CN114805311A

CN114805311A - Spirocyclic indenes

Info

Publication number: CN114805311A
Application number: CN202210064472.8A
Authority: CN
Inventors: 李超; 陈建勇; 胡文亮; 吴成喆; 黎流根; 叶高洁
Original assignee: Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Current assignee: Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Priority date: 2021-01-21
Filing date: 2022-01-21
Publication date: 2022-07-29
Also published as: WO2022156761A1

Abstract

The present disclosure provides compounds represented by formula I, wherein R ³ ,R ^8c ,R ^8d ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,E ¹ L, Q, Z, and

as defined in the specification, and pharmaceutically acceptable salts and solvates thereof. The compounds of formula I are KRAS inhibitors and are therefore useful in the treatment of cancer and other diseases.

Description

Spirocyclic indenes

Technical Field

The present invention provides KRAS inhibitors, synthetic intermediates useful for preparing KRAS inhibitors, and therapeutic methods for treating diseases and diseases (e.g., cancer) in which inhibition of KRAS would provide a benefit.

Background

RAS represents a group of 189 amino acid (molecular mass 21kDa) monomeric globular proteins associated with the plasma membrane and binding GDP or GTP. RAS acts as a molecular switch. When the RAS contains bound GDP, it will be in the resting or closed position and be "inactive". In response to exposure of the cells to certain growth-promoting stimuli, RAS will be induced to switch its bound GDP to GTP. Upon binding to GTP, RAS will be "turned on" and able to interact with and activate other proteins (their "downstream targets"). The inherent ability of RAS proteins to hydrolyze GTP back to GDP to turn itself off is very low. Turning RAS off requires an exogenous protein called the GTPase Activating Protein (GAP) that interacts with RAS and greatly accelerates the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAPs or convert GTP back to GDP will result in prolonged activation of the protein and thus prolonged signaling to the cell that tells it to continue growing and dividing. Because these signals lead to cell growth and division, hyperactive RAS signaling may ultimately lead to cancer. The most important RAS members are HRAS, KRAS and NRAS.

Structurally, the RAS protein contains a G domain that is responsible for the enzymatic activity of RAS, i.e., guanine nucleotide binding and hydrolysis (GTPase reaction). It also contains a C-terminal extension called the CAAX box, which can be post-translationally modified and is responsible for targeting the protein to the membrane. The G domain is approximately 21-25kDa in size and contains a phosphate binding ring (P-ring). The P-loop represents the pocket (pocket) to which nucleotides bind in proteins, and this is the rigid part of the domain with conserved amino acid residues (glycine 12, threonine 26 and lysine 16) that are essential for nucleotide binding and hydrolysis. The G domain also contains the switch I (residues 30-40) and switch II (residues 60-76) regions, both of which are dynamic parts of the protein, often denoted as "spring-loaded" mechanisms due to its ability to switch between resting and loaded states. The key interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the gamma-phosphate of GTP, which maintains the switch 1 and switch 2 regions, respectively, in their active conformations. After hydrolysis of GTP and release of phosphate, both relax into the inactive GDP conformation.

Mutations in the KRAS gene are a common event in human tumorigenesis. Indeed, mutations in KRAS are common in some of the most fatal cancer types: pancreatic cancer (95%), colorectal cancer (45%) and lung cancer (35%). The most common KRAS mutations are found at residues G12 and G13 and at residue Q61 in the P-loop.

Glycine-12 to cysteine (G12C) mutations are frequent mutations in the KRAS gene. This mutation has a causal relationship in 14% of lung adenocarcinomas and 5% of colorectal adenocarcinomas. Overall, KRAS-G12C mutation is implicated in a population of >100,000 individuals per year worldwide. See, e.g., Fell et al, ASC Med. chem. Lett.9:1230-1234 (2018); shin et al, ACS Med. chem. Lett.10: 1302-; canon et al, Nature 575: 217-. There is a need in the art for KRAS inhibitors for the treatment of cancer and other diseases.

Disclosure of Invention

In one aspect, the invention provides compounds represented by any one of the following formulas I-XV, LXII or LXIII, and pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof, collectively referred to as "compounds of the present disclosure. The compounds of the present disclosure are inhibitors of KRAS and thus may be used to treat or prevent diseases or disorders, such as cancer, in which inhibition of KRAS would provide a benefit.

In another aspect, the present disclosure provides compounds represented by any one of the following formulas XVI-LXI, and pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof, collectively referred to as "intermediates of the present disclosure". The intermediates of the present disclosure are synthetic intermediates useful for preparing the compounds of the present disclosure.

In another aspect, the present disclosure provides methods of treating or preventing a disease or disorder by administering to a subject, e.g., a human patient, in need thereof a therapeutically effective amount of a compound of the present disclosure. Target diseases or disorders treatable or preventable by inhibition of KRAS are, for example, cancer, chronic autoimmune disorders, inflammatory diseases, proliferative disorders, sepsis or viral infections. Also provided are methods of preventing proliferation of undesired proliferating cells (as in cancer) in a subject, comprising administering to a subject at risk of developing a disease characterized by undesired proliferating cells a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the compounds of the present disclosure can reduce proliferation of these undesirable cells by inducing apoptosis. In some embodiments, the compounds of the present disclosure are administered in combination with an optional therapeutic agent.

In another aspect, the present disclosure provides a method of inhibiting KRAS in a subject comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and/or a pharmaceutically acceptable carrier.

In another aspect, the present disclosure provides a composition comprising a compound of the present disclosure and an excipient and/or a pharmaceutically acceptable carrier for use in treating or preventing a disease or disorder in which inhibition of KRAS would provide a benefit, such as cancer.

In another aspect, the present disclosure provides a composition comprising: (a) a compound of the present disclosure; (b) a second therapeutically active agent; and (c) optionally an excipient and/or a pharmaceutically acceptable carrier.

In another aspect, the disclosure provides a compound of the disclosure for use in the treatment or prevention of a disease or disorder of interest (e.g., cancer).

In another aspect, the present disclosure provides the use of a compound of the present disclosure for the manufacture of a medicament for treating a target disease or disorder (e.g., cancer).

In another aspect, the disclosure provides a kit comprising a compound of the disclosure and optionally a packaged composition comprising an optional therapeutic agent useful in the treatment of a disease or disorder of interest, and a package insert containing instructions for use in the treatment of the disease or disorder (e.g., cancer).

In another aspect, the present disclosure provides methods of making compounds of the present disclosure and intermediates of the present disclosure.

Additional embodiments and advantages of the present disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the present disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

It is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

Detailed Description

I. Compounds of the present disclosure

In one embodiment, the compounds of the present disclosure are of formula I:

wherein

Z is

X represents a 6-to 12-membered monocyclic or bicyclic heterocycle;

R ¹ is selected from-C (═ O) R ^1a ,-C(＝O)-CR ^4a ＝CR ^4b R ^4c ,-C(＝O)-C≡CR ^5a ,-S(＝O) ₂ CR ^4e ＝CR ^4f R ^4g and-S (═ O) ₂ -C≡CR ^5b ；

R ^1a Is selected from C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl and C ₃ -C ₆ A cycloalkyl group;

R ^4a 、R ^4b and R ^4c Independently selected from hydrogenHalogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, (amino) C ₁ -C ₄ Alkyl, (hydroxy) C ₁ -C ₄ Alkyl, (alkoxy) C ₁ -C ₄ Alkyl and (hetero) C ₁ -C ₄ An alkyl group;

R ^5a selected from hydrogen, halogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, (amino) C ₁ -C ₄ Alkyl, (hydroxy) C ₁ -C ₄ Alkyl, (alkoxy) C ₁ -C ₄ Alkyl and (hetero) C ₁ -C ₄ An alkyl group;

R ^4e 、R ^4f and R ^4g Independently selected from hydrogen, halogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, (amino) C ₁ -C ₄ Alkyl, (hydroxy) C ₁ -C ₄ Alkyl, (alkoxy) C ₁ -C ₄ Alkyl and (hetero) C ₁ -C ₄ An alkyl group;

R ^5b selected from hydrogen, halogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, (amino) C ₁ -C ₄ Alkyl, (hydroxy) C ₁ -C ₄ Alkyl, (alkoxy) C ₁ -C ₄ Alkyl and (hetero) C ₁ -C ₄ An alkyl group;

R ^2a selected from hydrogen, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, (cyano) C ₁ -C ₄ Alkyl, (hydroxy) C ₁ -C ₄ Alkyl, (alkoxy) C ₁ -C ₄ Alkyl, (amino) C ₁ -C ₄ Alkyl, (heterocycle) C ₁ -C ₄ Alkyl, (aryl) C ₁ -C ₄ Alkyl, (heteroaryl) C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkynyl, heteroalkyl, cyano, -C (═ O) OR ^5c 、-C(＝O)NR ^5d R ^5e and-NR ^5f R ^5g ；

R ^2b And R ^2c Independently selected from hydrogen and C ₁ -C ₄ An alkyl group; or

R ^2b And R ^2c Are linked to the same carbon atom and together form a-C (═ O) -group;

R ^5c selected from hydrogen and C ₁ -C ₄ An alkyl group;

R ^5d and R ^5e Independently selected from hydrogen and C ₁ -C ₄ An alkyl group; or

R ^5d And R ^5e Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered heterocyclic ring;

R ^5f and R ^5g Independently selected from hydrogen and C ₁ -C ₄ An alkyl group; or

R ^5f And R ^5g Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered heterocyclic ring;

l is selected from the group consisting of-O-, -S-and-N (R) ⁷ ) -; or L is a bond;

R ⁷ selected from hydrogen and C ₁ -C ₄ An alkyl group;

R ³ selected from hydrogen, C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl, (amino) C ₁ -C ₄ Alkyl, (hydroxy) C ₁ -C ₄ Alkyl, (alkoxy) C ₁ -C ₄ Alkyl, (carboxamido) C ₁ -C ₄ Alkyl, (heterocycle) C ₁ -C ₄ Alkyl, (aryl) C ₁ -C ₄ Alkyl and (heteroaryl) C ₁ -C ₄ An alkyl group;

A is selected from- (CR) ^6a R ^6b ) _m -, -O-, -S-and-N (R) ^7a )-；

A ¹ Is selected from- (CR) ^6c R ^6d ) _n -, -O-, -S-and-N (R) ^7b )-；

A ² Is selected from- (CR) ^6e R ^6f ) _o -, -O-, -S-and-N (R) ^7c )-；

A ³ Is selected from- (CR) ^6g R ^6h ) _p -, -O-, -S-and-N (R) ^7d )-；

A ⁴ Selected from the group consisting of-O-, -S-and-N (R) ^7e ) -; or A ⁴ Is a bond;

the precondition is that:

(1) when A is-O-, -S-or-N (R) ^7a ) When is, A ⁴ Is a bond, A ¹ Is- (CR) ^6c R ^6d ) _n N is 1 or 2

(2) When A is ¹ is-O-, -S-or-N (R) ^7b ) When is, A ⁴ Is a bond, A is- (CR) ^6a R ^6b ) _m -, and m is 1 or 2;

(3) when A is ² is-O-, -S-or-N (R) ^7c ) When is, A ³ Is- (CR) ^6g R ^6h ) _p -, p is 1 or 2; and is

(4) When A is ³ is-O-, -S-or-N (R) ^7d ) When is, A ² Is- (CR) ^6e R ^6f ) _o And o is 1 or 2,

R ^6a 、R ^6b 、R ^6c 、R ^6d 、R ^6e 、R ^6f 、R ^6g and R ^6h Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group;

m is 0, 1 or 2;

n is 0, 1 or 2;

o is 0, 1 or 2;

p is 0, 1 or 2;

provided that the sum of m, n, o and p is 2, 3, 4 or 5;

R ^7a 、R ^7b 、R ^7c 、R ^7d and R ^7e Independently selected from hydrogen and C ₁ -C ₄ An alkyl group;

e is selected from- (CR) ^8a R ^8b ) _q -

E ¹ Is selected from- (CR) ^8e R ^8f ) _r -q is 0 or 1;

r is 0 or 1;

R ^8a and R ^8b Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group;

R ^8e and R ^8f Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group;

R ^8c selected from hydrogen,Halogen, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ A cycloalkyl group;

R ^8d selected from hydrogen, halogen, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ A cycloalkyl group;

q is selected from ═ C (R) ¹⁰ ) -and ═ N-;

R ¹⁰ selected from hydrogen, C ₁ -C ₄ Alkyl and C ₃ -C ₆ A cycloalkyl group;

represents an optionally substituted fused C ₃ -C ₈ Cycloalkyl, optionally substituted fused heterocycle, optionally substituted fused C ₆ -C ₁₀ Aryl or optionally substituted fused 5-to 10-membered heteroaryl; and is

Represents a single bond or a double bond,

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of formula I wherein q is 0 and r is 0 or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of formula I wherein q is 0 and r is 1 or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of formula I wherein q is 1 and r is 0 or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compound of the present disclosure is a compound of formula II:

whereinR ³ 、A、A ¹ 、A ² 、A ³ 、A ⁴ 、E、E ¹ 、R ^8c 、R ^8d 、L、Q、Z、

And

as defined in combination with formula I, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula II, wherein q is 0 and r is 0 or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of formula II wherein q is 0 and r is 1 or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of formula II wherein q is 1 and r is 0 or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compound of the present disclosure is a compound of formula III:

wherein R is ³ 、A、A ¹ 、A ² 、A ³ 、A ⁴ 、E、E ¹ 、R ^8c 、R ^8d 、L、Q、Z、

And

In another embodiment, the compounds of the present disclosure are of formula III, wherein q is 0 and r is 0 or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of formula III, wherein q is 0 and r is 1 or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of formula III, wherein q is 1 and r is 0 or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compound of the present disclosure is a compound of formula IV:

wherein R is ^11a 、R ^11b 、R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; and R is ³ 、A、A ¹ 、A ² 、A ³ 、A ⁴ 、E、R ^8c 、R ^8d L, Q and Z are as defined in combination with formula I, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula V:

wherein R is ^11a 、R ^11b 、R ^11c 、R ^11d 、R ³ 、A、A ¹ 、A ² 、A ³ 、A ⁴ 、E、R ^8c ,R ^8d L, Q and Z are as defined in combination with formula IV, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula VI:

In another embodiment, the compound of the present disclosure is a compound of formula VII:

wherein R is ^11a 、R ^11b 、R ^11c 、R ^11d 、R ³ 、A、E、R ^8c ,R ^8d L, Q and Z are as defined in combination with formula IV, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula VIII:

In another embodiment, the compound of the present disclosure is a compound of formula IX:

wherein R is ^11a 、R ^11b 、R ^11c 、R ^11d 、R ³ 、A、E、R ^8c ,R ^8d L, Q and Z are as defined in combination with formula IV, or a pharmaceutically acceptable salt thereofA salt or a solvate.

In another embodiment, the compounds of the present disclosure are compounds of any one of formulas I-IX, or a pharmaceutically acceptable salt or solvate thereof, wherein a is- (CH) ₂ ) m-and m is 0 or 1. In another embodiment, m is 1.

In another embodiment, the compound of the present disclosure is a compound of formula X:

wherein R is ^11a 、R ^11b 、R ^11c 、R ^11d 、R ³ 、A ¹ 、A ³ 、E、R ^8c 、R ^8d L, Q and Z are as defined in combination with formula IV, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XI:

In another embodiment, the compound of the present disclosure is a compound of formula XII:

In another embodiment, the compound of the present disclosure is a compound of formula XIII:

wherein A is ² Selected from the group consisting of-O-, -S-and-N (R) ^7c )-；R ^7c ,R ³ ,A ¹ ,E,R ^8c ,R ^8d L, Q and Z are as defined in connection with formula I, and R ^11a 、R ^11b 、R ^11c And R ^11d As defined in combination with formula IV, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XIV:

In another embodiment, the compounds of the present disclosure are of formula XV:

In another embodiment, the compounds of the present disclosure are of formula (la)A compound of any one of I-XV wherein E is- (CH) ₂ ) _q -or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein E is- (CH) ₂ ) _q -q is 1 or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein q is 0, i.e., E is a bond, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein Q is ═ N-, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein L is-O-, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein R ³ Selected from (amino) C ₁ -C ₄ Alkyl, (carboxamido) C ₁ -C ₄ Alkyl and (hetero) C ₁ -C ₄ An alkyl group, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV wherein R ³ Is (heterocyclic) CH ₂ -or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein R ³ Is (heterocyclic) CH ₂ -and the heterocycle is an optionally substituted 8-to 12-membered bicyclic group containing one or two nitrogen atoms, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, the heterocycle is an 8-membered bicyclic group containing one nitrogen atom.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein R ³ Selected from:

wherein:

x is selected from the group consisting of-O-and-CR ^22a R ^22b -；

Each R ²¹ Independently selected from halogen, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl and hydroxy C ₁ -C ₃ An alkyl group;

R ^22a and R ^22b Independently selected from hydrogen, halogen, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, hydroxy C ₁ -C ₃ An alkyl group;

R ^22a and R ^22b Together with the carbon atom to which they are attached form an optionally substituted 3-to 6-membered cycloalkyl;

u is 1, 2 or 3; and

v is 0,1 or 2;

with the proviso that when X is-O-u is 2 or 3,

Or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein R ³ Selected from the group consisting of:

and or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein R ³ Is that

Or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein Z is selected from

Or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein R ^2a is-CH ₂ CN or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein R ¹ Is selected from-C (═ O) -CR ^4a ＝CHR ^4b ,-C(＝O)-C≡CR ^5a and-S (═ O) ₂ CH＝CHR ^4f Or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein R ¹ Is selected from

Or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are of any one of formulas I-XV, wherein R ¹ Is that

Or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compounds of the present disclosure are compounds of formula LXII

Wherein

R ^8c And R ^8d As defined in formula I;

R ^11a ,R ^11b ,R ^11c and R ^11d As defined in formula IV

R ^22a And R ^22b Independently selected from hydrogen, halogen, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, hydroxy C ₁ -C ₃ Alkyl or

R ²³ selected from hydrogen and fluorine;

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the compounds of the present disclosure are compounds of formula LXIII

Wherein R is ^8c ,R ^8d ,R ^11a ,R ^11b ,R ^11c ,R ^11d ,R ^22a ,R ^22b And R ²³ The definition is shown as a formula LXII; or a pharmaceutically acceptable salt or solvate thereof

In another embodiment, the compound of the present disclosure is any one or more of the compounds listed in table 1, or a pharmaceutically acceptable salt or solvate thereof.

The present disclosure encompasses the preparation and use of salts of the compounds of the present disclosure. As used herein, the term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a compound of the present disclosure that is suitable for administration to a subject (e.g., a human). Salts of the compounds of the present disclosure may be prepared during the final isolation and purification of the compounds or separately by reacting the compounds with a suitable acid. A pharmaceutically acceptable salt of a compound of the present disclosure may be an acid addition salt formed with a pharmaceutically acceptable acid. Examples of acids that may be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and organic acids such as oxalic, maleic, succinic, and citric acids. Non-limiting examples of salts of the compounds of the present disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, biphosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, pivalate, propionate, trichloroacetate, picrate, and the like, Glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate and p-toluenesulfonate. Additionally, the available amino groups present in the compounds of the present disclosure may be quaternized with: methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl and diamyl sulfates; decyl, lauryl, myristyl and steryl chlorides, bromides and iodides; and benzyl and phenethyl bromides. In view of the foregoing, any reference to a compound of the present disclosure as appearing herein is intended to include the compounds of the present disclosure, as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.

The present disclosure encompasses the preparation and use of solvates of the compounds of the present disclosure. Solvates do not generally significantly alter the physiological activity or toxicity of the compound and are therefore useful as pharmacological equivalents. As used herein, the term "solvate" is a combination, physical association, and/or solvation of a compound of the present disclosure with a solvent molecule, such as, for example, a di-solvate, mono-solvate, or semi-solvate, wherein the ratio of solvent molecules to compounds of the present disclosure is about 2:1, about 1:1, or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates may be isolated, such as when one or more solvent molecules are introduced into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution phase and isolatable solvates. The compounds of the present disclosure may exist in solvated forms with pharmaceutically acceptable solvents such as water, methanol, and ethanol, and it is intended that the present disclosure include both solvated and unsolvated forms of the compounds of the present disclosure. One type of solvate is a hydrate. "hydrates" refers to solvates of a particular subgroup in which the solvent molecule is water. Solvates are generally useful as pharmacological equivalents. The preparation of solvates is known in the art. See, e.g., m.cairae et al, j.pharmaceut.sci.,93(3): 601-. E.c. van binder et al, AAPS pharm. sci. tech.,5(1): Article 12(2004) and a.l. bingham et al, chem. commu.603-604 (2001) describe similar preparations of solvates, hemisolvates, hydrates, etc. A typical, non-limiting method of preparing the solvate comprises dissolving a compound of the present disclosure in the desired solvent (organic, water, or mixtures thereof) at a temperature of from greater than 20 ℃ to about 25 ℃, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods (e.g., filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in the crystals of the solvate.

Intermediates of the present disclosure

The present disclosure also provides synthetic intermediates useful in the preparation of the compounds of the present disclosure, collectively referred to as "intermediates of the present disclosure".

In one embodiment, the intermediate of the present disclosure is a compound of formula XVI:

wherein:

Z ^l selected from the group consisting of halogen, -OR ¹⁷ And

x represents a 6-to 12-membered monocyclic or bicyclic heterocycle;

R ¹³ selected from hydrogen, -C (═ O) R ^14a and-C (═ O) OR ^14b A group of (a);

R ^14a is C ₁ -C ₆ An alkyl group;

R ^14b selected from the group consisting of C _1- C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl and aralkyl groups;

R ¹² selected from halogen, -SR ¹⁹ ,-S(＝O)R ²⁰ ,-S(＝O) ₂ R ²⁰ And LR ³ ；

R ¹⁷ Selected from hydrogen and-S (═ O)2R ¹⁸ A group of (a);

R ¹⁸ selected from the group consisting of C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl and optionally substituted phenyl;

R ¹⁹ selected from hydrogen and C ₁ -C ₄ An alkyl group; r ²⁰ Is C ₁ -C ₄ An alkyl group;

l is selected from the group consisting of-O-, -S-and-N (R) ⁷ ) -a group of compositions; or L is a bond;

R ⁷ selected from hydrogen and C ₁ -C ₄ An alkyl group;

R ^2a selected from hydrogen, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, (cyano) C ₁ -C ₄ Alkyl, (hydroxy) C ₁ -C ₄ Alkyl, (alkoxy) C ₁ -C ₄ Alkyl, (amino) C ₁ -C ₄ Alkyl, (heterocycle) C ₁ -C ₄ Alkyl, (aryl) C ₁ -C ₄ Alkyl, (heteroaryl) )C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkynyl, heteroalkyl, cyano, -C (═ O) OR ^5c 、-C(＝O)NR ^5d R ^5e and-NR ^5f R ^5g ；

R ^2b And R ^2c Are linked to the same carbon atom and together form a C (═ O) -group;

R ^5c selected from hydrogen and C ₁ -C ₄ An alkyl group;

a is selected from- (CR) ^6a R ^6b ) m-, -O-, -S-and-N (R) ^7a )-；

A ¹ Is selected from the group consisting of- (CR) ^6c R ^6d ) N-, -O-, -S-and-N (R) ^7b ) -a group of compositions;

A ² is selected from the group consisting of- (CR) ^6e R ^6f ) O-, -O-, -S-and-N (R) ^7c ) -a group of compositions;

A ³ is selected from the group consisting of- (CR) ^6g R ^6h ) p-, -O-, -S-and-N (R) ^7d ) -a group of compositions;

A ⁴ selected from the group consisting of-O-, -S-and-N (R) ^7e ) -a group of compositions; or a4 is a key, or a,

with the proviso that:

(1) when A is-O-, -S-or-N (R) ^7a ) When is, then A ⁴ Is a bond, A ¹ Is- (CR) ^6c R ^6d ) n-, n is 1 or 2;

(2) when A is ¹ is-O-, -S-or-N ((S))R ^7b ) When is, then A ⁴ Is a bond, A is- (CR) ^6a R ^6b ) m-, m is 1 or 2;

(3) when A is ² is-O-, -S-or-N (R) ^7c ) When is, then A ³ Is- (CR) ^6g R ^6h ) p-, p is 1 or 2; and

(4) when A is ³ is-O-, -S-or-N (R) ^7d ) When is, then A ² Is- (CR) ^6e R ^6f ) o-and o is 1 or 2,

R ^6a ,R ^6b ,R ^6c ,R ^6d ,R ^6e ,R ^6f ,R ^6g and R ^6h Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group;

m is 0,1, or 2;

n is 0,1, or 2;

o is 0,1, or 2;

p is 0,1, or 2;

with the proviso that the sum of m, n, o and p is 2, 3, 4 or 5

R ^7a ,R ^7b ,R ^7c ,R ^7d And R ^7e Independently selected from hydrogen and C ₁ -C ₄ An alkyl group;

e is- (CR) ^8a R ^8b ) _q -；

E ¹ Is- (CR) ^8e R ^8f ) _r --；

q is 0 or 1;

r is 0 or 1;

R ^8a and R ^8b Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group; r ^8c Selected from hydrogen, halogen, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl and C ₃ -C ₆ A cycloalkyl group;

R ^8d selected from hydrogen, halogen, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl and C ₃ -C ₆ A cycloalkyl group;

R ^8e and R ^8f Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group; or

Q is selected from the group consisting of ═ C (R) ¹⁰ ) -and-N-;

denotes fused optionally substituted C ₃ -C ₈ Cycloalkyl, fused optionally substituted heterocycle, fused optionally substituted C ₆ -C ₁₀ Aryl or fused, optionally substituted, 5-to 10-membered heteroaryl; and

represents a single bond or a double bond, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XVI, wherein q is 0 and r is 0, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XVI, wherein q is 0 and r is 1, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XVI, wherein q is 1 and r is 0, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XVII:

wherein R is ¹² ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,E ¹ ,R ^8c ,R ^8d ,Q,Z ¹ ,

And

the definition relating to formula XVI, orA salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XVII, wherein q is 0 and r is 0, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XVII, wherein q is 0 and r is 1, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XVII, wherein q is 1 and r is 0, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XVIII:

wherein R is ¹² ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,E ¹ ,R ^8c ,R ^8d ,Q,Z ¹ ,

And

a definition associated with formula XVI, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XVIII, wherein q is 0 and r is 0, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XVIII, wherein q is 0 and r is 1, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XVIII, wherein q is 1 and r is 0, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XIX:

wherein R is ^11a ,R ^11b ,R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; and R ¹² ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,R ^8c ,R ^8d Q, and Z ¹ As defined for formula XVI or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XX:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹² ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,R ^8c ,R ^8d Q and Z ¹ As defined for formula XIX or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XXI:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹² ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,R ^8c ,R ^8d Q, and Z ¹ As defined for formula XIX or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XXII:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹² ,A,E,R ^8c ,R ^8d Q, and Z ¹ As defined in relation to formula XIX, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XXIII:

In another embodiment, an intermediate of the present disclosure is a compound of formula XXIV:

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XIX, wherein a is- (CH) ₂ ) m-and m is 0 or 1, or a salt or solvate thereof.

In another embodiment, m is 1, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XXV:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹² ,A ¹ ,A ³ ,E,R ^8c ,R ^8d Q, and Z ¹ As defined in relation to formula XIX, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XXVI:

In another embodiment, an intermediate of the present disclosure is a compound of formula XXVII:

In another embodiment, an intermediate of the present disclosure is a compound of formula XXVIII:

wherein A is ² Selected from the group consisting of-O-, -S-and-N (R) ^7c ) -a group of compositions; r ^7c ,R ¹² ,A ¹ ,E,R ^8c ,R ^8d Q, and Z ¹ As defined in relation to formula XVI, and R ^11a ,R ^11b ,R ^11c And R ^11d As defined in relation to formula XIX, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XXIX:

In another embodiment, an intermediate of the present disclosure is a compound of formula XXX:

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein E is- (CH) ₂ ) q-, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein E is- (CH) ₂ ) q-; and q is 1, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein q is 0, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein Q is ═ N-, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXXA compound of formula (I) wherein Z ¹ is-OR ¹⁷ Or a salt or solvate thereof. In another embodiment, R ¹⁷ Is hydrogen. In another embodiment, R ¹⁷ is-CF ₃ 。

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein Z is ¹ Halogen, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein Z is ^l Selected from the group consisting of:

or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein R is ¹³ Is hydrogen, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein R is ¹³ is-C (═ O) OR ^14b Or a salt or solvate thereof. In another embodiment, R ^14b is-C (CH) ₃ ) ₃ 。

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein R is ^2a is-CH ₂ CN, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein R is ¹² is-SR ¹⁹ Or a salt or solvate thereof. In another embodiment, R ¹⁹ Is hydrogen. In another embodiment, R ¹⁹ is-CH ₃ 。

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein R is ¹² is-S (═ O) R ²⁰ Or a salt or solvate thereof. In another embodiment, R ²⁰ Is methyl.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein R is ¹² Is chlorine, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XVI-XXX, wherein R is ¹² is-LR ³ Or a salt or solvate thereof. In another embodiment, L is-O-. In another embodiment, R ³ Selected from (amino) C ₁ -C ₄ Alkyl, (carboxamido) C ₁ -C ₄ Alkyl and (hetero) C ₁ -C ₄ An alkyl group. In another embodiment, R ³ Is (heterocyclic) CH ₂ -。

In another embodiment, the intermediate of the present disclosure is any one or more of the compounds listed in table 2, or a salt or solvate thereof.

TABLE 2

In another embodiment, the intermediate of the present disclosure is a compound of formula XXXI:

wherein:

a is selected from- (CR) ^6a R ^6b ) m-, -O-, -S-and-N (R) ^7a )-；

A ⁴ selected from the group consisting of-O-, -S-and-N (R) ^7e ) -; or A ⁴ Is a key of the series of keys,

with the proviso that:

(2) When A is ¹ is-O-, -S-or-N (R) ^7b ) When is, then A ⁴ Is a bond, A is- (CR) ^6a R ^6b ) m-, m is 1 or 2;

m is 0,1, or 2;

n is 0,1, or 2;

o is 0,1, or 2;

p is 0,1, or 2;

provided that the sum of m, n, o and p is 2, 3, 4 or 5;

e is- (CR) ^8a R ^8b ) _q -；

E ¹ Is- (CR) ^8e R ^8f ) _r -；

q is 0or 1;

r is 0or 1;

R ^8c selected from hydrogen, halogen, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl and C ₃ -C ₆ A cycloalkyl group;

represents a single bond or a double bond, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XXXI, wherein q is 0 and r is 0, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XXXI, wherein q is 0 and r is 1, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XXXI, wherein q is 1 and r is 0, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XXXII:

a, A therein ¹ 、A ² 、A ³ 、A ⁴ 、E、E ¹ 、R ^8c 、R ^8d 、

And

as defined in relation to formula XXXI, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XXXIII:

a, A therein ¹ 、A ² 、A ³ 、A ⁴ 、E、E ¹ 、R ^8c 、R ^8d 、

And

as defined in relation to formula XXXI, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XXXIV:

wherein R is ^11a ,R ^11b ,R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; a, A ¹ ,A ² ,A ³ ,A ⁴ ,E,R ^8c And R ^8d As defined in relation to formula XXXI, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XXXV:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,R ^8c And R ^8d As defined in relation to formula XXXIV, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XXXVI:

In another embodiment, an intermediate of the present disclosure is a compound of formula XXXVII:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,A,E,R ^8c And R ^8d As defined for formula XXXIV or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XXXVIII:

In another embodiment, an intermediate of the present disclosure is a compound of formula XXXIX:

In another embodiment, the intermediates of the present disclosure are compounds of any one of formulas XXXI-XXXIX, wherein a is- (CH) ₂ ) m-and m is 0 or 1, or a salt or solvate thereof. In another embodiment, m is 1.

In another embodiment, an intermediate of the disclosure is a compound of formula XL:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,A ¹ ,A ³ ,E,R ^8c And R ^8d As defined in relation to formula XXXIV, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XLI:

In another embodiment, the intermediate of the present disclosure is a compound of formula XLII:

In another embodiment, the intermediate of the present disclosure is a compound of formula XLIII:

wherein A is ² Selected from the group consisting of-O-, -S-and-N (R) ^7c ) -a group of; r ^11a ,R ^11b ,R ^11c ,R ^11d ,A ¹ ,E,R ^8c And R ^8d As defined in relation to formula XXXIV; and R ^7c ,R ^8a ,R ^8b And q is as defined for formula XXXI or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XLIV:

wherein A is ² ,E,R ^11a ,R ^11b ,R ^11c ,R ^11d ,A ¹ ,R ^8c ,R ^8d As defined for formula XLIII or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XLV:

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XXXI-XLV, wherein E is- (CH) ₂ ) q-; or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XXXI-XLV, wherein q is 1, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XXXI-XLV, wherein E is a bond, i.e., E is- (CR) ^8a R ^8b ) q and q is 0.

In another embodiment, the intermediate of the present disclosure is a compound of formula XLVI:

wherein

R ¹⁵ Selected from hydrogen and-C (═ O) OR ¹⁶ A group of (a);

R ¹⁶ is C ₁ -C ₆ An alkyl group;

a is selected from- (CR) ^6a R ^6b ) _m -, -O-, -S-, and-N (R) ^7a )-

A ¹ Is selected from- (CR) ^6c R ^6d ) _n -, -O-, -S-, and-N (R) ^7b )-

A ² Is selected from- (CR) ^6e R ^6f ) _o -, -O-, -S-, and-N (R) ^7c )-

A ³ Is selected from- (CR) ^6g R ^6h ) _p -, -O-, -S-, and-N (R) ^7d )-

A ⁴ Selected from the group consisting of-O-, -S-, and-N (R) ^7e ) -; or A ⁴ Is a key, and is provided with a plurality of keys,

with the proviso that:

m is 0,1, or 2;

n is 0,1, or 2;

o is 0,1, or 2;

p is 0,1, or 2;

provided that the sum of m, n, o and p is 2, 3, 4 or 5;

e is- (CR) ^8a R ^8b ) _q -；

E ¹ Is- (CR) ^8e R ^8f ) _r -；

q is 0 or 1;

r is 0 or 1;

q is ═ N-;

represents a single bond or a double bond, or a salt or solvate thereof

In another embodiment, the compound of the present disclosure is a compound of formula XLVI, wherein q is 0 and r is 0, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XLVI, wherein q is 0 and r is 1, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XLVI, wherein q is 1 and r is 0, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XLVII:

wherein R is ¹⁵ ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,E ¹ ,R ^8c ,R ^8d ,

And

the same definition applies in relation to XLVI or salts or solvates thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XLVII, wherein q is 0 and r is 0, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XLVII, wherein q is 0 and r is 1, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XLVII, wherein q is 1 and r is 0, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula XLVIII:

wherein R is ¹⁵ ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,E ¹ ,R ^8c ,R ^8d ,

And

the same definition applies in relation to XLVI or salts or solvates thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XLVIII, wherein q is 0 and r is 0, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XLVIII, wherein q is 0 and r is 1, or a salt or solvate thereof.

In another embodiment, the compound of the present disclosure is a compound of formula XLVIII, wherein q is 1 and r is 0, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula XLIX:

wherein R is ^11a ,R ^11b ,R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; r ¹⁵ ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,R ^8c And R ^8d As defined in relation to formula XLVI, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula L:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹⁵ ,A,A ¹ ,A ² ,A ³ ,A ⁴ ,E,R ^8c And R ^8d As defined for formula XLIX or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula LI:

In another embodiment, an intermediate of the present disclosure is a compound of formula LII:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹⁵ ,A,E,R ^8c And R ^8d As defined for formula XLIX or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula LIII:

In another embodiment, an intermediate of the present disclosure is a compound of formula LIV:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹⁵ ,A, E,R ^8c And R ^8d As defined for formula XLIX or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XLVI-LIV, wherein A is- (CH) ₂ ) m-and m is 0 or 1, or a salt or solvate thereof. In another embodiment, m is 1.

In another embodiment, an intermediate of the present disclosure is a compound of formula LV:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹⁵ ,A ¹ ,A ³ ,E,R ^8c And R ^8d Such as AND typeXLIX related definition, or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula LVI:

wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹⁵ ,A ¹ ,A ³ ,E,R ^8c And R ^8d As defined in relation to formula XLIX, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of formula LVII:

Wherein R is ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹⁵ ,A ¹ ,A ³ ,E,E ¹ And E, and ² as defined for formula XLIX or a salt or solvate thereof.

In another embodiment, an intermediate of the present disclosure is a compound of formula LIX:

wherein A is ² Selected from the group consisting of-O-, -S-and-N (R) ^7c ) -a group of compositions; r ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹⁵ ,A ¹ ,E,R ^8c And R ^8d As defined in combination with XLIX; and R ^7c As defined for formula XLVI or a salt or solvate thereof.

In another embodiment, an intermediate of the disclosure is a compound of formula LX:

wherein A is ² ,E,R ^11a ,R ^11b ,R ^11c ,R ^11d ,R ¹⁵ ,A ¹ ,R ^8c And R ^8d As defined in relation to formula LIX, or a salt or solvate thereof.

In another embodiment, the intermediate of the disclosure is a compound of formula LXI:

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XLIX-LXI, wherein R is ^11a Selected from halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C- ₄ An alkyl group; r ^11b 、R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C- ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XLIX-LXI, wherein R is ^11b Selected from halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C- ₄ An alkyl group; r ^11a 、R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C- ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XLIX-LXI, wherein R is ^11c Selected from halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C- ₄ An alkyl group; r ^11a 、R ^11b And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C- ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XLIX-LXI, wherein R is ^11d Selected from halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C- ₄ An alkyl group; r ^11a 、R ^11b And R ^11c Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C- ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is of any one of formulas XLVI-LXIThe compound, wherein E is- (CH) ₂ ) q-; or a salt or solvate thereof.

In another embodiment, the intermediates of the present disclosure are compounds of any one of formulas XLVI-LXI, wherein E is- (CH) ₂ ) Or a salt or solvate thereof.

In another embodiment, the intermediates of the present disclosure are compounds of any one of formulas XLVI-LXI, wherein E is- (CR) ^8a R ^8b ) q and q is 0, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XLVI-LXI, wherein R is ¹⁵ Is hydrogen, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XLVI-LXI, wherein R is ¹⁵ is-C (═ O) OR ¹⁶ Or a salt or solvate thereof

In another embodiment, the intermediate of the present disclosure is a compound of any one of formulas XLVI-LXI, wherein R is ¹⁵ is-C (═ O) OR ¹⁶ And R is ¹⁶ Selected from methyl and ethyl, or a salt or solvate thereof.

In another embodiment, the intermediate of the present disclosure is a compound selected from any one or more of the compounds of table 3, or a salt or solvate thereof.

TABLE 3

III, methods for preparing Compounds and intermediates of the disclosure

The present disclosure also provides methods of making the compounds of the present disclosure and/or intermediates of the present disclosure.

Exemplary methods of preparing the compounds of the present disclosure and/or intermediates of the present disclosure are provided in general schemes 1 and 2 and in the examples.

Methods of treating diseases with compounds of the present disclosure

The compounds of the present disclosure will inhibit KRAS, e.g., KRAS-G12C, and thus may be useful in the treatment and prevention of a variety of diseases and disorders. In particular, the compounds of the present disclosure may be used in methods of treating or preventing diseases or disorders in which inhibition of KRAS would provide a benefit. The most important of these diseases and ailments are cancer and proliferative diseases. In one embodiment, such cancer is referred to as "KRAS-mediated cancer. KRAS-mediated cancers are known in the art. The methods of treatment of the present disclosure comprise administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a compound of the present disclosure. In addition to the compounds of the present disclosure, the methods of the invention also encompass optionally administering to the subject an optional therapeutic agent. The optional therapeutic agent is selected from drugs known to be useful in treating the disease or disorder afflicting a subject in need thereof, such as chemotherapeutic agents and/or radiation known to be useful in treating a particular cancer.

In another embodiment, the disclosure relates to a method of treating an individual having a disease or disorder in which inhibition of KRAS would provide a benefit, comprising administering a therapeutically effective amount of a compound of the disclosure.

Since the compounds of the present disclosure are inhibitors of KRAS, many diseases and disorders mediated by KRAS may be treated by employing these compounds. The present disclosure thus relates generally to a method of treating a disease or disorder responsive to KRAS inhibition in a subject (e.g., a human subject) having or at risk of having a disease or disorder responsive to KRAS inhibition, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure.

In another embodiment, the present disclosure relates to a method of inhibiting KRAS, e.g., KRAS-G12C, in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound of the present disclosure.

The methods of the present disclosure may be accomplished by administering the compounds of the present disclosure as pure compounds or as pharmaceutical compositions. Administration of a pharmaceutical composition or pure compound of a compound of the present disclosure may be performed during or after the onset of the disease or disorder of interest. Typically, the pharmaceutical compositions are sterile and free of toxic, carcinogenic, or mutagenic compounds that cause adverse reactions upon administration. Also provided are kits comprising a compound of the present disclosure and optionally an optional therapeutic agent, packaged separately or together, and an insert with instructions for using these active agents.

In one embodiment, combining a compound of the present disclosure with an optional therapeutic agent may be useful in the treatment of a disease or disorder where inhibition of KRAS would provide a benefit. The optional therapeutic agent is different from the compound of the present disclosure. The compounds of the present disclosure and optional therapeutic agents may be administered simultaneously or sequentially to achieve the desired effect. In addition, the compounds of the present disclosure and optional therapeutic agents can be administered from a single composition or from two separate compositions.

The optional therapeutic agent is administered in an amount that provides its desired therapeutic effect. Effective dosage ranges for each optional therapeutic agent are known in the art, and the optional therapeutic agent is administered to an individual in need thereof within such established ranges.

The compounds of the present disclosure and the optional therapeutic agent may be administered together as a single unit dose or separately as multiple unit doses, wherein the compound of the present disclosure is administered prior to the optional therapeutic agent, or vice versa. One or more doses of a compound of the present disclosure and/or one or more doses of an optional therapeutic agent may be administered. Thus, the compounds of the present disclosure may be used in combination with one or more optional therapeutic agents, such as, but not limited to, anti-cancer agents.

Diseases and disorders treatable by the methods of the present disclosure include, but are not limited to, cancer and other proliferative diseases, inflammatory diseases, sepsis, autoimmune diseases, and viral infections. In one embodiment, a human subject is treated with a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure, wherein the compound is administered in an amount sufficient to inhibit KRAS protein in the subject.

In another aspect, the present disclosure provides a method of treating cancer in a subject comprising administering a therapeutically effective amount of a compound of the present disclosure. While not limited to a particular mechanism, in some embodiments, the compounds of the present disclosure treat cancer by inhibiting KRAS. In another embodiment, the cancer is a KRAS-mutant cancer. In another embodiment, the cancer is a KRAS-G12C-mutant cancer.

In another embodiment, the KRAS-mutant cancer is lung, pancreatic or colorectal cancer.

In another embodiment, the KRAS-mutant cancer is lung cancer.

In another embodiment, the KRAS-mutant cancer is non-small cell lung cancer.

In another embodiment, the KRAS-mutant cancer is pancreatic cancer.

In another embodiment, the KRAS-mutant cancer is colorectal cancer.

In another embodiment, the present disclosure provides a method of treating a benign proliferative disease such as, but not limited to, benign soft tissue tumors, bone tumors, brain and spine tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine adenomas, nasal polyps, pituitary tumors, prolactinoma, pseudocerebroma, seborrheic keratosis, gastric polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, cysts, Castleman (Castleman) disease, chronic sinus tibetans, skin fibromas, hair cysts, pyogenic granulomas, and juvenile polyposis syndrome.

The compounds of the present disclosure can also treat infectious and non-infectious inflammatory events, as well as autoimmune and other inflammatory diseases, by administering an effective amount of the present compounds to a mammal (particularly a human) in need of such treatment. Examples of autoimmune and inflammatory diseases, disorders, and syndromes treated using the compounds and methods described herein include inflammatory pelvic disease, urethritis, sunburn of the skin, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, Chronic Obstructive Pulmonary Disease (COPD), autoimmune polyanalicular disease (also known as autoimmune polyaglandular syndrome), autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, rheumatoid arthritis, and rheumatoid arthritis, Scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, edison's disease, Parkinson's disease, Alzheimer's disease, type I diabetes, septic shock, Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-barren-Barre syndrome, Behcet's disease, scramerides, granulomatosis-like granulomatosis, acute respiratory inflammatory responses (such as ischemia/acute respiratory distress syndrome) and grave's reperfusion injury.

In another embodiment, the present disclosure provides a method of treating systemic inflammatory response syndrome such as LPS-induced endotoxic shock and/or bacterially-induced sepsis by administering to a mammal (particularly a human) in need of such treatment an effective amount of a compound of the present disclosure.

In another embodiment, the present disclosure provides a method of treating viral infections and diseases. Examples of viral infections and diseases treated using the compounds and methods described herein include episomal-based DNA viruses, including but not limited to human papilloma virus, herpes virus, Epstein-Barr (Epstein-Barr) virus, human immunodeficiency virus, hepatitis b virus, and hepatitis c virus.

In another embodiment, the present disclosure provides a method of treatment for modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in such diseases, particularly cancer, inflammatory diseases and/or viral diseases, by administering to a subject in need of such therapy a therapeutically effective amount of a compound of the present disclosure.

In another embodiment, the disclosure provides a method of modulating endogenous or heterologous promoter activity by contacting a cell with a compound of the disclosure.

In the methods of the present disclosure, a therapeutically effective amount of a compound of the present disclosure, typically formulated in accordance with pharmaceutical practice, is administered to a human in need thereof. Whether such treatment is required depends on the individual condition and is subject to medical assessment (diagnosis) taking into account the signs, symptoms and/or dysfunctions present, the risk of developing particular signs, symptoms and/or dysfunctions, and other factors.

The compounds of the present disclosure can be administered by any suitable route, for example, by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, lumbar puncture, transurethral, nasal, transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection, and/or surgical implantation at a specific site). Parenteral administration can be accomplished using needles and syringes or using high pressure techniques.

Pharmaceutical compositions include those in which a compound of the present disclosure is administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration and dosage are determined by the individual physician in light of the diagnosed disease or illness. The dosage and interval may be adjusted individually to provide a level of a compound of the disclosure sufficient to maintain a therapeutic effect.

Toxicity and therapeutic efficacy of the compounds of the present disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., determining the Maximum Tolerated Dose (MTD) of the compound, which is defined as the highest dose that is not toxic to the animal. The dose ratio between the maximum tolerated dose and the therapeutic effect (e.g., inhibition of tumor growth) is the therapeutic index. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Determination of a therapeutically effective amount is well within the ability of those skilled in the art, especially in light of the detailed disclosure provided herein.

The therapeutically effective amount of a compound of the present disclosure required for use in treatment will vary with the nature of the condition being treated, the length of time the activity is desired, and the age and condition of the subject, and will ultimately be at the discretion of the attendant physician. The dose and interval may be adjusted individually to provide plasma levels of the compounds of the present disclosure sufficient to maintain the desired therapeutic effect. The desired dose may be administered in a single administration or in multiple administrations at appropriate intervals, for example one, two, three, four or more sub-doses per day. Multiple administrations are often desired or required. For example, the compounds of the present disclosure may be administered at the following frequencies: four times per day (q4d x 4) at four day intervals; four times daily (q3d x 4) at three-day intervals; delivered once daily (qd x 5) at five day intervals; once per week for three weeks (qwk 3); five days daily, two days at rest, and five days again daily (5/2/5); alternatively, any dosage regimen appropriate for the situation is determined

The compounds of the present disclosure used in the methods of the present disclosure may be administered in an amount of from about 0.005 to about 500 milligrams per dose, from about 0.05 to about 250 milligrams per dose, or from about 0.5 to about 100 milligrams per dose. For example, a compound of the present disclosure may be administered in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams per dose, including all doses between 0.005 and 500 milligrams.

A dose of a composition containing a compound of the present disclosure or a composition containing a compound of the present disclosure may be about 1ng/kg to about 200mg/kg, about 1 μ g/kg to about 100mg/kg, or about 1mg/kg to about 50 mg/kg. The dosage of the composition can be any dosage including, but not limited to, about 1 μ g/kg. The dosage of the composition may be any dosage including, but not limited to, about 1 μ g/kg, about 10 μ g/kg, about 25 μ g/kg, about 50 μ g/kg, about 75 μ g/kg, about 100 μ g/kg, about 125 μ g/kg, about 150 μ g/kg, about 175 μ g/kg, about 200 μ g/kg, about 225 μ g/kg, about 250 μ g/kg, about 275 μ g/kg, about 300 μ g/kg, about 325 μ g/kg, about 350 μ g/kg, about 375 μ g/kg, about 400 μ g/kg, about 425 μ g/kg, about 450 μ g/kg, about 475 μ g/kg, about 500 μ g/kg, about 525 μ g/kg, about 550 μ g/kg, about 575 μ g/kg, about 600 μ g/kg, about 625 μ g/kg, About 650. mu.g/kg, about 675. mu.g/kg, about 700. mu.g/kg, about 725. mu.g/kg, about 750. mu.g/kg, about 775. mu.g/kg, about 800. mu.g/kg, about 825. mu.g/kg, about 850. mu.g/kg, about 875. mu.g/kg, about 900. mu.g/kg, about 925. mu.g/kg, about 950. mu.g/kg, about 975. mu.g/kg, about 1mg/kg, about 5mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 125mg/kg, About 150mg/kg, about 175mg/kg, about 200mg/kg or more. The above dosages are examples of general cases, but higher or lower dosages should be used in individual cases, and such dosages are within the scope of the present disclosure. In practice, the physician determines the actual dosing regimen that will best suit an individual subject, which may vary with the age, weight and response of the particular subject.

The compounds of the present disclosure are typically administered in admixture with a pharmaceutical carrier to give a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that will facilitate processing of the compounds of the present disclosure.

Such pharmaceutical compositions may be manufactured, for example, by means of conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping or lyophilizing processes. The correct formulation depends on the chosen route of administration. When a therapeutically effective amount of a compound of the present disclosure is administered orally, the composition is typically in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the compositions may also contain a solid carrier, such as gelatin or an adjuvant. Tablets, capsules, and powders contain from about 0.01% to about 95%, preferably from about 1% to about 50%, of a compound of the present disclosure. When applied in liquid form, a liquid carrier such as water, petroleum or oils of animal or vegetable origin may be added. The liquid form of the composition may also contain saline solution, dextrose or other sugar solution, or glycols. When applied in liquid form, the compositions contain from about 0.1% to about 90%, preferably from about 1% to about 50%, by weight of the compounds of the present disclosure.

When a therapeutically effective amount of a compound of the present disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions with due regard to pH, isotonicity, stability, etc., is within the skill of the art. Preferred compositions for intravenous, cutaneous or subcutaneous injection typically contain an isotonic vehicle.

The compounds of the present disclosure can be readily combined with pharmaceutically acceptable carriers well known in the art. Standard drug carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA,19th ed.1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained by post-processing a mixture of granules to obtain tablets or dragee cores, by adding a compound of the present disclosure to a solid excipient, optionally grinding the resulting mixture and, if desired, adding suitable auxiliaries. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant may be added.

The compounds of the present disclosure may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agents in water-soluble form. Additionally, suspensions of the compounds of the present disclosure may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound and allow for the preparation of highly concentrated solutions. Alternatively, the present compositions may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

The compounds of the present disclosure may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, the compounds of the present disclosure may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present disclosure can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins.

In particular, the compounds of the present disclosure may be administered orally, buccally or sublingually in the form of tablets containing excipients such as starch or lactose, or in capsules or soft capsules (ovule), alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid formulations may be prepared with pharmaceutically acceptable additives such as suspending agents. The compounds of the present disclosure may also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronary. For parenteral administration, the compounds of the present disclosure are generally used in the form of sterile aqueous solutions, which may contain other substances, for example salts or monosaccharides such as mannitol or glucose, to make the solution isotonic with blood.

V. optional therapeutic agent

In some methods of treatment and uses of the present disclosure, the compounds of the present disclosure are administered as a single drug to a subject having a disease, disorder or case, such as cancer. In other methods of treatment and uses of the present disclosure, the compounds of the present disclosure are administered to a subject having a disease, disorder or case, such as cancer, in combination with one or more optional therapeutic agents. In one embodiment, the compounds of the present disclosure are administered in combination with an optional therapeutic agent. In another embodiment, the compounds of the present disclosure are administered in combination with two optional therapeutic agents. In another embodiment, the compounds of the present disclosure are administered in combination with three optional therapeutic agents. Optional therapeutic agents useful in treating cancer patients include those known in the art and those that will be developed in the future.

The compounds of the present disclosure and the one or more optional therapeutic agents may be administered together as a single unit dose or separately as multiple unit doses and in any order, e.g., wherein the compounds of the present disclosure are administered prior to the one or more optional therapeutic agents, or vice versa. One or more doses of a compound of the present disclosure and the one or more optional therapeutic agents may be administered to the subject.

The present disclosure provides the following specific embodiments for treating a disease in a subject.

A method of treating a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein the subject has cancer, a chronic autoimmune disorder, an inflammatory disease, a proliferative disorder, sepsis, or a viral infection.

The method of embodiment I, wherein the subject has cancer.

Embodiment iii the method of embodiment II, wherein the cancer is a KRAS mutant cancer.

The method of embodiment II or III, wherein the cancer is lung cancer, pancreatic cancer or colorectal cancer.

The method of embodiment IV, wherein the cancer is non-small cell lung cancer.

The method of any one of embodiments I-V, further comprising administering a therapeutically effective amount of an optional therapeutic agent useful in treating the disease or disorder, e.g., an immune checkpoint inhibitor or other anti-cancer agent.

The method of any one of embodiments I-VI, wherein the compound of the present disclosure is a compound of any one of formulas IV-XV, or a pharmaceutically acceptable salt or solvate thereof.

The method of any one of embodiments I-VI, wherein the compound of the present disclosure is a compound of table 1, or a pharmaceutically acceptable salt or solvate thereof

Embodiment IX. a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient for use in treating cancer, a chronic autoimmune disorder, an inflammatory disease, a proliferative disorder, sepsis or a viral infection.

The pharmaceutical composition of embodiment IX for use in treating cancer.

Embodiment xi the pharmaceutical composition of embodiment X, wherein said cancer is a KRAS mutant cancer.

Embodiment xii. the pharmaceutical composition of embodiment X or XI, wherein the cancer is lung cancer, pancreatic cancer or colorectal cancer

Embodiment xiii the pharmaceutical composition of embodiment XII, wherein the cancer is non-small cell lung cancer.

The pharmaceutical composition of any one of embodiments IX-XIII, wherein the compound of the present disclosure is a compound of any one of formulas IV-XV, or a pharmaceutically acceptable salt or solvate thereof.

Embodiment XV. the pharmaceutical composition of any one of embodiments IX-XIII, wherein the compound of the present disclosure is a compound of table 1, or a pharmaceutically acceptable salt or solvate thereof.

Embodiment xvi a compound of the present disclosure for use in treating cancer, chronic autoimmune disorders, inflammatory diseases, proliferative disorders, sepsis, or viral infections.

Embodiment xvii the compound of embodiment XVI for use in the treatment of cancer.

Embodiment xviii the compound of embodiment XVII, wherein the cancer is a KRAS mutant cancer.

A compound of embodiment XVII or XVIII wherein the cancer is lung, pancreatic or colorectal cancer.

Embodiment XX. the compound of embodiment XIX wherein the cancer is non-small cell lung cancer.

A compound of any one of embodiments XVI-XX, wherein the compound of the present disclosure is a compound of any one of formulae IV-XV, or a pharmaceutically acceptable salt or solvate thereof.

A compound of any one of embodiments XVI-XX, wherein the compound of the present disclosure is a compound of table 1, or a pharmaceutically acceptable salt or solvate thereof.

Use of a compound of the present disclosure for the manufacture of a medicament for treating cancer, chronic autoimmune disorders, inflammatory diseases, proliferative disorders, sepsis, or viral infections.

Embodiment xxiv the use of embodiment XXIII for the treatment of cancer.

Embodiment xxv the use of embodiment XXIV wherein the cancer is a KRAS mutant cancer.

Embodiment xxvi. the use of embodiment XXIV or XXV, wherein the cancer is lung, pancreatic or colorectal cancer.

Embodiment xxvii the use of embodiment XXVI, wherein the cancer is non-small cell lung cancer.

Embodiment xxviii the use of any one of embodiments XXIII-XXVII, wherein the compound of the present disclosure is a compound of any one of formulae IV-XV, or a pharmaceutically acceptable salt or solvate thereof.

The use of any one of embodiments XXIII-XXVII, wherein the compound of the present disclosure is a compound of table 1, or a pharmaceutically acceptable salt or solvate thereof.

Embodiment xxx. a method of inhibiting KRAS in a cell of a subject in need thereof, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof.

Embodiment xxxi the method of embodiment XXX wherein the compound of the present disclosure is a compound of table 1, or a pharmaceutically acceptable salt or solvate thereof.

V. kits of the disclosure

In another embodiment, the present disclosure provides a kit comprising a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a manner that will facilitate its use in practicing the methods of the present disclosure. In one embodiment, a kit comprises a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a container, such as a sealed bottle or vessel, with or in the kit comprising a label describing use of the compound or composition to practice a method of the present disclosure (e.g., a method of any one of embodiments I-VI). In one embodiment, the compound or composition is packaged in unit dosage form. The kit may further comprise a device suitable for administering the composition according to the intended route of administration.

Definition of VI

The term "disease or disorder in which inhibition of KRAS would provide a benefit" or the like relates to a disease or disorder in which KRAS is important or essential, e.g., for the onset, progression, expression of the disease or disorder, or known to be treated by a KRAS inhibitor. Examples of such diseases include, but are not limited to, cancer, chronic autoimmune diseases, inflammatory diseases, proliferative diseases, sepsis, and viral infections. One of ordinary skill in the art can readily determine whether a compound treats a disease or disorder mediated by a KRAS inhibitor to any particular cell type, for example, by assays that can be conveniently used to assess the activity of a particular compound. See, e.g., Yue and Turkson, Expert Opinion Invest Drugs 18:45-56 (2009).

As used herein, the term "KRAS" refers collectively to wild-type KRAS genes and proteins and mutant forms thereof. The most frequent mutations found in the KRAS gene are mainly at codons 12, 13 or 61. KRAS mutations also occur in codons 63, 117, 119, and 146. Liu et al, Acta pharmaceutical Sinica B9: 871-.

As used herein, the term "KRAS inhibitor" refers to a compound that will inhibit wild-type KRAS and/or mutant KRAS and includes electrophilic compounds that form irreversible covalent bonds with KRAS proteins. Without wishing to be bound by any particular theory, the compounds of the present disclosure are KRAS inhibitors that will form an irreversible covalent bond with the nucleophilic sulfur atom of Cys12 and thus target the KRAS-G12C mutation while leaving wild-type KRAS unchanged.

As used herein, the term "KRAS mutant cancer" refers to a cancer containing a KRAS mutation. KRAS mutant cancers include, but are not limited to, KRAS mutant lung cancer, KRAS mutant pancreatic cancer, or KRAS mutant colorectal cancer. In some embodiments, the KRAS mutant cancer has the KRAS-G12C mutation.

The term "optional therapeutic agent" refers to a therapeutic agent that is different from the compounds of the present disclosure and is known to treat the disease or disorder of interest. For example, where cancer is the target disease or disorder, the optional therapeutic agent may be a known chemotherapeutic drug, such as, for example, paclitaxel or radiation.

The term "disease" or "illness" refers to a disorder and/or abnormality that is generally considered a pathological condition or function and may be manifested in the form of specific signs, symptoms, and/or dysfunctions. The compounds of the present disclosure are inhibitors of KRAS and are useful in the treatment or prevention of diseases and disorders in which inhibition of KRAS would provide a benefit.

As used herein, the terms "treat", "treating", and the like refer to the elimination, alleviation, or amelioration of a disease or disorder and/or symptoms associated therewith. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition, or symptoms associated therewith. The terms "treatment" and synonyms contemplate administration of a therapeutically effective amount of a compound of the disclosure to a subject in need of such treatment. Treatment may be symptomatic, e.g. to suppress symptoms. It can be done in the short term, either mid-term or long-term, as in the case of maintenance therapy.

As used herein, the terms "preventing", "preventing" and "prevention" refer to a method of preventing the onset of a disease or disorder and/or its attendant symptoms or arresting the development of a disease in a subject. As used herein, "preventing" also includes delaying the onset of a disease and/or its attendant symptoms and reducing the risk of a subject developing a disease. The term "preventing" can include "prophylactic treatment," which refers to reducing the likelihood of contracting a disease or disorder again or reducing the recurrence of a previously controlled disease or disorder in a subject who does not suffer from, but who is at risk of contracting the disease or disorder again.

As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of one or more active ingredients that is sufficient to effectively deliver the one or more active ingredients to treat a target disease or disorder when administered by the methods of the present disclosure to a subject in need thereof. In the case of cancer or other proliferative disorders, a therapeutically effective amount of a drug may reduce (i.e., slow or stop to some extent) undesired cell proliferation; reducing the number of cancer cells; reducing tumor size; inhibit (i.e., slow or stop to some extent) cancer cell infiltration into peripheral organs; inhibit (i.e., slow or stop to some extent) tumor metastasis; inhibit tumor growth to some extent; and/or relieve to some extent one or more of the symptoms associated with cancer. To the extent that the administered compound or composition hinders growth and/or kills existing cancer cells, it can be cytostatic and/or cytotoxic.

The term "container" refers to any receptacle and closure therefore suitable for storing, shipping, dispensing and/or handling pharmaceutical products.

The term "insert" refers to the information accompanying a pharmaceutical product that provides a description of how the product is to be administered and the safety and efficacy data required to allow physicians, pharmacists and subjects to make informed decisions about the use of the product. Package inserts are generally considered to be "labels" for pharmaceutical products.

"contemporaneously administering," "co-administering," "simultaneously administering," and similar expressions refer to the contemporaneous administration of two or more drugs to the subject being treated. By "contemporaneous" is meant that each drug is administered either simultaneously or sequentially in any order at different time points. However, if not administered simultaneously, it is meant that they are administered to the subject in a sequence and close enough in time to provide the desired therapeutic effect and may act synergistically. For example, a compound of the present disclosure may be administered simultaneously with an optional therapeutic agent or sequentially in any order at different time points with an optional therapeutic agent. The compounds of the present disclosure and optional therapeutic agents may be administered separately in any suitable form and by any suitable route. When the compounds of the present disclosure and optional therapeutic agents are administered non-concurrently, it is understood that they may be administered to a subject in need thereof in any order. For example, a compound of the disclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of an optional therapeutic treatment modality (e.g., radiation therapy) to a subject in need thereof. In various embodiments, the compound of the disclosure and the optional therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart. In one embodiment, the components of the combination therapy are administered at intervals of about 1 minute to about 24 hours.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the disclosure (especially in the context of the following claims) is to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

As used herein, the term "halogen" by itself or as part of another group refers to-Cl, -F, -Br, or-I.

As used herein, the term "nitro" by itself or as part of another group refers to-NO ₂ 。

As used herein, the term "cyano" by itself or as part of another group refers to — CN.

As used herein, the term "hydroxy" by itself or as part of another group refers to-OH.

The term "alkyl" as used herein by itself or as part of another group refers to straight or branched chain aliphatic hydrocarbons containing from one to twelve carbon atoms, i.e., C ₁ -C ₁₂ Alkyl radicals, or containing the specified number of carbon atoms, e.g. C ₁ Alkyl radicals such as methyl, C ₂ Alkyl groups such as ethyl, and the like. In one embodiment, alkyl is C ₁ -C ₁₀ An alkyl group. In another embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ An alkyl group. In another embodiment, alkyl is C ₁ -C ₃ Alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C ₁ -C ₁₂ The alkyl group includes methyl,Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl and decyl. In another embodiment, one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms, i.e., the alkyl group is isotopically labeled with deuterium. One non-limiting exemplary deuterated alkyl group is-CD ₃ . In another embodiment, none of the hydrogen atoms of the alkyl groups are replaced with deuterium atoms, i.e., the alkyl groups are labeled with deuterium isotopes.

The term "optionally substituted alkyl" as used herein by itself or as part of another group refers to an alkyl group that is unsubstituted or substituted with one, two or three substituents, wherein each substituent is independently nitro, haloalkoxy, aryloxy, aralkoxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carbamate, carboxyl, alkoxycarbonyl, carboxyalkyl, -N (R) ^56a )C(＝O)R ^56b 、-N(R ^56c )S(＝O) ₂ R ^56d 、-C(＝O)R ⁵⁷ 、-S(＝O)R ^56e or-S (═ O) ₂ R ⁵⁸ (ii) a Wherein:

R ^56a is hydrogen or alkyl;

R ^56b is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C ₆ -C ₁₀ Aryl, or optionally substituted heteroaryl;

R ^56c is hydrogen or alkyl;

R ^56d is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substitutedC ₆ -C ₁₀ Aryl, or optionally substituted heteroaryl;

R ^56e is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C ₆ -C ₁₀ Aryl, or optionally substituted heteroaryl;

R ⁵⁷ is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl; and is

R ⁵⁸ Is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy) alkyl, (aryl) alkyl, (heteroaryl) alkyl, (amino) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl. Non-limiting exemplary optionally substituted alkyl groups include-CH (CO) ₂ Me)CH ₂ CO ₂ Me and-CH (CH) ₃ )CH ₂ N(H)C(＝O)O(CH ₃ ) ₃ 。

As used herein, the term "alkenyl" by itself or as part of another group refers to an alkyl group that contains one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is C ₂ -C ₆ An alkenyl group. In another embodiment, the alkenyl group is C ₂ -C ₄ An alkenyl group. In another embodiment, the alkenyl group has one carbon-carbon double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

As used herein, the term "optionally substituted alkenyl" by itself or as part of another group refers to an alkenyl group that is unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle. Non-limiting exemplary optionally substituted alkenyl groups include-CH ═ CHPh.

As used herein, the term "alkynyl" by itself or as part of another group refers to an alkyl group containing one, two, or three carbon-carbon triple bonds. In one embodiment, alkynyl is C ₂ -C ₆ Alkynyl. In another embodiment, alkynyl is C ₂ -C ₄ Alkynyl. In another embodiment, alkynyl has one carbon-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.

As used herein, the term "optionally substituted alkynyl" by itself or as part of another group refers to an alkynyl group that is unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle. Non-limiting exemplary optionally substituted alkynyl groups include-C ≡ CPh and-CH (Ph) C ≡ CH.

As used herein, the term "haloalkyl" refers toBy itself or as part of another group is meant an alkyl group substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted with one, two or three fluorine and/or chlorine atoms. In another embodiment, the alkyl group is substituted with one, two or three fluorine atoms. In another embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ An alkyl group. In another embodiment, the alkyl group is C ₁ Or C ₂ An alkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1-difluoroethyl, 2,2, 2-trifluoroethyl, 3,3, 3-trifluoropropyl, 4,4, 4-trifluorobutyl, and trichloromethyl groups.

As used herein, the term "hydroxyalkyl" or "(hydroxy) alkyl" by itself or as part of another group refers to an alkyl group substituted with one, two, or three hydroxy groups. In one embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ An alkyl group. In another embodiment, alkyl is C ₁ Or C ₂ An alkyl group. In another embodiment, hydroxyalkyl is a hydroxyalkyl group, i.e., substituted with one hydroxyl group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxyl groups. Non-limiting exemplary (hydroxy) alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1, 3-dihydroxypropan-2-yl.

As used herein, the term "alkoxy" by itself or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, alkyl is C ₁ -C ₆ Alkyl and the resulting alkoxy group is therefore referred to as "C ₁ -C ₆ Alkoxy groups ". In another embodiment, alkyl is C ₁ -C ₄ Alkyl radical andand the resulting alkoxy group is therefore designated C ₁ -C ₄ An alkoxy group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and t-butoxy.

As used herein, the term "haloalkoxy" by itself or as part of another group refers to a haloalkyl group attached to a terminal oxygen atom. In one embodiment, the haloalkyl group is C ₁ -C ₆ A haloalkyl group. In another embodiment, the haloalkyl group is C ₁ -C ₄ A haloalkyl group. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy and 2,2, 2-trifluoroethoxy.

As used herein, the term "alkylthio" by itself or as part of another group refers to an alkyl group attached to a terminal sulfur atom. In one embodiment, the alkyl group is C ₁ -C ₄ An alkyl group. Non-limiting exemplary alkylthio groups include-SCH ₃ and-SCH ₂ CH ₃ 。

As used herein, the term "alkoxyalkyl" or "(alkoxy) alkyl" by itself or as part of another group refers to an alkyl group substituted with one alkoxy group. In one embodiment, alkoxy is C ₁ -C ₆ An alkoxy group. In another embodiment, alkoxy is C ₁ -C ₄ An alkoxy group. In another embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ An alkyl group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentoxymethyl.

As used herein, the term "heteroalkyl," by itself or as part of another group, refers to an unsubstituted straight or branched chain aliphatic radical containing from three to twenty chain atomsHydrocarbons, i.e. 3-to 20-membered heteroalkyl, or containing the indicated number of chain atoms, of which at least one-CH ₂ -is replaced by-O-, -N (H) -, -N (C) ₁ -C ₄ Alkyl) -or-S-. -O-, -N (H) -, -N (C) ₁ -C ₄ Alkyl) -or-S-can be independently located at any internal position of the aliphatic hydrocarbon chain, as long as each is-O-, -N (H) -, -N (C) ₁ -C ₄ Alkyl) -and-S-groups consisting of at least two-CH ₂ The groups are separated. In one embodiment, one-CH ₂ The-group is replaced by an-O-group. In another embodiment, two-CHs ₂ The-group is replaced by two-O-groups. In another embodiment, three-CH ₂ The-groups are replaced by three-O-groups. In another embodiment, four-CHs ₂ The-groups are replaced by four-O-groups. Non-limiting exemplary heteroalkyl groups include-CH ₂ OCH ₃ 、-CH ₂ OCH ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₂ OCH ₃ 、-CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₃ 、-CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₃ 。

As used herein, the term "cycloalkyl" by itself or as part of another group refers to saturated and partially saturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., C _3-12 Cycloalkyl radicals, or containing the specified number of carbons, e.g. C ₃ Cycloalkyl radicals such as cyclopropyl, C ₄ Cycloalkyl groups such as cyclobutyl and the like. In one embodiment, the cycloalkyl group is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl group is monocyclic, i.e., it has one ring. In another embodiment, cycloalkyl is C _3-8 A cycloalkyl group. In another embodiment, cycloalkyl is C _3-6 Cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, cycloalkyl is C ₅ Cycloalkyl, i.e., cyclopentyl. In another embodiment, the cycloalkyl groupIs C ₆ Cycloalkyl, i.e., cyclohexyl. Non-limiting exemplary C _3-12 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin (decalin), adamantyl, cyclohexenyl and spiro [3.3]Heptane.

As used herein, the term "optionally substituted cycloalkyl" by itself or as part of another group refers to a cycloalkyl group unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxy, amino (e.g., -NH ₂ Alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino or (hetero) alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxyl, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino) alkyl, (cyano) alkyl, (carboxamido) alkyl, mercaptoalkyl, (hetero) alkyl, (heteroaryl) alkyl, -N (R) alkyl ^56a )C(＝O)R ^56b 、-N(R ^56c )S(＝O) ₂ R ^56d 、-C(＝O)R ⁵⁷ 、-S(＝O)R ^56e 、-S(＝O) ₂ R ⁵⁸ OR-OR ⁵⁹ Wherein R is ^56a 、R ^56b 、R ^56c 、R ^56d 、R ^56e 、R ⁵⁷ And R ⁵⁸ Is as defined in connection with the term "optionally substituted alkyl" and R ⁵⁹ Is (hydroxy) alkyl or (amino) alkyl. The term optionally substituted cycloalkyl also includes cycloalkyl groups having fused optionally substituted aryl or optionally substituted heteroaryl groups, e.g.

Non-limiting exemplary optionally substituted cycloalkyl groups include:

as used herein, the term "heterocycle" by itself or as part of another group refers to a saturated or partially unsaturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic group containing three to fourteen ring members, i.e., a 3-to 14-membered heterocycle containing one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur or nitrogen. Each sulfur atom is independently oxidized to a sulfoxide, i.e., S (═ O), or a sulfone, i.e., S (═ O) ₂ 。

The term heterocycle includes those in which one or more-CH groups ₂ Groups in which the-group is replaced by one or more-C (═ O) -groups, include cyclic urea groups such as imidazolidin-2-one, cyclic amide groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidin-2-one.

The term heterocycle also includes groups having a fused optionally substituted aryl or optionally substituted heteroaryl group such as indoline, indolin-2-one, 2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine, 2,3,4, 5-tetrahydro-1H-benzo [ d ] azepine or 1,3,4, 5-tetrahydro-2H-benzo [ d ] azepine-2-one.

In one embodiment, the heterocyclic group is a 4-to 8-membered cyclic group containing one ring and one or two oxygen atoms, such as tetrahydrofuran or tetrahydropyran, or one or two nitrogen atoms, such as pyrrolidine, piperidine or piperazine, or one oxygen and one nitrogen atom, such as morpholine, and optionally, one-CH ₂ The-group is replaced by a-C (═ O) -group, for example pyrrolidin-2-one or piperazin-2-one. In another embodiment, the heterocyclic group is a 5-to 8-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally, one-CH ₂ -the group is replaced by a-C (═ O) -group. In another embodiment, the heterocyclic group is a 5-or 6-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally, one-CH ₂ -the group is replaced by a-C (═ O) -group. In another embodiment, heterocyclic groups are 8-to 12-membered cyclic groups containing two rings and one or two nitrogen atoms. The heterocyclic ring may be attached to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclic groups include:

as used herein, the term "optionally substituted heterocycle" by itself or as part of another group refers to a heterocyclic group that is unsubstituted or substituted with one to four substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxy, amino (e.g., -NH) ₂ Alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino or (hetero) alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxyl, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino) alkyl, (cyano) alkyl, (carboxamido) alkyl, mercaptoalkyl, (hetero) alkyl, (heteroaryl) alkyl, -N (R) alkyl ^56a )C(＝O)R ^56b 、-N(R ^56c )S(＝O) ₂ R ^56d 、-C(＝O)R ⁵⁷ 、-S(＝O)R ^56e 、-S(＝O) ₂ R ⁵⁸ OR-OR ⁵⁹ Wherein R is ^56a 、R ^56b 、R ^56c 、R ^56d 、R ^56e 、R ⁵⁷ 、R ⁵⁸ And R ⁵⁹ As defined in connection with the term "optionally substituted cycloalkyl". Substitution may occur at any available carbon or nitrogen atom of the heterocyclic group. Non-limiting exemplary optionally substituted heterocyclic groups include

As used herein, the term "aryl" by itself or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C ₆ -C ₁₄ And (4) an aryl group. Non-limiting exemplary aryl groups include phenyl (abbreviated "Ph"), naphthyl, phenanthryl, anthryl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

The term "optionally substituted aryl" as used herein by itself or as part of another group refers to aryl groups that are unsubstituted or substituted with one to five substituents, wherein each of the substituents is independently halogen, nitro, cyano, hydroxy, amino (e.g., -NH ₂ Alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino or (hetero) alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxyl, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino) alkyl, (cyano) alkyl, (carboxamido) alkyl, mercaptoalkyl, (hetero) alkyl, (heteroaryl) alkyl, -N (R) alkyl ^56a )C(＝O)R ^56b 、-N(R ^56c )S(＝O) ₂ R ^56d 、-C(＝O)R ⁵⁷ 、-S(＝O)R ^56e 、-S(＝O) ₂ R ⁵⁸ OR-OR ⁵⁹ Wherein R is ^56a 、R ^56b 、R ^56c 、R ^56d 、R ^56e 、R ⁵⁷ 、R ⁵⁸ And R ⁵⁹ As defined in connection with the term "optionally substituted cycloalkyl".

In one embodiment, optionally substituted aryl is optionally substituted phenyl. In another embodiment, the optionally substituted phenyl group has four substituents. In another embodiment, the optionally substituted phenyl group has three substituents. In another embodiment, the optionally substituted phenyl group has two substituents. In another embodiment, the optionally substituted phenyl group has one substituent. Non-limiting, exemplary optionally substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2, 6-difluorophenyl, 2, 6-dichlorophenyl, 2-methyl-3-methoxyphenyl, 2-ethyl-3-methoxyphenyl, 3, 4-dimethoxyphenyl, 3, 5-difluorophenyl, 3, 5-dimethylphenyl, 3, 5-dimethoxy-4-methylphenyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 6-dimethylphenyl, 3, 5-dimethoxy-4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl includes aryl groups having fused optionally substituted cycloalkyl groups and fused optionally substituted heterocyclic groups. Non-limiting examples include: 2, 3-dihydro-1H-inden-1-yl, 1,2,3, 4-tetrahydronaphthalen-1-yl, 1,3,4, 5-tetrahydro-2H-benzo [ c ] azepin-2-yl, 1,2,3, 4-tetrahydroisoquinolin-1-yl, and 2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ d ] azepin-1-yl.

As used herein, the term "heteroaryl" by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system having five to 14 fourteen ring atoms, i.e., a 5-to 14-membered heteroaryl group, which contains one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur or nitrogen. In one embodiment, the heteroaryl group has three heteroatoms. In another embodiment, the heteroaryl group has two heteroatoms. In another embodiment, the heteroaryl group has one heteroatom. In another embodiment, heteroaryl is 5-to 10-membered heteroaryl. In another embodiment, heteroaryl has 5 ring atoms, e.g., thienyl — a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl group has 6 ring atoms, e.g., pyridyl — a 6-membered heteroaryl group having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo [ b ] thienyl, naphtho [2,3-b ] thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuryl, benzoxazolonyl, chromenyl, xanthenyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, phthalazinyl, quinazolinyl, pteridinyl, 4 aH-carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, heteroaryl is selected from thienyl (e.g., thiophen-2-yl and thiophen-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), pyridyl (pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-3-yl, pyridazin-4-yl), pyridazinyl (e.g., pyridazin-2-yl, pyridazin-3-yl, pyridazin-2-yl, pyridazin-4-yl, pyridazin-2-yl, pyridazin-3-yl, and pyridazin-yl), pyridazin-4-yl, Pyrimidin-4-yl and pyrimidin-5-yl), thiazolyl (thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), isothiazolyl (isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl). The term heteroaryl also includes N-oxides. One non-limiting exemplary N-oxide is pyridyl N-oxide.

As used herein, the term "optionally substituted heteroaryl" by itself or as part of another group refers to heteroaryl unsubstituted or substituted with one to four substituents, wherein the substituents are independently halogen, nitro, cyano, hydroxy, amino (e.g., -NH) ₂ Alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino or (hetero) alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, carbonylamino, carboxyalkyl, haloalkoxy, carboxyalkyl and the like,Arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxyl, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino) alkyl, (cyano) alkyl, (carboxamido) alkyl, mercaptoalkyl, (heterocycle) alkyl, (heteroaryl) alkyl, -N (R) alkyl ^56a )C(＝O)R ^56b 、-N(R ^56c )S(＝O) ₂ R ^56d 、-C(＝O)R ⁵⁷ 、-S(＝O)R ^56e 、-S(＝O) ₂ R ⁵⁸ OR-OR ⁵⁹ Wherein R is ^56a 、R ^56b 、R ^56c 、R ^56d 、R ^56e 、R ⁵⁷ 、R ⁵⁸ And R ⁵⁹ As defined in connection with the term "optionally substituted cycloalkyl".

In one embodiment, an optionally substituted heteroaryl group has two substituents. In another embodiment, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom may be substituted.

As used herein, the term "aryloxy" by itself or as part of another group refers to an optionally substituted aryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-

As used herein, the term "aralkoxy" by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH ₂ O-。

As used herein, the term "(cyano) alkyl" by itself or as part of another group refers to an alkyl group substituted with one, two, or three cyano groups. In one embodiment, the alkyl group is substituted with one cyano group. In another embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ Alkyl and thus (cyano) alkyl is referred to as (cyano) C ₁ -C ₄ An alkyl group. Non-limiting exemplary (cyano) alkyl groups include-CH ₂ CN、-CH ₂ CH ₂ CN and-CH ₂ CH ₂ CH ₂ CN。

As used herein, the term "(cycloalkyl) alkyl" by itself or as part of another group refers to an alkyl group substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group is optionally substituted C ₃ -C ₆ A cycloalkyl group. In another embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ An alkyl group. In another embodiment, alkyl is C ₁ Or C ₂ An alkyl group. In another embodiment, the alkyl is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl is substituted with two optionally substituted cycloalkyl groups. Non-limiting exemplary (cycloalkyl) alkyl groups include

As used herein, the term "sulfonamido" by itself or as part of another group refers to a compound of the formula-SO ₂ NR ^50a R ^50b Wherein R is ^50a And R ^50b Each independently is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R ^50a And R ^50b Together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclic group. Non-limiting exemplary sulfonamido groups include-SO ₂ NH ₂ 、-SO ₂ N(H)CH ₃ and-SO ₂ N(H)Ph。

As used herein, the term "carboxamido" by itself or as part of another group refers to a compound of formula-C (═ O) NR ^50c R ^50d Wherein R is ^50c And R ^50d Each independently is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R ^50c And R ^50d Together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclic group. Non-limiting exemplary carboxamido groups include-C (═ O) NH ₂ 、-C(＝O)(H)CH ₃ and-C (═ O) N (CH) ₃ ) ₂ 。

As used herein, the term "(carboxamido) alkyl" by itself or as part of another group refers to an alkyl group substituted with one carboxamido group. In one embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ An alkyl group. In another embodiment, alkyl is C ₁ Or C ₂ An alkyl group. Non-limiting exemplary (carboxamido) alkyl groups include-CH ₂ C(＝O)NH ₂ 、-CH ₂ C(＝O)(H)CH ₃ and-CH ₂ C(＝O)N(CH ₃ ) ₂ 。

As used herein, the term "alkylcarbonyl" by itself or as part of another group refers to a carbonyl group substituted with an alkyl group, i.e., -C (═ O) -. In one embodiment, alkyl is C ₁ -C ₄ An alkyl group. One non-limiting exemplary alkylcarbonyl group is-COCH ₃ . As used herein, the term "arylcarbonyl" by itself or as part of another group refers to a carbonyl group substituted with an optionally substituted aryl group, i.e., -C (═ O) -. One non-limiting exemplary arylcarbonyl group is-COPh.

As used herein, the term "alkylsulfonyl" by itself or as part of another group refers to a sulfonyl group substituted with an alkyl group, i.e., -SO ₂ -. A non-limiting exemplary alkylsulfonyl group is-SO ₂ CH ₃ 。

The term "arylsulfonyl" as used herein by itself or as part of another group refers to a sulfonyl group substituted with an optionally substituted aryl group, i.e., -SO ₂ -. A non-limiting exemplary arylsulfonyl group is-SO ₂ Ph。

As used herein, the term "mercaptoalkyl" by itself or as part of another group refers to an alkyl group substituted with an — SH group.

As used herein, the term "carboxy" by itself or as part of another group refers to an atomic group of the formula-C (═ O) OH.

As used herein, the term "ureido" by itself or as part of another group refers to a compound of the formula-NR ^51a -C(＝O)-NR ^51b R ^51c Wherein R is ^51a Is hydrogen or alkyl; and R is ^51b And R ^51c Each independently is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl, or R ^51b And R ^51c Together with the nitrogen to which they are attached form a 4-to 8-membered optionally substituted heterocyclic group. Non-limiting exemplary ureido groups include-NH-C (C ═ O) -NH ₂ and-NH-C (C ═ O) -NHCH ₃ 。

As used herein, the term "guanidino" by itself or as part of another group refers to a compound of the formula-NR ^52a C(＝NR ⁵³ )NR ^52b R ^52c Wherein R is ^52a Is hydrogen or alkyl; r ^52b And R ^53c Each independently is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; or R ^52b And R ^52c Together with the nitrogen to which they are attached form a 4-to 8-membered optionally substituted heterocyclic group; and R is ⁵³ Is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido or sulfonamido. Non-limiting exemplary guanidino groups include-NH-C (C ═ NH) -NH ₂ 、-NHC(C＝NCN)-NH ₂ and-NH-C (C ═ NH) -NHCH ₃ 。

As used herein, the term "(heterocyclo) alkyl" by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclic groups. In one embodiment, the alkyl group is substituted with an optionally substituted 5-to 8-membered heterocyclic group. In another embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ An alkyl group. The heterocyclic group may be attached to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (hetero) alkyl groups include:

as used herein, the term "carbamate" by itself or as part of another group refers to the formula-NR ^54a C(＝O)OR ^54b Wherein R is ^54a Is hydrogen or alkyl, and R ^54b Is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl. One non-limiting exemplary carbamate group is-NH- (C ═ O) -OtBu.

As used herein, the term "(heteroaryl) alkyl" by itself or as part of another group refers to an alkyl group substituted with one or two optionally substituted heteroaryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5-to 14-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-to 14-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5-to 9-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-to 9-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5-or 6-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-or 6-membered heteroaryl groups. In one embodiment, the alkyl group is C ₁ -C ₆ An alkyl group. In another embodiment, the alkyl group is C ₁ -C ₄ An alkyl group. In another embodiment, the alkyl group is C ₁ Or C ₂ An alkyl group. Non-limiting exemplary (heteroaryl) alkyl groups include:

as used herein, the term "aralkyl" or "(aryl) alkyl" by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted aryl group. In another embodiment, the alkyl group is substituted with two optionally substituted aryl groups. In one embodiment, aryl is optionally substituted phenyl or optionally substituted naphthyl. In another embodiment, aryl is optionally substituted phenyl. In one embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ An alkyl group. In another embodiment, the alkyl group is C ₁ Or C ₂ An alkyl group. Non-limiting exemplary (aryl) alkyl groups include benzyl, phenethyl, -CHPh ₂ and-CH (4-F-Ph) ₂ 。

As used herein, the term "acylamino" by itself or as part of another group refers to a compound of formula-C (═ O) NR ^60a R ^60b Wherein R is ^60a And R ^60b Each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, (alkoxy) alkyl, (hydroxy) alkyl, (cyano) alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, (aryl) alkyl, (cycloalkyl) alkyl, (heterocycle) alkyl, or (heteroaryl) alkyl; or R ^60a And R ^60b Together with the nitrogen to which they are attached form a 4-to 8-membered optionally substituted heterocyclic group. In one embodiment, R ^60a And R ^60b Each independently is hydrogen or C ₁ -C ₆ An alkyl group.

As used herein, the term "amino" by itself or as part of another group refers to the formula-NR ^55a R ^55b Wherein R is ^55a And R ^55b Independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)) Alkyl, (alkoxy) alkyl, (amino) alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, (aryl) alkyl, (cycloalkyl) alkyl, (heterocycle) alkyl, or (heteroaryl) alkyl.

In one embodiment, amino is-NH ₂ 。

In another embodiment, amino is "alkylamino", i.e., wherein R is ^55a Is C _1-6 Alkyl and R ^55b Is an amino group of hydrogen. In one embodiment, R ^55a Is C ₁ -C ₄ An alkyl group. Non-limiting exemplary alkylamino groups include-N (H) CH ₃ and-N (H) CH ₂ CH ₃ . In another embodiment, amino is "dialkylamino", i.e., wherein R is ^55a And R ^55b Each independently is C _1-6 Amino group of alkyl. In one embodiment, R ^55a And R ^55b Each independently is C ₁ -C ₄ An alkyl group. Non-limiting exemplary dialkylamino groups include-N (CH) ₃ ) ₂ and-N (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ 。

In another embodiment, amino is "hydroxyalkylamino", i.e., wherein R is ^55a Is (hydroxy) alkyl and R ^55b Is hydrogen or C ₁ -C ₄ Amino group of alkyl

In another embodiment, amino is "cycloalkylamino", i.e., wherein R is ^55a Is optionally substituted cycloalkyl and R ^55b Is hydrogen or C ₁ -C ₄ Amino group of alkyl.

In another embodiment, amino is "aralkylamino", i.e., wherein R is ^55a Is aralkyl and R ^55b Is hydrogen or C ₁ -C ₄ Amino group of alkyl. Non-limiting exemplary aralkylamino groups include-N (H) CH ₂ Ph、-N(H)CHPh ₂ and-N (CH) ₃ )CH ₂ Ph。

In another embodiment, the amino group is "(cycloalkane)Yl) alkylamino ", i.e., wherein R is ^55a Is (cycloalkyl) alkyl and R ^55b Is hydrogen or C ₁ -C ₄ An amino group of an alkyl group. Non-limiting exemplary (cycloalkyl) alkylamino groups include:

in another embodiment, amino is "(heterocyclic) alkylamino", i.e., wherein R is ^55a Is (hetero) alkyl and R ^55b Is hydrogen or C ₁ -C ₄ An amino group of an alkyl group. Non-limiting exemplary (heterocyclic) alkylamino groups include:

as used herein, the term "(amino) alkyl" by itself or as part of another group refers to an alkyl group substituted with one amino group. In one embodiment, the amino group is-NH ₂ . In one embodiment, the amino group is alkylamino. In another embodiment, the amino group is a dialkylamino group. In another embodiment, alkyl is C ₁ -C ₆ An alkyl group. In another embodiment, alkyl is C ₁ -C ₄ An alkyl group. Non-limiting exemplary (amino) alkyl groups include-CH ₂ NH ₂ 、-CH ₂ CH ₂ N(H)CH ₃ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ N (H) cyclopropyl, -CH ₂ N (H) cyclobutyl and-CH ₂ N (H) cyclohexyl and-CH ₂ CH ₂ CH ₂ N(H)CH ₂ Ph and-CH ₂ CH ₂ CH ₂ N(H)CH ₂ (4-CF ₃ -Ph)。

The present disclosure encompasses any compound of the present disclosure that is isotopically labeled (i.e., radiolabeled) by replacing one or more atoms with atoms having a different atomic mass or mass number. Can be incorporated into the disclosure Examples of isotopes of (a) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, as respectively ² H (or deuterium (D)), (ii) and (iii) a salt of hydrogen, ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ cl, for example, ³ H、 ¹¹ c and ¹⁴ C. in one embodiment, a compound is provided wherein substantially all atoms at one position within the compound of the present disclosure are replaced with atoms having a different atomic mass or mass number. In another embodiment, a compound is provided wherein substantially all of the atoms at one position within the compounds of the present disclosure are replaced with deuterium atoms, e.g., -CH ₃ All hydrogen atoms of the group are replaced by deuterium atoms to give-CD ₃ A group. In another embodiment, a compound is provided wherein a portion of the atoms at a position within a compound of the disclosure are replaced, i.e., a compound of the disclosure is enriched at a position with atoms having a different atomic mass or mass number. In another embodiment, there is provided a compound wherein no atom of the compound of the present disclosure is replaced with an atom having a different atomic mass or mass number. Isotopically labeled compounds of the present disclosure can be prepared by methods known in the art.

The compounds of the present disclosure contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms as well as their racemic and resolved forms and mixtures thereof. In view of this disclosure, the individual enantiomers can be separated according to methods known in the art. When the compounds described herein contain ethylenic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that they include both E and Z geometric isomers. The present disclosure also encompasses all tautomers.

As used herein, the term "stereoisomer" is a collective term for all isomers of a single molecule that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereomers).

The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

The terms "enantiomer" and "enantiomer" refer to a molecule that is not superposed on its mirror image and is therefore optically active, in which the enantiomer rotates the plane of polarized light in one direction and the mirror image compound rotates the plane of polarized light in the opposite direction.

The term "racemic" refers to a mixture of equal parts of enantiomers and which is optically inactive. In one embodiment, the compounds of the present disclosure are racemic

The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

The stereochemical terms and conventions used in the specification are intended to be consistent with those described in Pure & appl. chem68:2193(1996), unless otherwise indicated.

The term "enantiomeric excess" or "ee" refers to a measure of how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as | R-S | 100, where R and S are the respective molar or weight fractions of the enantiomers in the mixture such that R + S ═ 1. Using knowledge of the optical rotation of chiral species, the percent enantiomeric excess is defined as ([ alpha ]] _obs /[α] _max ) 100, wherein [ α ]] _obs Is the optical rotation of a mixture of enantiomers, [ alpha ]] _max Optical rotation of pure enantiomer. Determination of the enantiomeric excess can be performed using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical polarization.

As used herein, the term "about" includes the stated number ± 10%. Thus, "about 10" means 9 to 11.

Examples

General Synthesis of Compounds of the disclosure

General formula 1

The compounds of the present disclosure may be prepared according to general scheme 1 from intermediates of the present disclosure. Briefly, in step 1, let R therein ¹⁵ Reaction of a compound of formula XLVI which is hydrogen with, for example, dimethyl carbonate in the presence of sodium hydride to give a compound wherein R is ¹⁵ A compound of formula XLVI which is-C (═ O) OMe.

In step 2, wherein R is treated with, for example, guanidine HCl first and then sodium nitrite ¹⁵ A compound of formula XLVI, which is-C (═ O) OMe, is converted to a compound of formula XXXI.

In step 3, a compound of formula XXXI is reacted with, for example, phosphorus oxychloride to give Z thereof ¹ is-Cl, R ¹² A compound of formula XVI which is-Cl and Q is ═ N-.

In step 4, let Z therein ¹ is-Cl, R ¹² A compound of formula XVI which is-Cl and Q is ═ N-and wherein R is ^2a 、R ^2b 、R ^2c And X is a compound of formula A as defined in connection with formula I to give a compound wherein R is ¹² is-Cl, R ¹³ A compound of formula XVI which is hydrogen and Q is ═ N-.

In step 5, the reaction of R ¹² is-Cl, R ¹³ A compound of formula XVI which is hydrogen and Q is ═ N-with R ¹³ -Cl、R ¹³ -OH or a similar reagent to give R ¹² is-Cl, R ¹³ is-C (═ O) R ^14a OR-C (═ O) OR ^14b And Q is N-a compound of formula XVI.

In step 6, the reaction of R ¹² is-Cl, R ¹³ is-C (═ O) R ^14a OR-C (═ O) OR ^14b Compounds of formula XVI in which Q is ═ N-and, for example, H-LR ³ Reaction to give R ¹² is-LR ³ 、R ¹³ is-C (═ O) R ^14a OR-C (═ O) OR ^14b And Q is N-a compound of formula XVI.

In step 7, for R ¹² is-LR ³ 、R ¹³ is-C (═ O) R ^14a OR-C (═ O) OR ^14b And deprotection of a compound of formula XVI wherein Q is ═ N-gives ¹² is-LR ³ 、R ¹³ A compound of formula XVI which is hydrogen and Q is ═ N-. For example, when R is ¹³ In the case of-C (═ O) OtBu, the-C (═ O) OtBu group can be removed, for example, by treating the compound of formula XVI with TFA.

In step 8, reacting R therein ¹² is-LR ³ 、R ¹³ A compound of formula XVI which is hydrogen and Q is ═ N-with R ¹ -Cl、R ¹ -OH or an analogous reagent to give a compound of formula I wherein Q is ═ N-.

In step 9, chirality is used, e.g. by Supercritical Fluid Chromatography (SFC), using chiral column chromatography techniques, e.g. by Supercritical Fluid Chromatography (SFC)

The ID column resolves isomers, e.g. diastereomers and/or enantiomers, of compounds of formula I wherein Q is ═ N-.

The compounds of the present disclosure may also be prepared according to general scheme 2 from intermediates of the present disclosure.

General scheme 2

The compounds of the present disclosure may also be prepared from intermediates of the present disclosure according to general scheme 2. Briefly, in step 1, a compound of formula XLVI, wherein R ¹⁵ is-C (═ O) OMe, is converted to a compound by treatment with, for example, thiourea, a compound of formula XVI, wherein Q is ═ N-, Z ¹ is-OH, and R ¹² is-SH.

In step 2, a compound of formula XVI, wherein Q is ═ N-, Z ¹ is-OH, and R ¹² To compounds of formula XVI in which Q is ═ N-, Z ¹ is-OH, and R ¹² is-SMe, for example by treatment with methyl iodide in the presence of a base such as NaOH.

In step 3Reacting a compound of formula XVI wherein Q is ═ N-, Z ¹ is-OH, and R ¹² is-SMe, e.g. with Tf ₂ O to give a compound of formula XVI wherein Q is ═ N-, Z ¹ is-OTf, and R ¹² is-SMe.

In step 4, a compound of formula XVI, wherein Q is ═ N-, Z ¹ is-OTf, and R ¹² Is the reaction of-SMe with a compound of formula A', wherein R ^2a 、R ^2b 、R ^2c And X is as defined for formula I, and R ¹³ Is Boc to give a compound of formula XVI wherein Q is ═ N-, R ¹² is-SMe, and R ¹³ Is Boc.

In step 5, a compound of formula XVI, wherein Q is ═ N-, R ¹² is-SMe, and R ¹³ Is Boc, with mCPBA or another oxidizing agent to give a compound of formula XVI, wherein Q is ═ N-, R ¹² is-S (═ O) Me, R ¹³ Is Boc.

In step 6, a compound of formula XVI, wherein Q is ═ N-, R ¹² is-S (═ O) Me, and R ¹³ Being Boc, e.g. with H-LR ³ Reaction to give the compound of formula XVI wherein R ¹² is-LR ³ Q is ═ N-, and R ¹³ Is Boc.

In step 7, a compound of formula XVI wherein R ¹² is-LR ³ Q is ═ N-, and R ¹³ Is Boc, e.g. deprotection with TFA, to give a compound of formula XVI wherein R ¹² is-LR ³ 、R ¹³ Is hydrogen; and Q is ═ N-.

In step 8, a compound of formula XVI wherein R ¹² is-LR ³ ，R ¹³ Is hydrogen; q is ═ N-and R ¹ -Cl、R ¹ -OH or similar reagents to give compounds of formula I wherein Q is ═ N-.

In step 9, isomers, e.g. diastereomers and/or enantiomers, of compounds of formula I, wherein Q is ═ N-are resolved using chiral chromatographic techniques, e.g. by using chiral Supercritical Fluid Chromatography (SFC) e.g.,

an ID column.

Example 1

Intermediates 1A and 1B: synthesis of (S) -2- (piperazin-2-yl) acetonitrile (TFA salt) and (R) -2- (piperazin-2-yl) acetonitrile (TFA salt)

Step 1: synthesis of 4-bromobut-2-enenitrile

To a solution of but-3-enenitrile (52.9g,788mmol) in a mixed solvent of t-BuOH (75mL) and hexane (300mL) was added a solution of bromine (126.0g,788mmol) in tBuOH (75mL) at 15 deg.C, over 30min, and the reaction mixture was stirred at room temperature for 2 h. After removing the volatiles under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate 4:1) to give the title compound (115g, quantitative) as a yellowish oil.

Step 2: synthesis of 2- (1, 4-dibenzylpiperazin-2-yl) acetonitrile

Under Ar at 0 ℃ to N ¹ ,N ² Dibenzylethane-1, 2-diamine (107g,445mmol) and Et ₃ To a solution of N (90g,890mmol) in dry toluene (400mL) was added dropwise a solution of 4-bromobut-2-enenitrile (step 1,65.0g,445mmol) in dry toluene (150 mL). The reaction mixture was stirred at room temperature overnight. After removing the volatiles under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate 4:1) to give the title compound (68g, 50%) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.40–7.22(m,10H),3.81(d,J＝13.3Hz,1H),3.59–3.45(m,3H),3.07–2.98(m,1H),2.91(dd,J＝16.6,8.0Hz,1H),2.71–2.54(m,4H),2.54–2.37(m,3H).

And step 3: synthesis of 2- (piperazin-2-yl) acetonitrile dihydrochloride

AcCl (97g,681mmol) was added dropwise to a solution of 2- (1, 4-dibenzylpiperazin-2-yl) acetonitrile (step 2,52g,170mmol) in DCE (300mL) at 0 ℃ under Ar for 30 min. The reaction mixture was stirred at 85 ℃ for 24 hours. After cooling to room temperature and removal of volatiles under reduced pressure, the residue was recrystallized from EtOH and water to give the title compound as an off-white solid (23.0g, 68%). ¹ H NMR(400MHz,D ₂ O)δ4.08–3.97(m,1H),3.89–3.68(m,3H),3.53–3.29(m,3H),3.15(d,J＝6.1Hz,2H).

And 4, step 4: synthesis of tert-butyl 3- (cyanomethyl) piperazine-1-carboxylate

To a solution of 2- (piperazin-2-yl) acetonitrile dihydrochloride (step 3,46g,0.23mol) in MeOH (400mL) at-15 deg.C under Ar was added Et ₃ N (78g,1.16mol) and Boc ₂ O (51g,0.23 mol); and the reaction mixture was stirred at 0 ℃ for 2 h. After removing the volatiles under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1:1) to give the title compound (31.4g, 63%) as a pale yellow oil. ¹ H NMR(400MHz,Chloroform-d)δ4.00–3.95(m,1H),3.91-3.82(m,1H),3.09–2.91(m,3H),2.89–2.58(m,2H),2.57–2.40(m,2H),1.81(s,1H),1.49(s,9H).

And 5: synthesis of tert-butyl (S) -3- (cyanomethyl) piperazine-1-carboxylate and tert-butyl (R) -3- (cyanomethyl) piperazine-1-carboxylate

By using

Chiral SFC resolution of 3- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (step 4,31.4g) on an AY-H column afforded the title compound as a white solid (isomer A: 14.9g, 100% ee; isomer B: 14.8g, 99.7% ee).

Step 6: synthesis of (S) -2- (piperazin-2-yl) acetonitrile (TFA salt) (intermediate 1A)

Tert-butyl (S) -3- (cyanomethyl) piperazine-1-carboxylate (isomer A of step 5, 2.2g,9.77mmol) was dissolved in a mixed solvent of DCM (30mL) and TFA (6mL), and the reaction mixture was stirred at room temperature for 1 h. After removing the volatiles under reduced pressure, the title compound (3.5g, quantitative) was used in the next step as a white solid without purification. MS:126.3(M + H) ⁺ )。

And 7: synthesis of (R) -2- (piperazin-2-yl) acetonitrile (TFA salt) (intermediate 1B)

Tert-butyl (R) -3- (cyanomethyl) piperazine-1-carboxylate (isomer B of step 5, 1.1g,9.77mmol) was dissolved in a mixed solvent of DCM (30mL) and TFA (6mL), and the reaction mixture was stirred at room temperature for 1 h. After removing the volatiles under reduced pressure, the title compound (1.7g, quantitative) was used in the next step as a white solid without purification. MS:126.3(M + H) ⁺ )。

Example 2

And (3) synthesis of an intermediate 2:3 '-methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Step 1 Synthesis of 2 '-bromo-5, 6-dihydro- [1,1' -biphenyl ] -3(4H) -one

Under Ar, a mixture of 1-bromo-2-iodobenzene (10g, 35.3mmol), 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohexyl-2-en-1-one (8.24g,37.1mmol), Na ₂ CO ₃ (11.24g,106mmol) and PdCl ₂ (dppf) (2.59g,3.53mmol) was stirred in DME (120mL) and water (30mL) at 90 deg.C for 2 h. After cooling to room temperature, water (100mL) was added and the resulting mixture was extracted twice with EA, the combined organic layers were washed with brine, Na ₂ SO ₄ Drying and concentration under reduced pressure gave a brown oil which was purified by column chromatography on silica gel eluting with 0% to 10% ethyl acetate/hexanes to give the title compound as a brown oil (7.12g, 80%). MS: 251.2, 253.2(M + H +).

Step 2 Synthesis of 3- (2-bromophenyl) -3-vinylcyclohex-1-one

To a mixture of copper (I) iodide (11.89g,62.4mmol) and LiCl (2.65g,62.4mmol) in anhydrous THF (150mL) at-78 deg.C under Ar was added dropwise vinyl magnesium bromide (16.4g, 124.8mmol) over 30 minutes, and the mixture was stirred at-78 deg.C for an additional 30 minutes. Dropwise adding 2 '-bromo-5, 6-dihydro- [1,1' -biphenyl ]A solution of-3 (4H) -one (step 1, 10.4g, 41.4mmol) in anhydrous THF (50mL) and then the reaction mixture was stirred at-78 ℃ for 1 hour and allowed to warm to room temperature for 1 hour. Adding saturated NH ₄ The reaction was quenched with Cl (150mL) and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, Na ₂ SO ₄ Drying and concentration under reduced pressure gave a brown oil which was purified by column chromatography on silica gel eluting with 0% to 10% ethyl acetate in hexanes to give the title compound (9.2g, 80%) as a colorless oil. MS: 279.2, 281.1(M + H +).

Step 3 Synthesis of 3- (2- (prop-1-en-2-yl) phenyl) -3-vinylcyclohex-1-one

4,4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborane (27.7g,165mmol), 3- (2-bromophenyl) -3-vinylcyclohex-1-one (step 2,9.2g,33.0mmol), K under Ar ₂ CO ₃ (9.11g,65.9mmol) and PdCl2(dppf) -CH ₂ Cl ₂ The adduct (1.346g,1.648mmol) was dissolved in DME (50mL) and water (10mL) and stirred at 90 deg.C overnight. The volatiles were removed under reduced pressure, extracted twice with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give a black oil which was purified by column chromatography on silica eluting with 0% to 10% ethyl acetate/hexanes to give the title compound as a colorless oil (5.02g, 63.4%). MS: 241.3(M + H +).

Step 4 Synthesis of 3 '-Methylspiro [ cyclohexane-1, 1' -indene ] -3-one

A mixture of (1, 3-bis- (2,4, 6-trimethylphenyl) -2-imidazolidinylidene) dichloro (o-isopropoxybenzylidene) ruthenium (3.71g, 5.92mmol), 3- (2- (prop-1-en-2-yl) phenyl) -3-vinylcyclohex-1-one (4.74g,19.72mmol) in toluene (100mL) under Ar was stirred at 80 deg.C overnight. After removing the volatiles under reduced pressure, the residue was purified by silica gel column chromatography and eluted from 0% to 15% with ethyl acetate/hexane to give the title compound (3.88g, 93%) as a colorless oil. MS: 213.3(M + H) ⁺ )。

Step 5 Synthesis of methyl 3 '-methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

To a solution of dimethyl carbonate (8.44g,94mmol) in anhydrous THF (30mL) under Ar was added NaH (3.75g,94mmol, 60%) portionwise, then the mixture was heated to 80 ℃ and the 3 '-methylspiro [ cyclohexane-1, 1' -indene ] at 80 ℃]-3-ketones (step 4, 3.98g, 18.75mmol) of THF was added to the mixture. The mixture was stirred at 80 ℃ for 4 hours. After cooling to room temperature, saturated NH was added ₄ The reaction was quenched with Cl and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with Na ₂ SO ₄ Drying and concentration under reduced pressure gave a pale yellow oil which was purified by silica gel column chromatography eluting with 5% to 20% ethyl acetate/hexanes to give the title compound (4.71g, 93%) as a pale yellow oil. MS: 271.3(M + H +).

Example 3

And (3) synthesis of an intermediate 3: (1R) -2' -fluoro-3 ' -methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Step 1 Synthesis of 2 '-vinyl-5, 6-dihydro- [1,1' -biphenyl ] -3(4H) -one

1-bromo-2-vinylbenzene (20g, 109mmol), 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohexyl-2-en-1-one (29.2g,131mmol), PdCl under Ar ₂ (dppf)-CH ₂ Cl ₂ The adduct (4g,4.90mmol) and sodium carbonate (29.0g,273mmol) were stirred in DME (160mL) and water (40mL) at 85 deg.C for 3 h. After cooling to room temperature, the mixture was cooled with ethyl acetate/H ₂ Partitioning, extraction with ethyl acetate twice, combining the organic layers, washing with brine, drying over anhydrous sodium sulfate, filtration and concentration to give a black oil, silica gel column purification chromatography eluting with ethyl acetate/hexanes from 0 to 25% to give the title compound as a yellow oil (21.6g, 100%). ¹ H NMR(400MHz,CDCl ₃ )δ7.59–7.53(m,1H),7.37–7.27(m,2H),7.17–7.13(m,1H),6.74(dd,J＝17.4,11.0Hz,1H),6.03(t,J＝1.5Hz,1H),5.70(dd,J＝17.5,0.9Hz,1H),5.30(dd,J＝11,0.9Hz,1H),2.61(td,J＝6.1,1.5Hz,2H),2.55–2.46(m,2H),2.20–2.20(m,2H).MS:199.2(M+H ⁺ ).

Step 2 Synthesis of 3-vinyl-3- (2-vinylphenyl) cyclohex-1-one

To copper (I) iodide (15.85g, 83mmol) and LiCl (3.53g, 83mmol) in anhydrous THF (150mL) at-78 deg.C under Ar over 30 minutes was added dropwise a 1M vinyl magnesium bromide solution (166mL,166mmol), the mixture was stirred at-78 deg.C for an additional 60 minutes, and then 2 '-vinyl-5, 6-dihydro- [1,1' -biphenyl was added]-3(4H) -one (step 1, 11g, 55.5mmol) in dry THF. The reaction was gently warmed to room temperature and stirred for 16 hours. Adding saturated NH ₄ The reaction was quenched with Cl (150mL) and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with Na ₂ SO ₄ Drying and concentration under reduced pressure gave a brown oil which was purified by silica gel column chromatography eluting with 0% to 10% ethyl acetate/hexanes to give the title compound (7.8g, 62.1%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.46–7.40(m,1H),7.36–7.30(m,1H),7.29–7.21(m,3H),6.01(dd,J＝17.5,10.7Hz,1H),5.46(dd,J＝17.3,1.4Hz,1H),5.22–5.14(m,2H),4.96(d,J＝17.5Hz,1H),2.74(q,J＝15.1Hz,2H),2.61–2.51(m,1H),2.30(t,J＝6.8Hz,2H),2.10–2.01(m,1H),1.90–1.79(m,1H),1.59–1.46(m,1H).MS:227.3(M+H ⁺ ).

Step 3 Synthesis of Spiro [ cyclohexane-1, 1' -indene ] -3-one

Under Ar, 3-vinyl-3- (2-vinylphenyl) cyclohex-1-one (step 2, 5.7g, 25.2mmol) and Grubbs-II reagent (4g, 4.71mmol) in DCM (350mL) 35

Stirring at the temperature of 17 h. The volatiles were removed under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with 0 to 8% hexane/ethyl acetate to give the title compound as a pale yellow oil (5g, 100%). MS: 199.2(M + H +).

Step 4 Synthesis of dispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ]

Under Ar, spiro [ cyclohexane-1, 1' -indene]A solution of-3-one (step 3, 32g, 161mmol), ethane-1, 2-diol (16.03g, 258mmol) and Ts-OH (4g,21.03mmol) in toluene (600mL) was stirred at 110 ℃ for 6 h. The volatiles were removed under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with 0 to 8% hexane/ethyl acetate to give the title compound as an oil (26g, 66.5%). ¹ H NMR(400MHz,CDCl ₃ )δ7.35–7.28(m,2H),7.28–7.16(m,2H),7.05(dd,J＝5.2,2.6Hz,1H),6.69(dd,J＝5.1,2.6Hz,1H),4.03–3.83(m,4H),2.10(dd,J＝13.5,2.2Hz,1H),1.98–1.69(m,5H),1.43(d,J＝13.5Hz,1H),1.30(d,J＝10.4Hz,1H).MS:243.2(M+H ⁺ ).

Step 5 Synthesis of dispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3(2H) -one

A mixture of dispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] (step 4, 10.5g, 43.3mmol) and 9-BBN in THF (0.5M,260mL) was stirred under Ar at 70 ℃ for 4 h. Concentration in vacuo gave a residue which was dissolved in anhydrous DCM (300mL) and PCC (93.3g, 433mmol, 10.0eq) was added dropwise. The reaction was stirred at room temperature for 2 hours. The filtrate was concentrated under reduced pressure to give a black residue which was purified by silica gel column chromatography and eluted with Hex/EA from 5% to 20% to give the title compound as a white solid (7.6g, 68%). MS: 259.4(M + H +).

Chiral SFC resolution column of total dispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3(2H) -one (19g) using CHIRALPAK IH column provided two isomers. The stereochemistry of the asymmetric spiro carbon atom of these compounds has not been determined.

The first eluting stereoisomer (8.6g, 100% ee) was arbitrarily assigned S stereochemistry at the spiro carbon atom, awaiting further analysis.

(S) -disuccincyclo [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane ] -3(2H) -one

The second eluting stereoisomer (7.8g, 99% ee) was arbitrarily assigned with R stereochemistry at the spiro carbon atom, to be further analyzed.

(R) -dispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane ] -3(2H) -ones

Step 6 Synthesis of (R) -2, 2-difluorodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane ] -3(2H) -one

A solution of a mixture of (R) -dispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3(2H) -one (step 5, 1.5g,5.81mmol), 1-butylamine (2.12g,29.00mmol) and 4-methylbenzenesulfonic acid hydrate (221mg,1.16mmol) in xylene (30mL) under Ar was stirred at 140 ℃ for 24H. The solvent was removed in vacuo to give a residue, which was dissolved in acetonitrile (50mL), and then sodium sulfate (8.25g,58.1mmol,10.0) and 1- (chloromethyl) -4-fluoro-1, 4-diazabicyclo [2.2.2] octane-1, 4-tetrafluoroborate-diinium (10.29g,29.00mmol) were added to the mixture and stirred at 60 ℃ for 2 hours. After cooling to room temperature, the filtrate was concentrated under reduced pressure to give a pale yellow residue, which was purified by silica gel column chromatography eluting with 0-20% ethyl acetate/hexane to give the title compound (1300mg, 76%) as a white solid. MS: 295.3(M + H +).

(S) -2, 2-Difluorobiospiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3(2H) -one was prepared in substantially the same manner using (S) -dispiro [ indene-1, 1 '-cyclohexane-3', 2" - [1,3] dioxolane ] -3(2H) -one as the starting intermediate.

Step 7 Synthesis of (R) -2, 2-difluoro-3-methylene-2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane

To a solution of methyltriphenylphosphonium bromide (2.48g, 6.95mmol) in tetrahydrofuran (20mL) at 0 deg.C under Ar was added potassium butoxide (709mg, 6.32 mmol). Then, the mixture was stirred at room temperature for 1 hour. (R) -2, 2-Difluorodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3]Dioxolanes]A solution of-3 (2H) -one (step 6, 930mg, 3.16mmol) in tetrahydrofuran (10mL) was added slowly to the reaction at-78 ℃. Stirring at room temperature overnight, adding saturated ammonium chloride into the reaction mixture, extracting with ethyl acetate twice, combining organic layers, concentrating to obtain crude product, purifying with silica gel column chromatography, eluting with ethyl acetate/hexane 0-20% to obtain (R) -2, 2-difluoro-3-methylene-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1, 3%]Dioxolanes](600mg, 65%) as a white solid. MS: 293.3(M + H) ⁺ )。

(S) -2, 2-difluoro-3-methylene-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] essentially in the same manner as (S) -2, 2-difluorodispiro [ indene-1, 1 '-cyclohexane-3', 2" - [1,3] dioxolane ] -3(2H) -one was used as a starting intermediate.

Step 8 Synthesis of (R) -2-fluoro-3-methyldiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane ]

To (R) -2, 2-difluoro-3-methylene-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] under Ar]Dioxolanes](step 7,600mg,2.05mmol) in tetrahydrofuran (10mL) A solution of lithium aluminum (III) hydride (312mg,8.21mmol) in tetrahydrofuran was added slowly at 0 deg.C. After the reaction, the mixture was quenched with 2N sodium hydroxide solution. The filtrate was concentrated under reduced pressure to give a colorless oil, which was purified by silica gel column chromatography and eluted with ethyl acetate/hexane from 0 to 5% to give the title compound as a colorless oil (550mg, 98%). MS: 275.4(M + H) ⁺ )。

(S) -2-fluoro-3-methyldisiospiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] was prepared in substantially the same manner using (S) -2, 2-difluoro-3-methylene-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2" - [1,3] dioxolane ] as a starting intermediate.

Step 9 Synthesis of (R) -2 ' -fluoro-3 ' -methyl Spiro [ cyclohexane-1, 1' -indene ] -3-one

Under Ar, (R) -2-fluoro-3-methyldiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3]Dioxolanes]A solution of the mixture of (step 8, 550mg 2.0mmol) and 4N HCl (10mL) in acetone (10mL) was stirred at room temperature for 1 hour. Extracting with ethyl acetate twice, combining organic layers, washing with brine, and removing anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with ethyl acetate/hexanes 0-30% to provide the title compound as a white solid (364mg, 79%). MS: 231.6(M + H) ⁺ )。

(S) -2' -fluoro-3 ' -methylspiro [ cyclohexane-1, 1' -indene ] -3-one was prepared in essentially the same manner using (S) -2-fluoro-3-methyldisipiro [ indene-1, 1' -cyclohexane-3 ',2 "- [1,3] dioxolane ] as the starting intermediate.

Step 10 Synthesis of (1R) -methyl 2' -fluoro-3 ' -methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

Under Ar, (R) -2' -fluoro-3 ' -methyl spiro [ cyclohexane-1, 1' -indene]Suspension of (E) -3-one (step 9, 360mg, 1.56mmol) and sodium hydride (188mg,4.69mmol) in tetrahydrofuran (6mL)Dimethyl carbonate (704mg,7.82mmol) was added at 80 ℃ and the mixture was stirred at this temperature for 1 h. After cooling to room temperature, saturated ammonium chloride was added to the reaction mixture, extracted twice with ethyl acetate, the organic layers were combined, concentrated to give the crude product, which was purified by silica gel column chromatography eluting with ethyl acetate/hexane from 0 to 10% to give the title compound (400mg, 89%) as a light brown solid. MS: 289.3(M + H) ⁺ )。

(1S) -2 '-fluoro-3' -methyl-3-oxospiro [ cyclohexane-1, 1 '-indene ] -4-carboxylic acid methyl ester was prepared in substantially the same manner using (S) -2' -fluoro-3 '-methylspiro [ cyclohexane-1, 1' -indene ] -3-one as a starting intermediate.

Example 4

Synthesis of intermediate 4: (1R) -2',3' -difluoro-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Step 1 Synthesis of (1R) -2, 2-difluoro-2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ] -3-ol

To (R) -2, 2-difluorodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] under Ar]Dioxolanes]A solution of (2H) -3(2H) -one (example 3: step 6, 980mg, 3.33mmol) in MeOH (30mL) was added sodium borohydride (252mg, 6.66mmol) at room temperature. After the reaction comes over, saturated NH is added ₄ Cl solution, volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate/H ₂ And (4) distributing among the O. The separated organic layer was washed with brine, and dried over anhydrous Na ₂ SO ₄ Drying and concentration gave the crude product which was purified by silica gel column chromatography eluting with 0% to 30% ethyl acetate/hexanes to give the title compound (1.0g, quant.) as a colorless oil. MS: 297.7(M + H) ⁺ )。

(1S) -2, 2-difluoro-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3-ol was prepared in substantially the same manner using (S) -2, 2-difluorodispiro [ indene-1, 1 '-cyclohexane-3', 2" - [1,3] dioxolane ] -3(2H) -one as a starting intermediate.

Step 2 (1R) -2,2, 3-trifluoro-2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ] synthesis

Under Ar, p- (1R) -2, 2-difluoro-2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3]Dioxolanes]A solution of-3-ol (step 1, 948mg, 3.20mmol) in anhydrous DCM (20mL) was added dropwise with DAST (1320mg, 8.19mmol) at 0 deg.C. After 2h, quench with water, extract 2 times with DCM, combine the organic layers, wash with brine, anhydrous Na ₂ SO ₄ Drying and concentration gave a residue which was purified by column chromatography on silica gel eluting with ethyl acetate/hexane from 0 to 10% to give the title compound as a colorless oil (860mg, 90%). MS: 299.3(M + H) ⁺ )。

(1S) -2,2, 3-trifluoro-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 '- [1,3] dioxolane ] was prepared in substantially the same manner starting from (1S) -2, 2-difluoro-2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ] -3-ol as an intermediate.

Step 3 Synthesis of (R) -2, 3-difluorodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane ]

Under Ar to (1R) -2,2, 3-trifluoro-2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3]A solution of dioxolane (step 2, 815mg, 2.73mmol) in dry THF (10mL) was added dropwise to a 1MKHMDS solution (15mL, 15.04mmol) at room temperature. After 1.5 h, the mixture was quenched with water, extracted twice with ethyl acetate, and the organic layer was washed with brine, over anhydrous Na ₂ SO ₄ Drying and concentrating to obtain a crude product (R) -2, 3-difluoro dispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3]]Dioxolanes](800mg, 100%) it need notFurther purification was used directly in the next step. MS: 279.3(M + H) ⁺ )。

(S) -2, 3-difluorodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] was prepared in substantially the same manner using (1S) -2,2, 3-trifluoro-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2" - [1,3] dioxolane ] as a starting intermediate.

Step 4 (R) -2',3' -difluorospiro [ cyclohexane-1, 1' -indene ] -3-ketone synthesis

Under Ar, (R) -2, 3-difluorodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3]]Dioxolanes]A solution of the mixture of (step 3, 815mg, 2.93mmol) and 4N HCl (10mL) in THF (20mL) was stirred at room temperature for 2 hours. Extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by silica gel column chromatography and eluted with ethyl acetate/hexanes from 0% to 10% to give the title compound as a colorless oil (600mg, 87%). MS: 235.3(M + H) ⁺ ). (S) -2',3' -Difluorospiro [ cyclohexane-1, 1' -indene](S) -2, 3-difluoro-dispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] is used as the (3-ketone]Dioxolanes ]As starting intermediates were prepared in essentially the same manner.

Step 5 Synthesis of (1R) -methyl 2',3' -difluoro-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

Under Ar, (R) -2',3' -difluorospiro [ cyclohexane-1, 1' -indene]A suspension of-3-one (step 4, 464mg, 1.981mmol) and sodium hydride (396mg,9.90mmol) in dry THF (15mL) was added dimethyl carbonate (892mg,9.90mmol) at 70 ℃. The mixture was stirred at this temperature for 8 hours. After cooling to room temperature, saturated NH was added ₄ Cl solution, ethyl acetate extraction two times, combined organic layers washed with brine, anhydrous Na ₂ SO ₄ Drying and concentrating to obtainBy crude product, column chromatography on silica gel eluting with ethyl acetate/hexane from 0 to 10% gave the title compound (570mg, 98%). MS: 293.3(M + H) ⁺ ). (1S) -2',3' -difluoro-3-oxospiro [ cyclohexane-1, 1' -indene](S) -2',3' -Difluorospiro [ cyclohexane-1, 1' -indene ] is used as methyl (4-carboxylate)]The-3-ketone is prepared in substantially the same manner as the starting intermediate.

Example 5

Synthesis of intermediate 5: (1S) -3-oxo-3 '- (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Step 1 Synthesis of (1R) -3- (trifluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ] -3-ol

Under Ar to (R) -dispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3]Dioxolanes]A mixture of-3 (2H) -one (example 3, step 5; 2g, 7.74mmol) and trimethyl (trifluoromethyl) silane (5.50g, 38.7mmol) in THF (10mL) was added TBAF (3.04g, 11.63mmol) at 0 deg.C and stirred at room temperature overnight. Extracting with water and ethyl acetate twice, mixing organic layers, washing with brine, and removing anhydrous Na ₂ SO ₄ Drying, concentration gave crude product, which was purified by column chromatography on silica gel eluting with ethyl acetate/hexane 5% to 20% to give the title compound (1.47g, 57.8%) as colorless oil. MS: 311.3 (M-H) ₂ O+H ⁺ ). (1S) -3- (trifluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3]Dioxolanes]-3-ol as (S) -dispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3]Dioxolanes]The preparation of (2) keto-3 (2H) -one as starting intermediate takes place in essentially the same manner.

Step 2 Synthesis of (1R) -3' -hydroxy-3 ' - (trifluoromethyl) -2',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -3-one

Under Ar, (1R) -3- (trifluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3]Dioxolanes]A mixture of-3-ol (step 1,1.47g,4.48mmol) in acetone (20mL) and HCl (6N,10mL) was stirred at 25 ℃ for 2 h. Saturated NaHCO ₃ Neutralizing, removing volatile under reduced pressure, extracting with ethyl acetate for 2 times, combining organic layers, washing with brine, and removing anhydrous Na ₂ SO ₄ Drying and concentration gave a pale yellow oil which was purified by column chromatography on silica gel eluting with 5% to 25% ethyl acetate/hexanes to give the title compound as a colorless oil (1.17g, 92%). ¹ H NMR(500MHz,DMSO-d6)δ7.48-7.33(m,4H),6.63(s,1H),2.87(d,J＝16.5Hz),2.54-2.50(m,1H),2.29-2.23(m,1H),2.20-2.19(m,5H),1.81-1.76(m,2H).MS:267.3(M-H ₂ O+H ⁺ ).

(1S) -3' -hydroxy-3 ' - (trifluoromethyl) -2',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -3-one was prepared in essentially the same manner using (1S) -3- (trifluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ',2 "- [1,3] dioxolan ] -3-ol as the starting intermediate.

Step 3 Synthesis of methyl (1R) -3' -hydroxy-3-oxo-3 ' - (trifluoromethyl) -2',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

To (1R) -3' -hydroxy-3 ' - (trifluoromethyl) -2',3' -dihydrospiro [ cyclohexane-1, 1' -indene under Ar]A solution of-3-one (step 2,1.17g,4.12mmol) and NaH (1.646g,41.2mmol) in THF (20mL) was added dimethyl carbonate (1.854g,20.58mmol) at room temperature, then the mixture was stirred at 70 ℃ for 4h after cooling to room temperature, water was added, ethyl acetate was extracted twice, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated to give a pale yellow oil, purified by silica gel column chromatography, ethyl acetate/hexane eluted from 5% to 25% to give the title compound (860mg, 61.0%) as a colorless oil. MS: 343.4(M + H) ⁺ )。

(1S) -3 '-hydroxy-3-oxo-3' - (trifluoromethyl) -2',3' -dihydrospiro [ cyclohexane-1, 1 '-indene ] -4-carboxylic acid methyl ester preparation using (1S) -3' -hydroxy-3 '- (trifluoromethyl) -2',3 '-dihydrospiro [ cyclohexane-1, 1' -indene ] -3-one as a starting intermediate was carried out in substantially the same manner as described below.

Step 4 Synthesis of methyl (1S) -3-oxo-3 '- (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

Under Ar, (1R) -3' -hydroxy-3-oxo-3 ' - (trifluoromethyl) -2',3' -dihydrospiro [ cyclohexane-1, 1' -indene]A mixture of methyl-4-carboxylate (step 3,860mg,2.51mmol) in Eton's reagent (10mL) was stirred at 25 ℃ for 3 hours. Saturated NaHCO ₃ Neutralizing, extracting with ethyl acetate for 2 times, combining organic layers, washing with brine, and removing anhydrous Na ₂ SO ₄ Dried and concentrated to give a pale yellow oil, which was purified by column chromatography on silica gel eluting with ethyl acetate/hexane 5% to 20% to give the title compound (520mg, 63.8%) as a colorless oil. MS: 325.3(M + H) ⁺ )。

(1R) -3-oxo-3 ' - (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester was prepared in essentially the same manner using (1S) -3' -hydroxy-3-oxo-3 ' - (trifluoromethyl) -2',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid ester as a starting intermediate.

Example 6

Synthesis of intermediate 6: 2 '-methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Step 1 Synthesis of 2-bromo-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3-ol

Under Ar, dispiro [ indene-1, 1' -cyclohexane-3 ', 2 ' - [1,3]]Dioxolanes](intermediate 3: step 4; 1.25g, 5.16mmol) in DMSO (10ml) and water (0.5ml) NBS and (918mg, 5.16mmol) were added portionwise at 0-10 ℃. The reaction mixture was stirred at room temperature for 1 hour. Extracting with water and ethyl acetate twice, mixing organic layers, washing with brine, and removing anhydrous Na ₂ SO ₄ Drying and concentration in vacuo afforded the residue which was purified by column chromatography on silica gel eluting with ethyl acetate/hexanes in the range of 5% to 10% to afford the title compound as a white solid (1.62g, 92.5%). MS: 339.3(M + H) ⁺ )。

Step 2 Synthesis of 2-Bromobiro [ indene-1, 1' -cyclohexane-3 ', 2 ' - [1,3] dioxolane ]

Under Ar, 4-methylbenzenesulfonic acid (40.6mg, 0.236mmol) and 2-bromo-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3]]Dioxolanes]A mixture of-3-ol (step 1,800mg,2.358mmol) in toluene (20mL) was stirred at 100 ℃ for 3 hours. After the reaction, the volatiles were removed under reduced pressure to give the crude title compound (758mg, 100%) as a colorless oil, which was used in the next step without further purification. MS: 321.2(M + H) ⁺ )。

Step 3 Synthesis of 2 '-Bromospiro [ cyclohexane-1, 1' -indene ] -3-one

Under Ar, crude 2-bromodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1, 3 ]]Dioxolanes](step 2, 758mg, 2.358mmol) A mixture of THF (12mL) and 6N aqueous HCl (6mL) was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate was extracted twice, and the organic layers were combined, washed with brine and anhydrous Na ₂ SO ₄ Drying, vacuum concentrating to obtain residue, purifying with silica gel column chromatography, eluting with ethyl acetate/hexane 2% to 30% to obtain colorless oilThe title compound (480mg, 69.6%). MS: 277.2(M + H) ⁺ )。

Step 4 Synthesis of 2 '-Methylspiro [ cyclohexane-1, 1' -indene ] -3-one

Under Ar, 2 '-bromospiro [ cyclohexane-1, 1' -indene]-3-one (step 3, 1.74g, 13.85mmol), 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxane (480mg,1.732mmol), PdCl ₂ A mixture of (dppf) (253mg,0.346mmol) and NaOBu (666mg,6.93mmol) in dioxane (30ml) was stirred at 100 ℃ for 1 h after cooling to room temperature, diluted with water, extracted 2 times with ethyl acetate, the organic layers combined, washed with brine, anhydrous Na ₂ SO ₄ Drying, vacuum concentrating to obtain residue, and purifying with silica gel column chromatography. Ethyl acetate/hexanes from 2% to 5% to give the title compound (350mg, 95%) as a colorless oil. MS: 213.3(M + H) ⁺ )。

Step 5 Synthesis of 2 '-methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Under Ar, 2 '-methyl spiro [ cyclohexane-1, 1' -indene]A suspension of-3-one (step 4, 350mg, 1.649mmol) and NaH (119mg, 4.94mmol) in dry THF (10mL) was added dimethyl carbonate (742mg, 8.245mmol) at 70 ℃. The mixture was stirred at 70 ℃ for 3 hours. After cooling to room temperature, with NH ₄ The Cl solution was quenched and extracted 3 times with EA. The combined organic layers were washed with brine, over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave a residue which was purified by silica gel column chromatography and eluted with ethyl acetate/hexane from 0% to 30% to give the title compound (400mg, 89.9%) as a colorless oil. MS: 271.3(M + H) ⁺ )。

Example 7

Synthesis of intermediate 7: (1S) -4' -chloro-3-oxo-3 ' - (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Step 1 Synthesis of 1-bromo-3-chloro-2-vinylbenzene

A solution of n-butyllithium (19.61g, 306mmol) in hexane is added dropwise to a solution of methyltriphenylphosphonium bromide (117g, 328mmol) in THF (300mL) at 0 ℃ over 60 minutes under Ar, the mixture is then stirred at this temperature for 1 hour and a solution of 2-bromo-6-chlorobenzaldehyde (60g, 273mmol) in THF (200mL) is added. After the reaction is finished, the mixture is saturated with NH ₄ Quenched with Cl (200mL) and extracted twice with ethyl acetate, and the combined organic layers were washed with brine, over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave a brown oil, which was purified by silica gel column chromatography eluting with hexane to give the title compound as a pale yellow oil (43g, 72.3%).

Step 2 Synthesis of 3' -chloro-2 ' -vinyl-5, 6-dihydro- [1,1' -biphenyl ] -3(4H) -one

1-bromo-3-chloro-2-vinylbenzene (step 1, 42g, 193mmol), 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-2-en-1-one (51.5g,232mmol), PdCl under Ar ₂ (dppf)-CH ₂ Cl ₂ Adduct (7.89g,9.66mmol), Na ₂ CO ₃ (61.4g,579mmol) in DME (500mL) and H ₂ The mixture in O (150mL) was stirred at 90 ℃ for 2 hours. After the reaction was complete, the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine and Na ₂ SO ₄ Drying and concentration in vacuo afforded a brown oil which was purified by silica gel column chromatography (hexane: ethyl acetate 15:1) to afford the title compound as a yellow oil (30g, 66.8%). ¹ H NMR(400MHz,CDCl ₃ )δ7.38(dt,J＝3.1,1.6Hz,1H),7.20(t,J＝7.8Hz,1H),7.05(dd,J＝7.7,1.3Hz,1H),6.92–6.82(m,1H),6.11(t,J＝1.6Hz,1H),5.55–5.42(m,2H),2.50-2.55(m,2H),2.49–2.43(m,2H),2.11–1.99(m,2H).MS:233.2(M+H ⁺ ).

Step 3 Synthesis of 3- (3-chloro-2-vinylphenyl) -3-vinylcyclohexan-1-one

To a mixture of copper (I) iodide (15.96g,84mmol) and LiCl (3.55g,84mmol) in anhydrous THF (200mL) at-78 deg.C under Ar, vinyl magnesium bromide (21.15g,161mmol) was added dropwise over 60 minutes; the mixture was then stirred at-78 ℃ for a further 60 minutes. Dropwise adding 3' -chloro-2 ' -vinyl-5, 6-dihydro- [1,1' -biphenyl ]A solution of-3 (4H) -one (step 2,15g,64.5mmol) in THF (160mL) and then the reaction mixture was stirred at-78 ℃ for 1 hour and allowed to warm to room temperature for 2 hours. Adding saturated NH ₄ The reaction was quenched with Cl (150mL) and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with Na ₂ SO ₄ Drying and concentration under reduced pressure gave a brown oil which was purified by column chromatography on silica gel eluting with 0% to 10% ethyl acetate/hexanes to give the title compound (7g, 41.6%) as a colorless oil. MS: 261.2(M + H) ⁺ )。

Step 4 Synthesis of 4 '-Chlorospiro [ cyclohexane-1, 1' -indene ] -3-one

A solution of a mixture of 3- (3-chloro-2-vinylphenyl) -3-vinylcyclohex-1-one (step 3, 10g, 38.3mmol) and Grubbs-II reagent (4.88g, 5.75mmol) in DCM (1L) under Ar was stirred overnight at 30 ℃. After removing the volatiles under reduced pressure, the residue was purified by silica gel column chromatography and eluted from 0% to 10% with ethyl acetate/hexane to give the title compound (4.5g, 50.2%) as a light brown oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.25–7.13(m,3H),6.88(d,J＝5.7Hz,1H),6.52(d,J＝5.7Hz,1H),2.70(d,J＝13.7Hz,1H),2.56(dd,J＝7.7,5.9Hz,2H),2.32–2.22(m,1H),2.19–1.99(m,3H),1.70–1.62(m,1H).MS:233.2(M+H ⁺ ) The use of a Lux Cellulose-4 column on Total 4 '-Chlorospiro [ cyclohexane-1, 1' -indene ]]Chiral SFC resolution of-3-ketones (20g) to give two isomers, i.e. the stereochemistry of the asymmetric spiro carbon atom of these compounds is not yet established.

(R) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] -3-one: the first eluting stereoisomer (10.9g, 99% ee) was arbitrarily assigned R stereochemistry at the spiro carbon atom, requiring more in-depth analysis.

(S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] -3-one: the first eluting stereoisomer (7.2g, 99% ee) was arbitrarily assigned to have S stereochemistry at the spiro carbon atom, requiring more in-depth analysis.

Step 5 Synthesis of 4-chlorodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane ]

Under Ar, 4 '-chloro spiro [ cyclohexane-1, 1' -indene]A mixture of (E) -3-one (step 4, 33g, 142mmol), ethane-1, 2-diol (17.60g, 284mmol) and 4-methylbenzenesulfonic acid hydrate (2.70g, 14.18mmol) was stirred at 100 ℃ for 12 hours. After cooling to room temperature, water was added, extracted twice with ethyl acetate, the organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the crude which was purified by silica gel column chromatography eluting with 0 to 20% ethyl acetate/hexanes to give the title compound (33g, 84%) as a light brown oil. MS: 277.3(M + H) ⁺ )。

Step 6 Synthesis of 4-chlorodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane ] -3(2H) -one

4-Chlorodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] at room temperature under Ar ]Dioxolanes](step 5, 16.5g, 59.6mmol, 1.0) to 0.5M 9-borabicyclo [3.3.1]Nonane (21.82g, 179mmol) in tetrahydrofuran (358 mL). After the mixture was stirred at 70 ℃ for 3 hours, the volatiles were removed under reduced pressure to give a residue, which was dissolved in dichloromethane (500mL) to give a clear solution. Pyridinium chlorochromate (103g, 477mmol) was slowly added to the mixture at room temperature, stirred at 40 ℃ for 2h, the filtrate was concentrated in vacuo to give a black residue, which was purified by silica gel column chromatography eluting with 0-15% ethyl acetate/hexanes to give the title compound (13.3g, 76%) as a white solid. MS: 293.3(M + H) ⁺ )。

Total 4-chlorodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3(2H) -one (22g) resolution using CHIRALPAK IH column chiral SFC provided two isomers, the stereochemistry of the asymmetric spiro carbon atom of these compounds was not determined.

(S) -4-Chlorobiospiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3(2H) -one the first eluting stereoisomer (9.5g, 99% ee) was arbitrarily assigned to have S stereochemistry at the spiro carbon atom, awaiting further analysis.

(R) -4-Chlorobiospiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3(2H) -one the second eluting stereoisomer (8.6g, 98% ee) was arbitrarily assigned with R stereochemistry at the spiro carbon atom, awaiting further analysis.

Step 7 Synthesis of (1R) -4-chloro-3- (trifluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ] -3-ol

To (R) -4-chlorodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] at 0 ℃ under Ar]Dioxolanes]To a solution of-3 (2H) -one (step 6,2.2g,7.51mmol) and trimethyl (trifluoromethyl) silane (5.34g,37.6mmol) in THF (10mL) was added TBAF (2.95g,11.27 mmol). After stirring overnight at 25 ℃, water was added, ethyl acetate was extracted twice, the organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with ethyl acetate/hexane from 0% to 20% to give the title compound (2.6g, 95%) as a colorless oil. MS: 363.3(M + H) ⁺ )。

Step 8 Synthesis of (1R) -4 '-chloro-3' -hydroxy-3 '- (trifluoromethyl) -2',3 '-dihydrospiro [ cyclohexane-1, 1' -indene ] -3-one

A mixture of (1R) -4-chloro-3- (trifluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3-ol (step 7, 2.6g, 7.17mmol) in acetone (20mL) and 6N HCl (10mL) under Ar was stirred at 25 ℃ for 2 hours. Neutralization with saturated sodium bicarbonate, extraction with ethyl acetate twice, combining the organic layers, washing with brine, drying over sodium sulfate, concentration in vacuo to give the crude product, purification by silica gel column chromatography eluting with ethyl acetate/hexanes 0% to 20% to give the title compound (2.1g, 92%) as a white solid. MS: 319.3(M + H +).

Step 9 Synthesis of methyl (1R) -4 '-chloro-3' -hydroxy-3-oxo-3 '- (trifluoromethyl) -2',3 '-dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

To (1R) -4 '-chloro-3' -hydroxy-3 '- (trifluoromethyl) -2',3 '-dihydrospiro [ cyclohexane-1, 1' -indene at 70 ℃ under Ar]To a solution of (step 8,2.1g,6.59mmol) of (E) -3-ketone and NaH (2.64g,65.9mmol) in THF (20mL) was added dimethyl carbonate (2.97g,32.9 mmol). The mixture was stirred at 70 ℃ for 4 hours. After cooling to room temperature, water was added, ethyl acetate was extracted 2 times, the organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel eluting with 0% to 30% ethyl acetate/hexanes to give the title compound as a colorless oil (2g, 81%). MS: 377.3(M + H) ⁺ )。

Step 10 Synthesis of methyl (1S) -4' -chloro-3-oxo-3 ' - (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

Under Ar, (1R) -4' -chloro-3 ' -hydroxy-3-oxo-3 ' - (trifluoromethyl) -2',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester (step 9, 2g, 5.31mmol) was stirred in a mixture of Eton's reagent (10mL) at 25 ℃ for 3 hours. The reaction was neutralized with saturated sodium bicarbonate, extracted twice with ethyl acetate, the combined organic layers washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel eluting with ethyl acetate/hexanes 0% to 20% to give the title compound as a colorless oil (982mg, 51.6%). MS: 359.2(M + H +).

Example 8

Synthesis of intermediate 8: (1R) -4' -chloro-3-oxo-3 ' - (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Step 1 Synthesis of (1S) -4-chloro-3- (trifluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ] -3-ol

(S) -4-chlorodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] at 0 ℃ under Ar]Dioxolanes]TBAF (2.0g, 7.65mmol) was added to a solution of (2.0g, 5.12mmol) 3(2H) -one (example 7, step 6; 1.5g, 5.12mmol) and trimethyl (trifluoromethyl) silane (3.64 g, 25.6mmol) in THF (10 ml). After stirring overnight at 25 ℃, water was added, ethyl acetate was extracted twice, the organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with ethyl acetate/hexane from 0% to 20% to give the title compound (1.73g, 93%) as a colorless oil. MS: 363.3(M + H) ⁺ )。

Step 2 Synthesis of (1S) -4 '-chloro-3' -hydroxy-3 '- (trifluoromethyl) -2', 3 '-dihydrospiro [ cyclohexane-1, 1' -indene ] -3-one

Under Ar, (1S) -4-chloro-3- (trifluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3]Dioxolanes]-3-ol (step 1, 1.73g, 4.77mmol) was stirred in a mixture of acetone (10mL) and 4N HCl (10mL) at 25 ℃ for 2 h. Neutralization with saturated sodium bicarbonate, extraction with ethyl acetate twice, combining the organic layers, washing with brine, drying over sodium sulfate, concentration in vacuo to give the crude product, purification by silica gel column chromatography eluting with ethyl acetate/hexanes in the range of 0% to 20% to give the title compound (1.35g, 89%) as a white solid. MS: 301.3(M-H2O + H) ⁺ )。

Step 3 Synthesis of methyl (1S) -4 '-chloro-3' -hydroxy-3-oxo-3 '- (trifluoromethyl) -2',3 '-dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

To (1R) -4 '-chloro-3' -hydroxy-3 '- (trifluoromethyl) -2',3 '-dihydrospiro [ cyclohexane-1, 1' -indene under Ar]Dissolution of (step 2,1.35g,4.24mmol) 3-one and NaH (508mg,12.72mmol) in THF (10mL)To the solution was added dimethyl carbonate (1.91g,21.2mmol) at 70 ℃. The mixture was stirred at 70 ℃ for 4 hours. After cooling to room temperature, water was added, extracted twice with ethyl acetate, the organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the crude which was purified by column chromatography on silica eluting with 0% to 10% ethyl acetate/hexanes to give the title compound as a colorless oil (1.3g, 81%). MS: 377.3(M + H) ⁺ )。

Step 4 Synthesis of methyl (1R) -4' -chloro-3-oxo-3 ' - (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

A mixture of (1S) -4' -chloro-3 ' -hydroxy-3-oxo-3 ' - (trifluoromethyl) -2',3' -dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester (step 3, 1.3g, 3.45mmol) in Eton ' S reagent (10mL) under Ar was stirred at 25 ℃ for 3 hours.

With saturated NaHCO ₃ Neutralization, extraction with ethyl acetate twice, washing of the combined organic layers with brine, drying over sodium sulfate, and concentration in vacuo afforded the crude product, which was purified by silica gel column chromatography and eluted with ethyl acetate/hexanes from 0% to 20% to afford the title compound as a colorless oil (550mg, 44%). MS: 359.2(M + H) ⁺⁾ 。

Example 9

Synthesis of intermediate 9: (1S) -4' -chloro-3 ' -methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Step 1 Synthesis of (1R) -4-chloro-3-methyl-2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane ] -3-ol

To (R) -4-chlorodispiro [ indene-1, 1 'under Ar'-cyclohexane-3', 2 "- [1,3]Dioxolanes]A solution of (2H) -3(2H) -one (example 7, step 6; 600mg, 2.1mmol) in dry THF (10mL) was added methylmagnesium bromide (489mg, 4.10mmol) at 0 deg.C, and the mixture was stirred at room temperature overnight. Saturated NH ₄ Quench Cl, extract 2 times with ethyl acetate, combine the organic layers, wash with brine, Na ₂ SO ₄ Dried and concentrated to give a colorless oil, which was purified by silica gel column chromatography eluting with ethyl acetate/hexane from 0% to 30% to give the title compound (622mg, 98%) as a colorless oil. MS: 291.3(M-H2O + H) ⁺ )。

Preparation of (1S) -4-chloro-3-methyl-2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3-ol (S) -4-chlorodispiro [ indene-1, 1 '-cyclohexane-3', 2" - [1,3] dioxolane ] -3(2H) -one was used as a starting intermediate in essentially the same manner.

Step 2 (S) -4' -chloro-3 ' -methyl spiro [ cyclohexane-1, 1' -indene ] -3-ketone synthesis

Under Ar, (1R) -4-chloro-3-methyl-2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ',2 ' - [1,3 ]Dioxolanes]A mixture of-3-ol (step 1, 622mg, 2.014mmol) in acetone (10mL) and 4N HCl (10.00mL) was stirred at 25 ℃ for 1 hour. Neutralized with saturated sodium bicarbonate, extracted twice with ethyl acetate, combined organic layers, washed with brine, dried over sodium sulfate, concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with ethyl acetate/hexanes in a range of 0% to 20% to give the title compound (406mg, 82%) as a colorless oil. MS: 247.3(M + H) ⁺ )。

(R) -4' -chloro-3 ' -methylspiro [ cyclohexane-1, 1' -indene ] -3-one was prepared in essentially the same manner using (1S) -4-chloro-3-methyl-2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ',2 "- [1,3] dioxolane ] -3-ol as the starting intermediate.

Step 3 Synthesis of (1S) -4' -chloro-3 ' -methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

To (S) -4' -chloro-3 ' -methylspiro [ cyclohexane-1, 1' -indene ] at 80 ℃ under Ar]A mixture of-3-one (step 2, 406mg, 1.645mmol) and NaH (658mg,16.45mmol) in dry THF (10mL) was added dimethyl carbonate (148mg,1.645mmol) and stirred at this temperature for 1 h. After cooling to room temperature, saturated NH ₄ Quench Cl, extract 2 times with ethyl acetate, combine the organic layers, wash with brine, Na ₂ SO ₄ Dried and concentrated to give a colorless oil, which was purified by column chromatography on silica gel eluting with ethyl acetate/hexane from 0% to 20% to give the title compound (445mg, 89%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ12.22(s,1H),7.21-7.19(m,1H),7.14-7.10(m,2H),6.18(s,1H),3.81(s,3H),2.66(d,J＝18Hz,1H),2.59-2.53(m,1H),2.43-2.35(m,4H),2.11(d,J＝18Hz，1H),1.86-1.79(m,1H),1.52-1.47(m,1H).MS:305.3(M+H ⁺ ).

(1R) -4 '-chloro-3' -methyl-3-oxospiro [ cyclohexane-1, 1 '-indene ] -4-carboxylic acid methyl ester was prepared in substantially the same manner using (R) -4' -chloro-3 '-methylspiro [ cyclohexane-1, 1' -indene ] -3-one as a starting intermediate.

Example 10

Synthesis of intermediate 10: (1S) -4' -chloro-3 ' - (methyl-d 3) -3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Intermediate 10 was prepared using substantially the same protocol as example 9, substituting (methyl-d 3) magnesium bromide for methylmagnesium bromide to give the title compound (470mg) as a colorless oil. ¹ H NMR(500MHz,CDCl ₃ )δ12.22(s,1H),7.21-7.19(m,1H),7.14-7.10(m,2H),6.18(s,1H),3.81(s,3H),2.66(d,J＝22.5Hz，1H),2.59-2.53(m,1H),2.43-2.35(m,1H),2.11(d,J＝22.5Hz，1H),1.86-1.79(m,1H),1.52-1.47(m,1H).MS:308.3(M+H ⁺ ).

Methyl (1R) -4' -chloro-3 ' - (methyl-d 3) -3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylate was prepared using essentially the same protocol as example 9, substituting (methyl-d 3) magnesium bromide for methyl magnesium bromide and (S) -4-chlorodispiro [ indene-1, 1' -cyclohexane-3 ', 2 "- [1,3] dioxolane ] -3(2H) -one as the starting intermediate.

Example 11

Synthesis of intermediate 11: (1R) -4 '-chloro-2', 3 '-difluoro-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Substantially the same protocol as described in example 4 was used to provide intermediate 11(300mg) as a colourless oil. MS: 327.2(M + H) ⁺ )。

Preparation of (1S) -4 '-chloro-2', 3 '-difluoro-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester using essentially the same protocol as described in example 4 using the appropriate starting intermediate

Example 12

Synthesis of intermediate 12: 4 '-fluoro-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Step 1 Synthesis of 1-bromo-3-fluoro-2-vinylbenzene

A solution of n-butyllithium (17.04g, 266mmol) in hexane is added dropwise to a solution of methyltriphenylphosphonium bromide (95g, 266mmol) in THF (200mL) at 0 ℃ under Ar for 40 minutes, the mixture is then stirred at this temperature for 1 hour, and a solution of 2-bromo-6-fluorobenzaldehyde (45g,222mmol) in THF (100mL) is added. After the reaction is finished, the reaction mixture is saturated with NH ₄ Cl (150mL) was quenched and extracted twice with ethyl acetate, and the combined EA layers were washed with brine, over Na ₂ SO ₄ Drying, concentrating under reduced pressureThis was condensed to give a yellow oil, which was purified by silica gel column chromatography (hexane: 100%) to give 1-bromo-3-fluoro-2-vinylbenzene (40g, 90%) as a pale yellow oil.

Step 2 Synthesis of 3' -fluoro-2 ' -vinyl-5, 6-dihydro- [1, 1' -biphenyl ] -3(4H) -one

Under Ar, 1-bromo-3-fluoro-2-vinylbenzene (step 1, 13.5g, 67.2mmol), 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-2-en-1-one (19.4g,87mmol), Pd (dppf) Cl ₂ DME (80mL) (2.74g,3.36mmol) and sodium carbonate (17.8g,168mmol) and water (20mL) were stirred at 90 deg.C for 3 hours. After the reaction, the mixture was extracted twice with EA, and the combined EA layers were washed with brine, anhydrous Na ₂ SO ₄ Drying and concentration in vacuo afforded a brown oil which was chromatographed on silica gel (hexane: ethyl acetate ═ 15:1) to afford the title compound as a yellow oil (13.1g, 90%). And (2) MS: 217.3(M + H) ⁺ )。

Step 3 Synthesis of 3- (3-fluoro-2-vinylphenyl) -3-vinylcyclohexan-1-one

To a mixture of copper (I) iodide (11.89g,62.4mmol) and LiCl (2.65g,62.4mmol) in anhydrous THF (150mL) at-78 deg.C under Ar was added dropwise vinylmagnesium bromide (16.4g, 124.8mmol) over 30 minutes, and the mixture was taken up at-78 deg.C

Stirring at deg.C for another 30 minutes. 3' -fluoro-2 ' -vinyl-5, 6-dihydro- [1,1' -biphenyl]A solution of-3 (4H) -one (step 2, 9g, 41.6mmol) in dry THF (70mL) was added dropwise, then the reaction mixture was stirred at-78 deg.C for 1 hour and allowed to warm to room temperature for 2 hours. Adding saturated NH ₄ The reaction was quenched with Cl (150mL) and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with Na ₂ SO ₄ Drying, concentrating under reduced pressure to give brown oil, purifying by silica gel column chromatography,elution with 5% to 30% ethyl acetate/hexanes provided the title compound (5.6g, 52%) as a pale yellow oil. ¹ HNMR(400MHz,CDCl ₃ )δ7.24–7.12(m,2H),7.08–6.98(m,1H),6.84(dd,J＝17.9,11.7Hz,1H),6.00(dd,J＝17.5,10.7Hz,1H),5.64–5.51(m,2H),5.19(d,J＝10.7Hz,1H),4.96(d,J＝17.5Hz,1H),2.81(d,J＝15.1Hz,1H),2.73(d,J＝15.2 Hz,1H),2.70–2.62(m,1H),2.32(t,J＝6.8Hz,2H),2.10–1.98(m,1H),1.94–1.79(m,1H),1.59–1.47(m,1H).MS:245.2(M+H ⁺ ).

Step 4 Synthesis of 4 '-Fluorospiro [ cyclohexane-1, 1' -indene ] -3-one

A mixture of 3- (3-fluoro-2-vinylphenyl) -3-vinylcyclohex-1-one (step 3, 12.5g, 51.0mmol) and Grubbs-II reagent (4.35g, 5.12mmol) in DCM (250mL) under Ar was stirred overnight at 30 ℃. After removing the volatiles under reduced pressure, the residue was purified by silica gel column chromatography and eluted from 0% to 15% with ethyl acetate/hexane to give the title compound (5.6g, 50.2%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.21(td,J＝7.8,4.9Hz,1H),7.13(d,J＝7.4Hz,1H),7.03–6.95(m,1H),6.88(d,J＝5.7Hz,1H),6.47(d,J＝5.7Hz,1H),2.73(d,J＝13.7Hz,1H),2.62–2.55(m,2H),2.36–2.24(m,1H),2.22–2.15(m,1H),2.14–2.10(m,1H),2.10–1.97(m,1H),1.74–1.63(m,1H).MS:217.3(M+H ⁺ ).

Step 5 Synthesis of 4 '-fluoro-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester

Under Ar, 4 '-fluorospiro [ cyclohexane-1, 1' -indene]A solution of-3-one (step 4, 450mg, 2.081mmol) in THF (10mL) was added dropwise to a mixture of NaH (832mg,20.81mmol) and dimethyl carbonate (1874mg,20.81mmol) in THF (20mL) at 80 ℃. The reaction mixture was refluxed for 2 hours. After cooling to room temperature, addSaturated NH ₄ The reaction was quenched with Cl and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with Na ₂ SO ₄ Drying, concentration under reduced pressure gave a pale yellow oil which was purified by silica gel column chromatography and eluted with ethyl acetate/hexane from 5% to 20% to give the title compound (514mg, 90%) as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ12.27(s,1H),7.24–7.15(m,1H),7.09(d,J＝7.3Hz,1H),7.01–6.95(m,1H),6.88(d,J＝5.7Hz,1H),6.49(d,J＝5.7Hz,1H),3.85(s,3H),2.69(dt,J＝18.2,2.0Hz,1H),2.65–2.56(m,1H),2.51–2.38(m,1H),2.23(dd,J＝18.1,1.4Hz,1H),1.88(m,1H),1.64–1.58(m,1H).MS:275.2(M+H ⁺ ).

Example 13

Synthesis of 2- ((2S) -1-acryloyl-4- (3-methyl-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.1 isomer A/B)

Step 1 Synthesis of 2 '-mercapto-3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -ol

Under Ar, 3 '-methyl-3-oxospiro [ cyclohexane-1, 1' -indene]A mixture of methyl-4-carboxylate (intermediate 2, 1.32g, 4.88mmol), thiourea (0.446g, 5.86mmol) and DBU (1.115g,7.32mmol) in ACN (16mL) was stirred at 80 ℃ for 3 h. After removal of volatiles under reduced pressure, the residue was dissolved in H ₂ In O, neutralized with HCl, the precipitate was collected and dried in vacuo to give the title compound as a light yellow solid (1.13g, 78%). MS: 297.5(M + H) ⁺ )。

Step 2 Synthesis of 3-methyl-2 '- (methylthio) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazoline ] -4' -ol

Methyl iodide (0.487g,3.43mmol) was added to a mixture of 3-methyl-2 ' -thioxo-2 ',3',5',8' -tetrahydro-1 ' H-spiro [ indene-1, 7' -quinazolin ] -4' (6' H) -one (step 1,1.13g,3.81mmol) and sodium hydroxide (0.137g,3.43mmol) in acetone (10mL) and water (2mL) under Ar, and the reaction was stirred at room temperature for 2 hours.

The solvent was removed in vacuo to give a residue, which was dissolved in water, pH adjusted to 6, and the precipitate was collected and dried in vacuo to give the title compound (770mg, 65.1%) as a pale yellow solid MS: 312.10(M + H) ⁺ )

Step 3 Synthesis of 3-methyl-2 '- (methylthio) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl trifluoromethanesulfonate

3-methyl-2 ' - (methylthio) -5',8' -dihydro-3 ' H-spiro [ indene-1, 7' -quinazoline at-40 ℃ under Ar]Suspension of-4 '(6' H) -one (step 2, 770mg, 2.481mmol) and DIEA (802mg, 6.20mmol) in DCM (3mL) was added Tf ₂ O (1050mg, 3.72 mmol). After 1 hour, water was added, extracted twice with DCM, and the combined organic layers were washed with brine, over anhydrous Na ₂ SO ₄ Drying and concentration gave the crude title compound (1g, 91%) which was used directly in the next step without further purification. MS: 443.3(M + H) ⁺ )。

Step 4 Synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (3-methyl-2 '- (methylthio) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate

To 3-methyl-2 ' - (methylthio) -5', 8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline at room temperature under Ar]-4' -Yl triflate (step 3,1g,2.260mmol) in DMF (1.5mL)DIEA (1.461g,11.30mmol) and (S) -2- (piperazin-2-yl) acetonitrile dihydrochloride (0.448g,2.260mmol) were added. After 1 hour LC-MS showed complete consumption of starting material and Boc was added ₂ O (2.466g, 11.30 mmol). The mixture was stirred at room temperature for another 1 hour. Extracting with water and DCM twice, mixing organic layers, washing with brine, and extracting with anhydrous Na ₂ SO ₄ Dried and concentrated to give a colorless oil, which was purified by column chromatography on silica gel eluting with ethyl acetate/hexane 0% to 30% to give the title compound (1.17g, 100%) as a colorless oil. MS: 518.5(M + H) ⁺ )。

Step 5 Synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (3-methyl-2 '- (methylsulfinyl) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate

Meta-CPBA (0.416g,2.051mmol) was added to tert-butyl (2S) -2- (cyanomethyl) -4- (3-methyl-2 ' - (methylthio) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline at 0 deg.C under Ar]-4' -yl) piperazine-1-carboxylate (step 4,1.18g,2.279mmol) in DCM (10 mL). After 30 min, water was added, extracted twice with DCM, the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried and concentrated to give the crude title compound as a foamy solid (744mg, 61.2%). MS: 534.5(M + H) ⁺ )。

Step 6 Synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- (3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate

To a solution of (S) - (1-methylpyrrolidin-2-yl) methanol (240mg, 2.080mmol) in THF (10mL) at 0-10 deg.C under Ar was added NaH (83mg, 2.080 mmol). After stirring for 10 minutes, tert-butyl (2S) -2- (cyanomethyl) -4- (3-methyl-2 ' - (methylsulfinyl) -5',8' -diHydro-6 'H-spiro [ indene-1, 7' -quinazoline]-4' -yl) piperazine-1-carboxylic acid ester (step 5, 370mg, 0.693mmol)]Was added at-20 ℃ in THF (10 mL). Finally, the mixture was stirred at room temperature for 30 minutes with NH ₄ Quenched with aqueous Cl, extracted twice with DCM, and the combined organic layers washed with brine, over Na ₂ SO ₄ Drying and concentration gave a residue which was purified by column chromatography on silica gel eluting with 2% to 20% MeOH/DCM to give the title compound as a colorless foam solid (400mg, 99%). MS: 585.7(M + H) ⁺ ). Step 7 2- ((2S) -1-acryloyl-4- (3-methyl-2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]Synthesis of (E) -4' -yl) piperazin-2-yl) acetonitrile

Under Ar, tert-butyl (2S) -2- (cyanomethyl) -4- (3-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]-4' -yl) piperazine-1-carboxylate (step 6,400mg,0.684mmol) in a mixture of DCM (5mL) and TFA (10mL) was stirred at room temperature for 1 hour. All volatiles were removed under reduced pressure to give TFA salt. This was dissolved in DCM (5mL) and TEA (350mg,3.4mmol) and acryloyl chloride (124mg,1.368mmol) were added at 0 deg.C. The mixture was stirred at 0 ℃ for 30 minutes. Water was added, extracted twice with DCM, washed with brine, and Na ₂ SO ₄ Drying and concentration gave a pale yellow residue which was purified by preparative HPLC to give Cpd.No.1 isomer A/B (65mg, 17.64%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.45–7.33(m,1H),7.50–7.32(m,2H),7.25–7.15(m,1H),6.86(br,1H),6.44–6.27(m,1H),6.26–6.14(m,1H),5.77(d,J＝10.9Hz,1H),5.05–3.45(m,7H),3.29–2.50(m,9H),2.48–2.33(m,4H),2.23–2.12(m,1H),2.09(s,3H),2.06–1.82(m,2H),1.73–1.41(m,4H).MS:539.6(M+H ⁺ ).

2- ((S) -1-acryloyl-4- ((S) - (3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) piperazin-2-yl) acetonitrile (cpd. No.1 isomer a) and 2- ((S) -1-acryloyl-4- ((R) -3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) piperazin-2-yl) acetonitrile (cpd. No.1 isoc. 1) Configuration B) was prepared in substantially the same manner using (1S) -3 '-methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester and (1R) -3 '-methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester, respectively, as starting materials.

Example 14

Synthesis of 2- ((S) -1-acryloyl-4- ((R) -2-fluoro-3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,8' -dihydro-6 'H-spiro [ indene-1, 7' -quinazolin-4 '-yl) piperazin-2-yl) ethane' (Cpd. No.2 isomer A)

Step 1 (R) -2-fluoro-2 ' -mercapto-3-methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline ] -4-ol synthesis

Under Ar, methyl (1R) -2' -fluoro-3 ' -methyl-3-oxospiro [ cyclohexane-1, 1' -indene]-methyl 4-carboxylate (intermediate 3, 400mg, 1.39mmol), thiourea (157mg,2.01mmol) and 2,3,4,6,7,8,9, 10-octahydropyrimido [1,2-a ]]A mixture of aza (422mg,2.77mmol) in acetonitrile (8mL) was stirred at 80 ℃ for 2 h. The volatiles were removed under reduced pressure to give a residue which was dissolved in water, neutralized with HCl solution, collected the precipitate and dried in vacuo to give the title compound (400mg, 92%) as a pale yellow solid. MS: 315.2(M + H) ⁺ )。

Step 2 (R) -2-fluoro-3-methyl-2 '- (methylthio) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazoline ] -4' -alcohol synthesis

Under Ar to (R) -2-fluoro-2 '-mercapto-3-methyl-5',8' -dihydro-3 ' H-spiro [ indene-1, 7' -quinazoline]A solution of-4 '(6' H) -one (step 1,400mg,1.27mmol) and sodium hydroxide (51mg,1.27mmol) in acetone (10 mL)/water (2mL) was added methyl iodide (180mg,1.27mmol) at room temperature. After 1 h, all volatiles were removed under reduced pressure, neutralized with HCl solution, and the precipitate was collected and dried in vacuo to give the title compound (430mg, crude) as a pale yellow solid. MS: 329.5(M + H) ⁺ )。

Step 3 Synthesis of (R) -2-fluoro-3-methyl-2 '- (methylthio) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl trifluoromethanesulfonate

Under Ar to (R) -2-fluoro-3-methyl-2 ' - (methylthio) -5',8' -dihydro-3 ' H-spiro [ indene-1, 7' -quinazoline]-4 '(6' H) -one (step 2,430mg,1.31mmol) and N, N diisopropylethylamine (432mg,3.27mmol) in a suspension in dichloromethane (10mL) was added trifluoromethanesulfonic anhydride (554mg,1.96mmol) at-40 ℃. The reaction was held at this temperature for 1 hour, water was added, extracted twice with DCM and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (600mg, 99%) which was used in the next step without further purification. MS: 461.5(M + H) ⁺ )。

Step 4 Synthesis of tert-butyl (S) -2- (cyanomethyl) -4- ((R) -2-fluoro-3-methyl-2 '- (methylthio) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) piperazine-1-carboxylate

To (R) -2-fluoro-3-methyl-2 ' - (methylthio) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline under Ar]To a solution of (4' -yl) trifluoromethanesulfonate (step 3, 600mg, 1.3mmol) and N, N-diisopropylethylamine (842mg, 6.5mmol) in N, N-dimethylformamide (5ml) was added (S) -2- (piperazin-2-yl) acetonitrile dihydrochloride (258mg, 0.13mmol) at room temperature. After 30 minutes, dicarbonate is added Tert-butyl ester (1422mg, 6.5mmol), and the mixture was stirred at room temperature for 1 hour. Water was added and extraction was performed 3 times with ethyl acetate. The organic layer was rinsed with brine, dried over sodium sulfate, and concentrated to give a residue, which was purified by silica gel column chromatography and eluted with ethyl acetate/hexane from 0 to 30% to give the title compound (600mg, 86%) as a colorless oil. MS: 536.8(M + H) ⁺ )。

Step 5 Synthesis of tert-butyl (2S) -2- (cyanomethyl) -4- ((1R) -2-fluoro-3-methyl-2 '- (methylsulfinyl) -5',8 '-dihydro-6' H spiro [ indene-1, 7 '-quinazolin ] -4' -yl) piperazine-1-carboxylate

3-Chloroperoxybenzoic acid (54mg, 0.27mmol, 85% purity) was added to tert-butyl (S) -2- (cyanomethyl) -4- ((R) -2-fluoro-3-methyl-2 ' - (methylthio) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline under Ar]-4' -yl) piperazine-1-carboxylate (step 4,150mg,0.28mmol) in dichloromethane (10mL), 0 ℃. After 30 min, water was added, extracted twice with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the title compound (140mg, 91%) as a foamy solid. MS: 552.5(M + H) ⁺ )。

Step 6 Synthesis of tert-butyl (S) -2- (cyanomethyl) -4- ((R) -2-fluoro-3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazine-1-carboxylate

To a solution of (S) - (1-methylpyrrolidin-2-yl) methanol (88mg, 0.76mmol) and sodium hydride (30mg, 0.76mmol) in tetrahydrofuran (10mL) at-20 deg.C under Ar was added tert-butyl (2S) -2- (cyanomethyl) -4- ((1R) -2-fluoro-3-methyl-2 ' - (methylsulfinyl) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]-4' -yl) piperazine-1-carboxylic acid ester in tetrahydrofuran (10 mL). The reaction was warmed to room temperature and stirred for 30 minutes. Adding water and acetic acidThe ethyl ester was extracted 2 times, the organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a residue which was purified by column chromatography on silica eluting with dichloromethane/methanol from 0 to 10% to give the title compound (132mg, 86%) as a colorless oil. MS: 603.8(M + H) ⁺ )。

Step 7 Synthesis of 2- ((S) -1-acryloyl-4- ((R) -2-fluoro-3-methyl-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile

Crude tert-butyl (S) -2- (cyanomethyl) -4- ((R) -2-fluoro-3-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline under Ar]A mixture of (E) -4' -yl) piperazine-1-carboxylate (step 6,132mg,0.22mmol) in dichloromethane (6mL) and trifluoroacetic acid (3mL) was stirred at room temperature for 1 hour. All volatiles were removed under reduced pressure to give a residue, which was dissolved in dichloromethane (5mL) and triethylamine (111mg, 1.1mmol) and acryloyl chloride (39mg, 0.44mmol) were added to the mixture at 0 deg.C. After 30 min, water was added, dichloromethane was extracted twice, the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give the crude product which was purified by preparative HPLC to give the title compound (36mg, 30%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.35-7.25(m,2H),7.25-7.12(m,2H),6.96-6.70(br,1H),6.18(dd,J＝16.6,2.1Hz,1H),5.77(dd,J＝10.5,2.1Hz,1H),5.05-4.70(m,1H),4.51-3.75(m,5H),3.30-2.50(m,11H),2.33(s,3H),2.24-2.10(m,1H),1.99-1.78(m,6H),1.73-1.51(m,3H).MS:577.8(M+H ⁺ ).

2- ((2S) -1-acryloyl-4- (2-fluoro-3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ inden-1, 7 '-quinazolin ] -4' -yl) piperazin-2-yl) acetonitrile (Cpd.2 isomer A/B) and 2- ((2S) -1-acryloyl-4- ((S) -2-fluoro-3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ inden-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.2 isomer B) was prepared in essentially the same manner using 2 '-fluoro-3' -methyl-3-oxospiro [ cyclohexane-1, 1 '-indene ] -4-carboxylic acid methyl ester and (1S) -2' -fluoro-3 '-methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester as starting materials, respectively.

Example 15

Synthesis of 2- ((S) -1-acryloyl-4- ((S) -2'- (((S) -1, 2-dimethylpyrrolidin-2-yl) methoxy) -2-fluoro-3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.3 isomer B)

Substantially the same protocol as described in example 14 was used to provide cpd.no.3 isomer B (30mg) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.34–7.26(m,2H),7.24–7.11(m,2H),6.96–6.72(br,1H),6.18(dd,J＝16.7,2.2Hz,1H),5.77(dd,J＝10.5,2.1Hz,1H),5.10–4.66(m,1H),4.56–3.60(m,5H),3.48–2.76(m,10H),2.67–1.2.54(m,1H),2.27(s,3H),2.10–1.80(m,6H),1.76–1.50(m,3H),1.02(s,3H).MS:571.6(M+H ⁺ ).

The essentially same protocol described in example 14 was also used to prepare 2- ((2S) -1-acryloyl-4- (2'- (((S) -1, 2-dimethylpyrrolidin-2-yl) methoxy) -2-fluoro-3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (cpd. No.3 isomer a/B) and 2- ((S) -1-acryloyl-4- ((R) -2'- (((S) -1, 2-dimethylpyrrolidin-2-yl) methoxy) -2-fluoro-3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.3 isomer A)

Example 16

Synthesis of 2- ((S) -1-acryloyl-4- ((R) -2, 3-difluoro-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. isomer A. 4)

Using essentially the same protocol as described in example 14, (1R) -2',3' -difluoro-3-oxospiro [ cyclohexane-1, 1' -indene]Methyl (4-carboxylate) (intermediate 4) as starting material to prepare cpd.no.4(62mg) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.65–7.35(m,3H),7.35–7.16(m,1H),7.00–6.72(br,1H),6.18(d,J＝16.5Hz,1H),5.77(d,J＝10.7Hz,1H),5.06–3.77(m,6H),4.50–2.50(m,10H),2.32(s,3H),2.24–1.85(m,4H),1.73–1.51(m,3H).MS:561.6(M+H ⁺ ).

The essentially same protocol described in example 14 was also used to prepare 2- ((2S) -1-acryloyl-4- (2, 3-difluoro-2 '- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (cpd. No.4 isomer a/B) and 2- ((S) -1-acryloyl-4- ((S) -2, 3-difluoro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Compound No.4 isomer B)

Example 17

Synthesis of 2- ((S) -1-acryloyl-4- ((S) -2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -3- (trifluoromethyl) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.5 isomer A)

Using essentially the same protocol as described in example 14, the (1S) -3-oxo-3 '- (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene ] was used]Methyl-4-carboxylate (intermediate 5) was prepared as starting material to give cpd.no.5 isomer a (65mg) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.63–7.55(m,1H),7.50–7.33(m,4H),6.87(s,1H),6.19(dd,J＝16.6,2.2Hz,1H),5.77(dd,J＝10.5,2.0Hz,1H),5.05–4.69(m,1H),4.53–3.51(m,5H),3.30–2.40(m,11H),2.33(s,3H),2.25–2.10(m,2H),1.97–1.83(m,1H),1.74–1.48(m,4H).MS:593.8(M+H ⁺ ).

The essentially same protocol described in example 14 was also used to prepare 2- ((2S) -1-acryloyl-4- (2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -3- (trifluoromethyl) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (cpd. No.5 isomer a/B) and 2- ((S) -1-acryloyl-4- ((R) -2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -3- (trifluoromethyl) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.5 isomer B)

Example 18

Synthesis of 2- ((2S) -1-acryloyl-4- (2-methyl-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.6 isomer A/B)

Using essentially the same protocol as described in example 14, 2 '-methyl-3-oxospiro [ cyclohexane-1, 1' -indene ] was used]Methyl (4-carboxylate) (intermediate 6) as starting material the title compound, Cpd No.6 isomer A/B (17mg), was prepared as a white solid. ¹ H NMR(400MHz,DMSO-d6)δ7.30–7.24(m,1H),7.23–7.16(m,1H),7.12–6.96(m,2H),6.95–6.74(br,1H),6.51(s,1H),6.24–6.12(m,1H),5.34–5.72(m,1H),5.08–4.67(m,1H),4.55–3.40(m,5H),3.30–2.50(m,9H),2.33(s,3H),2.32–2.10(m,2H),1.99–1.87(m,6H),1.70–1.55(m,3H),1.45–1.25(m,1H).MS:539.8(M+H ⁺ ).

The essentially same protocol described in example 14 was also used to prepare 2- ((S) -1-acryloyl-4- ((S) -2-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (cpd. No.6 isomer a) and 2- ((S) -1-acryloyl-4- ((R) -2-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.6 isomer B)

Example 19

Synthesis of 2- ((S) -1-acryloyl-4- ((S) -4-chloro-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3- (trifluoromethyl) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.7 isomer A)

The title compound was prepared using essentially the same protocol as described in example 14, using (1S) -4' -chloro-3-oxo-3 ' - (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene]Methyl-4-carboxylate (intermediate 7) as starting material gave Cpd.No.7 isomer A (106mg) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.70–7.54(m,2H),7.49–7.32(m,2H),5.97–6.72(br,1H),6.18(dd,J＝16.6,2.1Hz,1H),5.81–5.66(m,1H),5.07–3.53(m,6H),3.30–2.50(m,11H),2.33(s,3H),2.26–2.10(m,2H),1.91–1.85(m,1H),1.74–1.47(m,4H).MS:628.6(M+H ⁺ ).

Example 20

Synthesis of 2- ((S) -1-acryloyl-4- ((R) -4-chloro-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3- (trifluoromethyl) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.7 isomer B)

Using essentially the same protocol as described in example 14, (1R) -4' -chloro-3-oxo-3 ' - (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene]Methyl (4-carboxylate) (intermediate 8) as starting material gave Cpd.No.7 isomer B (51mg) as a white solid. ¹ H NMR(400MHz, DMSO-d ₆ )δ7.62–7.50(m,2H),7.48–7.34(m,2H),6.96–6.75(br,1H),6.18(dd,J＝16.7,2.1Hz,1H),5.77(dd,J＝10.5,2.1Hz,1H),5.07–3.78(m,6H),3.60–2.50(m,11H),2.36(s,3H),2.28–1.84(m,3H),1.73–1.53(m,4H).MS:628.6(M+H ⁺ ).

Using 4' -chloro-3-oxo-3 ' - (trifluoromethyl) spiro [ cyclohexane-1, 1' -indene ] -4-carboxylic acid methyl ester as starting material, the essentially same protocol described in example 14 was also used to prepare 2- ((2S) -1-acryloyl-4- (4-chloro-2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3- (trifluoromethyl) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazolin ] -4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.7 isomer A/B)

Example 21

Synthesis of 2- ((S) -1-acryloyl-4- ((S) -4-chloro-3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.8 isomer A)

Step 1 (S) -4-chloro-2 ' -mercapto-3-methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline ] -4-ol synthesis

Under Ar, (1S) -4' -chloro-3 ' -methyl-3-oxospiro [ cyclohexane-1, 1' -indene]-methyl 4-carboxylate (intermediate 9,440mg,1.444mmol), thiourea (121mg,1.588mmol) and 2,3,4,6,7,8,9, 10-octahydropyrimido [1,2-a ]]A mixture of aza (330mg,2.166mmol) in acetonitrile (16mL) was stirred at 80 ℃ for 2 h. All volatiles were removed under reduced pressure to give a residue, which was dissolved in water and neutralized with HCl. The precipitated solid was collected and dried in vacuo to give the title compound (441mg, 92%) as a pale yellow solid. And (2) MS: 331.3(M + H) ⁺ )。

Step 2 (S) -4-chloro-3-methyl-2 '- (methylthio) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazoline ] -4' -alcohol synthesis

To (S) -4-chloro-2 ' -mercapto-3-methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline under Ar]-4' -alcohols (step 1,440mg, 1.330mmol) and sodium hydroxide (53.2mg, 1.330mmol) in acetone (10 mL)/water (2mL) was added methyl iodide (189mg, 1.330mmol) at room temperature. After 1 hour, all volatiles were removed under reduced pressure, neutralized with HCl solution, and the precipitate was collected and dried in vacuo to give the title compound (400mg, 87%) as a pale yellow solid. MS: 345.3(M + H) ⁺ )。

Step 3 Synthesis of (S) -4-chloro-3-methyl-2 '- (methylthio) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl trifluoromethanesulfonate

To (R) -4-chloro-3-methyl-2 ' - (methylthio) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline at-40 ℃ under Ar]To a mixture of (4' -ol) (step 2, 400mg, 1.160mmol) and DIPEA (375mg, 2.90mmol) in DCM (10mL) was added Tf ₂ O (491mg, 1.740 mmol). After 1 hour, water was added, extracted twice with DCM, and the combined organic layers were washed with brine, over anhydrous Na ₂ SO ₄ The filtrate was dried and concentrated in vacuo to give the title compound as an oil (530mg, 96%) which was used directly in the next step. MS: 477.3(M + H) ⁺ )。

Step 4 Synthesis of tert-butyl (S) -4- ((S) -4-chloro-3-methyl-2 '- (methylthio) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate

To (S) -4-chloro-3-methyl-2 ' - (methylthio) -5', 8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline at room temperature under Ar]To a solution of (4' -yl) trifluoromethanesulfonate (step 3, 530mg, 1.111mmol) and N, N-diisopropylethylamine (718mg, 5.56mmol) in N, N-dimethylformamide (5mL) was added (S) -2- (piperazin-2-yl) acetonitrile dihydrochloride (220mg, 1.111 mmol). After 30 min di-tert-butyl dicarbonate (1213mg, 5.56mmol) was added and the mixture was stirred at room temperature for 1 h. Water was added and extraction was performed 3 times with ethyl acetate. Organic compoundsThe layer was rinsed with brine, dried over sodium sulfate and concentrated to give a residue which was purified by silica gel column chromatography and eluted with ethyl acetate/hexane from 0 to 30% to give the title compound (572mg, 93%) as a colorless oil. MS: 552.3(M + H) ⁺ )。

Step 5 Synthesis of tert-butyl (2S) -4- ((1S) -4-chloro-3-methyl-2 '- (methylsulfinyl) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate

Meta-CPBA (231mg, 1.140mmol, 1.1) was added to tert-butyl (S) -4- ((S) -4-chloro-3-methyl-2 ' - (methylthio) -5', 8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline at 0 ℃ under Ar ]-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate (572mg,1.036mmol) in DCM (10 mL). After 30 min, water was added, extracted twice with DCM, and the combined organic layers were washed with brine, washed with Na ₂ SO ₄ Drying and concentration gave the title compound (590mg, 100%) as a foamy solid. MS: 569.9(M + H) ⁺ )。

Step 6 Synthesis of tert-butyl (S) -4- ((S) -4-chloro-3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a suspension of (S) - (1-methylpyrrolidin-2-yl) methanol (359mg, 3.12mmol) and NaH (125mg, 3.12mmol) in THF (10mL) at-20 deg.C under Ar was added tert-butyl (2S) -4- ((1S) -4-chloro-3-methyl-2 ' - (methylsulfinyl) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate (step 5, 590mg, 1.038mmol) in THF (10 ml). The reaction was warmed to room temperature and stirred for 30 minutes. Extracting with water and ethyl acetate for 2 times, mixing organic layers, washing with brine, drying with sodium sulfate, vacuum concentrating to obtain residue,purification by column chromatography on silica gel eluting with dichloromethane/methanol from 0 to 20% gave the title compound (620mg, 96%) as a colourless oil. MS: 620.6(M + H) ⁺ )。

Step 7 Synthesis of 2- ((S) -1-acryloyl-4- ((S) -4-chloro-3-methyl-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile

Under Ar, tert-butyl (S) -4- ((S) -4-chloro-3-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate (step 6, 500mg, 0.807mmol) in a mixture of DCM (5mL) and TFA (10mL) was stirred at room temperature for 1 hour. All volatiles were removed under reduced pressure to give a residue, which was dissolved in DCM (5mL) and TEA (700mg, 6.8mmol) and acryloyl chloride (124mg, 1.368mmol) were added at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes. Water was added, extracted twice with DCM, washed with brine, and Na ₂ SO ₄ Drying and concentration gave a pale yellow residue which was purified by preparative HPLC to give the title compound (130mg, 28%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.41(d,J＝6.4Hz,1H),7.29–7.19(m,2H),6.92–6.75(m,1H),6.53(d,J＝1.2Hz,1H),6.18(dd,J＝16.7,2.1Hz,1H),5.77(dd,J＝10.5,2.0Hz,1H),5.05–3.52(m,6H),3.30–2.50(m,9H),2.44–2.2(m,8H),2.20–1.99(m,2H),1.98–1.84(m,1H),1.74–1.40(m,4H).MS:574.7(M+H ⁺ ).

2- ((2S) -1-acryloyl-4- (4-chloro-3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.8 isomer A/B) and 2- ((S) -1-acryloyl-4- ((R) -4-chloro-3-methyl-2 '- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd.No.8 isomer B) was prepared in essentially the same manner using the appropriate starting materials.

Example 22

Synthesis of 2- ((S) -4- ((S) -4-chloro-3-methyl-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.9 isomer A)

Step 1 Synthesis of 2- ((S) -4- ((S) -4-chloro-3-methyl-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile

Under Ar, tert-butyl (S) -4- ((S) -4-chloro-3-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]A mixture of-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate (example 21, step 6, 100mg,0.161mmol) in DCM (5mL) and TFA (10mL) was stirred at room temperature for 1 hour. All volatiles were removed under reduced pressure to give a residue, and saturated NaHCO was added ₃ The solution was extracted twice with DCM and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried and concentrated to give the title compound (80mg, 95%) as a brown oil. MS: 519.6(M + H) ⁺ )。

Step 2- ((S) -4- ((S) -4-chloro-3-methyl-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile

Under Ar, 2- ((S) -4- ((S) -4-chloro-3-methyl-2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]-4' -yl) piperazin-2-yl) acetonitrile (step 1, 80mg, 0.154mmol), 2-fluoroacrylic acid (1: (0.154 mmol)A mixture of 41.6mg,0.462mmol), TEA (46.8mg,0.462mmol),2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphine 2,4, 6-trioxide (147mg, 0.462mmol) and DMAP (18.83mg,0.154mmol) in DCM (10mL) was stirred at room temperature for 1 h. Water was added, extracted twice with DCM and the combined organic layers were washed with brine, washed with Na ₂ SO ₄ Drying and concentration gave a pale yellow residue which was purified by preparative HPLC to give cpd.no.9 isomer a (30mg, 32.9%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.41(d,J＝6.7Hz,1H),7.32–7.17(m,2H),6.51(s,1H),5.45–5.15(m,2H),5.05–3.45(m,6H),3.30–2.50(m,9H),2.40–2.23(m,8H),2.20–1.85(m,3H),1.72–1.41(m,4H).MS:591.6(M+H ⁺ ).

2- ((2S) -4- (4-chloro-3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Cpd. No.9 isomer A/B) and 2- ((S) -4- ((R) -4-chloro-3-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Cpd. No.9 isomer B) was prepared in essentially the same manner using the appropriate starting materials.

Example 23

Synthesis of 2- ((S) -1-acryloyl-4- ((S) -4-chloro-3- (methyl-d 3) -2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd.No.10 isomer A)

Using essentially the same protocol as described in example 21, methyl (1S) -4' -chloro-3 ' - (methyl-d 3) -3-oxospiro [ cyclohexane-1, 1' -indene ] was used]-4-carboxylate (intermediate 10) as starting material to give cpd.no.10 isomer a (79mg) as a pale yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.41(d,J＝7.0Hz,1H),7.29–7.17(m,2H),7.00–6.74(br,1H),6.53(s,1H),6.18(dd,J＝16.7,2.1Hz,1H),5.77(dd,J＝10.5,2.0Hz,1H),5.05–3.49(m,6H),3.30–2.50(m,10H),2.40–2.25(m,4H),2.22–1.83(m,3H),1.74–1.41(m,4H).MS:576.8(M+H ⁺ ).

Using the appropriate starting materials, 2- ((2S) -1-acryloyl-4- (4-chloro-3- (methyl-d 3) -2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (cpd. No.10 isomer a/B) and 2- ((2S) -1-acryloyl-4- (4-chloro-3- (methyl-d 3) -2'- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.10 isomer B)

Example 24

Synthesis of 2- ((S) -4- ((S) -4-chloro-3- (methyl-d 3) -2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Cpd. No.11 isomer A)

The title compound was prepared using essentially the same protocol as described in example 22 to afford cpd.no.11 isomer a (40mg) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.41(d,J＝7.1Hz,1H),7.29–7.17(m,2H),6.51(s,1H),5.47–5.12(m,2H),5.00–3.49(m,6H),3.30–2.50(m,9H),2.40–2.25(m,5H),2.20–1.84(m,3H),1.72–1.37(m,4H).594.7(M+H ⁺ ).

Using the appropriate starting materials, 2- ((2S) -4- (4-chloro-3- (methyl-d 3) -2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (cpd. No.11 isomer a/B) and 2- ((S) -4- ((R) -4-chloro-3- (methyl-d 3) -2'- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Cpd.No.11 isomer B).

Example 25

Synthesis of 2- ((S) -1-acryloyl-4- ((R) -4-chloro-2, 3-difluoro-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.12 isomer A)

Using essentially the same protocol as described in example 21, methyl (1R) -4 '-chloro-2', 3 '-difluoro-3-oxospiro [ cyclohexane-1, 1' -indene ] was used]-4-Carboxylic acid ester (intermediate 11) as starting material gave Cpd.No.12 isomer A (36mg) as a white solid. ¹ H NMR(400MHz,DMSO-d6)δ7.40(d,J＝7.6Hz,2H),7.36–7.28(m,1H),6.98–6.72(br,1H),6.18(dd,J＝16.7,2.1Hz,1H),5.77(dd,J＝10.5,2.1Hz,1H),5.50–3.76(m,6H),3.51–2.50(m,11H),2.32(s,3H),2.19–2.06(m,2H),1.96–1.85(m,2H),1.72–1.50(m,3H).MS:595.7(M+H ⁺ ).

Using the appropriate starting materials, 2- ((2S) -1-acryloyl-4- (4-chloro-2, 3-difluoro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (cpd. No.12 isomer a/B) and 2- ((S) -1-acryloyl-4- ((S) -4-chloro-2, 3-difluoro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (isomer B).

Example 26

Synthesis of 2- ((S) -4- ((R) -4-chloro-2, 3-difluoro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.13 isomer A)

The title compound was prepared using essentially the same protocol as described in example 22 to afford cpd.no.13 isomer a40mg, a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.44–7.29(m,3H),5.39(dd,J＝18.0,4.1Hz,1H),5.35–5.16(m,1H),5.05–3.50(m,6H),3.30–2.50(m,11H),2.37(s,3H),2.33–1.85(m,4H),1.75–1.53(m,3H).MS:613.7(M+H ⁺ ).

Using the appropriate starting materials, 2- ((2S) -4- (4-chloro-2, 3-difluoro-2 '- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropoxy) piperazin-2-yl) acetonitrile (cpd. No.13 isomer a/B) and 2- ((S) -4-chloro-2, 3-difluoro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (isomer B).

Example 27

Synthesis of 2- ((S) -1-acryloyl-4- ((S) -4-chloro-3-methyl-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.14 isomer A)

Step 1 Synthesis of tert-butyl (S) -4- ((S) -4-chloro-3-methyl-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a mixture of (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (55.9mg, 0.396mmol) and sodium hydride (31.7mg, 0.792mmol) in anhydrous THF (10mL) at 0 deg.C under Ar was added tert-butyl (2S) -4- ((1S) -4-chloro-3-methyl-2 ' - (methylsulfinyl) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylic acid ester (intermediate 9, step 5; 150mg, 0.264mmol), the resulting mixture was stirred at room temperature for 1 hour. Quench with water, extract twice with EA, combine the organic layers with saltWashing with water and Na ₂ SO ₄ Drying and concentration in vacuo gave a residue which was purified by silica gel column chromatography eluting with MeOH/DCM from 0% to 10% to give the title compound (110mg, 64.6%) as a light brown oil. MS: 645.9(M + H) ⁺ )。

Step 2 Synthesis of 2- ((S) -1-acryloyl-4- ((S) -4-chloro-3-methyl-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile

Under Ar, tert-butyl (S) -4- ((S) -4-chloro-3-methyl-2 ' - ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazoline]A mixture of-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate (step 1,110mg,0.170mmol) in DCM (10mL) and TFA (2mL) was stirred at room temperature for 1 hour. All volatiles were removed under reduced pressure to give a residue, which was dissolved in DCM (5mL) and TEA (102mg, 1mmol) and acryloyl chloride (23.14mg, 0.256mmol) were added at 0 deg.C. The mixture was stirred at 0 ℃ for 30 minutes. Water was added, extracted twice with DCM, washed with brine, and Na ₂ SO ₄ Drying and concentration gave a light yellow residue which was purified by preparative HPLC to give the title compound as a white solid (30mg, 29.4%). MS: 599.7(M + H) ⁺ )。

2- ((2S) -1-acryloyl-4- (4-chloro-3-methyl-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.14 isomer A/B) and 2- ((S) -1-acryloyl-4- ((R) -4-chloro-3-methyl-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd.No.14 isomer B) was prepared in essentially the same manner using the appropriate starting intermediates.

Example 28

Synthesis of 2- ((S) -4- ((S) -4-chloro-3-methyl-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.15 isomer A)

The title compound was prepared using essentially the same protocol as described in example 22 to afford cpd.no.15 isomer a (25mg) as a white solid. ¹ H NMR(400MHz,DMSO)δ7.45(d,J＝7.0Hz,1H),7.31(d,J＝7.9Hz,1H),7.29–7.22(m,1H),6.54(s,1H),5.48–5.20(m,2H),5.05–2.50(m,18H),2.41(d,J＝18.1Hz,1H),2.33(s,3H),2.14–1.84(m,9H),1.62–1.46(m,1H).MS:617.4(M+H ⁺ ).

Using the appropriate starting intermediates, 2- ((2S) -4- (4-chloro-3-methyl-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (cpd. No.15 isomer a/B) and 2- ((S) -4- ((R) -4-chloro-3-methyl-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Cpd.No.15 isomer B).

Example 29

Synthesis of 2- ((S) -4- ((S) -4-chloro-3-methyl-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) 5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.16 isomer A)

Using essentially the same protocol aS described in example 27 with ((2R,7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol instead of (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol, cpd.no.16 isomer a (55mg) was obtained aS a white solid. MS: 635.5(M + H) ⁺ )。

Using the appropriate starting intermediates, the same protocol aS essentially described in example 27 was used to prepare 2- ((2S) -4- (4-chloro-2 ' - (((2R,7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -3-methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazolin-4 ' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Cpd.No.16 isomer A/B) and 2- ((S) -4- ((R) -4-chloro-2 ' - ((2R,7aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) - Yl) methoxy) -3-methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazolin-4 ' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile (cpd. No.16 isomer B).

Example 30

Synthesis of 2- ((2S) -4- ((1S) -4-chloro-2 '- ((2, 2-difluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.17 isomer A)

Using essentially the same protocol as described in example 27, using (2, 2-difluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol in place of (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol gave Cpd.No.17 isomer A (44mg) as a white solid. MS: 653.5(M + H) ⁺ )。

Preparation of 2- ((2S) -4- (4-chloro-2 ' - ((2, 2-difluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -3-methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazolin-4 ' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.17 isomer A/B) and 2- ((2S) -4- ((1R) -4-chloro-2 ' - ((2, 2-difluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -3- Methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazolin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.17 isomer B)

Example 31

Synthesis of 2- ((2S) -4- ((1S) -4-chloro-2 '- ((hexahydro-1H-pyrrolizin-3-yl) methoxy) -3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.18 isomer A)

Intermediate step 1 Synthesis of benzyl (4- (methoxy (methyl) amino) -4-oxobutyl) carbamate

To a solution of 4- (((benzyloxy) carbonyl) amino) butyric acid (5.0g, 21.07mmol) and TEA (6.4g, 63.2mmol) in anhydrous DCM (100mL) under Ar was added T ₃ P (8.05g,25.3mmol) and N, O-dimethylhydroxylamine (1.93g,31.6mmol) were at 0 ℃. The mixture was then stirred at room temperature for 16 hours. Washing with water, brine, and anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo to give a residue which was purified by flash chromatography, eluting with a Hex/EA ratio of 3:1 to 1:1, to give the title compound (5.5g, 93%) as a colorless oil. MS: 281.3(M + H) ⁺ )。

Step 2 Synthesis of benzyl (4-oxooct-7-en-1-yl) carbamate

To a solution of benzyl (4- (methoxy (methyl) amino) -4-oxobutyl) carbamate (4.4g, 15.7mmol) in dry THF (50mL) at 0 deg.C under Ar was added but-3-en-1-ylmagnesium bromide (7.5g,47.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The pH was adjusted to 3-4 with HCl aq and extracted 3 times with EA. The combined EA layers were washed with brine, over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave a residue which was purified by flash chromatography, eluting with 10:1 to 3:1 Hex/EA, to give the title compound (3.3g, 76%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.35(m,5H),5.79(m,1H),5.09(s,2H),5.00(m,2H),4.82(s,1H),3.20(m,2H),2.54-2.42(m,4H),2.31(m,2H),1.84-1.73(m,2H).

Step 3 Synthesis of 2- (but-3-en-1-yl) pyrrolidin-1-yl ester

To a solution of triphenylsilane (5.62g, 21.6mmol) in anhydrous DCM (50ml) under Ar at room temperature was added BF ₃ OEt ₂ (6.23g, 43.9 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then cooled to-70 ℃. A solution of benzyl (4-oxooct-7-en-1-yl) carbamate (3.3g, 11.98mmol) in DCM (50mL) was added to the above mixture and stirred at-70 ℃ for 30 min. The reaction mixture was stirred at room temperature for 2 hours. With NaHCO ₃ aq was quenched and extracted 3 times with DCM. The combined DCM layers were washed with brine, over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by flash chromatography, eluting with Hex/EA from 10:1 to 4:1, to give the title compound (2.6g, 84%) as a colorless oil. ¹ H NMR(400MHz,DMSO)δ7.45-7.38(m,5H),5.83(m,1H),5.17(m,2H),5.05(d,J＝17.2Hz,1H),4.98(d,J＝10.2Hz,1H),3.90(m,1H),3.54-3.37(m,2H),2.15-2.01(m,2H),2.01-1.81(m,4H),1.77-1.68(m,1H),1.50-1.39(m,1H).

Step 4 Synthesis of benzyl 2- (2- (oxiranyl-2-yl) ethyl) pyrrolidine-1-carboxylate

To oxone (30.8g,50.1mmol) and NaHCO at 0 deg.C ₃ (12.63g,150mmol) in ACE/H ₂ To a solution in O (75mL/150mL) was added benzyl 2- (but-3-en-1-yl) pyrrolidine-1-carboxylate (2.6g,10.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. Diluted with water and extracted 3 times with EA. The combined EA layers were washed with brine, over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by flash chromatography, eluting with Hex/EA from 10:1 to 4:1, to give the title compound (1.8g, 65.2%) as a colorless oil. MS: 276.3(M + H) ⁺ )。

Step 5 Synthesis of (hexahydro-1H-pyrrolizin-3-yl) methanol

A mixture of benzyl 2- (2- (oxiran-2-yl) ethyl) pyrrolidine-1-carboxylate (1.8g, 6.54mmol, 1.0 eq) and Pd/C (600mg) in MeOH (50mL) at room temperature in H ₂ Stirred for 16 hours. Filtered and concentrated in vacuo. The residue was purified by flash chromatography with DCM/MeOH (1% NH) ₄ OH) eluted from 50:1 to 20:1 to give the title compound as a yellow oil (450mg, 49%). MS: 142.1(M + H) ⁺ )。 ¹ H NMR(400MHz,CDCl ₃ )δ4.02(s,1H),3.65-3.54(m,2H),3.46(dd,J＝10.8,5.2Hz,1H),3.04(m,1H),2.88(m,1H),2.71(m,1H),2.09-1.66 (m,6H),1.55-1.38(m,2H).

Step 6 Synthesis of 2- ((2S) -4- ((1S) -4-chloro-2 '- ((hexahydro-1H-pyrrolizin-3-yl) methoxy) -3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile

The title compound was prepared essentially following the protocol described in example 27 using (hexahydro-1H-pyrrolizin-3-yl) methanol to give cpd.no.18 isomer a (21mg) as a white solid. MS: 617.4(M + H) ⁺ )。

2- ((2S) -4- (4-chloro-2 '- ((hexahydro-1H-pyrrolizin-3-yl) methoxy) -3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoroacryl) piperazin-2-yl) acetonitrile (Cpd. No.18 isomer A/B) and 2- ((2S) -4- ((1R) -4-chloro-2 '- ((hexahydro-1H-pyrrolizin-3-yl) methoxy) -3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Cpd. No.18 isomer B) was prepared in essentially the same manner using the appropriate starting intermediates.

Example 32

Synthesis of 2- ((2S) -4- ((1S) -2'- (((2S) -1-azabicyclo [2.2.1] heptan-2-yl) methoxy) -4-chloro-3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Cpd. No.19 isomer A)

Step 1: synthesis of (2S) -4-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 1- (tert-butyl) 2-methyl (S) -4-oxopyrrolidine-1, 2-dicarboxylate (10g,41.1mmol) in THF (100mL) was added LiAlH4(3.12g,82mmol) at-40 deg.C and stirred for 30 min. Addition of 3.12mLH ₂ O, 3.12mL 15% NaOH and 9.36mLH ₂ O to quench the reaction. The mixture is mixed with Na ₂ SO ₄ Dried and filtered. The filtrate was concentrated to give the title compound as a yellow oil (8.8g, 99%).

Step 2 Synthesis of (2S) -2- ((benzyloxy) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl (2S) -4-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylate (8.8g, 40.5mmol) and benzyl bromide (6.93g, 40.5mmol) in MeCN (200mL) was added silver oxide (28.2g,122 mmol). The mixture was stirred at 80 ℃ for 16 h, filtered and concentrated under reduced pressure to give a residue which was purified through a silica gel column and eluted with 0-50% ethyl acetate/hexane to give the title compound (5.7g, 45.8%) as a yellow oil.

Step 3 Synthesis of (S) -2- ((benzyloxy) methyl) -4-oxopyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (2S) -2- ((benzyloxy) methyl) -4-hydroxypyrrolidine-1-carboxylate (5.7g, 18.54mmol) in DCM (100mL) was added DMP (11.80g, 27.8mmol) at 0 deg.C and stirred at room temperature for 2 h. Adding saturated NaHCO ₃ And Na ₂ S ₂ O ₃ The resulting mixture was extracted 3 times with DCM. The combined organic layers were concentrated in vacuo to give a residue which was purified through a silica gel column and eluted with 0 to 30% ethyl acetate/hexanes to give the title compound as a yellow oil (5.5g, 97%).

Step 4 Synthesis of tert-butyl (S, E) -2- ((benzyloxy) methyl) -4- (2-ethoxy-2-oxyethylene) pyrrolidine-1-carboxylate

To a solution of ethyl 2- (diethoxyphosphonyl) acetate (7.50g, 36.0mmol) in THF (20mL) at 0 deg.C was added NaH (1.081g, 27.0mmol) and stirred for 30 min. A solution of tert-butyl (S) -2- ((benzyloxy) methyl) -4-oxopyrrolidine-1-carboxylate (5.5g, 18.01mmol) in THF (20mL) was added dropwise and stirred at room temperature for 1 h. Saturated NH ₄ Cl was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were washed with Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by column on silica gel and eluted with 0 to 20% ethyl acetate/hexanes to give the title compound as a yellow oil (5.22g, 77%).

Step 5 Synthesis of tert-butyl (2S) -2- ((benzyloxy) methyl) -4- (2-ethoxy-2-oxoethyl) pyrrolidine-1-carboxylate

A solution of p-tert-butyl (S, E) -2- ((benzyloxy) methyl) -4- (2-ethoxy-2-oxyethylene) pyrrolidine-1-carboxylate (5.22g, 13.90mmol) in ethyl acetate (30mL), sodium carbonate (1.474g,13.90mmol) and platinum (IV) oxide (0.316g,1.390mmol) were added and the mixture was taken up in H ₂ The mixture was stirred under a balloon at 25 ℃ for 1 hour. The reaction mixture was filtered and concentrated to give the title compound as a yellow oil (5.2g, 99%). MS: 400.3(M + Na) ⁺ )。

Step 6 (2S) -2- ((benzyloxy) methyl) -4- (2-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (2S) -2- ((benzyloxy) methyl) -4- (2-ethoxy-2-oxoethyl) pyrrolidine-1-carboxylate (5.2g, 13.78mmol) in THF (40mL) was added LiAlH at-40 deg.C ₄ (0.784g, 20.66mmol) and stirred for 1 hour. Mixing with 0.78mLH ₂ O、0.78mL15％NaOH、2.34mLH ₂ Quenching with O and Na ₂ SO ₄ And (5) drying. The reaction mixture was filtered and concentrated to give the title compound as a yellow oil (4.6g, 100%). MS: 358.3(M + Na) ⁺ )。

Step 7 Synthesis of tert-butyl (2S) -2- ((benzyloxy) methyl) -4- (2- (toluenesulfonyloxy) ethyl) pyrrolidine-1-carboxylate

To a mixture of tert-butyl (2S) -2- ((benzyloxy) methyl) -4- (2-hydroxyethyl) pyrrolidine-1-carboxylate (4.6g, 13.71mmol) in DCM (30mL) was added DMAP (0.168g,1.371mmol), DIEA (3.54g,27.4mmol) and tosyl-Cl (3.92g,20.57mmol) under ice water conditions, and the mixture was stirred at room temperature for 48 hours. The volatiles were removed under reduced pressure to give a residue which was purified through a silica gel column and eluted with ethyl acetate/hexanes from 0 to 20% to give the title compound as a yellow oil (5.5g, 82%). MS: 512.4(M + Na) ⁺ )。

Step 8 Synthesis of (2S) -2- ((benzyloxy) methyl) -1-azabicyclo [2.2.1] heptane

To a solution of tert-butyl (2S) -2- ((benzyloxy) methyl) -4- (2- (toluenesulfonyloxy) ethyl) pyrrolidine-1-carboxylate (5.5g, 11.23mmol) in DCM (30mL) was added TFA (6mL) and the mixture was cooled in a chamberStir at room temperature for 1 hour. All volatiles were removed in vacuo to give the crude intermediate, which was dissolved in MeCN (50 mL). Adding K to the mixture ₂ CO ₃ (6.21g, 44.9mmol) and stirred for 2 hours. The reaction mixture was filtered and concentrated to give a residue which was purified through a silica gel column and eluted with 0 to 10% methanol in dichloromethane to give the title compound as a yellow oil (2.3g, 94%). ¹ H NMR(400MHz,CDCl ₃ )δ7.40–7.27(m,5H),4.63(d,J＝11.9Hz,1H),4.48(d,J＝11.9Hz,1H),4.04–3.92(m,2H),3.71–3.56(m,2H),3.31–3.20(m,2H),3.15–3.08(m,1H),2.88–2.83(m,1H),2.14–1.88(m,2H),1.72–1.47(m,2H).MS:218.3(M+H ⁺ ).

Step 9 Synthesis of ((2S) -1-azabicyclo [2.2.1] heptan-2-yl) methanol

(2S) -2- ((benzyloxy) methyl) -1-azabicyclo [2.2.1]A solution of heptane (1.5g, 6.90mmol) in THF (20 mL)/ethanol (5mL), Pd-C (800mg, 10 wt.%) was added and the mixture was H at 60 ℃ ₂ Stir under balloon for 24 hours. The reaction mixture was filtered through celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to provide the title compound as a white solid (800mg, 91%). ¹ H NMR(400MHz,DMSO-d6)δ5.58(t,J＝4.8Hz,1H),3.77–3.65(m,2H),3.62–3.51(m,1H),3.48–3.39(m,1H),3.27–3.20(m,1H),3.17–3.06(m,2H),2.76(t,J＝4.6Hz,1H),2.05–1.84(m,2H),1.57–1.43(m,1H),1.13–1.05(m,1H).MS:128.3(M+H ⁺ ).

Step 10 Synthesis of 2- ((2S) -4- ((1S) -2'- ((((2S) -1-azabicyclo [2.2.1] heptan-2-yl) methoxy) -4-chloro-3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile

Using ((2S) -1-azabicyclo [ 2.2.1)]Heptan-2-yl) methanol the title compound was prepared following essentially the same protocol as described in example 27 to afford Cpd.No.19 isomer A (26mg) as a white solid. MS: 603.3(M + H) ⁺ )。

2- ((2S) -4- (2 '- ((((2S) -1-azabicyclo [2.2.1] heptan-2-yl) methoxy) -4-chloro-3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (Cpd. No.19 isomer A/B) and 2- ((2S) -4- ((1R) -2'- ((((2S) -1-azabicyclo [2.2.1] heptan-2-yl) methoxy) -4-chloro-3-methyl-5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Cpd. No.19 isomer B) was prepared in essentially the same manner using the appropriate starting intermediates.

Example 33

Synthesis of 2- ((2S) -4- ((1S) -4-chloro-3-methyl-2 '- ((((3S) -2-methyl-2-azabicyclo [2.2.1] heptan-3-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile (Cpd. No.20 isomer A)

Step 1 Synthesis of (R) -2- ((1-phenylethyl) imino) ethyl acetate

To a solution of (R) -1-phenylethane-1-amine (15g,124mmol) in toluene (150mL) was added dropwise a solution of 50% ethyl 2-oxoacetate (25.3g,124mmol) in toluene and stirred for 2 hours. The solvent was removed in vacuo to give ethyl (R) -2- ((1-phenylethyl) imino) acetate (25g, 98%) as a yellow oil. And (2) MS: 206.2(M + H) ⁺ )。

Step 2 Synthesis of ethyl (3S) -2- ((R) -1-phenylethyl) -2-azabicyclo [2.2.1] hept-5-ene-3-carboxylate

To a solution of ethyl (R) -2- ((1-phenylethyl) imino) acetate (25g, 122mmol) in DMF (150mL) at 0 deg.C was addedTFA (13.89g, 122mmol) and stirred for 2 min. Cracked (Cracked) cyclopenta-1, 3-diene (16.10g,244mmol) was added and stirred at room temperature for 16 h. Saturated sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic layers were washed with Na ₂ SO ₄ Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography and eluted with ethyl acetate/hexane from 0% to 30% to give the title compound (22g, 66.6%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.41–7.10(m,5H),6.46–6.39(m,1H),6.30–6.23(m,1H),4.34–4.28(m,1H),3.87–3.73(m,2H),3.07–2.97(m,1H),2.94–2.85(m,1H),2.20(s,1H),2.15–2.08(m,1H),1.46–1.36(m,4H),0.95(t,J＝7.1Hz,3H).MS:272.2(M+H ⁺ ).

Step 3 Synthesis of (3S) -2-azabicyclo [2.2.1] heptane-3-carboxylic acid ethyl ester

(3S) -2- ((R) -1-phenylethyl) -2-azabicyclo [2.2.1]A solution of ethyl hept-5-ene-3-carboxylate (2.8g, 10.32mmol) in ethanol (20ml) was added Pd-C (300mg,10 wt.%). Mixing the mixture in H ₂ The mixture was stirred under a balloon at 25 ℃ for 24 hours. The reaction mixture was filtered through celite, the filter cake was rinsed with EtOH and concentrated to give the title compound as a yellow oil (1.6g, 92%). MS: 170.1(M + H) ⁺ )。

Step 4 Synthesis of 2- (tert-butyl) 3-ethyl (3S) -2-azabicyclo [2.2.1] heptane-2, 3-dicarboxylate

To (3S) -2-azabicyclo [2.2.1]To a mixture of heptane-3-carboxylic acid ethyl ester (1.6g,9.45mmol) in DCM (15mL) was added TEA (2.87g,28.4mmol) and Boc ₂ O (3.10g, 14.18 mmol). The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were washed with Na ₂ SO ₄ Drying, filtration and concentration in vacuo gave a residue which was purified through a silica gel column and eluted from 0% to 5% with methanol/dichloromethane to give the title compound (1.6g, 62.8%) as a yellow oil.

Step 5 Synthesis of ((3S) -2-methyl-2-azabicyclo [2.2.1] heptan-3-yl) methanol

For 2- (tert-butyl) 3-ethyl (3S) -2-azabicyclo [2.2.1]A solution of heptane-2, 3-dicarboxylate (1.6g, 5.94mmol) in THF (30mL) was added LiAlH4(0.902g, 23.76mmol) and the mixture was stirred at 80 ℃ for 8 h. 0.9ml of H was added ₂ O, 0.9ml of 15% NaOH and 2.7ml of H ₂ O to quench the reaction. The mixture was filtered and concentrated to provide the title compound (830mg, 98%). ¹ H NMR(400MHz,CDCl ₃ )δ3.47(dd,J＝10.7,5.9Hz,1H),3.34(dd,J＝10.7,5.2Hz,1H),3.21–3.16(m,1H),2.34(s,3H),2.16–2.12(m,1H),1.98–1.93(m,1H),1.93–1.86(m,1H),1.76–1.66(m,2H),1.62–1.52(m,1H),1.35–1.16(m,3H).MS:142.1(M+H ⁺ ).

Step 6 Synthesis of 2- ((2S) -4- ((1S) -4-chloro-3-methyl-2 '- (((3S) -2-methyl-2-azabicyclo [2.2.1] heptan-3-yl) methoxy) -5', 8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile

Using ((3S) -2-methyl-2-azabicyclo [2.2.1]]Heptan-3-yl) methanol the title compound was prepared following essentially the same protocol as described in example 27 to afford Cpd.No.20 isomer A (4.3mg) as a white solid. MS: 617.3(M + H) ⁺ )。

2- ((2S) -4- (4-chloro-3-methyl-2 '- (((3S) -2-methyl-2-azabicyclo [2.2.1] heptan-3-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Cpd. No.20 isomer A/B) and 2- ((2S) -4- ((1R) -4-chloro-3-methyl-2 '- (((3S) -2-methyl-2-azabicyclo [2.2.1] heptan-3-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.20 isomer B) was prepared in essentially the same manner using the appropriate starting intermediates.

Example 34

Synthesis of 2- ((2S) -4- ((1S) -4-chloro-2 ' - ((dihydro-1 ' H,3' H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a ' (5 ' H) -yl) methoxy) -3-methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7' -quinazolin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile (Cpd. No.21 isomer A)

Step 1 Synthesis of 1- (tert-butyl) 2-methyl 2- ((1- (bromomethyl) cyclopropyl) methyl) pyrrolidine-1, 2-dicarboxylate

To a solution of 1- (tert-butyl) 2-methylpyrrolidine-1, 2-dicarboxylate (1g, 4.37mmol) in THF (20mL) at-78 deg.C under Ar was added LiHMDS (6.55mmol) and stirred at-78 deg.C for 1 hour. A solution of 1, 1-bis (bromomethyl) cyclopropane (2.0g, 8.73mmol) in THF (20mL) was added dropwise to the mixture at-78 deg.C. The resulting mixture was stirred at room temperature overnight with NH ₄ Claq quench, then extract 3 times with EA, the combined organic layers are washed with brine, Na ₂ SO ₄ Drying, filtration and concentration in vacuo gave a residue which was purified by silica gel column chromatography (EA/HEX 0-20%) to afford the title compound as a yellow oil (1.4g, 29.9%).

Step 2 Synthesis of dihydro-1 ' H, 3' H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a ' (5' H) -carboxylic acid methyl ester

To 1- (tert-butyl) 2-methyl 2- ((1- (bromomethyl) cyclopropyl) methyl) pyrrolidine-1, 2-dicarboxylate (1.4g, 3.72mmol) in ethyl acetate (50mL) under ArTo this was added hydrogen chloride (6.78g, 186mmol) at room temperature, and the mixture was stirred at room temperature for 3 hours. Volatiles were removed under reduced pressure to give the crude intermediate, which was dissolved in MeCN (20 mL). Adding K to the mixture ₂ CO ₃ (0.514g, 3.72mmol) and stirred for 2 hours. The reaction mixture was filtered and concentrated to give a residue which was purified by silica gel column chromatography (EA/HEX0 to 50%) to give the title compound as a yellow oil (200mg, 27.5%). ¹ H NMR(400MHz,DMSO)δ3.60(s,3H),3.05–2.95(m,1H),2.84(d,J＝10.1Hz,1H),2.76–2.66(m,1H),2.61(d,J＝10.1Hz,1H),2.22–2.09(m,2H),1.89–1.65(m,4H),0.59–0.51(m,2H),0.45–0.33(m,2H).

Step 3 Synthesis of (dihydro-1 ' H,3' H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a ' (5' H) -yl) methanol

To dihydro-1 ' H,3' H-spiro [ cyclopropane-1, 2' -pyrrolizine at 0 ℃ under Ar]-7a '(5' H) -Carboxylic acid methyl ester (200mg, 1.024mmol) in THF (20mL) LiAlH was added ₄ (78mg, 2.049mmol), and the mixture was then stirred at room temperature for 30 minutes. Quench with water, then extract 3 times with EA, wash the combined organic layers with brine, and Na ₂ SO ₄ Drying, filtration and concentration in vacuo gave the title compound as a yellow oil (120mg, 69%). MS: 168.2(M + H) ⁺ )。

Step 4- ((2S) -4- ((1S) -4-chloro-2 ' - ((dihydro-1 ' H,3' H-spiro [ cyclopropane-1, 2' -pyrrolizine ] -7a ' (5' H) -yl) methoxy) -3-methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7 ' -quinazolin-4 ' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile

Using (dihydro-1 ' H,3' H-spiro [ cyclopropane-1, 2' -pyrrolizine)]-7a '(5' H) -yl) methanol the title compound was prepared essentially following the protocol described in example 27 to give Cpd.No.21 isomer A (11mg) as a white solid. MS: 644.3(M + H) ⁺ )。

2- ((2S) -4- (4-chloro-2 ' - ((dihydro-1 ' H,3' H-spiro [ cyclopropane-1, 2' -pyrrolizin ] -7a ' (5' H) -yl) methoxy) -3-methyl-5 ',8' -dihydro-6 ' H-spiro [ indene-1, 7 ' -quinazolin ] -4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile (cpd. No.21 isomer a/B) and 2- ((2S) -4- ((1R) -4-chloro-2 ' - ((dihydro-1 ' H,3' H-spiro [ cyclopropane-1, 2' -pyrrolizin ] -7a ' (5' H) -yl) methoxy) -3-methyl -5',8' -dihydro-6 ' H-spiro [ indene-1, 7 ' -quinazolin-4 ' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (cpd.no.21 isomer B) was prepared in essentially the same manner using the appropriate starting intermediates.

Example 35

Synthesis of 2- ((2S) -1-acryloyl-4- (4-fluoro-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.22 isomer A/B)

Using essentially the same protocol as described in example 21, 4 '-fluoro-3-oxospiro [ cyclohexane-1, 1' -indene ] was used]Preparation of the title compound as starting material from methyl-4-carboxylate (intermediate 12) afforded Cpd.No.22 isomer A/B (17mg) as a white solid. ¹ H NMR(400MHz,DMSO)δ7.40–7.05(m,3H),7.00–6.64(m,3H),6.27–6.12(m,1H),5.81–5.73(m,1H),5.05–3.50(m,6H),3.30–2.50(m,11H),2.32(s,3H),2.21–1.85(m,3H),1.72–1.46(m,4 H).MS:543.7(M+H ⁺ ).

Using the appropriate starting intermediates, 2- ((S) -1-acryloyl-4- ((S) -4-fluoro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (cpd. No.22 isomer a) and 2- ((S) -1-acryloyl-4- ((R) -4-fluoro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.22 isomer B).

Example 36

Synthesis of 2- ((S) -1-acryloyl-4- ((S) -4-chloro-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.23 isomer A)

Using essentially the same protocol as described in example 21, the (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] was used]-3-Ketone As starting material the title compound was prepared to afford Cpd.No.23 isomer A (124mg) as a white solid. ¹ H NMR(400MHz,DMSO-d6)δ7.44-7.22(m,3H),6.92-6.79(m,3H),6.21-6.16(m,1H),5.78-5.76(m,1H),4.96-4.77(m,1H),4.39-3.59(m,5H),3.29-2.77(m,9H),2.54-2.39(m,2H),2.32(s,3H),2.18-2.05(m,2H),1.95-1.86(s,1H),1.67-1.51(m,4H).MS:560.4(M+H ⁺ ).

Using a suitable starting intermediate, 2- ((2S) -1-acryloyl-4- (4-chloro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (cpd. No.23 isomer a/B) and 2- ((S) -1-acryloyl-4- ((R) -4-chloro-2 '- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.23 isomer B).

Example 37

Synthesis of 2- ((S) -4- ((S) -4-chloro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile (Cpd. No.24 isomer A)

Using essentially the same protocol as described in example 27, the (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] was used]-3-Ketone As starting material the title compound was prepared to give Cpd.No.24 isomer A (142mg) as a white solid. ¹ H NMR(400MHz,DMSO-d6)δ7.44-7.22(m,3H),6.89(s,2H),5.42-5.22(m,2H),4.93-4.83(m,1H),4.25-3.88(m,5H),3.30-2.81(m,9H),2.53-2.40(m,2H),2.32(s,3H),2.18-2.07(m,2H),1.95-1.86(m,1H),1.67-1.51(m,4H).MS:578.4(M+H ⁺ ).

Using the appropriate starting intermediates, 2- ((2S) -4- (4-chloro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (cpd. No.24 isomer a/B) and 2- ((S) -4- ((R) -4-chloro-2 '- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (cpd. No.24 isomer B).

Example 38

Synthesis of 2- ((S) -1- (acryloyl-d 3) -4- ((S) -4-chloro-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.25 isomer A)

Using essentially the same protocol as described in example 27, (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene]-3-Ketone as starting material the title compound was prepared to give Cpd.No.25 isomer A as a white solid. And (2) MS: 588.4(M + H) ⁺ )。

Using appropriate starting intermediates and essentially the same protocol as described in example 27 for the preparation of Cpd.No.25 isomer A/B) and Cpd.No.25 isomer B

Example 39

Synthesis of 2- ((S) -4- ((S) -4-chloro-2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.26 isomer A)

Using essentially the same protocol as described in example 27, the (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] was used]-3-one asStarting material the title compound was prepared to give cpd.no.26 isomer a as a white solid. MS: 603.5(M + H) ⁺ )。

Essentially the same protocol as described in example 27 for the preparation of Cpd.No.26 isomer A/B and Cpd.No.26 isomer B uses the appropriate starting intermediates.

Example 40

Cpd.No.27 isomer A

Using essentially the same protocol as described in example 27, the procedure is followed using (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene]-3-Ketone as starting material the title compound was prepared to give Cpd.No.27 isomer A as a white solid. NMR: ¹ HNMR(400MHz,DMSO-d ₆ )δ7.43-7.41(d,J＝7.6Hz,1H),7.33-7.31(d,J＝8.0Hz,1H),7.26-7.22(m,1H),6.88(s,2H),5.42-5.36(m,1H),5.34-5.22(m,1H),4.28-4.24(m,1H)4.05-3.97(m,2H),3.91-3.87(m,1H),3.26-3.16(m,2H),2.97-2.80(m,4H),2.75-2.71(m,1H),2.56-2.50(m,2H),2.47-2.40(m,2H),2.24(s,3H),2.56-2.50(m,2H),2.17-1.98(m,2H),1.52-1.41(m,5H),1.37-1.23(m,3H),1.12-1.05(m,1H),).MS:617.5(M+H ⁺ ).

essentially the same protocol as described in example 27 for the preparation of Cpd.No.27 isomer A/B and Cpd.No.27 isomer B uses the appropriate starting intermediates.

EXAMPLE 41

Synthesis of 2- ((2S) -4- ((1S) -4-chloro-2 '- ((3-methyltetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (Cpd. No.28 isomer A)

Using essentially the same protocol as described in example 27, the (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] was used]Preparation of the title Compound from (E) -3-Ketone as starting Material to give Cpd.No.28 isomerous Body a, a white solid. MS: 617.5(M + H) ⁺ )。

Using the appropriate starting intermediates, essentially the same protocol as described in example 27 was used to prepare Cpd.No.28 isomer A/B and Cpd.No.28 isomer B.

Example 42

Cpd.No.29 isomer A

Using essentially the same protocol as described in example 27, the (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] was used]-3-Ketone as starting material the title compound was prepared to give Cpd.No.29 isomer A as a white solid. ¹ H NMR(400MHz,DMSO)δ7.42(d,J＝7.3Hz,1H),7.32(d,J＝7.6Hz,1H),7.28–7.20(m,1H),6.89(s,2H),5.45–5.16(m,2H),5.01–4.17(m,1H),4.12–3.42(m,8H),3.27–3.13(m,4H),2.99–2.64(m,7H),2.44(d,J＝18.2Hz,1H),2.12–2.03(m,1H),2.00–1.87(m,2H),1.81–1.66(m,3H),1.64–1.35(m,4H)MS:633.5(M+H ⁺ ).

Using the appropriate starting intermediates, essentially the same protocol as described in example 27 was used to prepare Cpd.No.29 isomer A/B and Cpd.No.29 isomer B.

Example 43

Cpd.No.30 isomer A

Using essentially the same protocol as described in example 27, the (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] was used]-3-Ketone as starting material the title compound was prepared to give Cpd.No.30 isomer A as a white solid. ¹ H NMR(400MHz,DMSO)δ7.42(dd,J＝7.2,2.3Hz,1H),7.31(d,J＝7.6Hz,1H),7.27–7.19(m,1H),6.88(s,2H),5.44–5.16(m,2H),5.04–4.49(m,1H),4.33–3.57(m,8H),3.26–3.10(m,3H),2.97–2.72(m,12H),2.69–2.60(m,1H),2.5–2.40(m,1H),2.13–2.02(m,1H),2.02–1.95(m,1H),1.93–1.85(m,1H),1.83–1.70(m,3H),1.66–1.41(m,4H).MS:704.5(M+H ⁺ ).

Using the appropriate starting intermediates, essentially the same protocol as described in example 27 was used to prepare Cpd.No.30 isomer A/B and Cpd.No.30 isomer B.

Example 44

Synthesis of 2- ((2S) -4- ((1S) -4-chloro-2 '- ((3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile (Cpd. No.31 isomer A)

Using essentially the same protocol as described in example 27, the (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] was used]-3-Ketone as starting material the title compound was prepared to give Cpd.No.31 isomer A as a white solid. MS: 633.5(M + H) ⁺ )。

Using the appropriate starting intermediates, essentially the same protocol as described in example 27 was used to prepare Cpd.No.31 isomer A/B and Cpd.No.31 isomer B.

Example 45

Synthesis of 7a- ((((S) -4-chloro-4 '- ((S) -3- (cyanomethyl) -4- (2-fluoropropenyl) piperazin-1-yl) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-2' -yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyldimethylcarbamate (Cpd. No.32 isomer A)

Using essentially the same protocol as described in example 27, the (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] was used]-3-Ketone as starting material the title compound was prepared giving Cpd.No.32 isomer A as a white solid. ¹ H NMR(400MHz,DMSO)δ7.42(d,J＝7.2Hz,1H),7.32(d,J＝7.8Hz,1H),7.28–7.21(m,1H),6.88(s,2H),5.44–5.38(m,1H),5.35–5.18(m,1H),4.89–3.57(m,9H),3.26–3.14(m,4H),3.00–2.71(m,12H),2.47–2.39(m,1H),2.16–1.95(m,3H),1.84–1.60(m,5H),1.59–1.46(m,2H).MS:704.5(M+H ⁺ ) Using the appropriate starting intermediates, essentially the same protocol as described in example 27 was used to prepare cpd.no.32 isomer a/B and cpd.no.32 isomer B.

Example 46

Synthesis of 3- ((7a- (((S) -4-chloro-4 '- ((S) -3- (cyanomethyl) -4- (2-fluoroacryloyl) piperazin-1-yl) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-2' -yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl) -1, 1-dimethylurea (Cpd. No.33 isomer A)

The title compound was prepared using essentially the same protocol as described in example 27 using (S) -4 '-chlorospiro [ cyclohexane-1, 1' -indene ] -3-one as the starting material to give cpd.no.33 isomer a as a white solid. MS: 703.5(M + H +).

Using the appropriate starting intermediates, essentially the same protocol as described in example 27 was used to prepare Cpd.No.33 isomer A/B and Cpd.No.33 isomer B.

Example 47

Synthesis of 2- ((S) -1-acryloyl-4- ((S) -4-chloro-3- (difluoromethyl) -2'- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin ] -4' -yl) piperazin-2-yl) acetonitrile (Cpd.No.34 isomer A)

Step 1: synthesis of (1R) -4-chloro-3- (difluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ] -3-ol

A mixture of cesium fluoride (1.09g), 18-crown-6(1.89 g,7.17mmol) and (R) -4-chlorodispiro [ indene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ] -3(2H) -one (1.4g,4.78mmol) in DME (30mL) was added (difluoromethyl) trimethylsilane (1.78g,14.34mmol) at room temperature under Ar, the mixture stirred at room temperature for 3 hours, TBAF (9.6mL, 9.6mmol, 1M solution in THF) was added and stirred for an additional 30 minutes. Diluted with water and extracted 3 times with EA. The combined EA layers were washed with brine and concentrated in vacuo to give crude (1R) -4-chloro-3- (difluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3] dioxolane ] -3-ol (1.65g, 97%).

Step 2: synthesis of (1R) -4 '-chloro-3' - (difluoromethyl) -3 '-hydroxy-2', 3 '-dihydrospiro [ cyclohexane-1, 1' -indene ] -3-one

Under Ar, the crude product of (1R) -4-chloro-3- (difluoromethyl) -2, 3-dihydrodispiro [ indene-1, 1 '-cyclohexane-3', 2 "- [1,3 ]]Dioxolanes]A solution of-3-ol (1.6g,4.64mmol) in THF (12mL) and 6N HCl aq (4mL) was stirred at room temperature for 2 h. Dilute with water, extract 3 times with EA, wash the combined organic layers with brine, dry Na ₂ SO ₄ Drying and concentration in vacuo gave a residue which was purified by silica gel column and eluted with Hex/EA ═ 10:1-3:1 to give the title compound (1.2g, 86%) as a white solid.

And step 3: synthesis of methyl (1R) -4 '-chloro-3' - (difluoromethyl) -3 '-hydroxy-3-oxo-2', 3 '-dihydrospiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

Under Ar, (1R) -4 '-chloro-3' - (difluoromethyl) -3 '-hydroxy-2', 3 '-dihydrospiro [ cyclohexane-1, 1' -indene]A solution of-3-one (1.2g, 3.99mmol), NaH (638mg, 15.96mmol) and dimethyl carbonate (7.19g, 80mmol) in dry THF (20mL) was stirred at 70 ℃ for 2 h. After cooling to room temperature, with NH ₄ Clauq was quenched and extracted 3 times with EA. The combined organic layers were washed with brine and dried over sodium sulfateAnhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave a residue which was purified through a silica gel column and eluted with Hex/EA ═ 30:1 to give the title compound (1.15g, 80%) as a colorless oil.

And step 3: synthesis of methyl (1S) -4' -chloro-3 ' - (difluoromethyl) -3-oxospiro [ cyclohexane-1, 1' -indene ] -4-carboxylate

Under Ar, methyl (1R) -4 '-chloro-3' - (difluoromethyl) -3 '-hydroxy-3-oxo-2', 3 '-dihydrospiro [ cyclohexane-1, 1' -indene]A mixture of-4-carboxylate (1.15g,3.21mmol) and Eaton's (10mL) in DCM (5mL) was stirred at room temperature for 16 h. By slow addition of NaHCO ₃ aq and the resulting mixture was extracted 3 times with EA. The combined organic layers were washed with brine, over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave a residue which was purified through a silica gel column and eluted with Hex/EA ═ 20:1 to give the title compound (400mg, 36.6%) as a colourless oil.

And 4, step 4: synthesis of 2- ((S) -1-acryloyl-4- ((S) -4-chloro-3- (difluoromethyl) -2 '- ((tetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile

Using essentially the same protocol as described in example 27, the procedure was followed using (1S) -4' -chloro-3 ' - (difluoromethyl) -3-oxospiro [ cyclohexane-1, 1' -indene]Preparation of the title compound from methyl 4-carboxylate provides cpd.no.34 isomer a as a white solid. NMR: ¹ H NMR(400MHz,DMSO)δ7.57(d,J＝7.1Hz,1H),7.43-7.11(m,4H),6.89(m,1H),6.22(d,J＝16.6,1H),5.80(d,J＝12.3Hz,1H),4.89(m,1H),4.45-3.85(m,5H),3.64(m,1H),3.28(d,J＝18.1Hz,2H),3.07-2.68(m,7H),2.59(m,2H),2.45(d,J＝17.9Hz,1H),2.19(m,1H),1.95-1.70(m,6H),1.65-1.55(m,3H).MS:635.5(M+H ⁺ ).

using the appropriate starting intermediates, essentially the same protocol as described in example 27 was used to prepare Cpd.No.34 isomer A/B and Cpd.No.34 isomer B.

Example 48

Synthesis of 4'- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -3-methyl-2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8' -dihydro-6 'H-spiro [ indene-1, 7' -quinazoline ] -4-carbonitrile (Cpd. No.35 isomers A/B)

Using essentially the same protocol as described in example 21, with (1S) -4' -chloro-3 ' - (difluoromethyl) -3-oxaspiro [ cyclohexane-1, 1' -indene]Preparation of the title compound as starting material methyl-4-carboxylate afforded Cpd.No.35 isomer A/B as a white solid. MS:564.9(M + H) ⁺ )。

Using the appropriate starting intermediates, essentially the same protocol as described in example 21 was used to prepare cpd.no.35 isomer a and cpd.no.35 isomer B.

Example 49

Synthesis of 2- ((2S) -1-acryloyl-4- (3, 4-difluoro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-6' H-spiro [ indene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.36 isomers A/B)

Using essentially the same protocol as described in example 21, with (1S) -4' -chloro-3 ' - (difluoromethyl) -3-oxaspiro [ cyclohexane-1, 1' -indene]Methyl-4-carboxylate as starting material the title compound cpd.no.36 isomer a/B was prepared as a white solid. MS: 561.5(M + H) ⁺ )。

Using the appropriate starting intermediates, essentially the same protocol as described in example 21 was used to prepare Cpd.No.36 isomer A and Cpd.No.36 isomer B.

Example 50

Synthesis of 2- ((2S) -1-acryloyl-4- (5-fluoro-4-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5',8 '-dihydro-2H, 6' H-spiro [ naphthalene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile (Cpd. No.37 isomers A/B)

Step 1: synthesis of 1-bromo-2- (bromomethyl) -3-fluorobenzene

To 1-bromo-3-fluoro-2-methylbenzene (50g,265mmol) in CCl at room temperature under Ar ₄ To a solution in (300mL) was added NBS (47.1g,265mmol) and AIBN (17.37g,106 mmol). The reaction was stirred at 95 ℃ for 17 hours. After cooling to room temperature, the mixture was stirred in ethyl acetate/H ₂ And (4) distributing among the O. The organics were collected, washed with brine, and Na ₂ SO ₄ Drying and concentration under reduced pressure gave a residue which was purified through a silica gel column eluting with 0 to 20% ethyl acetate/hexanes to give the title compound (60g, 85%).

Step 2: synthesis of 2-allyl-1-bromo-3-fluorobenzene

Vinylmagnesium bromide (84mL, 84mmol, 1M in THF) was added dropwise to a solution of 1-bromo-2- (bromomethyl) -3-fluorobenzene (9g, 33.6mmol), copper (I) iodide (0.64g,3.36mmol) and 2,2' -bipyridine (0.525g,3.36mmol) in toluene (100mL) under Ar at-78 ℃. The reaction solution was warmed to room temperature gently and stirred for 17 hours. Addition of saturated NH ₄ And (4) Cl solution. The resulting mixture was in ethyl acetate/H ₂ And (4) distributing among the O. The organics were collected, washed with brine, and Na ₂ SO ₄ Drying and concentrating to give a residue which is purified by silica gel chromatography eluting with hexane to give the titled compoundCompound (6g, 82.8%).

And step 3: synthesis of 2' -allyl-3 ' -fluoro-5, 6-dihydro- [1,1' -biphenyl ] -3(4H) -one

Under Ar, 2-allyl-1-bromo-3-fluorobenzene (6g,27.9mmol),3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohexyl-2-en-1-one (8.05g,36.3mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ Adduct (1.14g,1.395mmol) and sodium carbonate (8.87g,84mmol) in DME (100mL) and H ₂ A mixture of O (25mL) was stirred at 85 ℃ for 3 h. The reaction solution was cooled to room temperature and the reaction solution was then cooled to ethyl acetate/H ₂ And (4) distributing among the O. Collecting organic matter, washing with brine, and passing through Na ₂ SO ₄ Drying and concentration gave a residue which was purified by silica gel chromatography eluting with 0 to 25% ethyl acetate/hexanes to give the title compound (5g, 78%) as a yellow oil. MS 231.4(M + H) ⁺ )

And 4, step 4: synthesis of 3- (2-allyl-3-fluorophenyl) -3-vinylcyclohexan-1-one

Vinylmagnesium bromide (19.5mL, 19.54mmol, 1M solution in THF) was added via funnel to a solution of copper (I) iodide (1.241g, 6.51mmol) and lithium chloride (0.276g, 6.51mmol) in dry THF (40mL) under Ar at-78 ℃. The mixture was held for 1 hour. Then 2' -allyl-3 ' -fluoro-5, 6-dihydro- [1,1' -biphenyl in anhydrous THF was added ]-3(4H) -one (1g,4.34 mmol). The reaction solution was gently warmed to room temperature and stirred for 16 hours. Adding saturated NH ₄ And (4) Cl solution. The resulting mixture was in ethyl acetate/H ₂ And (4) distributing among the O. The organics were collected, washed with brine, and Na ₂ SO ₄ Drying and concentration gave a residue which was purified by silica gel chromatography, eluting with 0 to 20% ethyl acetate/hexanes to give the title compound (518mg, 46.2%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.21–7.14(m,1H),7.13–7.09(m,1H),7.01–6.93(m,1H),6.10–5.99(m,1H),5.97–5.85(m,1H),5.13(d,J＝10.7Hz,1H),5.02(dd,J＝10.3,1.5Hz,1H),4.93–4.79(m,2H),3.61–3.45(m,2H),2.82–2.73(m,1H),2.62–2.54(m,1H),2.49–2.41(m,1H),2.38–2.25(m,2H),2.11–1.99(m,1H),1.91–1.79(m,1H),1.56–1.44(m,1H).MS:259.5(M+H ⁺ ).

And 5: synthesis of 5' -fluoro-4 ' H-spiro [ cyclohexane-1, 1' -naphthalene ] -3-one

A solution of 3- (2-allyl-3-fluorophenyl) -3-vinylcyclohexan-1-one (518mg,2.005mmol) and grubbs II (400mg,0.471mmol) in DCM (40mL) under Ar was stirred for 17 h at 35 ℃. The volatiles were removed under reduced pressure to give a residue which was purified by silica gel chromatography eluting with ethyl acetate/hexanes from 0 to 20% to give the title compound (455mg, 99%) as a yellow oil. MS 231.5(M + H) ⁺ ).

Step 6: synthesis of 5-fluoro-4H-dispiro [ naphthalene-1, 1' -cyclohexane-3 ',2 ' - [1,3] dioxolane ]

Under Ar, 5' -fluoro-4 ' H-spiro [ cyclohexane-1, 1' -naphthalene]A solution of-3-one (455mg,1.976mmol), ethane-1, 2-diol (208mg,3.35mmol) and Ts-OH (39mg,0.205mmol) in toluene (10mL) was stirred at 110 ℃ for 6 h. The volatiles were removed under reduced pressure to give a residue which was purified by silica gel chromatography eluting with 0 to 10% ethyl acetate/hexanes to give the title compound as a yellow oil (430mg, 79%). MS: 275.4(M + H) ⁺ )。

And 7: synthesis of 5-fluoro-3, 4-dihydro-2H-dispiro [ naphthalene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ]

5-fluoro-4H-dispiro [ naphthalene-1, 1 '-cyclohexane-3', 2 "- [1,3]Dioxolanes]A mixture of (430mg,1.567mmol) and 10% Pd/C (220mg, 2.067mmol)) in ethyl acetate (20mL) at room temperature and H ₂ Stirred under conditions for 5 hours. The solution was filtered and the filtrate was concentrated to give the crude title compound (440mg, crude) which was used directly in the next step. MS 277.4(M + H) ⁺ ).

And 8: synthesis of 5-fluoro-2, 3-dihydro-4H-dispiro [ naphthalene-1, 1' -cyclohexane-3 ', 2' - [1,3] dioxolane ] -4-one

5-fluoro-3, 4-dihydro-2H-dispiro [ naphthalene-1, 1 '-cyclohexane-3', 2 "- [1,3]Dioxolanes](324mg,1.172mmol) in acetone (8mL) at 0 deg.C was added MgSO ₄ (705mg, 5.86mmol) and water (2 mL). The KMnO is added in portions ₄ (926mg, 5.86 mmol). The reaction solution was stirred at room temperature for 24 hours and saturated Na was added ₂ S ₂ O ₃ The solution was quenched and filtered. The filtrate was in DCM/H ₂ And (4) distributing among the O. The organic was washed with brine and anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product, which was purified by silica gel chromatography eluting with 0 to 20% ethyl acetate/hexanes to give the title compound as an oil (193mg, 56.7%). ¹ H NMR(400MHz,CDCl ₃ )δ7.52–7.44(m,1H),7.29–7.25(m,1H),7.03–6.94(m,1H),4.01–3.95(m,2H),3.94–3.84(m,2H),2.75–2.59(m,2H),2.50–2.41(m,1H),2.15–2.05(m,1H),1.94–1.69(m,7H),1.62–1.57(m,1H).MS:291.3(M+H ⁺ ).

And step 9: synthesis of 2- ((2S) -1-acryloyl-4- (5-fluoro-4-methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5', 8 '-dihydro-2H, 6' H-spiro [ naphthalene-1, 7 '-quinazolin-4' -yl) piperazin-2-yl) acetonitrile

Using essentially the same protocol as described in example 21, 5-fluoro-2, 3-dihydro-4H-dispiro [ naphthalene-1, 1 '-cyclohexane-3', 2 "- [1,3 ″ ]]Dioxolanes]Preparation of the title Compound from (E) -4-Ketone as starting Material Cpd.No.37 isomer A/B as a white solid. MS:570.5(M + H) ⁺ )。

Using the appropriate starting intermediates, essentially the same protocol as described in example 21 was used to prepare Cpd.No.37 isomer A and Cpd.No.37 isomer B.

Example 38

Biological assays

Cell proliferation assay:

NCI-H358 cells and MIA PaCa-2 cells in RPMI-1640 supplemented with 10% FBS at 37 deg.C, 5% CO ₂ The humidified incubator of (1) for cultivation. To assess the effect of the compounds of the present disclosure on cell proliferation, exponentially growing cells (5000 cells/well) were seeded onto 96-well plates. After cell seeding, representative compounds of the disclosure were added to the cell culture medium (concentration range 0 to 10 μ M, 3-fold dilution series). After 3 days, 30. mu.L of Celltiter-Glo reagent was added and the luminescence signal was measured according to the supplier's instructions. Generation of dose response curves and IC Using Prism ₅₀ The value is obtained. The results are provided in table 4. TABLE 4

Example 39

Mouse PK study

Pharmacokinetic (PK) profiles in CD1 mice after a single i.v. and p.o. for representative compounds of the disclosure. CD1 mouse comes from Weitalhe laboratory animals science and technology Limited, Zhejiang. The results are provided in table 5. Three male rats weighing 200-300g were used. Compounds were prepared at a concentration of 0.4mg/mL using a formulation of 10% DMSO, 5% Solutol HS15, and 85% saline, and at a concentration of 2mg/mL using a formulation of 20% DMSO, 10% Solutol HS15, and 70% distilled water blood samples (0.3mL) were collected at 0.083,0.25,0.5,1,2,4,6,8,24h, and 0.25,0.5,1,2,4,6,8,24h after administration of i.v.2mg/kg, and p.o.10mg/kg.

The collected blood samples were centrifuged within 30 minutes, and plasma was separated and transferred to tubes, then stored at-75 ± 15 ℃ before analysis. Aliquots of plasma unknowns, blanks, and calibration standards were added to 200 μ L of acetonitrile containing the internal standard mixture, respectively, for precipitating proteins. The sample was then vortexed for 30 seconds. After centrifugation at 3900rpm for 15min at 4 ℃, the supernatant was diluted 3-fold with water. The supernatant was injected into an LC/MS/MS system for quantitative analysis.

The LC-MS/MS system consisted of two Shimadzu LC-30AD pumps, a DGU-20A5R degasser, a Rack changer II and an AB Sciex Triple Quad 5500 LC/MS/MS mass spectrometer. Chromatography was performed on a YMC-Triart C185 μm (50X 2.1mm) column at room temperature. The mobile phase is composed of A: 95% water (0.1% formic acid); b: 95% acetonitrile (0.1% formic acid). The flow rate was 0.6 mL/min. The amount of sample was 5. mu.L.

The sensitivity of test compound screening is improved. MRM method using positive electrospray ionization mode. Mass spectral data were acquired and analyzed using AB Sciex analysis version1.6.2 version. Pharmacokinetic parameters were derived using the standard non-compartmental approach of Phoneix WinNonlin Professional Version 6.1. The following pharmacokinetic parameters were calculated. The following pharmacokinetic parameters were calculated as much as possible from the plasma concentration versus time data:

IV administration: t is _1/2 (terminal half-life), C0, AUC _last 、AUC _inf 、MRT _inf Cl, Vss, regression points.

PO administration: t is _1/2 (terminal half-life period), C _max 、T _max 、MRT _inf 、AUC _inf 、AUC _last F%, regression points. Descriptive statistics such as mean, standard deviation are used to describe the pharmacokinetic data.

TABLE 5

Having now fully described the methods, compounds, and compositions herein, it will be appreciated by those of skill in the art that it is possible to work within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiment thereof.

All patents, patent applications, and publications cited herein are incorporated by reference in their entirety.

Claims

1. A compound of formula I:

wherein

Z is

X represents a 6-to 12-membered monocyclic or bicyclic heterocycle;

R ^4a 、R ^4b and R ^4c Independently selected from hydrogen, halogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, (amino) C ₁ -C ₄ Alkyl, (hydroxy) C ₁ -C ₄ Alkyl radical(alkoxy) C ₁ -C ₄ Alkyl and (hetero) C ₁ -C ₄ An alkyl group;

R ^5c selected from hydrogen and C ₁ -C ₄ An alkyl group;

R ⁷ selected from hydrogen and C ₁ -C ₄ An alkyl group;

a is selected from- (CR) ^6a R ^6b ) _m -, -O-, -S-and-N (R) ^7a )-；

A ¹ Is selected from- (CR) ^6c R ^6d ) _n -, -O-, -S-and-N (R) ^7b )-；

A ² Is selected from- (CR) ^6e R ^6f ) _o -, -O-, -S-and-N (R) ^7c )-；

A ³ Is selected from- (CR) ^6g R ^6h ) _p -, -O-, -S-and-N (R) ^7d )-；

the precondition is that:

m is 0, 1 or 2;

n is 0, 1 or 2;

o is 0, 1 or 2;

p is 0, 1 or 2;

provided that the sum of m, n, o and p is 2, 3, 4 or 5;

e is selected from- (CR) ^8a R ^8b ) _q -

E ¹ Is selected from- (CR) ^8e R ^8f ) _r -,

q is 0 or 1;

r is 0 or 1;

R ^8c selected from hydrogen, halogen, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ A cycloalkyl group;

q is selected from ═ C (R) ¹⁰ ) -and-N-;

Represents a single bond or a double bond,

or a pharmaceutically acceptable salt or solvate thereof.

2. A compound of formula II according to claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

3. A compound of formula III according to claim 1

Or a pharmaceutically acceptable salt or solvate thereof.

4. A compound of formula IV according to claim 1

Wherein R is ^11a 、R ^11b 、R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; or a pharmaceutically acceptable salt or solvate thereof.

5. A compound of formula V according to claim 4

Or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of formula VI according to claim 4

Or a pharmaceutically acceptable salt or solvate thereof.

7. A compound of formula VII according to claim 4

Or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of claim 7 of formula VIII

Or a pharmaceutically acceptable salt or solvate thereof.

9. The compound of formula IX of claim 7

Or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claims 1-9, wherein a is- (CH) ₂ ) m-and m is 0 or 1, or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 10, wherein m is 1, or a pharmaceutically acceptable salt or solvate thereof.

12. A compound of formula X according to claim 4

Or a pharmaceutically acceptable salt or solvate thereof.

13. The compound of formula XI of claim 12

Or a pharmaceutically acceptable salt or solvate thereof.

14. The compound of formula XII as defined in claim 12

Or a pharmaceutically acceptable salt or solvate thereof.

15. The compound of formula XIII according to claim 4

Wherein A is ² Selected from the group consisting of-O-, -S-and-N (R) ^7c ) -; or a pharmaceutically acceptable salt or solvate thereof.

16. A compound of formula XIV according to claim 15

Or a pharmaceutically acceptable salt or solvate thereof.

17. The compound of formula XV according to claim 15

Or a pharmaceutically acceptable salt or solvate thereof.

18. The compound of any one of claims 1-17, wherein E is- (CH) ₂ ) q-, or a pharmaceutically acceptable salt or solvate thereof.

19. The compound of any one of claims 1-18, wherein q is 1, or a pharmaceutically acceptable salt or solvate thereof.

20. The compound of any one of claims 1-18, wherein q is 0, or a pharmaceutically acceptable salt or solvate thereof.

21. The compound of any one of claims 1-3 or 18-20, wherein E ¹ Is- (CH) ₂ ) _r Or a pharmaceutically acceptable salt or solvate thereof.

22. The compound of claim 21, wherein r is 1, or a pharmaceutically acceptable salt or solvate thereof.

23. The compound of claim 21, wherein r is 0, or a pharmaceutically acceptable salt or solvate thereof.

24. The compound of any one of claims 1-23, wherein Q is ═ N-, or a pharmaceutically acceptable salt or solvate thereof.

25. The compound of any one of claims 1-24, wherein L is-O-, or a pharmaceutically acceptable salt or solvate thereof.

26. The compound of any one of claims 1-25, wherein R ³ Selected from (amino) C ₁ -C ₄ Alkyl, (carboxamido) C ₁ -C ₄ Alkyl, (heterocycle) C ₁ -C ₄ An alkyl group; or a pharmaceutically acceptable salt or solvate thereof.

27. The compound of any one of claims 1-26, wherein R ³ Selected from:

or a pharmaceutically acceptable salt or solvate thereof.

28. The compound of claims 1-26, wherein R ³ Is composed of

Or a pharmaceutically acceptable salt or solvate thereof.

29. The compound of any one of claims 1-28, wherein Z is selected from:

or a pharmaceutically acceptable salt or solvate thereof.

30. The compound of any one of claims 1-29, wherein R ^2a is-CH ₂ CN or a pharmaceutically acceptable salt or solvate thereof.

31. The compound of any one of claims 1-30, wherein R ¹ Is selected from-C (═ O) -CR ^4a ＝CHR ^4b ,-C(＝O)-C≡CR ^5a and-S (═ O) ₂ CH＝CHR ^4f Or a pharmaceutically acceptable salt or solvate thereof.

32. The compound of any one of claims 1-31, wherein R ¹ Selected from:

or a pharmaceutically acceptable salt or solvate thereof.

33. The compound of any one of claims 1-31, wherein R ¹ Comprises the following steps:

or a pharmaceutically acceptable salt or solvate thereof.

34. The compound of claim 1, selected from any one or more of the compounds in table 1, or a pharmaceutically acceptable salt or solvate thereof.

35. A compound of formula XVI

Wherein:

Z ¹ selected from halogen, -OR ¹⁷ And are and

x represents a 6-to 12-membered monocyclic or bicyclic heterocycle;

R ¹³ selected from hydrogen, -C (═ O) R ^14a and-C (═ O) OR ^14b ；

R ^14a Is C ₁ -C ₆ An alkyl group;

R ^14b is selected from C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl and aralkyl groups;

R ¹² selected from halogen, -SR ¹⁹ ,-S(＝O)R ²⁰ ,-S(＝O) ₂ R ²⁰ and-LR ³ ；

R ¹⁷ Selected from hydrogen and-S (═ O) ₂ R ¹⁸ ；

R ¹⁸ Is selected from C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, and optionally substituted phenyl;

R ¹⁹ selected from hydrogen and C ₁ -C ₄ An alkyl group;

R ²⁰ is C ₁ -C ₄ An alkyl group;

R ⁷ selected from hydrogen and C ₁ -C ₄ An alkyl group;

R ^5c selected from hydrogen and C ₁ -C ₄ An alkyl group;

R ^5f and R ^5g Selected from hydrogen and C ₁ -C ₄ An alkyl group;

A is selected from- (CR) ^6a R ^6b ) _m -, -O-, -S-and-N (R) ^7a )-；

A ¹ Is selected from- (CR) ^6c R ^6d ) _n -, -O-, -S-and-N (R) ^7b )-；

A ² Is selected from- (CR) ^6e R ^6f ) _o -, -O-, -S-and-N (R) ^7c )-；

A ³ Is selected from- (CR) ^6g R ^6h ) _p -, -O-, -S-and-N (R) ^7d )-；

the precondition is that:

m is 0, 1 or 2;

n is 0, 1 or 2;

o is 0, 1 or 2;

p is 0, 1 or 2;

provided that the sum of m, n, o and p is 2, 3, 4 or 5;

e is selected from- (CR) ^8a R ^8b ) _q -,

E ¹ Is selected from- (CR) ^8e R ^8f ) _r -,

q is 0 or 1;

r is 0 or 1;

q is selected from ═ C (R) ¹⁰ ) -and ═ N-;

Represents a single bond or a double bond,

or a salt or solvate thereof.

36. The compound of formula XVII of claim 35:

or a salt or solvate thereof.

37. The compound of formula XVIII of claim 35:

or a salt or solvate thereof.

38. The compound of formula XIX of claim 35:

wherein R is ^11a 、R ^11b 、R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; or a salt or solvate thereof.

39. A compound of formula XX according to claim 38:

or a salt or solvate thereof.

40. A compound of formula XXI according to claim 38:

or a salt or solvate thereof.

41. A compound of formula XXII according to claim 38:

or a salt or solvate thereof.

42. A compound of formula XXIII as claimed in claim 41:

or a salt or solvate thereof.

43. A compound of formula XXIV as claimed in claim 41:

or a salt or solvate thereof.

44. The compound of any one of claims 35-43, wherein A is- (CH) ₂ ) _m -and m is 0 or 1, or a salt or solvate thereof.

45. The compound of claim 44, wherein m is 1 or a salt or solvate thereof.

46. A compound of formula XXV according to claim 38:

or a salt or solvate thereof.

47. The compound of formula XXVI according to claim 46:

or a salt or solvate thereof.

48. The compound of formula XXVII of claim 46:

or a salt or solvate thereof.

49. A compound of formula XXVIII according to claim 38:

wherein A is ² Selected from the group consisting of-O-, -S-, and-N (R) ^7c ) -or a salt or solvate thereof.

50. The compound of claim 49 of formula XXIX:

or a salt or solvate thereof.

51. The compound of formula XXX of claim 49:

or a salt or solvate thereof.

52. The compound of any one of claims 35-51, wherein E is- (CH) ₂ ) _q Or a salt or solvate thereof.

53. The compound of any one of claims 35-52, wherein q is 1, or a salt or solvate thereof.

54. The compound of any one of claims 35-52, wherein q is 0, or a salt or solvate thereof.

55. The compound of any one of claims 35-37,44,45, or 52-54, wherein E ¹ Is- (CH) ₂ ) _r Or a salt or solvate thereof.

56. The compound of claim 55, wherein r is 1, or a salt or solvate thereof.

57. The compound of claim 55, wherein r is 0, or a salt or solvate thereof.

58. The compound of any one of claims 35-57, wherein Q is ═ N-or a salt or solvate thereof.

59. The compound of any one of claims 35-58, wherein Z ¹ Selected from halogen and-OR ¹⁷ Or a salt or solvate thereof.

60. The compound of any one of claims 35-58, Z ¹ Selected from:

or a salt or solvate thereof.

61. The compound of claim 60, wherein R ¹³ Is hydrogen, or a salt or solvate thereof.

62. The compound of claim 60, wherein R ¹³ is-C (═ O) OR ^14b A salt or solvate thereof.

63. The compound of claim 62, wherein R ^14b is-C (CH) ₃ ) ₃ Or a salt or solvate thereof.

64. The compound of any one of claims 35-63, wherein R ^2a is-CH ₂ CN, or a salt or solvate thereof.

65. The compound of any one of claims 35-63, wherein R ¹² Selected from chlorine, -SR ¹⁹ and-S (═ O) R ²⁰ Or a salt or solvate thereof.

66. The compound of any one of claims 35-63, wherein R ¹² is-LR ^3， Or a salt or solvate thereof.

67. The compound of claim 35, selected from any one or more of the compounds in table 2, or a salt or solvate thereof.

68. A compound of formula XXXI:

wherein:

a is selected from- (CR) ^6a R ^6b ) _m -, -O-, -S-and-N (R) ^7a )-；

A ¹ Is selected from- (CR) ^6c R ^6d ) _n -, -O-, -S-and-N (R) ^7b )-；

A ² Is selected from- (CR) ^6e R ^6f ) _o -, -O-, -S-and-N (R) ^7c )-；

A ³ Is selected from- (CR) ^6g R ^6h ) _p -, -O-, -S-and-N (R) ^7d )-；

the precondition is that:

m is 0, 1 or 2;

n is 0, 1 or 2;

o is 0, 1 or 2;

p is 0, 1 or 2;

provided that the sum of m, n, o and p is 2, 3, 4 or 5;

e is selected from- (CR) ^8a R ^8b ) _q -

E ¹ Is selected from- (CR) ^8e R ^8f ) _r -,

q is 0 or 1;

r is 0 or 1;

Represents a single bond or a double bond,

or a pharmaceutically acceptable salt or solvate thereof.

69. The compound of formula XXXII according to claim 68

Or a salt or solvate thereof.

70. The compound of formula XXXIII of claim 68

Or a salt or solvate thereof.

71. The compound of formula XXXIV of claim 68

Wherein R is ^11a ,R ^11b ,R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group;

or a salt or solvate thereof.

72. The compound of formula XXXV of claim 71

Or a salt or solvate thereof.

73. The compound of formula XXXVI of claim 71

Or a salt or solvate thereof.

74. The compound of formula XXXVII of claim 71

Or a salt or solvate thereof.

75. The compound of formula XXXVIII according to claim 74

Or a salt or solvate thereof.

76. The compound of formula XXXIX of claim 74

Or a salt or solvate thereof.

77. The compound of claims 68-76, wherein A is- (CH) ₂ ) _m -and m is 0 or 1, or a salt or solvate thereof.

78. The compound of claim 77, wherein m is 1, or a salt or solvate thereof.

79. The compound of claim 71 of formula XL,

or a salt or solvate thereof.

80. The compound of claim 79 of formula XLI,

or a salt or solvate thereof.

81. The compound of claim 79 of formula XLII:

or a salt or solvate thereof.

82. The compound of claim 71 of formula XLIII,

83. The compound of claim 82 of formula XLIV,

or a salt or solvate thereof.

84. Compound XLV of claim 82

Or a salt or solvate thereof.

85. The compound of any one of claims 68-84, wherein E is- (CH) ₂ ) _q -or a salt or solvate thereof.

86. The compound of claim 85 wherein q is 1 or a salt or solvate thereof.

87. The compound of claim 85 wherein q is 0, or a salt or solvate thereof.

88. The compound of any one of claims 68-70,77,78, or 85-87, wherein E ¹ Is- (CH) ₂ ) _r -or a salt or solvate thereof.

89. The compound of claim 88, wherein r is 1, or a salt or solvate thereof.

90. The compound of claim 88, wherein r is 0, or a salt or solvate thereof.

91. The compound of claim 68 selected from the group consisting of:

92. compounds of formula XLVI

Wherein:

R ¹⁵ selected from hydrogen and-C (═ O) OR ¹⁶ ；

R ¹⁶ Is C ₁ -C ₆ An alkyl group;

a is selected from- (CR) ^6a R ^6b ) _m -, -O-, -S-and-N (R) ^7a )-；

A ¹ Is selected from- (CR) ^6c R ^6d ) _n -, -O-, -S-and-N (R) ^7b )-；

A ² Is selected from- (CR) ^6e R ^6f ) _o -, -O-, -S-and-N (R) ^7c )-；

A ³ Is selected from- (CR) ^6g R ^6h ) _p -, -O-, -S-and-N (R) ^7d )-；

the precondition is that:

m is 0, 1 or 2;

n is 0, 1 or 2;

o is 0, 1 or 2;

p is 0, 1 or 2;

provided that the sum of m, n, o and p is 2, 3, 4 or 5;

e is selected from- (CR) ^8a R ^8b ) _q -

E ¹ Is selected from- (CR) ^8e R ^8f ) _r -,

q is 0 or 1;

r is 0 or 1;

q is ═ N-;

Represents a single bond or a double bond,

or a salt or solvate thereof.

93. The compound of claim 92 of formula XLVII:

or a salt or solvate thereof.

94. The compound of claim 92 of formula XLVIII:

or a salt or solvate thereof.

95. The compound of claim 92 of formula XLIX:

wherein R is ^11a ,R ^11b ,R ^11c And R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; or a salt or solvate thereof.

96. The compound of claim 95 of formula L:

or a salt or solvate thereof.

97. The compound of claim 95 of formula LI:

or a salt or solvate thereof.

98. The compound of claim 95 of formula LII:

or a salt or solvate thereof.

99. The compound of claim 98 of formula LIII:

or a salt or solvate thereof.

100. The compound of claim 98 of formula LIV:

or a salt or solvate thereof.

101. The compound of claims 92-100, wherein a is- (CH) ₂ ) _m -and m is 0 or 1, or a salt or solvate thereof.

102. The compound of claim 101, wherein m is 1, or a salt or solvate thereof.

103. A compound according to claim 94 of formula LV:

or a salt or solvate thereof.

104. A compound according to claim 103 of formula LVI

Or a salt or solvate thereof.

105. The compound of claim 103 of formula LVII:

or a salt or solvate thereof.

106. The compound of claim 95 of formula LIX:

wherein A is ² Selected from the group consisting of-O-, -S-, and-N (R) ^7c ) Or a salt or solvate thereof.

107. A compound of formula LX according to claim 106

Or a salt or solvate thereof.

108. A compound of formula LXI according to claim 106

Or a salt or solvate thereof.

109. The compound of any one of claims 95-108, wherein

R ^11a Selected from halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; and

R ^11b ,R ^11c and R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group, a carboxyl group,

or a salt or solvate thereof.

110. The compound of any one of claims 95-108,

R ^11b Selected from halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group, a carboxyl group,

R ^11a ,R ^11c and R ^11d Selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group, a carboxyl group,

or a salt or solvate thereof.

111. The compound of any one of claims 95-108,

R ^11c selected from halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; and

R ^11a ,R ^11b and R ^11d Selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group;

or a salt or solvate thereof.

112. The compound of any one of claims 95-108

R ^11d Selected from halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group; and

R ^11a ,R ^11b and R ^11c Selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group, a carboxyl group,

or a salt or solvate thereof.

113. The compound of any one of claims 92-112, wherein E is- (CH) ₂ ) _q Or a salt or solvate thereof.

114. The compound of claim 113, wherein q is 1, or a salt or solvate thereof.

115. The compound of claim 113, wherein q is 0, or a salt or solvate thereof.

116. The compound of any one of claims 92-94,101,102, or 113-115, wherein E ¹ Is- (CH) ₂ ) _r Or a salt or solvate thereof.

117. The compound of claim 116, wherein r is 1, or a salt or solvate thereof.

118. The compound of claim 116, wherein r is 0, or a salt or solvate thereof.

119. The compound of any one of claims 92-118, wherein R ¹⁵ Is hydrogen or a salt or solvate thereof.

120. The compound of any one of claims 92-118, wherein R ¹⁵ is-C (═ O) OR ¹⁶ Or a salt or solvate thereof.

121. The compound of claim 120, wherein R ¹⁶ Selected from methyl and ethyl or salts or solvates thereof.

122. The compound of claim 92, selected from any one or more of the compounds of Table 3, or a salt or solvate thereof.

123. The compound of claim 1 of formula LXII:

wherein:

R ^11a ,R ^11b ,R ^11c and R ^11d Independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy and (hydroxy) C ₁ -C ₄ An alkyl group;

R ^22a and R ^22b Independently selected from hydrogen, halogen, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, hydroxy C ₁ -C ₃ An alkyl group; or

R ²³ selected from the group consisting of hydrogen and fluorine, or a pharmaceutically acceptable salt or solvate thereof.

124. The compound of claim 1 of formula LXIII:

wherein:

R ^22a And R ^22b Together with the carbon atom to which they are attached form an optionally substituted 3-to 6-membered cycloalkyl group;

R ²³ selected from the group consisting of hydrogen and fluorine, or pharmaceutically acceptable thereofAn acceptable salt or solvate.

125. The compound of claim 34, or a pharmaceutically acceptable salt or solvate thereof, selected from cpd.no.14 isomer a, cpd.no.14 isomer B, cpd.no.15 isomer a, cpd.no.15 isomer B, cpd.no.16 isomer a, cpd.no.16 isomer B, cpd.no.23 isomer a, and cpd.no.23 isomer B.

126. A pharmaceutical composition comprising a compound of any one of claims 1-34 or 123-125, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

127. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-34 or 123-125, or a pharmaceutically acceptable salt or solvate thereof.

128. The method of claim 127, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

129. The method of claim 127 or 128, wherein the cancer is a KRAS mutant cancer.

130. The method of any one of claims 127-129, further comprising administering a therapeutically effective amount of an optional therapeutic agent useful for treating cancer.

131. The pharmaceutical composition of claim 126, for use in the treatment of cancer.

132. The pharmaceutical composition of claim 131, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

133. The pharmaceutical composition of claim 131 or 132, wherein the cancer is a KRAS mutant cancer.

134. The compound of any one of claims 1-34 or 123-125, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer.

135. The compound for use of claim 134, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

136. The compound for use according to claim 134 or 135, wherein the cancer is a KRAS mutant cancer.

137. Use of a compound of any one of claims 1-34 or 123-125, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

138. The use of claim 137, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

139. The use of claim 137 or 138, wherein the cancer is a KRAS mutant cancer.

140. A method of inhibiting KRAS in a cell in a subject in need thereof comprising administering to the subject a compound of any one of claims 1-34 or 123-125, or a pharmaceutically acceptable salt or solvate thereof.

141. The method of claim 139, wherein the KRAS is KRAS-G12C.

142. A kit comprising a compound of any one of claims 1-34 or 123-125, or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound, or pharmaceutically acceptable salt or solvate thereof, to a subject having cancer.

143. The kit of claim 142, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

144. The kit of claim 142 or 143, wherein the cancer is a KRAS mutant cancer.

145. A Protac compound, wherein the Protac compound is derived from a compound of any one of claims 1-144.