, respectively, including "N-alkylamino" and "N, N-dialkylamino"; the alkyl groups have the meaning described in the present invention. Some of these are, for example, alkylamino groups of one or two C _1-6 Alkyl groups are attached to the nitrogen atom to form lower alkylamino groups. Other embodiments are where the alkylamino group is one or two C _1-4 Is linked to an alkylamino group formed on the nitrogen atom. Suitable alkylamino groups may be mono-or dialkylamino, such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, N-methyl-N-ethylamino, and the like.

The term "alkoxy" means an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) ₃ ) Ethoxy (EtO, -OCH) ₂ CH ₃ ) 1-propoxy (n-PrO, n-propoxy, -OCH) ₂ CH ₂ CH ₃ ) And so on.

The terms "alkanoyl", "alkanoyl" denote an alkyl group attached to the remainder of the molecule through a carbonyl (-C (=O) -) groupThe alkyl groups have the meaning as described in the present invention. The alkanoyl group may be optionally substituted with one or more substituents described herein. Examples of alkanoyl groups include, but are not limited to, acetyl (-C (=o) CH ₃ ) Propionyl (-C (=O) CH ₂ CH ₃ ) Butyryl (-C (=O) CH ₂ CH ₂ CH ₃ ) Etc.

The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring carbon atoms, wherein the bicyclic, tricyclic or tetracyclic ring system is ring-formed in a fused or bridged or spiro manner. In some embodiments, cycloalkyl groups contain 3 to 10 ring carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 8 ring carbon atoms; in still other embodiments, cycloalkyl groups contain 3 to 6 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group may be optionally substituted with one or more substituents described herein.

The term "aryl" may be a monocyclic, bicyclic, and tricyclic carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system contains 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl. Aryl groups may be substituted with substituents described herein. The term "C _6-10 Aryl "means an aryl group having 6 to 10 carbon atoms and having the meaning as defined above.

The terms "heteroaryl", "heteroaryl ring" are used interchangeably herein to refer to a monocyclic, bicyclic, tricyclic or polycyclic ring system in which the bicyclic, tricyclic or tetracyclic heteroaromatic ring system is cyclic in a fused form. Wherein the heteroaromatic ring system as a whole is aromatic, one or more atoms of the ring being independently optionally replaced by heteroatoms (heteroatoms selected from N, O, P, S, where S or P are independently optionally replaced by one or more oxygen atoms to give a compound such as SO, SO ₂ 、PO、PO ₂ Is a group of (2). The heteroaromatic ring system may be substituted at any heteroatom or carbon atomThe daughter is attached to the main structure to form a stable compound. The heteroaryl system group may be a single ring of 3 to 7 atoms, or a double ring of 7 to 10 atoms, or a triple ring of 10 to 15 atoms. The bicyclo ring having 7-10 atoms may be bicyclo [4,5 ] ]，[5,5]，[5,6]Or [6,6 ]]The system, the tricyclic ring having 10 to 15 atoms may be tricyclo [5, 6 ]]、[5,7,6]Or [6,5,6 ]]A system. The term "5-12 membered heteroaryl" refers to a heteroaryl group having 5 to 12 atoms, at least one of which is a heteroatom selected from N, O, S or P, the heteroaryl group having the definition as above.

Still other embodiments are where the heteroaryl system (including heteroaryl groups, heteroaryl rings) includes the following examples, but is not limited to these examples: furan-2-yl, furan-3-yl, imidazolyl (e.g., N-imidazolyl, imidazol-2-yl), isoxazolyl (e.g., isoxazol-3-yl), oxazolyl (e.g., oxazol-2-yl), 4-methylisoxazol-5-yl, pyrrolyl (e.g., N-pyrrolyl, pyrrol-2-yl), pyridinyl (e.g., pyridin-2-yl), pyrimidinyl (e.g., pyrimidin-2-yl), pyridazinyl (e.g., pyridazin-3-yl), thiazolyl (e.g., thiazol-2-yl), tetrazolyl (e.g., tetrazol-5-yl), triazolyl (e.g., triazol-2-yl and triazol-5-yl), thiophen-2-yl, thiophen-3-yl, pyrazolyl (e.g., pyrazol-2-yl), isothiazolyl, 1,2,3 oxadiazolyl, 1,2, 3-thiodiazolyl, 1,3, 4-thiadiazolyl, 1,3, 4-thiadiazol-2-yl, imidazo [1,5-a ]]Pyridin-6-yl, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1, 8-naphthyridinyl, benzothienyl, benzothiazolyl, indolyl (e.g., indol-2-yl), quinolinyl (e.g., quinolin-2-yl), isoquinolinyl (e.g., isoquinolin-1-yl), benzopyrazolyl, benzimidazolyl, benzindolyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazole, benzothiopyranyl, benzoxazolyl, benzothiazolyl, β -carbolinyl, carbazolyl, phthalazinyl, dibenzofuranyl, imidazopyridinyl, imidazothiazolyl, indazolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, naphthyridinyloxy oxazolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridinyl, quinazolinyl, quinoxalinyl, thiophenyl, triazinyl, 2H-pyrrolo [3,4-c ] ]Pyridyl groupImidazo [2',1':2,3]Thiazolo [5,4-b]Pyridyl, pyrazolo [2',1':2,3]Thiazolo [4,5-b]Pyrazinyl, 1H-benzo [4,5 ]]Thieno [2,3-d ]]Imidazolyl, imidazo [2',1':2,3]Thiazolo [4,5-c]Pyridinyl, 1H-benzo [ f ]]Imidazo [4,5-b][1,4]ThiazasA base, etc. Heteroaryl groups may be substituted with substituents described herein.

The terms "heterocyclyl", "heterocycle", "heteroalicyclic", "heterocyclic" or "heterocycloalkyl" are used interchangeably herein to refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the bicyclic, tricyclic or tetracyclic ring system is ring-formed in fused or bridged or spiro-connected form, and wherein one or more carbon atoms in the ring are independently optionally replaced by a heteroatom selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S) and phosphorus (P). And the-CH 2-group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. The phosphorus atom of the ring may optionally be oxidized to a P-oxygen compound. The ring may be fully saturated or contain one or more unsaturations, but the heterocyclic ring system as a whole is not aromatic. For example, in some embodiments, a bicyclic heterocyclic group in which one ring has aromaticity and the other ring as a whole does not have aromaticity. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. The hydrogen atoms on one or more rings are independently optionally substituted with one or more substituents described herein. Some of these embodiments are "heterocyclyl", "heterocycle", "heteroalicyclic", "heterocyclic" or "heterocycloalkyl" groups which are 3-6 membered monocyclic rings (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, when the ring is a three-membered ring, only one of which is a heteroatom), or bicyclic rings consisting of 5-12 atoms (4-11 carbon atoms and 1-3 heteroatoms selected from N, O, P, S). The term "5-12 membered heterocycloalkyl" means that the number of atoms in the ring system in the heterocycloalkyl is 5 to 12, wherein heterocyclyl has the meaning as defined above.

"heterocyclyl" may be a carbon or heteroatom group. "heterocyclyl" also includes groups formed by the merging of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl (e.g., N-piperidinyl), thialkyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepinyl, thietanyl, morpholinyl (e.g., N-morpholinyl), thiomorpholinyl, piperazinyl (e.g., N-piperazinyl), homopiperazinyl, 1,2,3, 6-tetrahydropyridin-1-yl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, 2-indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxanyl, pyrazolinyl, dithianyl, dihydrothienyl, imidazolidinyl, 1,2, 6-thiadiazinon-1, 1-dioxo-2-yl, quinolizinyl, isoindolinyl, 1,2,3, 4-tetrahydroquinolinyl, dibenzofuranyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dioxolanyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1, 4-dithianyl, furanonyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolinyl, indolizinyl, isobenzothienyl, isobenzodihydropyranyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, decahydroindolyl, oxadiazolyl, oxazolidinyl, oxiranyl, 4-piperidonyl, pyrrolyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, 1,3, 5-trithianyl, 2-oxopyrrolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl 2-oxa-5-azabicyclo [2.2.1] hept-5-yl.

In heterocyclic groups-CH ₂ Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, pyrimidinedionyl, and the like. Examples of sulfur atoms in heterocyclyl groups that are oxidized include, but are not limited to, sulfolane, thiomorpholino 1, 1-dioxide, and the likeEtc.

The terms "n ring atoms" or "n-membered" are used interchangeably herein, where n is an integer, typically describing the number of ring forming atoms in a molecule in which the number of ring forming atoms is n. For example, a 5-12 membered heteroaryl represents a heteroaryl consisting of 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms. For another example, a piperidinyl group is a 6-ring-atom-composed heterocyclyl group or a 6-membered heterocyclyl group, and a pyridinyl group is a 6-ring-atom-composed heteroaryl group or a 6-membered heteroaryl group.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state forms of P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

As described herein, a ring system in which substituents are attached to a ring by a bond represents that any substitutable position on the ring may be substituted. For example, formula (a) represents that R substituents R may be substituted at any position on the pyridine ring that may be substituted, and when R is greater than 1, each R may be independently selected from the same or different substituents.

As described herein, a ring system (shown in formula b) in which a linker is attached to a ring represents that the linker may be attached to the remainder of the molecule at any available position on the ring system. Formula b represents that the 1-8 positions on the octahydrocyclopentopyrrole ring can be connected with the rest of the molecule.

As described herein, two points of attachment on ring Ar in formula c may be attached to the remainder of the molecule, e.g., as shown in formula c, unless explicitly indicated otherwise, either the E-terminus or the E' -terminus of formula c may be attached to the remainder of the molecule, i.e., the manner of attachment of the two ends may be interchanged.

In addition, unless explicitly indicated otherwise, the descriptions used throughout this document are interchangeable, "independently," "independently of each other," "independently selected from," "independently of each other," and should be understood broadly to mean that the particular choices expressed between the same symbols in different groups do not affect each other, or that the particular choices expressed between the same symbols in the same groups do not affect each other. For example, in formula f R1 "R" represent the same or different groups and do not affect each other; "r1" and "r2" represent the same or different values and do not affect each other.

The term "pharmaceutically acceptable" refers to those compositions which are physiologically tolerable and do not generally produce allergic or similar untoward reactions, such as gastrointestinal distress, dizziness, and the like, when administered to a human. Preferably, the term "pharmaceutically acceptable" as used herein refers to use in animals, particularly in humans, approved by the federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia.

The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences" of e.w. martin.

The term "hydrate" as used herein refers to a compound or salt thereof as provided herein, and includes water bound by non-covalent intermolecular forces in a stoichiometric or non-stoichiometric amount, and may be said to be an association of water with solvent molecules.

"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, meOH, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol.

The term "ester" as used herein refers to a compound of formula (I) -formula (II) containing a hydroxy group which forms an in vivo hydrolysable ester. Such esters are pharmaceutically acceptable esters which are hydrolyzed, for example, in the human or animal body to give the parent alcohol. The group of the in vivo hydrolysable ester of the compound of formula (I) -formula (II) containing a hydroxy group includes, but is not limited to, a phosphate group, an acetoxymethoxy group, a 2, 2-dimethylpropionyloxymethoxy group, an alkanoyl group, a benzoyl group, a benzoylacetyl group, an alkoxycarbonyl group, a dialkylcarbamoyl group, an N- (dialkylaminoethyl) -N-alkylcarbamoyl group, and the like.

"nitroxide" in the present invention means that when a compound contains several amine functions, 1 or more than 1 nitrogen atom can be oxidized to form a nitroxide. Specific examples of nitrogen oxides are nitrogen oxides of tertiary amines or nitrogen oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form a nitroxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, nitroxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514), wherein an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as DCM.

The compounds may exist in a variety of different geometric isomers and tautomers, and the compounds of formula (I) or formula (II) include all such forms. For the avoidance of doubt, when a compound exists as one of several geometric isomers or tautomers and only one is specifically described or shown, it is apparent that all other forms are included in formula (I) or formula (II).

The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I) -formula (II). Such transformation is hydrolyzed in blood by the prodrug or enzymatically converted in blood or tissue to the parent nodeInfluence of the structure. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi and V.stilla, pro-drugs as Novel Delivery Systems, vol.14 of the A.C.S. symposium Series, edward B.Roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51, 2328-2345.

All tautomeric forms of the compounds of the invention are included within the scope of the invention unless otherwise indicated.

In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms. The present invention includes isotopically-labeled compounds, which are identical to those recited in formula (I) -formula (II), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively, for example ² H、 ³ H、 ¹³ C、 ¹¹ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. The compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs thereof, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Some of the followingIsotopically-labelled compounds of the invention, e.g. by introducing a radioisotope (e.g. ³ H and ¹⁴ c) Those useful in drug and/or substrate tissue distribution assays. Isotopically-labeled compounds of formula (I) -formula (II) of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or examples and preparations below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.

"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

Various pharmaceutically acceptable salt forms of the compounds of the present invention are useful. The term "pharmaceutically acceptable salts" refers to those salt forms that are readily apparent to the pharmaceutical chemist, i.e., they are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, or excretion. Other factors, which are more practical in nature, are also important for selection: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity, and flowability of the resulting drug substance.

As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: S.M. Berge et al describe pharmaceutically acceptable salts in detail in J.pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, nitrate, and the like, and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, benzoate, mandelate, methanesulfonate, ethanesulfonate, toluenesulfonate, sulfosalicylate, and the like, or by other methods described in the literature such as ion exchange.

Other pharmaceutically acceptable salts include adipic acid salts, malic acid salts, 2-hydroxypropionic acid, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoates, bisulfate salts, borates, butyric acid salts, camphoric acid salts, camphorsulfonic acid salts, cyclopentylpropionates, digluconate salts, dodecylsulfate salts, ethanesulfonate salts, formate salts, fumaric acid salts, glucoheptonate salts, glycerophosphate, gluconate salts, hemisulfate salts, heptanoate salts, caproate salts, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionic acid salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, palmitate salts, pamoate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, picrate salts, pivalate salts, stearate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl group ₄ Is a salt of (a).

The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C _1-8 Sulfonate and aromatic sulfonate. Amine salts, such as, but not limited to, N-dibenzylethylenediamine, chlorprocaineThus, choline, ammonia, diethanolamine and other hydroxyalkyl amines, ethylenediamine, N-methyl reduced glucamine, procaine, N-benzyl phenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1' -ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkaline earth metal salts such as, but not limited to, barium, calcium, and magnesium; transition metal salts such as, but not limited to, zinc.

The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with another functional group. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature: t W.Greene, protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

"room temperature" in the context of the present invention means a temperature of from 10℃to 40 ℃. In some embodiments, "room temperature" refers to a temperature from 20 ℃ to 30 ℃; in other embodiments, "room temperature" refers to 25 ℃.

In this specification, a structure is dominant if there is any difference between a chemical name and a chemical structure.

Abbreviations for any protecting groups, amino acids and other compounds used in the present invention are, unless otherwise indicated, based on their commonly used, accepted abbreviations or with reference to IUPAC-IUB Commission on Biochemical Nomenclature (see biochem.1972, 11:942-944).

Description of the Compounds of the invention

The invention provides a compound or a pharmaceutical composition thereof, which can be used as an inhibitor of PD-1/PD-L1. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or disorders by inhibiting PD-1/PD-L1 activity with said compounds. The invention further describes a method for synthesizing the compounds. The compounds of the present invention exhibit good biological activity.

In one aspect, the invention provides a compound of a PD-1/PD-L1 small molecule inhibitor, which is a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug of the structure shown as a formula (I) or the structure shown as the formula (I),

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therein, A, X ¹ 、X ² 、R ¹ And R is ² Having the meaning described in the present invention.

In some embodiments, X as described in the present invention ¹ Selected from O, S, NH or CH ₂ ，X ² Selected from CH or N.

In some embodiments, formula I of the present invention isTherein, A, R ¹ And R is ² Having the meaning described in the present invention.

In some embodiments, R as described in the present invention ¹ And R is ² Each independently selected from the group consisting of-H, -D, -F, -Cl, -Br, -I, -OH, -CN, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl can be independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^a The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^a Having the meaning described in the present invention.

In some embodiments, each R as described herein ^a Independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl can be independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^d The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^d Having the meaning described in the present invention.

In some embodiments, each R as described herein ^d Independently selected from the group consisting of-D, -OH, -CN, oxo, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _1-6 An alkoxy group.

In some embodiments, R as described in the present invention ¹ And R is ² Each independently is preferably selected from the group consisting of-H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, methoxy and ethoxy groups May independently be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^a The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^a Having the meaning described in the present invention.

In some embodiments, each R as described herein ^a Independently preferably from-D, -F, -Cl, -Br, -I, oxo, methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy, ethoxy, acetyl, N-methylamino, N-ethylamino, N-diethylamino, N-methyl-N-ethylamino, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl or dioxanyl, wherein the methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, isobutyl, methoxy, ethoxy, acetyl, N-methylamino, N-ethylamino, N-diethylamino, N-methyl-N-ethylamino, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl and dioxanyl groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^d The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^d Having the meaning described in the present invention.

In some embodiments, R as described in the present invention ^d Each independently is preferably selected from the group consisting of-D, -OH, -CN, -NH ₂ Methyl, ethyl or methoxy.

In some embodiments, each R as described herein ^a Independently one of the groups formed from the following formulae is preferred:

in some embodiments, R as described in the present invention ¹ 、R ² Together with the carbon atoms to which they are attached form a 5-12 membered ring B, which may optionally contain 1 or 2 heteroatoms selected from N, O or S, which may optionally be substituted with 1, 2, 3 or 4 substituents selected from R ^b 。

In some embodiments, each R as described herein ^b Selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH、-CN、-NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl can be independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^e ；

In some embodiments, each R as described herein ^e Independently selected from the group consisting of-D, -OH, -CN, oxo, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _1-6 Alkoxy, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino and C _1-6 Alkoxy groups may independently be optionally substituted with 1, 2 or 3 substituents selected from-OH, -CN or-NH ₂ 。

In some embodiments, ring B of the present invention is preferably one of the groups formed by the following structural formulae:

In some embodiments, each R as described herein ^b Independently preferably selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy, ethoxyA group or acetyl group, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, methoxy and ethoxy groups may independently be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^e 。

In some embodiments, each R as described herein ^e Independently preferably from-D, -OH, -CN, -NH ₂ Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy or ethoxy groups may independently be optionally substituted with 1, 2 or 3 substituents selected from-OH, -CN or-NH ₂ 。

In other embodiments, each R as described herein ^b Independently one of the groups formed from the following formulae is preferred:

in some embodiments, R as described in the present invention ¹ And R is ² Each independently selected from the group consisting of-H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, methoxy and ethoxy may be independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of R ^a ；

Alternatively, R ¹ 、R ² Together with the carbon atoms to which they are attached, form a ring B, wherein the ring B is one of the groups formed by the following structural formulae:

wherein Z is ₁ And Z ₂ Each independently is CH ₂ NH, S or O; the ring B may beOptionally substituted with 1, 2, 3 or 4 substituents selected from R ^b ；

Wherein the R is ^a And R is ^b Having the meaning described in the present invention.

In some embodiments, A described herein isWherein R is ³ 、R ⁴ And R is ⁵ Having the meaning described in the present invention.

In some embodiments, R as described in the present invention ⁴ And R is ⁵ Each independently selected from the group consisting of-H, -D, -F, -Cl, -Br, -I, -OH, -CN, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl.

p and q are each independently 0, 1, 2, 3 or 4;

in some embodiments, R as described in the present invention ⁴ And R is ⁵ Each independently is preferably selected from-H, -F, -Cl, -Br, -CN, methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, n-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy.

In some embodiments, R as described in the present invention ³ Is thatm is 0, 1, 2, 3 or 4; wherein m, R ⁶ And R is ⁷ Having the meaning described in the present invention.

In some embodiments, R as described in the present invention ⁶ And R is ⁷ Each independently selected from the group consisting of-H, -D, -F, -Cl-Br, -I, oxo, -OH, -CN, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl may be independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、C _1-6 An alkyl group.

In some embodiments, R as described in the present invention ⁶ And R is ⁷ Each independently is preferably selected from-H, -D, methyl, ethyl or acetyl.

In some embodiments, R as described in the present invention ⁶ And R is ⁷ Together with the nitrogen atom to which they are attached, form a 5-12 membered heterocyclic ring C which is one of the groups formed by the following formulae:

wherein W is ₁ And W is ₂ Each independently is CH ₂ NH, S or O; the heterocyclic ring C may be optionally substituted with 1, 2, 3 or 4 substituents each independently selected from R ^c 。

wherein the heterocycle C may be independently optionally substituted with 1, 2, 3 or 4 substituents each independently selected from R ^c 。

In some embodiments, R as described in the present invention ^c Each independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、-CONH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkanoyl, C _6-10 Aryl, C _3-12 Cycloalkyl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl can be independently optionally substituted with 1, 2, 3 or 4 substituents selected from R ^f 。

In some embodiments, each R as described herein ^f Independently selected from the group consisting of-D, -OH, -CN, oxo, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _1-6 An alkoxy group.

In some embodiments, each R as described herein ^c Independently preferably from-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、-CONH ₂ Methyl groupEthyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy, ethoxy or acetyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy, ethoxy and acetyl groups may independently be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^f 。

In some embodiments, each R as described herein ^f Independently preferably from-OH, -CN, -NH ₂ Or methyl.

In some embodiments, R as described in the present invention ⁶ And R is ⁷ Each independently is preferably selected from-H, -D, methyl, ethyl or acetyl;

alternatively, R ⁶ And R is ⁷ Together with the nitrogen atom to which they are attached, form a 5-12 membered heterocyclic ring C which is one of the groups formed by the following formulae:

wherein the heterocycle C may be independently optionally substituted with 1, 2, 3 or 4 substituents each independently selected from R ^c The method comprises the steps of carrying out a first treatment on the surface of the Wherein the R is ^c Having the meaning described in the present invention.

In some embodiments, the compounds of the present invention are stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs of the structure shown in formula (II) or of the structure shown in formula (II),

wherein R is ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、X ¹ And X ² Having the meaning described in the present invention.

In some embodiments, the invention comprises a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of or of:

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In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (II) of the present invention, or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and pharmaceutically acceptable adjuvant or combination thereof.

In some embodiments, the cancers of the present invention include bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, hodgkin's disease, non-hodgkin's lymphoma, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary tract cancer, penile cancer, chronic or acute leukemia, childhood solid tumors, lymphomas, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system tumors, primary CNS lymphomas, tumor angiogenesis, spinal column tumors, brain stem glioma, pituitary adenomas, kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, and environmentally induced cancers, as well as combinations of the foregoing; wherein the chronic or acute leukemia comprises acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia.

In some embodiments, the infectious disease described herein is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease.

In some embodiments, the viral infectious disease of the present invention includes aids, hepatitis a, hepatitis b, hepatitis c, hepatitis d, a spore eruptive virus infection, a papilloma virus infection, or an influenza virus infection.

In some embodiments, the autoimmune diseases described herein include chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, syndrome of lung hemorrhagic nephritis, primary biliary cirrhosis, multiple cerebral spinal sclerosis, acute idiopathic polyneuritis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia

In another aspect, the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the immune response in the subject.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

As described herein, the pharmaceutical compositions of the present invention comprise any of the compounds of formula (I) or (II) of the present invention, further comprising pharmaceutically acceptable excipients, such as, for example, any solvents, solid excipients, diluents, binders, disintegrants, or other liquid excipients, dispersants, flavoring or suspending agents, surfactants, isotonicity agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, and the like, as used herein, are suitable for the particular target dosage form. As described in the following documents: in Remington, the Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, in combination with the teachings of the literature herein, shows that different excipients can be used In the preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. In addition to the extent to which any conventional adjuvant is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.

Substances that may be pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum proteins; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; a partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate; a wax; polyethylene-polyoxypropylene-block polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and cellulose acetate; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the clothing material; a sweetener; a flavoring agent; a perfume; preservatives and antioxidants. When the compound of the present invention is administered in the form of a medicament to a mammal such as a human, it may be administered as the compound itself or may be administered in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient and a pharmaceutically acceptable carrier.

"therapeutically effective amount" or "effective amount" refers to a sufficient amount of one or more compounds of the invention to treat, prevent, alleviate, ameliorate or eliminate one or more symptoms of a particular disease, disorder or syndrome, or to prevent or delay onset of one or more symptoms of a particular disease, disorder or syndrome described herein. In the case of treating cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; inhibit (i.e., slow to some extent or terminate) infiltration of cancer cells into surrounding organs; inhibit tumor metastasis; inhibit tumor growth to some extent; and/or to some extent, alleviate one or more symptoms associated with cancer. In the case of an infectious disease state, a therapeutically effective amount is an amount sufficient to reduce or ameliorate the symptoms of an infectious disease (caused by bacteria, viruses, and fungi). One of ordinary skill in the art will be able to study the factors contained herein and determine an effective amount of a compound of the present invention without undue experimentation.

The administration regimen can affect the effective amount of the formulation. The compounds of the invention may be administered to an individual either before or after the onset of a disorder associated with the PD-1/PD-L1 signaling pathway. Furthermore, multiple divided doses, as well as staggered doses, may be administered daily or sequentially, or may be administered as a continuous infusion, or may be administered as a bolus. Furthermore, the dosage of the compounds of the invention may be proportionally increased or decreased as appropriate according to the urgency of the therapeutic or prophylactic situation.

The compounds of the invention are useful for treating the conditions, disorders or diseases described herein, or for preparing pharmaceutical compositions for treating such diseases. The present invention relates to methods of using the compounds of the type described herein in the treatment of these diseases or pharmaceutical formulations containing the compounds of the present invention for use in the treatment of these diseases.

"pharmaceutically acceptable carrier" is art recognized and includes pharmaceutically acceptable materials, compositions or carriers suitable for administering the compounds of the invention to a mammal. The carrier includes a liquid or solid filler, diluent, excipient, solvent or encapsulating material that participates in carrying or transferring the pharmaceutically active ingredient from one organ or body to another organ or body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Some examples of materials that may be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc powder; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and antioxidant agents, may also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated Hydroxyanisole (BHA), butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelators such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Formulations of the invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient which can be combined with the carrier material to prepare a single dosage form is generally that amount of the compound which produces the therapeutic effect. Generally, the amount is from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10 to about 30%, in one percent.

The methods of preparing these formulations or compositions include the step of combining a compound of the invention with a carrier, independently optionally with one or more adjunct ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the compounds of the invention with liquid carriers or very finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, typically sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or elixirs or syrups, or pastilles (using an inert basis such as gelatin and glycerin, or sucrose and acacia) and/or mouthwashes and the like, each containing a predetermined amount of a compound of the invention as an active ingredient. The compounds of the present invention may also be administered in the form of a bolus, electuary or paste.

In the solid dosage forms of the invention (capsules, tablets, pills, dragees, powders, granules and the like) for oral administration, the active ingredient is admixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; binders, for example carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acid and sodium carbonate; solution retarders (solution retarding agent), such as paraffin; absorption promoters, such as quaternary ammonium compounds; wetting agents, for example, cetyl alcohol and glycerol monostearate; adsorbents such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and a colorant. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be used as fill in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like.

Tablets may be prepared by compression or moulding, optionally with the use of one or more accessory ingredients. Compressed tablets may be prepared with binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants or dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the invention such as dragees, capsules, pills and granules can optionally be scored or prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical arts. They may also be formulated such as with hydroxypropyl methylcellulose, other polymer matrices, liposomes and/or microspheres in varying proportions to provide the desired release properties for providing slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition which is soluble in sterile water or some other injectable sterile vehicle immediately prior to use. These compositions may also optionally contain opacifying agents and may be compositions which release the active ingredient only in, or preferentially in, a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate using one or more of the above-mentioned excipients.

Liquid dosage forms of the compounds of the present invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compounds, may contain adjuvants such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide (aluminum metahydroxide), bentonite, agar-agar, and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as suppositories which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycols, suppository waxes or salicylates, and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

Formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms of the compounds of the present invention for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants which may be required.

Ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, soaps, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can also contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the additional advantage of providing the body with controlled delivery of the compounds of the present invention. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable vehicle. Absorption enhancers may also be used to increase the flux of compounds through the skin. The rate of flow of such compounds can be controlled by providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.

Also included within the scope of the present invention are ophthalmic preparations, ophthalmic ointments, powders, solutions, and the like.

Pharmaceutical compositions of the invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions immediately prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as nipagin ester, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of substances which delay absorption, such as aluminum monostearate and gelatin.

In some cases, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using liquid suspensions of crystalline or amorphous materials that are poorly water soluble. Thus, the rate of absorption of a drug will depend on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, prolonged absorption of the parenterally administered pharmaceutical form is effected by dissolving or suspending the drug in an oily matrix.

The injectable depot form is prepared by forming a microencapsulated matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular compound used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations can also be prepared by encapsulation of the drug in liposomes or microemulsions which are compatible with body tissues.

The formulations of the present invention may be administered orally, parenterally, topically or rectally. They are of course administered in a form suitable for each route of administration. For example, they are administered in the form of tablets or capsules, by injection, inhalants, eye lotions, ointments, suppositories, etc., by injection, infusion or inhalation; is applied topically by lotion or ointment; is administered rectally via suppositories. Oral and/or intravenous administration is preferred.

The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, typically by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

The terms "systemic administration" and "peripheral administration" as used herein mean administration of a compound, drug or other material other than directly to the central nervous system, such that it enters the patient's system and thus undergoes metabolism and other similar processes, such as subcutaneous administration.

These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including oral, nasal (e.g., in the form of a spray), rectal, intravaginal, parenteral, intracisternal, and topical (in the form of powders, ointments or drops), including buccal and sublingual administration.

Regardless of the route of administration selected, the compounds of the invention and/or the pharmaceutical compositions of the invention, which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention may be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for the particular patient, composition and mode of administration, and that is non-toxic to the patient.

The dosage level selected will depend on a variety of factors including the activity of the particular compound of the invention or an ester, salt or amide thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound being employed, the age, sex, weight, condition, general health and past medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian may begin the dosage of the compound of the invention used in the pharmaceutical composition at a level lower than that required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above. Generally, the compounds of the present invention are administered to a patient at a dosage of about 0.001 to about 100mg/kg body weight/day, more preferably about 0.01 to about 80 mg/kg/day, and still more preferably about 1.0 to about 50 mg/kg/day.

If desired, an effective daily dose of the active compound may be administered in divided doses of two, three, four, five, six or more sub-doses at appropriate time intervals throughout the day, optionally in unit dosage forms.

For an individual of about 50-70kg, the pharmaceutical composition or combination of the invention may be a unit dose of about 1-1000mg of the active ingredient, or about 1-500mg or about 1-250mg or about 1-150mg or about 1-100mg or about 1-50mg of the active ingredient. The therapeutically effective dose of a compound, pharmaceutical composition or combination thereof depends on the type, weight, age and condition of the individual, the disorder or disease being treated or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the progress of the disorder or disease.

The above dosage properties can be demonstrated in vitro and in vivo assays using advantageous mammals, such as mice, rats, dogs, monkeys or related organs, tissues or preparations thereof. The compounds of the invention may be applied in vitro in the form of solutions, for example aqueous solutions, and in vivo in the form of enteral, parenteral, advantageously intravenous, for example as suspensions or aqueous solutions. The in vitro dosage range may be between about 10-3 molar and 10-9 molar. The in vivo therapeutically effective amount may range from about 0.1 to 500mg/kg or from about 1 to 100mg/kg, depending on the route of administration.

The term "individual" as used herein means an animal. Typically, the animal is a mammal. By individual is also meant, for example, a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In other embodiments, the individual is a human.

Although the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of a pharmaceutical composition.

Pharmaceutical combination

Combination therapy using one or more compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, in combination with other pharmaceutically active agents, is useful in the treatment of diseases and conditions described herein.

An effective amount of a compound or a composition comprising a therapeutically effective concentration of a compound formulated for oral, systemic delivery, including parenteral or intravenous delivery, or for topical or topical administration, is administered to an individual in need of treatment exhibiting symptoms of the disease or disorder. The amount is effective to treat, control or alleviate one or more symptoms of the disease or disorder.

Those of ordinary skill in the art will appreciate that the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided herein, including pharmaceutical compositions and formulations comprising these compounds, may be widely used in combination therapy to treat the disorders and diseases described herein. Accordingly, the present invention contemplates the use of the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided herein in combination with other active agents for the treatment of the diseases/disorders described herein.

Use of the compounds and compositions of the invention

The compounds or pharmaceutical compositions disclosed herein may be used in the manufacture of a medicament for the treatment, prevention, amelioration, control or alleviation of a disease associated with the PD-1/PD-L1 signaling pathway in a mammal, including a human.

In particular, the compounds or compositions of the present invention are effective in inhibiting the interaction of PD-1/PD-L1 and thus are useful as agents for treating, preventing, ameliorating, controlling or alleviating disorders associated with the PD-1/PD-L1 signaling pathway in mammals, including humans.

Such diseases include, but are in no way limited to, cancer, infectious diseases, and autoimmune diseases. Wherein the cancer comprises bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, hodgkin's disease, non-hodgkin's lymphoma, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary tract cancer, penile cancer, chronic or acute leukemia, childhood solid tumor, lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brain stem glioma, pituitary adenoma, kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, and environmentally induced cancers, combinations thereof; wherein the chronic or acute leukemia comprises acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia; infectious diseases include AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza; autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, syndrome of lung-bleeding nephritis, primary biliary cirrhosis, multiple cerebral spinal sclerosis, acute idiopathic polyneuritis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.

The compounds or compositions of the present invention may be applied to, but are in no way limited to, the treatment, prevention, amelioration, control or alleviation of cancer, infectious diseases and autoimmune diseases in mammals, including humans, using an effective amount of a compound or composition of the present invention administered to a patient.

The compounds and pharmaceutical compositions of the present invention are useful for veterinary treatment of mammals, in addition to human therapy, in pets, in animals of introduced species and in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

General synthetic method

In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined for the compounds of formulas (I) - (II). The following reaction schemes and examples are provided to further illustrate the present invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.

All temperatures are set forth in the examples described below, unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. The general reagents were purchased from Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin Chemie, inc., qingdao Tenglong chemical Co., ltd., and Qingdao ocean chemical works.

Anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous toluene and anhydrous diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and the anhydrous chloroform are obtained by reflux drying of calcium hydride. Anhydrous ethyl acetate, anhydrous petroleum ether, anhydrous N-hexane, anhydrous N, N-dimethylacetamide and anhydrous N, N-dimethylformamide are dried in advance by anhydrous sodium sulfate.

The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant. Nuclear magnetic resonance spectroscopy with CDC1 ₃ 、d ₆ -DMSO、CD ₃ OD or d ₆ Acetone as solvent (reported in ppm) with TMS (0 ppm) or chloroform (7.25 ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet, multiplet), m (multiplet ), br (broadside), dd (doublet of doublets, quartet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).

Low resolution Mass Spectrometry (MS) data were determined by a spectrometer of Agilent 6120 series LC-MS equipped with a G1311B quaternary pump and G1316ATCC (column temperature kept at 30 ℃), a G1329B autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

The above spectrometer was equipped with a Agilent Zorbax SB-C18 column, 2.1X130 mm,5 μm in size. The injection volume is determined by the sample concentration; the flow rate is 0.6mL/min; the peak of the HPLC was read by recording the UV-Vis wavelengths at 210nm and 254 nm. The mobile phase was a 0.1% acetonitrile formate solution (phase a) and a 0.1% ultrapure formate solution (phase B). Gradient elution conditions are shown in table 1:

TABLE 1

Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm on a Zorbax SB-C18 column, 2.1X130 mm,4 μm,10 min, flow rate of 0.6mL/min,5-95% (0.1% aqueous formic acid in acetonitrile) and column temperature maintained at 40 ℃.

The following abbreviations are used throughout the present invention:

the following synthetic schemes and synthetic intermediate schemes describe the steps for preparing the disclosed compounds of the invention, wherein, unless otherwise indicated, ring B ¹ Is a nitrogen-containing 5-6 membered heterocyclic ring, ring C ¹ Is a nitrogen-containing 5-12 membered heterocyclic ring, each p, q, m, X ¹ 、X ² 、R ⁴ 、R ⁵ 、R ^a And R is ^b Has the meaning as described in the present invention.

Synthesis scheme one

The invention may be further described in terms of the following embodiments, which, however, should not be taken as limiting the scope of the invention.

Scheme 1 for the Synthesis of intermediates

The intermediate (1 c) of the present invention can be obtained by a synthetic method of the synthetic intermediate scheme 1: the compound (1 a) and the compound (1 b) are heated to react under alkaline conditions to produce the compound (1 c).

Scheme 2 for the Synthesis of intermediates

The intermediate (2 e) of the invention can be obtained by a synthesis method of a synthetic intermediate scheme 2: compounds (2 a) and (pinB) ₂ Carrying out a coupling reaction under the action of a palladium catalyst to generate a compound (2 b); the compound (2 b) is sequentially mixed with the compounds (2 f) and (pinB) ₂ And the compound (1 c) is subjected to a coupling reaction to obtain a compound (2 e).

Scheme 3 for the Synthesis of intermediates

The intermediate (3 b) of the present invention can be obtained by a synthetic method of the synthetic intermediate scheme 3: the compound (2 e) is reacted with the compound (3 a) under basic conditions to produce the compound (3 b).

Synthetic intermediate scheme 4

The intermediate (4 a) of the present invention can be obtained by a synthetic method of the synthetic intermediate scheme 4: the compound (3 b) is reacted with trifluoroacetic acid to produce the compound (4 a).

Synthesis of end product scheme 1

The target product 1 can be obtained by the synthesis method of the final product synthesis scheme 1: the compound (4 a) and the compound (5 a) are subjected to reduction reaction in a proper solvent to obtain a target product.

Synthesis of end product FIG. 2

The target product 2 can be obtained by the synthesis method of the final product synthesis scheme 2: the compound (4 a) reacts with formaldehyde in a proper solvent to obtain a target product.

Synthesis scheme II

Scheme 3 'for the Synthesis of intermediate'

The intermediate (3 a ') of the present invention can be obtained by a synthetic method of the synthetic intermediate scheme 3': compound (2 e) was obtained by synthesis of synthetic intermediate scheme 2 of synthesis scheme one; the compound (2 e) is reacted with trifluoroacetic acid to produce the compound (3 a').

Synthetic intermediate scheme 4'

The intermediate (4 a ') of the present invention can be obtained by a synthetic method of the synthetic intermediate scheme 4': the compound (3 a') and the compound (5 a) undergo a reduction reaction in a proper solvent to obtain a target product.

Scheme 5 'for the Synthesis of intermediates'

The intermediate (5 b ') of the present invention can be obtained by a synthetic method of the synthetic intermediate scheme 5': the compound (4 a ') is reacted with the compound (5 a ') under basic conditions to produce the compound (5 b ').

Final product Synthesis of scheme 1'

The target product 3 can be obtained by the synthesis method of the final product synthesis scheme 1': the compound (5 b') reacts with trifluoroacetic acid in a proper solvent to obtain the target product.

Synthesis of a third embodiment

Scheme 1 "Synthesis of intermediate"

The intermediate (1 c ") of the present invention can be obtained by a synthetic method of synthetic intermediate scheme 1": the compound (1 a ') and the compound (1 b ') are subjected to a coupling reaction under the action of a palladium catalyst to generate a compound (1 c ').

Scheme 2 "for the synthesis of intermediates"

The intermediate (2 b ') of the present invention can be obtained by a synthetic method of synthetic intermediate scheme 2': compounds (2 a') and (pin) ₂ And B is subjected to coupling reaction under the action of a palladium catalyst to generate a compound (2B ").

Scheme 3 "Synthesis of intermediate"

The intermediate (3 c ") of the present invention can be obtained by a synthetic method of synthetic intermediate scheme 3″: reacting the compound (2 b ') with the compound (3 a ') under basic conditions to produce a compound (3 b '); the compound (3 b ') and the compound (1 c ') are subjected to a coupling reaction to obtain the compound (3 c ').

Scheme 4 "Synthesis of intermediate"

The intermediate (4 a ') of the present invention can be obtained by a synthetic method of synthetic intermediate scheme 4': the compound (3 c ") is reacted with the compound (3 a) under basic conditions to produce the compound (4 a").

Final product Synthesis scheme 1'

The desired product 4 can be obtained by the synthesis method of the final product synthesis scheme 1″: the compound (4 a ") and the compound (5 a") are reacted in a suitable solvent to obtain the target product.

The invention will be further described by the following examples, which should not be construed as limiting the scope of the invention.

Examples

Example 10

2- (2, 2' -dimethyl-3 ' - (3- (tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3-bromo-2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan

Pd (dppf) Cl ₂ (1.2 g,1.6 mmol), potassium acetate (1.3 g,13 mmol) and pinacol biborate (1.9 g,7.5 mmol) were dissolved in 1, 4-dioxane (20.1 mL), 1-bromo-3-iodo-2-methylbenzene (2.0 g,6.7 mmol) was added and stirred at 90 ℃24h. Stopping stirring, cooling to room temperature, passing through a diatomite adsorption column, washing with dichloromethane (50 mL), and concentrating the filtrate for the next step;

step 2) 2- (3-bromo-2-methylphenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3-bromo-2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (13.5 g,45.5 mmol) and 2-bromo-6, 7-dihydrothiazolo [5,4-c ]]Pyridine-5 (4H) -carboxylic acid tert-butyl ester (15.2 g,47.6 mmol) was added to a mixed solvent of 1, 4-dioxane (200 mL) and water (50 mL), followed by addition of potassium carbonate (6.91 g,50 mmol), pd (dppf) Cl ₂ (3.3 g,4.6 mmol), nitrogen protection, reflux reaction at 95℃for 12h. Stopping heating, cooling to room temperature, passing through a diatomite adsorption column, concentrating the solvent, and separating and purifying by a silica gel chromatographic column (PE/EA=10/1, v/v) to obtain 12g of yellow solid product with the yield of 64.5%;

LC-MS:(pos.ion)m/z：409.0[M+1] ⁺ 。

step 3) 2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3-bromo-2-methylphenyl) -6, 7-dihydrothiazolo [5,4-c]Pyridine-5 (4H) -carboxylic acid tert-butyl ester (9.6 g,23 mmol) and pinacol ester of biboronate (6.6 g,26 mmol) were added to 1, 4-dioxane (100 mL), followed by potassium acetate (6.9 g,70 mmol) and Pd (dppf) Cl ₂ Dichloromethane complex (1.9 g,2.3 mmol) was reacted at 120℃under reflux for 12h. Stopping heating, cooling to room temperature, passing through a diatomite adsorption column, concentrating the solvent, and separating and purifying by silica gel column chromatography (PE/EA=10/1, v/v) to obtain 6.1g of yellow oily liquid product with the yield of 64.5%;

LC-MS:(pos.ion)m/z：457.2[M+1] ⁺ 。

step 4) 1-bromo-3- (3-bromopropyloxy) -2-methylbenzene

3-bromo-2-methylphenol (2.0 g,11 mmol) was dissolved in acetone (20.1 mL), potassium carbonate (4.4 g,32 mmol) was added, followed by 1, 3-dibromopropane (2.7 mL,27 mmol) under nitrogen and reflux overnight at 60 ℃. Stirring was stopped, cooled to room temperature, and the potassium carbonate was removed by suction filtration and washed with methylene chloride (30 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane) to give 3.23g of a pale yellow oily liquid with a yield of 98%.

Step 5) 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (3.0G, 6.6 mmol) and 1-bromo-3- (3-bromopropyloxy) -2-methylbenzene (3.1G, 10 mmol) were added to tetrahydrofuran (60 mL), followed by potassium phosphate solution (60 mL,0.5 mol/L), nitrogen protection, stirring at room temperature for 30min, and X-Phos-Pd-G2 (104 mg,0.13 mmol), nitrogen protection, reaction at room temperature for 24H. Stopping stirring, diluting with water, extracting with ethyl acetate (100 mL. Times.3), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (PE/EA=10/1, v/v) to obtain 1.4g of yellow oily liquid with a yield of 38%;

LC-MS:(pos.ion)m/z：557.1[M+1] ⁺ 。

Step 6) 2- (2, 2' -dimethyl-3 ' - (3- (tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (500 mg,0.90 mmol) and hexahydro-1H-furo [3,4-c ] pyrrole hydrochloride (201 mg,1.34 mmol) were added to N, N-dimethylformamide (20 mL), followed by potassium carbonate (372 mg,2.69 mmol) and sodium iodide (202 mg,1.35 mmol) and reacted at 70℃for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 480mg of a pale yellow oil with a yield of 90.7%;

LC-MS:(pos.ion)m/z：590.3[M+1] ⁺ 。

step 7) 5- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) hexahydro-1H-furo [3,4-c ] pyrrole

To a solution of tert-butyl 2- (2, 2' -dimethyl-3 ' - (3- (tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (480 mg,0.81 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 390mg of red oil with a yield of 97.9%;

LC-MS:(pos.ion)m/z：490.2[M+1] ⁺ 。

Step 8) 2- (2, 2' -dimethyl-3 ' - (3- (tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

5- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) hexahydro-1H-furo [3,4-c ] pyrrole (920 mg,1.88 mmol) and 2-bromoethanol (700 mg,5.6 mmol) were added to acetonitrile (20 mL), followed by potassium carbonate (1.04 g,7.5 mmol) and sodium iodide (282 mg,1.88 mmol) under nitrogen and reflux at 60℃for 10H. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 100mg of yellow oil in 10% yield;

LC-MS:(pos.ion)m/z：534.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.60(dd,J＝17.1,7.5Hz,1H),7.36(dd,J＝18.1,7.7Hz,1H),7.20(dd,J＝16.5,7.9Hz,1H),7.14(d,J＝7.6Hz,1H),6.98(dd,J＝16.8,7.7Hz,1H),6.70(d,J＝7.4Hz,1H),4.19(s,2H),4.06(d,J＝5.6Hz,1H),4.00-3.86(m,4H),3.63(d,J＝10.4Hz,6H),3.25(s,2H),3.11(s,2H),2.95(s,2H),2.85(s,2H),2.72(s,1H),2.22(d,J＝10.2Hz,2H),2.12(d,J＝6.0Hz,4H),1.85(s,1H),1.81(s,1H),1.21(s,3H).

example 11

(2- (2- (3 ' - (3- (hexahydro-1H-pyrrolo [3,4-c ] pyridin-5 (6H) -yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol)

Step 1) 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (2.8 g,5.0 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the pH of the system to 8, extracting with dichloromethane (50 mL. Times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 2.2g of yellow oily substance with a yield of 96%;

LC-MS:(pos.ion)m/z：457.2[M+1] ⁺ 。

Step 2) 2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine (2.2 g,4.8 mmol) and 2-bromoethanol (3.0 g,24 mmol) in ethanol (20 mL) were added sodium carbonate (760 mg,7.17 mmol) and sodium iodide (720 mg,4.80 mmol), and the mixture was reacted at 60℃under nitrogen for 10 hours. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 1.2g of yellow oil in 50% yield;

LC-MS:(pos.ion)m/z：501.2[M+1] ⁺ 。

step 3) 5- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) hexahydro-1H-pyrrolo [3,4-c ] pyridine-2 (3H) -carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (510 mg,1.02 mmol) and tert-butyl hexahydro-1H-pyrrolo [3,4-c ] pyridine-2 (3H) -carboxylate (230 mg,1.01 mmol) were added to N, N-dimethylformamide (20 mL), followed by potassium carbonate (240 mg,1.74 mmol) and sodium iodide (260 mg,1.73 mmol) for 16H at 70 ℃. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give the product as a yellow oil in 300mg, 45.6% yield;

LC-MS:(pos.ion)m/z：647.3[M+1] ⁺ 。

Step 4) (2- (2- (3 ' - (3- (hexahydro-1H-pyrrolo [3,4-c ] pyridin-5 (6H) -yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol)

To a solution of tert-butyl 5- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) hexahydro-1H-pyrrolo [3,4-c ] pyridine-2 (3H) -carboxylate (300 mg,0.46 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system pH to 8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (DCM/meoh=5/1, v/v), to give 27mg of yellow sticky material with a yield of 11%;

LC-MS:(pos.ion)m/z：547.3[M+1] ⁺ 。

example 12

1- (3- ((3 ' - (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

Step 1) 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol

3-bromo-2-methylphenol (5.01 g,26.8 mmol) and pinacol diboronate (10.9 g,42.9 mmol) were dissolved in 1, 4-dioxane solution (80 mL) followed by the sequential addition of Pd (dppf) Cl ₂ Dichloromethane complex (2.55 g,3.12 mmol) and potassium acetate (7.9 g,80 mmol) were heated to 90 ℃ and the tube was capped for 24h. Stopping stirring, cooling to room temperature, passing through a diatomite adsorption column, and concentrating the filtrate. Silica gel column chromatography (PE/ea=12/1, v/v) gave 5.8g of yellow solid with 92% yield;

LC-MS:(pos.ion)m/z：235.1[M+1] ⁺ 。

step 2) 2- (3- (3-bromopropyloxy) -2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane

2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (3.0 g,13 mmol) was dissolved in acetone solution (40 mL), potassium carbonate (3.5 g,25 mmol) and 1, 3-dibromopropane (2.0 mL,20 mmol) were added and heated to 65℃for 16h. Stirring was stopped, cooled to room temperature, passed through a celite adsorption column, concentrated, and purified by column chromatography on silica gel (PE/ea=30/1, v/v) to give 2.0g of pale yellow liquid with a yield of 44%.

Step 3) 2- (3-bromo-2-methylphenyl) thiazole-5-carbaldehyde

3-bromo-2-methylbenzeneboronic acid (5.0 g,23 mmol) and 2-bromo-5-aldehyde thiazole (3.0 g,16 mmol) were dissolved in a mixture of 1, 4-dioxane (80 mL) and water (20 mL). Then Pd (dppf) Cl is added in sequence ₂ (1.2 g,1.6 mmol) and potassium carbonate (5.4 g,39 mmol), under nitrogen, were heated to 100deg.C and reacted for 16h. Stopping stirring, cooling to room temperature, passing through a diatomite adsorption column, concentrating the filtrate, and separating and purifying by silica gel column chromatography (PE/EA=4/1, v/v) to obtain 3.18g of tan oily substance with a yield of 72%;

LC-MS:(pos.ion)m/z：284.0[M+2] ⁺ 。

Step 4) 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde

2- (3- (3-bromopropyloxy) -2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (2.0G, 5.6 mmol) and 2- (3-bromo-2-methylphenyl) thiazole-5-carbaldehyde (2.1G, 7.4 mmol) were dissolved in tetrahydrofuran (30 mL), a potassium phosphate solution (30 mL,20mmol, 0.5M) was added, and stirred for 15min under nitrogen, followed by XPhos-Pd-G2 (90 mg,0.11 mmol), nitrogen, and stirring at room temperature for 18h. Stopping stirring, cooling to room temperature, passing through a diatomite adsorption column, concentrating the filtrate, and separating and purifying by silica gel column chromatography (PE/EA=8/1, v/v) to obtain yellow oily matter 1.1g with a yield of 45%;

LC-MS:(pos.ion)m/z：432.1[M+2] ⁺ 。

step 5) 2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde (400 mg,0.93 mmol) and 4-hydroxypiperidine (122 mg,1.21 mmol) were dissolved in N, N-dimethylformamide (15 mL), potassium carbonate (385 mg,2.78 mmol) and sodium iodide (167 mg,1.11 mmol) were added and reacted at 70℃for 6h, diluted with water (80 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM/MeOH=12/1, v/v) to give 400mg as a yellow solid in 95.5% yield;

LC-MS:(pos.ion)m/z：451.3[M+1] ⁺ 。

Step 6) 1- (3- ((3 ' - (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde (400 mg,0.89 mmol) and 2-aminoethanol (0.11 mL,1.8 mmol) were dissolved in methanol (20 mL), acetic acid (0.1 mL) was added, the reaction was stirred at room temperature for 10min, sodium cyanoborohydride (280 mg,4.46 mmol) was slowly added, the reaction was stirred at room temperature for 6 h, stirring was stopped, the reaction was quenched by the addition of saturated sodium carbonate solution (60 mL), extracted with ethyl acetate (50 Ml. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and purification by column chromatography on silica gel (DCM/meoh=12/1, v/v) gave 80mg of a pale yellow solid in 18.2% yield;

LC-MS:(pos.ion)m/z：496.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.92(s,1H),7.64(d,J＝7.4Hz,1H),7.38(t,J＝7.6Hz,1H),7.27–7.15(m,2H),6.99(d,J＝8.1Hz,1H),6.73(d,J＝7.3Hz,1H),4.88(s,2H),4.23(s,2H),4.08(d,J＝5.7Hz,2H),3.63(d,J＝35.4Hz,4H),3.10(s,3H),2.96(s,3H),2.81(s,4H),2.15(s,5H),1.87(s,5H),1.62(s,2H).

example 1

1- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

Step 1) 2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.35 g,0.63 mmol) and piperidin-4-ol (95.0 mg,0.939 mmol) were dissolved in N, N-dimethylformamide (15.1 mL), followed by addition of potassium carbonate (0.13 g,0.94 mmol) and sodium iodide (94.0 mg,0.627 mmol) and stirring at 75℃for 12H. Stirring was stopped, cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (20 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered off with suction, washed, concentrated, separated by column chromatography on silica gel (DCM/meoh=5/1, v/v) to give 0.34g of red oil with a yield of 94%;

LC-MS:(pos.ion)m/z：578.3[M+1] ⁺ 。

Step 2) 1- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3- (yl) oxy) propyl) piperidin-4-ol hydrochloride

2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.34 g,0.59 mmol) was dissolved in dioxane hydrochloride solution (15.2 mL,61 mmol) and stirred at room temperature for 5H. Stopping stirring, concentrating and directly using for the next step;

LC-MS:(pos.ion)m/z：478.2[M+1] ⁺ 。

step 3) 1- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

1- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3- (yloxy) propyl) piperidin-4-ol hydrochloride (300.0 mg,0.6 mmol) and 2-bromoethanol (0.5 mL,7 mmol) were dissolved in acetonitrile (20.1 mL,80 mmol), potassium carbonate (300.0 mg,2 mmol) and sodium iodide (90.0 mg,0.600 mmol) were added, nitrogen protection, stirring was stopped at 60 ℃ overnight, the system was concentrated under reduced pressure, diluted with water (30 mL), the aqueous phase was sequentially extracted with ethyl acetate (20 ml×3), dichloromethane (20 ml×1), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, washed with suction, silica gel column chromatography purification (DCM/meoh=10/1, v/v) to give 94.9mg of yellow viscous material with a yield of 30%;

LC-MS:(pos.ion)m/z：522.2[M+1] ⁺ 。

¹ H NMR(600MHz,d ₆ -DMSO)δ7.59(d,J＝5.0Hz,1H),7.42-7.30(m,1H),7.27-7.10(m,2H),6.97(d,J＝5.3Hz,1H),6.70(d,J＝4.2Hz,1H),4.58(d,J＝47.9Hz,2H),4.04(s,2H),3.79(s,2H),3.59(s,2H),3.51(s,1H),2.88(s,2H),2.81(d,J＝25.0Hz,4H),2.64(s,2H),2.13(s,5H),1.93(s,2H),1.86(s,3H),1.73(s,2H),1.42(s,2H).

Example 2

2- (2- (3 ' - (3, 3-difluoropyrrolidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3, 3-difluoropyrrolidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl-6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (90.0 mg,0.161 mmol) and 3, 3-difluoropyrrolidine hydrochloride (34.8 mg,0.242 mmol) were dissolved in N, N-dimethylformamide (6.1 mL), potassium carbonate (66.9 mg, 0.254 mmol) and sodium iodide (24.2 mg,0.161 mmol) were added sequentially and stirred at 75deg.C for 12H. Cooling to room temperature, dilution with water (30 mL), extraction with ethyl acetate (20 mL. Times.3), drying of the combined organic phases and separation and purification on a suction filtration wash concentrated silica gel column (DCM) gave 90.2mg of red viscous material in 96% yield;

LC-MS:(pos.ion)m/z：584.2[M+1] ⁺ 。

step 2) 2- (3 ' - (3, 3-difluoropyrrolidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine 2, 2-trifluoroacetate

2- (3 ' - (3, 3-difluoropyrrolidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.14 g,0.24 mmol) was dissolved in dichloromethane (10.2 mL), trifluoroacetic acid (5.1 mL) was added and stirred overnight at room temperature. Stopping stirring, and concentrating to be directly used for the next step;

LC-MS:(pos.ion)m/z：484.2[M+1] ⁺ 。

Step 3) 2- (2- (3 ' - (3, 3-difluoropyrrolidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

2- (3 ' - (3, 3-difluoropyrrolidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine 2, 2-trifluoroacetate (0.14 g,0.23 mmol) and 2-bromoethanol (0.19 mL,2.7 mmol) were dissolved in acetonitrile (10.1 mL,40 mmol), potassium carbonate (0.13 g,0.94 mmol) and sodium iodide (36.0 mg,0.240 mmol) were added and stirred overnight at 60 ℃. Stopping stirring, concentrating the system under reduced pressure, diluting with water (30 mL), extracting with dichloromethane (30 ml×3), combining the organic phases and washing with saturated brine (30 mL), drying over anhydrous sodium sulfate, carrying out suction filtration, washing, concentrating, separating, concentrating, removing acetonitrile, diluting the residue with water (10 mL), adjusting the system pH to 7-8 with potassium carbonate solution (ph=9), extracting with dichloromethane (20 ml×3), combining the organic phases and drying over anhydrous sodium sulfate, suction filtration, washing, concentrating to obtain 17.4mg of milky sticky matter with a yield of 14%;

LC-MS:(pos.ion)m/z：528.2[M+1] ⁺ 。

¹ H NMR(600MHz,CDCl ₃ )δ7.55(d,J＝7.3Hz,1H),7.28(s,1H),7.19-7.17(m,2H),6.85(d,J＝7.4Hz,1H),6.74(d,J＝6.8Hz,1H),4.14-4.01(m,2H),3.92(s,2H),3.76(s,2H),3.66(s,1H),3.04(d,J＝10.4Hz,4H),2.94(t,J＝12.9Hz,2H),2.86(s,2H),2.77(t,J＝5.8Hz,2H),2.73-2.65(m,2H),2.32-2.25(m,2H),2.19(s,3H),2.03-2.00(m,2H),1.94(s,3H).

example 3

1- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2' -methyl-2- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

Step 1) 1-bromo-3- (3-bromopropyloxy) -2- (trifluoromethyl) benzene

3-bromo-2- (trifluoromethyl) phenol (1.5 g,6.2 mmol) was dissolved in acetone (15.1 mL), potassium carbonate (2.6 g,19 mmol) was added, followed by 1, 3-dibromopropane (1.6 mL,16 mmol) under nitrogen and reflux overnight at 60 ℃. Stopping stirring, cooling to room temperature, suction-filtering, washing with dichloromethane (30 mL), and concentrating under reduced pressure to obtain 2.22g of pale yellow oily liquid with 99% yield;

step 2) 2- (3-bromo-2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan

The synthesis of 2- (3-bromo-2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan was as described in example 10, step 1.

Step 3) 2- (3-bromo-2-methylphenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

The synthesis of tert-butyl 2- (3-bromo-2-methylphenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate was as described in example 10, step 2.

Step 4) 2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

The synthesis of tert-butyl 2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate was as described in example 10, step 3.

Step 5) 2- (3 ' - (3-bromopropyloxy) -2-methyl-2 ' - (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.5G, 1 mmol), 1-bromo-3- (3-bromopropyloxy) -2- (trifluoromethyl) benzene (0.6G, 2 mmol) was dissolved in tetrahydrofuran (10.0 mL), potassium phosphate solution (10.0 mL,5.0mmol, 0.5M) was added, nitrogen-protected, stirred at room temperature for 30min, XPhos-Pd-G2 (0.2G, 0.3 mmol) was added, nitrogen-protected, and stirred at room temperature for 48H. Stirring was stopped, the aqueous phase was extracted with ethyl acetate (20 ml×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered off with suction, washed, concentrated, purified by column chromatography on silica gel (PE/ea=10/1, v/v) to give 0.37g of yellow dope in 60% yield;

LC-MS:(pos.ion)m/z：612.2[M+1] ⁺ 。

step 6) 2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2-methyl-2 ' - (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydro-oxazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2-methyl-2 ' - (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.16 g,0.26 mmol) and piperidin-4-ol (40.0 mg, 0.399mmol) were dissolved in N, N-dimethylformamide (8.1 mL,32 mmol), followed by potassium carbonate (54.0 mg,0.391 mmol) and sodium iodide (39.0 mg,0.260 mmol) and stirred overnight at 75 ℃. Stirring was stopped, cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (20 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered off with suction, washed, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 0.11g of a pale red thick material with a yield of 67%;

LC-MS:(pos.ion)m/z：632.2[M+1] ⁺ 。

Step 7) 1- (3- ((2 ' -methyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2-methyl-2 ' - (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydro-oxazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.36 g,0.57 mmol) was dissolved in dichloromethane (8.1 mL), dioxane hydrochloride solution (30.2 mL,120 mmol) was added and stirred at room temperature for 3.5H. Stopping stirring, concentrating the system, adding water (20 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (20 mL×2) and dichloromethane (20 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration for the next step;

LC-MS:(pos.ion)m/z：532.2[M+1] ⁺ 。

step 8) 1- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2' -methyl-2- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

1- (3- ((2 ' -methyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol (0.3 g,0.6 mmol) and 2-bromoethanol (60.0. Mu.L, 0.847 mmol) were dissolved in ethanol (20.1 mL), sodium carbonate (0.1 g,0.9 mmol) and sodium iodide (80.0 mg, 0.284 mmol) were added and refluxed for 16h at 80℃under nitrogen. Stopping stirring, concentrating the system under reduced pressure, diluting with water (30 mL), extracting the aqueous phase with ethyl acetate (20 ml×2) and dichloromethane (20 ml×2) in sequence, combining the organic phases and drying over anhydrous sodium sulfate, suction-filtering, washing and concentrating, separating and purifying by silica gel chromatography column (DCM/meoh=4/1, v/v) to obtain 88.3mg of pale yellow viscous solid with a yield of 30%;

LC-MS:(pos.ion)m/z：576.3[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.54(d,J＝7.2Hz,1H),7.50-7.36(m,1H),7.28-7.22(m,1H),7.13(d,J＝6.9Hz,1H),7.02(d,J＝7.8Hz,1H),6.74(d,J＝7.1Hz,1H),4.35-4.04(m,2H),3.85(s,2H),3.72(d,J＝3.3Hz,3H),3.66(s,2H),3.62-3.49(m,1H),2.99(s,3H),2.81(d,J＝4.3Hz,4H),2.66-2.55(m,2H),2.43-2.24(m,2H),2.20(s,3H),2.11-2.00(m,2H),2.00-1.84(m,2H),1.70-1.51(m,2H).

Example 4

1- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2-methyl-2 ' - (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

Step 1) 1-bromo-3- (3-bromopropyloxy) -2-methylbenzene

The synthesis of 1-bromo-3- (3-bromopropyloxy) -2-methylbenzene is as described in example 10, step 4.

Step 2) 2- (3-bromo-2- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane

Pd (dppf) Cl ₂ (40.0 mg,0.0547 mmol), potassium acetate (0.1 g,1 mmol), pinacol ester of biboronate (0.2 g,0.8 mmol) were dissolved in 1, 4-dioxane (10.1 mL), and 1-bromo-3-iodo-2- (trifluoromethyl) benzene (0.2 g,0.6 mmol) was added and reacted at 90℃for 24h. Stopping stirring, cooling to room temperature, passing through a diatomite adsorption column, washing with dichloromethane (20 mL), and concentrating the filtrate for the next step;

step 3) 2- (3-bromo-2- (trifluoromethyl) phenyl) -6, 7-dihydrothiazole [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3-bromo-2- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (1.5 g,4.3 mmol), 2-bromo-6, 7-dihydrothiazolo [5,4-c ]]A mixed solvent of pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.5 g,2 mmol) dissolved in 1, 4-dioxane (32.2 mL) and water (8.1 mL) was added potassium carbonate (0.54 g,3.9 mmol) and Pd (dppf) Cl ₂ (0.23 g,0.31 mmol), nitrogen protection, and reaction at 95℃overnight. Stirring was stopped, diluted with ethyl acetate (30 mL), passed through a celite adsorption column, the filtrate was extracted with ethyl acetate (30 ml×3), the organic phase was collected and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and purified by silica gel chromatography (PE/ea=7/1, v/v) to give 0.15g of red dope with a yield of 20%;

LC-MS:(pos.ion)m/z：464.2[M+1] ⁺ 。

step 4) 2- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) phenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Pd (dppf) Cl ₂ Dichloromethane complex (46.0 mg,0.0563 mmol), potassium acetate (0.17 g,1.7 mmol), pinacol biborate (0.17 g,0.67 mmol) were dissolved in 1, 4-dioxane (8.1 mL) and 2- (3-bromo-2- (trifluoromethyl) phenyl) -6, 7-dihydrothiazole [5,4-c ] was added]Pyridine-5 (4H) -carboxylic acid tert-butyl ester (A, 0.26g,0.56 mmol), 100℃and microwave stirring for 3H. Stopping stirring, and concentrating, separating and purifying by silica gel column (PE/EA=9/1, v/v) to obtain yellow solid 0.16g with yield of 56%;

LC-MS:(pos.ion)m/z：511.2[M+1] ⁺ 。

step 5) 2- (3 ' - (3-bromopropyloxy) -2' -methyl-2- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) phenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.16G, 0.31 mmol), 1-bromo-3- (3-bromopropyloxy) -2-methylbenzene (0.13G, 0.42 mmol) was dissolved in tetrahydrofuran (3.1 mL), potassium phosphate solution (3.1 mL,1.6mmol, 0.5M) was added, nitrogen was stirred at room temperature for 30min, XPhos-Pd-G2 (49.0 mg,0.0624 mmol) was added, nitrogen was stirred at room temperature for 48H. Stopping stirring, separating, extracting the aqueous phase with ethyl acetate (20 ml×3), combining the organic phases and drying with anhydrous sodium sulfate, suction filtering, washing, concentrating, and purifying by silica gel chromatography (PE/ea=9/1, v/v) to obtain 0.16g of red oil with a yield of 83%;

LC-MS:(pos.ion)m/z：612.1[M+1] ⁺ 。

step 6) tert-butyl 2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl-2- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate

2- (3 ' - (3-bromopropyloxy) -2' -methyl-2- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (81.3 mg,0.133 mmol) and piperidin-4-ol (20.2 mg,0.200 mmol) were dissolved in N, N-dimethylformamide (6.1 mL), and potassium carbonate (45.9 mg,0.332 mmol) and sodium iodide (19.9 mg,0.133 mmol) were added in sequence and reacted at 75℃overnight. Stopping stirring, cooling to room temperature, diluting with water (30 mL), extracting with ethyl acetate (20 mL×3), mixing the organic phases, drying over anhydrous sodium sulfate, suction filtering, washing, and concentrating for use in the next step;

LC-MS:(pos.ion)m/z：632.3[M+1] ⁺ 。

Step 7) 1- (3- ((2-methyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2' - (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

Tert-butyl 2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2' -methyl-2- (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (84.0 mg,0.133 mmol) was dissolved in dichloromethane (4.1 mL), dioxane hydrochloride solution (10.2 mL,41 mmol) was added and stirred at room temperature for 5.5H. Stopping stirring, concentrating the system, adding water (20 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (20 mL multiplied by 2) and dichloromethane (20 mL multiplied by 2), collecting an organic phase, drying with anhydrous sodium sulfate, filtering, washing, concentrating, and directly acting on the next step;

LC-MS:(pos.ion)m/z：532.2[M+1] ⁺ 。

step 8) 1- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2-methyl-2 ' - (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

1- (3- ((2-methyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2' - (trifluoromethyl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol (70.7 mg,0.133 mmol) and 2-bromoethanol (14.1. Mu.L, 0.199 mmol) were dissolved in ethanol (8.1 mL), sodium carbonate (28.2 mg,0.266 mmol) and sodium iodide (19.9 mg,0.133 mmol) were added and the reaction was refluxed at 80℃for 16h under nitrogen. The stirring was stopped, the system was concentrated under reduced pressure, diluted with water (30 mL), the aqueous phase was extracted sequentially with ethyl acetate (20 ml×2) and dichloromethane (20 ml×2) and the combined organic phases were dried over anhydrous sodium sulfate, washed with suction and concentrated, and purified by silica gel chromatography (DCM/meoh=1/2, v/v) to give 19.5mg of pale yellow oily liquid in 26% yield;

LC-MS:(pos.ion)m/z：576.3[M+1] ⁺ 。

¹ H NMR(600MHz,CDCl ₃ )δ7.59-7.49(m,2H),7.30(d,J＝7.1Hz,1H),7.15(t,J＝7.7Hz,1H),6.85(d,J＝8.1Hz,1H),6.77(d,J＝7.4Hz,1H),4.06(d,J＝2.6Hz,2H),3.87(s,1H),3.72(s,4H),3.66(s,4H),3.61-3.59(m,4H),3.00(s,2H),2.93(s,2H),2.83-2.81(m,2H),2.72(s,2H),2.44(s,1H),2.13-2.11(m,1H),2.03-2.01(m,1H),1.96(s,3H),1.70-1.69(m,1H).

Example 5

1- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

Step 1) 2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.15 g,0.27 mmol) and piperidin-4-ol (41.0 mg,0.405 mmol) were dissolved in N, N-dimethylformamide (10.1 mL,40 mmol), followed by potassium carbonate (56.0 mg,0.405 mmol) and sodium iodide (40.0 mg, 0.227 mmol) and stirred at 75℃for 12H. Stopping stirring, cooling to room temperature, adding water (30 mL), diluting, extracting with ethyl acetate (20 mL×3), mixing the organic phases, drying with anhydrous sodium sulfate, suction filtering, washing, and concentrating to obtain yellow oily liquid, which is directly used in the next step;

LC-MS:(pos.ion)m/z：578.4[M+1] ⁺ 。

step 2) 1- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3- (yl) oxy) propyl) piperidin-4-ol hydrochloride

2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.16 g,0.28 mmol) was dissolved in dioxane hydrochloride solution (8.2 mL,33 mmol) and stirred at room temperature for 4H. Stopping stirring, and concentrating to be directly used for the next step;

LC-MS:(pos.ion)m/z：478.2[M+1] ⁺ 。

Step 3) 1- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

1- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3- (yloxy) propyl) piperidin-4-ol hydrochloride (0.14 g,0.27 mmol), aqueous formaldehyde (94.0 μl,1.36 mmol) was dissolved in methanol (10.1 mL), acetic acid (0.11 mL,1.9 mmol) was added, nitrogen protected, stirred at room temperature for 30min, sodium cyanoborohydride (86.0 mg,1.37 mmol), nitrogen protected, stirred at room temperature overnight. Stirring was stopped, quenched with hydrochloric acid (5 mL,0.5 m), saturated sodium bicarbonate (20 mL) solution and system, ethyl acetate (25 ml×3) was extracted, the combined organic phases were dried over anhydrous sodium sulfate, washed and concentrated by suction, thin layer chromatography (DCM/meoh=8/1, v/v) was separated to give 43.7mg yellow solid with a yield of 33%;

LC-MS:(pos.ion)m/z：492.2[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.55(d,J＝7.1Hz,1H),7.27(s,1H),7.20-7.14(m,2H),6.83-6.76(m,2H),4.12(s,2H),3.76(s,2H),3.66(s,1H),3.34-2.97(m,7H),2.90-2.87(m,2H),2.56(s,3H),2.42(s,5H),2.16(s,3H),2.02-1.83(m,6H).

example 6

1- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

Step 1) 2- (3-bromo-2-methylphenyl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3-bromo-2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (2.0 g,6.7 mmol), 2-bromo-6, 7-dihydrothiazolo [4,5-c ] ]A mixed solvent of pyridine-5 (4H) -carboxylic acid tert-butyl ester (1.0 g,3.1 mmol) dissolved in 1, 4-dioxane (20.2 mL) and water (5.1 mL) was added potassium carbonate (1.1 g,8.0 mmol) and Pd (dppf) Cl was added ₂ (0.46 g,0.63 mmol), under nitrogen, at 95℃for 24h. Stirring was stopped, diluted with ethyl acetate (20 mL), passed through celite adsorption column, ethyl acetate (20 ml×3) extracted, the organic phase was collected and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel chromatography column separation (PE/ea=20/1, v/v) to give 0.22g of red brown oil with 17% yield;

LC-MS:(pos.ion)m/z：410.0[M+1] ⁺ 。

step 2) 2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Pd (dppf) Cl ₂ Dichloromethane complex (44.0 mg,0.0539 mmol), potassium acetate (0.16 g,1.6 mmol), pinacol biborate (0.16 g,0.63 mmol) were dissolved in 1, 4-dioxane (10.1 mL) and 2- (3-bromo-2-methylphenyl) -6, 7-dihydrothiazolo [4,5-c ] was added]Pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.22 g,0.54 mmol) was stirred at 130℃for 17H under closed tube conditions. Stirring was stopped, cooled to room temperature, concentrated and purified by silica gel chromatography (PE/ethyl acetate (v/v) =15/1) to give 88.7mg of a yellow oily liquid in 36% yield;

LC-MS:(pos.ion)m/z：457.3[M+1] ⁺ 。

Step 3) 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.14G, 0.31 mmol), 1-bromo-3- (3-bromopropyloxy) -2-methylbenzene (0.12G, 0.39 mmol) was dissolved in tetrahydrofuran (3.0 mL), potassium phosphate solution (3.0 mL,2mmol, 0.5M) was added, nitrogen-protected, stirred at room temperature for 30min, XPhos-Pd-G2 (48.0 mg,0.0611 mmol) was added, nitrogen-protected, and stirred at room temperature for 48H. Stirring was stopped, the aqueous phase was extracted with ethyl acetate (20 ml×3), the organic phases were combined and dried over anhydrous sodium sulfate, washed with suction, concentrated, and purified by silica gel chromatography (PE/ea=20/1, v/v) to give 145mg of yellow solid with a yield of 85%;

LC-MS:(pos.ion)m/z：558.1[M+1] ⁺ 。

step 4) 2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.15 g,0.27 mmol) and piperidin-4-ol (41.0 mg,0.405 mmol) were dissolved in N, N-dimethylformamide (10.1 mL,40 mmol), followed by potassium carbonate (56.0 mg,0.405 mmol) and sodium iodide (40.0 mg, 0.227 mmol) and stirred at 75℃for 12H. Stopping stirring, cooling to room temperature, diluting with water (30 mL), extracting with ethyl acetate (20 mL×3), mixing the organic phases, drying with anhydrous sodium sulfate, suction filtering, washing, and concentrating to obtain yellow oily liquid which is directly used in the next step;

LC-MS:(pos.ion)m/z：578.4[M+1] ⁺ 。

Step 5) 1- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3- (yl) oxy) propyl) piperidin-4-ol

2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.16 g,0.28 mmol) was dissolved in dioxane hydrochloride solution (8.2 mL,33 mmol) and stirred at room temperature for 4H. Stopping stirring, concentrating the system, adding water (20 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (20 mL×2) and dichloromethane (20 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration for the next step;

LC-MS:(pos.ion)m/z：478.2[M+1] ⁺ 。

step 6) 1- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

1- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3- (yloxy) propyl) piperidin-4-ol (0.13 mL,1.8 mmol) was dissolved in ethanol (20.1 mL), sodium carbonate (0.3 g,3 mmol) and sodium iodide (0.2 g,1 mmol) were added, nitrogen protection, reflux overnight at 80 ℃ was stopped stirring, the system was concentrated under reduced pressure, diluted with water (30 mL), the aqueous phase was extracted sequentially with ethyl acetate (30 mL x 2) and dichloromethane (30 mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, washed and concentrated by suction filtration, and purified by column chromatography on silica gel (DCM/meoh=6/1, v/v) to give 76.0mg of yellow viscous material in 10% yield;

LC-MS:(pos.ion)m/z：522.1[M+1] ⁺ 。

¹ H NMR(600MHz,CDCl ₃ )δ7.55(d,J＝7.3Hz,1H),7.27(d,J＝8.7Hz,2H),7.17(t,J＝6.9Hz,2H),6.84(d,J＝8.0Hz,1H),6.74(d,J＝7.3Hz,1H),4.11-4.01(m,2H),3.86(s,2H),3.73(s,3H),3.00(s,4H),2.85(s,2H),2.83-2.78(m,2H),2.66-2.58(m,2H),2.27(s,5H),2.23(s,1H),2.18(s,3H),2.09-2.03(m,2H),1.94(s,5H).

Example 7

2- (2- (3 ' - (3- (hexahydro-2H-pyrano [3,2-c ] pyridin-6 (7H) -yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H-yl) ethanol

Step 1) 2- (3 ' - (3- (hexahydro-2H-pyrano [3,2-c ] pyridin-6 (7H) -yl) propoxy) -2,2' -dimethyl- [1,1' -tert-butylbiphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazole [5,4-c ] pyridine-tert-butyl-5 (4H) -carboxylic acid tert-butyl ester (400 mg,0.72 mmol) and octahydro-2H-pyrano [3,2-c ] pyridine (152 mg,1.07 mmol) were dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (200 mg,1.45 mmol) and sodium iodide (130 mg,0.87 mmol) were added. Heated to 75℃and reacted for 15h. Heating was stopped, cooled to room temperature, diluted with water (70 mL), extracted with ethyl acetate (50 ml×3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography (DCM/meoh=8/1, v/v) gave 265mg of tan dope in 59.8% yield;

LC-MS:(pos.ion)m/z：618.3[M+1] ⁺ 。

step 2) 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) octahydro-2H-pyrano [3,2-c ] pyridine

2- (3 ' - (3- (hexahydro-2H-pyrano [3,2-c ] pyridin-6 (7H) -yl) propoxy) -2,2' -dimethyl- [1,1' -tert-butylbiphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (260 mg,0.42 mmol) was dissolved in dioxane hydrochloride solution (25 mL,100 mmol) and the reaction stirred at room temperature for 12H. Stirring was stopped, the solvent was concentrated, diluted with water (60 mL), and saturated potassium carbonate solution was added to adjust the pH to 8. The ethyl acetate was extracted three times (50 mL. Times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave 190mg of yellow dope in 87.2% yield;

LC-MS:(pos.ion)m/z：518.3[M+1] ⁺ 。

step 3) 2- (2- (3 ' - (3- (hexahydro-2H-pyrano [3,2-c ] pyridin-6 (7H) -yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H-yl) ethanol

6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) octahydro-2H-pyrano [3,2-c ] pyridine (190 mg,0.37 mmol) and 2-bromoethanol (0.13 mL,1.8 mmol) were dissolved in acetonitrile (25 mL), potassium carbonate (480 mg,3.47 mmol) and sodium iodide (55 mg,0.37 mmol) were added and heated to 65℃for 15H. Stopping the reaction, cooling to room temperature, passing through a diatomite adsorption column, concentrating the filtrate, and separating and purifying by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 30mg of pale yellow sticky substance with the yield of 14.6%;

LC-MS:(pos.ion)m/z：562.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.59(d,J＝7.8Hz,1H),7.35(t,J＝7.7Hz,1H),7.21(t,J＝8.0Hz,1H),7.15(d,J＝7.5Hz,1H),6.96(d,J＝8.2Hz,1H),6.70(d,J＝7.6Hz,1H),4.59(d,J＝18.3Hz,1H),4.05(d,J＝6.4Hz,2H),3.85(d,J＝11.5Hz,2H),3.79(s,2H),3.59(d,J＝5.2Hz,2H),3.49-3.46(m,2H),2.89(s,2H),2.83(s,2H),2.66(d,J＝6.0Hz,2H),2.13(s,3H),2.00(d,J＝8.0Hz,4H),1.85(s,3H),1.75(s,2H),1.62(d,J＝12.2Hz,2H),1.54(s,4H),1.12(s,2H).

Example 8

2- (2, 2' -dimethyl-3 ' - (3- ((4 AR,7 AS) -tetrahydro-2H- [1,4] dioxadieno [2,3-c ] pyrrol-6- (3H) -yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (2, 2' -dimethyl-3 ' - (3- ((4 aR,7 aS) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (510 mg,0.90 mmol) and (4 aR,7 aS) -hexahydro-2H- [1,4] dioxin [2,3-c ] pyrrole hydrochloride (227 mg,1.37 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (380 mg,2.75 mmol) and sodium iodide (206 mg,1.37 mmol), and the mixture was heated to 70℃to react for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 430mg of a pale yellow oily product in 77.6% yield;

LC-MS:(pos.ion)m/z：606.3[M+1] ⁺ 。

step 2) (4 aR,7 aS) -6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) hexahydro-2H- [1,4] dioxadieno [2,3-c ] pyrrole

To a solution of (2- (2, 2' -dimethyl-3 ' - (3- ((4 ar,7 as) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -t-butyl-yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid t-butyl ester) (430 mg,0.71 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 335mg of red oil with a yield of 93.3%;

LC-MS:(pos.ion)m/z：506.3[M+1] ⁺ 。

step 3) 2- (2, 2' -dimethyl-3 ' - (3- ((4 AR,7 AS) -tetrahydro-2H- [1,4] dioxadieno [2,3-c ] pyrrol-6- (3H) -yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To an ethanol solution (20 mL) of (4 AR,7 AS) -6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) hexahydro-2H- [1,4] dioxadieno [2,3-c ] pyrrole (335 mg,0.66 mmol) and 2-bromoethanol (124 mg,1 mmol) were added sodium carbonate (105.3 mg,1 mmol) and sodium iodide (99.3 mg,0.66 mmol), and the mixture was reacted at 60℃for 10 hours under nitrogen. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 120mg of yellow oil in 33% yield;

LC-MS:(pos.ion)m/z：550.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.58(d,J＝7.6Hz,1H),7.33(t,J＝7.6Hz,1H),7.20(t,J＝7.8Hz,1H),7.14(d,J＝7.4Hz,1H),6.95(d,J＝8.1Hz,1H),6.69(d,J＝7.5Hz,1H),4.11-3.98(m,5H),3.79(s,2H),3.72-3.67(m,3H),3.48(dd,J＝10.1,5.0Hz,3H),2.96(d,J＝4.4Hz,2H),2.92(s,1H),2.87(d,J＝4.9Hz,3H),2.82(s,4H),2.65(t,J＝5.8Hz,2H),2.12(s,3H),1.99-1.91(m,2H),1.85(s,3H).

Example 9

2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) octahydrocyclopenta [ c ] pyrrol-5-ol

Step 1) octahydrocyclopenta [ c ] pyrrole-5-ol hydrochloride

Tert-butyl 5-hydroxycyclopenta [ c ] pyrrole-2 (1H) -carboxylate (0.5 g,2 mmol) was dissolved in dioxane hydrochloride solution (15.0 mL,60.0 mmol) and stirred at room temperature for 5H. Stopping stirring, and directly using the concentrated system for the next step;

LC-MS:(pos.ion)m/z：128.2[M+1] ⁺ 。

step 2) 2- (3 ' - (3- (5-Hydroxyhexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.8 g,1 mmol) and octahydrocyclopenta [ c ] pyrrole-5-ol hydrochloride (0.4 g,2 mmol) were dissolved in N, N-dimethylformamide (20.1 mL), followed by potassium carbonate (0.8 g,6 mmol) and sodium iodide (0.2 g,1 mmol) and stirred at 75℃for 12H. Stopping stirring, cooling to room temperature, adding water (30 mL), diluting, sequentially extracting with dichloromethane (30 mL×2) and ethyl acetate (30 mL×2), mixing the organic phases, drying with anhydrous sodium sulfate, suction filtering, washing, and concentrating, and directly using for the next step;

LC-MS:(pos.ion)m/z：604.3[M+1] ⁺ 。

Step 3) 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) octahydrocyclopenta [ c ] pyrrol-5-ol

2- (3 ' - (3- (5-Hydroxyhexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.9 g,1 mmol) was dissolved in dichloromethane (24.1 mL), trifluoroacetic acid (8.2 mL,33 mmol) was added and stirred at room temperature for 5H. Stopping stirring, concentrating the system, adding water (30 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (30 mL×2) and dichloromethane (30 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration for the next step;

LC-MS:(pos.ion)m/z：504.2[M+1] ⁺ 。

step 4) 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) octahydrocyclopenta [ c ] pyrrol-5-ol

2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) octahydrocyclopenta [ c ] pyrrol-5-ol (0.8 g,2 mmol) and 2-bromoethanol (0.2 mL,3 mmol) were dissolved in ethanol (20.1 mL), sodium carbonate (0.3 g,3 mmol) and sodium iodide (0.2 g,1 mmol) were added, and refluxed for 10h at 80 ℃. Stopping stirring, concentrating the system under reduced pressure, diluting with water (30 mL), extracting the aqueous phase with ethyl acetate (30 ml×2), dichloromethane (30 ml×2), collecting the organic phase, drying over anhydrous sodium sulfate, suction filtration, washing, concentrating, separating by thin layer chromatography (DCM/meoh=12/1, v/v), obtaining 25.6mg of yellow viscous material with 3% yield;

LC-MS:(pos.ion)m/z：548.3[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.55(d,J＝7.3Hz,1H),7.27(t,J＝6.9Hz,2H),7.18-7.12(m,2H),6.84(d,J＝7.9Hz,1H),6.73(d,J＝7.3Hz,1H),4.15-3.99(m,3H),3.87(s,2H),3.78-3.70(m,2H),3.00(s,4H),2.97(s,1H),2.95(s,1H),2.85-2.79(m,2H),2.74(s,4H),2.23(s,2H),2.18(s,3H),2.11-2.04(m,2H),1.99-1.88(m,5H),1.73(t,J＝6.4Hz,1H),1.70(s,1H).

Example 13

1- (3- ((2, 2' -dimethyl-3 ' - (5- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol

2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde (400 mg,0.89 mmol) and N-methylpiperazine (0.2 mL,2.0 mmol) were dissolved in methanol (20 mL), acetic acid (0.1 mL) was added, and the reaction was stirred at room temperature for 10min, sodium cyanoborohydride (278 mg,4.42 mmol) was slowly added and the reaction was stirred at room temperature for 6.5 h. The stirring was stopped, the reaction was quenched by addition of saturated sodium carbonate solution (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by thin silica gel chromatography (DCM/meoh=5/1, v/v) to give 80mg of a pale yellow solid in 16.85% yield;

LC-MS:(pos.ion)m/z：535.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.81(s,1H),7.65(d,J＝7.7Hz,1H),7.37(t,J＝7.6Hz,1H),7.23(t,J＝7.9Hz,1H),7.17(d,J＝7.1Hz,1H),6.99(d,J＝7.6Hz,1H),6.73(d,J＝7.4Hz,1H),4.96(s,1H),4.09(d,J＝5.5Hz,2H),3.83(s,2H),3.71(s,2H),3.18(s,2H),3.07(s,2H),2.76(s,4H),2.59(s,4H),2.45(s,3H),2.16(s,5H),1.87(s,5H),1.66(s,2H).

example 14

1- (3- ((3 ' - (5- (((2-hydroxyethyl) (methyl) amino) methyl) thiazol-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) piperidin-4-ol

1- (3- ((3 ' - (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) piperidin-4-ol (500 mg,1.0 mmol) and aqueous formaldehyde (0.06 mL,2.0 mmol) were dissolved in methanol (25 mL), acetic acid (0.1 mL) was added, stirred at room temperature for 10min, and sodium cyanoborohydride (316 mg,5.03 mmol) was slowly added and stirred at room temperature for 4 h. The stirring was stopped, the reaction was quenched by addition of saturated sodium carbonate solution (60 mL), extracted three times with ethyl acetate (50 mL. Times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, thin-layer chromatography on silica gel (DCM/meoh=12/1, v/v) gave 62mg of pale yellow dope in 12.1% yield;

LC-MS:(pos.ion)m/z：510.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.79(s,1H),7.65(d,J＝7.5Hz,1H),7.37(t,J＝7.7Hz,1H),7.23(t,J＝7.9Hz,1H),7.16(d,J＝7.2Hz,1H),6.98(d,J＝8.2Hz,1H),6.73(d,J＝7.5Hz,1H),4.95(s,1H),4.51(s,1H),4.08(d,J＝6.0Hz,2H),3.86(s,2H),3.71(s,1H),3.53(d,J＝4.5Hz,2H),3.12(d,J＝49.3Hz,6H),2.89(s,2H),2.26(s,3H),2.15(s,5H),1.89(d,J＝13.4Hz,5H),1.64(s,2H).

Example 15

2,2'- ((2- (3' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2 '-dimethyl- [1,1' -biphenyl ] -3-yl) thiazol-5-yl) methyl) azetidinediyl) ethanol

2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde (760 mg,1.69 mmol) and diethanolamine (0.3 mL,3.0 mmol) were dissolved in methanol (20 mL), acetic acid (0.1 mL) was added, and the reaction was stirred at room temperature for 10min, sodium cyanoborohydride (481 mg,7.65 mmol) was slowly added and the reaction was stirred at room temperature for 6 hours. Stirring was stopped, saturated sodium carbonate solution (50 mL), ethyl acetate extraction (50 mL. Times.3) was added, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, thin-layer chromatography on silica gel (DCM/meoh=6/1, v/v) gave 88mg of a pale yellow solid, 10.6% yield;

LC-MS:(pos.ion)m/z：540.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.79(s,1H),7.65(d,J＝7.6Hz,1H),7.36(t,J＝7.6Hz,1H),7.23(t,J＝7.8Hz,1H),7.16(d,J＝7.4Hz,1H),6.98(d,J＝8.1Hz,1H),6.72(d,J＝7.4Hz,1H),4.93(s,1H),4.47(s,2H),4.08(d,J＝5.8Hz,2H),3.99(s,2H),3.68(s,1H),3.49(s,6H),3.16(s,2H),3.02(s,2H),2.60(t,J＝5.7Hz,4H),2.15(s,5H),1.87(s,5H),1.64(s,2H).

example 16

2- (3 ' - (3- (4-hydroxypiperidin-1-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde (400 mg,0.89 mmol) and 4-hydroxypiperidine (180 mg,1.78 mmol) were dissolved in methanol (20 mL), acetic acid (0.1 mL) was added, and the reaction was stirred at room temperature for 10min, and sodium cyanoborohydride (280 mg,4.46 mmol) was slowly added and the reaction was stirred at room temperature for 6 hours. Stirring was stopped, saturated sodium carbonate solution (50 mL) was added, extracted three times with ethyl acetate (50 mL. Times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, thin-layer chromatography on silica gel (DCM/meoh=6/1, v/v) gave 82mg of a pale yellow solid in 17.2% yield;

LC-MS:(pos.ion)m/z：536.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.78(s,1H),7.65(d,J＝7.6Hz,1H),7.36(t,J＝7.6Hz,1H),7.23(t,J＝7.7Hz,1H),7.16(d,J＝7.4Hz,1H),6.98(d,J＝8.1Hz,1H),6.72(d,J＝7.5Hz,1H),4.96(s,1H),4.62(s,1H),4.08(d,J＝5.7Hz,2H),3.77(s,4H),3.13(d,J＝55.0Hz,6H),2.75(s,2H),2.15(s,7H),1.87(s,5H),1.71(s,4H),1.42(s,2H).

Example 17

9- (3- ((3 ' - (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 9-diazaspiro [5.5] undecan-2-one

Step 1) 2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde

1, 9-diazaspiro [5.5] undec-2-one hydrochloride (310 mg,1.51 mmol) was dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (480 mg,3.47 mmol) was added thereto and stirred at room temperature for 5min. 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde (500 mg,1.16 mmol) and sodium iodide (210 mg,1.40 mmol) were successively added, and the mixture was heated to 70℃and stirred for reaction for 8 hours. Water (80 mL) was added for dilution, ethyl acetate was used for extraction (50 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 370mg of a pale yellow solid in 61.5% yield;

LC-MS:(pos.ion)m/z：518.2[M+1] ⁺ 。

step 2) 9- (3- ((3 ' - (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 9-diazaspiro [5.5] undec-2-one

2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -3-yl) thiazole-5-carbaldehyde (370 mg,0.71 mmol) and 2-aminoethanol (0.09 mL,1 mmol) were dissolved in methanol (20 mL), acetic acid (0.1 mL) was added, and the reaction was stirred at room temperature for 10min, and sodium cyanoborohydride (225 mg,3.58 mmol) was slowly added and the reaction stirred at room temperature for 6 hours. Stirring was stopped, saturated sodium carbonate solution (60 mL) was added, extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, column chromatography on silica gel (DCM/meoh=10/1, v/v) gave 75mg of a pale yellow viscous material, 18.7% yield;

LC-MS:(pos.ion)m/z：563.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.89(s,1H),7.63(d,J＝7.5Hz,1H),7.52(s,1H),7.40-7.33(m,1H),7.20(dd,J＝20.7,7.4Hz,2H),6.97(d,J＝8.2Hz,1H),6.71(d,J＝7.0Hz,1H),4.84(s,1H),4.18(s,2H),4.06(d,J＝5.3Hz,2H),3.56(s,2H),3.16(s,1H),2.90(s,2H),2.78(s,4H),2.58(s,2H),2.15(s,3H),2.10(s,2H),2.04(s,2H),1.86(s,3H),1.71(s,4H),1.63(s,4H).

Example 18

N- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) acetamide

Step 1) 3- (3-bromo-2-methylphenoxy) propan-1-amine

1-bromo-3- (3-bromopropyloxy) -2-methylbenzene (1.0 g,3.2 mmol) was dissolved in methanol (35.1 mL), aqueous ammonia (90.2 mL, 560 mmol) was added, and the mixture was stirred at room temperature for 2 days. Stopping stirring, concentrating the system, adding water (15 mL), diluting, sequentially extracting with ethyl acetate (50 mL×2) and dichloromethane (50 mL×2), mixing the organic phases, drying with anhydrous sodium sulfate, suction filtering, washing, concentrating under reduced pressure, and separating and purifying by silica gel column chromatography to obtain white solid (0.7 g) with yield of 90%;

LC-MS:(pos.ion)m/z：245.1[M+1] ⁺ 。

step 2) N- (3- (3-bromo-2-methylphenoxy) propyl) acetamide

3- (3-bromo-2-methylphenoxy) propan-1-amine (2.0 g,8.2 mmol) was dissolved in tetrahydrofuran (25.1 mL), triethylamine (2.3 mL,17 mmol) was added, cooled to 0℃and acetic anhydride (1.5 mL,16 mmol) was slowly added dropwise under nitrogen, and stirred at this temperature for 10min. Then warmed to room temperature and stirred overnight. Stopping stirring, concentrating the system, dissolving ethyl acetate (30 mL), sequentially washing the organic phase with hydrochloric acid solution (2 mol/L,30 mL), saturated sodium bicarbonate solution (30 mL), saturated saline (30 mL), drying with anhydrous sodium sulfate, suction-filtering, washing, concentrating under reduced pressure, and separating and purifying by silica gel column chromatography (DCM/MeOH=10/1, v/v), to obtain 0.71g of red-brown oil with a yield of 30%;

LC-MS:(pos.ion)m/z：287.0[M+1] ⁺ 。

Step 3) 2- (3-bromo-2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan

Step 4) 2- (3-bromo-2-methylphenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Step 5) 2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Step 6) 2- (3 ' - (3-Acetaminopropoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Tert-butyl 2- (2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (0.5G, 1 mmol), N- (3- (3-bromo-2-methylphenoxy) propyl) acetamide (0.5G, 2 mmol) was dissolved in tetrahydrofuran (10.0 mL), potassium phosphate solution (10.0 mL,5.0mmol, 0.5M) was added, nitrogen sparged, stirred at room temperature for 30min, XPhos-Pd-G2 (0.2G, 0.3 mmol) was added, nitrogen sparge, and stirred at room temperature for 48H. Stirring was stopped, the aqueous phase was extracted with ethyl acetate (20 ml×3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated by suction filtration and washing on silica gel column chromatography (PE/ea=1/2, v/v) to give 0.5g of a red oily liquid with a yield of 90%;

LC-MS:(pos.ion)m/z：536.2[M+1] ⁺ 。

Step 7) N- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) acetamide hydrochloride

2- (3 ' - (3-Acetamopropoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.5 g,0.9 mmol) was dissolved in dichloromethane (10.1 mL), dioxane hydrochloride solution (40.2 mL,160 mmol) was added and stirred overnight at room temperature. Stopping stirring, and concentrating to be directly used for the next step;

LC-MS:(pos.ion)m/z：436.2[M+1] ⁺ 。

step 8) N- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) acetamide

N- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) acetamide hydrochloride (0.43 g,0.99 mmol) and 2-bromoethanol (0.1 mL,1 mmol) were dissolved in ethanol (20.1 mL), sodium carbonate (0.21 g,2.0 mmol) and sodium iodide (0.15 g,1.0 mmol) were added and refluxed for 12h at 80℃under nitrogen. Stopping stirring, concentrating under reduced pressure, diluting with water (20 mL), extracting the aqueous phase with ethyl acetate (30 mL. Times.2) and dichloromethane (30 mL. Times.2) sequentially, mixing the organic phases, drying over anhydrous sodium sulfate, suction filtering, washing, concentrating, and separating and purifying with silica gel chromatography column (DCM/MeOH=15/1, v/v) to obtain 42.6mg of yellow viscous solid with yield of 9%;

LC-MS:(pos.ion)m/z：480.2[M+1] ⁺ 。

1H NMR(400MHz,CDCl3)δ7.56(d,J＝7.5Hz,1H),7.29(d,J＝7.7Hz,1H),7.22-7.16(m,2H),6.85(d,J＝8.1Hz,1H),6.77(d,J＝7.5Hz,1H),5.98(s,1H),4.17-4.05(m,2H),3.87(s,2H),3.78-3.70(m,2H),3.66(s,1H),3.53-3.48(m,2H),3.00(s,4H),2.82(t,J＝5.1Hz,2H),2.19(s,3H),2.09-2.04(m,2H),1.97(s,6H).

Example 19

7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] nonane-2-carboxamide

Step 1) 7-azaspiro [3.5] nonane-2-carboxamide hydrochloride

Tert-butyl 2-cyano-7-azaspiro [3.5] nonane-7-carboxylate (650 mg,2.60 mmol) was dissolved in dioxane hydrochloride solution (30 mL,120 mmol) and the reaction stirred at room temperature for 12h. Stirring was stopped and the solvent was concentrated to give 475mg of yellow solid in 88.87% yield;

LC-MS:(pos.ion)m/z：169.1[M+1] ⁺ 。

step 2) 2- (3 ' - (3- (2-carbamoyl-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-tert-butyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazole [5,4-c ] pyridine-tert-butyl-5 (4H) -carboxylic acid tert-butyl ester (400 mg,0.72 mmol) and 7-azaspiro [3.5] nonane-2-carboxamide hydrochloride (220 mg,1.08 mmol) were dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (400 mg,2.9 mmol) and sodium iodide (130 mg,0.87 mmol) were added. Heated to 75℃and reacted for 15h. Heating was stopped, cooled to room temperature, diluted with water (70 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 156mg of yellow dope in 33.7% yield;

LC-MS:(pos.ion)m/z：645.3[M+1] ⁺ 。

Step 3) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) spiro [3.5] nonane-2-carboxamide

2- (3 ' - (3- (2-carbamoyl-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-tert-butyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (156 mg,0.24 mmol) was dissolved in 25mL,100mmol of dioxane hydrochloride solution and the reaction was stirred at room temperature for 12H. Stirring was stopped, the solvent was concentrated, 60mL of water was added, the pH was adjusted to 8 by adding saturated potassium carbonate solution, extracted three times with ethyl acetate (50 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate to obtain 135mg of yellow sticky substance with the yield of 98.6%;

LC-MS:(pos.ion)m/z：545.3[M+1] ⁺ 。

step 4) 7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] nonane-2-carboxamide

7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) spiro [3.5] nonane-2-carboxamide (130 mg,0.24 mmol) and 2-bromoethanol (0.08 mL,1.0 mmol) were dissolved in acetonitrile (25 mL), potassium carbonate (233 mg,1.69 mmol) and sodium iodide (35 mg,0.23 mmol) were added and heated to 65℃for 15h. Stopping the reaction, cooling to room temperature, passing through a diatomite adsorption column, and concentrating the filtrate. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 25mg of white solid in 17.8% yield;

LC-MS:(pos.ion)m/z：589.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.60(d,J＝7.8Hz,1H),7.36(t,J＝7.7Hz,1H),7.27-7.11(m,3H),6.98(d,J＝8.0Hz,1H),6.73(d,J＝6.9Hz,2H),4.57(s,1H),4.09(d,J＝6.0Hz,2H),3.82(s,2H),3.60(s,2H),2.89(dd,J＝20.8,12.8Hz,6H),2.67(s,2H),2.18(s,2H),2.13(s,3H),2.05-1.65(m,12H),1.23(s,4H).

Example 20

2- (2- (3 ' - (3- (2-oxa-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3- (2-oxa-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (550 mg,0.99 mmol) and 2-oxa-7-azaspiro [3.5] nonane oxalate (321 mg,1.48 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (614 mg,4.44 mmol) and sodium iodide (222 mg,1.48 mmol), and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by chromatography on silica gel column (DCM/meoh=20/1, v/v) to give 250mg of pale yellow oily liquid in 42% yield;

LC-MS:(pos.ion)m/z：604.3[M+1] ⁺ 。

step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-oxa-7-azaspiro [3.5] nonane

To a solution of tert-butyl 2- (3 ' - (3- (2-oxa-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (250 mg,0.41 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stirring was stopped, the solvent was concentrated, dichloromethane (20 mL) and water (20 mL) were added, saturated sodium bicarbonate solution was added to adjust the pH of the system to 8, dichloromethane extraction (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 185mg of red oil in 88.7% yield;

LC-MS:(pos.ion)m/z：504.2[M+1] ⁺ 。

step 3) 2- (2- (3 ' - (3- (2-oxa-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-oxa-7-azaspiro [3.5] nonane (185 mg,1.15 mmol) and 2-bromoethanol (230 mg,1.84 mmol) in ethanol (20 mL) was added sodium carbonate (59 mg,0.56 mmol) and sodium iodide (55 mg,0.37 mmol), and the mixture was reacted at 60℃under nitrogen for 10 hours. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by chromatography on silica gel column (DCM/meoh=10/1, v/v) to give 50mg of yellow oil in 24.8% yield;

LC-MS:(pos.ion)m/z：548.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.58(d,J＝7.5Hz,1H),7.34(t,J＝7.7Hz,1H),7.20(t,J＝7.9Hz,1H),7.14(d,J＝7.5Hz,1H),6.94(d,J＝8.2Hz,1H),6.69(d,J＝7.5Hz,1H),4.26(s,4H),4.02(dd,J＝12.2,6.0Hz,2H),3.77(s,2H),3.58(t,J＝5.8Hz,2H),2.86(d,J＝4.7Hz,2H),2.82(d,J＝4.4Hz,2H),2.64(t,J＝6.1Hz,2H),2.46(t,J＝6.9Hz,2H),2.33(s,3H),2.12(s,3H),1.90(dd,J＝13.5,6.7Hz,2H),1.84(s,3H),1.76(s,4H),1.21(s,2H).

Example 21

9- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxypropyl-1, 9-diazaspiro [5.5] undecan-2-one

Step 1) 2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -tert-butyl-pyridin-3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazole [5,4-c ] pyridine-tert-butyl-5 (4H) -carboxylic acid tert-butyl ester (500 mg,0.90 mmol) and 1, 9-diazaspiro [5.5] undec-2-one hydrochloride (275 mg,1.34 mmol) were dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (495mg, 3.58 mmol) and sodium iodide (161 mg,1.07 mmol) were added. Heated to 75℃and reacted for 15h. Stopping heating and cooling to room temperature. Water was added to dilute (70 mL), ethyl acetate was used for extraction (50 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 360mg of yellow solid in 62.2% yield;

LC-MS:(pos.ion)m/z：645.3[M+1] ⁺ 。

step 2) 9- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -1, 9-diazaspiro [5.5] undec-2-one

2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -tert-butyl-pyridin-3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (360 mg,0.56 mmol) was dissolved in dioxane hydrochloride solution (25 mL,100 mmol) and stirred at room temperature for 12H. Stirring was stopped, the solvent was concentrated, diluted with water (60 mL), and saturated potassium carbonate solution was added to adjust the pH to 8. Ethyl acetate extraction (50 ml×3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering and concentrating the filtrate. 300mg of yellow sticky substance is obtained, and the yield is 98.6%;

LC-MS:(pos.ion)m/z：545.2[M+1] ⁺ 。

step 3) 9- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxypropyl-1, 9-diazaspiro [5.5] undecan-2-one

9- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -1, 9-diazaspiro [5.5] undec-2-one (300 mg,0.55 mmol) and 2-bromoethanol (0.40 mL,6.0 mmol) were dissolved in acetonitrile (25 mL), potassium carbonate (720 mg,5.21 mmol) and sodium iodide (82 mg,0.55 mmol) were added and heated to 65℃for 15h. Stopping the reaction, cooling to room temperature, passing through a diatomite adsorption column, and concentrating the filtrate. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 45mg of yellow dope in 13.9% yield;

LC-MS:(pos.ion)m/z：589.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.59(d,J＝7.7Hz,1H),7.35(t,J＝7.6Hz,1H),7.22(t,J＝7.9Hz,1H),7.15(d,J＝7.4Hz,1H),6.97(d,J＝8.2Hz,1H),6.71(d,J＝7.6Hz,1H),4.55(s,1H),4.07(d,J＝6.0Hz,2H),3.80(s,2H),3.59(s,2H),3.51(s,2H),2.95-2.79(m,6H),2.65(t,J＝5.7Hz,2H),2.12(d,J＝12.2Hz,7H),1.86(s,3H),1.68(d,J＝35.5Hz,8H),1.23(s,2H).

Example 22

7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-1-ol

Step 1) 7-azaspiro [3.5] non-1-ol hydrochloride

1-hydroxy-7-azaspiro [1-3] nonane-7-carboxylic acid tert-butyl ester (0.5 g,2 mmol) was dissolved in dioxane hydrochloride solution (15.0 mL,60.0 mmol) and stirred at room temperature for 5h. Stopping stirring, and directly using the concentrated system for the next step;

LC-MS:(pos.ion)m/z：142.2[M+1] ⁺ 。

step 2) 2- (3 ' - (3- (1-hydroxy-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.5 g,0.9 mmol) and 7-azaspiro [3.5] non-1-ol hydrochloride (0.4 g,2 mmol) were dissolved in N, N-dimethylformamide (15.1 mL), followed by potassium carbonate (0.6 g,4 mmol) and sodium iodide (0.1 g,0.7 mmol) and stirred overnight at 75 ℃. Stopping stirring, cooling to room temperature, diluting with water (30 mL), extracting with ethyl acetate (20 mL×3), mixing the organic phases, drying over anhydrous sodium sulfate, suction filtering, washing, and concentrating for the next step;

LC-MS:(pos.ion)m/z：618.3[M+1] ⁺ 。

Step 3) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-1-ol

2- (3 ' - (3- (1-hydroxy-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.6 g,1 mmol) was dissolved in dichloromethane (8.1 mL), dioxane hydrochloride solution (20.2 mL,81 mmol) was added and stirred overnight at room temperature. Stopping stirring, concentrating the system, adding water (30 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, adding dichloromethane (30 mL×2) for extraction, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration on the organic phase for the next step;

LC-MS:(pos.ion)m/z：518.2[M+1] ⁺ 。

step 4) 7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-1-ol

7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-1-ol (0.5 g,1 mmol) and 2-bromoethanol (90.0 μl,1.27 mmol) were dissolved in ethanol (20.1 mL), sodium carbonate (0.2 g,2 mmol) and sodium iodide (0.1 g,0.7 mmol) were added, and refluxed for 17h at 80 ℃. Stopping stirring, concentrating the system under reduced pressure, diluting with water (30 mL), extracting the aqueous phase with dichloromethane (30 ml×3), combining the organic phases and drying over anhydrous sodium sulfate, suction filtration, washing, concentrating, and separating and purifying with silica gel chromatography column (DCM/meoh=8/1, v/v) to obtain 18.1mg of pale yellow viscous solid with 3% yield;

LC-MS:(pos.ion)m/z：562.3[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.55(d,J＝7.3Hz,1H),7.26(s,1H),7.17(t,J＝6.4Hz,2H),6.84(d,J＝8.1Hz,1H),6.74(d,J＝7.5Hz,1H),4.08-4.04(m,2H),3.95(t,J＝7.5Hz,1H),3.86(s,2H),3.75-3.71(m,2H),3.66(d,J＝2.5Hz,4H),3.00(s,4H),2.93-2.85(m,1H),2.85-2.78(m,2H),2.75(d,J＝9.1Hz,1H),2.68-2.60(m,2H),2.36(s,2H),2.18(s,3H),2.12-2.07(m,4H),2.04(s,2H),1.93(s,3H),1.68(s,1H),1.66(s,1H)

Example 23

2- (2- (3 ' - (3- (2-oxa-7-azaspiro [4.5] dec-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3- (2-oxa-6-azaspiro [3.5] non-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (544 mg,0.98 mmol) and 2-oxa-6-azaspiro [3.5] nonane oxalate (318 mg,1.46 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (603 mg,4.4 mmol) and sodium iodide (220 mg,1.47 mmol), and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/meoh=10/1, v/v) to give 350mg of the pale yellow oily product in 59% yield;

LC-MS:(pos.ion)m/z：604.3[M+1] ⁺ 。

step 2) 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-oxa-6-azaspiro [3.5] nonane

To a solution of tert-butyl 2- (3 ' - (3- (2-oxa-6-azaspiro [3.5] non-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (350 mg,0.58 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 289mg of red oil with 99% yield;

LC-MS:(pos.ion)m/z：504.2[M+1] ⁺ 。

step 3) 2- (2- (3 ' - (3- (2-oxa-7-azaspiro [4.5] dec-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-oxa-6-azaspiro [3.5] nonane (289 mg,0.57 mmol) and 2-bromoethanol (108 mg,0.86 mmol) in ethanol (20 mL) was added sodium carbonate (92 mg,0.87 mmol) and sodium iodide (86 mg,0.57 mmol), and the mixture was reacted at 60℃under nitrogen for 10 hours. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 110mg of yellow oil in 35% yield;

LC-MS:(pos.ion)m/z：548.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.56(d,J＝7.6Hz,1H),7.31(t,J＝7.6Hz,1H),7.18(t,J＝7.8Hz,1H),7.12(d,J＝7.4Hz,1H),6.92(d,J＝8.2Hz,1H),6.66(d,J＝7.5Hz,1H),4.18(s,4H),4.02(d,J＝4.3Hz,2H),3.75(s,2H),3.58(s,3H),2.84(d,J＝4.4Hz,2H),2.81(s,2H),2.63(t,J＝5.9Hz,2H),2.48-2.42(m,2H),2.22(s,2H),2.11(s,3H),1.89(dd,J＝12.9,6.6Hz,3H),1.83(s,3H),1.58(s,2H),1.39(d,J＝5.2Hz,2H),1.18(s,1H).

Example 24

6- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-aza-spiro [2.5] octane-1-carbonitrile

Step 1) 6-azaspiro [2.5] octane-1-carbonitrile hydrochloride

1-cyano-6-azaspiro [2-4] octane-6-carboxylic acid tert-butyl ester (0.5 g,2 mmol) was dissolved in dioxane hydrochloride solution (15.0 mL,60.0 mmol), and stirred at room temperature for 4h. Stopping stirring, and directly using the concentrated system for the next step;

LC-MS:(pos.ion)m/z：137.2[M+1] ⁺ 。

step 2) 2- (3 ' - (3- (1-cyano-6-azaspiro [2.5] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.8 g,1 mmol) and 6-azaspiro [2.5] octane-1-carbonitrile hydrochloride (0.4 g,2 mmol) were dissolved in N, N-dimethylformamide (20.1 mL), followed by potassium carbonate (0.4 g,3 mmol) and sodium iodide (0.2 g,1 mmol) and stirred at 75℃for 12H. Stopping stirring, cooling to room temperature, adding water (30 mL) for dilution, sequentially extracting with dichloromethane (30 mL multiplied by 2) and ethyl acetate (30 mL multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration on the organic phases for the next step;

LC-MS:(pos.ion)m/z：613.3[M+1] ⁺ 。

Step 3) 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-aza-spiro [2.5] octane-1-carbonitrile

2- (3 ' - (3- (1-cyano-6-azaspiro [2.5] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.9 g,1 mmol) was dissolved in dichloromethane (6.1 mL), dioxane hydrochloride solution (30.2 mL,120 mmol) was added and stirred at room temperature for 6H. Stopping stirring, concentrating the system, adding water (30 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (30 mL×2) and dichloromethane (30 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration for the next step;

LC-MS:(pos.ion)m/z：513.3[M+1] ⁺ 。

step 4) 6- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-aza-spiro [2.5] octane-1-carbonitrile

6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-aza-spiro [2.5] octane-1-carbonitrile (0.8 g,2 mmol) and 2-bromoethanol (0.2 mL,3 mmol) were dissolved in ethanol (20.1 mL), sodium carbonate (0.3 g,3 mmol) and sodium iodide (0.2 g,1 mmol) were added, and refluxed for 12h at 80℃under nitrogen. Stopping stirring, concentrating the system under reduced pressure, diluting with water (30 mL), extracting the aqueous phase with ethyl acetate (30 ml×2) and dichloromethane (30 ml×2), mixing the organic phases, drying over anhydrous sodium sulfate, suction filtering, washing, concentrating, and separating and purifying with silica gel chromatography column (DCM/meoh=20/1, v/v) to obtain 98.3mg of pale yellow viscous material with 10% yield;

LC-MS:(pos.ion)m/z：557.3[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.55(d,J＝7.4Hz,1H),7.31-7.27(m,1H),7.18(t,J＝7.7Hz,2H),6.86(d,J＝8.1Hz,1H),6.74(d,J＝7.5Hz,1H),4.13-4.03(m,2H),3.86(s,2H),3.73(t,J＝5.1Hz,2H),3.66(t,J＝5.2Hz,1H),2.99(s,3H),2.89(s,3H),2.81(t,J＝5.2Hz,2H),2.71-2.65(m,3H),2.64-2.60(m,2H),2.50(d,J＝8.0Hz,1H),2.19(s,2H),2.14-2.05(m,2H),1.95(s,3H),1.78-1.67(m,3H),1.10-0.98(m,3H).

Example 25

2- (2- (3 ' - (3- (6-oxa-2-azaspiro [3.4] oct-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3- (6-oxa-2-azaspiro [3.4] oct-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazole [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (700 mg,1.26 mmol) and 6-oxa-2-azaspiro [3.4] octanediooxalate (516 mg,1.63 mmol) were dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (520 mg,3.76 mmol) and sodium iodide (225 mg,1.50 mmol) were added. Heated to 75℃and reacted for 10h. Heating was stopped, cooled to room temperature, diluted with water (70 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 550mg of tan dope in 74.3% yield;

LC-MS:(pos.ion)m/z：590.6[M+1] ⁺ 。

step 2) 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -6-oxa-2-azaspiro [3.4] octane

2- (3 ' - (3- (6-oxa-2-azaspiro [3.4] oct-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-t-butyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid t-butyl ester (800 mg,1.35 mmol) was dissolved in dioxane hydrochloride solution (25 mL,100 mmol) and the reaction was stirred at room temperature for 12H. Stirring was stopped, the solvent was concentrated, diluted with water (60 mL), and saturated potassium carbonate solution was added to adjust the pH to 8. Ethyl acetate extraction (50 ml×3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering and concentrating the filtrate. 560mg of yellow sticky substance is obtained, and the yield is 84.3%;

LC-MS:(pos.ion)m/z：490.1[M+1] ⁺ 。

step 3) 2- (2- (3 ' - (3- (6-oxa-2-azaspiro [3.4] oct-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -6-oxa-2-azaspiro [3.4] octane (560 mg,1.14 mmol) and 2-bromoethanol (0.80 mL,10.0 mmol) were dissolved in acetonitrile (25 mL), potassium carbonate (704 mg,3.43 mmol) and sodium iodide (170 mg,1.13 mmol) were added and heated to 65℃for reaction for 15h. Stopping the reaction, cooling to room temperature, passing through a diatomite adsorption column, and concentrating the filtrate. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 115mg of yellow-brown solid in 18.8% yield;

LC-MS:(pos.ion)m/z：534.6[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.59(d,J＝7.3Hz,1H),7.35(t,J＝7.3Hz,1H),7.23(t,J＝7.5Hz,1H),7.15(d,J＝7.0Hz,1H),6.97(d,J＝7.9Hz,1H),6.72(d,J＝7.2Hz,1H),4.54(s,1H),4.06(d,J＝5.3Hz,2H),3.91(s,2H),3.82(s,2H),3.77(s,2H),3.69-3.65(m,2H),3.60(s,4H),3.20(s,2H),2.91(s,2H),2.84(s,2H),2.68(s,2H),2.15(d,J＝19.4Hz,5H),1.93(s,2H),1.87(s,3H).

Example 26

2- (2- (3 ' - (3- (2-oxa-7-azaspiro [4.4] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3- (2-oxa-7-azaspiro [4.4] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (569 mg,1.00 mmol) and 2-oxa-7-azaspiro [4.4] nonane (195 mg,1.53 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (212 mg,1.53 mmol) and sodium iodide (230 mg,1.53 mmol), and the mixture was heated to 70℃to react for 16H. Stirring was stopped, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 460mg of product as a reddish brown oily liquid in 75% yield;

LC-MS:(pos.ion)m/z：604.3[M+1] ⁺ 。

step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-azaspiro [4.4] nonane

To a solution of tert-butyl 2- (3 ' - (3- (2-oxa-7-azaspiro [4.4] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (460 mg,0.76 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stirring was stopped, the solvent was concentrated, dichloromethane (30 mL) was added, saturated sodium bicarbonate solution was added to adjust the system ph=8, dichloromethane was extracted (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 380mg of red oil in 99% yield;

LC-MS:(pos.ion)m/z：504.3[M+1] ⁺ 。

step 3) 2- (2- (3 ' - (3- (2-oxa-7-azaspiro [4.4] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-azaspiro [4.4] nonane (385 mg,0.76 mmol) and 2-bromoethanol (143 mg,1.00 mmol) in ethanol (20 mL) were added sodium carbonate (122 mg,1.15 mmol) and sodium iodide (115 mg,0.77 mmol), and the mixture was reacted at 60℃under nitrogen for 10h. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 177mg of yellow oil in 42% yield;

LC-MS:(pos.ion)m/z：548.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.56(d,J＝7.6Hz,1H),7.31(t,J＝7.7Hz,1H),7.18(t,J＝7.8Hz,1H),7.11(d,J＝7.4Hz,1H),6.94(d,J＝8.2Hz,1H),6.67(d,J＝7.5Hz,1H),4.04(d,J＝5.4Hz,2H),3.76(s,3H),3.57(dd,J＝13.7,7.3Hz,4H),3.47(t,J＝10.1Hz,2H),2.87(t,J＝14.1Hz,7H),2.79(dd,J＝16.1,7.3Hz,3H),2.64(t,J＝5.8Hz,2H),2.11(s,3H),2.04-1.95(m,2H),1.91(dd,J＝12.3,6.9Hz,1H),1.86-1.79(m,6H).

Example 27

Step 1) 2- (3 ' - (3- (2-oxa-7-azaspiro [4.5] dec-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (540 mg,0.97 mmol) and 2-oxa-7-azaspiro [4.5] decane hydrochloride (258 mg,1.45 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (402 mg,2.91 mmol) and sodium iodide (218 mg,1.45 mmol), and the mixture was heated to 70℃for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 550mg of a pale yellow oily product in 92% yield;

LC-MS:(pos.ion)m/z：618.3[M+1] ⁺ 。

step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-oxa-7-aza-spiro [4.5] decane

To a solution of tert-butyl 2- (3 ' - (3- (2-oxa-7-azaspiro [4.5] dec-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (550 mg,0.89 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane to dissolve (30 mL), adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to give 410mg of red oil, yield 88.9%;

LC-MS:(pos.ion)m/z：518.3[M+1] ⁺ 。

To a solution of 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-oxa-7-aza-spiro [4.5] decane (410 mg,0.79 mmol) and 2-bromoethanol (148 mg,1.2 mmol) in ethanol (20 mL) were added sodium carbonate (126 mg,1.2 mmol) and sodium iodide (119 mg,0.8 mmol), and the mixture was reacted at 60℃under nitrogen for 10 hours. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 120mg of yellow oil in 27% yield;

LC-MS:(pos.ion)m/z：562.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.58(d,J＝7.6Hz,1H),7.33(t,J＝7.6Hz,1H),7.20(t,J＝7.8Hz,1H),7.14(d,J＝7.5Hz,1H),6.94(d,J＝8.2Hz,1H),6.68(d,J＝7.5Hz,1H),4.03(d,J＝5.1Hz,2H),3.78(s,2H),3.70-3.63(m,2H),3.58(dd,J＝11.8,5.9Hz,3H),3.32(d,J＝8.3Hz,2H),2.87(d,J＝4.7Hz,2H),2.83(d,J＝4.1Hz,2H),2.64(t,J＝5.9Hz,2H),2.30(d,J＝17.4Hz,2H),2.19(d,J＝21.4Hz,1H),2.12(s,3H),1.91(t,J＝6.1Hz,2H),1.84(s,3H),1.70(d,J＝5.6Hz,1H),1.59-1.30(m,6H),1.21(s,2H).

Example 28

7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-2-ol

Step 1) 2- (3 ' - (3- (2-hydroxy-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.5 g,0.9 mmol) and 7-azaspiro [3.5] nonane-2-hydroxy hydrochloride (0.2 g,1 mmol) were dissolved in N, N-dimethylformamide (20.1 mL), followed by potassium carbonate (0.3 g,2 mmol) and sodium iodide (0.1 g,0.7 mmol) and stirred overnight at 75 ℃. Stirring was stopped, cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (20 ml×3), the combined organic phases dried over anhydrous sodium sulfate, washed with suction, concentrated, and purified by column chromatography on silica gel (DCM/meoh=9/1, v/v) to give 0.41g of yellow dope with a yield of 70%;

LC-MS:(pos.ion)m/z：618.4[M+1] ⁺ 。

step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-2-ol

2- (3 ' - (3- (2-hydroxy-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.18 g,0.29 mmol) was dissolved in dichloromethane (4.1 mL), dioxane hydrochloride solution (10.2 mL,41 mmol) was added and stirred at room temperature for 5H. Stopping stirring, concentrating the system, adding water (20 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (20 mL×2) and dichloromethane (20 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, filtering, washing, and concentrating to obtain yellow sticky material 0.14g with a yield of 93%;

LC-MS:(pos.ion)m/z：518.3[M+1] ⁺ 。

Step 3) 7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-2-ol

7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-2-ol (0.8 g,2 mmol) and 2-bromoethanol (0.16 mL,2.3 mmol) were dissolved in ethanol (30.1 mL), sodium carbonate (0.33 g,3.1 mmol) and sodium iodide (0.23 g,1.5 mmol) were added and refluxed for 8h at 80℃under nitrogen. Stopping stirring, concentrating the system under reduced pressure, diluting with water (30 mL), extracting the aqueous phase with ethyl acetate (30 ml×2) and dichloromethane (30 ml×2) in sequence, combining the organic phases, drying over anhydrous sodium sulfate, suction-filtering, washing, concentrating, separating and purifying by silica gel chromatography (DCM/meoh=9/1, v/v), separating to obtain a pale yellow viscous solid 29.3mg, yield 3%;

LC-MS:(pos.ion)m/z：562.2[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.55(d,J＝7.2Hz,1H),7.31-7.23(m,3H),7.20-7.12(m,2H),6.84(d,J＝8.1Hz,1H),6.73(d,J＝7.5Hz,1H),4.34-4.25(m,1H),4.10-3.99(m,2H),3.86(s,2H),3.77-3.70(m,2H),3.66(s,1H),3.00(s,4H),2.82(t,J＝5.1Hz,2H),2.61-2.53(m,2H),2.41(s,4H),2.28-2.25(m,2H),2.23(s,1H),2.18(s,3H),2.12-1.99(m,4H),1.93(s,3H),1.65(s,4H).

example 29

2- (2- (3 ' - (3- (2-amino-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

The synthesis of 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine was as described in example 11, step 1.

The synthesis of 2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol was as described in example 11, step 2.

Step 3) (7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-2-yl) carbamic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (0.2 g,0.4 mmol) and tert-butyl 7-azaspiro [3-4] nonan-2-ylcarbamate (0.14 g,0.58 mmol) were dissolved in N, N-dimethylformamide (10.1 mL), followed by potassium carbonate (0.14 g,1.0 mmol) and sodium iodide (60.0 mg,0.400 mmol) and stirred at 75℃for 12H. Stopping stirring, cooling to room temperature, adding water (30 mL) for dilution, sequentially extracting the water phase with ethyl acetate (30 mL multiplied by 2) and dichloromethane (30 mL multiplied by 2), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration on the organic phases for the next step;

LC-MS:(pos.ion)m/z：661.3[M+1] ⁺ 。

step 4) 2- (2- (3 ' - (3- (2-amino-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Tert-butyl (7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-azaspiro [3.5] non-2-yl) carbamate (0.26 g,0.39 mmol) was dissolved in dichloromethane (5.1 mL), dioxane hydrochloride solution (15.2 mL,61 mmol) was added and stirred at room temperature for 6h. Stopping stirring, concentrating the system, adding water (20 mL) for dilution, adding potassium carbonate solution (ph=9) for adjusting the system pH to 7-8, extracting sequentially with ethyl acetate (20 ml×2) and dichloromethane (20 ml×2), collecting the organic phase, drying with anhydrous sodium sulfate, suction-filtering, washing and concentrating, and obtaining brown solid 20.3mg by thin-layer chromatography (DCM/meoh=5.5/1, v/v) with yield of 9%;

LC-MS:(pos.ion)m/z：561.4[M+1] ⁺ 。

¹ H NMR(600MHz,d ₆ -DMSO)δ7.60(d,J＝7.7Hz,1H),7.42-7.33(m,1H),7.28-7.20(m,1H),7.16(d,J＝7.1Hz,1H),6.98(d,J＝8.9Hz,1H),6.73(d,J＝8.6Hz,1H),4.59(s,1H),4.54(s,1H),4.27-4.20(m,1H),4.07(s,2H),3.80(s,2H),3.71-3.63(m,2H),3.63-3.58(m,2H),3.52(s,6H),3.50-3.48(m,2H),3.23-3.00(m,4H),2.87(d,J＝31.4Hz,2H),2.64(d,J＝18.9Hz,2H),2.40(s,2H),2.14(s,3H),2.06-1.93(m,3H),1.87(s,3H).

example 30

2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-aza-spiro [3.4] oct-6-ol

Step 1) 2-aza-spiro [3.4] oct-6-ol

6-hydroxy-2-azaspiro [ tert-butyl ] [3.4] octane-2-carboxylic acid tert-butyl ester (800 mg,3.52 mmol) was dissolved in methylene chloride (20 mL), trifluoroacetic acid (10 mL) was added thereto, and the reaction was stirred at room temperature. Stirring was stopped and the solvent was concentrated. Diluting with water (30 mL), adding saturated potassium carbonate solution, adjusting pH to 8, extracting with ethyl acetate (30 mL. Times.3), and collecting 360mg light yellow viscous material with yield of 80.42%;

LC-MS:(pos.ion)m/z：128.2[M+1] ⁺ 。

Step 2) 2- (3 ' - (3- (6-hydroxy-2-azaspiro [3.4] oct-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-tert-butyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazole [5,4-c ] pyridine-tert-butyl-5 (4H) -carboxylic acid tert-butyl ester (800 mg,1.44 mmol) and 2-aza-spiro [3.4] oct-6-ol (352 mg,2.15 mmol) were dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (793 mg,5.74 mmol) and sodium iodide (215 mg,1.43 mmol) were added. Heated to 75℃and reacted for 15h. Heating was stopped, cooled to room temperature, diluted with water (70 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 660mg of yellow dope in 76.2% yield;

LC-MS:(pos.ion)m/z：604.5[M+1] ⁺ 。

step 3) 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-aza-spiro [3.4] oct-6-ol

2- (3 ' - (3- (6-hydroxy-2-azaspiro [3.4] oct-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-t-butyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid t-butyl ester (660 mg,1.09 mmol) was dissolved in dioxane hydrochloride solution (25 mL,100 mmol), and the reaction was stirred at room temperature for 12H. Stirring was stopped, the solvent was concentrated, diluted with water (60 mL), and saturated potassium carbonate solution was added to adjust the pH to 8. Ethyl acetate extraction (50 ml×3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering and concentrating the filtrate. 400mg of yellow dope was obtained, and the yield was 72.6%;

LC-MS:(pos.ion)m/z：504.4[M+1] ⁺ 。

Step 4) 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-aza-spiro [3.4] oct-6-ol

2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-aza-spiro [3.4] oct-6-ol (400 mg,0.79 mmol) and 2-bromoethanol (0.56 mL,7.9 mmol) were dissolved in acetonitrile (25 mL), potassium carbonate (776 mg,5.61 mmol) and sodium iodide (120 mg,0.80 mmol) were added and heated to 65 ℃ for reaction 15h. Stopping the reaction, cooling to room temperature, passing through a diatomite adsorption column, and concentrating the filtrate. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 25mg of a tan viscous material in 5.75% yield;

LC-MS:(pos.ion)m/z：548.3[M+1] ⁺ 。

example 31

7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one

Step 1) 2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 7-diazaspiro [4.4] non-7-yl) propoxy) - [1,1' -biphenyl ] -tert-butyl-pyridin-3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazole [5,4-c ] pyridine-tert-butyl-5 (4H) -carboxylic acid tert-butyl ester (800 mg,1.44 mmol) and 1, 7-diazaspiro [4.4] nonan-2-one trifluoroacetate (547 mg,2.15 mmol) were dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (793 mg,5.74 mmol) and sodium iodide (258 mg,1.72 mmol) were added. Heated to 75℃and reacted for 15h. Heating was stopped, cooled to room temperature, diluted with water (70 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (DCM/meoh=10/1, v/v) afforded 580mg of a yellow solid in 65.5% yield.

LC-MS:(pos.ion)m/z：617.3[M+1] ⁺ 。

Step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one

2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 7-diazaspiro [4.4] non-7-yl) propoxy) - [1,1' -biphenyl ] -tert-butyl-pyridin-3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (580 mg,0.94 mmol) was dissolved in dioxane hydrochloride solution (25 mL,100 mmol) and the reaction stirred at room temperature for 12H. Stirring was stopped, the solvent was concentrated, diluted with water (60 mL), and saturated potassium carbonate solution was added to adjust the pH to 8. Ethyl acetate extraction (50 ml×3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering and concentrating the filtrate. 337mg of yellow dope was obtained in a yield of 69.4%;

LC-MS:(pos.ion)m/z：517.2[M+1] ⁺ 。

step 3) 7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one

7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one (337 mg,0.65 mmol) and 2-bromoethanol (0.46 mL,6.5 mmol) were dissolved in acetonitrile (25 mL), potassium carbonate (850 mg,6.15 mmol) and sodium iodide (97 mg,0.65 mmol) were added and heated to 65 ℃ for reaction for 15h. Stopping the reaction, cooling to room temperature, passing through a diatomite adsorption column, and concentrating the filtrate. Silica gel column chromatography (DCM/meoh=8/1, v/v) gave 193mg of pale yellow viscous material in 52.8% yield;

LC-MS:(pos.ion)m/z：561.2[M+1] ⁺ 。

¹ H(400MHz,d ₆ -DMSO)δ7.91(1H,s),7.58(1H,d,J 7.5),7.34(1H,t,J 7.6),7.20(1H,t,J 7.7),7.14(1H,d,J 7.4),6.96(1H,d,J 8.1),6.69(1H,d,J 7.4),4.55(1H,s),4.06(2H,d,J 5.4),3.80(2H,s),3.58(2H,d,J 5.4),2.89(2H,d,J 4.8),2.83(4H,s),2.72(3H,s),2.68-2.62(2H,m),2.60(1H,s),2.50(1H,s),2.16(5H,dd,J 19.0,10.8),1.96(3H,d,J 7.0),1.92-1.82(5H,m)

Example 32

2- (2- (3 ' - (3- (7-oxa-2-azaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3- (7-oxa-2-azaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (500 mg,0.90 mmol) and 7-oxa-2-azaspiro [4.5] decane half oxalate (234 mg,0.63 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (310 mg,2.24 mmol) and sodium iodide (202 mg,1.35 mmol), and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/meoh=20/1 v/v) to give 388mg of pale yellow oily product in 70% yield;

LC-MS:(pos.ion)m/z：618.3[M+1] ⁺ 。

step 2) 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -7-oxa-2-azaspiro [4.5] decane

To a solution of tert-butyl 2- (3 ' - (3- (7-oxa-2-azaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (3838 mg,0.63 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 2H. Stopping stirring, concentrating the solvent, adding dichloromethane to dissolve (30 mL), adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 320mg of red oil with a yield of 98.4%;

LC-MS:(pos.ion)m/z：518.2[M+1] ⁺ 。

step 3) 2- (2- (3 ' - (3- (7-oxa-2-azaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -7-oxa-2-azaspiro [4.5] decane (787 mg,1.25 mmol) and 2-bromoethanol (470 mg,3.74 mmol) in acetonitrile (20 mL) was added potassium carbonate (689 mg,4.98 mmol) and sodium iodide (186 mg,1.24 mmol), and the mixture was reacted under reflux at 60℃for 10h under nitrogen. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/meoh=10/1, v/v) to give 100mg of yellow oil in 14.3% yield;

LC-MS:(pos.ion)m/z：562.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.56(d,J＝7.4Hz,1H),7.33(t,J＝7.4Hz,1H),7.19(t,J＝7.6Hz,1H),7.12(d,J＝7.2Hz,1H),6.95(d,J＝7.9Hz,1H),6.68(d,J＝7.2Hz,1H),4.06(d,J＝5.1Hz,2H),3.79(s,3H),3.46-3.37(m,4H),3.29(d,J＝10.9Hz,2H),3.11(s,6H),2.84(d,J＝25.1Hz,6H),2.65(s,2H),2.10(s,6H),1.86(d,J＝12.5Hz,4H),1.64(ddd,J＝44.0,13.7,7.7Hz,5H),1.47(s,2H),1.19(s,1H).

Example 33

7- (3- ((3 '- (5- (2- (2-hydroxyethoxy) ethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2, 2-dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one

Step 1) 2- (3 ' - (3- (8-oxa-2-azaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (559 mg,1.00 mmol) and 8-oxa-2-azaspiro [4.5] decane (212 mg,1.50 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (208 mg,1.50 mmol) and sodium iodide (226 mg,1.51 mmol), and the mixture was heated to 70℃to react for 16H. Stirring was stopped, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 365mg of product as a reddish brown oil in 59% yield.

LC-MS:(pos.ion)m/z：618.3[M+1] ⁺ 。

Step 2) 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -8-oxa-2-azaspiro [4.5] decane

To a solution of tert-butyl 2- (3 ' - (3- (8-oxa-2-azaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (365 mg,0.59 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 2H. Stopping stirring, concentrating the solvent, adding dichloromethane to dissolve (30 mL), adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 300mg of red oil with a yield of 98.1%;

LC-MS:(pos.ion)m/z：518.2[M+1] ⁺ 。

step 7) 2- (2- (3- (3- (8-oxa-2-azaspiro [4.5] dec-2-yl) propoxy) -2,2 '-dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -8-oxa-2-azaspiro [4.5] decane (340 mg,0.66 mmol) and 2-bromoethanol (123 mg,1.00 mmol) in ethanol (20 mL) were added sodium carbonate (104 mg,0.98 mmol) and sodium iodide (98 mg,0.65 mmol), and the mixture was reacted at 60℃under nitrogen for 10 hours. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/meoh=10/1, v/v) to give 95mg of yellow oil in 25.8% yield;

LC-MS:(pos.ion)m/z：562.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.57(d,J＝7.5Hz,1H),7.33(t,J＝7.6Hz,1H),7.19(t,J＝7.8Hz,1H),7.13(d,J＝7.4Hz,1H),6.94(d,J＝8.1Hz,1H),6.68(d,J＝7.5Hz,1H),4.03(d,J＝5.2Hz,2H),3.76(s,2H),3.58(t,J＝5.8Hz,3H),2.85(d,J＝4.2Hz,2H),2.82(s,2H),2.62(dd,J＝10.8,5.3Hz,7H),2.45(s,2H),2.12(s,3H),1.96-1.88(m,2H),1.84(s,3H),1.60(t,J＝6.6Hz,2H),1.46(dt,J＝18.8,10.4Hz,5H),1.20(s,1H).

Example 34

Step 1) 7- (3- ((3 '- (5- (2- (2-hydroxyethoxy) ethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2, 2-dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one

7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one (500 mg,0.97 mmol) and 2-bromoethanol (0.69 mL,9.7 mmol) were dissolved in acetonitrile (25 mL), potassium carbonate (535 mg,3.87 mmol) and sodium iodide (145 mg,0.96 mmol) were added and heated to 65 ℃ for reaction for 15h. Stopping the reaction, cooling to room temperature, passing through a diatomite adsorption column, and concentrating the filtrate. Silica gel column chromatography (DCM/meoh=8/1, v/v) gave 25mg of pale yellow solid in 4.3% yield;

LC-MS:(pos.ion)m/z：605.5[M+1] ⁺ 。

¹ H NMR(600MHz,d ₆ -DMSO)δ8.07(d,J＝13.0Hz,1H),7.59(d,J＝7.6Hz,1H),7.35(t,J＝7.6Hz,1H),7.22(t,J＝7.8Hz,1H),7.18-7.13(m,1H),6.98(d,J＝8.2Hz,1H),6.71(d,J＝7.4Hz,1H),4.54(s,1H),4.18(s,2H),4.10(dd,J＝10.7,5.9Hz,2H),3.78(s,2H),3.58(d,J＝5.3Hz,2H),3.30-3.19(m,2H),2.87(d,J＝5.2Hz,2H),2.82(s,2H),2.64(t,J＝5.9Hz,2H),2.22(d,J＝8.2Hz,2H),2.13(s,3H),2.07(d,J＝4.2Hz,2H),1.96(dt,J＝14.8,7.5Hz,2H),1.92-1.80(m,5H),1.33(s,1H),1.22(d,J＝5.2Hz,4H),0.85(t,J＝6.8Hz,1H).

example 35

2- (2- (3 ' - (3- (2-oxa-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3- (2-oxa-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (550 mg,0.99 mmol) and 2-oxa-6-azaspiro [3.4] octanedioxalate (219 mg,0.69 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (309 mg,2.96 mmol) and sodium iodide (222 mg,1.48 mmol), and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/meoh=20/1, v/v) to give 400mg of a reddish brown oily product in 68.7% yield;

LC-MS:(pos.ion)m/z：590.3[M+1] ⁺ 。

Step 2) 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-oxa-6-azaspiro [3.4] octane

To a solution of tert-butyl 2- (3 ' - (3- (2-oxa-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (400 mg,0.76 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 2H. Stopping stirring, concentrating the solvent, adding dichloromethane to dissolve (30 mL), adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 330mg of red oil with 99% yield;

LC-MS:(pos.ion)m/z：490.2[M+1] ⁺ 。

step 3) 2- (2- (3 ' - (3- (2-oxa-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -2-oxa-6-azaspiro [3.4] octane (330 mg,0.67 mmol) and 2-bromoethanol (426 mg,3.40 mmol) in ethanol (20 mL) were added sodium carbonate (107 mg,1.01 mmol) and sodium iodide (101 mg,0.67 mmol), and the mixture was reacted at 60℃under nitrogen for 10 hours. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 60mg of yellow oil in 16.7% yield;

LC-MS:(pos.ion)m/z：534.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.58(d,J＝7.6Hz,1H),7.34(t,J＝7.7Hz,1H),7.20(t,J＝7.9Hz,1H),7.14(d,J＝7.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.69(d,J＝7.4Hz,1H),4.47(s,4H),4.03(dd,J＝11.7,5.8Hz,2H),3.77(s,2H),3.58(t,J＝6.0Hz,3H),2.86(d,J＝4.8Hz,2H),2.84(s,2H),2.63(dd,J＝14.0,7.7Hz,4H),2.55(t,J＝6.8Hz,2H),2.12(s,3H),2.05(t,J＝7.0Hz,2H),1.95-1.89(m,2H),1.84(s,3H),1.21(s,2H).

Example 36

2- (2- (3 ' - (3- (3-oxa-9-azaspiro [5.5] undecan-9-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 3-oxa-9-azaspiro [5.5] undecane

To a solution of 3-oxa-9-azaspiro [5.5] undecane-9-carboxylic acid tert-butyl ester (1.0 g,3.9 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 3h. Stopping stirring, concentrating the solvent, adding dichloromethane to dissolve (10 mL), concentrating the solvent, and directly using in the next step;

LC-MS:(pos.ion)m/z：156.3[M+1] ⁺ 。

step 2) 2- (3 ' - (3- (3-oxa-9-azaspiro [5.5] undecan-9-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (900 mg,1.61 mmol) and 3-oxa 9-azaspiro [5.5] undecane (652 mg,2.42 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (1.34 g,9.7 mmol) and sodium iodide (403 mg,2.69 mmol), and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 594mg of the product as a yellow oil in 58.2% yield;

LC-MS:(pos.ion)m/z：632.3[M+1] ⁺ 。

Step 3) 2- (3- ((2, 2' -dimethyl-3 ' - (9- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -3-oxa-9-azaspiro [5.5] undecane)

To a solution of tert-butyl 2- (3 ' - (3- (3-oxa-9-azaspiro [5.5] undec-9-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (594 mg,0.93 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 490mg of red oil with a yield of 98.7%;

LC-MS:(pos.ion)m/z：532.2[M+1] ⁺ 。

step 4) 2- (2- (3 ' - (3- (3-oxa-9-azaspiro [5.5] undec-9-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 2- (3- ((2, 2' -dimethyl-3 ' - (9- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -3-oxa-9-azaspiro [5.5] undecane (630 mg,1.18 mmol) and 2-bromoethanol (740 mg,5.9 mmol) in ethanol (20 mL) was added sodium carbonate (188 mg,1.77 mmol) and sodium iodide (178 mg,1.18 mmol), nitrogen protection, reacted at 60 ℃ for 10h, warmed to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 mL x 3) and ethyl acetate (100 mL), combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM/meoh=10/1, v/v) to give 200mg as a yellow oil with a yield of 29.3 mg;

LC-MS:(pos.ion)m/z：576.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.56(d,J＝7.5Hz,1H),7.29(t,J＝7.5Hz,1H),7.16(t,J＝7.8Hz,1H),7.10(d,J＝7.4Hz,1H),6.90(d,J＝8.1Hz,1H),6.65(d,J＝7.4Hz,1H),3.99(d,J＝5.5Hz,2H),3.74(s,2H),3.59(s,2H),3.48(s,5H),2.87-2.77(m,4H),2.62(t,J＝5.6Hz,2H),2.47(d,J＝6.4Hz,1H),2.37(s,4H),2.11(s,3H),1.87(d,J＝13.1Hz,2H),1.82(s,3H),1.44(s,4H),1.33(s,4H),1.16(s,1H).

Example 37

2- (2- (3 ' - (3- (2, 6-diazaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -tert-butyl dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 6-diazaspiro [3.5] nonane-6-carboxylic acid ethyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (450 mg,0.90 mmol) and tert-butyl 2, 6-diazaspiro [3.5] nonane-6-carboxylate half oxalate (570 mg,1.05 mmol) were dissolved in N, N-dimethylformamide (15 mL), followed by addition of potassium carbonate (335 mg,2.42 mmol) and sodium iodide (145 mg,0.97 mmol) and heating to 75℃to stir the reaction for 8H. Heating was stopped, cooled to room temperature, diluted with water (80 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (DCM/meoh=8/1, v/v) afforded 500mg of tan dope in 86.13% yield.

LC-MS:(pos.ion)m/z：647.3[M+1] ⁺ 。

Step 2) 2- (2- (3 ' - (3- (2, 6-diazaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Ethyl 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -tert-butyl dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 6-diazaspiro [3.5] nonane-6-carboxylate (580 mg,0.90 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added and the reaction stirred at room temperature for 12h. Stirring was stopped, the solvent was concentrated, saturated potassium carbonate solution (50 mL) was added, and stirring was performed at room temperature for 15min. Ethyl acetate extraction (30 ml×3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering and concentrating the filtrate. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 35mg of pale yellow dope in 7.14% yield;

LC-MS:(pos.ion)m/z：547.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.59(d,J＝7.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.21(t,J＝7.9Hz,1H),7.14(dd,J＝10.0,4.9Hz,1H),6.95(d,J＝8.5Hz,1H),6.70(d,J＝7.4Hz,1H),4.55(s,1H),4.03(d,J＝5.8Hz,2H),3.78(s,2H),3.58(t,J＝5.9Hz,2H),3.23(s,3H),3.11(s,2H),3.02(s,2H),2.87(d,J＝4.5Hz,4H),2.83(d,J＝4.5Hz,2H),2.72(d,J＝8.3Hz,2H),2.64(t,J＝6.0Hz,2H),2.13(s,3H),1.85(s,3H),1.82-1.76(m,2H),1.73(s,2H),1.60(s,2H).

example 38

2- (2- (3 ' - (3- (2, 9-diazaspiro [5.5] undec-9-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 9- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 9-diazaspiro [5.5] undecane-2-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (0.17 g,0.34 mmol) and tert-butyl 2, 9-diazaspiro [5.5] undecane-2-carboxylate (0.13 g,0.51 mmol) were dissolved in N, N-dimethylformamide (10.1 mL), followed by potassium carbonate (0.12 g,0.87 mmol) and sodium iodide (51.0 mg,0.340 mmol) and stirred overnight at 75 ℃. Stopping stirring, cooling to room temperature, adding water (30 mL) for dilution, sequentially extracting the water phase with ethyl acetate (30 mL multiplied by 2) and dichloromethane (30 mL multiplied by 2), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration on the organic phases for the next step;

LC-MS:(pos.ion)m/z：675.4[M+1] ⁺ 。

Step 2) 2- (2- (3 ' - (3- (2, 9-diazaspiro [5.5] undec-9-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

9- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 9-diazaspiro [5.5] undecane-2-carboxylic acid tert-butyl ester (0.23 g,0.34 mmol) was dissolved in dichloromethane (5.1 mL), dioxane hydrochloride solution (15.2 mL,61 mmol) was added and stirred at room temperature for 3h. Stopping stirring, concentrating the system, adding water (20 mL) for dilution, adding potassium carbonate solution (ph=9) for adjusting the system pH to 7-8, extracting with ethyl acetate (20 ml×2) and dichloromethane (20 ml×2) in sequence, collecting the organic phase, drying with anhydrous sodium sulfate, suction-filtering, washing and concentrating, separating to obtain yellow solid 6.3mg with yield of 3% by thin-layer chromatography (DCM/meoh=6/1, v/v);

LC-MS:(pos.ion)m/z：575.6[M+1] ⁺ 。

¹ H NMR(600MHz,CDCl ₃ )δ7.54(s,1H),7.29-7.24(m,3H),7.16(t,J＝7.7Hz,2H),6.83(d,J＝8.1Hz,1H),6.74(d,J＝7.6Hz,1H),4.41-4.24(m,4H),4.09-4.03(m,2H),3.86(s,2H),3.76-3.71(m,2H),3.08(s,2H),3.00(s,6H),2.84-2.80(m,3H),2.73(s,4H),2.18(s,3H),2.15(s,2H),1.93(s,3H),1.83(s,4H),1.57(s,2H).

example 39

2- (2- (3 ' - (3- (2, 9-diazaspiro [5.5] undec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 9-diazaspiro [5.5] undecane-9-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (550 mg,1.1 mmol) and tert-butyl 2, 9-diazaspiro [5.5] undecane-9-carboxylate (418 mg,1.64 mmol) were added to N, N-dimethylformamide (20 mL), followed by potassium carbonate (45 mg,3.3 mmol) and sodium iodide (247 mg,1.65 mmol) and heated to 70℃for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 355mg of a yellow oily product in 48% yield;

LC-MS:(pos.ion)m/z：675.4[M+1] ⁺ 。

step 2) 2- (2- (3 ' - (3- (2, 9-diazaspiro [5.5] undec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of tert-butyl 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 9-diazaspiro [5.5] undecane-9-carboxylate (355 mg,0.53 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid and the mixture was reacted at room temperature for 3h. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution for adjusting the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (DCM/meoh=5/1, v/v) to obtain 33mg of yellow sticky substance with a yield of 11%;

LC-MS:(pos.ion)m/z：575.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ8.86(s,1H),7.60(d,J＝7.6Hz,1H),7.36(t,J＝7.6Hz,1H),7.22(t,J＝7.9Hz,1H),7.16(d,J＝7.4Hz,1H),6.98(d,J＝8.2Hz,1H),6.72(d,J＝7.5Hz,1H),4.74(s,1H),4.07(d,J＝5.3Hz,2H),3.97(s,2H),3.65(s,2H),3.51(s,1H),3.41(s,4H),3.04(s,7H),2.90(s,3H),2.80(s,2H),2.14(s,3H),1.87(s,3H),1.65(s,6H),1.23(s,2H),0.84(d,J＝7.0Hz,1H).

Example 40

6- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-aza-spiro [3.4] octan-2-ol

/>

Step 1) 6-azaspiro [3.4] octan-2-ol

To a solution of tert-butyl 2-hydroxy-6-azaspiro [3.4] octane-6-carboxylate (1.0 g,4.40 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 3h. Stopping stirring, and concentrating the solvent for direct use in the next step;

LC-MS:(pos.ion)m/z：128.2[M+1] ⁺ 。

step 2) 2- (3 ' - (3- (2-hydroxy-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-tert-butyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of 2- (3 ' - (3-bromopropyloxy-2, 2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (1.1 g,2.0 mmol) and 6-azaspiro [3.4] octane-2-ol trifluoroacetate (710 mg,2.94 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (630 mg,5.93 mmol) and sodium iodide (440 mg,2.93 mmol), and the reaction was heated to 70 ℃ for 16H, the stirring was stopped, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/20/1, v/v) to give 530mg of a yellow oily liquid product with a yield of 44%;

LC-MS:(pos.ion)m/z：604.3[M+1] ⁺ 。

Step 3) 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -6-aza-spiro [3.4] octan-2-ol

To a solution of tert-butyl 2- (3 ' - (3- (2-hydroxy-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-tert-butyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (530 mg,0.88 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 2H. Stopping stirring, concentrating the solvent, adding dichloromethane to dissolve (20 mL), adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 440mg of red oil with 99% yield;

LC-MS:(pos.ion)m/z：504.3[M+1] ⁺ 。

step 4) 6- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-aza-spiro [3.4] octan-2-ol

To a solution of 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -6-aza-spiro [3.4] octan-2-ol (230 mg,0.46 mmol) and 2-bromoethanol (570 mg,4.50 mmol) in ethanol (20 mL) was added sodium carbonate (73 mg,0.69 mmol) and sodium iodide (68 mg,0.45 mmol), nitrogen and the mixture was refluxed at 60℃for 10h. Stopping heating, cooling to room temperature, diluting with water (100 mL), extracting with dichloromethane (100 mL×3) and ethyl acetate (100 mL), mixing the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and preparing, separating and purifying to obtain brown oily substance 60mg with yield of 24%;

LC-MS:(pos.ion)m/z：548.4[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.59(d,J＝7.4Hz,1H),7.34(t,J＝7.6Hz,1H),7.21(t,J＝7.9Hz,1H),7.15(d,J＝7.3Hz,1H),6.96(d,J＝8.1Hz,1H),6.70(d,J＝7.5Hz,1H),4.95(s,1H),4.53(s,1H),4.05(d,J＝5.4Hz,2H),3.78(s,2H),3.58(t,J＝5.6Hz,2H),3.50(s,1H),2.87(d,J＝4.7Hz,2H),2.83(d,J＝4.3Hz,2H),2.64(t,J＝5.8Hz,4H),2.57(s,1H),2.54(s,1H),2.21(d,J＝9.0Hz,2H),2.13(s,3H),1.97-1.90(m,2H),1.85(s,3H),1.78(d,J＝6.5Hz,4H),1.23(s,2H).

Example 41

2- (2- (3 ' - (3- (2, 7-diazaspiro [4.4] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [4.4] nonane-2-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (200 mg,0.4 mmol) and tert-butyl 2, 7-diazaspiro [4.4] nonane-2-carboxylate (135 mg,0.6 mmol) were added to N, N-dimethylformamide (20 mL), followed by potassium carbonate (165 mg,1.2 mmol) and sodium iodide (90 mg,0.6 mmol) and heated to 70℃for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 123mg of the product as a yellow solid with a yield of 48%;

LC-MS:(pos.ion)m/z：324.3[0.5M+1] ⁺ 。

step 2) 2- (2- (3 ' - (3- (2, 7-diazaspiro [4.4] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of tert-butyl 7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (123 mg,0.2 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) and the mixture was reacted at room temperature for 3h. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (DCM/meoh=5/1, v/v), to give 27mg of yellow sticky material with a yield of 26%;

LC-MS:(pos.ion)m/z：547.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ9.18(s,1H),7.59(d,J＝7.7Hz,1H),7.35(t,J＝7.7Hz,1H),7.22(t,J＝7.9Hz,1H),7.15(d,J＝7.4Hz,1H),6.97(d,J＝8.2Hz,1H),6.71(d,J＝7.5Hz,1H),4.56(s,1H),4.08(d,J＝5.8Hz,2H),3.81(s,2H),3.60(s,2H),3.23-3.16(m,3H),3.14(s,1H),3.06(d,J＝11.5Hz,1H),2.90(s,3H),2.84(s,3H),2.67(s,2H),2.13(s,3H),2.05-1.90(m,5H),1.86(s,3H),1.23(s,3H),0.84(d,J＝6.6Hz,1H).

example 42

2- (2- (3 ' - (3- (2, 8-diazaspiro [5.5] undec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 8- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazol [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 8-diazaspiro [5.5] undecane-2-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (0.25 g,0.50 mmol) and tert-butyl 2, 8-diazaspiro [5.5] undecane-2-carboxylate (0.19 g,0.75 mmol) were dissolved in N, N-dimethylformamide (10.1 mL), followed by potassium carbonate (0.17 g,1.2 mmol) and sodium iodide (75.0 mg,0.500 mmol) and stirred at 75℃for 12H. Stopping stirring, cooling to room temperature, adding water (30 mL) for dilution, sequentially extracting the water phase with ethyl acetate (30 mL multiplied by 2) and dichloromethane (30 mL multiplied by 2), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration on the organic phases for the next step;

LC-MS:(pos.ion)m/z：675.3[M+1] ⁺ 。

Step 2) 2- (2- (3 ' - (3- (2, 8-diazaspiro [5.5] undec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

8- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazol [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 8-diazaspiro [5.5] undecane-2-carboxylic acid tert-butyl ester (0.34 g,0.50 mmol) was dissolved in dichloromethane (5.1 mL), dioxane hydrochloride solution (15.2 mL,61 mmol) was added and stirred at room temperature for 5.5h. Stopping stirring, concentrating the system, adding water (20 mL) for dilution, adding potassium carbonate solution (ph=9) for adjusting the system pH to 7-8, extracting with ethyl acetate (20 ml×2) and dichloromethane (20 ml×2) in sequence, collecting the organic phase, drying with anhydrous sodium sulfate, suction-filtering, washing and concentrating, separating to obtain yellow solid (20.6 mg, yield 7% by thin-layer chromatography (DCM/meoh=5/1, v/v);

LC-MS:(pos.ion)m/z：575.3[M+1] ⁺ 。

¹ H NMR(600MHz,d ₆ -DMSO)δ7.61(d,J＝6.9Hz,1H),7.41-7.33(m,1H),7.26-7.20(m,1H),7.17(d,J＝6.8Hz,1H),6.98(d,J＝8.2Hz,1H),6.72(d,J＝6.9Hz,1H),4.69-4.59(m,2H),4.07(s,2H),3.95-3.83(m,2H),3.69-3.60(m,3H),3.52(s,4H),3.50-3.48(m,2H),3.04-2.83(m,8H),2.79-2.69(m,2H),2.14(s,3H),2.05-1.95(m,3H),1.87(s,3H),1.67-1.60(m,2H),1.58-1.52(m,2H),1.48-1.45(m,2H).

example 43

2- (2- (3 ' - (3- (7-oxa-2-azaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3- (7-oxa-2-azaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (700 mg,1.26 mmol) and 7-oxa-2-azaspiro [3.5] nonane half oxalate (348 mg,1.00 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (603 mg,4.40 mmol) and sodium iodide (282 mg,1.88 mmol), and the mixture was heated to 70℃for 16H. Stirring was stopped, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 750mg of the product as a pale yellow oil in 99% yield;

LC-MS:(pos.ion)m/z：604.3[M+1] ⁺ 。

step 2) 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -7-oxa-2-azaspiro [3.5] nonane

To a solution of tert-butyl 2- (3 ' - (3- (7-oxa-2-azaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (800 mg,1.30 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 630mg of red oil with a yield of 94.4%;

LC-MS:(pos.ion)m/z：504.2[M+1] ⁺ 。

Step 3) 2- (2- (3 ' - (3- (7-oxa-2-azaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -7-oxa-2-azaspiro [3.5] nonane (630 mg,1.25 mmol) and 2-bromoethanol (782 mg,6.2 mmol) in ethanol (20 mL) was added sodium carbonate (199mg, 1.88 mmol) and sodium iodide (188 mg,1.25 mmol), and the mixture was reacted at 60℃under nitrogen for 10h. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 47mg of red solid product in 6.9% yield;

LC-MS:(pos.ion)m/z：548.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.59(d,J＝7.5Hz,1H),7.35(t,J＝7.7Hz,1H),7.23(t,J＝7.7Hz,1H),7.14(d,J＝7.3Hz,1H),6.97(d,J＝8.1Hz,1H),6.72(d,J＝7.6Hz,1H),4.07(d,J＝5.9Hz,2H),3.84(d,J＝10.4Hz,7H),3.64(s,2H),3.33(d,J＝7.1Hz,4H),2.92(s,2H),2.83(s,2H),2.68(s,2H),2.12(s,3H),1.96(s,2H),1.87(s,3H),1.75(s,4H),1.21(s,2H).

example 44

2- (2- (3 ' - (3- (2, 6-diazaspiro [3.4] oct-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazol [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 6-diazaspiro [3.4] octane-6-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (0.25 g,0.50 mmol) and tert-butyl 2, 6-diazaspiro [3.4] octane-6-carboxylate hydrochloride (0.19 g,0.76 mmol) were dissolved in N, N-dimethylformamide (10.1 mL), followed by potassium carbonate (0.24 g,1.7 mmol) and sodium iodide (75.0 mg,0.500 mmol) and stirred at 75℃for 12H. Stopping stirring, cooling to room temperature, adding water (30 mL) for dilution, sequentially extracting the water phase with ethyl acetate (30 mL multiplied by 2) and dichloromethane (30 mL multiplied by 2), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration on the organic phases for the next step;

LC-MS:(pos.ion)m/z：633.2[M+1] ⁺ 。

step 2) 2- (2- (3 ' - (3- (2, 6-diazaspiro [3.4] oct-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazol [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 6-diazaspiro [3.4] octane-6-carboxylic acid tert-butyl ester (0.32 g,0.51 mmol) was dissolved in dichloromethane (5.1 mL), dioxane hydrochloride solution (15.2 mL,61 mmol) was added and stirred at room temperature for 5.5h. Stopping stirring, concentrating the system, adding water (20 mL) for dilution, adding potassium carbonate solution (ph=9) for adjusting the system pH to 7-8, extracting with ethyl acetate (20 ml×2) and dichloromethane (20 ml×2) in sequence, collecting the organic phase, drying with anhydrous sodium sulfate, suction-filtering, washing and concentrating, separating yellow solid (DCM/meoh=6/1, v/v) to obtain 27.9mg with yield of 10%;

LC-MS:(pos.ion)m/z：533.2[M+1] ⁺ 。

¹ H NMR(600MHz,d ₆ -DMSO)δ7.61(d,J＝9.4Hz,1H),7.37(d,J＝6.0Hz,1H),7.23-7.20(m,1H),7.16(d,J＝7.3Hz,1H),6.98(d,J＝10.8Hz,1H),6.73(d,J＝7.4Hz,1H),4.64-4.57(m,2H),4.10-4.04(m,2H),3.81-3.76(m,2H),3.63-3.60(m,3H),3.52(s,4H),2.89-2.81(m,4H),2.19(s,1H),2.14(s,3H),2.04-1.98(m,6H),1.88(s,3H),1.50-1.44(m,4H)

Example 45

2- (2- (3 ' - (3- (9-oxa-2-azaspiro [5.5] undecan-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3- (9-oxa-2-azaspiro [5.5] undecan-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (284 mg,1.05 mmol) and 9-oxa-2-azaspiro [5.5] undecane (244 mg,1.57 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (217 mg,1.57 mmol) and sodium iodide (236 mg,1.57 mmol), and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 660mg of a pale yellow oily product in 99.7% yield;

LC-MS:(pos.ion)m/z：632.3[M+1] ⁺ 。

step 2) 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -9-oxa-2-azaspiro [5.5] undecane

To a solution of tert-butyl 2- (3 ' - (3- (9-oxa-2-azaspiro [5.5] undec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (660 mg,1.04 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 550mg of red oil with 99% yield;

LC-MS:(pos.ion)m/z：532.3[M+1] ⁺ 。

step 3) 2- (2- (3 ' - (3- (9-oxa-2-azaspiro [5.5] undec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -9-oxa-2-azaspiro [5.5] undecane (610 mg,1.15 mmol) and 2-bromoethanol (215 mg,1.72 mmol) in ethanol (20 mL) were added sodium carbonate (183 mg,1.73 mmol) and sodium iodide (172 mg,1.15 mmol), and the mixture was reacted at 60℃under nitrogen for 10 hours. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/meoh=10/1, v/v) to give 142mg of yellow oil in 21.5% yield;

LC-MS:(pos.ion)m/z：576.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.57(d,J＝7.5Hz,1H),7.29(t,J＝7.6Hz,1H),7.15(t,J＝7.9Hz,1H),7.10(d,J＝7.5Hz,1H),6.89(d,J＝8.2Hz,1H),6.65(d,J＝7.5Hz,1H),4.00(d,J＝5.1Hz,2H),3.75(s,2H),3.58(t,J＝6.0Hz,5H),2.84(d,J＝4.4Hz,2H),2.81(s,2H),2.63(t,J＝6.0Hz,2H),2.38(t,J＝6.8Hz,2H),2.28(d,J＝9.4Hz,2H),2.15(d,J＝11.5Hz,2H),2.12(s,3H),1.83(s,3H),1.48-1.41(m,3H),1.39(s,2H),1.32(d,J＝5.9Hz,2H),1.27(d,J＝9.3Hz,3H),1.17(s,2H).

Example 46

2- (2- (3 ' - (3- (2, 8-diazaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazol [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 8-diazaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (0.25 g,0.50 mmol) and tert-butyl 2, 8-diazaspiro [4.5] decane-8-carboxylate (0.18 g,0.75 mmol) were dissolved in N, N-dimethylformamide (10.1 mL), followed by addition of potassium carbonate (0.17 g,1.2 mmol) and sodium iodide (75.0 mg,0.500 mmol) and stirring at 75℃for 12H. Stopping stirring, cooling to room temperature, adding water (30 mL) for dilution, sequentially extracting the water phase with ethyl acetate (30 mL multiplied by 2) and dichloromethane (30 mL multiplied by 2), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration on the organic phases for the next step;

LC-MS:(pos.ion)m/z：661.3[M+1] ⁺ 。

step 2) 2- (2- (3 ' - (3- (2, 8-diazaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 8-diazaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (0.33 g,0.50 mmol) was dissolved in dichloromethane (5.1 mL), dioxane hydrochloride solution (15.2 mL,61 mmol) was added, stirring was stopped at room temperature for 5.5h, the system was concentrated, diluted with water (20 mL), potassium carbonate solution (ph=9) was added to adjust the pH of the system to 7-8, the organic phase was collected and dried with anhydrous sodium sulfate MeOH, suction-washed and concentrated, thin layer chromatography (DCM/6/1, v/v) was separated to give a yellow solid 22.3mg, yield 8%;

LC-MS:(pos.ion)m/z：561.3[M+1] ⁺ 。

¹ H NMR(600MHz,d ₆ -DMSO)δ7.61(d,J＝6.4Hz,1H),7.39-7.36(m,1H),7.21(d,J＝2.4Hz,1H),7.17(d,J＝6.5Hz,1H),7.00(d,J＝7.5Hz,1H),6.75(d,J＝5.9Hz,1H),4.64-4.57(m,2H),4.14-4.09(m,2H),3.87-3.77(m,3H),3.64-3.62(m,2H),3.52(s,6H),3.50-3.47(m,4H),3.10-3.06(m,2H),2.90-2.79(m,4H),2.15(s,3H),2.05-1.96(m,6H),1.88(d,J＝11.8Hz,4H).

Example 47

2- (2- (3 ' - (3- (6-oxa-2-azaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3 ' - (3- (6-oxa-2-azaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (700 mg,1.26 mmol) and 6-oxa-2-azaspiro [3.5] nonane half oxalate (348 mg,1.00 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (603 mg,4.40 mmol) and sodium iodide (282 mg,1.88 mmol), and the mixture was heated to 70℃for 16H. Stirring was stopped, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 740mg of product as a red oil in 97.6% yield;

LC-MS:(pos.ion)m/z：604.3[M+1] ⁺ 。

step 2) 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -6-oxa-2-azaspiro [3.5] nonane

To a solution of tert-butyl 2- (3 ' - (3- (6-oxa-2-azaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (813 mg,1.35 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution for adjusting the system ph=8, extracting with dichloromethane (50 ml×3), combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 670mg of red oily substance, and obtaining 98.8% yield;

LC-MS:(pos.ion)m/z：504.3[M+1] ⁺ 。

step 3) 2- (2- (3 ' - (3- (6-oxa-2-azaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -pyridin-3-yl) oxy) propyl) -6-oxa-2-azaspiro [3.5] nonane (460 mg,1.37 mmol) and 2-bromoethanol (850 mg,6.9 mmol) in ethanol (20 mL) was added sodium carbonate (218 mg,2.06 mmol) and sodium iodide (205 mg,1.37 mmol), and the mixture was reacted at 60℃for 10h under nitrogen. Heating was stopped, cooled to room temperature, diluted with water (100 mL), extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 160mg of yellow solid with a yield of 21.3%;

LC-MS:(pos.ion)m/z：548.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.57(d,J＝7.5Hz,1H),7.33(t,J＝7.6Hz,1H),7.20(t,J＝7.7Hz,1H),7.13(d,J＝7.4Hz,1H),6.95(d,J＝8.0Hz,1H),6.69(d,J＝7.4Hz,1H),4.04(d,J＝5.2Hz,2H),3.77(s,2H),3.55-3.48(m,5H),3.48-3.39(m,5H),3.06(s,2H),2.86(d,J＝4.4Hz,2H),2.81(s,2H),2.64(t,J＝5.5Hz,2H),2.11(s,3H),1.87(d,J＝16.2Hz,5H),1.77(s,2H),1.43(s,2H),1.20(s,1H).

Example 48

2- (2- (3 ' - (3, 9-diazaspiro [5.5] undec-3-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 9- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazol [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -3, 9-diazaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (0.17 g,0.34 mmol) and 3, 9-diazaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester hydrochloride (0.15 g,0.52 mmol) were dissolved in N, N-dimethylformamide (10.1 mL), potassium carbonate (0.16 g,1.2 mmol) and sodium iodide (51.0 mg,0.340 mmol) were added sequentially and stirred overnight at 75 ℃. Stopping stirring, cooling to room temperature, adding water (30 mL) for dilution, sequentially extracting the water phase with ethyl acetate (30 mL multiplied by 2) and dichloromethane (30 mL multiplied by 2), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, and filtering, washing and concentrating the organic phases for direct use in the next step;

LC-MS:(pos.ion)m/z：675.3[M+1] ⁺ 。

step 2) 2- (2- (3 ' - (3, 9-diazaspiro [5.5] undec-3-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

9- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazol [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -3, 9-diazaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester (0.23 g,0.34 mmol) was dissolved in dichloromethane (5.1 mL), dioxane hydrochloride solution (15.2 mL,61 mmol) was added and stirred at room temperature for 3h. Stopping stirring, concentrating the system, adding water (20 mL) for dilution, adding potassium carbonate solution (ph=9) for adjusting the system pH to 7-8, extracting with ethyl acetate (20 ml×2) and dichloromethane (20 ml×2) in sequence, collecting the organic phase, drying with anhydrous sodium sulfate, suction-filtering, washing and concentrating, separating by thin-layer chromatography (DCM/meoh=6/1, v/v) to obtain 26.7mg of yellow solid with yield of 14%;

LC-MS:(pos.ion)m/z：575.3[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.55(d,J＝7.3Hz,1H),7.28(d,J＝9.1Hz,3H),7.17(t,J＝7.6Hz,2H),6.84(d,J＝8.1Hz,1H),6.74(d,J＝7.3Hz,1H),4.12-4.00(m,2H),3.87(s,2H),3.77-3.70(m,2H),3.66(s,1H),3.14(s,4H),3.00(s,4H),2.85-2.78(m,2H),2.69-2.62(m,2H),2.53(s,4H),2.20(s,1H),2.18(s,3H),2.11-2.04(m,2H),1.93(s,3H),1.79(s,4H),1.66(s,4H).

example 49

2- (2- (3 ' - (3- (2, 7-diazaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [4.5] decane-7-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (660 mg,1.32 mmol) and tert-butyl 2, 7-diazaspiro [4.5] decane-7-carboxylate (470 mg,2.0 mmol) were added to N, N-dimethylformamide (20 mL), followed by potassium carbonate (2793 mg,2.0 mmol) and sodium iodide (292 mg,2.0 mmol) and heated to 70℃for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 300mg of the product as a yellow oil in 34.5% yield;

LC-MS:(pos.ion)m/z：661.4[M+1] ⁺ 。

Step 2) 2- (2- (3 ' - (3- (2, 7-diazaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of tert-butyl 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [4.5] decane-7-carboxylate (300 mg,0.45 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid and the mixture was reacted at room temperature for 3h. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (DCM/meoh=5/1, v/v), to give 27mg of yellow sticky material with a yield of 16%;

LC-MS:(pos.ion)m/z：561.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ8.64(s,1H),7.61(d,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.23(t,J＝7.9Hz,1H),7.16(d,J＝7.6Hz,1H),6.98(d,J＝8.2Hz,1H),6.73(d,J＝7.5Hz,1H),4.63(d,J＝26.8Hz,1H),4.10(d,J＝5.6Hz,2H),3.86(s,1H),3.62(d,J＝4.9Hz,2H),3.29(s,1H),2.97(s,4H),2.86(s,2H),2.71(s,2H),2.14(s,3H),2.09-1.95(m,3H),1.88(s,3H),1.66(s,4H),1.46(s,1H),1.35(d,J＝6.5Hz,1H),1.25(d,J＝9.2Hz,6H),0.86(t,J＝6.6Hz,1H).

example 50

2- (2- (3 ' - (3- (2, 6-diazaspiro [3.5] non-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 6- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 6-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (580 mg,1.16 mmol) and tert-butyl 2, 6-diazaspiro [3.5] nonane-2-carboxylate half oxalate (386 mg,0.71 mmol) were added to N, N-dimethylformamide (20 mL), followed by potassium carbonate (351 mg,2.54 mmol) and sodium iodide (229 mg,1.53 mmol) and heated to 70℃for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 323mg of the product as a yellow oil in 43.2% yield.

LC-MS:(pos.ion)m/z：647.4[M+1] ⁺ 。

Step 2) 2- (2- (3 ' - (3- (2, 6-diazaspiro [3.5] non-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of tert-butyl 6- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 6-diazaspiro [3.5] nonane-2-carboxylate (323 mg,0.5 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) and the mixture was reacted at room temperature for 3h. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (DCM/meoh=5/1, v/v), to give 43mg of yellow sticky substance, yield 16%;

LC-MS:(pos.ion)m/z：547.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ8.77(s,1H),7.60(d,J＝7.6Hz,1H),7.35(t,J＝7.6Hz,1H),7.22(t,J＝7.9Hz,1H),7.16(d,J＝7.4Hz,1H),6.97(d,J＝8.1Hz,1H),6.71(d,J＝7.5Hz,1H),4.64(d,J＝11.8Hz,1H),4.06(dd,J＝11.9,5.9Hz,2H),3.88(s,2H),3.66(s,3H),3.62(s,2H),2.97(s,2H),2.86(s,2H),2.72(s,2H),2.55(s,1H),2.37-2.29(m,1H),2.13(s,3H),1.96(s,2H),1.86(s,3H),1.61(s,2H),1.47(s,2H),1.36-1.33(m,1H),1.23(s,3H),0.85(t,J＝6.8Hz,1H).

Example 51

2- (2- (3 ' - (3- (2, 7-diazaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 3) 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -tert-butyl dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid ethyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (425 mg,0.85 mmol) and tert-butyl 2, 7-diazaspiro [3.5] nonane-7-carboxylate (250 mg,1.10 mmol) were dissolved in N, N-dimethylformamide (15 mL), potassium carbonate (350 mg,2.53 mmol) and sodium iodide (152 mg,1.01 mmol) were added and heated to 75℃and the reaction stirred for 8H. Stopping heating and cooling to room temperature. Water was added to dilute (80 mL), ethyl acetate was used for extraction (50 mL. Times.3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography (DCM/meoh=8/1, v/v) gave 520mg of tan dope in 94.85% yield;

LC-MS:(pos.ion)m/z：647.3[M+1] ⁺ 。

Step 4) 2- (2- (3 ' - (3- (2, 7-diazaspiro [3.5] non-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Ethyl 2- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -tert-butyl dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (520 mg,0.80 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added and the reaction stirred at room temperature for 12h. Stirring was stopped, the solvent was concentrated, saturated potassium carbonate solution (50 mL) was added, and stirring was performed at room temperature for 15min. Ethyl acetate extraction (30 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate. Silica gel column chromatography (DCM/meoh=10/1, v/v) gave 15mg of pale yellow dope in 3.4% yield;

LC-MS:(pos.ion)m/z：547.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.59(d,J＝7.6Hz,1H),7.35(t,J＝7.6Hz,1H),7.21(t,J＝7.8Hz,1H),7.15(d,J＝7.6Hz,1H),6.95(d,J＝8.2Hz,1H),6.70(d,J＝7.3Hz,1H),4.56(s,1H),4.03(d,J＝5.7Hz,2H),3.78(s,2H),3.58(s,4H),3.13(s,4H),2.95(s,4H),2.87(d,J＝4.7Hz,2H),2.83(s,2H),2.70(s,2H),2.64(t,J＝6.0Hz,2H),2.12(s,3H),1.86(s,3H),1.85(s,3H),1.80(s,2H).

example 52

9- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 9-diazaspiro [5.5] undec-2-one

Step 1) 2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (740 mg,1.33 mmol) and 1, 9-diazaspiro [5.5] undec-2-one hydrochloride (326 mg,1.6 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (458 mg,3.3 mmol) and sodium iodide (298 mg,2.0 mmol), and the mixture was heated to 70℃for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 590mg of a pale yellow solid with a yield of 69%;

LC-MS:(pos.ion)m/z：645.4[M+1] ⁺ 。

step 2) 9- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 9-diazaspiro [5.5] undec-2-one

To a solution of tert-butyl 2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (290 mg,0.45 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid and the mixture was reacted at room temperature for 3H. Stirring was stopped, the solvent was concentrated, dichloromethane (20 mL) and water (20 mL) were added, saturated sodium bicarbonate solution was added to adjust the system ph=8, dichloromethane extraction (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 180mg of yellow oil with a yield of 74%;

LC-MS:(pos.ion)m/z：545.3[M+1] ⁺ 。

Step 3) 9- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 9-diazaspiro [5.5] undecan-2-one

To methanol (20 mL) to which 9- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 9-diazaspiro [5.5] undec-2-one (180 mg,0.33 mmol) and an aqueous formaldehyde solution (50 mg,2 mmol) were added acetic acid until the pH of the system was adjusted to 5, nitrogen protection, reaction was continued at room temperature for 0.5h, and sodium cyanoborohydride (104 mg,1.65 mmol) was added to the system and reaction was continued at room temperature for 10h. Stirring was stopped, saturated potassium carbonate solution (50 mL) was added, stirred for 30min, extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 50mg of pale yellow solid with a yield of 27%;

LC-MS:(pos.ion)m/z：559.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.60(d,J＝7.6Hz,1H),7.43(s,1H),7.35(t,J＝7.7Hz,1H),7.21(t,J＝7.8Hz,1H),7.15(d,J＝7.4Hz,1H),6.96(d,J＝8.2Hz,1H),6.70(d,J＝7.5Hz,1H),4.04(dd,J＝12.1,5.9Hz,2H),3.67(s,2H),2.83(d,J＝5.3Hz,2H),2.76(t,J＝5.4Hz,4H),2.64(s,2H),2.41(s,3H),2.13(s,3H),2.08(d,J＝5.3Hz,2H),1.97(d,J＝7.0Hz,2H),1.85(s,3H),1.68(dd,J＝17.1,7.5Hz,3H),1.63(s,5H),1.23(s,2H).

example 53

7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-aza-spiro [4.5] decane

Step 1) 2- (3 ' - (3- (2-oxa-7-azaspiro [4.5] dec-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] 3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (380 mg,0.68 mmol) and 2-oxa-7-azaspiro [4.5] decane hydrochloride (182 mg,1.0 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (283 mg,2.0 mmol) and sodium iodide (153 mg,1.0 mmol), and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 400mg of product as a red oil with a yield of 95%;

LC-MS:(pos.ion)m/z：618.4[M+1] ⁺ 。

step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-aza-spiro [4.5] decane

To a solution of tert-butyl 2- (3 ' - (3- (2-oxa-7-azaspiro [4.5] dec-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (400 mg,0.65 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stirring was stopped, the solvent was concentrated, dichloromethane (20 mL) and water (20 mL) were added, saturated sodium bicarbonate solution was added to adjust the system ph=8, dichloromethane extraction (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 310mg of yellow oil in 98% yield;

LC-MS:(pos.ion)m/z：518.4[M+1] ⁺ 。

Step 3) 7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-aza-spiro [4.5] decane

To methanol (20 mL) to which 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-aza-spiro [4.5] decane (450 mg,1.51 mmol) and aqueous formaldehyde (131 mg,4.3 mmol) were added acetic acid until the pH of the system was adjusted = 5, nitrogen protection, reaction at room temperature was carried out for 0.5h, and sodium cyanoborohydride (279 mg,4.34 mmol) was added to the system, nitrogen protection was carried out, and the reaction was continued at room temperature for 10h. Stirring was stopped, saturated potassium carbonate solution (50 mL) was added, stirred for 30min, extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 130mg of yellow oil in 28% yield;

LC-MS:(pos.ion)m/z：532.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.59(d,J＝7.7Hz,1H),7.33(t,J＝7.6Hz,1H),7.20(t,J＝7.9Hz,1H),7.14(d,J＝7.5Hz,1H),6.94(d,J＝8.2Hz,1H),6.68(d,J＝7.5Hz,1H),4.03(d,J＝5.2Hz,2H),3.69-3.62(m,4H),3.54(d,J＝8.3Hz,1H),3.31(d,J＝8.3Hz,1H),2.82(d,J＝5.1Hz,2H),2.74(t,J＝5.5Hz,2H),2.43(t,J＝6.8Hz,3H),2.39(s,3H),2.31-2.22(m,1H),2.12(s,3H),1.89(dd,J＝12.8,6.3Hz,2H),1.84(s,3H),1.69(d,J＝5.9Hz,1H),1.58-1.47(m,2H),1.42(d,J＝10.4Hz,2H),1.37-1.29(m,1H),1.21(s,2H).

example 54

7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-azaspiro [3.5] nonane

Step 1) 2- (3 ' - (3- (2-oxa-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To N, N-dimethylformamide (20 mL) to which were added tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (350 mg,0.63 mmol) and 2-oxa-7-azaspiro [3.5] nonanoate (205 mg,0.94 mmol), potassium carbonate (390 mg,2.8 mmol) and sodium iodide (141 mg,0.94 mmol) were added and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 150mg of the product as a yellow oil in 40% yield;

LC-MS:(pos.ion)m/z：604.4[M+1] ⁺ 。

step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-azaspiro [3.5] nonane

To dichloromethane (20 mL) to which was added tert-butyl 2- (3 ' - (3- (2-oxa-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (150 mg,0.25 mmol), trifluoroacetic acid (4 mL) was added and reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 125mg of yellow oil, yield 100%;

LC-MS:(pos.ion)m/z：504.4[M+1] ⁺ 。

Step 3) 7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-azaspiro [3.5] nonane

To methanol (20 mL) to which 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-azaspiro [3.5] nonane (240 mg,0.48 mmol) and aqueous formaldehyde (80 mg,3 mmol) were added acetic acid, the pH of the system was adjusted to 5, nitrogen protection, room temperature reaction was continued for 0.5h, and sodium cyanoborohydride (150 mg,2.39 mmol) was added to the system, nitrogen protection was continued at room temperature for 10h. Stirring was stopped, saturated potassium carbonate solution (50 mL) was added, stirred for 30min, extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 50mg of yellow oil in 20% yield;

LC-MS:(pos.ion)m/z：518.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.60(d,J＝7.7Hz,1H),7.35(t,J＝7.6Hz,1H),7.21(t,J＝7.9Hz,1H),7.15(d,J＝7.4Hz,1H),6.96(d,J＝8.2Hz,1H),6.71(d,J＝7.5Hz,1H),4.31(s,4H),4.06(td,J＝9.5,3.6Hz,2H),3.74(s,2H),2.98-2.73(m,10H),2.45(s,3H),2.13(s,4H),1.97(d,J＝2.9Hz,4H),1.86(s,3H),1.22(s,1H).

example 55

6- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-azaspiro [3.4] octan-2-ol

Step 1) 6-azaspiro [3.4] octan-2-ol trifluoroacetate salt

To a solution of tert-butyl 2-hydroxy-6-azaspiro [3.4] octane-6-carboxylate (500 mg,2.2 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 3h. Stirring was stopped and the solvent was concentrated to give 500mg of the product as a red oil in 94% yield.

LC-MS:(pos.ion)m/z：128.1[M+1] ⁺ 。

Step 2) 2- (3 ' - (3- (2-hydroxy-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To N, N-dimethylformamide (20 mL) to which were added tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (290 mg,0.52 mmol) and 6-azaspiro [3.4] octan-2-ol trifluoroacetate (99.2 mg,0.78 mmol), potassium carbonate (108 mg,0.78 mmol) and sodium iodide (117 mg,0.78 mmol) were added and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 270mg of the product as a red oily liquid in 89.86% yield;

LC-MS:(pos.ion)m/z：604.3[M+1] ⁺ 。

step 3) 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-azaspiro [3.4] octan-2-ol

To a solution of tert-butyl 2- (3 ' - (3- (2-hydroxy-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (270 mg,0.45 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 220mg of yellow oil, yield 98%;

LC-MS:(pos.ion)m/z：504.2[M+1] ⁺ 。

Step 4) 6- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-azaspiro [3.4] octan-2-ol

To methanol (20 mL) to which 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -6-azaspiro [3.4] octan-2-ol (240 mg,0.48 mmol) and aqueous formaldehyde (80 mg,3.0 mmol) were added acetic acid, the pH of the system was adjusted to 5, nitrogen protection, room temperature reaction was continued for 0.5h, and sodium cyanoborohydride (150 mg,2.4 mmol) was added to the system, nitrogen protection was continued at room temperature for 10h. Stirring was stopped, saturated potassium carbonate solution (50 mL) was added, stirred for 30min, extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 42mg of pale yellow solid with 17% yield;

LC-MS:(pos.ion)m/z：518.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.61(d,J＝7.7Hz,1H),7.36(t,J＝7.6Hz,1H),7.23(t,J＝7.9Hz,1H),7.16(d,J＝7.4Hz,1H),6.98(d,J＝8.2Hz,1H),6.72(d,J＝7.5Hz,1H),4.12-3.99(m,3H),3.69(s,2H),3.09(s,6H),2.85(d,J＝4.9Hz,2H),2.79(d,J＝5.1Hz,2H),2.42(s,3H),2.37(d,J＝7.9Hz,1H),2.27-2.19(m,1H),2.14(s,3H),2.12(s,2H),1.97-1.90(m,3H),1.87(s,4H),1.23(s,1H).

example 56

7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-aza-spiro [4.4] nonane

Step 1) 2- (3 ' - (3- (2-oxa-7-azaspiro [4.4] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (330 mg,0.59 mmol) and 2-oxa-7-azaspiro [4.4] nonane (113 mg,0.89 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (123 mg,0.89 mmol) and sodium iodide (133 mg,0.89 mmol), and the mixture was heated to 70℃to react for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 275mg of a reddish brown oily product in 77% yield;

LC-MS:(pos.ion)m/z：604.5[M+1] ⁺ 。

step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-azaspiro [4.4] nonane

To a solution of tert-butyl 2- (3 ' - (3- (2-oxa-7-azaspiro [4.4] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (275 mg,0.46 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 196mg of yellow oil with a yield of 85%;

LC-MS:(pos.ion)m/z：504.3[M+1] ⁺ 。

Step 3) 7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-aza-spiro [4.4] nonane

To methanol (20 mL) to which 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-7-azaspiro [4.4] nonane (196 mg,0.39 mmol) and aqueous formaldehyde (60 mg,2.0 mmol) were added acetic acid until the pH of the system was adjusted = 5, nitrogen protection, reaction was performed at room temperature for 0.5h, and sodium cyanoborohydride (122 mg,1.94 mmol) was added to the system, nitrogen protection, and reaction was continued at room temperature for 10h. Stirring was stopped, saturated potassium carbonate solution (50 mL) was added, stirred for 30min, extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 103mg of pale yellow solid with a yield of 51%;

LC-MS:(pos.ion)m/z：518.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.59(d,J＝7.6Hz,1H),7.34(t,J＝7.7Hz,1H),7.21(t,J＝7.9Hz,1H),7.14(d,J＝7.4Hz,1H),6.96(d,J＝8.2Hz,1H),6.70(d,J＝7.5Hz,1H),4.12-4.02(m,2H),3.72(dd,J＝12.3,4.8Hz,4H),3.67(s,2H),2.99-2.87(m,5H),2.84(d,J＝3.2Hz,2H),2.77(t,J＝5.5Hz,2H),2.41(s,3H),2.13(s,3H),2.07-1.98(m,2H),1.92-1.89(m,1H),1.88-1.83(m,6H),1.21(s,1H).

example 57

7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-2-ol

Step 1) 2- (3 ' - (3- (2-hydroxy-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.7 g,1 mmol) and 7-azaspiro [3.5] nonane-2-ol hydrochloride (0.6 g,3 mmol) were dissolved in N, N-dimethylformamide (15.1 mL), followed by potassium carbonate (0.9 g,7 mmol) and sodium iodide (0.2 g,1 mmol) and stirred at 75℃for 11H. Stopping stirring, cooling to room temperature, adding water (30 mL), diluting, extracting with ethyl acetate (30 mL×3), mixing the organic phases, drying with anhydrous sodium sulfate, suction filtering, washing, and concentrating to obtain yellow oily liquid, which is directly used in the next step;

LC-MS:(pos.ion)m/z：618.2[M+1] ⁺ 。

step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-2-ol

2- (3 ' - (3- (2-hydroxy-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.8 g,1 mmol) was dissolved in dichloromethane (8.1 mL), dioxane hydrochloride solution (20.2 mL,81 mmol) was added and stirred at room temperature for 5H. Stopping stirring, concentrating the system, adding water (30 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (30 mL×2) and dichloromethane (30 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, and directly carrying out suction filtration, washing and concentration for the next step;

LC-MS:(pos.ion)m/z：518.4[M+1] ⁺ 。

Step 3) 7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-2-ol

7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-2-ol (0.7 g,1 mmol), aqueous formaldehyde (0.5 mL,7 mmol) was dissolved in methanol (20.1 mL), acetic acid (0.5 mL,9 mmol) was added, nitrogen sparged, stirred at room temperature for 30min, sodium cyanoborohydride (0.4 g,6 mmol) was added, nitrogen sparged, and stirred at room temperature for 10h. The stirring was stopped, the reaction was quenched with hydrochloric acid (0.5 m,10 mL), concentrated to remove methanol, saturated sodium bicarbonate (30 mL) was added, the aqueous phase was extracted sequentially with ethyl acetate (25 ml×2), dichloromethane (25 ml×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered off with suction, washed, concentrated, chromatographed on a silica gel column (DCM/meoh=10/1, v/v) to give 0.13g of yellow solid in 20% yield;

LC-MS:(pos.ion)m/z：532.4[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.54(s,1H),7.26(s,1H),7.16(s,2H),6.79(d,J＝43.3Hz,2H),4.36-4.18(m,1H),4.04(s,2H),3.73(s,2H),3.01(s,2H),2.87(s,2H),2.53(s,5H),2.37(s,4H),2.23(s,3H),2.17(s,3H),2.02(s,2H),1.93(s,3H),1.63(t,J＝25.2Hz,6H).

example 58

9- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -3-oxa-9-azaspiro [5.5] undecane

Step 1) 3-oxa-9-azaspiro [5.5] undecane trifluoroacetate salt

To a solution of 3-oxa-9-azaspiro [5.5] undecane-9-carboxylic acid tert-butyl ester (500 mg,2.0 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 3h. Stirring was stopped and the solvent was concentrated to give 520mg of the product as a red oil in 99% yield.

LC-MS:(pos.ion)m/z：156.3[M+1] ⁺ 。

Step 2) 2- (3 ' - (3- (3-oxa-9-azaspiro [5.5] undecan-9-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To N, N-dimethylformamide (20 mL) to which were added tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (270 mg,0.48 mmol) and 3-oxa-9-azaspiro [5.5] undecane trifluoroacetate (113 mg,0.73 mmol), potassium carbonate (100 mg,0.72 mmol) and sodium iodide (109 mg,0.73 mmol) were added and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 275mg of the product as a red oily liquid with a yield of 89.86%;

LC-MS:(pos.ion)m/z：632.3[M+1] ⁺ 。

step 3) 9- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -3-oxa-9-azaspiro [5.5] undecane

To a solution of tert-butyl 2- (3 ' - (3- (3-oxa-9-azaspiro [5.5] undec-9-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (375 mg,0.59 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 310mg of red oil with 98% yield;

LC-MS:(pos.ion)m/z：532.3[M+1] ⁺ 。

step 4) 9- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -3-oxa-9-azaspiro [5.5] undecane

To methanol (20 mL) to which 9- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -3-oxa-9-azaspiro [5.5] undecane (340 mg,0.64 mmol) and aqueous formaldehyde (100 mg,3.0 mmol) were added, acetic acid was added, the pH of the system was adjusted=5, nitrogen protection was performed, room temperature reaction was performed for 0.5h, and sodium cyanoborohydride (200 mg,3.2 mmol) was further added to the system, nitrogen protection was performed, and the reaction was continued at room temperature for 10h. Stirring was stopped, saturated potassium carbonate solution (50 mL) was added, stirred for 30min, extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 142mg of pale yellow solid with 41% yield;

LC-MS:(pos.ion)m/z：546.3[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.60(d,J＝7.6Hz,1H),7.34(t,J＝7.7Hz,1H),7.21(t,J＝7.9Hz,1H),7.15(d,J＝7.5Hz,1H),6.96(d,J＝8.2Hz,1H),6.71(d,J＝7.5Hz,1H),4.06(dd,J＝12.3,6.2Hz,2H),3.66(s,2H),3.55-3.51(m,4H),2.84(d,J＝5.3Hz,4H),2.77(d,J＝5.1Hz,6H),2.41(s,3H),2.14(s,3H),2.09-2.00(m,2H),1.86(s,3H),1.59(s,4H),1.42(s,4H).

Example 59

6- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-6-azaspiro [3.4] octane

Step 1) 2- (3 ' - (3- (2-oxa-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (430 mg,0.77 mmol) and 2-oxa-6-azaspiro [3.4] octane half oxalate (171 mg,0.54 mmol) in N, N-dimethylformamide (20 mL) were added potassium carbonate (320 mg,2.3 mmol) and sodium iodide (173 mg,1.15 mmol), and the mixture was heated to 70℃to react for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 347mg of product as a red oily liquid in 76.3% yield;

LC-MS:(pos.ion)m/z：590.3[M+1] ⁺ 。

step 2) 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-6-azaspiro [3.4] octane

To a solution of tert-butyl 2- (3 ' - (3- (2-oxa-6-azaspiro [3.4] oct-6-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (347 mg,0.59 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to give 280mg of red oil with 97% yield;

LC-MS:(pos.ion)m/z：490.2[M+1] ⁺ 。

step 3) 6- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-6-azaspiro [3.4] octane

To methanol (20 mL) to which 6- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -2-oxa-6-azaspiro [3.4] octane (298 mg,0.61 mmol) and aqueous formaldehyde (91 mg,3.0 mmol) were added acetic acid, the pH of the system was adjusted=5, nitrogen protection, room temperature reaction was continued for 0.5h, and sodium cyanoborohydride (191 mg,3.0 mmol) was added to the system, nitrogen protection was continued at room temperature for 10h. Stirring was stopped, saturated potassium carbonate solution (50 mL) was added, stirred for 30min, extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 90mg of pale yellow solid with 29% yield;

LC-MS:(pos.ion)m/z：504.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.60(d,J＝7.6Hz,1H),7.35(t,J＝7.7Hz,1H),7.22(t,J＝7.9Hz,1H),7.16(d,J＝7.5Hz,1H),6.97(d,J＝8.2Hz,1H),6.71(d,J＝7.5Hz,1H),4.54(d,J＝5.9Hz,2H),4.48(d,J＝5.9Hz,2H),4.08(d,J＝5.9Hz,2H),3.71(s,2H),3.21-3.11(m,1H),2.90(s,2H),2.85(d,J＝4.8Hz,3H),2.81(d,J＝4.8Hz,3H),2.43(s,3H),2.19(s,2H),2.14(s,3H),2.05(s,2H),1.86(s,3H),1.23(s,1H).

Example 60

7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one

Step 1) 2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 7-diazaspiro [4.4] non-7-yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.7 g,1 mmol) and 1, 7-diazaspiro [4.4] nonan-2-one 2, 2-trifluoroacetate (0.8 g,3 mmol) were dissolved in N, N-dimethylformamide (15.1 mL), followed by potassium carbonate (0.9 g,7 mmol) and sodium iodide (0.2 g,1 mmol) and stirred overnight at 75 ℃. Stopping stirring, cooling to room temperature, adding water (30 mL) for dilution, sequentially extracting the water phase with ethyl acetate (30 mL multiplied by 2) and dichloromethane (30 mL multiplied by 2), combining the organic phases, drying with anhydrous sodium sulfate, carrying out suction filtration, washing and concentrating to obtain yellow oily liquid, and directly using the yellow oily liquid in the next step;

LC-MS:(pos.ion)m/z：617.2[M+1] ⁺ 。

step 2) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one

2- (2, 2' -dimethyl-3 ' - (3- (2-oxo-1, 7-diazaspiro [4.4] non-7-yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.8 g,1 mmol) was dissolved in dichloromethane (8.1 mL), dioxane hydrochloride solution (20.2 mL,81 mmol) was added, stirring at room temperature for 5H, stirring stopped, the system was concentrated, diluted with water (30 mL), potassium carbonate solution (ph=9) was added to adjust the pH of the system to 7-8, extracted sequentially with ethyl acetate (30 ml×2) and dichloromethane (30 ml×2), the organic phase was collected and dried over anhydrous sodium sulfate, suction filtered, washed and concentrated for the next step directly;

LC-MS:(pos.ion)m/z：517.4[M+1] ⁺ 。

Step 3) 7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one

7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -1, 7-diazaspiro [4.4] non-2-one (0.7 g,1 mmol), aqueous formaldehyde (0.5 mL,7 mmol) was dissolved in methanol (20.1 mL), acetic acid (0.5 mL,9 mmol) was added, nitrogen blanketed, stirred at room temperature for 30min, sodium cyanoborohydride (0.4 g,6 mmol) was added, nitrogen blanketed, and stirred at room temperature overnight. Stopping stirring, concentrating the system, adding water to dilute (10 mL), adding hydrochloric acid (0.5M, 10 mL) to quench the reaction, adding saturated sodium bicarbonate (30 mL) to neutralize the system, extracting the aqueous phase with ethyl acetate (25 mL×2) and dichloromethane (25 mL×2) sequentially, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, suction filtering, washing and concentrating, and separating and purifying by a silica gel chromatographic column (DCM/MeOH=9/1, v/v) to obtain a white solid 123.9mg with the yield of 20%;

LC-MS:(pos.ion)m/z：531.1[M+1] ⁺ 。

¹ H NMR(600MHz,CDCl ₃ )δ7.54(d,J＝7.5Hz,1H),7.29-7.23(m,1H),7.18-7.14(m,2H),6.83(d,J＝8.2Hz,1H),6.73(d,J＝7.5Hz,1H),6.68(s,1H),4.11-4.01(m,2H),3.73(s,2H),3.01(t,J＝10.0Hz,2H),2.98-2.94(m,1H),2.87(t,J＝5.6Hz,3H),2.83(s,1H),2.71(t,J＝6.3Hz,2H),2.54(s,3H),2.51-2.45(m,2H),2.43-2.37(m,2H),2.17(s,3H),2.13-2.08(m,1H),2.05-2.01(m,4H),1.93(s,3H).

example 61

2- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -8-oxa-2-azaspiro [4.5] decane

Step 1) 2- (3 ' - (3- (8-oxa-2-azaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (441 mg,0.79 mmol) and 8-oxa-2-azaspiro [4.5] decane (167 mg,1.18 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (164 mg,1.19 mmol) and sodium iodide (178 mg,1.19 mmol), and the mixture was heated to 70℃for reaction for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=20/1, v/v) to give 392mg of product as a reddish brown oil in 80.21% yield;

LC-MS:(pos.ion)m/z：618.4[M+1] ⁺ 。

step 2) 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -8-oxa-2-azaspiro [4.5] decane

To a solution of tert-butyl 2- (3 ' - (3- (8-oxa-2-azaspiro [4.5] dec-2-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (399mg, 0.63 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL) and the mixture was reacted at room temperature for 3H. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain 320mg of red oil with 97% yield;

LC-MS:(pos.ion)m/z：518.4[M+1] ⁺ 。

Step 3) 2- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -8-oxa-2-azaspiro [4.5] decane

To methanol (20 mL) to which 2- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -8-oxa-2-azaspiro [4.5] decane (530 mg,1.0 mmol) and an aqueous formaldehyde solution (154 mg,5.0 mmol) were added, acetic acid was added, the pH of the system was adjusted=5, nitrogen protection was performed, room temperature reaction was performed for 0.5h, sodium cyanoborohydride (322 mg,5.12 mmol) was further added to the system, nitrogen protection was performed, and the reaction was continued at room temperature for 10h. Stirring was stopped, saturated potassium carbonate solution (50 mL) was added, stirred for 30min, extracted with dichloromethane (100 ml×3) and ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 130mg of pale red solid with 24% yield;

LC-MS:(pos.ion)m/z：532.2[M+1] ⁺ 。

¹ H NMR(400MHz,d ₆ -DMSO)δ7.60(d,J＝7.4Hz,1H),7.34(t,J＝7.7Hz,1H),7.21(t,J＝7.9Hz,1H),7.15(d,J＝7.4Hz,1H),6.96(d,J＝8.2Hz,1H),6.70(d,J＝7.5Hz,1H),4.06(dd,J＝11.6,5.7Hz,2H),3.54-3.50(m,6H),2.85(dd,J＝17.5,11.4Hz,5H),2.76(t,J＝5.4Hz,3H),2.40(s,3H),2.13(s,3H),2.06-1.97(m,2H),1.86(s,3H),1.72(t,J＝6.9Hz,2H),1.58-1.42(m,5H),1.22(s,1H).

example 62

7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-1-ol

Step 1) 7-azaspiro [3.5] non-1-ol hydrochloride

1-hydroxy-7-azaspiro [1-3] nonane-7-carboxylic acid tert-butyl ester (0.5 g,2 mmol) was dissolved in dioxane hydrochloride solution (15.0 mL,60.0 mmol), stirred at room temperature for 5h, stopped stirring, and the concentrated system was directly used in the next step;

LC-MS:(pos.ion)m/z：142.2[M+1] ⁺ 。

Step 2) 2- (3 ' - (3- (1-hydroxy-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.7 g,1 mmol) and 7-azaspiro [3.5] non-1-alkoxide (0.6 g,3 mmol) were dissolved in N, N-dimethylformamide (15.1 mL), followed by potassium carbonate (0.9 g,7 mmol) and sodium iodide (0.2 g,1 mmol) and stirred at 75℃for 11H. Stopping stirring, cooling to room temperature, adding water (30 mL), diluting, extracting with ethyl acetate (30 mL×3), mixing the organic phases, drying with anhydrous sodium sulfate, suction filtering, washing, and concentrating to obtain yellow oily liquid, which is directly used in the next step;

LC-MS:(pos.ion)m/z：618.2[M+1] ⁺ 。

step 3) 7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-1-ol

2- (3 ' - (3- (1-hydroxy-7-azaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.8 g,1 mmol) was dissolved in dichloromethane (8.1 mL), dioxane hydrochloride solution (20.2 mL,81 mmol) was added and stirred at room temperature for 5H. Stopping stirring, concentrating the system, adding water (30 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, extracting sequentially with ethyl acetate (30 mL×2) and dichloromethane (30 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, and concentrating for direct use in the next step;

LC-MS:(pos.ion)m/z：518.4[M+1] ⁺ 。

Step 4) 7- (3- ((2, 2' -dimethyl-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-1-ol

7- (3- ((2, 2' -dimethyl-3 ' - (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) oxy) propyl) -7-aza-spiro [3.5] non-1-ol (0.7 g,1 mmol) and aqueous formaldehyde (0.5 mL,7 mmol) were dissolved in methanol (20.1 mL), acetic acid (0.5 mL,9 mmol) was added, nitrogen blanketed, stirred at room temperature for 30min, sodium cyanoborohydride (0.4 g,6 mmol) was added, nitrogen blanketed, and stirred at room temperature for 10h. The stirring was stopped, the reaction was quenched with hydrochloric acid (0.5 m,10 mL), concentrated to remove methanol, the system was neutralized with saturated sodium bicarbonate (30 mL), the aqueous phase was extracted sequentially with ethyl acetate (25 ml×2), dichloromethane (25 ml×2), the organic phases were combined and dried over anhydrous sodium sulfate, washed with suction and concentrated, and purified by silica gel chromatography (DCM/meoh=10/1, v/v) to give 0.19g of yellow solid with a yield of 30%;

LC-MS:(pos.ion)m/z：532.4[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.54(d,J＝7.5Hz,1H),7.28-7.24(m,1H),7.16(t,J＝6.4Hz,2H),6.84(d,J＝8.1Hz,1H),6.73(d,J＝7.5Hz,1H),4.09-4.00(m,2H),3.90(t,J＝7.5Hz,1H),3.72(s,2H),3.01(t,J＝5.5Hz,2H),2.86(t,J＝5.7Hz,2H),2.80-2.79(m,1H),2.67-2.64(m,2H),2.56(s,1H),2.53(s,5H),2.27-2.20(m,2H),2.17(s,3H),2.12-2.00(m,3H),1.94(s,3H),1.84-1.70(m,3H),1.64(t,J＝10.9Hz,2H),1.47(d,J＝12.6Hz,1H).

example 63

2' -methyl-3- (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) -3' - (3- (2-oxo-1, 9-azaspiro [5.5] undecan-9-yl) propoxy) - [1,1' -biphenyl ] -2-carbonitrile

Step 1) 2- (3-bromo-2-cyanophenyl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2-bromo-6, 7-dihydrothiazolo [4,5-c]A mixed solution of pyridine-5 (4H) -carboxylic acid tert-butyl ester (1.0 g,3.1 mmol) in dioxane (30.1 mL) and water (5.1 mL) was added potassium carbonate (1.7 g,12 mmol), tetrabutylammonium bromide (0.2 g,0.6 mmol) and Pd (dppf) Cl ₂ (0.46 g,0.63 mmol), a solution of (3-bromo-2-cyanophenyl) boronic acid (1.4 g,6.2 mmol) in 1, 4-dioxane (20.1 mL) was added dropwise under nitrogen and refluxed for 10h at 95 ℃. Stirring was stopped, cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases combined and dried over anhydrous sodium sulfate, and purified by silica gel chromatography (PE/ea=6/1, v/v) to give 0.55g of yellow solid with a yield of 42%;

LC-MS:(pos.ion)m/z：421.0[M+1] ⁺ 。

step 2) 2- (3 ' - (3-bromopropyloxy) -2-cyano-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3- (3-bromopropyloxy) -2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (0.4G, 1 mmol), tert-butyl 2- (3-bromo-2-cyanophenyl) -6, 7-dihydrothiazolo [4,5-c ] pyridine-5 (4H) -carboxylate (0.39G, 0.93 mmol) was dissolved in tetrahydrofuran (9.3 mL), potassium phosphate solution (9.3 mL,4.7mmol, 0.5M) was added, nitrogen blanket, stirred at room temperature for 30min, XPhos-Pd-G2 (0.11G, 0.14 mmol) was added, nitrogen blanket, and stirred at room temperature for 30H. Stirring was stopped, the aqueous phase was extracted with ethyl acetate (30 ml×3), the organic phases were combined and dried over anhydrous sodium sulfate, washed with suction and concentrated, and purified by silica gel chromatography (PE/ea=3/1, v/v) to give 0.5g of red oil in 90% yield;

LC-MS:(pos.ion)m/z：569.9[M+1] ⁺ 。

Step 3) 2- (2-cyano-2 ' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3 ' - (3-bromopropyloxy) -2-cyano-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.5 g,0.9 mmol) and 1, 9-diazaspiro [5.5] undec-2-one hydrochloride (0.5 g,2 mmol) were dissolved in N, N-dimethylformamide (15.1 mL), followed by potassium carbonate (0.6 g,4 mmol) and sodium iodide (0.1 g,0.7 mmol) and stirred at 75℃for 10H. Stopping stirring, cooling to room temperature, diluting with water (15 mL), extracting with ethyl acetate (15 ml×3), combining the organic phases and drying over anhydrous sodium sulfate, suction filtration, washing and concentrating, and separating and purifying with silica gel chromatography column (DCM/meoh=10/1, v/v) to obtain yellow viscous oil 0.34g with a yield of 60%;

LC-MS:(pos.ion)m/z：656.1[M+1] ⁺ 。

step 4) 2' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) -3- (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -2-carbonitrile

2- (2-cyano-2 ' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydro [4,5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.383 g, 0.284 mmol) was dissolved in dichloromethane (12.1 mL), trifluoroacetic acid (4.2 mL) was added and stirred at room temperature for 5H. Stopping stirring, concentrating the system, adding water (15 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (15 mL×2) and dichloromethane (15 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, filtering, washing, concentrating to obtain yellow oily liquid, and directly using the yellow oily liquid in the next step;

LC-MS:(pos.ion)m/z：556.3[M+1] ⁺ 。

Step 5) 2' -methyl-3- (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) -3' - (3- (2-oxo-1, 9-azaspiro [5.5] undecan-9-yl) propoxy) - [1,1' -biphenyl ] -2-carbonitrile

2' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) -3- (4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) - [1,1' -biphenyl ] -2-carbonitrile (0.325 g,0.585 mmol) and aqueous formaldehyde (0.2 mL,3 mmol) were dissolved in methanol (15.1 mL), acetic acid (0.27 mL,4.7 mmol) was added, nitrogen blanketed, stirred at room temperature for 30min, sodium cyanoborohydride (0.184 g,2.93 mmol) was added, nitrogen blanketed, and stirred at room temperature for 7h. Stopping stirring, concentrating the system, adding water to dilute (20 mL), adding hydrochloric acid (0.5M, 20 mL) to quench the reaction, adding saturated sodium bicarbonate (30 mL) to neutralize the system, sequentially extracting the aqueous phase with ethyl acetate (30 mL×2) and dichloromethane (30 mL×2), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, suction-filtering, washing and concentrating, and separating and purifying by a silica gel chromatographic column (DCM/MeOH=9/1, v/v) to obtain 134.4mg of white solid with the yield of 40%;

LC-MS:(pos.ion)m/z：570.3[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.98(d,J＝7.9Hz,1H),7.66(t,J＝7.8Hz,1H),7.37(d,J＝7.6Hz,1H),7.24(t,J＝8.0Hz,1H),6.92(d,J＝8.1Hz,1H),6.85(d,J＝7.6Hz,1H),6.59(s,1H),4.09(t,J＝5.7Hz,2H),3.76(s,2H),3.04(t,J＝5.6Hz,2H),2.88(t,J＝5.8Hz,2H),2.79-2.61(m,6H),2.54(s,3H),2.33(t,J＝6.4Hz,2H),2.12-2.07(m,2H),2.04(s,3H),1.86-1.75(m,6H),1.73-1.69(m,2H).

example 64

2- (2- (3 ' - (3- (2, 7-diazaspiro [4.5] decan-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [4.5] decane-2-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (195 mg,0.39 mmol) and tert-butyl 2, 7-diazaspiro [4.5] decane-2-carboxylate half oxalate (155 mg,0.27 mmol) were added to N, N-dimethylformamide (20 mL), followed by potassium carbonate (161 mg,1.2 mmol) and sodium iodide (87 mg,0.6 mmol) and heated to 70℃and stirred for 16H. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 ml×3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (DCM/meoh=10/1, v/v) to give 114mg of the product as a yellow solid in 44% yield;

LC-MS:(pos.ion)m/z：661.4[M+1] ⁺ 。

step 2) 2- (2- (3 ' - (3- (2, 7-diazaspiro [4.5] decan-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

To a solution of tert-butyl 7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [4.5] decane-2-carboxylate (114 mg,0.17 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid and the mixture was reacted at room temperature for 3h. Stopping stirring, concentrating the solvent, adding dichloromethane (20 mL) and water (20 mL) for dissolution, adding saturated sodium bicarbonate solution to adjust the system ph=8, extracting with dichloromethane (50 ml×3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (DCM/meoh=5/1, v/v), to give 27mg of yellow sticky material with a yield of 28%;

LC-MS:(pos.ion)m/z：561.3[M+1] ⁺ 。

Example 65

3- (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -2-carbonitrile

Step 1) 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol

The synthesis of 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol is as described in example 12, step 1.

The synthesis of 2- (3- (3-bromopropyloxy) -2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane was as described in example 12, step 2.

Step 3) 2- (3-bromo-2-cyanophenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2-bromo-6, 7-dihydrothiazolo [5,4-c]A mixed solution of pyridine-5 (4H) -carboxylic acid tert-butyl ester (1.1 g,3.4 mmol) in 1, 4-dioxane (30.1 mL) and water (5.1 mL) was added potassium carbonate (1.9 g,14 mmol), tetrabutylammonium bromide (0.3 g,0.9 mmol) and Pd (dppf) Cl ₂ (0.5 g,0.7 mmol), a solution of (3-bromo-2-cyanophenyl) boronic acid (1.5 g,6.6 mmol) in 1, 4-dioxane (20.1 mL) was added dropwise under nitrogen and refluxed for 10h at 95 ℃. The stirring is stopped and the stirring is stopped, Cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases combined and dried over anhydrous sodium sulfate, purified by chromatography on silica gel column (PE/ea=6/1, v/v) to give 0.53g of yellow solid with a yield of 37%;

LC-MS:(pos.ion)m/z：420.9[M+1] ⁺ 。

step 4) 2- (3 ' - (3-bromopropyloxy) -2-cyano-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- (3- (3-bromopropyloxy) -2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (0.54G, 1.5 mmol), tert-butyl 2- (3-bromo-2-cyanophenyl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (0.53G, 1.3 mmol) was dissolved in tetrahydrofuran (13.0 mL), potassium phosphate solution (13.0 mL,6.5mmol, 0.5M) was added, nitrogen blanketed, stirred at room temperature for 30min, XPhos-Pd-G2 (0.15G, 0.19 mmol) was added, and stirred at room temperature. Stirring was stopped, the aqueous phase was extracted with ethyl acetate (30 ml×3), the organic phases were combined and dried over anhydrous sodium sulfate, washed with suction, concentrated, and purified by silica gel chromatography (PE/ea=3/1, v/v) to give 0.53g of yellow solid with a yield of 74%;

LC-MS:(pos.ion)m/z：569.9[M+1] ⁺ 。

step 5) 2- (2-cyano-2 ' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Tert-butyl 2- (3 ' - (3-bromopropyloxy) -2-cyano-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylate (0.53 g,0.93 mmol) and 1, 9-diazaspiro [5.5] undec-2-one hydrochloride (0.48 g,2.3 mmol) were dissolved in N, N-dimethylformamide (15.1 mL), followed by potassium carbonate (0.64 g,4.6 mmol) and sodium iodide (0.14 g,0.93 mmol) and stirred overnight at 75 ℃. Stirring was stopped, cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (15 ml×3), the combined organic phases dried over anhydrous sodium sulfate, washed with suction, concentrated, and purified by silica gel chromatography (DCM/meoh=10/1, v/v) to give 0.25g of yellow solid with a yield of 41%;

LC-MS:(pos.ion)m/z：656.1[M+1] ⁺ 。

step 6) 2' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) -3- (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -2-carbonitrile

2- (2-cyano-2 ' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (0.25 g,0.38 mmol) was dissolved in dichloromethane (12.1 mL), trifluoroacetic acid (4.2 mL) was added and stirred at room temperature for 4H. Stopping stirring, concentrating the system, adding water (15 mL), diluting, adding potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (15 mL×2) and dichloromethane (15 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, filtering, washing, concentrating to obtain yellow oily liquid, and directly using the yellow oily liquid in the next step;

LC-MS:(pos.ion)m/z：556.3[M+1] ⁺ 。

Step 7) 3- (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) - [1,1' -biphenyl ] -2-carbonitrile

2' -methyl-3 ' - (3- (2-oxo-1, 9-diazaspiro [5.5] undec-9-yl) propoxy) -3- (4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -2-carbonitrile (0.22 g,0.40 mmol) and 2-bromoethanol (42.0. Mu.L, 0.593 mmol) were dissolved in ethanol (10.1 mL), sodium carbonate (84.0 mg,0.793 mmol) and sodium iodide (59.0 mg,0.394 mmol) were added, and refluxed overnight at 80 ℃. Stopping stirring, concentrating the system under reduced pressure, diluting with water (30 mL), extracting the aqueous phase with ethyl acetate (30 ml×2) and dichloromethane (30 ml×2) in sequence, combining the organic phases and drying over anhydrous sodium sulfate, suction filtration, washing, concentrating, and separating and purifying with silica gel chromatography column (DCM/meoh=8/1, v/v), to obtain 71.9mg of yellow solid with a yield of 30%;

LC-MS:(pos.ion)m/z：600.4[M+1] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.96(d,J＝6.8Hz,1H),7.67(t,J＝7.7Hz,1H),7.38(d,J＝6.2Hz,1H),7.23(d,J＝8.4Hz,1H),6.92(d,J＝7.1Hz,1H),6.85(d,J＝7.3Hz,1H),6.28(s,1H),4.09(s,2H),3.89(s,2H),3.73(s,2H),3.02(s,4H),2.86-2.48(m,8H),2.34(t,J＝9.8Hz,2H),2.10(s,2H),2.05(s,3H),1.96-1.56(m,9H).

example 66

2- (2- (3 ' - (3- (2, 7-diazaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

Step 1) 7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazol [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester

2- (2- (3 ' - (3-bromopropyloxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol (0.35 g,0.70 mmol) and tert-butyl 2, 7-diazaspiro [3.5] nonane-2-carboxylate (0.24 g,1.1 mmol) were dissolved in N, N-dimethylformamide (10.1 mL), followed by potassium carbonate (0.24 g,1.7 mmol) and sodium iodide (0.1 g,0.7 mmol) and stirred at 75℃for 12H. Stopping stirring, cooling to room temperature, adding water (30 mL), diluting, extracting the water phase with ethyl acetate (30 mL×2), combining the organic phases, drying with anhydrous sodium sulfate, and suction filtering, washing and concentrating for the next step;

LC-MS:(pos.ion)m/z：647.3[M+1] ⁺ 。

step 2) 2- (2- (3 ' - (3- (2, 7-diazaspiro [3.5] non-7-yl) propoxy) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) -6, 7-dihydrothiazolo [5,4-c ] pyridin-5 (4H) -yl) ethanol

7- (3- ((3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazol [5,4-c ] pyridin-2-yl) -2,2' -dimethyl- [1,1' -biphenyl ] -3-yl) oxy) propyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (0.45 g,0.70 mmol) was dissolved in dichloromethane (5.1 mL), dioxane hydrochloride solution (15.2 mL,61 mmol) was added and stirred at room temperature for 5h. Stopping stirring, concentrating the system, adding water (20 mL), diluting the system, adding a potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (20 mL×2) and dichloromethane (20 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, carrying out suction filtration, washing, concentrating and preparation separation, adding water for dilution, adding a potassium carbonate solution (pH=9) to adjust the pH of the system to 7-8, sequentially extracting with ethyl acetate (20 mL×2) and dichloromethane (20 mL×2), collecting an organic phase, drying with anhydrous sodium sulfate, carrying out suction filtration, washing, concentrating, separating to obtain 17.0mg of yellow sticky matter with the yield of 5 percent;

LC-MS:(pos.ion)m/z：547.3[M+1] ⁺ 。

¹ H NMR(600MHz,d ₆ -DMSO)δ7.60(d,J＝7.9Hz,1H),7.37(t,J＝7.6Hz,1H),7.23(t,J＝7.9Hz,1H),7.16(d,J＝7.6Hz,1H),6.98(d,J＝8.2Hz,1H),6.73(d,J＝7.4Hz,1H),4.13-4.05(m,2H),3.73(s,4H),3.65-3.60(m,3H),3.58-3.55(m,2H),3.50-3.49(m,2H),3.34(s,2H),3.32(d,J＝3.3Hz,2H),3.31-3.24(m,4H),2.87(s,2H),2.72(s,2H),2.55(s,1H),2.14(s,3H),2.06-1.94(m,4H),1.87(s,3H).

In vitro antitumor Activity assay of the Compounds of the invention

The detection method of the in vitro enzymatic level adopts a detection kit of the Cisbio company PD-1/PD-L1 binding assay kit

1. Experimental principle:

PD-1 protein carries an HIS tag, PD-L1 ligand of PD-1 carries an hFc tag, and Eu-labeled anti-hFc antibody and XL 665-labeled anti-HIS antibody are respectively combined with the two tag proteins. After laser excitation, energy can be transferred from the donor Eu to the acceptor XL665, causing the XL665 to emit light. After the inhibitor is added, the combination of PD-1 and the ligand PD-L1 is blocked, so that Eu and XL665 are far away, energy cannot be transferred, and XL665 does not emit light.

2. The experimental method comprises the following steps:

PD-1/PD-L1 binding assays were performed using the HTRF assay kit from Cisbio Bioassys (catalog number 64ICP01 PEG), and specific procedures were performed with reference to the kit instructions. Briefly described, compounds were dissolved in DMSO solution at a concentration of 10mM using 384 well white elisa plates. Stock solutions of compounds were first diluted 40-fold with diluent and then diluted 5-fold with kit dilution buffer containing 2.5% dmso. To each well 4 μl of the diluent or diluted target compound was added and the final DMSO concentration was 0.5%. PD1 and PD-L1 solubles The solution was added at 3. Mu.l per well, and 10. Mu.l of the detection antibody prepared according to the product instructions was added to each well after pre-incubation of the compound with PD1 and PD-L1 for 10 minutes. After incubating the plates overnight at room temperature, data were obtained by reading the plates in a PHARMASTAR FS microplate reader (BMG, germany). The HTRF signal is calculated to be 10000× (665/620 ratio). The calculated signals for each compound were fit to an S-shaped dose-response curve with variable slope and IC was obtained by curve fitting (GraphPad Prism 7) ₅₀ Values.

The experimental results are as follows:

TABLE 2 Experimental results of the inhibitory Activity of the Compounds of the invention on the molecular level on the PD-1/PD-L1 interaction

Examples numbering	IC ₅₀ (nM)	Examples numbering	IC ₅₀ (nM)	Examples numbering	IC ₅₀ (nM)
						1	5.5	24	10.2	48	6.4
5	1.95	25	5.7	49	7.3
						6	4.43	26	4.2	50	9.0
7	12.0	27	3.8	52	2.6
						8	10.0	28	3.6	53	2.6
9	10.1	31	3.7	54	4.2
						10	9.6	32	7.3	55	1.08
11	4.3	36	4.3	56	1.79
						12	7.9	38	8.7	57	2.01
16	8.6	39	4.6	58	2.08
						17	4.5	40	3.2	59	1.42
19	4.6	41	4.2	60	0.76
						20	4.4	42	7.0	61	3.23
21	3.4	43	12.2	62	2.40
						22	3.6	45	4.2
23	5.5	47	5.4

Conclusion of experiment:

as can be seen from the table, the compounds of the present invention significantly inhibit the interaction of PD-1 with PD-L1 at the molecular level and are therefore useful in the treatment of diseases associated with the interaction of PD-1/PD-L1.

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

1. A compound represented by formula (I)

Or a pharmaceutically acceptable salt of a compound of formula (I), wherein:

X ¹ selected from O or S;

X ² selected from N;

R ¹ 、R ² together with the carbon atoms to which they are attached, form a ring B, which is one of the groups formed by the following structural formulae:

wherein Z is ₁ And Z ₂ Each independently is CH ₂ NH, S or O; the ring B may be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^b ；

Each R is as follows ^b Independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy, ethoxy, or acetyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, methoxy, and ethoxy groups may independently be optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of R ^e ；

Each R is as follows ^e Independently selected from the group consisting of-D, -OH, -CN, -NH ₂ Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy and ethoxy groups may independently be optionally substituted with 1, 2 or 3 substituents selected from-OH, -CN or-NH ₂ ；

A is

p and q are each independently 0, 1, 2, 3 or 4;

R ³ is that

R ⁶ And R is ⁷ Each independently selected from-H, -D, C _1-6 Alkyl or C _1-6 An alkanoyl group;

or R is ⁶ 、R ⁷ Together with the nitrogen atom to which they are attached, form a heterocycle C, which is one of the groups formed by the following structural formulae:

wherein W is ₁ And W is ₂ Each independently is CH ₂ NH, S or O; the heterocyclic ring C may be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^c ；

m is 1, 2, 3 or 4;

each R is ^c Independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN, -NH ₂ 、-CONH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy or C _1-6 Alkanoyl, wherein said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino, C _1-6 Alkoxy and C _1-6 Alkanoyl groups may independently be optionally substituted with 1, 2, 3 or 4 substituents selected from R ^f ；

Each R is ^f Independently selected from the group consisting of-D, -OH, -CN, oxo, -NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkylamino or C _1-6 An alkoxy group.

2. The compound of claim 1, wherein the heterocycle C is one of the groups formed by the following structural formula:

wherein the heterocycle C may be optionally substituted with 1, 2, 3 or 4 substituents each independently selected from R ^c ；

Each R is as follows ^c Independently selected from the group consisting of-D, -F, -Cl, -Br, -I, oxo, -OH, -CN,-NH ₂ 、-CONH ₂ Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy, ethoxy or acetyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy, ethoxy and acetyl groups may independently optionally be substituted with 1, 2, 3 or 4 substituents selected from R ^f ；

Each R is as follows ^f Independently selected from-OH, -CN, -NH ₂ Or methyl.

3. The compound of claim 1, wherein R ⁶ And R is ⁷ Each independently selected from-H, -D, methyl, ethyl or acetyl.

4. The compound of claim 1, which is a compound of formula (II), or a pharmaceutically acceptable salt thereof;

5. a compound comprising a compound of one of the following or a pharmaceutically acceptable salt of a compound of one of the following:

6. a pharmaceutical composition comprising a compound according to any one of claims 1-5, and pharmaceutically acceptable excipients or combinations thereof.

7. Use of a compound according to any one of claims 1-5 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the treatment, prevention, amelioration, control or alleviation of a disease associated with the PD-1/PD-L1 signaling pathway in a patient; wherein the disease related to PD-1/PD-L1 signaling pathway is cancer, an infectious disease or an autoimmune disease.

8. The use of claim 7, wherein the cancer comprises bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, hodgkin's disease, non-hodgkin's lymphoma, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary tract cancer, penile cancer, chronic or acute leukemia, childhood solid tumors, lymphomas, bladder cancer, renal or ureteral cancer, renal pelvis cancer, central nervous system tumors, primary CNS lymphomas, tumor angiogenesis, spinal tumors, brain stem glioma, pituitary adenomas, kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, and environmentally induced cancers, and combinations thereof; wherein the chronic or acute leukemia comprises acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia; wherein the infectious disease comprises aids, hepatitis a, hepatitis b, hepatitis c, hepatitis d, herpes virus infection, papillomavirus infection, and influenza; wherein the autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, syndrome of pulmonary hemorrhagic nephritis, primary biliary cirrhosis, multiple cerebral spinal sclerosis, acute idiopathic polyneuritis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.