WO2024149389A1 - Substituted bridge ring inhibitor, preparation method therefor, and application thereof - Google Patents

Abstract

The present invention relates to a substituted bridge ring inhibitor, a preparation method therefor, and an application thereof. Specifically, the compound of the present invention has the structure represented by formula (A0). The present invention likewise discloses a preparation method for the compound and an application thereof as a KRAS^G12D inhibitor. The compound has a good selective inhibition effect on KRAS^G12D, and has better pharmacodynamic and pharmacokinetic properties and lower toxic side effects.

Description

Substituted bridge ring inhibitors and preparation method and application thereof Technical Field

The invention belongs to the field of medicine, and specifically relates to a substituted bridge ring inhibitor and a preparation method and application thereof.

Background technique

About a quarter of all human tumors are caused by RAS mutations, and nearly one million people lose their lives each year. In the RAS family, KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mainly non-small cell lung cancer). The most important mutations in KRAS mutations are G12C and G12D mutations, of which G12C mutations mainly occur in HSCLC, while G12D mutations mainly occur in pancreatic cancer. So far, there are still no drugs approved for the KRAS ^G12D mutation on the market.

At present, conventional treatments for pancreatic cancer in clinical practice include gemcitabine monotherapy, gemcitabine combined with albumin-paclitaxel, and FOLFIRINOX regimen (oxaliplatin + irinotecan + 5-FU/LV). Among them, liposomal irinotecan is suitable for the treatment of patients with advanced pancreatic cancer who have not responded well to gemcitabine chemotherapy (second-line therapy) in combination with fluorouracil and folinic acid. But in general, there are currently limited effective treatments for pancreatic cancer, and the overall survival time of patients does not exceed 1 year. Although drug exploration for patients with advanced pancreatic cancer is ongoing, research progress has been relatively slow so far.

Since the KRAS ^G12D target protein is pathologically associated with a variety of diseases, especially pancreatic cancer, new KRAS ^G12D inhibitors are currently needed for clinical treatment. Highly selective and highly active KRAS ^G12D inhibitors can more effectively treat diseases such as cancer caused by KRAS ^G12D mutations, and have the potential to reduce off-target effects, so they have more urgent clinical needs.

Summary of the invention

The object of the present invention is to provide a novel class of compounds having selective inhibitory effects on KRAS ^G12D and/or better pharmacodynamic properties and uses thereof.

In a first aspect, the present invention provides a compound of formula (A0), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:

Ring C is selected from the following group:

Y is selected from: a bond, O, NH, N(C ₁ -C ₃ alkyl);

Z is a substituted or unsubstituted C ₁ -C ₆ alkylene group; wherein the substitution refers to substitution by one or more R;

W is selected from: substituted or unsubstituted C ₃ -C ₁₄ cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group;

Wherein, the substitution refers to substitution by one or more R;

Selected from the following groups: Wherein, X is selected from: N, CH, CD, CF, C(CN);

R ¹ is selected from: -L ₁ -QL ₂ -L ₃ ;

in:

L ₁ is selected from: substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R;

Q is selected from: O, S, SO ₂ , NH, or N(C ₁ -C ₃ alkyl);

L ₂ is selected from: none, substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R;

L ₃ is selected from the following substituted or unsubstituted groups: -C ₁ -C ₆ alkyl, -C ₃ -C ₆ cycloalkyl, -C ₄ -C ₆ heterocyclyl, -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyl), -C ₁ -C ₆ alkylene (C ₁ -C ₆ alkoxy), -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyloxy), or -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyloxy); wherein the substitution refers to substitution by one or more R;

n is an integer of 0, 1, 2, 3, 4, 5 or 6; provided that when W is a monocyclic or bicyclic ring, n is not 0;

R ¹⁰ is selected from the following substituted or unsubstituted groups: C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more Ra;

R ¹¹ is independently selected from the following substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, _{4-6 membered heterocyclyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyloxy , 4-6 membered heterocyclyloxy} ; wherein the substitution refers to substitution by one or more R;

Ra are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _NH2 , OH, _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl ₎ , _SONH2 , _SO2NH2 , _NHSO2 (C1- _C6 alkyl), _NHSO2 ( _C3 - _C6 cycloalkyl), _C1 - _C6 alkyl, C1- _C6 deuterated alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, _{C2 - C6} alkenyl, _C2 - _C6 alkynyl, _C3 -C20 cycloalkyl, _4-20 membered heterocycle, _C3 - _C20 cycloalkyloxy, 4-20 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R _;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

Each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyl)C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkoxy)C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyloxy)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl) vinyl, deuterated (C ₁ -C ₆ alkyl) vinyl, halogenated (C ₁ -C ₆ alkyl) vinyl, (C ₁ -C 6 alkyl) ethynyl, deuterated (C ₁ -C ₆ alkyl) ethynyl, halogenated (C ₁ -C ₆ alkyl) -C ₆ alkyl)ethynyl, (C ₃ -C ₁₄ cycloalkyl)ethynyl, (4-14 membered heterocyclyl)ethynyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, 4-20 membered heterocyclyl C(O), C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

In another preferred embodiment, ring C is selected from the following group:

In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates A compound, solvate or prodrug having a structure shown in formula (A):

Y is selected from: a bond, O, NH, N(C ₁ -C ₃ alkyl);

Z is a substituted or unsubstituted C ₁ -C ₆ alkylene group; wherein the substitution refers to substitution by one or more R;

W is selected from: substituted or unsubstituted C ₃ -C ₁₄ cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R;

Selected from the following groups: Wherein, X is selected from: N, CH, CD, CF, C(CN);

R ¹ is selected from: -L ₁ -QL ₂ -L ₃ ;

in:

L ₁ is selected from: substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R;

Q is selected from: O, S, SO ₂ , NH, or N(C ₁ -C ₃ alkyl);

L ₂ is selected from: none, substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R;

L ₃ is selected from the following substituted or unsubstituted groups: -C ₁ -C ₆ alkyl, -C ₃ -C ₆ cycloalkyl, -C ₄ -C ₆ heterocyclyl, -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyl), -C ₁ -C ₆ alkylene (C ₁ -C ₆ alkoxy), -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyloxy), or -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyloxy); wherein the substitution refers to substitution by one or more R;

n is an integer of 0, 1, 2, 3, 4, 5 or 6; provided that when W is a monocyclic or bicyclic ring, n is not 0;

R ¹⁰ is selected from the group consisting of substituted or unsubstituted C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more Ra;

R ¹¹ is each independently selected from the following substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, 4-6 _{membered heterocyclyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyloxy , 4-6 membered heterocyclyloxy} ;

Ra is independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _NH2 , OH, _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl ₎ , _SONH2 , _SO2NH2 , _NHSO2 (C1- _C6 alkyl), _NHSO2 ( _C3 -C6 cycloalkyl), _{C1 - C6} alkyl, C1- _C6 deuterated alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, _{C2 - C6} alkenyl, _C2 - _C6 alkynyl, _C3 - _C20 cycloalkyl, 4-20 membered heterocyclyl, _C3 - _C20 cycloalkyloxy, 4-20 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R _;

m is an integer of 0, 1, 2, 3, 4, 5 or 6;

Each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyl)C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkoxy)C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyloxy)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl) vinyl, deuterated (C ₁ -C ₆ alkyl) vinyl, halogenated (C ₁ -C ₆ alkyl) vinyl, (C ₁ -C ₆ alkyl) ethynyl, deuterated (C ₁ -C ₆ alkyl) ethynyl, halogenated (C ₁ -C ₆ alkyl) ethynyl, (C ₃ -C ₁₄ cycloalkyl) ethynyl, (4-14 membered heterocyclyl) ethynyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, 4-20 membered heterocyclyl C (O), C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C _1-4 membered aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

In another preferred embodiment, Ra are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, OH, SONH ₂ , NHSO ₂ CH ₃ , C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C 6 haloalkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl; wherein the substitution refers to substitution by one or more R; R is defined as _above .

In another preferred embodiment, the compound has a structure shown in A'

Preferably, it has the structure shown in A"

In the formula, n, Y, Z, W, L ₁ , L ₂ , L ₃ , Q, R ¹⁰ , R ¹¹ , m and ring A have the same meanings as described above.

In another preferred embodiment, Selected from the following groups:

In another preferred embodiment, the compound has a structure shown in formula A'

^R2 and ^R3 are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _C1 - _C6 alkyl, _C1 - _C6 deuterated alkyl, _C1 - _{C6 haloalkyl, C1-C6 alkoxy ;} wherein the substitution refers to substitution by one or more R;

X, Y, Z, W, R ¹ , n and R ¹⁰ are as defined above.

In another preferred embodiment, ^R3 is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _C1 - _C6 alkyl, C1- _C6 deuterated alkyl, _C1 -C6 haloalkyl, _C1 - _C6 alkoxy, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl _{, C3} - _C6 cycloalkyl, _C3 - _C6 cycloalkyloxy, 4-6 membered heterocyclyl, 4-6 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more _R.

In another preferred embodiment, R ¹⁰ is selected from: substituted or unsubstituted phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyridyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, _NH2 , _C1 - _{C6 alkyl} , halogenated C1- _{C6 alkyl, C1-C6 alkoxy , halogenated C1-C6 alkoxy , C3} - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl: Preferably, ^R10 is selected from:

In another preferred embodiment, R ⁸ is selected from: NH ₂ , OH, SONH ₂ , NHSO ₂ CH ₃ .

In another preferred embodiment, R ¹⁰ is

In another preferred embodiment, U is selected from: N, CH, CD, CF;

R ⁴ is selected from the group consisting of substituted or unsubstituted halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl;

R ⁵ , R ⁶ , R ⁷ , and R ⁹ are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

^R8 is selected from the _group consisting of: _NH2 , OH, _SONH2 , _NHSO2CH3 .

In another preferred embodiment, U, R ⁶ , R ⁷ , R ⁹ and R ⁸ are as defined above;

R ⁵ is selected from the group consisting of substituted or unsubstituted H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R;

^R4 is selected from the following groups which are substituted or unsubstituted: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 - _C3 alkyl, ( _NH2 ) _-C3 - _C6 cycloalkyl, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl), _{SO2NH2 , NHSO2} ( _C1 - _C6 alkyl), _NHSO2 ( _C3 -C ₆ cycloalkyl); wherein the substitution refers to substitution by one or more R.

In another preferred embodiment, R ⁴ and R ⁵ are as defined above, U is CH, R ⁶ , R ⁷ and R ⁹ are H _v , and R ₈ is NH ₂ .

In another preferred embodiment, R ¹⁰ is

In another preferred embodiment, U' is selected from: O, or S;

U" is selected from: N, or C(CN);

R ^7' , R ^8' , R ^9' are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

R ^5' is selected from the group consisting of: H, D, halogen, CN, NH ₂ , OH, CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SONH ₂ , SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy.

In another preferred embodiment, R ¹⁰ is wherein _V1 , _V2 , _V3 , _V4 and _V5 are each independently selected from: N, or _CRv ; _Rv are the same or different and are each independently selected from: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl _, (NH2)-C1- _C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the heterocyclic group is optionally substituted with one or more oxo groups (═O).

In another preferred embodiment, V ₁ , V ₂ , V ₃ and V ₅ are each independently CR _v , wherein R _v is as defined above, and V ₄ is CR _v , and R _v is NH ₂ .

In another preferred embodiment, R ¹⁰ is wherein _Rv1 , _Rv2 , _Rv3 , _Rv4 and _Rv5 are each independently selected from the group consisting of H, _C1 - _C3 alkyl, C3- _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _{C3 - C6} cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl (e.g., _CF3 , _{CF2CF3 )} , halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C1- _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl _, ( _NH2 ) _-C1 - _C3 alkyl, (NH2) _{-C3 - C6} cycloalkyl, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), _{-C 6} cycloalkyl, SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl)H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C ₁ -C ₃ alkyl, halogenated C ₃ -C ₆ cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C ₁ -C ₃ alkyl, (HO)-C ₃ -C ₆ cycloalkyl, (NH ₂ )-C ₁ -C ₃ alkyl, (NH ₂ )-C ₃ -C ₆ cycloalkyl, halogen, CN, -C≡CH, OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), the heterocyclic group is optionally substituted by one or more oxo groups (═O).

In another preferred embodiment, R _v5 is selected from: halogenated C ₁ -C ₃ alkyl (such as CF ₃ , CF ₂ CF ₃ ).

In another preferred embodiment, R _v1 is selected from: H.

In another preferred embodiment, R _v1 is selected from: NH ₂ .

In another preferred embodiment, a compound of formula (IA) or formula (IB), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof is provided:

In the formula,

U is selected from: N, CH, CD, CF;

U' is selected from: O, or S;

U" is selected from: N, or C(CN);

X is selected from the group consisting of: N, CH, CD, CF, C(CN);

Y is selected from: a bond, O, NH, N(C ₁ -C ₃ alkyl);

Z is a substituted or unsubstituted C ₁ -C ₆ alkylene group; wherein the substitution refers to substitution by one or more R;

W is selected from: substituted or unsubstituted C ₃ -C ₁₄ cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R;

R ¹ is selected from: -L ₁ -QL ₂ -L ₃ ; wherein:

L ₁ is selected from: substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R;

Q is selected from: O, S, SO ₂ , NH, or N(C ₁ -C ₃ alkyl);

L ₂ is selected from: none, substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R;

L ₃ is selected from the following substituted or unsubstituted groups: -C ₁ -C ₆ alkyl, -C ₃ -C ₆ cycloalkyl, -C ₄ -C ₆ heterocyclyl, -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyl), -C ₁ -C ₆ alkylene (C ₁ -C ₆ alkoxy), -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyloxy), or -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyloxy); wherein the substitution refers to substitution by one or more R;

n is an integer of 1, 2, 3, 4, 5 or 6;

^R2 and ^R3 are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _C1 - _C6 alkyl, _C1 - _C6 deuterated alkyl, _C1 - _{C6 haloalkyl, C1-C6 alkoxy ;} wherein the substitution refers to substitution by one or more R;

R ⁴ is selected from the group consisting of substituted or unsubstituted halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; wherein the substitution refers to substitution by one or more R;

R ⁸ is selected from: OH, SONH ₂ , NHSO ₂ CH ₃ ;

R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ^7' , R ^8' , R ^9' are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

R ^5' is selected from the group consisting of: H, D, halogen, CN, NH ₂ , OH, CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SONH ₂ , SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy;

Each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyl)C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkoxy)C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyloxy)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl) vinyl, deuterated (C ₁ -C ₆ alkyl) vinyl, halogenated (C ₁ -C ₆ alkyl) vinyl, (C ₁ -C 6 alkyl) ethynyl, deuterated (C ₁ -C ₆ alkyl) ethynyl, halogenated (C ₁ -C ₆ alkyl) -C ₆ alkyl)ethynyl, (C ₃ -C ₁₄ cycloalkyl)ethynyl, (4-14 membered heterocyclyl)ethynyl, C ₁ -C ₁₈ alkoxy, deuterated C _{1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy} , C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

In another preferred embodiment, each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyl)C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkoxy)C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyloxy)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl)vinyl, deuterated (C ₁ -C ₆ alkyl)vinyl, halogenated (C ₁ -C ₆ alkyl)vinyl, (C ₁ -C ₆ alkyl)ethynyl, deuterated (C ₁ -C 6 alkyl)vinyl, The invention also includes but is not limited to: _a (C ₁ -C ₆ alkyl)ethynyl, a halo(C 1 -C 6 alkyl)ethynyl, a (C ₃ -C ₁₄ cycloalkyl)ethynyl, a (4-14 membered heterocyclyl)ethynyl, a C ₁ -C ₁₈ alkoxy, a deuterated C ₁ -C ₁₈ alkoxy, a haloC ₁ -C ₁₈ alkoxy, a C ₃ -C ₂₀ cycloalkyl, a 4-20 membered heterocyclyl, a C ₆ -C ₁₄ aryl, a 5-14 membered heteroaryl, a halogen, a nitro, a hydroxyl, an oxo, a cyano, an ester, an amine, an amide, a sulfone or an urea.

In another preferred embodiment, each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₆ alkyl, deuterated C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, (C ₃ -C ₁₀ cycloalkyl)C ₁ -C ₆ alkyl, (4-10 membered heterocyclyl)C ₁ -C ₆ alkyl, (C ₁ -C ₆ alkoxy)C ₁ -C ₆ alkyl, (C ₃ -C ₆ cycloalkyloxy)C ₁ -C ₆ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl)vinyl, deuterated (C ₁ -C ₆ alkyl)vinyl, halogenated (C ₁ -C ₆ alkyl)vinyl, (C ₁ -C ₆ alkyl)ethynyl, deuterated (C ₁ -C ₆ alkyl)ethynyl, halogenated (C ₁ -C ₆ alkyl) ethynyl, (C ₃ -C ₁₀ cycloalkyl) ethynyl, (4-10 membered heterocyclyl) ethynyl, C ₁ -C 6 alkoxy, deuterated C ₁ -C _{6 alkoxy} , halogenated C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

In another preferred embodiment, the compound of formula I has a structure shown in formula (I'A) or formula (I'B):

Preferably, it has the structure shown in formula (I"A) or formula (I"B)

Wherein, n, U, U', U", X, Y, Z, W, _L1 , _L2 , _L3 , Q, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , R7, ^R8 , ^R9 , R5 ^' , ^{R7 '} , R8 ^' , R9 ^' are as defined above.

In another preferred embodiment, the compound has a structure shown by formula (IIA) or formula (IIB):

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R 7 , R ⁸ , R ⁹ , R ^{5 ′} , R ^7′ , R ^8′ , R ^9′ , U, U′, U″, X, Z, W and n are as defined above.

In another preferred embodiment, the compound has a structure represented by formula (IIIA) or formula (IIIB):

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R 7 , R ⁸ , R ⁹ , R ^{5 ′} , R ^7′ , R ^8′ , R ^9′ , U, U′, U″, Z, W and n are as defined above.

In another preferred embodiment, R ³ is selected from: H, D, F, Cl, Br, CN, methyl, ethyl, propyl, isopropyl, deuterated methyl, CH ₂ F, CHF ₂ , CF ₃ , methoxy, ethoxy, propoxy, OCH ₂ F, OCHF ₂ , OCF ₃ .

In another preferred embodiment, the compound has a structure shown in formula (IVA) or formula (IVB):

wherein R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R 8 , R ⁹ , R ^{5 ′} , R ^7′ , R ^8′ , R ^9′ , U, U′, U″, Z, W and n are as defined above.

In another preferred embodiment, the compound has a structure shown in Formula (VA) or Formula (VB):

wherein R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ^7′ , R ^8′ , R ^9′ , U, U′, U″, Z, W and n are as defined above.

In another preferred embodiment, the compound has a structure represented by formula (VIA) or formula (VIB):

wherein R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ^7′ , R ^8′ , R ^9′ , U″, Z, W and n are as defined above.

In another preferred embodiment, the compound has a structure represented by formula (VIIA) or formula (VIIB):

wherein R ¹ , R ⁴ , R ⁵ , R ^7′ , R ^8′ , R ^9′ , Z, W and n are as defined above.

In another preferred embodiment, the compound has a structure represented by formula (VIIIA) or formula (VIIIB):

wherein R ¹ , R ⁴ , R ⁵ , R ^7′ , R ^9′ , Z, W and n are as defined above.

In another preferred embodiment, W is substituted or unsubstituted with the following groups: C ₃ -C ₆ monocyclic cycloalkyl, C ₇ -C ₁₀ bicyclic or C ₇ -C ₁₁ tricyclic cycloalkyl, 4-6 membered saturated or unsaturated monocyclic heterocyclyl, 7-10 membered bicyclic or 7-11 membered tricyclic heterocyclyl; preferably, W is selected from: substituted or unsubstituted 7-10 membered saturated or unsaturated bridged heterocyclyl, substituted or unsubstituted 7-10 membered saturated or unsaturated fused heterocyclyl.

In another preferred embodiment, W is selected from:

Wherein, n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R is defined as above, and R can be substituted on any one ring of a polycyclic ring (such as a bridged ring or a spiro ring).

In another preferred embodiment, when W is selected from:

When n' is 1 or 2, more preferably, n' is 1, and R is as defined above, and R can be substituted on any one ring of a polycyclic ring (such as a bridged ring or a spiro ring).

In another preferred embodiment, when W is selected from:

When n' can be 0, 1 or 2, R is as defined above, and R can be substituted on any one ring of a polycyclic ring (such as a bridged ring or a spiro ring).

In another preferred embodiment, when W is selected from:

When n' can be 0, 1 or 2, R is as defined above, and R can be substituted on any one of the polycyclic rings (such as bridged rings or spiro rings).

In another preferred embodiment, R is selected from the group consisting of deuterium, C ₁ -C ₆ alkyl, deuterated C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, (C ₃ -C ₆ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-6 membered heterocyclyl)C ₁ -C ₆ alkyl, (C ₁ -C ₆ alkoxy)C ₁ -C ₆ alkyl, (C ₃ -C ₆ cycloalkyloxy)C ₁ -C ₆ alkyl, (4-6 membered heterocyclyloxy)C ₁ -C ₆ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl)vinyl, deuterated (C ₁ -C ₆ alkyl)vinyl, halogenated (C ₁ -C ₆ alkyl)vinyl, (C ₁ -C ₆ alkyl)ethynyl, deuterated (C 1 -C ₆ alkyl)ethynyl, halogenated (C _{1 -C 6} alkyl)ethynyl, (C ₃ -C 6 alkyl) -C ₆ cycloalkyl)ethynyl, (4-6 membered heterocyclyl)ethynyl, C ₁ -C ₆ alkoxy, deuterated C 1 -C ₆ alkoxy, halogenated C ₁ -C ₆ alkoxy, 4-6 membered heterocyclyl C(O), C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl ₍ preferably 5-6 membered), halogen, nitro, hydroxy, oxo, cyano, COOC ₁ -C ₆ alkyl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONH ₂ , CONHC ₁ -C ₆ alkyl, CON(C ₁ -C ₆ alkyl) ₂ , SO2C ₁ -C ₆ alkyl, -NHCONH ₂ , -NHCO NHC ₁ -C ₆ alkyl, -NHCON(C ₁ -C ₆ alkyl) ₂ .

In another preferred embodiment, Z is a substituted or unsubstituted C ₁ -C ₃ alkylene group, preferably a methylene group, an ethylene group, or a propylene group.

In another preferred embodiment, Z is CD ₂ .

In another preferred embodiment, the compound has a structure represented by formula (IXA) or formula (IXB):

Wherein, n' is an integer of 0, 1, 2, 3, 4, 5, or 6;

R ⁵ , R, L ₁ , Q, L ₂ , L ₃ and n are as defined above.

In another preferred embodiment, R ⁴ is selected from the following substituted or unsubstituted groups: halogen, methyl, ethyl, propyl, vinyl, propenyl, allyl, butenyl, ethynyl, propynyl, butynyl.

In another preferred embodiment, Selected from:

In another preferred embodiment, the compound has a structure shown in formula (X):

_V1 , _V2 , _V3 , _V4 and _V5 are each independently selected from: N, or _CRv ; _Rv are the same or different and are each independently selected from: H, _C1 - _C3 alkyl, _C3 -C6 cycloalkyl, _4-6 membered heterocyclyl, _C1 - _C3 alkoxy, C3- _{C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C1-C3 alkyl , halogenated C3} - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 - _C3 alkyl, ( _NH2 ) _-C3 - _C6 cycloalkyl, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the heterocyclic group is optionally substituted by one or more oxo groups (═O);

^R2 and ^R3 are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _C1 - _C6 alkyl, _C1 - _C6 deuterated alkyl, _C1 - _{C6 haloalkyl, C1-C6 alkoxy ;} wherein the substitution refers to substitution by one or more R;

Ring C, R, X, Z, W and n are as defined above.

In another preferred embodiment, the compound has a structure shown in formula (XI):

_V1 , _V2 , _V3 , _V4 , and _V5 are each independently selected from: N, or _CRv ; _Rv are the same or different, and are each independently selected from: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6-membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6-membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6-membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 -C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the heterocyclic group is optionally substituted by one or Multiple oxo (=O) substitutions;

^R2 and ^R3 are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _C1 - _C6 alkyl, _C1 - _C6 deuterated alkyl, _C1 - _{C6 haloalkyl, C1-C6 alkoxy ;} wherein the substitution refers to substitution by one or more R;

wherein R, R ¹ , X, Z, W and n are as defined above.

In another preferred embodiment, the compound has a structure shown in formula (XII):

_V1 , _V2 , _V3 , _V4 , and _V5 are each independently selected from: N, or _CRv ; _Rv are the same or different, and are each independently selected from: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6-membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6-membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6-membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 -C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the heterocyclic group is optionally substituted by one or more oxo groups (═O);

R ³ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

wherein R, R ¹ , X, Z, W and n are as defined above.

In another preferred embodiment, the compound has a structure shown in formula (XIII):

_V1 , _V2 , _V3 , _V4 , and _V5 are each independently selected from: N, or _CRv ; _Rv are the same or different, and are each independently selected from: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6-membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6-membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6-membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 -C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the heterocyclic group is optionally substituted by one or more oxo groups (═O);

R ³ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

wherein R, R ¹ , Z, W and n are as defined above.

In another preferred embodiment, R _v is independently selected from: H, halogen, CN, -C≡CH, or NH ₂ .

In another preferred embodiment, the compound has a structure represented by formula (XIV-A) or formula (XIV-B), or formula (XV-A) or formula (XV-B) or formula (XV-C), or formula (XVI-A) or formula (XVI-B), or formula (XVII-A) or formula (XVII-B) or formula (XVII-C) or formula (XVII-D):

_V1 , _V2 , _V3 , _V5 are each independently selected from: _CRv ; _Rv are the same or different and are each independently selected from the following substituted or unsubstituted groups: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _{C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C1-C3 alkyl ,} halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl _, (NH2)-C1- _C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the substitution refers to substitution by one or more R;

^R4 is selected from the following groups which are substituted or unsubstituted: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 - _C3 alkyl, ( _NH2 ) _-C3 - _C6 cycloalkyl, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl), _{SO2NH2 , NHSO2} ( _C1 - _C6 alkyl), _NHSO2 ( _C3 -C ₆ cycloalkyl), wherein the substitution refers to substitution by one or more R;

R ⁵ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

R ² and R ³ are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; wherein R, R ¹ , Z, W and n are as defined above.

In another preferred embodiment, the compound has a structure represented by formula (XVIII-A) or formula (XVIII-B), or formula (XIX-A) or formula (XIX-B) or formula (XIX-C), or formula (XX-A) or formula (XX-B), or formula (XXI-A) or formula (XXI-B) or formula (XXI-C) or formula (XXI-D):

V ₂ , V ₃ , and V ₅ are each independently selected from: CR _v ; R _v are the same or different and are each independently selected from the following substituted or unsubstituted groups: H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C ₁ -C ₃ alkyl, halogenated C ₃ -C ₆ cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C ₁ -C ₃ alkyl, (HO)-C ₃ -C ₆ cycloalkyl, (NH ₂ )-C ₁ -C ₃ alkyl, (NH ₂ )-C ₃ -C ₆ cycloalkyl, halogen, CN, -C≡CH, OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the substitution refers to substitution by one or more R;

^R4 is selected from the following groups which are substituted or unsubstituted: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 - _C3 alkyl, ( _NH2 ) _-C3 - _C6 cycloalkyl, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl), _{SO2NH2 , NHSO2} ( _C1 - _C6 alkyl), _NHSO2 ( _C3 -C ₆ cycloalkyl), wherein the substitution refers to substitution by one or more R;

R ⁵ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

R ¹² are the same or different and are each independently selected from hydrogen or deuterium;

R ² and R ³ are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

o is 0, 1, or 2;

Wherein, R is defined as described above.

In another preferred embodiment, R ⁴ is selected from the following substituted or unsubstituted groups: halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; wherein the substitution refers to substitution by one or more Rs.

In another preferred embodiment, R ⁵ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R.

In another preferred embodiment, _L1 is selected from: substituted or unsubstituted methylene or substituted or unsubstituted ethylene; Q is selected from: O; _L2 is selected from: none, substituted or unsubstituted methylene; _L3 is selected from the following substituted or unsubstituted groups: _-C1 - _C6 alkyl, _-C3 - _C6 cycloalkyl, _-C4 - _{C6 heterocyclyl, -C1-C6 alkylene ( C3} - _C6 cycloalkyl), _-C1 - _C6 alkylene ( _C4 - _C6 heterocyclyl), _-C1 - _C6 alkylene ( _C1 - _C6 alkoxy), _-C1 - _C6 alkylene ( _C3 - _C6 cycloalkyloxy), or _-C1 - _C6 alkylene (C4- _C6 heterocyclyloxy); wherein the substitution refers to substitution by one or more groups selected from the following group: deuterium _{, C1} - _C6 alkyl, deuterated _C1 -C6 C ₁ -C ₆ alkyl, halogenated C 1 -C 6 alkyl, vinyl, ethynyl, C _{1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy ,} halogenated C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C _{6 -C 14} aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfone or urea.

In another preferred embodiment, -L ₁ -QL ₂ -L ₃ is selected from:

In another preferred embodiment, for Preferably

In another preferred embodiment, for Preferably

In another preferred embodiment, Selected from:

Or choose from:

wherein n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R, ^R1 and n are as defined above, and R, ^R1 may be substituted on any one of the polycyclic rings (such as bridged rings or spiro rings).

Or choose from:

wherein n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R is as defined above, and R may be substituted on any one of the polycyclic rings (eg, bridged ring or spiro ring).

In another preferred embodiment, Selected from:

In another preferred embodiment, W is selected from:

In another preferred embodiment, W is selected from:

In another preferred embodiment, W is selected from:

In another preferred embodiment, the prodrug of the compound has a structure as shown in the following formula (B):

C' is selected from:

PG is selected from:

or,

PG is -L ^PG1 -W ¹ -L ^PG2 -W ² -L ^PG3 -R ^PG1 or -L ^PG1 -W ⁴ -(W ⁵ -L ^PG6 -W ⁶ -R ^PG5 ) ₂ ; wherein,

L ^PG1 is zero, substituted or unsubstituted C ₁ -C ₆ alkylene (preferably zero or methylene); wherein the substitution refers to substitution by one or more R;

W ¹ is selected from the following group: none, -O-, -C(O)-, -C(O)O-, -OC(O)O-, -C(O)OCH(R ^PG2 )OC(O)-, -OC(O)N(R ^PG2 )-; wherein R ^PG2 is selected from the following group which is substituted or unsubstituted: C ₁ -C ₆ alkyl, C ₃ -C ₁₄ cycloalkyl, 4-14 membered saturated or unsaturated heterocyclic group, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl (preferably, C ₁ -C ₆ alkyl, phenyl); the substitution refers to substitution by one or more R;

L ^PG2 is absent or selected from the following substituted or unsubstituted divalent groups: C ₁ -C ₆ alkylene, C ₃ -C ₁₄ cycloalkylene, 4-14-membered saturated or unsaturated heterocyclylene, C ₆ -C ₁₀ arylene, 5-10-membered heteroarylene, C ₁ -C ₆ alkylene-C ₃ -C ₁₄ cycloalkylene, 4-14-membered saturated or unsaturated heterocyclylene, C ₆ -C ₁₀ arylene, 5-10-membered heteroarylene (preferably, absent, C ₁ -C ₆ alkylene, -C ₁ -C ₆ alkylene-phenylene-, -C ₁ -C ₆ alkylene-pyridylene-); wherein the substitution refers to substitution by one or more R;

W ² is selected from: none, -N(R ^PG3 )C(O)-, -OC(O)N(R ^PG3 )-, -OC(O)-; wherein R ^PG3 is selected from the following substituted or unsubstituted groups: H, C ₁ -C ₆ alkyl; the substitution refers to substitution by one or more R or;

L ^PG3 is a C ₁ -C ₆ alkylene group which is free, substituted or unsubstituted; wherein the substitution refers to substitution by one or more R;

R ^PG1 is selected from the following substituted or unsubstituted groups: C ₁ -C ₂₀ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₄ cycloalkyl, 4-14 membered saturated or unsaturated heterocyclyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl; wherein the substitution refers to substitution by one or more R or -L ^PG4 -W ³ -L ^PG5 -W ² -R ^PG4 ;

L ^PG4 and L ^PG5 are each independently a C ₁ -C ₆ alkylene group without or with substitution or without substitution; wherein the substitution refers to substitution with one or more R;

W ³ is selected from the group consisting of none, -O-, -C(O)-, -C(O)O-, -OC(O)O-;

R ^PG4 is selected from the following substituted or unsubstituted groups: -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -CH(NH ₂ )COOH, -CH(NH ₂ )COO-C1-C6 alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₄ cycloalkyl, 4-14 membered saturated or unsaturated heterocyclic group, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl; wherein the substitution refers to substitution by one or more R;

W ⁴ is -P(O)=;

W ⁵ are each independently selected from the group consisting of none, O, NH;

L ^PG6 is a C ₁ -C ₆ alkylene group which is free, substituted or unsubstituted; wherein the substitution refers to substitution by one or more R;

W ⁶ is each independently selected from the group consisting of none, -O-, -C(O)-, -C(O)O-, -OC(O)O-;

R ^PG5 is selected from the following substituted or unsubstituted groups: H, C ₁ -C ₆ alkyl, C ₃ -C ₁₄ cycloalkyl, 4-14 membered saturated or unsaturated heterocyclic group, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl; wherein the substitution refers to substitution by one or more R or -L ^PG4 -W ³ -L ^PG5 -W ² -R ^PG4 ;

Y, Z, W, Ring A, R ¹ , R ¹⁰ , R ¹¹ , m and n are as defined above.

In another preferred embodiment, the prodrug of the compound is selected from the following group:

In another preferred embodiment,

n＝0;

Z is a substituted or unsubstituted C ₁ -C ₆ alkylene group (preferably, a methylene group); wherein the substitution refers to substitution by one or more R (preferably, in Z, R is D);

W is (Preferably, in W, n' is 0, 1 or 2, and R is D).

In another preferred embodiment, m, ring A, n, U, X, Y, Z, W, _L1 , _L2 , _L3 , Q, ^R2 , ^R3 , R4, ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 and ^R11 have the groups corresponding to the specific compounds in the embodiments ^.

In another preferred embodiment, V ₁ , V ₂ , V ₃ , V ₄ , V ₅ , ring C, and PG have groups corresponding to the specific compounds in the examples.

In another preferred embodiment, the compound is selected from the following group:

Or choose from:

Or choose from:

Or choose from:

Or choose from:

Or choose from:

Or choose from:

Or choose from:

Or choose from:

Or choose from:

In another preferred embodiment, the compound is preferably the compound prepared in the examples.

In a second aspect, the present invention provides a method for preparing a compound of formula (A0), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, which comprises the steps (taking formula IA as an example):

(i) reacting a compound of formula V-1 with a compound of formula V-2 in an inert solvent in the presence of a base, with or without a Pd catalyst, with or without a condensing agent to obtain a compound of formula V-3;

(ii) reacting a compound of formula V-3 with a compound of formula V-4 in an inert solvent in the presence of a base with or without a Pd catalyst to obtain a compound of formula V-5;

(iii) reacting the compound of formula V-5 with the compound of formula V-6 in an inert solvent in the presence of a base and in the presence of a Pd catalyst to obtain a compound of formula V-7;

(iv) removing the protective group PG1 from the compound of formula V-7 under the action of an acid (such as TFA, HCl, etc.) or under Pd-catalyzed hydrogenation conditions to obtain a compound of formula (IA);

In the formula,

X ₁ , X ₂ and X ₃ are each independently selected from: OH, halogen, OTf, OTs or OMs;

PG1 is selected from: Boc, Cbz, or Bn;

LG1 is selected from: -B(OH) ₂ , -B(KBF ₃ ), -Sn( ⁿ Bu) ₃ ,

^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , U, X, Y, Z, W and n are as defined above.

The third aspect of the present invention provides a pharmaceutical composition comprising one or more compounds described in the first aspect, their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the following group: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or the above drugs, biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzu mab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-14 8. NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipali sib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tuc idinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, tacedinaline, etc.), CDK inhibitors (such as palbociclib, ribociclib, abemaciclib, milciclib, trilaciclib, lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof.

In a fourth aspect, the present invention provides a use of the compound described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition described in the third aspect, for preparing a drug for preventing and/or treating a disease related to the activity or expression of KRAS ^G12D .

In another preferred embodiment, the disease is a tumor or a disorder.

In another preferred embodiment, the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.

In a fourth aspect, the present invention provides a non-diagnostic, non-therapeutic method for inhibiting KRAS ^G12D , comprising the steps of administering to a subject in need thereof an effective amount of the compound as described in the first aspect, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering the pharmaceutical composition as described above.

In another preferred embodiment, the subject is a mammal, preferably a human.

In a fifth aspect, the present invention provides a method for inhibiting KRAS ^G12D activity in vitro, comprising the steps of contacting the compound as described in the first aspect, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described above with proteins or cells, thereby inhibiting the activity of KRAS ^G12D .

In another preferred embodiment, the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.

In another preferred embodiment, the cells are from rodents (such as mice and rats) or primates (such as humans).

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

Detailed ways

After long-term and in-depth research, the inventor unexpectedly prepared a new type of compound with selective KRAS ^G12D inhibition and/or better pharmacodynamic properties. On this basis, the inventor completed the present invention.

the term

In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

The term "alkyl" refers to a straight or branched alkane group containing 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably 1-10 carbon atoms (C1-C10), and more preferably 1-6 carbon atoms (C1-C6). Typical "alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, The term "alkyl" refers to alkyl radicals which are substituted with 1 to 4 substituents, and the alkyl radicals ... Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl ₃ ), cyano, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, _alkenyl , _cycloalkenyl , alkynyl, heterocyclic, aromatic _, ORa, _SRa , S(=O) _Re , S(=O) _2Re , P(=O) _2Re , S(=O) _2ORe , P(=O) _2ORe , NRbRc _{, NRbS(=O)2Re, NRbP(=O)2Re , S ( = O ) 2NRbRc , P ( =} O ₎ 2NRbRc _{, C} (=O) _ORd , C(=O) _Ra , C(=O) _{NRbRc ,} OC(=O _{) Ra} , OC(＝O)NR _b R _c , NR _b C(＝O)OR _e , NR _d C(＝O)NR _b R _c , NR _d S(＝O) ₂ NR _b R _c , NR _d P(＝O) ₂ NR _b R _c , NR _b C(＝O)R _a , or NR _b P(＝O) ₂ R _e , wherein _Ra appearing herein may independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, a 5-14 membered heterocycle or a C6-C14 aromatic ring, R _b , R _c and R _d may independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, a 5-14 membered heterocycle or a C6-C14 aromatic ring, or R _b and R _c together with the N atom may form a heterocycle; R _e can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring can be optionally substituted.

The term "alkylene" refers to a group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, such as methylene, ethylene, Propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as ), heptylene (such as ), Etc. In addition, the term also includes a methylene group of an alkylene group (such as C1-C18 alkylene group) replaced by a cycloalkylene group (such as C3-C20 cycloalkylene group), for example, "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene".

The term "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning and refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, such as wait.

In the present invention, the term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. Alkenyl is preferably C2-C6 alkenyl, more preferably C2-C4 alkenyl. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. In the present invention, alkenyl includes substituted alkenyl.

The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. Alkynyl is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl. Alkynyl includes, but is not limited to, ethynyl, propynyl or similar groups. In the present invention, alkynyl also includes substituted alkynyl, and the substituent may be halo, hydroxyl, cyano, nitro, etc.

In the present invention, the term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms. The term " _C3 - _C20 " refers to a cycloalkyl containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The cycloalkyl is preferably a _C3 - _C14 cycloalkyl, more preferably a _C3 - _C10 cycloalkyl, more preferably a _C3 - _C6 monocyclic cycloalkyl, a _C7 - _C10 bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" refers to a cycloalkyl in which one or more positions are substituted, especially 1-4 substituents, which can be substituted at any position. In the present invention, "cycloalkyl" includes substituted cycloalkyl, typical substitutions include but are not limited to one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl containing Cl ₃ ), cyano, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, _cycloalkenyl , alkynyl _{, heterocycle ,} aromatic ring, ORa, _{SRa ,} S(=O) _{Re ,} S(=O) _2Re , P(=O) _2Re , S(=O) _2ORe , P(=O _{) 2ORe} , _{NRbRc , NRbS (} =O) _{2Re , NRbP ( =} O) _{2Re ,} S(=O) _2NRbRc , P(=O) _2NRbRc , C(=O) _ORd , C(=O) _Ra , C(=O) _NRbRc , OC(＝O)R _a , OC(＝O)NR _b R _c , NR _b C(＝O)OR _e , NR _d C(＝O)NR _b R _c , NR _d S(＝O) ₂ NR _b R _c , NR _d P(＝O) ₂ NR _b R _c , NR _b C(＝O)R _a , or NR _b P(＝O) _{2 Re} , wherein _Ra appearing herein may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, a heterocyclic ring or an aromatic ring, R _b , R _c and R _d may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, a heterocyclic ring or an aromatic ring, or R _b and R _c together with the N atom may form a heterocyclic ring; _Re may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Heterocycle or aromatic ring. The above typical substituents can be optionally substituted. Typical substitutions also include spirocycle, bridged ring or condensed ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocycle (excluding heteroaromatic ring), bridged ring alkyl, bridged ring alkenyl, bridged ring heterocycle (excluding heteroaromatic ring), condensed ring alkyl, condensed ring alkenyl, condensed ring heterocyclic radical or condensed ring aromatic ring radical, and the above cycloalkyl, cycloalkenyl, heterocyclic radical and heterocyclic aromatic radical can be optionally substituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc.

The term "C3-C20 cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: wait.

In the present invention, the term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic or 8-16 membered tricyclic or polycyclic system), wherein at least one heteroatom is present in the ring having at least one carbon atom. The term "4-20 membered heterocyclyl" refers to a heterocyclyl containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms. "Heterocyclyl" has the same meaning as "saturated or unsaturated heterocyclyl". "Heterocyclyl" is preferably a 4-14 membered heterocyclyl (including but not limited to a 4-6 membered monocyclic, 7-10 membered bicyclic or 8-14 membered tricyclic or polycyclic system), more preferably a 4-12 membered heterocyclyl, more preferably a 4-10 membered heterocyclyl, such as a 4-6 membered monocyclic heterocyclyl, a 7-10 membered bicyclic or tricyclic heterocyclyl, more preferably a 4-8 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl. Each heterocyclic ring containing heteroatoms may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen atoms or sulfur atoms may be oxidized and the nitrogen atoms may be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of the ring or ring system molecule, preferably to N or C atoms on the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl and tetrahydro-1,1-dioxythiophene, and the like. The polycyclic heterocyclic group includes spirocyclic, condensed and bridged heterocyclic groups; wherein the spirocyclic, condensed and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, thiol, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

The term "C4-C20 heterocyclylene" refers to a group formed by removing two hydrogen atoms from a heterocyclyl group, such as: wait.

In the present invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group having 1-5 rings, especially monocyclic and bicyclic groups. Among them, "C ₆ -C ₁₄ aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms. Aryl includes phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl are substituted, especially 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl containing Cl ₃ ), cyano, nitro, Oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, _ORa , _SRa , S(=O) _Re , S(=O) _2Re , _P (=O) _{2Re ,} S(=O) _2ORe , _{P(=O)2ORe, NRbRc , NRbS ( = O )2Re, NRbP(=O)2Re , S ( = O ) 2NRbRc ,} P(=O) _{2NRbRc , C} (=O) _ORd , C(=O _{) Ra} , C(=O) _NRbRc , OC(=O) _Ra , OC(=O) _NRbRc , _{NRbC (} =O) _ORe , _NRdC (=O) _{NRbRc , NRdS} (=O) _2NRb R _c , NR _d P (= O) ₂ NR _b R _c , NR _b C (= O) _Ra , or NR _b P (= O) _{2 Re} , wherein _Ra appearing herein can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R _b and R _c together with the N atom can form a heterocyclic ring; _Re can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring. The above typical substituents can be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, and the above cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic group can be optionally substituted.

The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1 to 4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Among them, "5-14 membered heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms. The heteroaryl is preferably 5 to 10 rings, more preferably 5 or 6, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

In the present invention, the term "alkoxy" refers to a straight chain or branched alkoxy group, including alkyl-O-, alkyl-O-alkyl, wherein "C ₁ -C ₁₈ alkoxy" refers to a straight chain or branched alkoxy group having 1 to 18 carbon atoms, including C ₁ -C ₁₈ alkyl-O-, -C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is C ₁ -C ₈ alkoxy, more preferably C1 -C ₆ alkoxy.

In the present invention, the term "cycloalkyloxy" refers to cycloalkyl-O-, wherein "C ₃ -C ₂₀ cycloalkyloxy" refers to C ₃ -C ₂₀ cycloalkyl-O-, wherein C ₃ -C ₂₀ cycloalkyl is as defined above.

In the present invention, the term "heterocyclyloxy" refers to heterocyclyl-O-, wherein "4-20 membered heterocyclyloxy" refers to 4-20 membered heterocyclyl-O-, wherein the 4-20 membered heterocyclyl is as defined above.

In the present invention, the term "C ₁ -C ₁₈ alkyleneoxy group" refers to a group obtained by removing a hydrogen atom from a "C ₁ -C ₁₈ alkoxy group".

In the present invention, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, and iodine.

In the present invention, the term "halogenated" means substituted with halogen.

In the present invention, the term "deuterated" means substituted with deuterium.

In the present invention, the term "hydroxyl" refers to a group having the structure OH.

In the present invention, the term "nitro" refers to a group having the structure NO ₂ .

In the present invention, the term "cyano group" refers to a group having the structure CN.

In the present invention, the term "ester group" refers to a group with the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle. The ester group is preferably -COO C ₁ -C ₆ alkyl.

The term "amino" refers to a group having the structure -NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or cycloalkyl. Alkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R' may be the same or different in the dialkylamine fragment. The amine group is preferably _NH2 , NH _C1 - _C6 alkyl, N( _C1 - _C6 alkyl) ₂ .

The term "amido" refers to a group with the structure -CONRR' or -NRCOR', wherein R and R' can each independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. The amide group is preferably _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl).

The term "sulfonamido" refers to a group with the structure _-S2ONRR ' or _-NRSO2R ', wherein R and R' can each independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, _{cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. The sulfonamido is preferably SO2NH2 , NHSO2} ( _C1 - _C6 alkyl), _NHSO2 ( _C3 - _C6 cycloalkyl).

The term "sulfone" refers to a group having the structure _-SO2R , wherein R may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.

The term "urea group" refers to a group having the structure -NRCONR'R", wherein R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine fragment.

The term "alkylaminoalkyl" refers to a group having the structure -RNHR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different.

The term "dialkylaminoalkyl" refers to a group having the structure -RNHR'R", wherein R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.

The term "heterocyclylalkyl" refers to a group with the structure -RR', wherein R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; and R' represents a heterocycle or a substituted heterocycle.

In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 urea group, etc.

Unless otherwise stated, any heteroatom with insufficient valence is assumed to have sufficient hydrogen atoms to complete its valence.

When a substituent is a non-terminal substituent, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.

In the present invention, a plurality refers to 2, 3, 4, or 5.

Active ingredients

As used herein, "compounds of the present invention" refers to compounds of formula I, and also includes stereoisomers of compounds of formula I or an optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate.

The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. The term "salt" used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included in the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps in the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount of acid or base, such as an equivalent amount, and is salted out in a medium, or freeze-dried in an aqueous solution.

The compounds of the present invention contain basic fragments, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide. [0013] The invention also includes but is not limited to the following: esters, isothioates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonates, dodecanoates, and the like.

Certain compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromides), etc.

Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention. The term "prodrug" herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All these tautomers are part of the present invention.

All stereoisomers of the compounds (e.g., those that may exist due to various substitutions, asymmetric carbon atoms), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer with a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the International Union of Pure and Applied Chemistry (IUPAC) in 1974. Suggested definition. Racemic forms can be resolved by physical methods such as fractional crystallization, or by crystallization of diastereoisomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

The compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.

All configurational isomers of the compounds of the present invention are within the scope of the invention, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are described in detail below. For purposes of the present invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.

According to the present invention, the ratio of isomers contained in the mixture of isomers can be various. For example, in the mixture of only two isomers, there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by those of ordinary skill in the art, and ratios for more complex mixtures of isomers are also within the scope of the present invention.

The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number from the original atoms. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as ^2H , ^3H , ^13C , ^11C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36Cl , respectively. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioactive isotopes of ^3H and ^14C , are also included, which are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. ^3H and carbon-14, i.e. ^14C , are relatively easy to prepare and detect. is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. ² H, may be preferred in some cases due to their good metabolic stability, which has advantages in certain therapies, such as increasing half-life in vivo or reducing dosage. Isotope-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

If one is to design the synthesis of a specific enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis, or by chiral The diastereomeric mixture is separated by derivatization with an auxiliary agent, and the chiral auxiliary agent is removed to obtain the pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer is obtained.

As described herein, the compounds of the present invention can be replaced with any number of substituents or functional groups to expand its scope. Generally, the term "substituted" appears before or after the term "optional", and the general formula including substituents in the formulation of the present invention refers to the use of a specified structural substituent to replace the hydrogen free radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents can be the same or different at each position. The term "substituted" used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence. In addition, the present invention is not intended to limit the allowed substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases. As used herein, the term "stable" refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application in vivo, are also included in the claims of the present application. In the present invention, the term "prodrug" refers to a compound that is inactive or less active in vitro after the drug is modified by chemical structure to introduce an easy leaving group, but releases active drugs in vivo through conversion with the participation of enzymes (such as hydrolases, oxidases, etc.) or non-enzymes (such as pH, light, radiation, etc.) to exert its pharmacological effect. The prodrugs include (but are not limited to): carboxylates, phosphates, carbamates, carbonates, etc. The structure of the easy leaving group is (but is not limited to):

Preparation

The preparation method of the compound of formula (A0) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by a technician in the field to which the present invention belongs.

Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

Preferably, the compound of the present invention is prepared by the following method (taking Formula IA as an example):

(i) reacting a compound of formula V-1 with a compound of formula V-2 in an inert solvent in the presence of a base, with or without a Pd catalyst, with or without a condensing agent to obtain a compound of formula V-3;

(ii) reacting a compound of formula V-3 with a compound of formula V-4 in an inert solvent in the presence of a base with or without a Pd catalyst to obtain a compound of formula V-5;

(iii) reacting the compound of formula V-5 with the compound of formula V-6 in an inert solvent in the presence of a base and in the presence of a Pd catalyst to obtain a compound of formula V-7;

(iv) removing the protective group PG1 from the compound of formula V-7 under the action of an acid (such as TFA, HCl, etc.) or under Pd-catalyzed hydrogenation conditions to obtain a compound of formula (IA);

In the formula,

X ₁ , X ₂ and X ₃ are each independently selected from: OH, halogen, OTf, OTs or OMs;

PG1 is selected from: Boc, Cbz, or Bn;

LG1 is selected from: -B(OH) ₂ , -B(KBF ₃ ), -Sn( ⁿ Bu) ₃ ,

^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , U, X, Y, Z, W and n are as defined above.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

The compound of general formula (A0) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug can remain unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula (A0) is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I. Drug combination also includes taking the compound of formula (A0) and one or more other known drugs in overlapping time periods. When the compound of formula (A0) is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drugs may be lower than that when they are used alone.

The drugs or active ingredients that can be used in combination with the compound of general formula (A0) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, L ZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, o binutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX- 148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, occatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Om ipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof. The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.

The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to) In): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.

The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the general formula (A0) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

The present invention also provides a treatment method, which comprises the steps of administering the compound of general formula (A0) of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition of the present invention to a subject in need of treatment, for selectively inhibiting KRAS ^G12D .

Compared with the prior art, the present invention has the following main advantages:

(1) The compound has a good selective inhibitory effect on KRAS ^G12D ;

(2) The compound has better pharmacodynamics, pharmacokinetic properties and lower toxic side effects.

The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally carried out according to conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

NMR was measured using a Bruker AVANCE-400 NMR spectrometer. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated acetone (CD ₃ COCD ₃ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol (CD ₃ OD). Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).

Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer. HPLC was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm column).

The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

Example

Preparation of Intermediate 1-1 (3-(Methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

Step 1: Preparation of 1-benzyl 2-methyl 2-(but-3-en-1-yl)pyrroline-1,2-dicarboxylate

Under nitrogen protection, a solution of 1-benzyl 2-methyl (S)-pyrroline-1,2-dicarboxylate (50.0 g, 190 mmol, 1.00 eq) in THF (100 mL) was added dropwise to LiHMDS (1.00 M, 285 mL, 1.50 eq) at -70°C. The resulting reaction solution was reacted at -70°C for 2 h, followed by the addition of 4-bromobut-1-ene (51.2 g, 380 mmol, 38.6 mL, 2.00 eq). The resulting reaction solution was warmed to 25°C and reacted for 16 h, followed by quenching with saturated NH ₄ Cl (200 mL) aqueous solution, and then extracted with EtOAc (100 mL*3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (38.0 g, 120 mmol, 63.1% yield).

¹ H NMR(400MHz, CDCl ₃ )δ7.33(m,5H)5.77(m,1H)5.07(m,4H)3.72(m,3H)3.48(m,2H)2.01(m,8H)

Step 2: Preparation of 1-benzyl 2-methyl 2-(2-(epoxypropane-2-yl)ethyl)pyrroline-1,2-dicarboxylate

At 0°C, m-CPBA (60.0 g, 295 mmol, 85.0% purity, 2.50 eq) was added in batches to a solution of 1-benzyl 2-methyl 2-(but-3-en-1-yl) pyrroline-1,2-dicarboxylate (37.5 g, 118 mmol, 1.00 eq) in DCM (650 mL). The resulting reaction solution was reacted at 25°C for 16 h, and then washed with saturated Na ₂ SO ₃ (300 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (29.0 g, 87.0 mmol, 73.6% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.33 (br d, J = 7.88Hz, 5H) 5.11 (m, 2H) 3.70 (m, 3H) 3.48 (m, 2H) 2.73 (m, 2H) 2.36 (m ,2H)1.98(m,5H)1.50(m,2H)

Step 3: Preparation of 3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-formic acid methyl ester

Pd/C (6.00 g, 10.0% wt) was added to a solution of 1-benzyl 2-methyl 2-(2-(epoxypropane-2-yl)ethyl)pyrroline-1,2-dicarboxylate (28.0 g, 84.0 mmol, 1.00 eq) in MeOH (600 mL). The reactants were reacted at 25 °C for 16 h under a hydrogen atmosphere and then filtered. The filtrate was concentrated under reduced pressure to obtain the target product (16.8 g). It was used directly in the next step without purification.

3-(Hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester was subjected to chiral separation to give cis-3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester and trans-3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester.

Step 4: Preparation of 3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-formic acid methyl ester

Under nitrogen protection, NaH (602 mg, 15.1 mmol, 60.0% wt, 3.00 eq) was added to a solution of 3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester (1.00 g, 5.02 mmol, 1.00 eq) in THF (20 mL) at 0°C. The reaction solution was reacted at 25°C for 0.5 h, and then MeI (1.42 g, 10.0 mmol, 625 uL, 2.00 eq) was added. The resulting reaction solution was reacted at 25°C for 3 h, and then quenched with H ₂ O (10 mL) at 0°C and extracted with EtOAc (30 mL*2). The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (1.0 g, 1.88 mmol, 37.5% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ3.66-3.72(m,3H)3.30-3.33(m,3H)2.22-2.43(m,1H)1.83-2.12(m,6H)1.56-1.72(m,1H ).

Cis-3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester and trans-3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester were used as starting materials to obtain cis-3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester and trans-3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester, respectively.

Step 5: Preparation of (3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-yl)methanol

Under nitrogen protection, LiAlH ₄ (356 mg, 9.38 mmol, 2.00 eq) was added to a solution of 3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester (1.00 g, 4.69 mmol, 1.00 eq) in THF (10 mL) at 0°C. The reaction solution was reacted at 25°C for 1 h, and then H ₂ O (10 mL), 15% NaOH (10 mL) and H ₂ O (30 mL) were added in sequence at 0°C to quench, and then extracted with EtOAc (50 mL*2). The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (1.1 g).

LC-MS: m/z 186(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ4.39 (dd, J＝10.54, 9.03Hz, 1H) 4.26 (br d, J＝6.53Hz, 1H) 3.97-4.06 (m, 1H) 3.80-3.96 (m, 2H)3.68-3.76(m,2H)3.50(s,3H)2.04-2.40(m,6H)1.78-1.93(m,2H)

The following compounds were synthesized using the same synthetic method as intermediate 1-1 with different starting materials:

Intermediate 1-1A and Intermediate 1-1B cis-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol and trans-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

Intermediate 1-1A

LC-MS: m/z 186 (M+H) ⁺ .

Intermediate 1-1B

LC-MS: m/z 186 (M+H) ⁺ .

Intermediate 1-2 (3-((ethoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

LC-MS: m/z 200 (M+H) ⁺ .

Intermediate 1-3 (3-((isopropoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

LC-MS: m/z 214 (M+H) ⁺ .

Intermediate 1-4 (3-((cyclopropylmethoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

LC-MS: m/z 226 (M+H) ⁺ .

Intermediate 1-5 (3-(cyclopropyloxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

LC-MS: m/z 212 (M+H) ⁺ .

Intermediate 1-6 ((2R)-2-fluoro-5-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

LC-MS: m/z 204 (M+H) ⁺ .

Intermediate 1-7 ((2R)-2-fluoro-5-(cyclopropyloxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

LC-MS: m/z 230 (M+H) ⁺ .

Preparation of Intermediate 1-8 (Dihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Step 1: Preparation of (1-((Benzyloxy)methyl)cyclopropyl)methanol

At 0°C, NaH (9.79 g, 245 mmol, 60.0% wt, 1.00 eq) was added to a solution of cyclopropane-1,1-dimethanol (25.0 g, 245 mmol, 1.00 eq) in THF (500 mL). The mixture was stirred at 25°C for 30 min, followed by the addition of BnBr (41.9 g, 245 mmol, 29.1 mL, 1.00 eq). The resulting reaction solution was reacted at 25°C for 18 h, then quenched with saturated NH ₄ Cl aqueous solution (50 mL), and then extracted with EtOAc (50 mL*3). The combined organic phase was washed with saturated brine (20 mL*3), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (26.00 g, 108 mmol, 44.1% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.35(s,5H),4.56(s,2H),3.58(s,2H),3.47(s,2H),0.64-0.44(m,4H)

Step 2: Preparation of (((1-(bromomethyl)cyclopropyl)methoxy)methyl)benzene

PPh ₃ (39.0 g, 149 mmol, 1.10 eq) and NBS (26.5 g, 148 mmol, 1.10 eq) were added to a solution of (1-((benzyloxy)methyl)cyclopropyl)methanol (26.0 g, 135 mmol, 1.00 eq) in DCM (300 mL) at 0°C. The reaction solution was reacted at 25°C for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (24.0 g, 84.7 mmol, 62.6% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.27(s,5H),4.47(s,2H),3.49(s,2H),3.38(s,2H),0.54-0.27(m,4H)

Step 3: Preparation of 1-(tert-butyl)2-methyl 2-((1-((benzyloxy)methyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate

At -70°C, LiHMDS (1.00M, 78.5mL, 1.20eq) was added dropwise to 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylate (15.0g, 65.4mmol, 1.00eq) in THF (150mL). The resulting reaction solution was reacted at the current temperature for 2h, followed by the addition of (((1-(bromomethyl)cyclopropyl)methoxy)methyl)benzene (21.7g, 85.1mmol, 1.30eq) and HMPA (44.5g, 249mmol, 43.7mL, 3.80eq). The resulting reaction solution was reacted at 25°C for 16h, then quenched with water (100mL) and extracted with EtOAc (100mL*2). The combined organic phase was washed with saturated brine (50mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (12.0 g, 26.8 mmol, 40.9% yield).

¹ H NMR (400MHz, CD ₃ OD) δ7.46-7.21(m,5H),4.68-4.35(m,2H),3.79-3.56(m,4H),3.45-3.26(m,3H),2.59- 2.38(m,2H),2.09-1.82(m,4H),1.47-1.37(m,9H),0.54-0.42(m,4H)

Step 4: Preparation of 1-(tert-butyl)2-methyl 2-((1-(hydroxymethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate

Under nitrogen protection, Pd/C (10% wt, 1.50 g) was added to a solution of 1-(tert-butyl)2-methyl 2-((1-((benzyloxy)methyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate (11.0 g, 27.3 mmol, 1.00 eq) in MeOH (100 mL). The resulting reaction solution was reacted at 25°C for 16 h under a hydrogen atmosphere (15 psi). The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (10.0 g, 25.5 mmol, 93.6% yield).

¹ H NMR (400MHz, CD ₃ OD) δ3.73-3.60(m,4H),3.37(s,5H),2.08-1.90(m,4H),1.48-1.42(m,9H),0.59-0.36( m,4H)

Step 5: Preparation of 1-(tert-butyl)2-methyl 2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate

CBr ₄ (7.94 g, 23.9 mmol, 1.50 eq) and PPh 3 (6.11 g, 23.3 mmol, 1.46 eq) were added to a solution of 1-(tert-butyl) 2-methyl 2-((1-(hydroxymethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate (5.00 g, 16.0 mmol, 1.00 eq) in DCM (50 mL). The resulting mixture was reacted at 25° C. _for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (0.50 g, 1.20 mmol, 7.50% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ3.80-3.70 (m, 5H), 3.52-3.42 (m, 1H), 3.19-3.02 (m, 1H), 2.82 (dd, J＝7.0, 15.6Hz, 1H ),2.45-2.20(m,1H),2.13-1.89(m,4H),1.49-1.44(m,9H),1.00-0.51(m,4H).

Step 6: Preparation of methyl 2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-2-carboxylate

TFA (64.7 g, 567.3 mmol, 42.0 mL, 152 eq) was added to a solution of 1-(tert-butyl)2-methyl 2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate (1.40 g, 3.72 mmol, 1.00 eq) in DCM (14 mL). The reaction was allowed to react at 0 °C for 2 h and then concentrated under reduced pressure to give the desired product (0.60 g, 1.74 mmol, 46.7% yield). The product was used directly in the next step without purification.

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

K ₂ CO ₃ (1.20 g, 8.69 mmol, 4.00 eq) was added to a solution of methyl 2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-2-carboxylate (0.60 g, 2.17 mmol, 1.00 eq) in DMF (10 mL). The resulting reaction solution was reacted at 25° C. for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (0.60 g, 1.84 mmol, 84.9% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ3.75 (s, 3H), 3.31-3.18 (m, 1H), 3.01 (d, J = 10.0Hz, 1H), 2.81(s,1H),2.71(d,J=10.0Hz,1H),2.28-2.22(m,2H),1.94-1.84(m,4H),0.64-0.45(m,4H).

Step 8: Preparation of (dihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Under nitrogen protection, LAH (174.9 mg, 4.61 mmol, 1.50 eq) was added to a solution of dihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylic acid methyl ester (0.60 g, 3.07 mmol, 1.00 eq) in THF (1 mL). The resulting reaction solution was reacted at 0°C for 4 h, then water (0.3 mL) was added to quench, and then MgSO ₄ (2 g) was added. The resulting reaction solution was stirred at room temperature for 30 min and then filtered. The filtrate was concentrated under reduced pressure to obtain the target product (0.200 g, 1.08 mmol, 35.0% yield).

LC-MS: m/z 168(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ3.50-3.43 (m, 1H), 3.39-3.31 (m, 1H), 3.10-3.03 (m, 1H), 2.90 (d, J = 10.3Hz, 1H), 2.80(td,J＝6.3,10.5Hz,1H), 2.69(d,J＝10.5Hz,1H), 1.98-1.82(m,6H), 0.62-0.46(m,4H).

The following compounds were synthesized using the same synthetic method as intermediate 1-8 with different starting materials:

Intermediate 1-9 ((6'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

LC-MS: m/z 186(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.00(s,1H),5.44-4.99(m,1H),3.60-3.25(m,3H),3.23-2.95(m,3H),2.88-2.51(m ,1H),2.36-2.03(m,4H),1.96-1.57(m,1H),1.43-1.25(m,1H),0.67-0.38(m,4H)

Intermediate 1-10 ((6'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

LC-MS: m/z 186(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.15-5.43 (m, 1H) 3.41-3.54 (m, 3H) 3.00-3.14 (m, 3H) 2.56 (d, J = 11.22Hz, 1H) 2.22-2.36 ( m,1H)2.00-2.17(m,1H)1.94(d,J＝12.98Hz,1H)1.64(d,J＝12.76Hz,1H)0.44-0.69(m,4H).

Preparation of intermediate 1-11A ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and 1-11B and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Route 1

Step 1: Preparation of ethyl 2,2-difluoro-5'-oxadihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylate (Intermediate 1-11-I)

TBAB (222 mg, 688 umol, 0.03 eq) and [bromo(difluoro)methyl]-trimethyl-silane (14.0 g, 68.8 mmol, 3.00 eq) were added to a toluene (75 mL) solution of ethyl 2-methylene-5-oxotetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylate (4.8 g, 22.9 mmol, 1.00 eq). The reaction solution was reacted at 110°C for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (5.2 g, 87.6% yield).

LC-MS: m/z 260 (M+H) ⁺ .

Step 2: Preparation of ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (Intermediates 1-11A and 1-11B)

LAH (2.1 g, 57.6 mmol, 6.00 eq) was added to a solution of ethyl 2,2-difluoro-5'-oxadihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylate (2.40 g, 9.26 mmol, 1.00 eq) in THF (40 mL) at 0°C. The reaction solution was reacted at 60°C for 2 h and then quenched with Na ₂ SO ₄ .10H ₂ O (20 g) at 0°C and filtered. The filter cake was washed with THF (40 mL). The filtrate was concentrated under reduced pressure to obtain intermediate 1-11 ((2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol).

LC-MS: m/z 204 (M+H) ⁺ .

Intermediate 1-11 was separated by silica gel column chromatography (DCM:MeOH:NH ₃ .H ₂ O=20:1:0.05) to give ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol.

Isomer 1-11A ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (0.50 g):

LC-MS: m/z 204(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ3.44-3.35 (m, 2H), 3.19-3.13 (m, 2H), 2.83 (d, J = 12.1Hz, 1H), 2.73-2.59 (m, 1H), 2.73-2.59(m,1H),2.05(dd,J＝6.3,13.3Hz,1H),1.93-1.84(m,3H),1.83-1.74(m,1H),1.74-1.63(m,1H), 1.36(ddd,J=4.0,8.1,12.1Hz,1H), 1.28(ddd,J=4.2,8.1,12.4Hz,1H).

Isomer 1-11B ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (0.64 g):

LC-MS: m/z 204(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ3.32 (d, J = 2.0Hz, 2H), 3.24 (d, J = 11.0Hz, 1H), 3.12-3.02 (m, 1H), 2.83-2.71 (m, 2H),2.05(d,J＝13.2Hz,1H),1.98-1.89(m,2H),1.89-1.81(m,1H),1.81-1.70(m,2H),1.36-1.28(m,2H) .

Preparation of intermediate 1-11A ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and 1-11B ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Route 2

Step 1: (trans)-2,2-difluoro-5'-oxadihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid ethyl Preparation of esters and (cis)-2,2-difluoro-5'-oxadihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid ethyl ester (Intermediate 1-11-IA and Intermediate 1-11-IB)

Intermediate 1-11-I (6 g) was separated by silica gel column chromatography ( 40g Silica Flash Column, eluent: 0-50% THF/petroleum ether 40 mL/min) to obtain intermediate I-11-IA (2.80 g, 10.8 mmol, 47% yield) and intermediate I-11-IB (2.40 g, 9.26 mmol, 40% yield) in turn.

Step 2: Preparation of ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (Intermediate 1-11-A and Intermediate 1-11-B)

According to the same method as in preparation route 1, intermediate 1-11A was synthesized from intermediate 1-11-IA.

According to the same method as in preparation route 1, intermediate 1-11B was synthesized from intermediate 1-11-IB.

Isomer 1-11A was subjected to chiral separation to obtain isomer 1-11A-1 (((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol) and isomer 1-11A-2 (((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol).

Step 1: Preparation of Intermediates 1-11A-I1 and 1-11A-I2

Imidazole (6.03 g, 88.6 mmol, 2.00 eq) and TBDPSCl (14.6 g, 53.1 mmol, 13.6 mL, 1.20 eq) were added to a DMF (100 mL) solution of intermediate 1-11A (9.00 g, 44.3 mmol, 1.00 eq). The reaction solution was reacted at 25 ° C for 16 h and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain the target product intermediate 1-11A-I (20.0 g, 41.7 mmol, 94.1% yield).

LC-MS: m/z 442(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.77-7.62(m,4H),7.53-7.34(m,6H),3.51(s,2H),3.14-3.02(m,2H),2.79(d,J ＝12.0Hz,1H),2.65-2.54(m,1H),2.13-1.99(m,2H),1.90(d,J＝13.3Hz,1H),1.86-1.77(m,1H),1.72-1.61( m,2H),1.23-1.16(m,2H),1.10(s,9H).

Intermediate 1-11A-I was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IC (250 mm*50 mm, 10 um); mobile phase: [CO ₂ -EtOH (0.1% NH ₃ H ₂ O)]; 15% Bisocrate elution mode) to obtain two isomers:

Intermediate 1-11A-I1 (4.50 g, 10.2 mmol, 45.0% yield): RT 1.931 min. LC-MS: m/z 442 (M+H) ⁺ .

Intermediate 1-11A-I2 (4.20 g, 9.51 mmol, 42.0% yield): RT 2.412 min. LC-MS: m/z 442 (M+H) ⁺ .

Step 2: Preparation of Intermediates 1-11A-1 and 1-11A-2

To a solution of intermediate 1-11A-I1 (4.50 g, 10.2 mmol, 1.00 eq) in MeOH (50 mL) was added KHF ₂ (15.9 g, 203mmol, 6.72mL, 20.0eq). The reaction solution was reacted at 25°C for 16h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( 20g Silica Flash Column, eluent: 0-25% MeOH/DCM@40 mL/min) was used to separate the target product 1-11A-1 (1.71 g, 7.98 mmol, 78.3% yield). LC-MS: m/z 204 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.40-3.16 (m, 2H), 3.03 (dd, J=7.4, 12.1 Hz, 2H), 2.73 (d, J=12.1 Hz, 1H), 2.66-2.43 (m, 1H), 2.00-1.86 (m, 1H), 1.84-1.73 (m, 3H), 1.72-1.54 (m, 2H), 1.33-1.10 (m, 2H).

Intermediate 1-11A-2 (1.79 g, 8.38 mmol, 88.1% yield) was synthesized in the same manner:

LC-MS: m/z 204(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ3.35-3.20 (m, 2H), 3.10-2.96 (m, 2H), 2.73 (d, J = 12.1Hz, 1H), 2.63-2.49 (m, 1H), 1.97-1.87(m,1H),1.84-1.74(m,3H),1.72-1.53(m,2H),1.31-1.11(m,2H).

Intermediate D-1-11A-1 (((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methane-d2-ol) and intermediate D-1-11A-2 (((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methane-d2-ol) were synthesized by the same method as intermediate 1-11A-1 and intermediate 1-11A-2.

Intermediate D-1-11A-1. LC-MS: m/z 208(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ2.81-3.08(m,2H)2.73(d,J＝12.13Hz,1H)1.92(dd,J＝13.26,6.13Hz,1H)1.73-1.83(m,3H )1.52-1.71(m,2H)1.08-1.33(m,2H).

Intermediate D-1-11A-2. LC-MS: m/z 208(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ3.03 (dd, J＝12.13, 7.25Hz, 2H) 2.73 (d, J＝12.13Hz, 1H) 1.92 (dd, J＝13.26, 6.25Hz, 1H) 1.74- 1.83(m,3H)1.53-1.70(m,2H)1.13-1.32(m,2H).

Preparation of Intermediate 1-12 (Tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Step 1: Preparation of (S)-5-(((tert-butylmethylsilyl)oxy)methyl)pyrrolidine-2-one

TBSCl (78.6 g, 521 mmol, 63.9 mL, 1.20 eq) was added in batches to a solution of (S)-5-(hydroxymethyl)pyrrolidine- _{2-one (50.0 g, 434 mmol, 1.00 eq) and imidazole (59.1 g, 868 mmol, 2.00 eq) in DCM (1000 mL). The reaction solution was reacted at 25°C for 2 h, and then H 2} O (1000 mL) was added dropwise at 0°C, and then DCM (1000 mL) was added to dilute. The mixed solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the target product. It was directly used in the next step without purification.

¹ H NMR (400MHz, CDCl ₃ ) δ6.43(br s,1H)3.71(m,1H)3.57(m,1H)3.44(m,1H)2.30(m,2H)2.13(m,1H)1.74( m,1H)0.85(s,9H)0.02(m,6H).

Step 2: Preparation of (S)-1-benzyl-5-(((tert-butylmethylsilyl)oxy)methyl)pyrrolidine-2-one

Under nitrogen protection, NaH (72.7 g, 1.82 mol, 60.0% wt, 4.17 eq) was added in batches to a solution of (S)-5-(((tert-butylmethylsilyl)oxy)methyl)pyrrolidine-2-one (100 g, 436 mmol, 1.00 eq) in THF (1250 mL) at 0°C for 2 h. The mixture was reacted at 0°C for 0.5 h, and then BnBr (112 g, 654 mmol, 77.7 mL, 1.50 eq) was added. The resulting mixture was reacted at 25°C for 16 h, and then quenched with saturated NH ₄ Cl aqueous solution (1000 mL) at 0-10°C under nitrogen protection, and then extracted with EtOAc (1000 mL*2). The combined organic phase was washed with saturated brine (1000 mL), dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (122 g, 382 mmol, 87.6% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.29 (m, 5H) 5.02 (d, J = 14.97Hz, 1H) 4.06 (d, J = 14.97Hz, 1H) 3.69 (m, 1H) 3.54 (m, 2H )2.55(m,1H)2.38(m,1H)2.05(m,1H)1.91(m,1H)0.89(s,9H)0.04(s,6H)

Step 3: Preparation of (S)-4-benzyl-5-(((tert-butylmethylsilyl)oxy)methyl)-4-azaspiro[2.4]heptane

Under nitrogen protection, Ti(OiPr) ₄ (224 g, 789 mmol, 2.25 eq) was added to a toluene (263 mL) solution of TiCl ₄ (49.9 g, 263 mmol, 0.750 eq) at 0°C. The reaction solution was reacted at 25°C for 2 h, and then MeLi (1.60 M, 657 mL, 3.00 eq) was added dropwise at 0°C. The obtained compound was reacted at 25°C for 1 h, and then a THF (560 mL) solution of (S)-1-benzyl-5-(((tert-butylmethylsilyl)oxy)methyl)pyrrolin-2-one (112 g, 351 mmol, 1.00 eq) was added, and then EtMgBr (3.00 M, 400 mL, 3.42 eq) was added dropwise at 0°C within 2 h. The obtained mixture was reacted at 25°C for 2 h, and then water (700 mL) was added dropwise at 0°C to quench the reaction and then filtered. The filter cake was washed with EtOAc (1000 mL). The combined organic phase was washed with saturated brine (500 mL*2), dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (19.0 g, 57.3 mmol, 16.4% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.29 (m, 5H) 3.75 (d, J = 13.82Hz, 1H) 3.54 (d, J = 13.82Hz, 1H) 3.40 (m, 2H) 3.03 (m, 1H )2.07(m,1H)1.95(dt,J＝11.80,8.22Hz,1H)1.78(m,1H)1.55(ddd,J＝12.01,8.04,4.40Hz,1H)0.84(s,9H)0.79(m ,1H)0.56(m,1H)0.48(m,1H)0.41(m,1H)-0.06(d,J＝9.17Hz,6H)

Step 4: Preparation of (S)-(4-benzyl-4-azaspiro[2.4]heptane-5-yl)methanol

To a solution of (S)-4-benzyl-5-(((tert-butylmethylsilyl)oxy)methyl)-4-azaspiro[2.4]heptane (19.0 g, 57.3 mmol, 1.00 eq) in THF (300 mL) was added TBAF (1.00 M, 57.3 mL, 1.00 eq). The mixture was reacted at 25°C for 16 h, and then diluted with EtOAc (500 mL). The resulting mixture was washed with H ₂ O (100 mL) and saturated brine (100 mL), dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (5.30 g, 24.4 mmol, 42.6% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.28 (m, 4H) 7.20 (m, 1H) 4.14 (br t, J = 5.39Hz, 1H) 3.67 (d, J = 14.09Hz, 1H) 3.50 (d, J＝14.08Hz,1H)3.24(m,1H)3.14(m,1H)2.91(m,1H)1.96(m,2H)1.65(m,1H)1.49(ddd,J＝11.50,8.20,3.41Hz, 1H)0.80(m,1H)0.45(m,2H)0.37(m,1H).

Step 5: Preparation of (S)-(4-azaspiro[2.4]heptane-5-yl)methanol hydrochloride

Under nitrogen protection, a solution of (S)-(4-benzyl-4-azaspiro[2.4]heptane-5-yl)methanol (5.00 g, 23.0 mmol, 1.00 eq) in MeOH (50.0 mL) was added with Pd/C (500 mg, 10.0% wt) and HCl (12.0 M, 8.00 mL, 4.17 eq). The mixture was reacted at 30 ° C for 3 days under a hydrogen atmosphere and then filtered. The filtrate was concentrated under reduced pressure to obtain the target product (4.50 g, crude product). It was used directly in the next step without further purification.

¹ H NMR(400MHz, CDCl ₃ )δ9.67(br s,1H)8.97(br s,1H)3.60(m,3H)2.07(m,1H)1.92(m,2H)1.79(m,1H)1.14 (m,2H)0.77(m,2H).

Step 6: Preparation of (S)-5-(hydroxymethyl)-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester

TEA (3.34 g, 33.0 mmol, 4.59 mL, 1.20 eq) and Boc ₂ O (7.20 g, 33.0 mmol, 7.58 mL, 1.20 eq) were added to a solution of (S)-(4-azaspiro[2.4]heptane-5-yl)methanol hydrochloride (4.50 g, 27.5 mmol, 1.00 eq) in DCM (90.0 mL). The mixture was reacted at 25°C for 16 h, then quenched by adding water (50 mL) at 0°C and extracted with DCM (50 mL*2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (5.90 g, 26.0 mmol, 94.4% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ3.85 (br d, J＝5.94Hz, 1H) 3.52 (ddd, J＝9.96, 5.56, 3.85Hz, 1H) 3.25 (ddd, J＝10.12, 8.58, 5.94Hz ,1H)2.14(m,1H)1.85(m,2H)1.50(br s,1H)1.35(s,9H)1.15(m,1H)0.84(m,1H)0.39(m,2H).

Step 7: Preparation of (S)-4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane-5-carboxylic acid

At 0°C, a solution of NaIO ₄ (11.7 g, 54.7 mmol, 3.03 mL, 2.54 eq) in H ₂ O (18.0 mL) was added with a mixed solution of (S)-5-(hydroxymethyl)-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (4.90 g, 21.6 mmol, 1.00 eq) in ACN (12.0 mL) and CCl ₄ (12.0 mL), followed by the addition of RuCl ₃ .H ₂ O (206 mg, 912 μmol, 0.0423 eq). The mixture was reacted at 25°C for 16 h, then water (30 mL) was added dropwise at 0°C to quench the reaction, and then extracted with DCM (50 mL*2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (4.70 g, crude product). It was used directly in the next reaction without further purification.

LC-MS: m/z 242 (M+H) ⁺ .

Step 8: Preparation of (S)-4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane-5-carboxylic acid methyl ester

At 0°C, MeI (5.53 g, 39.0 mmol, 2.43 mL, 2.00 eq) and K 2 CO 3 (8.08 g, 58.4 mmol, 3.00 eq) were added to a solution of (S)-4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane- ₅ -carboxylic acid (4.70 g, 19.5 mmol, 1.00 eq) in acetone (50.0 mL). The mixture was reacted at 25°C for 16 h, and then water (30 mL) _was added dropwise at 0°C to quench the reaction, and then extracted with DCM (50 mL*2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous MgSO ₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (1.10 g, 4.31 mmol, 22.1% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ4.33 (br dd, J＝8.44, 3.79Hz, 1H) 3.65 (m, 3H) 2.20 (m, 1H) 1.81 (m, 3H) 1.39 (m, 1H) 1.30 (br s,9H)0.86(m,1H)0.48(br s,2H).

Step 9: Preparation of 4-(tert-butyl)5-methyl5-(3-chloropropyl)-4-azaspiro[2.4]heptane-4,5-dicarboxylate

Under nitrogen protection, LiHMDS (1.00M, 5.88mL, 1.50eq) was added to a solution of (S)-4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane-5-carboxylic acid methyl ester (1.00g, 3.92mmol, 1.00eq) in THF (10.0mL) at -70℃. The reaction solution was reacted at -70℃ for 1h, and then 1-chloro-3-iodo-propane (2.40g, 11.8mmol, 1.26mL, 3.00eq) was added. The resulting mixture was reacted at -70℃ for 1h, and then at 25℃ for 40h. The mixture was quenched with saturated NH ₄ Cl (20mL) at -0℃ and extracted with EtOAc (30mL*2). The combined organic phase was washed with saturated brine (50mL), dried over anhydrous MgSO _4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (767 mg, 2.31 mmol, 59.0% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ3.73 (s, 3H) 3.59 (br t, J = 6.27Hz, 2H) 2.39 (m, 1H) 2.07 (m, 4H) 1.89 (m, 1H) 1.74 (m ,2H)1.44(m,1H)1.39(m,9H)0.90(br dd,J＝14.97,7.04Hz,1H)0.50(m,2H).

Step 10: Preparation of 5-methyl 5-(3-chloropropyl)-4-azaspiro[2.4]heptane-5-carboxylate hydrochloride

HCl/dioxane (4.00 M, 4.00 mL, 7.58 eq) was added to a solution of 4-(tert-butyl)-5-methyl-5-(3-chloropropyl)-4-azaspiro[2.4]heptane-4,5-dicarboxylate (700 mg, 2.11 mmol, 1.00 eq) in DCM (8.00 mL). The mixture was reacted at 25 °C for 1 h and then concentrated under reduced pressure to obtain the target product (698 mg, crude). It was used directly in the next step without further purification.

LC-MS: m/z 232 (M+H) ⁺ .

Step 11: Preparation of tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid methyl ester

K ₂ CO ₃ (1.08 g, 7.81 mmol, 3.00 eq) was added to a solution of 5-methyl 5-(3-chloropropyl)-4-azaspiro[2.4]heptane-5-carboxylate hydrochloride (698 mg, 2.60 mmol, 1.00 eq) in ACN (8.00 mL). The mixture was reacted at 25°C for 16 h and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (412 mg, 2.11 mmol, 81.1% yield). It was used directly in the next step without further purification.

¹ H NMR (400MHz, CDCl ₃ ) δ3.74 (m, 3H) 3.15 (dt, J = 9.24, 4.62Hz, 1H) 2.73 (m, 1H) 2.45 (m, 2H) 2.13 (td, J = 11.55, 7.92Hz,1H)1.94(m,1H)1.77(m,4H)1.31(m,2H)0.97(m,1H)0.66(m,2H)0.37(m,1H)

Step 12: Preparation of (tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Under nitrogen protection, LiAlH ₄ (135 mg, 3.56 mmol, 2.00 eq) was added to a solution of tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid methyl ester (412 mg, 1.78 mmol, 1.00 eq) in THF (4.00 mL) at 0°C. The reaction solution was reacted at 25°C for 1 h, and then H ₂ O (0.04 mL), NaOH aqueous solution (15% wt, 0.04 mL) and H ₂ O (0.12 mL) were added in sequence to quench. The mixture was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (263 mg, 1.57 mmol).

LC-MS: m/z 168(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ3.40 (d, J = 10.15Hz, 1H) 3.28 (d, J = 10.15Hz, 1H) 2.99 (m, 1H) 2.73 (m, 1H) 2.19 (m, 1H )1.91(m,2H)1.69(m,4H)1.26(m,2H)0.86(m,1H)0.61(dt,J＝9.81,5.73Hz,1H)0.50(dt,J＝10.18,5.00Hz,1H )0.38(ddd,J=9.90,6.05,4.10Hz,1H).

Intermediates 1-13A and 13B were synthesized by the same method as intermediate 1-12: ((cis)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((trans)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Intermediate 1-13A

LC-MS: m/z 186(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.26-5.02(m,1H),3.48(d,J＝10.8Hz,1H),3.42-3.13(m,3H),2.96-2.57(m,1H), 2.52-2.29(m,2H),2.18-1.94(m,2H),1.87-1.74(m,1H),1.40-1.29(m,1H),0.95-0.82(m,1H),0.76-0.59(m ,2H),0.53-0.38(m,1H),0.53-0.38(m,1H).

Intermediate 1-13B

LC-MS: m/z 186(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.30-5.06(m,1H),3.57-3.41(m,2H),3.33(br dd,J＝12.4,18.8Hz,1H),3.07-2.86(m,1H),2.82-2.42(m,1H),2.40-2.27(m,1H),2.25-2.12(m,1H),2.11- 1.93(m,2H),1.73(ddd,J＝2.0,8.8,12.5Hz,1H),1.34(ddd,J＝1.8,7.8,12.2Hz,1H),0.92-0.81(m,1H),0.77- 0.57(m,2H),0.44(ddd,J＝3.8,5.9,9.6Hz,1H).

Intermediate 1-14 was synthesized by the same method as Intermediate 1-8 with different starting materials: (7',7'-difluorodihydro-3'H-spiro[cyclopropane-1,2'-indolizine]-8a'(1'H)-yl)methanol

LC-MS: m/z 218(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ3.66 (dd, J = 10.88, 2.32Hz, 1H) 3.24 (d, J = 10.88Hz, 1H) 2.97 (m, 4H) 2.26 (d, J = 11.62Hz, 1H)1.95(m,6H)0.58(m,4H).

Intermediate 1-15 was synthesized by the same method as Intermediate 1-8 with different starting materials: (6',6'-difluorodihydro-3'H-spiro[cyclopropane-1,2'-indolizine]-8a'(1'H)-yl)methanol

LC-MS: m/z 218(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ 3.68 (d, J = 10.39 Hz, 1H) 3.29 (m, 2H) 2.96 (m, 4H) 2.04 (m, 6H) 0.55 (m, 4H).

Preparation of Intermediates 1-16A and 1-16B ((1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Step 1: Preparation of (3R,6R,7aS)-3-(tert-butyl)-6-fluorotetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one

2,2-Dimethylpropanal (17.3 g, 200 mmol, 22.1 mL, 2.00 eq), trimethoxymethane (31.9 g, 300 mmol, 32.9 mL, 3.00 eq) and TFA (1.14 g, 10.0 mmol, 744 μL, 0.100 eq) were added to a solution of (2S, 4R)-4-fluoropyrrolidine-2-carboxylic acid (13.3 g, 100 mmol, 1.00 eq) in THF (40 mL). The mixture was reacted at 57 ° C for 16 h and then concentrated under reduced pressure to obtain the target product (22.0 g, crude product). It was used directly in the next step without purification.

¹ H NMR (400MHz, CDCl ₃ ) δppm 5.27 (m, 1H) 4.52 (s, 1H) 4.09 (t, J = 8.14Hz, 1H) 3.56 (m, 1H) 2.94 (m, 1H) 2.54 (m, 1H )2.20(m,1H)0.96(m,9H).

Step 2: Preparation of (3R,6R,7aS)-3-(tert-butyl)-7a-(2-(chloromethyl)propenyl)-6-fluorotetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one

Under nitrogen protection, LDA (2.00M, 82.0mL, 1.50eq) and DMPU (28.0g, 219mmol, 26.3mL, 2.00eq) were added dropwise to a solution of (3R,6R,7aS)-3-(tert-butyl)-6-fluorotetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one (22.0g, 109mmol, 1.00eq) in THF (220mL) at -70°C. The mixture was reacted at -70°C for 2h, followed by the addition of 3-chloro-2-(chloromethyl)prop-1-ene (17.8g, 142mmol, 16.5mL, 1.30eq). The resulting mixture was reacted at 25°C for 16h, then quenched by the addition of saturated aqueous NH ₄ Cl solution (250mL) at 0°C, and then extracted with EtOAc (250mL*2). The combined organic phase was washed with saturated brine (250 mL), dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (16.7 g, 57.6 mmol, 52.7% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ5.37(m,1H)5.33(s,1H)5.24(m,1H)5.17(s,1H)4.21(m,3H)3.43(m,1H)3.23(m ,1H)2.72(s,2H)2.37(m,1H)2.12(m,1H)0.91(s,9H).

Step 3: Preparation of (2R,7aS)-2-fluoro-6-methyltetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester

To a solution of (3R,6R,7aS)-3-(tert-butyl)-7a-(2-(chloromethyl)propenyl)-6-fluorotetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one (11.2 g, 38.7 mmol, 1.00 eq) in MeOH (56 mL) was added NaI (6.95 g, 46.4 mmol, 1.20 eq). The mixture was reacted at 68°C for 16 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was slurried with acetone (12 mL) at 25°C for 30 min and then filtered. ACN (70 mL) and K ₂ CO ₃ (12 g) were added to the solid, and then reacted at 25°C for 3 h and filtered. The filtrate was concentrated under reduced pressure, and the residue was filtered after adding THF (70 mL). The filtrate was concentrated under reduced pressure to give the target product (3.50 g, 17.6 mmol, 45.5% yield). It was used directly in the next step without purification.

¹ H NMR (400MHz, CDCl ₃ ) δ5.29 (m, 1H) 4.97 (dt, J = 11.44, 1.87Hz, 2H) 3.82 (br d, J = 13.86Hz, 1H) 3.72 (m, 3H) 3.59 ( br d,J＝13.86Hz,1H)3.26(m,2H)3.04(br d,J＝16.07Hz,1H)2.81(br d,J＝16.07Hz,1H)2.56(m,1H)2.30(m, 1H).

Step 4: Preparation of (1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid methyl ester and (1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid methyl ester

Under nitrogen protection, NaI (752 mg, 5.02 mmol, 0.500 eq) and TMSCF 3 (3.57 g, 25.1 mmol, 2.50 eq) were added to a solution of (2R, 7aS)-2-fluoro-6-methyltetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester (2.00 g, 10.0 mmol, 1.00 eq) in THF (20 mL). The reaction solution was reacted at 80° C. _for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( 20g Silica Flash Column, eluent: 10.3% THF/PE@60 mL/min) to give Isomer A (269 mg, 1.08 mmol, 10.8% yield) and Isomer B (372 mg, 1.49 mmol, 14.9% yield) in turn.

Isomer A: ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.33 (m, 1H) 3.78 (s, 3H) 3.49 (d, J=9.90 Hz, 1H) 3.27 (m, 3H) 2.45 (m, 4H) 1.37 (m, 2H).

Isomer B: ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.26 (m, 1H) 3.78 (m, 3H) 3.31 (m, 4H) 2.54 (m, 2H) 2.35 (m, 2H) 1.36 (m, 2H).

Step 5: Preparation of Intermediates 1-16A and 1-16B ((1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Under nitrogen protection, LAH (81.9 mg, 2.16 mmol, 2.00 eq) was added to a solution of isomer A (269 mg, 1.08 mmol, 1.00 eq) in THF (3 mL) at 0°C. The mixture was reacted at 25°C for 1 h, and then H ₂ O (0.03 mL), NaOH aqueous solution (15% wt, 0.03 mL) and H ₂ O (0.09 mL) were added in sequence at 0°C. The obtained mixture was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target product intermediate 1-16A (193 mg, 871 μmol, 80.7% yield). It was directly used in the next step without further purification.

LC-MS: m/z 222(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.34 (br s, 1H) 5.21 (br d, J = 2.64Hz, 1H) 3.24 (m, 5H) 2.77 (br s, 1H) 2.19 (m, 3H) 1.88 (d,J=12.98Hz,1H)1.33(m,2H).

Intermediate 1-16B was synthesized using the same method using isomer B obtained in the previous step.

LC-MS: m/z 222(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.28(m,1H)5.14(m,1H)3.27(m,5H)2.80(m,1H)2.20(m,3H)1.82(br dd,J＝13.31, 4.73Hz,1H)1.30(m,2H).

The following compounds were synthesized using the same method as intermediates 1-16A and 1-16B with different starting materials:

Intermediates 1-16C and 1-16D: ((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Intermediate 1-16C

LC-MS: m/z 222(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.31 (m, 1H) 5.17 (m, 1H) 3.56 (m, 1H) 3.43 (m, 2H) 3.21 (dd, J = 12.53, 7.52Hz, 1H) 2.78 ( d,J＝12.59Hz,2H)2.10(m,4H)1.29(s,2H).

Intermediate 1-16D

LC-MS: m/z 222(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.38 (br t, J = 4.95Hz, 1H) 5.24 (m, 1H) 3.75 (m, 1H) 3.42 (m, 2H) 3.06 (m, 1H) 2.68 (m ,2H)2.26(m,3H)1.82(m,1H)1.34(m,2H).

Intermediates 1-16E and 1-16F: ((1S,6'S,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'S,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Intermediate 1-16E

LC-MS: m/z 222(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.31 (m, 1H) 5.18 (t, J = 4.29Hz, 1H) 3.57 (d, J = 11.00Hz, 1H) 3.45 (m, 2H) 3.21 (dd, J =12.54,7.48Hz,1H)2.83(m,2H)2.10(m,4H)1.34(m,2H).

Intermediate 1-16F

LC-MS: m/z 222(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.36 (m, 1H) 5.22 (br d, J = 4.40Hz, 1H) 3.74 (m, 1H) 3.42 (m, 2H) 3.03 (m, 1H) 2.72 (m ,2H)2.35(m,1H)2.13(m,2H)1.78(dd,J＝13.53,6.05Hz,1H)1.33(m,2H).

Intermediates 1-16G and 1-16H: ((1S,6'S,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'S,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

Intermediate 1-16G

LC-MS: m/z 222(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.35(br s,1H)5.18(m,1H)3.73(m,1H)3.28(m,5H)2.25(m,3H)1.87(m,1H)1.32( m,2H).

Intermediate 1-16H

LC-MS: m/z 222(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ5.05(m,1H)3.48(m,1H)3.06(m,5H)2.03(m,3H)1.62(m,1H)1.08(m,2H).

Preparation of Intermediate 1-17 (1-methyltetrahydro-1H-spiro[cyclopentane[b]pyrrol-2,1'-cyclopropane]-3a(3H)-yl)methanol

Step 1: Preparation of methyl 1-(2-ethoxy-2-oxyethyl)-2-oxycyclopropane-1-carboxylate

K ₂ CO ₃ (29.2 g, 211 mmol, 1.50 eq) was added to a solution of methyl 2-oxocyclopentane-1-carboxylate (20.0 g, 141 mmol, 17.5 mL, 1.00 eq) and ethyl 2-bromoacetate (25.9 g, 15.5 mmol, 17.1 mL, 1.10 eq) in ACN (200 mL). The reaction solution was reacted at 70°C for 16 h, then filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (32.0 g). It was used directly in the next step without further purification.

¹ H NMR (400MHz, CDCl ₃ ) δ4.16-4.06(m,2H),3.71(s,3H),3.03-2.76(m,2H),2.65-2.53(m,1H),2.51-2.35(m ,1H),2.51-2.35(m,1H),2.17-1.95(m,1H),2.17-1.95(m,2H),1.26-1.20(m,1H),1.26-1.20(m,1H),1.24 (t,J=7.2Hz,1H).

Step 2: Preparation of 1-methyl-2-oxohexahydrocyclopentane[b]pyrrole-3a(1H)-carboxylic acid methyl ester

Methylamine methanol solution (2.0M, 16.4mL, 1.50eq), AcOH (1.32g, 21.9mmol, 1.25mL, 1.00eq) and NaBH 3 CN (1.79g, 28.5mmol, 1.30eq) were added to a solution of 1-(2-ethoxy-2-oxoethyl)-2-oxocyclopropane-1 _- carboxylic acid methyl ester (5.00g, 21.9mmol, 1.00eq) in MeOH (50mL). The reaction solution was reacted at 80°C for 24h and then concentrated under reduced pressure. The residue was washed with 3.0M HCl (50mL) and extracted with DCM (500mL x 3). The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was separated by silica gel column chromatography to obtain the target product (700mg, 3.02mmol, 13.8% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ4.15 (d, J = 5.6 Hz, 1H), 3.76-3.74 (m, 3H), 3.10 (d, J = 17.9 Hz, 1H), 2.81 (s, 3H) ,2.39(d,J＝17.9Hz,1H),2.23-2.11(m,1H),1.91-1.73(m,4H),1.70-1.57(m,1H).

Step 3: Preparation of 3a-(hydroxymethyl)-1-methylhexahydrocyclopentane[b]pyrrol-2(1H)-one

At 0°C, NaBH ₄ (277 mg, 3.29 mmol, 2.20 eq) in MeOH (10 mL) was added to 1-methyl-2-oxohexahydrocyclopentane[b]pyrrole-3a(1H)-carboxylic acid methyl ester (650 mg, 3.30 mmol, 1.00 eq) in MeOH (10 mL). The reaction solution was reacted at 25°C for 4 h, then quenched by adding 2 mL of 1M HCl and concentrated under reduced pressure. The residue was diluted with DCM (200 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (390 mg). It was used directly in the next step without further purification.

LC-MS: m/z 170 (M+H) ⁺ .

Step 4: Preparation of 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydrocyclopentane[b]pyrrol-2(1H)-one

At room temperature, TBDPSCl (702 mg, 2.55 mmol, 1.20 eq) and imidazole (290 mg, 4.25 mmol, 2.00 eq) were added to a solution of 3a-(hydroxymethyl)-1-methylhexahydrocyclopentane[b]pyrrole-2(1H)-one (360 mg, 2.13 mmol, 1.00 eq) in DCM (5 mL). The reaction solution was reacted at room temperature for 2 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (540 mg, 1.19 mmol, 56.04% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.70-7.59(m,4H),7.52-7.37(m,6H),3.64-3.46(m,2H),2.80(s,3H),2.61(d,J ＝17.5Hz,1H),2.25(d,J＝17.5Hz,1H),2.08-1.84(m,1H),1.83-1.75(m,1H),1.74-1.65(m,2H),1.65-1.51( m,3H),1.08(s,9H).

Step 5: Preparation of 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydro-1H-spiro[cyclopentane[b]pyrrole-2,1'-cyclopropane]

Under nitrogen protection, MeTi(OiPr) 3 (1.0M, 3.07mL, 2.50eq) and EtMgBr (3.0M, 2.45mL, 6.00eq) were added to a solution of 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydrocyclopentane[b]pyrrol-2(1H) _-one (500mg, 1.23mmol, 1.00eq) in THF (10mL) at 0°C. The reaction solution was reacted at 25°C for 16h, then diluted with water (10mL) and extracted with EtOAc (100mL*2). The combined organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (190mg, 385μmol, 31.4% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.68 (br t, J = 5.7Hz, 4H), 7.54-7.35 (m, 6H), 3.73-3.42 (m, 2H), 2.77-2.50 (m, 1H) ,2.12-1.39(m,11H),1.09(s,9H),0.96--0.27(m,1H),0.96--0.31(m,1H).

Step 6: Preparation of (1-methyltetrahydro-1H-spiro[cyclopentane[b]pyrrol-2,1'-cyclopropane]-3a(3H)-yl)methanol

KHF ₂ (707 mg, 9.05 mmol, 298 μL, 20.0 eq) was added to a solution of 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydro-1H-spiro[cyclopentane[b]pyrrole-2,1'-cyclopropane] (190 mg, 453 μmol, 1.00 eq) in MeOH (5 mL). The reaction solution was reacted at 70° C. for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (72.6 mg, 360 μmol, 79.6% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ3.70-3.44(m,3H),3.70-3.44(m,1H),2.97-2.70(m,2H),2.21-1.94(m,3H),1.87(br d,J＝13.4Hz,3H),1.73-1.50(m,3H),1.37(t,J＝7.6Hz,1H),1.11-1.00(m,1H),0.99-0.73(m,1H),0.58 -0.13(m,1H).

Preparation of Intermediate 2-1 ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

Step 1: Preparation of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

Under nitrogen protection, ruthenium dichloride 1-isopropyl-4-methyl-benzene (1.20 g, 1.96 mmol, 0.07 eq) was added to a solution of 7-fluoronaphthalene-1,3-diol (5 g, 28.1 mmol, 1 eq), (bromoacetylene) triisopropylsilane (7.33 g, 28.1 mmol, 1 eq), and potassium acetate (5.51 g, 56.1 mmol, 2 eq) in dioxane (120 mL) at room temperature. The reaction solution was reacted at 110 ° C for 16 h and then filtered. The filter cake was washed with EtOAc (200 mL * 2). The combined organic phase was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (8 g, 22.3 mmol, 79.5% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ9.19 (m, 1H) 7.60 (dd, J = 9.17, 5.62Hz, 1H) 7.18 (m, 1H) 6.73 (m, 2H) 5.29 (br s, 1H) 1.22 (m,21H)

Step 2: Preparation of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol

MOMCl (1.66 g, 20.6 mmol, 1.57 mL, 1.06 eq) was added to a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (7 g, 19.5 mmol, 1 eq) and DIEA (5.05 g, 39.0 mmol, 6.80 mL, 2 eq) in DCM (100 mL) at 0°C. The resulting reaction solution was reacted at 25°C for 1.5 h and then quenched with H ₂ O (200 mL), adjusted to pH 6-7 with 1N HCl, and extracted with DCM (80.0 mL x 2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (4.2 g, 10.4 mmol, 53.4% yield).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.94-9.20 (m, 1H) 8.93-9.13 (m, 1H) 7.58 (dd, J = 9.07, 5.69Hz, 1H) 7.10 (t, J = 8.82Hz ,1H)6.89(d,J＝2.50Hz,1H)6.73(d,J＝1.88Hz,1H)5.12-5.24(m,2H)3.43(s,3H)1.09-1.13(m,21H)

Step 3: Preparation of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

DIEA (3.85 g, 29.8 mmol, 5.19 mL, 3 eq) and Tf 2 O (4.21 g, 14.9 mmol, 2.46 mL, 1.5 eq) were added to a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (4 g, 9.94 mmol, 1 eq) in DCM (40 mL) at -40°C. The resulting reaction solution was reacted at -40°C for 0.5 h, then diluted with H _{2 O} (20 mL) and extracted with DCM (50 mL*2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product as a yellow oil (5 g, 8.88 mmol, 89.4% yield, 95% purity).

¹ H NMR (400MHz, CDCl ₃ ) δ7.72 (dd, J＝9.03, 5.27Hz, 1H) 7.44 (d, J＝2.26Hz, 1H) 7.36-7.39 (m, 1H) 7.31-7.35 (m, 1H )5.20-5.37(m,2H)3.46-3.63(m,3H)1.17-1.33(m,17H)

Step 4: Preparation of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane

Under nitrogen protection, Pd(dppf)Cl 2 (684 mg, 935 umol, 0.1 eq) was added to a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (5 g, 9.35 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 _- yl)-1,3,2-dioxaborolane (4.75 g, 18.70 mmol, 2 eq) and AcOK (2.75 g, 28.06 mmol, 3 eq) in toluene (100 mL). The resulting reaction solution was reacted at 130°C for 8 h and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (3.5 g, 6.49 mmol, 69.3% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.68 (dd, J = 8.93, 5.62Hz, 1H) 7.52 (d, J = 2.45Hz, 1H) 7.39 (d, J = 2.57Hz, 1H) 7.24 (t, J＝8.80Hz,1H)5.18-5.39(m,2H)3.43-3.58(m,3H)1.45(s,12H) 1.15-1.21(m,20H)

Preparation of Intermediate 3-1 (1R, 5S)-3-(2,7-dichloro-8-fluoropyridin-4,3-d)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

Step 1: Preparation of 2-chloro-3-fluoro-5-iodopyridin-4-amine

To a solution of 2-chloro-3-fluoropyridin-4-amine (10 g, 68.5 mmol) and NIS (18.5 g, 82.2 mmol, 1.2 eq) in acetonitrile (50 mL) was added p-toluenesulfonic acid monohydrate (0.65 g, 3.43 mmol, 0.05 eq). The reaction solution was stirred at 70 ° C for 16 hours, and then diluted with water (30 mL) and EtOAc (200 mL). The separated organic phase was washed with S.aq.Na ₂ CO ₃ , S.aq.Na ₂ SO ₃ and saturated brine in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (16.6 g, 61 mmol, yield: 89%). It was used directly in the next step without purification.

LC-MS: m/z 273 (M+H) ⁺ .

Step 2: Preparation of 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester

Under nitrogen atmosphere, Pd(PPh ₃ ) ₂ Cl ₂ (2.1 g, 3 mmol, 0.1 eq) and TEA (11.1 g, 0.11 mmol, 3.6 eq) were added to a solution of 2-chloro-3-fluoro-5-iodopyridin-4-amine (8.2 g, 30 mmol, 1.0 eq) in EtOH (150 mL). The resulting reaction solution was reacted at 80° C. for 15 hours under CO ₂ atmosphere and then filtered. The filtrate was concentrated to 70-80% of the original volume under reduced pressure and then filtered again. The filter cake was collected and combined and then dried under vacuum to obtain the target product (quantitative yield). It was used directly in the next step without purification.

LC-MS: m/z 219 (M+H) ⁺ .

Step 3: Preparation of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol

At 0°C, trichloroacetyl isocyanate (673 mg, 3.6 mmol, 1.2 eq) was added to a THF (7 mL) solution of 4-amino-6-chloro-5-fluoronicotinate (657 mg, 3 mmol) obtained above. The reaction solution was reacted at rt for 30 min and then concentrated under reduced pressure. MeOH (15 mL) was added to the residue and cooled to 0°C, followed by addition of NH ₃ methanol solution (7 M in MeOH, 15 mL, 105 mmol). The resulting reaction solution was reacted at rt for 16 hours and then filtered. The filter cake was washed with methanol and then dried in vacuo to obtain the target product (quantitative yield). No purification was required and it was directly used in the next step.

LC-MS: m/z 216 (M+H) ⁺ .

Step 4: Preparation of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

A solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (500 mg, 2.4 mmol) and DIPEA (1.55 g, 12 mmol, 5.0 eq) in POCl ₃ (5 mL) was reacted at 100°C for 1 hour and then concentrated under reduced pressure to obtain the target compound (quantitative yield). It was used directly without purification. Next step reaction.

LC-MS: m/z 252 (M+H) ⁺ .

Step 5: Preparation of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

At -40°C, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.4 mmol) was added to a DCM (2 mL) solution of the above-obtained 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine and DIPEA (2 g, 15.5 mmol). The resulting reaction solution was reacted at the current temperature for 0.5 h, then diluted with water (2 mL) and extracted with DCM (2 x 2 mL). The organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (400 mg, crude yield: 38.9%). It was used directly in the next step without purification.

LC-MS: m/z 428 (M+H) ⁺ .

Preparation of intermediate 4-1 (1R, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

Step 1: Preparation of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

DIEA (7.24 g, 56.0 mmol, 9.76 mL, 3.00 eq) was added to tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00 g, 18.7 mmol, 1.00 eq) and 2,2,2-trifluoroethanol (56.1 g, 560 mmol, 40.3 mL, 30.0 eq). The resulting reaction solution was reacted at 70°C for 2 h and then concentrated under reduced pressure. The residue was diluted with H ₂ O (100 mL) and then extracted with EtOAc (100 mL*3). The combined organic phase was washed with saturated laboratory water (100 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (9 g, 18.3 mmol, 97.9% yield).

LC-MS: m/z 492(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.71 (s, 1H), 4.82 (q, J = 8.4Hz, 2H), 4.44 (br d, J = 12.0Hz, 2H), 4.31 (br s, 2H),3.63(br s,2H),1.95-1.83(m,2H),1.68-1.58(m,2H),1.45(s,9H)

Step 2: Preparation of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

CataCXium Pd was added to a mixed solution of (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (9.00 g, 18.3 mmol, 1.00 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (9.85 g, 19.2 mmol, 1.05 eq) and Cs ₂ CO ₃ (11.9 g, 36.6 mmol, 2.00 eq) in H ₂ O (20.0 mL) and dioxane (100 mL) under nitrogen atmosphere. G2 (611 mg, 915 umol, 0.05 eq). The resulting reaction solution was reacted at 100°C for 1 h, then quenched with H ₂ O (50 mL) and extracted with EtOAc (100 mL*3). The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (14.8 g, 17.6 mmol, 96.10% yield).

LC-MS: m/z 842(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.25 (s, 1H), 8.11 (dd, J = 5.9, 9.2Hz, 1H), 7.75 (d, J = 2.5Hz, 1H), 7.57 (t, J＝8.9Hz,1H),7.35(d,J＝2.4Hz,1H),5.76(s,1H),5.46-5.27(m,2H),5.21-4.91(m,2H),4.81(d ,J＝12.4Hz,1H),4.38-4.17(m,3H),3.81(d,J＝12.0Hz,1H),3.60-3.52(m,1H),3.43(s,3H),1.63(d, J＝7.4Hz,1H),1.46(s,9H),0.80(t,J＝7.8Hz,20H),0.57-0.38(m,3H).

According to the synthesis method of intermediate 4-1, the following compounds were synthesized with different starting materials:

Intermediate 4-2(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 872(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.15 (s, 1H), 7.17 (br d, J = 8.4Hz, 4H), 6.88 (br d, J = 8.4Hz, 4H), 6.82 (s, 1H),5.08(q,J＝8.9Hz,2H),4.69(br s,4H),4.55(br d,J＝12.1Hz,2H),4.27(br s,2H),3.73(s,6H) ,3.70-3.62(m,2H),2.39(br s,3H),1.85-1.76(m,2H),1.68(br d,J=7.5Hz,2H),1.47(s,9H).

Intermediate 4-3 (1R,5S)-3-(7-(2-((tert-butyloxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 724 (M+H) ⁺ .

Intermediate 4-4 (1R, 5S)-3-(7-(2-((tert-butyloxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 748(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.79 (s, 1H), 9.21 (s, 1H), 7.61 (dd, J = 5.3, 8.4Hz, 1H), 7.42 (t, J = 8.8Hz, 1H),5.11(q,J＝9.1Hz,2H),4.57(br d,J＝12.5Hz,2H),4.28(br s,2H),3.78-3.67(m,2H),1.82(br d, J=4.8Hz, 2H), 1.61 (br d, J=7.5Hz, 2H), 1.52 (s, 9H), 1.48 (s, 9H).

Intermediate 4-5 (1R, 5S)-3-(8-fluoro-7-(6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(2,2,2-trifluoro tert-Butyl (ethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 690 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.29 (s, 1H) 7.75-7.81 (m, 2H) 5.86 (dd, J＝9.68, 1.98Hz, 1H) 5.12 (q, J＝9.17Hz, 2H) 4.51-4.72 (m, 2H) 4.29 (br s, 2H) 3.91 (br d, J＝ 11.88Hz,1H)3.76-3.84(m,1H)3.62-3.75(m,2H)2.32-2.47(m,1H)2.16-2.24(m,1H)2.19(s,2H)1.94-2.08(m,2H)1.83(br d,J＝3.30Hz,2H)1.70(br d,J＝7.48Hz,3H)1.59(br s,2H)1.48(s,9H).

Intermediate 4-6 (1R, 5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 782(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.26 (s, 1H) 8.24 (m, 2H) 7.66 (m, 3H) 5.08 (m, 2H) 4.83 (br d, J = 12.59Hz, 1H) 4.34 (m,3H)3.83(br d,J＝11.86Hz,1H)3.41(m,1H)1.91(br d,J＝8.44Hz,2H)1.82(m,1H)1.65(m,1H)1.48(s ,9H)0.82(m,18H)0.50(m,3H).

Intermediate 4-7 (1R, 5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 690(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ9.08 (s, 1H) 7.71 (dd, J = 9.01, 5.88Hz, 1H) 7.55 (d, J = 2.63Hz, 1H) 7.28 (s, 1H) 7.23 (d ,J＝2.50Hz,1H)5.31(d,J＝2.13Hz,2H)4.94(q,J＝8.38Hz,2H)4.54-4.67(m,2H)4.44(br s,2H)3.60-3.90(m ,2H)3.53(s,3H)2.51(br dd,J＝13.95,7.07Hz,1H)2.23(ddd,J＝14.32,7.32,2.75Hz,1H)2.00-2.06(m,2H)1.81(br d,J＝8.38Hz,2H)1.26(s, 9H)0.85(t,J=7.44Hz,3H).

Intermediate 4-8 tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate

LC-MS: m/z 856(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.15-9.32(m,1H)8.05-8.19(m,1H)7.76(br d,J＝2.32Hz,1H)7.50-7.64(m,1H)7.14-7.46(m,1H)5.28-5.43(m,2H)4.94-5.20(m,2H)4.08-4.51(m,4H)3.49 -3.80(m,1H)3.39-3.48(m,3H)3.29-3.34(m,3H)2.01-2.21(m,2H)1.50-1.77(m,2H)1.44(s,3H)1.20(s,3H )0.94-1.06(m,3H)0.81(t,J=6.48Hz,18H)0.40-0.61(m,3H).

Intermediate 4-9 (1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-yl)carbamic acid tert-butyl ester

LC-MS: m/z 842(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ9.01-9.27(m,1H)8.12(dd,J＝9.17,5.87Hz,1H)7.73-7.80(m,1H)7.58(t,J＝8.93Hz ,1H)7.35-7.41(m,1H)7.12-7.20(m,1H)6.41-6.65(m,1H)5.32-5.42(m,2H)5.08-5.19(m,1H)4.92-5.05(m,1H )4.40(br d,J＝12.35Hz,1H)3.63-3.74(m,1H)3.44(s,3H)3.35-3.41(m,1H)3.28-3.34(m,2H)2.01-2.14(m,1H)1.84-1.95 (m,1H)1.50-1.83(m,2H)1.30-1.41(m,3H)1.21-1.27(m,2H)1.12(s,6H)0.72-0.88(m,18H)0.34-0.58(m,3H )

Intermediate 4-10 (1R, 5S)-3-(7-(3-((bis-tert-butyloxycarbonyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 849(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.24 (s, 1H) 7.82 (d, J = 9.26Hz, 1H) 5.11 (q, J = 9.01Hz, 2H) 4.57 (br d, J = 12.38Hz ,2H)4.29(br s,2H)3.69(br d,J＝12.26Hz,2H)2.28(br s,3H)1.82(br d,J＝4.13Hz,2H)1.66(br d,J＝7.50Hz ,2H)1.47(s,9H)1.38(s,18H).

Intermediate 4-11 (1R, 5S)-3-(7-(2-((bis-tert-butyloxycarbonyl)amino)-3,5-dichloro-6-fluorophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 835(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ9.00 (s, 1H) 7.68 (d, J = 7.09Hz, 1H) 4.81-5.01 (m, 2H) 4.64-4.77 (m, 1H) 4.34-4.49 (m, 3H)3.59-3.89(m,2H)2.02(br d,J＝1.47Hz,2H)1.79-1.86(m,4H)1.78-1.86(m,1H)1.53-1.59(m,10H)1.43-1.51( m,9H)1.16-1.27(m,8H).

Intermediate 4-12 (1R, 5S)-3-(7-(5-((bis-tert-butyloxycarbonyl)amino)-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 851(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.06 (br s, 1H) 7.52 (s, 1H) 7.20 (br s, 1H) 4.92 (br d, J = 7.46Hz, 2H) 4.44 (br s, 4H)3.74(br s,2H)2.02(br s,2H)1.78(br s,2H)1.55(s,9H)1.48(s,18H).

Intermediate 4-13 (1R, 5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-8-methoxy-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 901 (M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ8.99-9.10(m,1H)7.26-7.45(m,1H)7.02-7.23(m,4H)6.75-6.96(m,4H)4.98-5.21(m,2H)4.47-4.55(m,2H)4.21-4.29(m,2H )4.04-4.13(m,4H)3.81-3.88(m,3H)3.71-3.78(m,6H)3.60-3.69(m,2H)2.00-2.12(m,3H)1.77-1.87(m,2H)1.62-1.71(m,2H)1.41-1.51(m,9H).

Intermediate 4-14 (1R, 5S)-3-(7-(5-(bis(tert-butylcarbonyl)amino)-3-chloro-2-(trifluoromethyl)phenyl)-8-yloxy-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 863(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.06 (s, 1H), 7.88 (s, 1H), 7.37-7.27 (m, 1H), 5.09 (br d, J = 9.0Hz, 2H), 4.65 -4.39(m,2H),4.28(br s,2H),3.95-3.87(m,3H),3.76-3.53(m,2H),1.82(br s,2H),1.74-1.57(m,2H) ,1.47(s,9H),1.42-1.39(m,18H)

Intermediate 4-15 (1R, 5S)-3-(7-(3-acetylamino-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 711(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.37 (s, 1H), 9.24 (s, 1H), 8.68 (br d, J = 6.9Hz, 1H), 5.10 (q, J = 9.0Hz, 2H ),4.56(br d,J＝8.6Hz,2H),4.29(br s,2H),3.69(br t,J＝12.2Hz,2H),2.19(s,3H),1.82(br s,2H) ,1.71(br d,J＝9.6Hz,2H),1.47(s,9H).

Intermediate 4-16 (1R, 5S)-3-(7-(3-acetylamino-2,5-dichloro-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 727(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.99 (s, 1H) 9.25 (s, 1H) 8.51 (s, 1H) 4.98-5.20 (m, 2H) 4.54 (br d, J＝11.66Hz, 2H )4.29(br s,2H)3.68(br d,J＝7.48Hz,2H)2.21(s,3H)1.82(br d,J＝3.30Hz,2H)1.70(br d,J＝7.92Hz,2H) 1.46(s,9H).

Intermediate 4-17 (1R, 5S)-3-(7-(3-acetylamino-2-chloro-5-fluoro-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 711(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.98 (s, 1H) 9.26 (s, 1H) 8.34 (d, J = 13.63Hz, 1H) 5.11 (q, J = 8.84Hz, 2H) 4.48-4.62 (m,2H)4.22-4.36(m,2H)3.59-3.79(m,1H)3.69(br t,J＝12.82Hz,1H)2.18-2.26(m,3H)1.79-1.88(m,2H)1.71 (br d,J＝7.75Hz,2H)1.42-1.51(m,9H).

Intermediate 4-18 (1R, 5S)-3-(7-(3-amino-2,6-dichloro-5-fluorophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 635 (M+H) ⁺ .

Intermediate 4-19 (1R, 5S)-3-(7-(5-acetylamino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 693(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.60 (s, 1H), 9.19 (s, 1H), 8.09-7.97 (m, 1H), 7.73 (s, 1H), 5.10 (q, J = 9.1 Hz,2H),4.56(br s,2H),4.28(br s,2H),3.76-3.63(m,2H),2.11(s,3H),1.82(br s,2H),1.73-1.63(m ,2H),1.47(s,9H).

Intermediate 4-20 (1R, 5S)-3-(7-(3-chloro-5-(methylsulfonamido)-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 729(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.81 (s, 1H), 9.20 (s, 1H), 7.58 (d, J = 1.8Hz, 1H), 7.22 (d, J = 1.9Hz, 1H) ,5.10(q,J＝9.0Hz,2H),4.56(br s,2H),4.28(br s,2H),3.69(br d,J＝12.5Hz,2H),3.23(s,3H),1.81 (br s, 2H), 1.68 (br d, J = 7.3Hz, 2H), 1.47 (s, 9H).

Intermediate 4-21 (1R, 5S)-3-(7-(5-(bis-tert-butyloxycarbonylamino)-3-chloro-4-fluoro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 869(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ9.03 (br s, 1H), 7.26-7.21 (m, 1H), 4.90 (br d, J = 6.8Hz, 2H), 4.66-4.34 (m, 4H), 3.85-3.59(m,2H),2.00(br s,2H),1.76(br s,2H),1.52(s,9H),1.45(s,18H)

Intermediate 4-22 (1R, 5S)-3-(7-(5-(bis(4-methoxybenzyl)amino)-3-methyl-4-fluoro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 889(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.93-8.86(m,1H),7.10-7.02(m,4H),6.85-6.71(m,4H),6.66-6.53(m,1H),4.94 -4.76(m,2H),4.57-4.29(m,4H),4.26(s,4H),3.72(s,6H),3.68-3.55(m,2H),2.47-2.32(m,3H),1.95 -1.87(m,2H),1.68(br d,J＝7.9Hz,2H),1.45(s,9H).

Intermediate 4-23 (1R, 5S)-3-(7-(5-amino-3-fluoro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 635 (M+H) ⁺ .

Intermediate 4-24 (1R, 5S)-3-(7-(5-amino-3-cyano-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 642(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ9.39-8.96(m,1H),7.41(br s,1H),6.91-6.73(m,1H),6.62(br s,2H),5.24-4.96(m ,2H),4.54(br s,2H),4.28(br s,2H),3.68(br d,J＝10.4Hz,2H),1.81(br s,2H),1.68(br s,2H),1.55 -1.36(m,9H).

Intermediate 4-25 (1R, 5S)-3-(7-(5-amino-3-chloro-2-fluorophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 601(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.20 (s, 1H), 6.82 (m, 2H), 5.50 (s, 2H), 5.11 (q, J = 9.0Hz, 2H), 4.57 (d, J＝12.5Hz,2H),4.28(s,2H),3.68(d,J＝12.3Hz,2H),1.80(s,2H),1.68(d,J＝7.3Hz,2H),1.44(s, 9H).

Intermediate 4-26 (1R, 5S) -3- (7- (5-amino-3-chloro-2-cyanophenyl) -8-fluoro-2- (2,2,2-trifluoroethoxy) pyridine [4,3-d] Pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 608(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.21 (s, 1H), 6.87 (d, J = 2.1Hz, 1H), 6.80 (d, J = 1.8Hz, 1H), 5.10 (q, J = 9.0Hz,2H),4.56(d,J＝12.1Hz,2H),4.28(s,2H),3.68(d,J＝12.2Hz,2H),1.81(s,2H),1.68(d,J＝ 7.4Hz,2H),1.47(s,9H).

Intermediate 4-27 (1R, 5S)-3-(7-(5-amino-2-chloro-3-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 651 (M+H) ⁺ .

Intermediate 4-28 (1R, 5S)-3-(7-(5-amino-2-cyano-3-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 642 (M+H) ⁺ .

Intermediate 4-29 (1R, 5S)-3-(7-(5-amino-2-chloro-3-cyanophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 608(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.21 (s, 1H), 7.14 (d, J = 2.7Hz, 1H), 7.02 (d, J = 2.7Hz, 1H), 5.10 (dt, J = 9.1,7.0Hz,2H),4.56(s,2H),4.29(s,2H),3.68(d,J＝12.2Hz,2H),1.81(s,2H),1.69(d,J＝7.5Hz, 2H),1.48(s,11H).

Intermediate 4-30 (1R, 5S)-3-(7-(5-amino-2,3-dichlorophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 617 (M+H) ⁺ .

Intermediate 4-31 (1R, 5S)-3-(7-(3-amino-6-chloro-2-cyanophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 608(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.27 (s, 1H), 7.53 (d, J = 9.1Hz, 1H), 6.97 (d, J = 9.1Hz, 1H), 6.46 (s, 2H) ,5.10(q,J＝9.0Hz,2H),4.64(d,J＝12.3Hz,1H),4.47(d,J＝11.9Hz,1H),4.28(s,2H),3.76(d,J＝ 11.4Hz,1H),3.59(s,1H),1.83-1.64(m,4H),1.47(s,8H).

Intermediate 4-32 (1R, 5S)-3-(7-(5-(benzyloxy)-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 742 (M+H) ⁺ .

Intermediate 4-33 (1R, 5S)-3-(7-(5-amino-2-(trifluoromethyl)pyridin-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 618(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.18 (s, 1H) 8.12 (d, J = 2.20Hz, 1H) 6.87 (s, 1H) 6.32 (br d, J = 4.18Hz, 2H) 5.09 ( q,J＝9.17Hz,2H)4.55(br d,J＝12.10Hz,2H)4.27(br s,2H)3.67(br d,J＝11.44Hz,2H)1.93(br s,2H)1.80(br s,2H)1.35(s,9H).

Intermediate 4-34 (1R, 5S)-3-(7-(5-amino-4-(trifluoromethyl)pyridin-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 618(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.18 (s, 1H), 8.38 (s, 1H), 7.73 (s, 1H), 6.26 (s, 2H), 5.09 (q, J = 9.0Hz, 2H),4.55(br d,J＝11.6Hz,2H),4.28(br s,2H),3.67(br d,J＝10.3Hz,2H),1.82(br s,2H),1.67(br d, J＝7.5Hz,2H),1.47(s,9H).

Intermediate 4-35 (1R, 5S)-3-(7-(5-amino-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 632(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.23 (s, 1H) 8.12 (s, 1H) 6.02-6.16 (m, 2H) 5.00-5.21 (m, 2H) 4.55 (br t, J＝14.42Hz ,2H)4.30(br s,2H)3.60-3.80(m,2H)2.40-2.48(m,3H)1.83(br d,J＝1.76Hz,2H)1.70(br d,J＝7.92Hz,2H) 1.47(s,9H).

Intermediate 4-36 (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 872(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.12 (s, 1H), 7.26-7.11 (m, 4H), 6.89 (d, J = 8.4Hz, 4H), 6.50 (s, 1H), 5.07 ( q,J＝9.0Hz,2H),4.85-4.68(m,4H),4.59-4.43(m,2H),4.32-4.21(m,2H),3.73(s,6H),3.70-3.60(m, 2H),2.60(s,3H),1.85-1.76(m,2H),1.69-1.60(m,2H),1.46(s,9H).

Intermediate 4-37 (1R, 5S)-3-(8-fluoro-7-(1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

LC-MS: m/z 726(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.27 (d, J = 5.0 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 6.09 -5.93(m,1H),5.21-5.02(m,2H),4.59(t,J＝12.0Hz,2H),4.45-4.18(m,2H),3.92(d,J＝7.8Hz,1H), 3.85-3.54(m,3H),2.38(dd,J＝22.2,12.9Hz, 1H), 2.03 (d, J = 6.9Hz, 2H), 1.94-1.66 (m, 5H), 1.61 (s, 2H), 1.47 (s, 9H).

Preparation of Intermediate 5-1 Tert-butyl (1R, 5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step 1: Preparation of tert-butyl (1R,5S)-3-(8-fluoro-2-(2,2,2-trifluoroethoxy)-7-(trimethyltinyl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under nitrogen protection, a solution of tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.00 g, 6.10 mmol, 1.00 eq), trimethyl(trimethyltinyl)stannane (7.45 g, 22.7 mmol, 4.72 mL, 3.73 eq) and dichloropalladium-triphenylphosphine complex (428 mg, 609 μmol, 0.10 eq) in dioxane (25 mL) was reacted at 110 ° C for 2 h. The resulting mixture was quenched with a saturated aqueous solution of KF (10 mL) at 0 ° C and extracted with EtOAc (30 mL × 2). The combined organic phase was dried over anhydrous MgSO ₄ and filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by alumina column chromatography to obtain the target product (700 mg, 1.13 mmol, 18.5% yield).

LC-MS: m/z 622(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ9.06 (s, 1H) 4.81 (d, J = 8.46Hz, 2H) 4.44 (br d, J = 12.52Hz, 2H) 4.28 (br d, J = 1.43Hz, 2H)3.58(br d,J＝9.78Hz,2H)1.85-1.92(m,2H)1.66(d,J＝7.63Hz,2H)1.44(s,9H)0.29-0.49(m,9H).

Step 2: Preparation of tert-butyl (1R, 5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Under nitrogen protection, CuI (10.7 mg, 55.9 μmol, 0.30 eq) and Pd(PPh 3 ) 4 (43.1 mg, 37.3 μmol, 0.20 eq) were added to a solution of 3-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline (0.10 g, 186 μmol, 1.00 eq) and tert-butyl (1R,5S)-3-(8-fluoro-2-(2,2,2-trifluoroethoxy)-7-(trimethyltinyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- ₈ -carboxylate (208 mg, 336 μmol, 1.80 eq) in dioxane (1.0 mL) _. The obtained mixture was reacted at 120°C for 2h under microwave. The same test was carried out for 4 batches. The reaction solutions were combined and diluted with water (50mL) and extracted with EtOAc (100mL*2). The combined organic phase was washed with water (50mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (0.20g, 210μmol, 28.1% yield).

LC-MS: m/z 913(M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ9.09 (s, 1H), 7.16 (d, J = 8.4Hz, 4H), 7.12-7.05 (m, 1H), 6.87 (d, J = 8.6Hz, 4H) ,5.02-4.83(m,2H),4.74-4.52(m,2H),4.49-4.27(m,6H),3.82(s,6H),3.79-3.65(m,2H),2.05(s,3H) ,2.03-1.96(m,2H),1.79(br d,J=9.5Hz,2H),1.54(s,9H).

The following compounds were synthesized using the same method as intermediate 5-1 with different starting materials:

Intermediate 5-2: tert-butyl 3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 927 (M+H) ⁺ .

Intermediate 5-3: tert-butyl (1R, 5S)-3-(7-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-(prop-1-yn-1-yl)-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 913 (M+H) ⁺ .

Intermediate 5-4: tert-butyl (1R, 5S)-3-(7-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-(prop-1-yn-1-yl)-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 927 (M+H) ⁺ .

Intermediate 5-5: tert-butyl (1R, 5S)-3-(7-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-(prop-1-yn-1-yl)-2-(trifluoromethyl)phenyl)-8-fluoro-5-methyl 2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 927 (M+H) ⁺ .

Example 1 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(methoxymethyl)tetrahydro-1H- Preparation of pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step 1: Preparation of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of (3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol (1.01 g, 5.45 mmol, 4.59 eq) and (1R,5S)-tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.19 mmol, 1.00 eq) in THF (20 mL) was added t-BuONa (913 mg, 9.50 mmol, 8.00 eq). The reaction solution was reacted at 25°C for 16 h, then quenched with H ₂ O (10 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with saturated laboratory water (100 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (723 mg, 257 umol, 21.7% yield, 33.0% purity). It was directly used for the next step without purification.

Step 2: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxymethyl)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

To a solution of (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (670 mg, 238 umol, 33.0% purity, 1.00 eq) in DCM (6 mL) was added HCl/dioxane (4.00 M, 945 uL, 15.8 eq). The reaction solution was reacted at 25°C for 2 h, and then concentrated under reduced pressure to obtain the target product (430 mg, crude). It was used directly in the next step without purification.

Step 3: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

CsF (497 mg, 3.27 mmol, 121 uL, 20.0 eq) was added to a solution of 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxymethyl)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (400 mg, 163 umol, 32.0% purity, 1.00 eq) in DMF (6 mL). The reaction solution was reacted at 25° C. for 16 h and then filtered. The filtrate was concentrated under reduced pressure and the residue was separated by prep-HPLC to obtain the target product (63.0 mg).

LC-MS: m/z 627 (M+H) ⁺ .

Isomer 1 of Example 1 (11.3 mg, 17.6 umol, 10.8% yield) and Isomer 2 of Example 1 (19.2 mg, 29.9 umol, 18.3% yield) were obtained by chiral SFC separation.

Example 1 Isomer 1

LC-MS: m/z 627(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.17 (br s, 1H) 9.03 (s, 1H) 7.98 (dd, J = 9.16, 5.90Hz, 1H) 7.47 (t, J = 8.91Hz, 1H) 7.39(d,J＝2.51Hz,1H)7.18(d,J＝2.26Hz,1H)4.48(br d,J＝11.80Hz,1H)4.31(br d,J＝12.30Hz,1H)3.95-4.08( m,2H)3.94(s,1H)3.64(br d,J＝12.05Hz,1H)3.57(br s,3H)3.17-3.28(m,5H)2.79-2.94(m,2H)2.65-2.70(m,1H)1.90-2.06(m,2H)1.78(br d,J＝4.52Hz,3H)1.51- 1.69(m,8H).

Example 1 Isomer 2

LC-MS: m/z 627(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.17 (br s, 1H) 9.04 (s, 1H) 7.98 (dd, J = 9.16, 5.90Hz, 1H) 7.47 (t, J = 9.03Hz, 1H) 7.40(d,J＝2.51Hz,1H)7.18(d,J＝2.26Hz,1H)4.49(br d,J＝12.05Hz,1H)4.32(br d,J＝12.30Hz,1H)3.96-4.10( m,2H)3.94(s,1H)3.65(br d,J＝14.31Hz,1H)3.56-3.62(br s,3H)3.17-3.28(m,5H)2.80-2.95(m,2H)2.68(br d,J＝1.76Hz,1H)1.90-2.03(m,2H)1.78(br s,3H)1.51-1.72 (m,8H).

Example 1 Isomer 1 and Example 1 Isomer 2 were separated again by SFC to obtain Example 1 Isomer 1A, Example 1 Isomer 1B, Example 1 Isomer 2A and Example 1 Isomer 2B: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3S,7aR)-(3-(methoxymethyl)tetrahydro-1H- 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3R,7aS)-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3R,7aS)-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3R,7aR)-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3S,7aS)-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 1 Isomer 1A

LC-MS: m/z 627(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.14(s,1H),9.03(s,1H),7.98(dd,J＝9.20,5.92Hz,1H),7.46(t,J＝9.00Hz,1H),7.39(d,J＝2.64 Hz,1H),7.17(d,J＝2.56Hz,1H),4.47(d,J＝12.44Hz,1H),4.30(d,J＝12.32Hz,1H),3.97-4.07(m,2H), 3.92(s,1H),3.56-3.66(m,4H),3.17-3.27(m,5H),2.79-2.92(m,2H),2.63-2.69(m,1H),1.51-2.03(m,13H ).

Example 1 Isomer 1B

LC-MS: m/z 627(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.14 (s, 1H), 9.03 (s, 1H), 7.98 (dd, J = 9.24, 5.92Hz, 1H), 7.46 (t, J = 9.00Hz, 1H),7.39(d,J＝2.56Hz,1H),7.17(d,J＝2.60Hz,1 H),4.47(d,J＝12.32Hz,1H),4.30(d,J＝12.24Hz,1H),3.97-4.07(m,2H),3.92(s,1H),3.56-3.66(m,4H ),3.17-3.27(m,5H),2.80-2.92(m,2H),2.63-2.68(m,1H),1.51-2.04(m,13H).

Example 1 Isomer 2A

LC-MS: m/z 627(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.15 (s, 1H), 9.03 (s, 1H), 7.99-7.95 (m, 1H), 7.46 (t, J = 8Hz, 1H), 7.39 (s ,1H),7.18(s,1H),4.47(d,J＝8Hz,1H),4.30(d,J＝8Hz,1H),4.11(d,J＝4Hz,1H),4.01(d,J＝ 4Hz,1H) ,3.93(s,1H),3.63(d,J＝8Hz,1H),3.57-3.53(m,3H),3.44-3.40(m,1H),3.25(s,3H),3.19(s,2H) ,2.72-2.64(m,2H),2.05-1.97(m,2H),1.71-1.56(m,9H),1.52-1.44(m,1H).

Example 1 Isomer 2B

LC-MS: m/z 627(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.15 (s, 1H), 9.04 (s, 1H), 7.96 (m, 1H), 7.46 (t, J = 8Hz, 1H), 7.39 (m, 1H ),7.18(m,1H),4.65-4.56(m,1H),4.48-4.39(m,1H),4.30(d,J＝8Hz,1H),4.15-4.06(m,1H),4.02(t ,J＝4Hz,1H),3. 93(s,1H),3.85-3.75(m,1H),3.63(d,J＝4Hz,1H),3.58-3.54(m,3H),3.44-3.40(m,2H),3.25(s,3H ),3.18(s,2H),2.72-2.66(m,2H),2.07-2.02(m,3H),1.71-1.57(m,7H),1.51-1.44(m,1H).

The following examples were synthesized with different starting materials according to the method of Example 1:

Example 2 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-((ethoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 641(M+H) ⁺ .

Example 3 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-((isopropoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 655 (M+H) ⁺ .

Example 4 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-((cyclopropylmethyloxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 667 (M+H) ⁺ .

Example 5 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(cyclopropyloxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 653 (M+H) ⁺ .

Example 6 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 645 (M+H) ⁺ .

Isomer 6A and isomer 6B were obtained by chiral separation: cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl -6-fluoronaphthalen-2-ol and trans-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Isomer 6A

LCMS: m/z 645(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.17(s,1H),9.03(s,1H),7.97(q,J＝8Hz,1H) ,7.47(t,J＝8Hz,1H),7.39(s,1H),7.18(d,J＝4Hz,1H),5.47-5.32(m,1H),4.50(d,J＝8Hz,1H), 4.31(d,J＝8Hz,1H),4.07( s,2H),3.96(s,1H),3.66(d,J＝12Hz,1H),3.56(s,3H),3.28-3.21(m,6H),3.00-2.85(m,3H),2.36- 2.24(m,1H),2.087-1.92(m,3H),1.86-1.82(m,1H),1.73-1.58(m,6H).

Isomer 6B

LCMS: m/z 645(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.14(s,1H),9.03(s,1H),7.98(dd,J＝5.92Hz,9.20Hz,1H),7.46(t,J＝9.00Hz,1H),7.38(d,J＝ 2.52Hz,1H),7.17(d,J＝2.48Hz,1H),5.34(m,0.5H),5.20(m,0.5H),4.47(m,1H),4.29(m,1H),4.18( m,1H),4.10(m,1H),3.94(d,J＝5.28Hz,1H),3.63(m,1H),3.48(m,5H),3.26(s,3H),3.00(m,2H ),2.29(m,1H),1.72(m,9H).

Example 7 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R)-5-(cyclopropyloxymethyl)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 671(M+H)+.

Example 8A and Example 8B cis 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(trifluoromethoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and trans 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(trifluoromethoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 8A

LCMS: m/z 681(M+H) ⁺ .

Example 8B

LCMS: m/z 681(M+H) ⁺ .

Example 9 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(dihydro-1'H,3'H-spiro[1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro-naphthalen-2-ol

LCMS: m/z 609 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.15 (s, 1H), 9.03 (m, 1H), 7.97 (t, J = 8Hz, 1H) ,7.46(t,J＝8Hz,1H),7.39(d,J＝4Hz,1H),7.18-7.17(m,1H),4.47(t,J＝8Hz,1H),4.34-4.21(m,2H ),4.08-4.04(m,1H), 3.94(d,J＝4Hz,1H),3.63(t,J＝8Hz,1H),3.55(s,3H),2.99-2.94(m,1H),2.74-2.61(m,3H),2.03-1.85 (m,3H),1.83-1.76(m,3H),1.71-1.66(m,4H),0.49-0.45(m,4H).

Example 10 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 627 (M+H) ⁺ .

Example 10 was chiral resolved to give isomers 10A and 10B: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl Alkynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Isomer 10A:

LCMS: m/z 627(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.18(s,1H),9.06(s,1H),7.99(dd,J＝5.92,9.24Hz,1H),7.48(t,J＝9.00Hz,1H),7.40(d,J＝2.56 Hz,1H),7.19(m,1H),5.41(m,0.5H),5.28(m,0.5H),4.49(m,1H),4.35(m,2H),4.09(d,J＝10.24Hz ,1H),3.95(m,1H),3.58(m,4H),3.27(m,2H),3.11(m,3H),2.70(m,1H),2.16(m,3H),1.68(m, 4H),0.51(m,4H).

Isomer 10B:

LCMS: m/z 627 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.02 (s, 1H), 7.99 (dd, J = 5.96, 9.16Hz, 1H), 7.48 (t ,J＝9.04Hz,1H),7.40(d,J＝2.52Hz,1H),7.16(m,1H),5.48(m,0.5H),5.35(m,0.5H),4.48(m,1H) ,4.30(m,2H),4.12(m,1H),3. 93(s,1H),3.58(m,4H),3.26(m,2H),3.01(m,0.5H),2.89(m,0.5H),2.80(d,J＝9.92Hz,1H),2.62 (d,J=9.92Hz,1H),2.32(m,1H),2.03(m,2H),1.82(m,3H),1.65(m,3H),0.48(m,4H).

Example 11 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 609(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ9.03(m,1H),7.95(dd,J＝6.00,9.28Hz,1H),7.45(t,J＝9.00Hz,1H),7.37(d,J＝2.56Hz,1H),7.18( m,1H),4.49(m,2H),4.32(m,1H),4.14(m,2H),3.92(m,1H),3.76(m,1H),3.62(m,1H),3.58(m ,1H),2.90(m,1H),2.63(m,1H),2.04(m,7H),1.63(m,6H),1.24(m,1H),0.75(m,1H),0.58(m, 1H),0.43(m,1H),0.33(m,1H).

Examples 12A and 12B were synthesized using intermediates 1-13A and 1-13B as raw materials: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((trans)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidine-7- 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((cis)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 12A

LCMS: m/z 627(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.15(s,1H),9.04(s,1H),7.99-7.95(m,1H),7.46 (t,J＝8Hz,1H),7.39(d,J＝4Hz 1H),7.18(d,J＝4Hz 1H),5.25(d,J＝4Hz,1H),4.49(d,J＝12Hz,1H ),4.32(d,J＝12Hz,1H),4.25-4.17(m,2H),3.94(s,1H),3.65(d,J＝12Hz,1H),3.57(d,J＝8Hz,3H) ,3.26-3.14(m,1H),3. 05-2.96(m,1H),2.39-2.22(m,2H),2.15-2.05(m,1H),2.00-1.95(m,2H),1.65(s,4H),1.34-1.23(m,1H ),0.85-0.75(m,1H),0.61-0.55(m,1H),0.45-0.37(m,2H).

Example 12B

LCMS: m/z 627(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.19(s,1H),9.03(s,1H),7.99-7.95(m,1H),7.46 (t,J＝8Hz,1H),7.39(d,J＝4Hz 1H),7.18(d,J＝4Hz 1H),5.34(d,J＝4Hz,1H),4.50(d,J＝12Hz,1H),4.31-4.27(m,1H),4.27-4.16(m,2H),3.95(d,J＝4Hz ,1H),3.66(d,J＝12Hz,1H),3.57(d,J＝12Hz,3H),3.23-3.15(m,1H),2.99-2. 85(m,1H),2.40-2.31(m,1H),2.17-2.09(m,1H),2.05-1.86(m,3H),1.65(s,4H),1.34-1.23(m,2H), 0.81-0.76(m,1H),0.64-0.58(m,1H),0.52-0.46(m,1H),0.38-0.33(m,1H).

Example 13 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((7',7'-difluorotetrahydro-3'-H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-8a'(1'H)-yl)methoxy)-8-fluoropyridin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate

LCMS: m/z 659(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.25(br,1H),9.42(m,1H),9.15(m,2H),8.00(dd ,J＝6.00,9.20Hz,1H),7.47(t,J＝9.20Hz,1H),7.42(d,J＝2.40Hz,1H),7.19(m,1H),4.63(m,5H),4.23 (s,2H),3.91(m,4H),3.52(m,1H),3.39(m,4H),3.52(m,1H),3.39(m,1H),2.53(m,1H),1.97( m,5H),0.74(m,4H).

Example 14 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((6',6'-difluorotetrahydro-3'-H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-8a'(1'H)-yl)methoxy)-8-fluoropyridin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 645(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.15(s,1H),9.05(s,1H),7.97(dd,J＝5.92,9.24Hz ,1H),7.46(t,J＝9.00Hz,1H),7.39(d,J＝2.60Hz,1H),7.18(s,1H),4.64(dd,J＝2.92,10.88Hz,1H),4.47 (d,J＝12.64Hz,1H),4.35(m,2H),3.93(m,1H),3.60(m,4H),3.10(m,4H),2.81 (dd,J=3.96,8.68Hz,1H),2.84(m,1H),2.02(m,1H),1.91(m,3H),1.68(m,5H),0.52(m,4H).

Using intermediates 1-16A and 1-16B, Examples 15A and 15B were synthesized according to the method of Example 1:

4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 15A

LCMS: m/z 663(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.16(s,1H),9.05(s,1H),7.98(dd,J＝5.92,9.16Hz,1H),7.47(t,J＝9.04Hz,1H),7.40(d,J＝2.64 Hz,1H),7.18(m,1H),5.43(m,0.5H),5.29(m,0.5H),4.51(t,J＝12.16Hz,1H),4.31(m,1H),4.05(m ,2H),3.94(d,J＝4.16Hz,1H),3.61(m,4H),3.12(m,4H),2.22(m,5H),1.69(s,4H),1.54(m,2H) .

Example 15B

LCMS: m/z 663(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.17(s,1H),9.06(s,1H),7.98(dd,J＝5.92,9.12Hz,1H),7.47(t,J＝9.00Hz,1H),7.40(d,J＝2.68 Hz,1H),7.18(m,1H),5.35(m,0.5H),521(m,0.5H),4.48(m,1H),4.31(m,2H),4.18(m,1H),3.94 (s,1H),3.61(m,4H),3.21(m,2H),3.01(m,2H),2.16(m,5H),1.69(s,4H),1.54(m,2H).

Example 15C and 15D were synthesized from intermediates 1-16C and 1-16D according to the method of Example 1.

4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 15C

LCMS: m/z 663(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.20(s,1H),9.05(s,1H),7.98(dd,J＝5.92,9.28Hz,1H),7.48(t,J＝8.96Hz,1H),7.40(d,J＝2.52 Hz,1H),7.19(d,J＝2.52Hz,1H),5.45(m,0.5H),5.32(m,0.5H),4.48(d,J＝11.56Hz,1H),4.30(m,3H ),3.96(d,J＝2.88Hz,1H),3.59(m,4H),3.31(m,2H),3.01(m,2H),2.16(m,5H),1.69(s,4H),1.54 (m,2H).

Example 15D

LCMS: m/z 663(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.16(s,1H),9.04(s,1H),7.98(dd,J＝6.00,9.28Hz,1H),7.48(t,J＝9.04Hz,1H),7.40(d,J＝2.44 Hz,1H),7.19(m,1H),5.51(m,0.5H),5.37(m,0.5H),4.50(m,1H),4.30(m,1H),4.16(m,1H),3.98 (m,2H),3.61(m,4H),3.28(m,1H),3.07(m,1H),2.79(m,1H),2.21(m,5H),1.59(s,6H).

Using intermediates 1-16E and 1-16F, examples 15E and 15F were synthesized according to the method of example 1.

4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'S,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'S,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 15E

LCMS: m/z 663(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.15(s,1H), 9.05(s,1H), 7.97(dd,J＝5.92,9.16Hz,1H), 7.46(t,J＝9.00Hz,1H), 7.39(d,J＝2.52 Hz,1H), 7.17(d,J＝2.52Hz,1H), 5.44(m,0.5H), 5.30(m,0.5H), 4.48(d,J＝11.72Hz,1H), 4.30(m,3H ), 3.93(d,J=2.84Hz,1H), 3.61(m,4H), 3.16(m,2H), 2.77(m,2H), 2.14(m,5H), 1.61(s,6H).

Example 15F

LCMS: m/z 663(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.16(s,1H), 9.04(s,1H), 7.97(dd,J＝5.92,9.16Hz,1H), 7.46(t,J＝8.96Hz,1H), 7.39(d,J＝2.60 Hz,1H), 7.18(m,1H), 5.50(m,0.5H), 5.36(m,0.5H), 4.50(m,1H), 4.29(m,1H), 4.14(m,1H), 4.01 (m,1H), 3.94(s,1H), 3.60(m,4H), 3.28(m,1H), 3.03(m,2H), 2.78(m,1H), 2.16(m,5H), 1.65( s,6H).

Using intermediates 1-16G and 1-16H, examples 15G and 15H were synthesized according to the method of example 1:

4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'S,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'S,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 15G

LCMS: m/z 663(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.17(s,1H), 9.04(s,1H), 7.97(dd, J＝5.96,9.20Hz,1H), 7.46(t,J＝9.00Hz,1H), 7.39(d,J＝2.56Hz,1H), 7.17(m,1H), 5.42(m,0.5H), 5.28 (m,0.5H), 4.49(m,1H), 4.29(m,1H), 4.04(m,2H), 3.93(m,1H), 3.62(m,4H), 3.09(m,4H), 2.11 (m,5H), 1.56(s,6H).

Example 15H

LCMS: m/z 663(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.01(s,1H), 7.66(m,1H), 7.21(m,1H), 7.01(m ,2H), 5.34(m,0.5H), 5.20(m,0.5H), 4.28(m,4H), 3.75(m,1H), 3.58(m,3H), 3.17(m,3H), 2.99( m,2H), 2.19(m,5H), 1.56(s,6H).

Using intermediates 1-11A and 1-11B as starting materials, the following examples were synthesized according to the method of Example 1:

Examples 16A and 16B 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 16A 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 645(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.14(s,1H),9.03(s,1H),7.99-7.95(m,1H),7.46 (t,J＝8Hz,1H),7.39(s,1H),7.18(t,J＝4Hz,1H),4.49(t,J＝12Hz,1H),4.31(t,J＝12Hz,1H), 4.09(d,J＝12Hz,1H),3.98(d,J＝4Hz,1H),3.95-3.93(m,1H), 3.65(t,J＝8Hz,1H),3.59-3.56(m,3H),3.06(d,J＝12Hz,1H),3.00-2.95(m,1H),2.80-2.76(m,1H),2.71 -2.65(m,1H),2.14-2.10(m,1H),1.96-1.87(m,3H),1.84-1.75(m,2H),1.66(s,4H),1.56-1.51(m,2H) .

Example 16B 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS: m/z 645(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.17(s,1H),9.04(s,1H),7.99-7.95(m,1H),7.46 (t,J＝8Hz,1H),7.39(s,1H),7.18(d,J＝4Hz,1H),4.49(t,J＝12Hz,1H),4.33(d,J＝12Hz,1H), 4.22-4.15(m,2H),3.92(s,1H),3.95-3.93(m,1H),3.65(d,J ＝12Hz,1H),3.58-3.56(m,3H),3.12-3.08(m,1H),3.04-3.00(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m, 1H), 2.10-2.05 (m, 1H), 2.01-1.97 (m, 1H), 1.92 (d, J = 16Hz, 1H), 1.84-1.75 (m, 2H), 1.66-1.44 (m, 7H).

Example 16B was separated by chiral HPLC (SFC-150 (Waters), column: IG 20*250 mm, 10 um (Daicel), column temperature: 35°C, mobile phase: _CO2 /EtOH [0.5% _NH3 (7M in MeOH)] = 120/40) to give isomers Example 16B-1 and Example 16B-2.

Example 16B-1 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

RT: 15.079min. LCMS: m/z 645 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.04 (s, 1H), 7.93-7.89 (m, 1H), 7.41 (d, J = 8Hz, 1H),7.32(s,1H),7.17(s,1H),4.49(d,J＝12Hz,1H),4.35(d,J＝12Hz,1H),4.20-4.16(m,2H),3.89( s,1H),3.64-3.55(m,5H), 3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.02-1.98 (m,1H),1.92(d,J＝12Hz,1H),1.84-1.75(m,3H),1.66-1.47(m,8H).

Example 16B-2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

RT: 20.572min. LCMS: m/z 645 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.04 (s, 1H), 7.95-7.99 (m, 1H), 7.46 (t, J = 8Hz, 1H),7.39(s,1H),7.18(s,1H),4.49(d,J＝12Hz,1H),4.35(d,J＝12Hz,1H),4.20-4.18(m,2H),392( s,1H),3.65-3.56(m,5H),3 .13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.02- 1.98(m,1H),1.92(d,J=12Hz,1H),1.84-1.74(m,3H),1.67-1.45(m,8H).

Using intermediate 1-11A as the starting material, the following examples were synthesized according to the method of Example 1:

Example 17: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

LCMS: m/z 649 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.01 (s, 1H), 9.10 (s, 1H), 7.77 (q, J = 4Hz, 1H) ,7.38(d,J＝8Hz,1H),7.34(d,J＝4Hz,1H),7.03(d,J＝4Hz,1H),4.44(d,J＝12Hz,2H),4.26-4.17(m ,2H),3.62(t,J＝12Hz,2H),3.55(s,2H),3.13(q,J＝8Hz,1H),3.04 -2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.39-2.34(m,1H),2.15(t,J＝8Hz,1H),2.12- 2.06(m,1H),2.02-1.98(m,1H),1.92(d,J＝12Hz,1H),1.80-1.73(m,2H),1.63-1.44(m,7H),7.38(t,J =8Hz,3H).

Two isomers were obtained by chiral HPLC separation:

Example 17A: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

RT: 14.093 min (U3000 (ThermoFisher); column: CHIRALPAK IF-3 4.6 mm*150 mm, 3 um; column temperature: 40°C; mobile phase: n-hexane: ethanol-diethylamine = 85/15-0.1%). LCMS: m/z 649 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.94(s,1H),9.11(s,1H),7.77(q,J＝4Hz,1H),7.38(d,J＝8Hz,1H),7.34(s,1H),7.04(d,J＝4Hz,1H),4.44(d,J＝12Hz,2H),4.26-4.17(m,2H),3.65-3 .56(m,4H),3.13(q,J＝8Hz,1H ),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.54(m,1H),2.39-2.34(m,1H),2.17-2.00(m,2H),2.00-1.98(m,1H),1.92(d,J＝12Hz,1H),1.82-1 .44(m,10H),0.73(t,J＝8Hz,3H).

Example 17B: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

RT: 14.840 min (U3000 (ThermoFisher); column: CHIRALPAK IF-3 4.6 mm*150 mm, 3 um; column temperature: 40°C; mobile phase: n-hexane: ethanol-diethylamine = 85/15-0.1%). LCMS: m/z 649 (M+H) ⁺ .1H NMR (400 MHz, DMSO-d ₆ )δ9.96(s,1H),9.11(s,1H),7.77(q,J＝4Hz,1H),7.38(d,J＝8Hz,1H),7.34(s,1H),7.03(d,J＝4Hz,1H),4.45(d,J＝16Hz,2H),4.26-4.17(m,2H),3.65-3 .55(m,4H),3.13(q,J＝8Hz,1H ),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.54(m,1H),2.39-2.34(m,1H),2.17-2.00(m,2H),2.00-1.98(m,1H),1.92(d,J＝12Hz,1H),1.80-1 .44(m,10H),0.73(t,J＝8Hz,3H).

Example 18: 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

LCMS: m/z 635 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.01 (s, 1H), 6.78 (s, 1H), 4.36 (d, J = 9.20Hz, 1H ),4.17(m,2H),3.55(m,4H),3.09(m,1H),2.99(m,1H),2.70(m,2H),2.54(m,1H),2.36(m,3H) ,2.05(m,1H),1.97(m,1H),1.99(m,1H),1.79(m,2H),1.56(m,7H).

Example 19: 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3d]pyrimidin-7-yl)-4-methyl-5-(pentafluoroethyl)pyrrolidine Pyridin-2-amine

LCMS: m/z 685 (M+H) ⁺ .

Using intermediate 1-11A-1 as the starting material, the following examples were synthesized according to the method of Example 1:

Example 20: 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthol-2-ol

LCMS: m/z 659(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.20(br,1H),9.06(s,1H),7.98(dd,J＝5.88Hz,J ＝9.20Hz,1H),7.48(t,J＝9.00Hz,1H),7.40(d,J＝2.64Hz,1H),7.19(s,1H),4.30(m,4H),3.94(s,1H ),3.58(m,2H),3.11(m,1H),3.02(m,1H),2.71(d,J＝11.96Hz,1H),2.55(m,1H),2.06(m,2H),1.71 (m,10H),1.25(m,5H).

Chiral separation (SFC-150 (Waters); column: OD 20*250 mm, 10 um (Daicel)) gave isomers 20A and 20B: 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl )-5-ethynyl-6-fluoronaphthol-2-ol and 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthol-2-ol

Isomer 20A

RT:0.905min. LCMS: m/z 659(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.18(s,1H),9.07(s,1H),8.01-7.97(m,1H),7.48 (t,J＝8Hz,1H),7.40(d,J＝4Hz,1H),7.19(s,1H),4.44(t,J＝12Hz,1H),4.35-4.15(m,3H),3.94( s,1H),3.60-3.57(m,2H),3.3 8(s,1H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-1.99(m ,2H),1.93(d,J=16Hz,1H),1.84-1.46(m,9H),1.38-1.32(m,1H),1.26(s,3H).

Isomer 20B

RT:1.419min. LCMS: m/z 659(M+H) ⁺ . ¹ H NMR(400MHz, DMSO-d ₆ )δ10.20(s,1H),9.07(s,1H),8.01-7.97(m,1H),7.48 (t,J＝8Hz,1H),7.40(d,J＝4Hz,1H),7.20(s,1H),4.49-4.35(m,2H),4.31(d,J＝12Hz,1H),4.20( s,2H),3.95(s,1H),3.64-3.56(m ,2H),3.43(d,J＝16Hz,1H),3.13-3.09(m,1H),3.04-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m, 1H),2.11-2.07(m,1H),2.02-1.99(m,1H),1.82-1.35(m,10H),1.29-1.24(m,3H).

Example 21: (1S, 7a'S)-7a'-(((4-(1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthol-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]

LC-MS: m/z 609(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.07(s,1H),8.25(d,J＝8Hz,1H),8.22(d,J＝8Hz,1H),7.79-7.60(m,3H),4.51(d,J＝12Hz,1H ),4.38(d,J＝12Hz,1H),4.24-4.19(m,2H),4.02(s,1H),3.67-3.62(m,4H),3.14-3.09(m,1H),3.05-3.00 (m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.02-1.90(m,2H),1.82-1.45(m, 9H).

Example 22: (1S, 7a'S)-7a'-(((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]

LC-MS: m/z 609(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.21 (s, 1H), 9.20 (s, 1H), 7.74 (s, 1H), 7.50 (d, J = 8Hz, 1H), 4.47 (s, 2H ),4.25-4.19(m,2H),3.64-3.58(m,3H),3.14(q,J＝7Hz,J＝5Hz,1H),3.05-3.00(m,1H),2.74(d,J＝ 12Hz,1H),2.57-2.55(m,4H),2.19(s,2H),2.12-1.45(m,8H).

Example 23: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin-7-yl)-7-fluorobenzo[d]thiazol-2-amine

LC-MS: m/z 627(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 7.91 (s, 1H), 7.42 (dd, J = 5.80, 8.48Hz, 1H), 7.07 (t, J = 8.88Hz, 1H),4.38(d,J＝12.12Hz,2H),4.19(m,2H),3.57(m,4H),3.09(m,1H),3.01(m,1H),2.70(d,J＝11.84 Hz,1H),2.54(m,1H),2.08(m,1H),1.98(m,1H),1.88(d, J＝13.32Hz,1H),1.63(m,9H).

Example 24: 4-(4-((1R,5S)-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

LC-MS: m/z 651(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.07(s,1H),8.10(s,2H),7.44-7.40(m,1H),7.15(t,J＝8Hz,1H),4.43(d,J＝12Hz,2H),4.23- 4.17(m,2H),3.63(d,J＝12Hz,2H),3.53(s,2H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz ,1H),2.57-2.55(m,1H),2.12-2.07(m,1H),2.03-1.97(m,1H),1.92-1.89(m,2H),1.86-1.71(m,2H),1.64 -1.44(m,7H).

Example 25: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4,6-dichloro-3-fluoroaniline

LC-MS: m/z 638(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.18(s,1H),9.59(s,1H),9.36(s,1H),9.25(s,1H),7.71(d,J＝7.56Hz, 1H),5.76(s,2H),4.67(m,4H),4.21(m,2H),3.64(m,2H),3.13(m,1H),2.47(m,1H),2.28(m,4H ),1.88(m,9H).

Example 26: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 652(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.10 (s, 1H), 6.84 (d, J = 8.7Hz, 1H), 6.01 (s, 2H), 4.48-4.37 (m, 2H), 4.27- 4.13(m,2H),3.75-3.58(m,4H),3.13-3.06(m,1H),3.04-2.98(m,1H),2.75-2.68(m,1H),2.55(m,1H), 2.36(d,3H),2.15-1.37(m,13H).

Example 27: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

LC-MS: m/z 654(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.06 (s, 1H), 6.89 (s, 1H), 6.48 (s, 1H), 6.34 (s, 1H), 4.39 (d, J = 12.08Hz, 2H),4.20(m,2H),3.59(m,4H),3.10(m,1H),3.02(m,1H),2.71(d,J＝11.88Hz,1H),2.56(m,1H), 2.07(m,1H),1.99(m,1H),1.88(d,J＝13.32Hz,1H),1.62(m,10H).

Example 28: 4-(4-(3,9-diazabicyclo[4.2.1]non-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LC-MS: m/z 659(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.20 (s, 1H), 9.09 (d, J = 16Hz, 1H), 8.00-7.95 (m, 1H), 7.47 (t, J = 8Hz, 1H) ,7.40(s,1H),7.22-7.19(m,1H),4.71(d,J＝12Hz,1H),4.42(d,J＝12Hz,1H),4.25-4.15(m,2H),4.09- 3.99(m,2H),3 .92-3.82(m,2H),3.73-3.67(m,2H),3.13-3.08(m,1H),3.04-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57- 2.55(m,1H),2.11-1.95(m,3H),1.92-1.89(m,3H),1.84-1.72(m,3H),1.65-1.45(m,5H).

Example 29: 4-(4-(3-amino-3-methylpiperidin-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LC-MS: m/z 647(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.16 (s, 2H), 9.25 (d, J = 56Hz, 1H), 7.99-7.96 (m, 1H), 7.46 (t, J = 8Hz, 1H) ,7.40(d,J＝4Hz,1H),7.22-7.20(m,1H),4.24-4.16(m,2H),4.10(m,1H),4.03-4.00(d,J＝12Hz,1H), 3.95(s,1H),3.89(d,J＝12Hz,1H),3.73 -3.65(m,1H),3.60-3.47(m,2H),3.13-2.99(m,2H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.10-2.05( m,1H),2.02-1.97(m,2H),1.92(s,1H),1.89(s,1H),1.83-1.74(m,3H),1.64-1.44(m,5H),1.10(d, J=4Hz,3H).

Example 30 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-methoxypyridin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 664(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.96 (s, 1H), 7.18 (d, J = 11.68Hz, 1H), 5.67 (s, 2H), 4.35 (d, J = 12.40Hz, 2H) , 4.20(m,2H), 3.85(s,3H), 3.53(m,4H), 3.11(m,1H), 3.02(m,1H), 2.71(m,1H), 1.73(m,17H).

Example 31: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-methoxypyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

LC-MS: m/z 666(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 6.82 (d, J = 2.24Hz, 1H), 6.36 (d, J = 2.28Hz, 1H), 6.19 (s, 2H) , 4.36(m,2H), 4.20(m,2H), 3.89(s,3H), 3.57(m,4H), 3.09(m,1H), 3.00(m,1H), 2.70(m,1H), 2.55(m,1H), 1.64(m,13H).

Example 32: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-amino-6-fluorobenzo[b]thiophene-3-carbonitrile

LC-MS: m/z 651 (M+H) ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δδ9.07(s,1H),7.82-7.80(m,2H),7.28-7.25(m,1H),4.42(d,J＝12Hz,2H),4.22-4.16(m,2H),3.62(d,J＝12Hz,2H),3.51(s,2H),3.12-3.08(m,1H),3.04-2.99(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.11-2.06(m,1H),2.02-1.96(m,1H),1.91-1.71(m,4H),1.63-1.45(m,7H)。

Example 33: (1S, 7a'S)-7a'-(((4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(5-(trifluoromethyl)-1H-indazol-4-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]

LC-MS: m/z 645(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.71 (s, 1H), 9.17 (s, 1H), 7.86 (m, 3H), 4.46 (m, 2H), 4.21 (m, 2H), 3.63 ( m,4H), 3.10(m,1H), 3.02(m,1H), 2.71(m,1H), 2.55(m,1H), 2.08(m,1H), 2.00(m,1H), 1.89(m ,1H), 1.67(m,10H).

Example 34: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)aniline

LC-MS: m/z 672(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.11 (s, 1H), 7.09 (d, J = 7.92Hz, 1H), 6.48 (s, 2H), 4.39 (m, 2H), 4.20 (m, 2H), 3.61(m,4H), 3.10(m,1H), 3.00(m,1H), 2.70(m,1H), 2.54(m,1H), 2.06(m,1H), 1.99(m,1H ), 1.88(m,1H), 1.64(m,10H).

Example 35: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2,5-dichloro-4-(trifluoromethyl)aniline

LC-MS: m/z 688(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.12 (s, 1H), 7.15 (s, 1H), 6.64 (s, 2H), 4.39 (m, 2H), 4.20 (m, 2H), 3.59 ( m,4H), 3.10(m,1H), 3.00(m,1H), 2.70(m,1H), 2.54(m,1H), 2.06(m,1H), 1.97(m,1H), 1.88(m ,1H), 1.64(m,10H).

Example 36: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-chloro-5-fluoro-4-(trifluoromethyl)aniline

LC-MS: m/z 672(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.13 (s, 1H), 6.86 (d, J = 13.68Hz, 1H), 6.68 (s, 2H), 4.38 (d, J = 12.32Hz, 2H) , 4.19(m,2H), 3.58(m,4H), 3.10(m,1H), 3.00(m,1H), 2.71(m,1H), 2.53(m,1H), 2.07(m,1H), 2.00(m,1H), 1.89(m,1H), 1.65(m,10H).

Example 37: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2,4-dichloro-5-fluoroaniline

LC-MS: m/z 638(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(s,1H),6.94(d,J＝12Hz,1H),6.05(s,2H),4.49(d,J＝12Hz,2H),4.25-4.18(m,2H),3.78( s,2H),3.71(d,J＝16Hz,2H),3.12-3.08(m,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m ,1H),2.10-2.05(m,1H),2.02-1.95(m,1H),1.92(d,J＝16Hz,1H),1.84-1.70(m,6H),1.65-1.44(m,4H) .

Example 38: N-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin-7-yl)-5-chloro-4-(trifluoromethyl)phenyl)acetamide

LC-MS: m/z 696(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.50(s,1H),9.09(s,1H),8.03(s,1H),7.70(s,1H),4.43-4.40(m,2H), 4.22-4.15(m,2H),3.58(m,4H),3.12-3.07(m,1H),3.03-2.98(m,1H),2.73(d,J＝12Hz,1H),2.55-2.53(m ,1H),2.10(s,3H),2.08-1.95(m,2H),1.91-1.70(m,3H),1.63-1.44(m,8H).

Example 39: N-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenyl)methanesulfonamide

LC-MS: m/z 732(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.12 (s, 1H), 8.03 (s, 1H), 7.33 (s, 1H), 6.99 (s, 1H), 4.51 (t, J = 12Hz, 2H ),4.25-4.19(m,2H),3.85(s,2H),3.75-3.65(m,2H),3.14-3.09(m,1H),3.05-3.01(m,1H),2.99(s,3H ),2.75(d,J＝12Hz,1H),2.58-2.55(m,1H),2.11-2.05(m,1H),2.03-1.97(m, 1H), 1.92 (d, J = 12Hz, 1H), 1.83-1.78 (m, 6H), 1.65-1.45 (m, 4H).

Example 40: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl))-5-chloro-4-(trifluoromethyl)phenol

LC-MS: m/z 655(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 7.20 (d, J = 2.44Hz, 1H), 6.80 (d, J = 2.40Hz, 1H), 4.40 (d, J = 12.04Hz,2H), 4.20(m,2H), 3.59(m,4H), 3.10(m,1H), 3.01(m,1H), 2.71(m,1H), 2.55(m,1H), 2.07( m,1H), 1.99(m,1H), 1.87(m,1H), 1.64(m,10H).

Example 41: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-3-chloro-2-fluoro-4-(trifluoromethyl)aniline

LC-MS: m/z 672(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.05 (s, 1H), 6.69 (d, J = 8.28Hz, 1H), 6.49 (s, 2H), 4.38 (d, J = 12.44Hz, 2H) , 4.18(m,2H), 3.57(m,4H), 3.09(m,1H), 3.00(m,1H), 2.70(m,1H), 2.53(m,1H), 2.06(m,1H), 1.99(m,1H), 1.87(m,1H), 1.61(m,10H).

Example 42: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 652(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.04(s,1H),6.57(d,J＝8Hz,1H),6.02(s,2H),4.43(d,J＝12Hz,2H),4.21-4.15(m,2H),3.62- 3.59(m,4H),3.12-3.07(m,1H),3.03-2.98(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.34(s,3H ),2.09-2.04(m,1H),2.01-1.95(m,1H),1.91(d,J＝16Hz,1H),1.83-1.70(m,3H),1.65-1.44(m,7H).

Example 43: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-amino-2-(trifluoromethyl)benzonitrile

LC-MS: m/z 645(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 7.22 (d, J = 2.40Hz, 1H), 6.83 (d, J = 2.32Hz, 1H), 6.61 (s, 2H) , 4.39(m,2H), 4.20(m,2H), 3.58(m,4H), 3.10(m,1H), 3.00(m,1H), 2.71(m,1H), 2.55(m,1H), 2.07(m,1H), 2.00(m,1H), 1.88(m,1H), 1.64(m,10H).

Example 44: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-fluoro-4-(trifluoromethyl)aniline

LC-MS: m/z 638(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.06(s,1H),6.60(d,J＝16Hz,1H),6.39(d,J＝4Hz,3H),4.42(d,J＝12Hz,2H),4.22-4.16(m,2H ),3.62(s,1H),3.59(s,3H),3.13-3.08(m,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.54(m ,1H),2.10-2.05(m,1H),2.02-1.95(m,1H),1.92(d,J＝16Hz,1H),1.83-1.71(m,3H),1.63-1.44(m,7H) .

Example 45: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-chloro-5-(trifluoromethyl)aniline

LC-MS: m/z 654(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.11(s,1H),7.17(d,J＝4Hz,1H),6.91(d,J＝4Hz,1H),5.95(s,2H),4.44(d,J＝12Hz,2H), 4.24-4.18(m,2H),3.62(s,1H),3.59(s,3H),3.13-3.08(m,1H),3.04-3.00(m,1H),2.74(d,J＝12Hz,1H ),2.58-2.54(m,1H),2.11-2.05(m,1H),2.02-1.96(m,1H),1.92(d,J＝12Hz,1H),1.84-1.73(m,3H),1.67 -1.45(m,7H).

Example 46: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-fluoroaniline

LC-MS: m/z 604(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.10 (s, 1H), 6.85-6.82 (m, 1H), 6.78-6.75 (m, 1H), 5.47 (s, 2H), 4.42 (d, J ＝12Hz,2H),4.23-4.17(m,2H),3.60(d,J＝12Hz,2H),3.53(s,2H),3.13-3.08(m,1H ),3.04-3.00(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.02-1.97(m,1H),1.92 (d,J＝12Hz,1H),1.85-1.71(m,3H),1.64-1.45(m,7H).

Example 47: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4,5-dichloroaniline

LC-MS: m/z 620(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 6.89 (d, J = 2.60Hz, 2H), 6.65 (d, J = 2.68Hz, 2H), 5.74 (s, 2H) , 4.38(d,J=11.84Hz,2H), 4.18(m,2H), 3.54(m,4H), 3.10(m,1H), 3.00(m,1H), 2.70(m,1H), 2.53( m,1H), 2.06(m,1H), 1.98(m,1H), 1.87(m,1H), 1.58(m,10H).

Example 48: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-amino-2-chlorobenzonitrile

LC-MS: m/z 611(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.11 (s, 1H), 7.13 (d, J = 2.72Hz, 1H), 7.01 (d, J = 2.76Hz, 1H), 6.01 (s, 2H) , 4.40(d,J=12.00Hz,2H), 4.20(m,2H), 3.60(m,4H), 3.10(m,1H), 3.01(m,1H), 2.70(m,1H), 2.54( m,1H), 2.09(m,1H), 1.99(m,1H), 1.88(m,1H), 1.61(m,10H).

Example 49: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-amino-6-chlorobenzonitrile

LC-MS: m/z 611(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.11 (s, 1H), 6.86 (d, J = 4Hz, 1H), 6.79 (d, J = 4Hz, 1H), 6.71 (s, 2H), 4.42 (d,J＝12Hz,2H),4.23-4.17(m,2H),3.62(d,J＝12Hz,1H),3.55(s,3H),3.12-3.07(m,1 H),3.03-2.99(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.10-2.05(m,1H),2.02-1.96(m,1H), 1.91(d,J=12Hz,1H),1.83-1.70(m,3H),1.65-1.44(m,7H).

Example 50: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro 1,2'-bis-fused pyrrolidine-7a'(5'H)-yl)methoxy)-8-fluoropyridin-7-yl)-4-amino-6-(trifluoromethyl)benzonitrile

LC-MS: m/z 645(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(s,1H),7.17(d,J＝4Hz,1H),7.02(d,J＝4Hz,1H),6.95(s,2H),4.45(d,J＝12Hz,2H), 4.25-4.19(m,2H),3.65(s,1H),3.62(s,3H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J＝12Hz,1H ),2.57-2.55(m,1H),2.13-2.05(m,1H),2.03-1.97(m,1H),1.92(d,J＝12Hz,1H),1.83-1.76(m,3H),1.65 -1.45(m,7H).

Example 51: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-amino-3-chlorobenzonitrile

LC-MS: m/z 611(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.17 (s, 1H), 7.51 (d, J = 9.04Hz, 1H), 6.95 (d, J = 9.04Hz, 1H), 6.45 (s, 2H) , 4.50(m,1H), 4.34(m,1H), 4.20(m,2H), 3.64(m,4H), 3.09(m,1H), 3.01(m,1H), 2.70(m,1H), 2.56(m,1H), 2.07(m,1H), 1.99(m,1H), 1.91(m,1H), 1.67(m,10H).

Example 52: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)pyridin-3-amine

LC-MS: m/z 621(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.12 (s, 1H), 8.13 (d, J = 4Hz, 1H), 6.97 (d, J = 4Hz, 1H), 6.31 (s, 2H), 4.51 (d,J＝12Hz,2H),4.25-4.19(m,2H),3.83(s,2H),3.73(d,J＝12Hz,2H),3.13-3.09(m,1 H),3.04-3.00(m,1H),2.75(d,J＝12Hz,1H),2.58-2.55(m,1H),2.11-2.06(m,1H),2.02-1.96(m,1H), 1.93(d,J=12Hz,1H),1.84-1.74(m,3H),1.65-1.45(m,7H).

Example 53: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)pyridin-3-amine

LC-MS: m/z 621(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.09 (s, 1H), 8.38 (s, 1H), 7.14 (s, 1H), 6.24 (s, 2H), 4.42 (d, J = 12.24Hz, 2H), 4.19(m,2H), 3.62(m,4H), 3.10(m,1H), 3.01(m,1H), 2.71(m,1H), 2.55(m,1H), 2.07(m,1H ), 1.98(m,1H), 1.89(m,1H), 1.64(m,10H).

Example 54: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-4-methyl-6-(trifluoromethyl)pyridin-3-amine

LC-MS: m/z 635 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.12 (s, 1H), 8.10 (s, 1H), 6.06 (s, 2H), 4.41 (d, J = 12Hz, 2H), 4.23-4.15 (m, 2H), 3.63 (d, J = 12Hz, 1H), 3.57 (s, 3H), 3.12-3.07 ( m,1H),3.03-2.98(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.09-2.05(m,1H),2.01-1.95(m,1H),1.91(d,J＝12Hz,1H),1.83-1.76(m,6H),1.64 -1.43(m,7H).

Example 55: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

LC-MS: m/z 635(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.10 (s, 1H), 6.69 (s, 2H), 6.26 (s, 1H), 4.51 (d, J = 13.00Hz, 2H), 4.21 (m, 2H), 3.94(m,2H), 3.79(d,J＝13.16Hz,2H), 3.10(m,1H), 3.03(m,1H), 2.72(m,1H), 2.54(m,1H), 2.49(m,3H), 2.08(m,1H), 1.99(m,1H), 1.89(m,1H), 1.65(m,10H).

Example 56: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-chloro-3-(trifluoromethyl)aniline

LC-MS: m/z 654 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.12 (s, 1H), 7.47 (d, J = 8Hz, 1H), 7.14 (d, J = 8Hz, 1H), 6.09 (s, 2H), 4.48 (d, J = 12Hz, 2H), 4.24-4.19 (m, 2H), 3.69-3.65 (m, 4H), 3 .13-3.08(m,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.54(m,1H),2.12-2.05(m,1H),2.01-1.97(m,1H),1.92(d,J＝16Hz,1H),1.83-1.44( m,10H).

Example 57: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-2-(trifluoromethyl)aniline

LC-MS: m/z 654 (M+H) ⁺ .

Example 58: (1R, 5S)-3-(7-(2-cyclopropyl-4-methylpyridin-3-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-amine

LC-MS: m/z 607(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.17 (s, 1H), 8.38 (d, J = 4Hz, 1H), 7.16 (d, J = 4Hz, 1H), 4.43 (t, J = 12Hz, 2H),4.23-4.16(m,2H),3.63-3.57(m,4H),3.12-3.07(m,1H),3.03-2.98(m,1H),2.73(d,J＝ 12Hz,1H),2.56-2.52(m,1H),2.10-1.96(m,5H),1.91(d,J＝12Hz,1H),1.84-1.70(m,2H),1.64-1.44(m,8H ),1.03-0.97(m,1H),0.92-0.85(m,2H),0.80-0.70(m,2H).

Example 59: 3-Chloro-5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 668 (M+H) ⁺ .

Example 59 was subjected to chiral separation (SFC-150 (Waters); column: OD 20*250 mm, 10 um (Daicel)) to give isomers 59A and 59B: 3-chloro-5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin 3-Chloro-5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline

Isomer 59A

LC-MS: m/z 668(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.05(s,1H),6.88(s,1H),6.48(s,1H), 6.32(s,2H),4.44-4.30(m,2H),4.24-4.16(m,2H),3.56-3.48(m,2H),3.38(s,1H),3.11-3.07(m,1H), 3.03-2.98(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.09-2.04(m,1H),2.01-1.95(m,1H),1.91(d ,J＝12Hz,1H),1.80-1.43(m,9H),1.35-1.29(m,1H),1.24(s,3H).

Isomer 59B

LC-MS: m/z 668(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.07(s,1H),6.89(s,1H),6.48(s,1H),6.33(s,2H),4.45-4.33(m,2H),4.20(s,2H),3.54-3.44 (m,2H),3.42(s,1H),3.12-3.07(m,1H),3.03-2.99(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H) ,2.10-2.05(m,1H),2.01-1.95(m,1H),1.91(d,J=12Hz,1H),1.82-1.37(m,9H),1.28-1.24(m,4H).

Example 60 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

LC-MS: m/z 670(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.11(s,1H),6.87(s,1H),6.36(s,1H),6.29(s,2H),4.44-4.36(m,2H),4.25-4.20(m,2H),3.65 -3.63(m,1H),3.60-3.57(m,3H),3.13-3.08(m,1H),3.04-2.99(m,1H),2.74(d,J＝12Hz,1H),2.57-2.55( m,1H),2.11-2.06(m,1H),2.03-1.97(m,1H),1.93(d,J＝16Hz,1H),1.84-1.73(m,3H),1.68-1.45(m,7H ).

Example 61 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin-7-yl)-6-amino-4-chloro-3-(trifluoromethyl)benzonitrile

LC-MS: m/z 679(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.14(s,1H),7.29(s,2H),7.19(s,1H),4.45-4.32(m,2H),4.24-4.16(m,2H ),3.67-3.59(m,4H),3.12-3.07(m,1H),3.03-2.99(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.10 -2.05(m,1H),2.01-1.95(m,1H),1.91(d,J＝12Hz,1H),1.81-1.43(m,10H).

Example 62 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-2-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 668 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.09(s,1H),6.97(s,1H),6.10(s,2H),4.40-4.37(m,2H),4.22-4.14(m,2H),3.62-3.56(m,4H),3.12-3.07(m,1H),3.03-2. 98(m,1H),2.73(d,J＝12Hz,2H),2.56-2.53(m,1H),2.09-2.04(m,1H),2.0 1-1.95(m,1H),1.91(d,J＝16Hz,1H),1.79-1.71(m,2H),1.63-1.44(m,10H) .

Example 63 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol

LC-MS: m/z 627(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.98(s,1H),9.10(s,1H),6.95(s,1H),6.77(s,1H),4.45(d,J＝12Hz,2H),4.23-4.16(m,2H) ,3.63-3.60(m,4H),3.12-3.07(m,1H),3.03-2.99(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.10- 2.05(m,1H),2.02-1.96(m,1H),1.91(d,J＝13Hz,1H),1.83-1.44(m,11H),0.59(m,2H),-0.028(m,2H) .

Example 64: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-3-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 652(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.09 (s, 1H), 7.31 (d, J = 11.76Hz, 1H), 5.86 (s, 1H), 4.42 (d, J = 11.40Hz, 2H) ,4.19(d,J＝3.24Hz,2H),3.61(m,4H),3.11(m,1H),3.02(m,1H),2.71(d,J＝11.84Hz,1H),2.55(m, 1H), 2.17 (s, 3H), 2.09 (m, 1H), 2.00 (m, 1H), 1.88 (d, J = 13.32Hz, 1H), 1.64 (m, 10H).

Example 65: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 676(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.11(s,1H),7.06(d,J＝12Hz,1H),6.21(s,2H),4.45(d,J＝12Hz,2H),4.23-4.16(m,2H),3.71- 3.62(m,4H),3.12-3.07(m,1H),3.03-2.98(m,1H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.09-2.05(m ,4H),2.01-1.96(m,1H),1.91(d,J＝12Hz,1H),1.85-1.75(m,2H),1.73-1.67(m,4H),1.64-1.44(m,4H) .

Example 66: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

LC-MS: m/z 668(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ ¹ H NMR (400MHz, DMSO-d ₆ ) δ6.87 (d, J = 2.2 Hz, 1H), 6.54-6.46 (m, 1H), 6.29 (s, 2H),4.19(d,J＝2.1Hz,2H),3.78-3.51(m,4H),3.14-3.06(m,1H),3.04-2.97(m,1H),2.72(d,J＝11.9Hz ,1H),2.59-2.54(m,1H),2.51(s,3H),2.09-1.12(m,14H).

Example 67: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 666(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ6.61 (d, J = 8.6 Hz, 1H), 5.99 (s, 2H), 4.21-4.13 (m, 2H), 3.71-3.39 (m, 5H), 3.14-3.06(m,1H),3.05-2.98(m,1H),2.77-2.68(m,1H),2.59-2.54(m,1H),2.51(s,3H),2.33(s,3H), 2.07-2.02(m,1H),2.02-1.94(m,3H),1.93-1.38(m,10H).

Example 68A: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-3-ethyl-2-fluoro-4-(trifluoromethyl)aniline

LC-MS: m/z 666(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.06 (s, 1H), 7.38 (s, 1H), 6.58 (d, J = 8.6Hz, 1H), 6.05 (s, 2H), 4.50 (d ,J＝12.9Hz,2H),4.26-4.12(m,2H),3.87(s,2H),3.80-3.62(m,2H), 3.15-2.97(m,2H),2.83-2.68(m,3H),2.11-1.46(m,13H),1.21(t,J＝7.4Hz,3H).

Example 68B: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoro-2-(trifluoromethyl)aniline

LC-MS: m/z 666 (M+H) ⁺ .

Example 69: 5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]oct-3-ylpyridin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 666(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.06(s,1H),6.57(d,J＝8.7Hz,1H),6.04(s,2H),4.51-4.30(m,2H),4.25-4.14(m,2H),3.69-3.48 (m,2H),3.45-3.29(m,2H),3.09(dd,J＝11.9,6.7Hz,1H),3.04-2.97(m,1H),2.72(d,J＝11.8Hz,1H), 2.58-2.52(m,1H),2.11-2.03(m,1H),2.02-1.95(m,1H),1.89(d,J＝13.2Hz,1H),1.83-1.32(m,9H),1.27( s,3H).

Example 69 was subjected to chiral separation (SFC-150 (Waters); chiral separation column: IC 25*250nm, 10um (Regis)) to obtain two isomers Example 69A and Example 69B: 5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-ylpyridin-7-ylpyridin-3 ... 5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-ylpyridin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

Example 69A

LC-MS: m/z 666(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.06 (s, 1H), 6.58 (d, J = 8.6Hz, 1H), 6.04 (s, 2H), 4.46-4.29 (m, 2H), 4.20 ( q,J＝10.6Hz,2H),3.60-3.47(m,2H),3.41-3.26(m,2H),3.10(dd,J＝11.9,6.7Hz,1H), 3.06-2.98(m,1H),2.72(d,J＝11.7Hz,1H),2.59-2.53(m,1H),2.34(s,3H),2.12-2.05(m,1H),2.03-1.94( m,1H),1.94-1.86(m,1H),1.85-1.41(m,8H),1.38-1.26 (m,1H),1.24(s,3H).

Example 69B

LC-MS: m/z 666(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.06 (s, 1H), 6.58 (d, J = 8.9Hz, 1H), 6.04 (s, 2H), 4.48-4.27 (m, 2H), 4.20 ( s,2H),3.59-3.45(m,2H),3.40-3.26(m,2H),3.10(dd,J＝11.8,6.7Hz,1H),3.05-2.97(m,1H),2. 72(d,J＝11.9Hz,1H),2.58-2.52(m,1H),2.34(s,3H),2.08(dd,J＝13.3,5.9Hz,1H),2.03-1.96(m,1H) ,1.94-1.88(m,1H),1.86-1.41(m,8H),1.37-1.26(m,1H),1.24(s,3H).

Example 70 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-amine

LC-MS: m/z 644(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.06 (s, 1H), 7.79-7.76 (m, 1H), 7.41-7.27 (m, 2H), 7.06-7.03 (m, 2H), 5.66 (s ,2H),4.60(d,J＝12Hz,1H),4.44(d,J＝12Hz,1H),4.24-4.16(m,2H),3.95(s,2H),3.86(s,1H), 3.82-3.69(m,2H),3.13-2.99(m,2H),2.74(d,J＝12Hz,1H),2.57-2.53(m,1H),2.10-2.05(m,1H),2.02-1.97 (m,1H),1.92-1.89(m,1H),1.84-1.72(m,5H),1.65-1.45(m,4H).

Example 71 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-amine

LC-MS: m/z 658(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05 (s, 1H), 9.54-9.49 (m, 2H), 9.21 (d, J = 4Hz, 1H), 7.84-7.80 (m, 1H), 7.37 (t,J＝8Hz,1H),7.14-7.00(m,2H),4.72-4.60(m,4H),4.53-4.49(m,1H),4.28(s, 1H),3.89-3.76(m,4H),3.72-3.65(m,1H),3.49(d,J＝12Hz,1H),3.19-3.13(m,1H),2.46-2.45(m,1H), 2.34-1.89(m,11H),1.83-1.73(m,1H),1.54(d,J＝8Hz,3H).

Example 71 was subjected to chiral separation (SFC-150 (Waters); chiral separation column: OD100 25*250 mm, 10 um (Daicel)) to obtain two isomers Example 71A and Example 71B: 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridine[4,3-d ]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine and 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine

Example 71A

LC-MS: m/z 658(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.05 (s, 1H), 7.79-7.75 (m, 1H), 7.33 (t, J = 8Hz, 1H), 7.05-7.03 (m, 2H), 5.65 (s,2H),4.47-4.27(m,2H),4.24-4.15(m,2H),3.86(d,J=4Hz,1H),3.65-3.54(m,2H),3. 41-3.36(m,1H),3.12-2.99(m,2H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.10-1.98(m,2H),1.91(d ,J＝12Hz,1H),1.83-1.69(m,5H),1.64-1.35(m,5H),1.27(s,3H).

Example 71B

LC-MS: m/z 658(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.04 (s, 1H), 7.79-7.75 (m, 1H), 7.33 (t, J = 8Hz, 1H), 7.05-7.03 (m, 2H), 5.65 (s,2H),4.47-4.25(m,2H),4.19-4.18(m,2H),3.86(s,1H),3.59-3.52(m,2H),3.39- 3.36(m,1H),3.12-2.99(m,2H),2.73(d,J＝12Hz,1H),2.56-2.54(m,1H),2.10-1.97(m,2H),1.92(d,J =12Hz,1H),1.84-1.43(m,9H),1.38-1.32(m,1H),1.26(s,3H).

Example 72 3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 690(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.57 (s, 1H), 9.17 (d, J = 2.6Hz, 1H), 7.07 (d, J = 8.6Hz, 1H), 6.24 (s, 2H) ,4.68-4.40(m,2H),4.35-4.17(m,2H),4.14-4.00(m,1H),3.89-3.67(m,2H),3.20-2.99(m,2H),2.85-2.69( m,1H),2.64-2.53(m,1H),2.10-1.46(m,19H).

Example 72 was subjected to chiral separation to give two isomers Example 72A and Example 72B: 3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(propan-1- 3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

Example 72A

LC-MS: m/z 690 (M+H) ⁺ .

Example 72B

LC-MS: m/z 690 (M+H) ⁺ .

Example 73 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-5-methylpyridin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-amine

LC-MS: m/z 658 (M+H) ⁺ .

Example 74 5-(2-(((1S,7a'S)-2,2-1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-3,8-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-3-ethyl-2-fluoro-4-(trifluoromethyl)aniline

LC-MS: m/z 680(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ11.02(s,1H),9.46(s,2H),9.18(s,1H),6.58(d,J＝8Hz,1H),6.11(s,2H),4.78-4.52(m,4H) ,4.24(s,1H),3.85-3.64(m,4H),3.48(d,J＝12Hz,1H),3.17-3.11(m,1H),2.77-2.75(m,2H),2.45-2.44( m,1H),2.33-2.16(m,3H),2.10-1.87(m,6H),1.76-1.69(m,1H),1.50(s,3H),1.21(t,J=8Hz,3H).

Example 74 was subjected to chiral separation to give two isomers Example 74A and Example 74B: 5-(2-(((1S,7a'S)-2,2-1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1S,5R)-1-methyl-3,8-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-3- Ethyl-2-fluoro-4-(trifluoromethyl)aniline and 5-(2-(((1S,7a'S)-2,2-1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1R,5S)-1-methyl-3,8-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-3-ethyl-2-fluoro-4-(trifluoromethyl)aniline

Example 74A

LC-MS: m/z 680 (M+H) ⁺ .

Example 74B

LC-MS: m/z 680 (M+H) ⁺ .

Example 75 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro [Cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-5-methylpyridinyl[4,3-d]pyrimidin-7-yl)-3-ethyl-2-fluoro-4-(trifluoromethyl)aniline

LC-MS: m/z 680(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.02 (s, 1H), 9.44 (s, 1H), 9.20 (s, 1H), 6.60 (d, J = 8Hz, 1H), 6.06 (s, 2H ),4.67-4.60(m,2H),4.30(s,2H),4.12(s,2H),3.89(s,2H),3.78-3.75(m,2H),3.67-3.61(m, 2H),3.47(d,J＝12Hz,1H),3.17-3.11(m,1H),2.76-2.75(m,2H),2.59(s,2H),2.45-2.44(m,1H),2.33- 2.14(m,3H),2.10-1.84(m,6H),1.62(s,1H),1.20(t,J＝8Hz,3H).

Example 76 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-3-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 676 (M+H) ⁺ .

Example 77 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-3-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 690 (M+H) ⁺ .

Example 78 5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-diazabicyclo[3.2.1]oct-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-2-fluoro-3-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 690 (M+H) ⁺ .

Example 78 was subjected to chiral separation to obtain two isomers Example 78A and Example 78B: 5-(2-(((1S,7a'S)-2,2- difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1R,5S)-1-methyl-diazabicyclo[3.2.1]oct-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-2-fluoro-3-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline and 5-(2-(((1S 7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1S,5R)-1-methyl-diazabicyclo[3.2.1]oct-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-2-fluoro-3-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

Example 78A

LC-MS: m/z 690 (M+H) ⁺ .

Example 78B

LC-MS: m/z 690 (M+H) ⁺ .

Example 79 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin-7-yl)-5-ethyl-6-fluoronaphthalen-2-amine

LC-MS: m/z 648 (M+H) ⁺ .

Example 80 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-amine trifluoroacetate

LC-MS: m/z 662 (M+H) ⁺ .

Example 80 was subjected to chiral separation to obtain two isomers Example 80A and Example 80B: 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidine-7 -yl)-5-ethyl-6-fluoronaphthalen-2-amine and 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-amine

Example 80A

LC-MS: m/z 662 (M+H) ⁺ .

Example 80B

LC-MS: m/z 662 (M+H) ⁺ .

Example 81 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-5-methylpyridin-7-yl)-5-ethyl-6-fluoronaphthalene-2-amine

LC-MS: m/z 662 (M+H) ⁺ .

Example 82 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 690 (M+H) ⁺ .

Example B1: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-5,8-dihydropyridine[3,4-d]pyrimidin-7(6H)-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 662 (M+H) ⁺ .

Example B2: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-methyl-5,8-dihydropyridine[3,4-d]pyrimidin-7(6H)-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 676 (M+H) ⁺ .

Example B2 was subjected to chiral separation to give two isomers, Example B2A and Example B2B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-methyl-5,8-dihydropyridine[3,4-d]pyrimidin-7(6H)-yl)-2-fluoro-5-(prop-1-yne- 1-yl)-4-(trifluoromethyl)aniline and 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

Example B2A

LC-MS: m/z 676 (M+H) ⁺ .

Example B2B

LC-MS: m/z 676 (M+H) ⁺ .

Example B3 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-5,8-dihydropyridine[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalene-2-amine

LC-MS: m/z 630 (M+H) ⁺ .

Example B4 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-methyl-5,8-dihydropyridin-[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalene-2-amine

LC-MS: m/z 644 (M+H) ⁺ .

Example B4 was subjected to chiral separation to obtain two isomers, Example B4A and Example B4B: 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-methyl-5,8-dihydropyridine[3,4-d]pyrimidin-7(6H)-yl) -5-ethynyl-6-fluoronaphthalen-2-amine and 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-methyl-5,8-dihydropyridin-[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalen-2-amine

Example B4A

LC-MS: m/z 644 (M+H) ⁺ .

Example B4B

LC-MS: m/z 644 (M+H) ⁺ .

Example B5 4-(2-(((1S,7a'S)-2,2-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalene-2-amine

LC-MS: m/z 644 (M+H) ⁺ .

Example B5 was subjected to chiral separation to obtain two isomers, Example B5A and Example B5B: 4-(2-(((1S,7a'S)-2,2-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-dihydropyridine[3,4-d]pyrimidin-7(6H)-yl) -5-ethynyl-6-fluoronaphthalen-2-amine and 4-(2-(((1S,7a'S)-2,2-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethynyl-6-fluoronaphthalen-2-amine

Example B5A

LC-MS: m/z 644 (M+H) ⁺ .

Example B5B

LC-MS: m/z 644 (M+H) ⁺ .

Example B6 4-(2-(((1S,7a'S)-2,2-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-dihydropyridin[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalene-2-amine

LC-MS: m/z 648 (M+H) ⁺ .

Example B6 was subjected to chiral separation to give two isomers, Example B6A and Example B6B: 4-(2-(((1S,7a'S)-2,2-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-dihydropyridine[3,4-d]pyrimidin-7(6H)-yl )-5-ethyl-6-fluoronaphthalene-2-amine and 4-(2-(((1S,7a'S)-2,2-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-dihydropyridin-[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalene-2-amine

Example B6A

LC-MS: m/z 648 (M+H) ⁺ .

Example B6B

LC-MS: m/z 648 (M+H) ⁺ .

Example C1: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

Step 1: (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2- Preparation of difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (78 mg, 0.81 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of sodium tert-butoxide (78 mg, 0.81 mmol). The mixture was stirred at room temperature for 1 min, and then a solution of (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(methylsulfinyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (230 mg, 0.27 mmol) in tetrahydrofuran (1 mL) was added. The resulting mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (150 mg).

Step 2: Preparation of (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

Under argon protection, (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150 mg, 0.15 mmol) was dissolved in toluene (3 mL), followed by the addition of tributyl(1-propynyl)tin (198 mg, 0.60 mmol) and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (32 mg, 0.045 mmol). The resulting mixture was stirred at 110 °C for 2 h under an argon atmosphere, then quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (110 mg).

Step 3: Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

(1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (110 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (4 mL). The resulting mixture was stirred at 40°C for 2 h and then concentrated under reduced pressure. The residue was separated by preparative liquid phase to obtain the target product (40 mg).

LC-MS: m/z 663(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.93 (s, 1H), 6.90 (d, J = 8.4Hz, 1H), 6.07 (s, 2H), 5.10-5.00 (m, 1H), 4.84 -4.72(m,1H),4.65-4.56(m,1H),4.09-3.93(m,3H),3.90-3.80(m,2H),3.59-3.42(m,3H),3.14-2.95(m, 4H),2.86-2.78(m,1H),2.77-2.66(m,1H),2.12-1.40(m,16H).

Example C1 was subjected to chiral separation to give two isomers, Example C1A and Example C1B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy )-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline and 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane -1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

Example C1A

LC-MS: m/z 663 (M+H) ⁺ .

Example C1B

LC-MS: m/z 663 (M+H) ⁺ .

Example C2 3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-(1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 677 (M+H) ⁺ .

Example C2 was subjected to chiral separation to give two isomers, Example C2A, Example C2B, Example C2C and Example C2D: 3-((S)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine- 7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline, 3-((R)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline (Propan-1-yn-1-yl)-4-(trifluoromethyl)aniline, 3-((S)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl) -4-(trifluoromethyl)aniline, and 3-((R)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

Example C2A

LC-MS: m/z 677 (M+H) ⁺ .

Example C2B

LC-MS: m/z 677 (M+H) ⁺ .

Example C2C

LC-MS: m/z 677 (M+H) ⁺ .

Example C2D

LC-MS: m/z 677 (M+H) ⁺ .

Using intermediate D-1-11A-1 as the starting material, the following examples were synthesized according to the method of Example 1:

Example D1: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methoxy-d2)-8-fluoropyridin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LC-MS: m/z 649(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.15(s,1H), 9.05(s,1H), 7.98(dd,J＝5.92,9.24Hz,1H), 7.47(t,J＝9.04Hz,1H), 7.40(d,J＝2.60 Hz,1H), 7.18(d,J＝2.64Hz,1H), 4.47(d,J＝12.36Hz,1H), 4.31(m,1H), 3.94(s,1H), 3.63(m,4H), 3.29(m,1H), 3.10(m,1H), 2.71(d,J＝11.72Hz,1H), 2.07(m,1H), 1.99(m,1H), 1.89(m,1H), 1.67(m ,1H).

Using intermediate D-1-11A-2 as the starting material, the following examples were synthesized according to the method of Example 1:

Example D2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methoxy-d2)-8-fluoropyridin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LC-MS: m/z 649(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.15(s,1H), 9.05(s,1H), 7.98(dd,J＝5.96,9.20Hz,1H), 7.47(t,J＝9.04Hz,1H), 7.40(d,J＝2.60 Hz,1H), 7.18(d,J＝2.56Hz,1H), 4.47(d,J＝12.20Hz,1H), 4.32(m,1H), 3.94(s,1H), 3.63(m,4H), 3.29(m,1H), 3.10(m,1H), 2.71(d,J＝11.72Hz,1H), 2.07(m,1H), 1.99(m,1H), 1.89(m,1H), 1.67(m ,1H).

Using intermediate D-1-11A-1 as the starting material, the following examples were synthesized according to the method of Example 1:

Example D3: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy-d2)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

LC-MS: m/z 658(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 6.90 (d, J = 4Hz, 1H), 6.48 (d, J = 4Hz, 1H), 6.34 (s, 2H), 4.46 (d,J＝12Hz,2H),3.69-3.63(m,4H),3.13-3.08(m,1H),2.74(d,J＝12Hz,1H),2.10-2.05(m,1H),2.02- 1.95(m,1H),1.92(d,J＝16Hz,1H),1.84-1.73(m,3H),1.69-1.45(m,7H).

Example D4: 3-Chloro-5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methoxy-d2)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 672 (M+H) ⁺ .

Example D4 was subjected to chiral separation (SFC-150 (Waters); chiral separation column: OD 20*250 mm, 10 um (Daicel)) to give isomers D4A and D4B: 3-chloro-5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methoxy-d2)-8-fluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidine 3-Chloro-5-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methoxy-d2)-8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline

Isomer D4A

LC-MS: m/z 672(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.07(s,1H),6.89(d,J＝2.2Hz,1H),6.48(d,J＝2.4Hz,1H),6.35(s,2H),4.50-4.26(m,2H), 3.61-3.46(m,2H),3.36-3.23(m,2H),3.09(dd,J＝11.9,6.8Hz,1H),2.72(d,J＝11.8Hz,1H),2.07(dd,J＝ 13.4,5.7Hz,1H),2.04-1.95(m,1H),1.89(d,J＝13.3Hz,1H),1.86-1.42(m,8H),1.37-1.26(m,1H),1.24(s ,3H).

Isomer D4B

LC-MS: m/z 672(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 6.89 (d, J = 2.2Hz, 1H), 6.48 (d, J = 2.3Hz, 1H), 6.35 (s, 2H) ,4.49-4.25(m,2H),3.60-3.46(m,2H),3.35-3.27(m,2H),3.09(dd,J＝11.9,6.7Hz,1H),2.72(d,J＝11.7Hz ,1H),2.08(dd,J＝13.4,5.7Hz,1H),2.03-1.93(m,1H), 1.89(d,J＝13.3Hz,1H),1.85-1.43(m,8H),1.39-1.26(m,1H),1.24(s,3H).

Example D05: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy-d2)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 656(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 6.56 (d, J = 8Hz, 1H), 6.04 (s, 2H), 4.53 (d, J = 12Hz, 2H), 3.90 (s,2H),3.72(d,J＝12Hz,2H),3.12-3.07(m,1H),2.74(d,J＝12Hz,1H),2.34(s,3H),2.09-2.04(m, 1H),2.01-1.95(m,1H),1.91(d,J＝12Hz,1H),1.84-1.69(m,6H),1.64-1.44(m,3H).

Using intermediate 1-17 as the starting material, the following examples were synthesized according to the method of Example 1:

Example E1: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-methyltetrahydro-1H-spiro[cyclopentane[b]pyrrol-2,1'-cyclopropane]-3a(3H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LC-MS: m/z 623 (M+H) ⁺ .

Example P01: Preparation of ((1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl isobutyrate trifluoroacetate

Example 16B-1 (100 mg, 0.155 mmol) was dissolved in THF (5 mL), and 2,6-dimethylpyridine (83 mg, 0.775 mmol) and iodomethyl isobutyrate (189 mg, 0.775 mmol) were added in sequence. After the addition, the mixture was stirred at room temperature for 16 h, and then acetonitrile was added to dissolve the mixture and the target product (28 mg) was obtained by separation using preparative HPLC.

LC-MS: m/z 745(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.28 (s, 1H), 9.45 (d, J = 9.64Hz, 1H), 9.19 (m, 2H), 8.00 (dd, J = 5.96, 9.20Hz, 1H),7.49(t,J＝9.04Hz,1H),7.43(d,J＝2.52Hz,1H),7.18(d,J＝2.60Hz,1H),5.59(m,2H),4.95(s, 2H),4.72(m,1H),4.56(m,1H),4.25(s,2H),4.12(m,1H), 3.88(m,5H),3.73(m,2H),2.70(m,2H),2.40(m,2H),2.22(m,3H),1.98(m,7H),1.15(m,6H).

The following compounds were synthesized in the same manner as in Example P01:

Example P02: (1R, 5S)-3-(2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid isopropyl ester

LC-MS: m/z 731(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 7.97 (dd, J = 5.96, 9.24Hz, 1H), 7.46 (t, J = 9.04Hz, 1H), 7.39 (d, J＝2.56Hz,1H),7.18(d,J＝2.48Hz,1H),4.87(m,1H),4.56(m,1H),4.41(m,3H),4.20(m,2H ),3.92(s,1H),3.64(m,2H),3.10(m,1H),3.01(m,1H),2.70(d,J＝11.84Hz,1H),2.54(m,1H),2.06 (m,1H),1.99(m,1H),1.81(m,7H),1.61(m,3H),1.24(d,J＝6.48Hz,6H).

Example P03: ((1R, 5S)-3-(2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl isopropyl carbonate

LC-MS: m/z 761(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.28(s,1H),9.57(s,1H),9.29(s,1H),9.19(s,1H),8.01(t,J＝8Hz,1H ),7.52-7.44(m,2H),7.19(s,1H),5.65-5.56(m,2H),4.95(s,2H),4.87-4.74(m,2H),4.60(d,J＝12Hz ,1H), 4.25(s,2H),4.18(d,J＝12Hz,1H),3.93-3.86(m,5H),3.77-3.74(m,2H),2.70-2.66(m,2H),2.60(s,1H ),2.43-2.34(m,2H),2.25-2.18(m,3H),1.99-1.90(m,6H),1.25-1.24(m,6H).

Example P04 and Example P05: 1-(isobutyryloxy)ethyl (1R, 5S)-3-(2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(((1-(isobutyryloxy)ethoxy)carbonyl)oxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo Preparation of [3.2.1] octane-8-carboxylate and 1-(isobutyryloxy)ethyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step 1: Preparation of 1-(isobutyryloxy)ethyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(((1-(isobutyryloxy)ethoxy)carbonyl)oxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Example 16B-1 (100 mg, 0.155 mmol) was dissolved in DCM (4 mL), and DIPEA (100 mg, 0.775 mmol) was added, and 1-(((4-nitrophenoxy)carbonyl)oxy)isobutyric acid ethyl ester (184 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness, acetonitrile was added to dissolve it, and then the target product (65 mg) was directly separated by preparative HPLC.

LC-MS: m/z 961(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.08(s,1H),8.25(dd,J＝5.92Hz,9.28Hz,1H),8.15(d,J＝2.52Hz,1H),7.68(t,J＝9.00Hz,1H),7.62 (m,1H),6.75(m,2H),4.46(m,4H),4.20(m,2H),4.08(s,1H),3.68(m,2H),3.09(m,1H),3.00( m,1H),2.07(d,J＝11.84Hz,1H),2.61(m,3H),2.09(m,1H),1.99(m,1H),1.85(m,7H),1.57(m,9H ),1.09(m,12H).

Step 1: Preparation of 1-(isobutyryloxy)ethyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Example P04 (105 mg, 0.109 mmol) was dissolved in acetonitrile (4 mL), and aqueous ammonia (10 drops) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated to dryness, acetonitrile was added to dissolve it, and then the target product (65 mg) was directly separated by preparative HPLC.

LC-MS: m/z 803(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.16(s,1H),9.06(s,1H),7.98(dd,J＝5.92,9.24Hz,1H),7.47(t,J＝9.00Hz,1H),7.40(d,J＝2.60 Hz,1H),7.18(d,J＝2.52Hz,1H),6.74(m,1H),4.59(m,1H),4.39(m,3H),4.22(m,2H),3.93(s,1H ),3.67(m,2H),3.11(m,2H),2.71(d,J＝11.84Hz,1H),2.55(m,1H),1.98(m,10H),1.56(m,6H),1.08 (d,J=7.16Hz,6H).

The following compounds were synthesized in the same manner as in Example P05:

Example P06: 1-(isobutyryloxy)ethyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 812 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 6.89 (d, J = 2.20Hz, 1H), 6.73 (dd, J = 5.32Hz, J = 10.76Hz, 1H), 6.47 (d, J = 2.28Hz, 1H), 6.35 (s, 2H), 4.53 (m, 2H), 4.3 6(m,2H), 4.23(m,2H), 3.67(m,2H), 3.10(m,1H), 3.01(m,1H), 2.71(m,1H), 2.55(m,1H), 2.09(m,1H), 1.98(m,1H), 1.65(m,14H).

Example P11: 1-(isobutyryloxy)ethyl (1R, 5S)-3-(7-(3-acetoxy-8-ethynyl-7-fluoronaphthalen-1-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 845(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 8.22 (dd, J = 9.2, 5.9Hz, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.65 (t, J＝9.0Hz,1H),7.52(s,1H),6.74(q,J＝5.4Hz,1H),4.65-4.54(m,1H),4.50-4.35(m,3H), 4.33-4.12(m,2H),4.06(s,1H),3.79-3.46(m,2H),3.20-2.95(m,2H),2.80-2.65(m,1H),2.61-2.53(m,1H ),2.34(s,3H),2.15-1.37(m,16H),1.09(d,J＝6.9Hz,6H)

Example P17: (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid methyl ester

LC-MS: m/z 703(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.16 (s, 1H), 9.07 (s, 1H), 7.99 (dd, J = 9.3, 5.9Hz, 1H), 7.48 (t, J = 9.0Hz, 1H),7.41(d,J＝2.5Hz,1H),7.19(d,J＝2.5Hz,1H),4.63-4.55(m,1H),4.48-4.35(m,3H),4.27-4.1 7(m,2H),3.94(s,1H),3.74-3.62(m,5H),3.16-3.09(m,1H),3.06-2.99(m,1H),2.77-2.67(m,1H), 2.12-2.05(m,1H),2.04-1.97(m,1H),1.94-1.73(m,7H),1.67-1.43(m,3H).

Example P18: (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-((methylcarbamoyl)oxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid methyl ester

LC-MS: m/z 760(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.13-9.04(m,1H),8.21(dd,J＝9.2,5.9Hz,1H),8.05-7.93(m,1H),7.86-7.78(m,1H),7.64(t,J＝ 9.0Hz,1H),7.49-7.44(m,1H),4.65-4.55(m,1H),4.52-4.36(m,3H),4.30-4.18(m,2H),4.05(s,1H),3.76 -3.62(m,4H),3.19-2.99(m,2H),2.81-2.67(m,2H),2.62-2.54(m,1H),2.17-1.43(m,12H).

Example P20: 1-(isobutyryloxy)ethyl (1R, 5S)-3-(2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-((methylcarbamoyl)oxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 860(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.09 (s, 1H), 8.21 (dd, J = 9.3, 5.9Hz, 1H), 7.97 (d, J = 2.5Hz, 1H), 7.81 (q, J＝4.6Hz,1H),7.63(t,J＝9.0Hz,1H),7.46(d,J＝2.5Hz,1H),6.76(q,J＝5.4Hz,1H),4.65-4.55(m, 1H),4.52-4.35(m,3H),4.29-4.18(m,2H), 4.04(s,1H),3.77-3.56(m,2H),3.17-3.08(m,1H),3.08-2.99(m,1H),2.79-2.68(m,4H),2.62-2.53(m,2H ),2.10(dd,J＝13.4,5.6Hz,1H),2.05-1.97(m,1H),1.96-1.72(m,7H),1.69-1.42(m,6H),1.19-1.04(m,6H ).

Example P22: (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid methyl ester

LC-MS: m/z 712(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.06(s,1H),6.89(d,J＝2.2Hz,1H),6.48(d,J＝2.2Hz,1H),6.32(s,2H),4.58-4.45(m,2H), 4.40-4.33(m,2H),4.28-4.18(m,2H),3.73-3.58(m,5H),3.16-2.99(m,2H),2.75(d,J＝11.8Hz,1H),2.61- 2.52(m,1H),2.09(dd,J＝13.4,5.5Hz,1H),2.05-1.96(m,1H),1.91(d,J＝13.4Hz,1H),1.88-1.43(m,9H) .

Example P25: 1-(Butyryloxy)ethyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 812(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 6.90 (d, J = 2.3Hz, 1H), 6.77 (q, J = 5.4Hz, 1H), 6.49 (d, J = 2.3Hz,1H),6.32(s,2H),4.61-4.47(m,2H),4.42-4.34(m,2H),4.30-4.17(m,2H),3.75-3.49(m,2H),3.11 (dd,J＝11.8,6.7Hz ,1H),3.07-2.98(m,1H),2.74(d,J＝11.8Hz,1H),2.60-2.53(m,1H),2.39-2.26(m,2H),2.09(dd,J＝13.4 ,5.7Hz,1H),2.05-1.96(m,1H),1.95-1.68(m,7H),1.67-1.43(m,8H),0.90(t,J＝7.4Hz,3H).

Example P30: 1-(Butyryloxy)ethyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5', 5'-d2)methoxy-d2)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 816(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 6.90 (d, J = 2.2Hz, 1H), 6.76 (q, J = 5.4Hz, 1H), 6.48 (d, J = 2.4Hz,1H),6.33(s,2H),4.60-4.46(m,2H),4.41-4.34(m,2H),3.74-3.57(m,2H),3.10(dd,J＝11 .9,6.7Hz,1H),2.73(d,J＝11.8Hz,1H),2.37-2.27(m,2H),2.08(dd,J＝13.4,5.7Hz,1H),2.03-1.95(m, 1H),1.93-1.69(m,7H),1.66-1.42(m,8H),0.90(t,J=7.4Hz,3H).

Example P31: 1-(3-methylbutyryloxy)ethyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5', 5'-d2)methoxy-d2)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 830(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 6.90 (d, J = 2.3Hz, 1H), 6.77 (q, J = 5.4Hz, 1H), 6.48 (d, J = 2.3Hz,1H),6.33(s,2H),4.62-4.45(m,2H),4.41-4.34(m,2H),3.72-3.59(m,2H),3.10(dd,J＝11 .9,6.7Hz,1H),2.73(d,J＝11.8Hz,1H),2.27-2.16(m,2H),2.08(dd,J＝13.2,5.8Hz,1H),2.04-1.95(m, 2H),1.93-1.68(m,7H),1.66-1.43(m,6H),0.92(d,J＝6.6Hz,6H).

Example P32: Thiazol-5-ylmethyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy -d2)-8-Fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 795(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.12(s,1H),9.06(s,1H),7.99(s,1H),6.88(s,1H),6.46(s,1H),6.33( s,2H),5.41(s,2H),4.52(m,2H),4.38-4.27(m,4H),3.62(s,2H),3.14(m,2H),2.86(s,1H),2.16 -2.03(m,3H),1.84-1.82(m,4H),1.71-1.51(m,6H),

Example P33: (2,5-dimethyloxazol-4-yl)methyl (1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 807 (M+H) ⁺ .

Example P34: (S)-tetrahydrofuran-3-yl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 768(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.09 (s, 1H), 6.90 (d, J = 1.8Hz, 1H), 6.49 (d, J = 1.9Hz, 1H), 6.35 (s, 2H) ,5.25(d,J＝1.8Hz,1H),4.52(s,2H),4.36(s,2H),4.31-4.15(m,2H),3.89-3.58(m,6H),3.18-2.99(m ,2H),2.75(d,J＝11.8Hz,1H),2.56(m,1H),2.21-1.45(m,14H).

Example P35: 1,1-dioxotetrahydrothiophene-3-yl(1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 816(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.85 (s, 1H), 9.12 (s, 1H), 6.89 (d, J = 1.9 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H) ,5.45(d,J＝3.8Hz,1H),4.70-4.47(m,4H),4.38(s,2H),3.75(m,4H),3.52-3.40(m,4H),3.32-3.22(m ,2H),3.17-3.09(m,1H),2.47(m,3H),2.24(m,3H),2.11-1.81(m,7H),1.71(m,2H).

Example P36: (3R,3aS,6aR)-hexahydrofuranyl[2,3-b]furan-3-yl(1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 810 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.09 (s, 1H), 6.90 (d, J = 1.8Hz, 1H), 6.48 (d, J = 1.9Hz, 1H), 6.35 (s, 2H), 5.64 (d, J = 5.2Hz, 1H), 5.14 (m, 1H), 4.53 (s, 2H), 4.39 (s ,2H),4.22(q,J＝10.5Hz,2H),3.93(m,2H),3.83-3.60(m,4H),3.14-2.97(m,3H),2.73(d,J＝11.8Hz,1H),2.55(m,1H),2.12-1.69(m,11H),1.67-1.44 (m,3H).

Example P37: (S)-2-amino-3-(4-(((1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid)oxy)phenyl)propanoic acid

LC-MS: m/z 861 (M+H) ⁺ .

Example P38: (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid pentyl ester

LC-MS: m/z 768 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 6.91 (d, J = 1.7Hz, 1H), 6.49 (d, J = 1.8Hz, 1H), 6.34 (s, 2H), 4.52 (s, 2H), 4.37 (s, 2H), 4.22 (q, J = 10.6Hz, 2H), 4.08 ( t,J＝6.6Hz,2H),3.65(s,2H),3.17-2.97(m,2H),2.73(d,J＝11.8Hz,1H),2.55(m,1H),2.13-1.98(m,2H),1.94-1.45(m,12H),1.36-1.28(m,4H),0. 90(t,J＝7.0Hz,3H).

Example P39: Pyridin-3-ylmethyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 789 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.09 (s, 1H), 8.65 (s, 1H), 8.56 (d, J = 3.6Hz, 1H), 7.86 (d, J = 7.8Hz, 1H), 7.44 (m, 1H), 6.90 (s, 1H), 6.48 (s, 1H), 6.34 (s, 2H), 5. 22(s,2H),4.47(m,4H),4.22(d,J＝4.2Hz,2H),3.68(d,J＝7.9Hz,2H),3.15-2.99(m,2H),2.74(d,J＝11.8Hz,1H),2.57(m,1H),2.12-1.43(m,12H).

Example P40: 4-methoxyphenyl (1R, 5S) -3- (7- (5-amino-3-chloro-2- (trifluoromethyl) phenyl) -2- (( (1S, 7a'S) -2,2-difluorodihydro-1'H, 3'H-spiro [cyclopropane-1,2'-bis-fused pyrrolidine] -7a'(5'H) -yl) methoxy -d2) -8-fluoropyrido [4,3-d] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate

LC-MS: m/z 804(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.13 (s, 1H), 7.22-7.11 (m, 2H), 7.00-6.94 (m, 2H), 6.91 (d, J = 1.9Hz, 1H), 6.51(d,J＝2.0Hz,1H),6.35(s,2H),4.59(s,3H),4.43(s,1H),4.25(q,J＝10.6Hz,2H),3.94-3.68(m ,5H),3.16-2.98(m,2H),2.74(d,J＝11.8Hz,1H),2.55(m,1H),2.14-1.42(m,12H).

Example P41: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 810(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 6.90 (d, J = 1.9 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 6.36 (s, 2H) ,5.02(s,2H),4.53(s,2H),4.39(s,2H),4.22(q,J＝10.5Hz,2H), 3.65(s,2H),3.15-2.96(m,2H),2.73(d,J＝11.9Hz,1H),2.60-2.51(m,1H),2.20(s,3H),2.04(m,2H) ,1.93-1.68(m,7H),1.67-1.43(m,3H).

Example P42: 4-(((1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-5-methyl-1,3-dioxol-2-one

LC-MS: m/z 766(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.43 (s, 1H), 11.92 (s, 1H), 9.14 (s, 1H), 6.94 (d, J = 1.9Hz, 1H), 6.52 (d, J＝2.0Hz,1H),4.73(d,J＝12.2Hz,4H),4.40-4.19(m,5H),3.85-3.58(m,2H),3.41(d,J＝12.3Hz,1H), 3.11(m,1H),2.47(m,1H),2.34-1.83(m,15H).

Example P43: (5-(methoxymethyl)-2-oxo-1,3-dioxol-4-yl)methyl (1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 840 (M+H) ⁺ .

Example P44: (2-oxo-5-phenyl-1,3-oxol-4-yl)methyl (1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 872 (M+H) ⁺ .

Example P45: (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl (1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 836 (M+H) ⁺ .

Example P46: 4-methyltetrahydro-2H-thiopyran-4-yl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 812 (M+H) ⁺ .

Example P47: (3aS, 5R, 6aR)-hexahydro-2H-cyclopenta[b]furan-5-yl(1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 808 (M+H) ⁺ .

Example P48: 4-(((pentyloxy)formyl)amide)benzyl(1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 917 (M+H) ⁺ .

Example P49: 2-acetylaminoethyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8- Fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 783 (M+H) ⁺ .

Example P50: 2-amino-1-((1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-one

LC-MS: m/z 711(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.93 (s, 1H), 9.12 (s, 1H), 8.42 (s, 3H), 6.93 (d, J = 1.9Hz, 1H), 6.52 (d, J＝2.0Hz,1H),4.81-4.42(m,6H),4.05-3.75(m,4H),3.66(m,2H),3.41(d,J＝12.3Hz,1H),3.11(d,J ＝11.0,4.4Hz,1H),2.50-2.44(m,1H),2.33-1.67(m,11H).

Example P51: 2-((L-valine)oxy)ethyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride

LC-MS: m/z 841 (M+H) ⁺ .

Example P52: Phenyl ((1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(methoxymethyl)phosphite

LC-MS: m/z 838 (M+H) ⁺ .

Example P53: ((1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl isobutyrate

LC-MS: m/z 754(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.35 (d, J = 9.9 Hz, 1H), 10.10 (s, 1H), 9.14 (s, 1H), 6.92 (d, J = 2.2 Hz, 1H) ,6.50(d,J＝2.3Hz,1H),5.67-5.55(m,2H),5.02-4.88(m,2H),4.74-4.58(m,2H),4.22- 4.01(m,3H),3.95-3.84(m,1H),2.95(s,2H),2.79(s,2H),2.77-2.67(m,2H),2.41-2.32(m,1H),2.30- 2.13(m,4H),2.08-1.81(m,8H),1.13(dd,J=7.0,2.5Hz,6H).

Example P54: ((1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl dodecanoate

LC-MS: m/z 866 (M+H) ⁺ .

Example P55: ((1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl diethyl phosphate

LC-MS: m/z 820 (M+H) ⁺ .

Example P56: ((1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl dihydrogen phosphate

LC-MS: m/z 764 (M+H) ⁺ .

Example P57: (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid dodecyl ester

LC-MS: m/z 866 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 6.90 (d, J = 1.8Hz, 1H), 6.48 (d, J = 1.9Hz, 1H), 6.34 (s, 2H), 4.52 (s, 2H), 4.36 (s, 2H), 4.23 (t, J = 7.5Hz, 2H), 4.08 (t . 83(t,J＝6.7Hz,3H).

Example P58: 2-((1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methoxy)ethyl L-valine ester hydrochloride

LC-MS: m/z 827 (M+H) ⁺ .

Example P59: (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbaldehyde

LC-MS: m/z 682(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 8.22 (s, 1H), 6.90 (d, J＝ 2.2Hz,1H),6.48(d,J＝2.3Hz,1H),6.34(s,2H),4.67-4.52(m,3H),4.42-4.36(m,1H),4.28-4.17(m,2H ),3.72-3.53(m,2H),3.11(dd,J＝11.9,6.7Hz,1H),3.06-2.98(m,1H),2.73(d,J＝11.8Hz,1H),2.59-2.52( m,1H),2.11-2.05(m,1H),2.05-1.96(m,1H),1.95-1.88(m,1H),1.88-1.69(m,6H),1.66-1.44(m,3H).

Example P60: (1R, 3S, 5S, 7S)-adamantan-2-yl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride

LC-MS: m/z 832 (M+H) ⁺ .

Example P61: (3S,5S,7S)-adamantan-1-yl(1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride

LC-MS: m/z 832 (M+H) ⁺ .

Example P62: 1-(Butyryloxy)-2-methylpropyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 840 (M+H) ⁺ .

Example P63: 2-methyl-1-(pivaloyloxy)propyl(1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 854 (M+H) ⁺ .

Example P64: Phenyl(pivaloyloxy)methyl(1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 888 (M+H) ⁺ .

Example P65: 1-methyl-1,4-dihydropyridin-3-yl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 791 (M+H) ⁺ .

Example P66: 1-((Dimethyl-L-valine)oxy)ethyl (1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 869(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 6.90 (d, J = 2.2Hz, 1H), 6.84 (q, J = 5.4Hz, 1H), 6.49 (d, J = 2.2Hz,1H),6.34(s,2H),4.61-4.47(m,2H),4.44-4.33(m,2H), 4.28-4.17(m,2H),3.77-3.48(m,2H),3.11(dd,J＝11.8,6.7Hz,1H),3.07-2.98(m,1H),2.77-2.66(m,2H), 2.60-2.52(m,1H),2.24(s,6H),2.13-2.05(m,1H),2.04-1.97(m,1H),1.96-1.68(m,8H),1.67-1.42(m,6H ),0.91(dd,J＝6.6,3.2Hz,3H),0.84(d,J＝6.7Hz,3H).

Example P67: 1-((Dimethyl-L-valine)oxy)-2-methylpropyl(1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 897 (M+H) ⁺ .

Example P68: ((Dimethyl-L-valine)oxy)(phenyl)methyl (1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 931 (M+H) ⁺ .

Example P74: 4-acetoxybenzyl (1R, 5S) -3- (7- (5-amino-3-chloro-2- (trifluoromethyl) phenyl) -2- (( (1S, 7a'S) -2,2-difluorodihydro-1'H, 3'H-spiro [cyclopropane-1,2'-bis-fused pyrrolidine] -7a'(5'H) -yl) methoxy) -8-fluoropyrido [4,3-d] pyrimidin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate

LC-MS: m/z 846 (M+H) ⁺ .

Example P75: 1-(Butyryloxy)butyl (1R, 5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

LC-MS: m/z 840 (M+H) ⁺ .

Biological test cases

The following biological test examples further describe and explain the present invention, but these examples are not intended to limit the scope of the present invention.

KRAS ^Gl2D binding inhibition assay

Experimental procedures

TR-FRET technology was used to detect the binding ability of the compounds to KRAS ^G12D protein. Biotin-labeled GDP-loaded KRAS ^G12D recombinant human protein was co-incubated with Cy5-labeled tracer, europium-labeled streptavidin, and compounds (2% DMSO final concentration) in buffer (HEPES (pH 7.5), MgCl ₂ , Tween-20 and DTT). After incubation at 22°C for 60 minutes, the reaction activity was detected by EnVision multi-function microplate reader dual wavelength technology, and the protein binding capacity (POC) was calculated using ratiometric emission factor.

100POC means no compound; 0POC means that the control compound completely inhibits the binding of the tracer to KRAS ^G12D at this concentration. The POC value is fitted by a four-parameter logistic model curve, and _IC50 represents the 50POC concentration value.

The results showed that the compounds of the present invention showed good inhibitory activity against KRAS ^G12D .

ERK phosphorylation inhibition assay

Experimental procedures

KRAS ^G12D mutant cells (such as GP2D, AGS, etc.) were seeded in a 384-well plate and cultured overnight in a 37° C., 5% CO 2 incubator.

Add 200 nL of the diluted compound using Echo 500, with a final DMSO concentration of 0.5%, and incubate in a 37°C, 5% CO2 incubator for 1 hour. Add hEGF and allow to react for 10 minutes.

Remove the culture medium, add cell fixative, and fix the cells.

Wash once with PBS and incubate in cold 100% methanol.

Remove the methanol and add PBS to wash once.

Remove PBS, add Li-Cor blocking buffer to each well, and block for 1 hr at room temperature.

Remove the blocking solution, add primary antibody mixture to each well, and incubate at 4°C overnight.

Remove the primary antibody mixture and add PBST to wash three times.

Add the secondary antibody mixture and incubate at room temperature in the dark for 45 min.

Remove the secondary antibody mixture, add PBST and wash 3 times, finally aspirate PBST, invert and centrifuge at 1000 rpm for 1 min.

Odyssey CLx readings. The test results are shown in Tables 1 and 2 below.

The structure of the reference compound MRTX1133 is as follows:

Table 1 Results of GP2D ERK phosphorylation inhibition experiment

Table 2 Results of AGS ERK phosphorylation inhibition experiment

The results showed that the compounds of the present invention showed good inhibitory activity on ERK phosphorylation in KRAS ^G12D mutant cells.

Inhibitory effect of compounds on proliferation of KRAS G12D mutant cells

Experimental procedures

1. Cell Culture

(a) Resuscitate cells in T75 cell culture flasks:

(b) When the cell confluence reached 80-90%, the cells were passaged.

2. Cell Proliferation Assay

Experimental procedures

Use a nanoliter pipetting system to add the diluted test compound to a 384-well cell culture plate, set up duplicate wells, add an equal volume of culture medium to the positive control group, add an equal volume of DMSO to the negative control group, and centrifuge at 1000 rpm for 1 min at room temperature.

The cells were inoculated into a) 384 culture plate, and the negative control group was added with an equal volume of cells, and the positive control group was added with an equal volume of culture medium only. Centrifuged at 1000 rpm for 1 min at room temperature, and the final DMSO concentration of the compound was 0.5%, and incubated in a 37°C, 5% CO2 constant temperature incubator for 7 days.

Add 20 μL/well 3D to b) in a 384-well cell culture plate, shake at 320 rpm for 20 min in the dark, and incubate at room temperature for 2 hrs in the dark.

The luminescence value was read using Envision multi-function microplate reader.

3. Data Analysis

The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control)/(RLU solvent control-RLU blank control))*100%. The inhibition rates of the compounds at different concentrations were calculated in Excel, and then the inhibition curves were plotted and related parameters, including the minimum inhibition rate, the maximum inhibition rate and _IC50 , were calculated using GraphPad Prism software. The experimental results are shown in Table 3.

Table 3 Cell proliferation inhibition activity of the compounds in the examples of the present invention

Pharmacokinetic testing evaluation

Male ICR mice, weighing 22-24 g, were fasted overnight and orally administered with a 30 mg/kg solution of the compound of the present invention or a control compound [10% DMSO + 60% PEG400 + 30% aqueous solution]. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 24 h after administration of the compound of the present invention, and the concentration of the compound of the present invention or the control compound in plasma was determined by LC/MS/MS.

Table 4 Main pharmacokinetic parameters in plasma

BLOQ: below the limit of detection; NA: not obtained

The test results show that the compound of the present invention has good oral pharmacokinetic properties.

Pharmacokinetic testing evaluation

Male SD rats, weighing about 220 g, were fasted overnight and orally administered with a 30 mg/kg solution of the compound of the present invention or the reference compound [10% DMSO + 60% PEG400 + 30% aqueous solution]. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 24 h after administration of the compound of the present invention, and the concentration of the compound of the present invention or the reference compound in plasma was determined by LC/MS/MS.

It can be seen from the test results that the compound of the present invention has good pharmacokinetic properties.

Anti-tumor activity pharmacodynamics test evaluation (AsPC-1CDX tumor model)

100uL of 5x10 ⁶ AsPC-1 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. The health of mice was monitored daily, and the measurement began when the tumor grew to a palpable size. The tumor volume was calculated using the formula: 0.5xLxW ² , where L and W represent the length and width of the tumor, respectively. When the tumor grew to ～200mm ³ , the mice were randomly divided into groups. The mice were intraperitoneally injected or orally with the corresponding dose of compound every day, and their general condition was monitored at the same time. The tumor was measured 3 times a week, and the body weight was measured twice a week.

It can be seen from the test results that the compound of the present invention has a good anti-tumor effect.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (20)

The compound of formula (A0), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
Ring C is selected from the following group: Y is selected from: a bond, O, NH, N(C ₁ -C ₃ alkyl); Z is a substituted or unsubstituted C ₁ -C ₆ alkylene group; wherein the substitution refers to substitution by one or more R; W is selected from: substituted or unsubstituted C ₃ -C ₁₄ cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R; Selected from the following groups: Wherein, X is selected from: N, CH, CD, CF, C(CN); R ¹ is selected from: -L ₁ -QL ₂ -L ₃ ; in: L ₁ is selected from: substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R; Q is selected from: O, S, SO ₂ , NH, or N(C ₁ -C ₃ alkyl); L ₂ is selected from: none, substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R; L ₃ is selected from the following substituted or unsubstituted groups: -C ₁ -C ₆ alkyl, -C ₃ -C ₆ cycloalkyl, -C ₄ -C ₆ heterocyclyl, -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyl), -C ₁ -C ₆ alkylene (C ₁ -C ₆ alkoxy), -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyloxy), or -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyloxy); wherein the substitution refers to substitution by one or more R; n is an integer of 0, 1, 2, 3, 4, 5 or 6; provided that when W is a monocyclic or bicyclic ring, n is not 0; R ¹⁰ is selected from the following substituted or unsubstituted groups: C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more Ra; R ¹¹ is independently selected from the following substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, _{4-6 membered heterocyclyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyloxy , 4-6 membered heterocyclyloxy} ; wherein the substitution refers to substitution by one or more R; Ra is independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _NH2 , OH, _CONH2 , NHCO ( _C1 - _C6 alkyl), NHCO ( _C3 - _C6 cycloalkyl ₎ , _SONH2 , _SO2NH2 , _NHSO2 ( _C1 - _C6 alkyl), _NHSO2 ( _C3 - _C6 cycloalkyl), _C1 - _C6 Alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C _{1 -C 6 alkoxy, C 2 -C 6} alkenyl, _{C 2} -C ₆ alkynyl, C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl, C ₃ -C ₂₀ cycloalkyloxy, 4-20 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R; m is an integer of 0, 1, 2, 3, 4, 5 or 6; Each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyl)C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkoxy)C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyloxy)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl) vinyl, deuterated (C ₁ -C ₆ alkyl) vinyl, halogenated (C ₁ -C ₆ alkyl) vinyl, (C ₁ -C 6 alkyl) ethynyl, deuterated (C ₁ -C ₆ alkyl) ethynyl, halogenated (C ₁ -C ₆ alkyl) -C ₆ alkyl)ethynyl, (C ₃ -C ₁₄ cycloalkyl)ethynyl, (4-14 membered heterocyclyl)ethynyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, 4-20 membered heterocyclyl C(O), C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea. The compound according to claim 1, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has a structure represented by formula (A):
Y is selected from: a bond, O, NH, N(C ₁ -C ₃ alkyl); Z is a substituted or unsubstituted C ₁ -C ₆ alkylene group; wherein the substitution refers to substitution by one or more R; W is selected from: substituted or unsubstituted C ₃ -C ₁₄ cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R; Selected from the following groups: Wherein, X is selected from: N, CH, CD, CF, C(CN); R ¹ is selected from: -L ₁ -QL ₂ -L ₃ ; in: L ₁ is selected from: substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R; Q is selected from: O, S, SO ₂ , NH, or N(C ₁ -C ₃ alkyl); L ₂ is selected from: none, substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R; L ₃ is selected from the following substituted or unsubstituted groups: -C ₁ -C ₆ alkyl, -C ₃ -C ₆ cycloalkyl, -C ₄ -C ₆ heterocyclyl, -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyl), -C ₁ -C ₆ alkylene (C ₁ -C ₆ alkoxy), -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyloxy), or -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyloxy); wherein the substitution refers to substitution by one or more R; n is an integer of 0, 1, 2, 3, 4, 5 or 6; provided that when W is a monocyclic or bicyclic ring, n is not 0; R ¹⁰ is selected from the group consisting of substituted or unsubstituted C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl; wherein the substitution refers to the substitution of one or Multiple Ra substitutions; R ¹¹ is each independently selected from the following substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C ₁ -C ₆ alkyl, C 1 -C 6 deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, 4-6 _{membered heterocyclyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyloxy , 4-6 membered heterocyclyloxy} ; Ra is independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _NH2 , OH, _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl ₎ , _SONH2 , _SO2NH2 , _NHSO2 (C1- _C6 alkyl), _NHSO2 ( _C3 -C6 cycloalkyl), _{C1 - C6} alkyl, C1- _C6 deuterated alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, _{C2 - C6} alkenyl, _C2 - _C6 alkynyl, _C3 - _C20 cycloalkyl, 4-20 membered heterocyclyl, _C3 - _C20 cycloalkyloxy, 4-20 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R _; m is an integer of 0, 1, 2, 3, 4, 5 or 6; Each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyl)C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkoxy)C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyloxy)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl) vinyl, deuterated (C ₁ -C ₆ alkyl) vinyl, halogenated (C ₁ -C ₆ alkyl) vinyl, (C ₁ -C 6 alkyl) ethynyl, deuterated (C ₁ -C ₆ alkyl) ethynyl, halogenated (C ₁ -C ₆ alkyl) -C ₆ alkyl)ethynyl, (C ₃ -C ₁₄ cycloalkyl)ethynyl, (4-14 membered heterocyclyl)ethynyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, 4-20 membered heterocyclyl C(O), C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea. The compound according to any one of claims 1 to 2, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has a structure represented by formula (IA) or formula (IB):
In the formula, U is selected from: N, CH, CD, CF; U' is selected from: O, or S; U" is selected from: N, or C(CN); X is selected from the group consisting of: N, CH, CD, CF, C(CN); Y is selected from: a bond, O, NH, N(C ₁ -C ₃ alkyl); Z is a substituted or unsubstituted C ₁ -C ₆ alkylene group; wherein the substitution refers to substitution by one or more R; W is selected from: substituted or unsubstituted C ₃ -C ₁₄ cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R; R ¹ is selected from: -L ₁ -QL ₂ -L ₃ ; wherein: L ₁ is selected from: substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R; Q is selected from: O, S, SO ₂ , NH, or N(C ₁ -C ₃ alkyl); L ₂ is selected from: none, substituted or unsubstituted C ₁ -C ₆ alkylene; wherein the substitution refers to substitution by one or more R; L ₃ is selected from the following substituted or unsubstituted groups: -C ₁ -C ₆ alkyl, -C ₃ -C ₆ cycloalkyl, -C ₄ -C ₆ heterocyclyl, -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyl), -C ₁ -C ₆ alkylene (C ₁ -C ₆ alkoxy), -C ₁ -C ₆ alkylene (C ₃ -C ₆ cycloalkyloxy), or -C ₁ -C ₆ alkylene (C ₄ -C ₆ heterocyclyloxy); wherein the substitution refers to substitution by one or more R; n is an integer of 1, 2, 3, 4, 5 or 6; ^R2 and ^R3 are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _C1 - _C6 alkyl, _C1 - _C6 deuterated alkyl, _C1 - _{C6 haloalkyl, C1-C6 alkoxy ;} wherein the substitution refers to substitution by one or more R; R ⁴ is selected from the group consisting of substituted or unsubstituted halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; wherein the substitution refers to substitution by one or more R; R ⁸ is selected from: OH, SONH ₂ , NHSO ₂ CH ₃ ; R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ^7' , R ^8' , R ^9' are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; R ^5' is selected from the group consisting of: H, D, halogen, CN, NH ₂ , OH, CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SONH ₂ , SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; Each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyl)C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkoxy)C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyloxy)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl) vinyl, deuterated (C ₁ -C ₆ alkyl) vinyl, halogenated (C ₁ -C ₆ alkyl) vinyl, (C ₁ -C 6 alkyl) ethynyl, deuterated (C ₁ -C ₆ alkyl) ethynyl, halogenated (C ₁ -C ₆ alkyl) -C ₆ alkyl)ethynyl, (C ₃ -C ₁₄ cycloalkyl)ethynyl, (4-14 membered heterocyclyl)ethynyl, C ₁ -C ₁₈ alkoxy, deuterated C _{1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy} , C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 3, characterized in that it has a structure represented by formula (IIA) or formula (IIB):
Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^5' , R ^7' , R ^8' , R ^9' , U, U', U", X, Z, W and n are as defined in claim 3. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1, characterized in that it has a structure represented by formula (VA) or formula (VB):
wherein R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ^7′ , R ^8′ , R ^9′ , U, U′, U″, Z, W and n are as defined in claim 3. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1, characterized in that it has a structure represented by formula (VIA) or formula (VIB):
Wherein, R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ^7′ , R ^8′ , R ^9′ , U″, Z, W and n are as defined in claim 3. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1, characterized in that it has a structure represented by formula (VIIA) or formula (VIIB):
wherein R ¹ , R ⁴ , R ⁵ , R ^7′ , R ^8′ , R ^9′ , Z, W and n are as defined in claim 3. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1, characterized in that it has a structure represented by formula (VIIIA) or formula (VIIIB):
wherein R ¹ , R ⁴ , R ⁵ , R ^7′ , R ^9′ , Z, W and n are as defined in claim 3. The compound according to claim 1, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has a structure represented by formula (IXA) or formula (IXB):
Wherein, n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R ⁵ , R, R ⁷ , R ⁹ , R ^7′ , R ^9′ , L ₁ , Q, L ₂ , L ₃ and n are as defined in claim 3. The compound according to claim 1, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has a structure represented by formula (X):
in, _V1 , _V2 , _V3 , _V4 and _V5 are each independently selected from: N, or _CRv ; _Rv are the same or different and are each independently selected from: H, _C1 - _C3 alkyl, _C3 -C6 cycloalkyl, _4-6 membered heterocyclyl, _C1 - _C3 alkoxy, C3- _{C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C1-C3 alkyl , halogenated C3} - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 - _C3 alkyl, ( _NH2 ) _-C3 - _C6 cycloalkyl, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the heterocyclic group is optionally substituted by one or more oxo groups (═O); ^R2 and ^R3 are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _C1 - _C6 alkyl, _C1 - _C6 deuterated alkyl, _C1 - _{C6 haloalkyl, C1-C6 alkoxy ;} wherein the substitution refers to substitution by one or more R; Ring C, R, R ¹ , X, Z, W and n are as defined in claim 1; Preferably, the compound has a structure shown in formula (XI):
_V1 , _V2 , _V3 , _V4 , and _V5 are each independently selected from: N, or _CRv ; _Rv are the same or different, and are each independently selected from: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6-membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6-membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6-membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 -C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the heterocyclic group is optionally substituted by one or more oxo groups (═O); ^R2 and ^R3 are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, _C1 - _C6 alkyl, _C1 - _C6 deuterated alkyl, _C1 - _{C6 haloalkyl, C1-C6 alkoxy ;} wherein the substitution refers to substitution by one or more R; Wherein, R, R ¹ , X, Z, W and n are as defined in claim 1; Preferably, the compound has a structure shown in formula (XII):
V ₁ , V ₂ , V ₃ , V ₄ , and V ₅ are each independently selected from: N, or CR _v ; R _{v are} the same or different, and are each independently selected from: H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₁ -C ₃ alkoxy, C 3 -C 6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C ₁ -C ₃ alkyl, halogenated C ₃ -C ₆ cycloalkyl, halogenated _4-6 membered heterocyclyl, (HO)-C ₁ -C ₃ alkyl, (HO)-C ₃ -C ₆ cycloalkyl, (NH ₂ )-C ₁ -C ₃ alkyl, (NH _{2 )} -C ₃ -C ₆ cycloalkyl, halogen, CN, -C≡CH, OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C 6 cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), ₆ cycloalkyl), wherein the heterocyclic group is optionally substituted by one or more oxo groups (═O); R ³ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; Wherein, R, R ¹ , X, Z, W and n are as defined in claim 1; Preferably, the compound has a structure shown in formula (XIII):
_V1 , _V2 , _V3 , _V4 , and _V5 are each independently selected from: N, or _CRv ; _Rv are the same or different, and are each independently selected from: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6-membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6-membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6-membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 -C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the heterocyclic group is optionally substituted by one or more oxo groups (═O); R ³ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; Wherein, R, R ¹ , Z, W and n are as defined in claim 1. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that R ¹⁰ is Preferably, R ¹⁰ is wherein _Rv1 , _Rv2 , _Rv3 , _Rv4 and _Rv5 are each independently selected from the group consisting of H, _C1 - _C3 alkyl, C3- _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _{C3 - C6} cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl (e.g., _CF3 , _{CF2CF3 )} , halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C1- _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl _, ( _NH2 ) _-C1 - _C3 alkyl, (NH2) _{-C3 - C6} cycloalkyl, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl _, 4-6 membered heterocyclyl, C 1 -C ₃ alkoxy, _{C 3} -C ₆ cycloalkyloxy, 4-6 membered heterocyclyloxy, _halogenated C ₁ -C ₃ alkyl, halogenated _{C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C 1 -C 3 alkyl, (HO)-C 3 -C 6 cycloalkyl , ( NH 2 ) -C 1 -C 3 alkyl , ( NH 2 ) -C 3 -C 6} cycloalkyl _, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl ₎ , NHCO( _C3 - _C6 cycloalkyl), _SO2NH2 , _NHSO2 ( _C1 - _C6 alkyl), _NHSO2 ( _C3 - _C6 cycloalkyl), the heterocyclyl group is optionally substituted with one or more oxo groups (=O). The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has a structure represented by formula (XIV-A) or formula (XIV-B), or formula (XV-A) or formula (XV-B) or formula (XV-C), or formula (XVI-A) or formula (XVI-B), or formula (XVII-A) or formula (XVII-B) or formula (XVII-C) or formula (XVII-D):
_V1 , _V2 , _V3 , _V5 are each independently selected from: _CRv ; _Rv are the same or different and are each independently selected from the following substituted or unsubstituted groups: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _{C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C1-C3 alkyl ,} halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl _, (NH2)-C1- _C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 -C6 cycloalkyl), ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the substitution refers to substitution by one or more R; ^R4 is selected from the following groups which are substituted or unsubstituted: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 - _C3 alkyl, ( _NH2 ) _-C3 - _C6 cycloalkyl, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl), _{SO2NH2 , NHSO2} ( _C1 - _C6 alkyl), _NHSO2 ( _C3 -C ₆ ring Alkyl), wherein the substitution refers to substitution by one or more R; R ⁵ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; R ² and R ³ are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; Wherein, R, R ¹ , Z, W and n are as defined in claim 1. The compound according to claim 12, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has a structure represented by formula (XVIII-A) or formula (XVIII-B), or formula (XIX-A) or formula (XIX-B) or formula (XIX-C), or formula (XX-A) or formula (XX-B), or formula (XXI-A) or formula (XXI-B) or formula (XXI-C) or formula (XXI-D):
V ₂ , V ₃ , and V ₅ are each independently selected from: CR _v ; R _v are the same or different and are each independently selected from the following substituted or unsubstituted groups: H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C ₁ -C ₃ alkyl, halogenated C ₃ -C ₆ cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C ₁ -C ₃ alkyl, (HO)-C ₃ -C ₆ cycloalkyl, (NH ₂ )-C ₁ -C ₃ alkyl, (NH ₂ )-C ₃ -C ₆ cycloalkyl, halogen, CN, -C≡CH, OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the substitution refers to the substitution of one or more R replace; ^R4 is selected from the following groups which are substituted or unsubstituted: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 ) _-C1 - _C3 alkyl, ( _NH2 ) _-C3 - _C6 cycloalkyl, halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl), _{SO2NH2 , NHSO2} ( _C1 - _C6 alkyl), _NHSO2 ( _C3 -C ₆ cycloalkyl), wherein the substitution refers to substitution by one or more R; R ⁵ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; R ¹² are the same or different and are each independently selected from hydrogen or deuterium; R ² and R ³ are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; o is 0, 1, or 2; Wherein, R is defined as in claim 1. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 10, characterized in that R ¹⁰ is selected from the following group of substituted or unsubstituted groups: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyridyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, NH ₂ , C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, _{C 1} -C 6 alkoxy, halogenated C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; preferably, R ¹⁰ is selected from: The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 12, characterized in that W is selected from: Wherein, n' is an integer of 0, 1, 2, 3, 4, 5, or 6; Preferably, when W is selected from: When n' can be 0, 1 or 2, R is as defined in claim 1, and R can be substituted on any one ring of a polycyclic ring (such as a bridged ring or a spiro ring). The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 15, characterized in that the compound is selected from the following group:

Or choose from:
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The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 15, characterized in that the prodrug of the compound has a structure shown in the following formula (B):
C' is selected from: PG is selected from:
or, PG is -L ^PG1 -W ¹ -L ^PG2 -W ² -L ^PG3 -R ^PG1 or -L ^PG1 -W ⁴ -(W ⁵ -L ^PG6 -W ⁶ -R ^PG5 ) ₂ ; wherein, L ^PG1 is zero, substituted or unsubstituted C ₁ -C ₆ alkylene (preferably zero or methylene); wherein the substitution refers to substitution by one or more R; W ¹ is selected from the following group: none, -O-, -C(O)-, -C(O)O-, -OC(O)O-, -C(O)OCH(R ^PG2 )OC(O)-, -OC(O)N(R ^PG2 )-; wherein R ^PG2 is selected from the following group which is substituted or unsubstituted: C ₁ -C ₆ alkyl, C ₃ -C ₁₄ cycloalkyl, 4-14 membered saturated or unsaturated heterocyclic group, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl (preferably, C ₁ -C ₆ alkyl, phenyl); the substitution refers to substitution by one or more R; L ^PG2 is absent or selected from the following substituted or unsubstituted divalent groups: C ₁ -C ₆ alkylene, C ₃ -C ₁₄ cycloalkylene, 4-14-membered saturated or unsaturated heterocyclylene, C ₆ -C ₁₀ arylene, 5-10-membered heteroarylene, C ₁ -C ₆ alkylene-C ₃ -C ₁₄ cycloalkylene, 4-14-membered saturated or unsaturated heterocyclylene, C ₆ -C ₁₀ arylene, 5-10-membered heteroarylene (preferably, absent, C ₁ -C ₆ alkylene, -C ₁ -C ₆ alkylene-phenylene-, -C ₁ -C ₆ alkylene-pyridylene-); wherein the substitution refers to substitution by one or more R; W ² is selected from: none, -N(R ^PG3 )C(O)-, -OC(O)N(R ^PG3 )-, -OC(O)-; wherein R ^PG3 is selected from the following substituted or unsubstituted groups: H, C ₁ -C ₆ alkyl; the substitution refers to substitution by one or more R or; L ^PG3 is a C ₁ -C ₆ alkylene group which is free, substituted or unsubstituted; wherein the substitution refers to substitution by one or more R; R ^PG1 is selected from the following substituted or unsubstituted groups: C ₁ -C ₂₀ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₁₄ cycloalkyl, 4-14 membered saturated or unsaturated heterocyclyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl; wherein the substitution refers to substitution by one or more R or -L ^PG4 -W ³ -L ^PG5 -W ² -R ^PG4 ; L ^PG4 and L ^PG5 are each independently a C ₁ -C ₆ alkylene group without or with substitution or without substitution; wherein the substitution refers to substitution with one or more R; W ³ is selected from the group consisting of none, -O-, -C(O)-, -C(O)O-, -OC(O)O-; R ^PG4 is selected from the following substituted or unsubstituted groups: -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -CH(NH ₂ )COOH, -CH(NH ₂ )COO-C1-C6 alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₄ cycloalkyl, 4-14 membered saturated or unsaturated heterocyclic group, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl; wherein the substitution refers to substitution by one or more R; W ⁴ is -P(O)=; W ⁵ are each independently selected from the group consisting of none, O, NH; L ^PG6 is a C ₁ -C ₆ alkylene group which is free, substituted or unsubstituted; wherein the substitution refers to substitution by one or more R; W ⁶ is each independently selected from the group consisting of none, -O-, -C(O)-, -C(O)O-, -OC(O)O-; R ^PG5 is selected from the following substituted or unsubstituted groups: H, C ₁ -C ₆ alkyl, C ₃ -C ₁₄ cycloalkyl, 4-14 membered saturated or unsaturated heterocyclic group, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl; wherein the substitution refers to substitution by one or more R or -L ^PG4 -W ³ -L ^PG5 -W ² -R ^PG4 ; Y, Z, W, Ring A, R ¹ , R ¹⁰ , R ¹¹ , m and n are as defined in claim 1. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 15 and 17, characterized in that the prodrug of the compound is selected from the following group:

A pharmaceutical composition, characterized in that it comprises one or more compounds according to any one of claims 1 to 18, their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and a pharmaceutically acceptable carrier. A use of a compound according to any one of claims 1 to 18, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or the pharmaceutical composition according to claim 17, characterized in that it is used to prepare a drug for preventing and/or treating a disease related to the activity or expression of KRAS ^G12D .