RU2806033C2 - Inhibitors, a method of their preparation and use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula Y or a pharmaceutically acceptable salt thereof, where A represents CH; Ar is either thiazolyl, pyrazolyl or pyridinyl; wherein the thiazolyl, pyrazolyl or pyridinyl is substituted with either one or two substituents independently selected from C_1-6 alkyl, C_3-6 cycloalkyl, 5–7 membered heterocyclyl containing 1–2 ring heteroatoms independently selected from O and N, -O-R¹⁰⁰ and -SR¹⁰⁷ wherein each R¹⁰⁰ is independently selected from phenyl; each R¹⁰⁷ is independently selected from C_1-6 alkyl; wherein each heterocyclyl is optionally substituted with one or more substituents, each independently selected from 1) C_1-7 alkyl, optionally substituted with 1–3 substituents, each independently selected from halogen, and 10) piperazinyl; L represents -O-(C_1-4 alkylene); and ring B is selected from

; n is either 0 or 1, each R^A is independently selected from halogen, optionally substituted with C_1-6 alkyl, wherein the substituent is selected from F, -NH₂, -N(CH₃)₂, optionally substituted with C_1-6 alkoxy, where the substituent is selected from F, R^B and R^C each independently selected from optionally substituted C_1-6 alkyl, where the substituent is selected from F, CF₃; unsubstituted C_2-6 alkenyl, or R^B and R^C together form an optionally substituted C_3-6 cycloalkyl, where the substituent is selected from oxo, -CH₃ where the triple bond in Formula Y is in the meta position relative to the linker L. The invention also relates to a pharmaceutical composition for inhibiting HPK1 activity based on these compounds.

Formula (Y)

EFFECT: obtaining new compounds and a pharmaceutical composition based on them which can be used in medicine in the treatment of cancer.

18 cl, 1 dwg, 2 tbl, 39 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to Chinese Application Nos. 201810381425.X filed April 25, 2018, 201810945948.2 filed August 20, 2018, and 201810946081.2 filed August 20, 2018, the contents of each of which are incorporated herein application by reference in its entirety.

Field of technology to which the invention relates

The present invention relates to the field of medicine and, in particular, relates to NRK1 inhibitors and a method for their preparation.

Prerequisites for creating the invention

Hematopoietic precursor kinase 1 (HPK1) is involved in many signaling cascades, including growth factor signaling, MAPK signaling, cytokine signaling, apoptosis signaling, and antigen receptor signaling. HNK1 is a key functional activating factor of the JNK/SAPK signaling pathway. When activated, it selectively activates the C-Jun N-terminal kinase (JNK) MAPK signaling pathway.

HNK1, as a possible target for immunotherapy, is activated by lymphocyte antigen receptors and inhibits AP-1, while AP-1 promotes cell proliferation, inhibits differentiation, and promotes tumor cell invasion during tumor formation and progression. Targeted disruption of HKK1 alleles confers T cells with an increased ability to produce Th1 cytokines in response to TCR binding.

HpK1 (-/-) T cells have been reported to proliferate faster than their haplotype-matched wild-type counterpart and are resistant to prostaglandin E2(PGE 2)-mediated suppression, S Sawasdikosol (HpK1 as a novel target for cancer immunotherapy, Immunol Res, 54 (2012), pp.262-265). Most strikingly, mice given adoptive transfer of HKK1(-/-) T cells became resistant to lung tumor growth. In addition, loss of HKK1 by dendritic cells (DCs) endows them with superior antigen presentation capacity, allowing HKK1(−/−) DCs to elicit a stronger antitumor immune response when used as a cancer vaccine. It is likely that blocking HNK1 kinase activity with a small molecule inhibitor may activate the superior antitumor activity of both cell types, resulting in a synergistic enhancement of antitumor potential. Given that HKP1 is not expressed in any major organs, it is unlikely that an inhibitor of HKK1 kinase activity would cause any serious side effects.

US 2016158360 A1 discloses compositions and methods for enhancing the immune response and treating cancer. Compositions include PD-1 axis antagonists and NRK1 antagonists. NRK1 antagonists include compounds that inhibit the serine/threonine kinase activity of NRK1.

HKK1 plays a key role in the treatment of diseases, especially cancer, and the discovery of small molecule HKK1 inhibitors has become an important focus in anticancer drug research.

Brief description of drawings

Fig. 1 presents histograms showing that representative compounds of the present invention are effective in increasing the cytotoxicity of the tested Car-T cells. In FIG. 1, "con" refers to the control group. PRJ1-58 corresponds to Al connection, PRJ1-108 corresponds to A3 connection, PRJ1-211 corresponds to A31 connection, PRJ1-165 corresponds to A32 connection, PRJ1-215 corresponds to A52 connection, PRJ1-217 corresponds to A53 connection, PRJ1-223 corresponds to A54 connection, PRJ1 -168 corresponds to compound A19, PRJ1-176 corresponds to compound A42, PRJ1-167 corresponds to compound A59, PRJ1-225 corresponds to compound A48, PRJ1-191 corresponds to compound A23, PRJ1-197 corresponds to compound A28.

Description

In one aspect, the present disclosure provides HKP1 inhibitors and a method for preparing them. In one aspect, the present application discloses the use of HKK1 inhibitors for the prevention and/or treatment of cancer. In another aspect, the present invention provides the use of HKK1 inhibitors in cancer immunotherapy. In some embodiments, the present invention provides the use of HKK1 inhibitors for the production of a medicament for the prevention and/or treatment of cancer.

Formula X

In some embodiments, the present invention provides a compound of Formula X, or a pharmaceutically acceptable salt thereof:

Formula X

Where: A represents N or CH;

Ar represents optionally substituted aryl or heteroaryl; preferably an optionally substituted 5 or 6 membered heteroaryl containing 1-4 (1, 2, 3 or 4) ring heteroatoms independently selected from O, S, and N;

L is a linker of the formula J ¹ -J ² -J ³ wherein J ¹ , J ² and J ³ are each independently zero, O, S, SO, SO ₂ , C=O, NH, optionally substituted with C _{1- 4} alkylene, provided that L does not contain an O-O, O-N, SS, NS, O-S or N-N bond, and not more than one of J ¹ , J ² and J ³ is SO, SO2 or C =O; And

Cy ¹ is optionally substituted aryl or heteroaryl; preferably an optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl containing 1-4 (1, 2, 3 or 4) ring heteroatoms independently selected from O, S and N.

Typically the A in Formula X is CH. However, in some embodiments, A in Formula X may also be N.

Ar in Formula X is typically an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl. A 5 or 6 membered heteroaryl, if applicable, typically contains 1-4 (1, 2, 3 or 4) ring heteroatoms, more preferably 1-3 ring heteroatoms independently selected from O, S, and N. For example, in some In embodiments, Ar is an optionally substituted thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. It should be understood that, when applicable, two adjacent Ar substituents can form an optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl ring. It should also be understood that any of the 5- or 6-membered heteroaryl attachment points can be used to attach to the pyridine or pyrazine ring in Formula X. For example, as shown herein, both 2-thiazolyl, and 5-thiazolyl , are suitable where the thiazolyl ring may be further substituted with 1 or 2 substituents as described herein. Other 5- or 6-membered heteroaryl should be understood similarly. In some embodiments, Ar is thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, which is optionally substituted with one or more substituents (e.g., 1-3 if valence permits ), independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ¹⁰⁰ , -NR ¹⁰¹ R ¹⁰² , -C(=O)-R ¹⁰³ , -NR ¹⁰¹ -C(=O)-R ¹⁰³ , -NR ¹⁰¹ -SO ₂ -R ¹⁰⁴ , -SO ₂ -R ¹⁰⁴ , -NR ¹⁰¹ -POR ¹⁰⁵ R ¹⁰⁶ , -POR ¹⁰⁵ R ¹⁰⁶ , -SR ¹⁰⁷ , halogen and -CN,

wherein each R ¹⁰⁰ is independently selected from hydrogen, oxygen protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R ¹⁰¹ or R ¹⁰² is independently selected from hydrogen, nitrogen protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R ¹⁰³ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-R ¹⁰⁰ and -NR ¹⁰¹ R ¹⁰² ;

each R ¹⁰⁴ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-R ¹⁰⁰ and -NR ¹⁰¹ R ¹⁰² ;

each R ¹⁰⁵ or R ¹⁰⁶ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-R ¹⁰⁰ and -NR ¹⁰¹ R ¹⁰² ;

each R ¹⁰⁷ is independently selected from hydrogen, thiol protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted, for example, with one or more (e.g., 1-5 if valency permits) substituents, each independently selected from 1) C _1-7 alkyl (eg C _1-4 alkyl), optionally substituted with 1-3 substituents, each independently selected from halogen (eg F), oxo, -OH or protected OH, optionally substituted with C _1-4 alkoxy, -NH ₂ or protected NH ₂ , -N(C _0-4 alkyl) (C _0-4 alkyl), optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl and optionally substituted 4-8-membered heterocyclyl; 2) halogen; 3) -OH or protected OH; 4) optionally substituted C _1-4 alkoxy; 5) -NH ₂ or protected NH ₂ ; b) -N(C _0-4 alkyl) (C _0-4 alkyl), where alkyl is optionally substituted; 7) optionally substituted C _3-6 cycloalkyl; 8) optionally substituted phenyl; 9) optionally substituted 5- or 6-membered heteroaryl; and 10) an optionally substituted 4-8 membered heterocyclyl. In the context of the present application, for groups such as -N(C _0-4 alkyl) (C _0-4 alkyl), the two C _0-4 alkyls are independently selected and may be the same or different from each other.

Typically, Ar in Formula X is aryl or heteroaryl, which is substituted with at least one substituent, for example, as described herein. In some embodiments, Ar in Formula X is thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, which is substituted with one substituent. For illustration, when Ar is 5-thiazolyl substituted with one substituent, Formula X may be Formula X-1,

,

where R ₁ represents one substituent. One substituent can be attached to any available position. However, in some preferred embodiments, one substituent is attached at a position other than the ortho position with respect to the pyridine or pyrazine ring in Formula X. For example, in Formula X-1, the preferred position for one substituent is the thiazolyl 2-position:

In some embodiments, one substituent may be an optionally substituted heterocycle (eg, an optionally substituted 4-8 membered heterocyclyl). In some embodiments, one substituent may be a C _1-7 alkyl (e.g., C _1-4 alkyl), optionally substituted with 1-3 substituents, each independently selected from halogen (e.g., F), oxo, -OH, or protected OH, optionally substituted C _1-4 alkoxy, -NH ₂ or protected NH ₂ , -N(C _0-4 alkyl) (C _0-4 alkyl), optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5 - or 6-membered heteroaryl and optionally substituted 4-8-membered heterocyclyl. For example, in some embodiments, one substituent may be C _1-7 alkyl (eg, C _1-4 alkyl), such as methyl or isopropyl. In some embodiments, one substituent may be an optionally substituted cycloalkyl (eg, C _3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, one substituent may be -O-R ¹⁰⁰ , where R ¹⁰⁰ is defined herein, for example, one substituent may be -OPh. In some embodiments, one substituent may be -SO ₂ -R ¹⁰⁴ or -SR ¹⁰⁷ , where R ¹⁰⁴ and R ¹⁰⁷ are defined herein. For example, in some embodiments, one substituent may be -SO ₂ -Me or SMe.

In some embodiments, one substituent is an optionally substituted 4-10 membered heterocyclic ring containing 1-4 (1, 2, 3 or 4) ring heteroatoms, more preferably 1-3 ring heteroatoms independently selected from S, O and N, where S and N are optionally oxidized. In some embodiments, the 4-10 membered heterocyclic ring may be optionally substituted with 1-5 substituents, each of which independently represents 1) an optionally substituted 5- or 6-membered heterocyclic ring containing 1 or 2 ring heteroatoms independently selected from S , O and N, where S and N are optionally oxidized; 2) C _1-7 alkyl (for example, C _1-4 alkyl), optionally substituted with 1-3 substituents, each independently selected from halogen (for example, F), oxo, -OH or protected OH, optionally substituted with C _{1- 4} alkoxy, -NH ₂ or protected NH ₂ , -N(C _0-4 alkyl) (C _0-4 alkyl), optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl and optionally substituted 4-8 membered heterocyclyl; 3) optionally substituted cycloalkyl (for example, C _3-6 cycloalkyl); 4) halogen (for example, F); 5) oxo; or b) a nitrogen protecting group if applicable.

In some preferred embodiments, said one substituent is an optionally substituted 5- or 6-membered heterocyclic ring containing 1 or 2 ring heteroatoms independently selected from S, O, and N, wherein S and N are optionally oxidized. In some embodiments, the 5- or 6-membered heterocyclic ring is optionally substituted with 1-5 substituents, each of which independently represents 1) an optionally substituted 5- or 6-membered heterocyclic ring containing 1 or 2 ring heteroatoms independently selected from S, O and N, where S and N are optionally oxidized; 2) C _1-7 alkyl (for example, C _1-4 alkyl), optionally substituted with 1-3 substituents, each independently selected from halogen (for example, F), oxo, -OH or protected OH, optionally substituted with C _{1- 4} alkoxy, -NH ₂ or protected NH ₂ , -N(C _0-4 alkyl) (C _0-4 alkyl), optionally substituted C _3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl and optionally substituted 4-8 membered heterocyclyl; 3) optionally substituted cycloalkyl (for example, C _3-6 cycloalkyl); 4) halogen (for example, F); 5) oxo; or b) a nitrogen protecting group, if applicable. In some embodiments, the 5- or 6-membered heterocyclic ring is optionally substituted with 1-3 substituents, each independently selected from 1) halogen; 2) C _1-7 alkyl (for example, C _1-4 alkyl), optionally substituted with 1-3 fluorine atoms; and 3) a 5- or 6-membered heterocyclic ring containing 1 or 2 ring heteroatoms independently selected from S, O and N, wherein S and N are optionally oxidized, which is optionally substituted with 1-3 substituents, each independently selected from halogen (eg F) and C _1-7 alkyl (eg C _1-4 alkyl) optionally substituted with 1-3 fluorine atoms. In some embodiments, the optionally substituted 5- or 6-membered heterocyclic ring is a ring selected from:

which is optionally substituted (for example, as described herein), for example, unsubstituted or substituted with 1-3 substituents, each independently selected from halogen (for example, F) and C _1-7 alkyl (for example, C _1-4 alkyl ), optionally substituted with 1-3 fluorine atoms. In some embodiments, the 5- or 6-membered heterocyclic ring is a ring selected from:

which is optionally substituted (for example, as described herein), for example, unsubstituted or substituted with 1-3 substituents, each independently selected from halogen (for example, F) and C _1-7 alkyl (for example, C _1-4 alkyl ), optionally substituted with 1-3 fluorine atoms. A 5- or 6-membered heterocyclic ring can be attached to Ar in Formula X through any point of attachment, such as a carbon or nitrogen point of addition. For illustration, using 2-piperidinyl-5-thiazolyl as an example of Ar, in some embodiments, a compound of Formula X may be represented by Formula X-2:

wherein piperidinyl may be further substituted as described herein, for example, with one or more methyl groups on the ring, including at the nitrogen atom. Other substituents for Ar, such as the 5- or 6-membered heterocyclic ring described herein, should be understood in a similar manner.

In some embodiments, the Ar in Formula X is thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, which is substituted with two substituents, where one substituent is any of suitable substituents described above, and the other substituent is selected from halogen, C _1-7 alkyl (eg, C _1-4 alkyl), NH ₂ and protected NH ₂ . Preferably, the substituent at the ortho position to the pyridine or pyrazine ring in Formula X, if present, is selected from halogen, C _1-7 alkyl (eg, C _1-4 alkyl), NH ₂ and protected NH ₂ . Using 5-thiazolyl as an example, where it is stated that 5-thiazolyl is substituted with two substituents, i.e. both R ₀ and R ₁ are not hydrogen in Formula X-1B,

,

it is then preferred that R ₀ is halogen (eg F, Cl), C _1-7 alkyl (eg C _1-4 alkyl), NH ₂ and protected NH ₂ and R ₁ is a substituent as described herein (eg one substituent described above). In some embodiments, the Ar in Formula X is thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, which is substituted with one or two substituents, where one substituent is selected from

the other substituent, when present, is selected from halogen (eg F, Cl), methyl, ethyl, NH ₂ or protected NH ₂ .

In some embodiments, Ar in Formula X (including any of the subformulas described herein, such as Formula X-1, X-2, etc.) is:

where R ₁ is selected from

selected from hydrogen, halogen (eg F, Cl), methyl, ethyl, NH ₂ or protected NH ₂ , provided that in R ₁ is not a group with an N, S or O attachment point.

Various linkers of the formula J ¹ -J ² -J ³ may be used as L. In some embodiments, J ¹ , J ² and J ³ may each be independently zero, O, S, SO, SO ₂ , C=O, NH, optionally substituted C _1-4 alkylene, provided that L does not contain an OO, ON, SS, NS, OS or NN bond, and not more than one of J ¹ , J2 and J3 is SO, SO ₂ or C =O. For example, in some embodiments, one of J ¹ , J ² and J ³ may be zero. In some embodiments, two of J ¹ , J ² and J ³ may be zero. In some embodiments, one of J ¹ , J ² and J ³ may be O. In some embodiments, none of J ¹ , J ² and J ³ is S, NH, SO, SO ₂ or C=O. In some embodiments, one of J ¹ , J ² and J ³ is SO, SO2 or C=O. In some embodiments, one of J ¹ , J ² and J ³ is NH. In some embodiments, one of J ¹ , J ² and J ³ may be C _1-4 alkylene. Preferably, L in Formula X is a linker -O- (C _1-4 alkylene), -S- (C _1-4 alkylene) or C _1-4 alkylene, where each of the C _1-4 alkylene is optionally substituted, for example, 1-3 substituents selected from F, methyl or fluoro-substituted methyl. In some embodiments, L is -O- (C _1-4 alkylene), wherein the C _1-4 alkylene is unsubstituted. Preferably, L is attached to Cy ¹ via a carbon atom. For example, in some preferred embodiments, L is -O-CH ₂ -, where CH ₂ is directly attached to Cy ¹ . For illustration, in some embodiments, compounds of Formula X may be characterized as having Formula X-3:

the variables A, Ar and Cy ¹ are defined and preferred.

Cy ¹ in Formula X is typically a 5- or 6-membered aryl or heteroaryl, preferably a 6-membered aryl or heteroaryl. When Cy ¹ in Formula X is a 5- or 6-membered heteroaryl, it typically has 1-4 (e.g., 1, 2, 3, or 4) ring heteroatoms, more preferably 1-3 ring heteroatoms independently selected from N, S and O. For example, in some embodiments, Cy ¹ is optionally substituted phenyl or pyridinyl, for example, optionally substituted with 1-3 substituents, each independently selected from halogen (e.g., F), optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, CN, OH, optionally substituted alkoxyl, optionally substituted cycloalkyl, optionally substituted cycloalkoxyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl, where, when applicable, two adjacent substituents may form optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl ring. In some embodiments, Cy ¹ is phenyl or pyridinyl substituted with 1 or 2 substituents, where one of the substituents is an optionally substituted alkyne; preferably, the alkyne is in the meta position relative to the linker L and has the formula -C≡CR ₁₀ where R ₁₀ is selected from H, optionally substituted C _1-5 alkyl, optionally substituted _3-10 cycloalkyl or wherein each of R ₁₁ and R ₁₂ is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or R ₁₁ and R ₁₂ together form optionally substituted cycloalkyl or optionally substituted heterocyclyl.

In some preferred embodiments, Cy ¹ may be phenyl or pyridinyl substituted with an alkyne. For example, in some embodiments, Cy ¹ may be phenyl or pyridinyl substituted with one substituent that is an optionally substituted alkyne. In some embodiments, Cy ¹ is phenyl or pyridinyl substituted with two substituents, wherein one of the substituents is an optionally substituted alkyne and the other of the substituents (preferably in the meta or para position relative to the alkyne, if applicable) is selected from halogen (eg F or Cl), C _1-7 alkyl (eg C _1-4 alkyl), optionally substituted with one or more (preferably 1-3) substituents, each independently selected from halogen, -OH and NH ₂ , (for example, CF ₃ , CH ₂ OH, CH ₂ NH ₂ , etc.), -CN, -OH, C _1-4 alkoxy, optionally substituted with 1-3 fluorine atoms, C _3-6 cycloalkyl, optional substituted with 1 or 2 substituents, each independently selected from F and C _1-7 alkyl (e.g., C _1-4 alkyl), and C _3-6 cycloalkoxy, optionally substituted with 1 or 2 substituents, each independently selected from F and C _1-7 alkyl (eg, C _1-4 alkyl).

Preferably, the para position to linker L, if applicable, is unsubstituted. For clarity, in the context of this application, when Cy ¹ is a 5-membered heteroaryl, there will be either an ortho or meta position, but not a para position relative to the linker L.

In some specific embodiments, Cy ¹ may be phenyl or pyridinyl substituted at the meta position with respect to linker L with an optionally substituted alkyne, having the formula where R ₁₁ and R ₁₂ are each independently chosen from hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , (-CH(CH ₃ ) ₂ ), (-CH ₂ CH(CH ₃ ) ₂ ),

or represents

In some specific embodiments, Cy ¹ may be phenyl or pyridinyl substituted at the meta position with respect to linker L with an optionally substituted alkyne having the formula where R ₁₁ and R ₁₂ are both methyl. In some embodiments, Cy ¹ may be phenyl or pyridinyl substituted at the meta position with respect to linker L with an optionally substituted alkyne having formula where represents , preferably Formula Y or Z In some embodiments, a compound of Formula X may be characterized as having Formula Y or Z:

where A, Ar, L are defined and preferred as in Formula X, ring B is aryl or heteroaryl; preferably phenyl or 5 or 6 membered heteroaryl containing 1-4 (1, 2, 3 or 4) ring heteroatoms independently selected from O, S and N;

n has the value 0, 1, 2 or 3, as valency allows,

each R ^A is independently selected from halogen (e.g., F), optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, CN, OH, optionally substituted alkoxyl, optionally substituted cycloalkyl, optionally substituted cycloalkoxyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, where, when applicable, two adjacent R ^A substituents may form an optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl ring,

R ^B and R ^C are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or R ^B and R ^C together form an optionally substituted cycloalkyl or optionally substituted heterocyclyl,

wherein R ^D in Formula Z is hydrogen, optionally substituted C _1-5 alkyl, optionally substituted _3-10 cycloalkyl, or optionally substituted 4-7 membered heterocyclyl,

wherein the triple bond in Formula Y or Z is in a meta position relative to linker L. To avoid confusion, in the context of this application, when ring B is a 5-membered ring, the triple bond in Formula Y is in a meta position relative to linker L, provided that it is not in the ortho position to the L linker.

In some specific embodiments, ring B in Formula Y or Z may be selected from:

It should be understood that any of the available aryl or heteroaryl ring attachment points described herein can be used to couple with linker L and an alkyne group in Formula Y or Z. Using pyridine as an example for illustration, Formula Y with pyridine in as a ring B may have any of the following formulas:

Another aryl or heteroaryl as ring B should be understood similarly.

In some embodiments, ring B in Formula Y or Z may also be a 5,5-bicyclic or 5,6-bicyclic heteroaryl ring.

In some specific embodiments, ^RB and ^RC in formula Y may be independently selected from hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₃ , -CH ₂ CH ₃ , -CH-CH ₂ , or represents

In some specific embodiments, R ^B and R ^C in Formula Y may each be methyl. In some embodiments in Formula Y can represent or , preferably or .

In some embodiments, R ^D in Formula Z may be hydrogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₃ , -CH ₂ CH ₃ , CH=CH ₂ .

In some embodiments, n is 0, i.e. ring B is not further substituted.

In some embodiments, p is 1 and R ^A can be halogen (e.g., F or Cl), C _1-7 alkyl (e.g., C _1-4 alkyl), optionally substituted with one or more (preferably 1-3) substituents, each independently selected from halogen, -OH and NH ₂ (for example, CF ₃ , CH ₂ OH, CH ₂ NH ₂ , etc.), -CN, -OH, C _1-4 alkoxy, optionally substituted with 1-3 fluorine atoms, C _3-6 cycloalkyl, optionally substituted with 1 or 2 substituents, each independently selected from F and C _1-7 alkyl (for example, C _1-4 alkyl), and C _3-6 cycloalkoxy , optionally substituted with 1 or 2 substituents, each independently selected from F and C _1-7 alkyl (eg, C _1-4 alkyl).

In some embodiments, L in Formula Y or Z is -O-CH ₂ - with CH ₂ directly attached to ring B.

In some embodiments, the present disclosure also provides a compound selected from any of compounds A1 to A85, or a pharmaceutically acceptable salt thereof. Some compounds in the Examples section (Examples 1-23) are associated with two numbers, for example, Example 1 shows compound A1 as well as compound 8. For clarity, compounds A1 - A85 include such compounds associated with two numbers, provided that one of numbers belong to one of A1 - A85.

Formula I or II

In one aspect, the present invention provides a compound of formula (I):

where, A represents C or N; B represents C or N.

Ar is a five-membered heteroaryl, six-membered heteroaryl or phenyl, wherein the five-membered heteroaryl is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl or thiazolyl; six-membered heteroaryl selected from pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, wherein the five-membered heteroaryl, six-membered heteroaryl or phenyl is optionally substituted with a group selected from -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _{0 -10} alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON (C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, - OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl, wherein the alkyl moiety may optionally be substituted by one or more of the following groups: -SO ₂ , SO ₂ N(C( _0-10 alkyl) ( C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl ) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, _3-10 cycloalkyl, -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl.

Preferably, at least one H in the five-membered heteroaryl, six-membered heteroaryl or phenyl is substituted with a group selected from the following: -SO ₂ , -SO ₂ NH ₂ , -NHSO ₂ , -CONH(C _0-10 alkyl), halogen, -CN, -OCF ₃ , -O heterocyclyl, -N heterocyclyl, C _1-10 linear/branched alkyl, -OC _0-10 alkyl, _3-10 cycloalkyl or -N(C _0-10 alkyl) (C _{0 -10} alkyl). More preferably, at least one H in the five-membered heteroaryl, six-membered heteroaryl or phenyl is substituted with -O heterocyclyl or -N heterocyclyl.

In some preferred embodiments, Ar is thiazolyl, selenothiazolyl, imidazolyl, pyrazolyl, or pyridyl.

In some preferred embodiments, Ar is

Q represents O or S; x and z are integers from 0 to 6; y has the value 0 or 1.

Preferably, x and z are integers from 0 to 2, such as 0, 1 or 2.

In some preferred embodiments, the compound is Formula (II):

Preferably, the compound may have the following formulas:

R ₀ is independently selected from: -H, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl or _3-10 cycloalkyl.

Preferably, R ₀ is selected from C _1-5 linear/branched alkyl or -N(C _0-10 alkyl) (C _0-10 alkyl).

In some preferred embodiments, R ₀ is -CH ₃ , -CH ₂ CH ₃ or -NH ₂ .

R ₁ is selected from: -H, -O heterocyclyl, -N heterocyclyl, C _1-10 linear/branched alkyl, _3-10 cycloalkyl, -OC _0-10 alkyl, -N(C _0-10 alkyl) (C _{0- 10} alkyl), -SO2 (C _0-10 alkyl), -O (C _0-10 alkyl), -O-phenyl, -S (C _0-10 alkyl), -N heteroaryl, -O heteroaryl or -S heteroaryl wherein the H on the C or heteroatom is optionally substituted with one group selected from C _1-3 linear alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -CF ₃ .

Preferably, R ₁ is selected from: -O heterocyclyl, -N heterocyclyl, -SO2 (C _0-3 alkyl), -O-phenyl, -S (C _0-4 alkyl), C _3-6 cycloalkyl, C _3-5 linear/branched alkyl, wherein the H on the C or heteroatom is optionally replaced by a -CH ₃ , -NH ₂ or -CF ₃ group.

In some preferred embodiments, R ₁ is selected from the following:

R ₂ is selected from: -H, halogen, NO ₂ , -CN, C _1-5 linear/branched alkyl, _3-10 cycloalkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F or -OC _0-10 alkyl.

Preferably, R _{2 is} selected from: -NO ₂ , -N(C _0-10 alkyl), -OCF ₃ or -OC _0-10 alkyl.

In some preferred embodiments, R ₂ is -NH ₂ or -NO ₂ .

When B is N, R ₃ does not exist; when B is C, R ₃ is selected from: -H, halogen, -OC _0-10 alkyl, C _1-10 straight/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl) or _{3 -10} cycloalkyl.

Preferably, R ₃ is selected from: -H, halogen, -OC _0-10 alkyl or C _1-10 linear/branched alkyl.

In some preferred embodiments, R ₃ is -H, -F or -OCH ₃ .

R ₄ is selected from: -H, halogen, -OC _0-10 alkyl, -CN, _3-10 cycloalkyl, -C≡CR ₁₀ , C _1-10 linear/branched alkyl, N(C _0-10 alkyl) (C _0-10 alkyl), -O heterocyclyl or -N heterocyclyl.

Preferably, R ₄ is selected from: -H, halogen, -OC _0-10 alkyl, -CN, _3-10 cycloalkyl, -C≡CR ¹⁰ .

In some preferred embodiments, R ₄ is selected from: -H, -F, -Cl, -OCH ₃ , -CN, or -C≡CR ₁₀ .

Rio selected from: H, C _1-5 linear/branched alkyl, _3-10 cycloalkyl or .

R ₁₁ , R ₁₂ are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C(C _0-10 alkyl) (C _{0- 10} alkyl), -C=C(C _0-10 alkyl), _3-10 cycloalkyl, five-membered heteroaryl or six-membered heteroaryl, or R ₁₁ and R ₁₂ together with the atom(s) to which they are attached form C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, C _4-9 fused cycloalkyl, C _3-7 lactam, C _3-7 lactone or C _3-7 cyclic ketone, where H on C is optionally substituted by alkyl or halogen.

Preferably, R ₁₁ , R ₁₂ are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C(C _0-10 alkyl) (C _0-10 alkyl), _3-10 cycloalkyl or six-membered heteroaryl, or R ₁₁ and R ₁₂ together with the atom(s) to which they are attached form C _3-8 cycloalkyl, C _3-7 fused cycloalkyl, C _{3 -7} lactam, C _3-7 lactone or C _3-7 cyclic ketone, where H on C is optionally replaced by alkyl or F.

Preferably, R ₁₁ , R ₁₂ are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=CH(C _0-10 alkyl), _{3 -10} cycloalkyl or six-membered heteroaryl, or R ₁₁ and R ₁₂ together with the atom(s) to which they are attached form C _3-6 cycloalkyl, C _4-6 fused cycloalkyl, C _3-7 lactam, C _{3- 7} lactone or C _3-7 cyclic ketone, where H on C is optionally replaced by alkyl or F.

In some preferred embodiments, R ₁₁ , R ₁₂ are independently selected from: -H, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , (-CH(CH ₃ ) ₂ ), (-CH ₂ CH (CH ₃ ) ₂ ), , or R ₁₁ and R ₁₂ together with the atom(s) to which they are attached form:

R ₅ , R ₆ , R ₇ are independently selected from: -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), _3-10 cycloalkyl, -C=CR ¹⁰ , -O heterocyclyl or -N heterocyclyl, or R ₆ and R ₇ together with the atom(s) to which they are attached form C _3-8 cycloalkyl, C _{3- 8} heterocyclyl containing O or S, -N heteroaryl, -O heteroaryl, -S heteroaryl or phenyl, where H on C is optionally substituted by one or more of the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _{0- 10} alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, - CN, -OCH ₂ F, OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl.

Preferably, R ₅ , R ₆ , R ₇ are independently selected from: -H, halogen, C _3-6 cycloalkyl, -OC _0-5 alkyl, C _1-5 linear/branched alkyl, C _1-5 linear/branched alkyl, containing O or N, or R ₆ and R ₇ together with the atom(s) to which they are attached form a C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, where H on C is optionally replaced by an F atom.

Preferably, R ₅ , R ₆ , R ₇ are independently selected from: -H, halogen, -OC _0-3 alkyl, C _1-3 linear/branched alkyl, C _1-3 linear/branched alkyl containing N, or R ₆ and R ₇ together with the atom(s) to which they are attached form a C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O, where H on C is optionally replaced by an F atom.

In some preferred embodiments, R ₅ , R ₆ , R ₇ are independently selected from -H, -F, -Cl, -CH ₃ , -CH ₂ NH ₂ , -CN or -OCH ₃ , or R ₆ and R ₇ together with the atom(s) to which they are attached form a five-membered cycloalkyl containing O.

R ₈ , R ₉ are independently selected from: -H, halogen or C _1-10 linear/branched alkyl.

Preferably, R ₈ , R ₉ are independently selected from: -H or C _1-10 linear/branched alkyl.

In some preferred embodiments, R ₈ , R ₉ are independently selected from -H or C _1-3 linear/branched alkyl.

In some preferred embodiments, R ₈ , R ₉ are independently selected from -H or -CH ₃ .

Formula V

In one aspect, the present invention disclosed herein is a compound of formula (V):

where A' represents C or N; B ₁ , B ₂ , B ₃ , B ₄ or B ₅ are independently selected from C or N.

Preferably, _B1 , _B2 , _B3 , _B4 or _B5 is C, or at least one of _B1 , _B2 , _B3 , _B4 or _B5 is N.

Preferably, when B ₂ is C, at least one of B ₁ , B ₃ , B ₄ or B ₅ is N. In some embodiments, B ₂ is C, B ₁ is N, or B ₂ is C, B ₃ is N or B ₂ is C, B ₄ is N, or B ₂ is C, B ₅ is N. In one embodiment, B ₂ is C, B ₃ and B ₄ are N, or B ₃ and B ₅ represent N.

Q' represents O or S; x' and z' are integers from 0 to 6; y' has the value 0 or 1.

Preferably, x' and z' are integers from 0 to 2, such as 0, 1 or 2.

Ar' represents a five-membered heteroaryl, six-membered heteroaryl or phenyl, wherein the five-membered heteroaryl is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl or thiazolyl; the six-membered heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; where H on a five-membered heteroaryl, six-membered heteroaryl or phenyl may be replaced by a group selected from -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _{0- 10} alkyl) SO2 (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N( C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl , -O heteroaryl or -S heteroaryl, wherein the alkyl moiety may optionally be substituted by one or more of the following groups: -SO ₂ , SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _{0 -10} alkyl) SO2 (C _0-10 alkyl), CON (C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N( C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, _3-10 cycloalkyl, -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl.

Preferably, at least one H in the five-membered heteroaryl, six-membered heteroaryl or phenyl is substituted with a group selected from: -SO ₂ , -SO ₂ NH ₂ , -NHSO ₂ , -CONH(C _0-10 alkyl), halogen , -CN, -OCF ₃ , -O heterocyclyl, -N heterocyclyl, C _1-10 linear/branched alkyl, -OC _0-10 alkyl, C _3-10 cycloalkyl or -N(C _0-10 alkyl) (C _{0 -10} alkyl). More preferably, at least one H in the five-membered heteroaryl, six-membered heteroaryl or phenyl is substituted with -O heterocyclyl or -N heterocyclyl.

In some preferred embodiments, Ar' is thiazolyl, selenothiazolyl, imidazolyl, pyrazolyl, or pyridyl.

In some preferred embodiments, Ar' is

Preferably, the compound has a formula selected from the following:

Preferably, the compound has the following formula:

Preferably, the compound has one of the following formulas:

R ₀ ' is selected from: -H, C _1-10 linear/branched alkyl, N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl or C _3-10 cycloalkyl.

Preferably, R ₀ ' is selected from: C _1-5 linear/branched alkyl or -N(C _0-10 alkyl) (C _0-10 alkyl).

In some preferred embodiments, R ₀ ' is -CH ₃ , -CH ₂ CH ₃ or -NH ₂ .

R ₁ ' is selected from: -H, -O heterocyclyl, -N heterocyclyl, C _1-10 linear/branched alkyl, C _3-10 cycloalkyl, -OC _0-10 alkyl, -N(C _1-10 alkyl) (C _0-10 alkyl), -SO2 (C _0-10 alkyl), -O (C _0-10 alkyl), -O-phenyl, -S (C _0-10 alkyl), -N heteroaryl, -O heteroaryl or - S heteroaryl, wherein the H on the C or heteroatom is optionally substituted with one group selected from C _1-3 linear alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -CF ₃ .

Preferably, R ₁ ' is selected from: -O heterocyclyl, -N heterocyclyl, -SO2 (C _0-3 alkyl), -O-phenyl, -S (C _0-4 alkyl), C _3-6 cycloalkyl, C _{3- 5} linear/branched alkyl, where the H on the C or heteroatom is optionally replaced by a -CH ₃ , -NH ₂ or -CF ₃ group.

In some preferred embodiments, R ₁ ' is selected from the following:

When R ₀ ' is adjacent to R ₁ ', R ₀ ' and R ₄ ' together with the atom(s) to which they are attached form a C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, -N heteroaryl, -O heteroaryl, -S heteroaryl or phenyl.

R ₂ ' is selected from: -H, halogen, NO ₂ , -CN, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), - CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F or -OC _0-10 alkyl.

Preferably, R ₂ ' _is selected from: -NO ₂ , -N(C _0-10 alkyl), -OCF ₃ or -OC _0-10 alkyl.

In some preferred embodiments, R ₂ ' is -NH ₂ or -NO ₂ .

When _B1 , _B2 , _B3 , _B4 or _B5 is N, _R3 ', _R4 ', _R5 ', _R6 ' or _R7 ' does not exist; when B ₁ , B ₂ , B ₃ , B ₄ or B ₅ is C, R ₃ ', R ₄ ', R ₅ ', R ₆ ' or R ₇ ' independently selected from: -H, halogen, -CN, -OS _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl, -C≡CR ¹⁰ , -O heterocyclyl or - N of heterocyclyl or R ₅ and R ₄ , R ₄ and R ₃ , R ₃ and R ₇ or R ₇ and R ₆ together with the atom(s) to which they are attached form C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, -N heteroaryl, -O heteroaryl, -S heteroaryl or phenyl, where H on C is optionally replaced by one or more of the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO2 (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, - OCH ₂ F, OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl.

Preferably, R ₃ ' is selected from: -H, halogen, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl.

Preferably, R ₃ ' is selected from: -H, halogen, -OC _0-10 alkyl or C _1-10 linear/branched alkyl.

In some preferred embodiments, R ₃ ' is -H, -F or -OCH ₃ .

R ₄ ' is selected from: -H, halogen, -OC _0-10 alkyl, -CN, C _3-10 cycloalkyl, -C≡CR ₁₀ ', C _1-10 linear/branched alkyl, N(C _0-10 alkyl ) (C _0-10 alkyl), -O heterocyclyl or -N heterocyclyl.

Preferably, R ₄ ' is selected from: -H, halogen, -OC _0-10 alkyl, -CN, C _3-10 cycloalkyl, -C≡CR ₁₀ '.

In some preferred embodiments, R ₄ ' is selected from: -H, -F, -Cl, -OCH ₃ , -CN, or -C≡CR ₁₀ '.

R ₅ ', R ₆ ', R ₇ ' are independently selected from: -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl, -C≡CR ₁₀ ', -O heterocyclyl or -N heterocyclyl, or R ₆ ' and R ₇ ' together with the atom(s) to which they are attached form C _{3 -8} cycloalkyl, C _3-8 heterocyclyl containing O or S, where H on C is optionally replaced by an F atom.

Preferably, R ₅ ', R ₆ ', R ₇ ' are independently selected from: -H, halogen, -OC _0-3 alkyl, C _1-3 linear/branched alkyl, C _1-3 linear/branched alkyl containing or N , or R ₆ ' and R ₇ ' together with the atom(s) to which they are attached form a C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, where H on C is optionally replaced by an F atom.

In some preferred embodiments, R ₅ ', R ₆ ', R ₇ ' are independently selected from -H, -F, -Cl, -CH ₃ , -CH ₂ NH ₂ , -CN or -OCH ₃ , or R ₆ - and R ₇ ' together with the atom(s) to which they are attached form a five-membered cycloalkyl containing O.

R ₁₀ ' is selected from: H, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl or .

Preferably, R ₁₁ ', R ₁₂ ' are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C (C _0-10 alkyl) ( _C0-10 alkyl), _C3-10 cycloalkyl, five-membered heteroaryl or six-membered heteroaryl, or _R11 ' and _R12 ' together with the atom(s) to which they are attached form _C3-8 cycloalkyl , C _3-8 heterocyclyl containing O or S, C _4-9 fused cycloalkyl, C _5-10 spiro-cycloalkyl, C _4-9 bridged cycloalkyl, C _3-7 lactam, C _3-7 lactone or C _3-7 cyclic ketone, where H on C is optionally replaced by a group selected from -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO2 ( C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl ) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear /branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), OS _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or - S heteroaryl, wherein the alkyl moiety may optionally be substituted with one or more of the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO2 (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C3 cycloalkyl, -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl.

Preferably, R ₁₁ ', R ₁₂ ' are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C (C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl or six-membered heteroaryl, or R ₁₁ ' and R ₁₂ ' together with the atom(s) to which they are attached form C _3-8 cycloalkyl, C _4-9 fused cycloalkyl, C _5-10 spiro-cycloalkyl, C _4-9 bridged cycloalkyl, C _3-7 lactam, C _3-7 lactone or C _3-7 cyclic ketone, wherein H on C is optionally substituted by one group selected from -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO2 (C _0-10 alkyl), -CON(C _0-10 alkyl ) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _{0 -10} alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl, wherein the alkyl moiety may optionally be substituted by one or more of the following groups: -SO ₂ , -SO2N(C0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO2 (C _0-10 alkyl), -CON(C _0-10 alkyl) ( C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, _3-10 cycloalkyl, -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl.

Preferably, R ₁₁ ', R ₁₂ ' are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-5 linear/branched alkyl, -CH=CH(C _0-10 alkyl) , C _3-10 cycloalkyl or six-membered heteroaryl, or R ₁₁ ' and R ₁₂ ' together with the atom(s) to which they are attached form C _3-6 cycloalkyl, C _4-6 fused cycloalkyl, C _5-8 spiro-cycloalkyl, C _4-8 cycloalkyl bridged, C _3-7 lactam, C _3-7 lactone or C _3-7 cyclic ketone, wherein H on C is optionally substituted by a group selected from -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO2 (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl) , -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _{0- 10} alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OS _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl, where the alkyl moiety may optionally be substituted by one or more of the following groups: -SO ₂ , SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO2 (C _0-10 alkyl), CON (C _0-10 alkyl) (C _0-10 alkyl) , -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _{0- 10} alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, _3-10 cycloalkyl , -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl.

In some preferred embodiments, R ₁₁ ', R ₁₂ ' are independently selected from: -H, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , (-CH(CH ₃ ) ₂ ), (-CH ₂ CH (CH ₃ ) ₂ ), , or R ₁₁ ' and R ₁₂ ' together with the atom(s) to which they are attached form:

R ₈ ', R ₉ ' are independently selected from the following: -H, halogen or C _1-10 linear/branched alkyl.

Preferably, R ₈ ', R ₉ ' are independently selected from the following: -H or C _1-10 linear/branched alkyl.

In some preferred embodiments, _R8 ', R9' are independently selected from the following: -H or _C1-3 linear/branched alkyl.

In some preferred embodiments, R ₈ ', R ₉ ' are independently selected from -H or -CH ₃ .

In one embodiment, the present disclosure provides a compound selected from any of the specifically defined compounds in Embodiment 15 in the Exemplary Embodiments section.

The compounds of the present disclosure (e.g., Formulas I, II, V, X, Y or Z or any of compounds A1 to A85, or any of the specifically defined compounds in Embodiment 15 in the Illustrative Embodiments section) also include a pharmaceutically acceptable salt thereof, a stereoisomer , ester, prodrug, solvate or deuterated compound.

Pharmaceutically acceptable salts include acid addition salts and base addition salts.

Acid addition salts include salts of inorganic acids and salts of organic acids. Inorganic acid salts include, but are not limited to, salts of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid and phosphonic acid. Organic acid salts include, but are not limited to, aliphatic monocarboxylic acid, aliphatic dicarboxylic acid, phenylalkanoic acid, hydroxyalkanoic acid, alkanedioic acid and sulfonic acid salts. More specifically, the acid addition salt includes one or more of the following: sulfates, pyrosulfates, hydrogen sulfates, sulfites, bisulfites, nitrates, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, octoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, amygdalate, benzoate, chlorobenzoate, benzoate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and salt of arginine, glucose acid, galacturonic acid. The acid addition salt can be prepared by methods well known in the art.

Basic addition salts include alkali and alkaline earth metal hydroxides or organic ammonium salts. Alkali and alkaline earth metal salts include, but are not limited to, sodium, potassium, magnesium or calcium salts. Examples of amine salts include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine and procaine salts. Base addition salts can be prepared by methods well known in the art.

Stereoisomers as used herein include enantiomers, diastereomers and geometric isomers. The present disclosure is intended to include all such possible isomers, including racemic mixtures, scalemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or separated using conventional methods. If the compound contains a double bond, the substituent may have the E- or Z-configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. Inclusion of all tautomeric forms is also intended.

"Solvate" refers to the physical association of a compound disclosed herein with one or more solvent molecules. Physical association includes electrostatic adsorption, covalent bonding and hydrogen bonding. In some cases, a solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solution phases and liberated solvates, representative solvates include ethanolates, methanolates, etc. "Hydrate" is a solvate in which one or more solvent molecules are H ₂ 0.

Prodrug refers to chemically modified versions of a pharmacologically active compound that undergo chemical or enzymatic conversion in vivo to release the active compound described herein. More specifically, functional groups amenable to chemical or enzymatic conversion are added to pharmacologically active compounds to improve drug targeting.

Synthesis method

The compounds of the present invention can be prepared by those skilled in the art, taking into account the present disclosure. Typical synthesis procedures are described in the Examples section.

For example, in some embodiments, compounds of formula X can be prepared by the method shown in Scheme 1. In some embodiments, the method may include the combination of a compound S-1, wherein G ¹ is a leaving group, such as a halogen or oxygen leaving group, such as a tosylate , mesylate, triflate, etc., with compound S-2, where G ² is a metal ion (Zn, Mg, etc., i.e. Ar-G ² is an organozinc or organomagnesium reagent, etc. etc.), boronic acid or ester residue (for example, -B(OH) ₂ or etc., i.e. Ar-G ² is an organoboron reagent with a boron atom attached directly to Ar), tin (such as -SnBu ₃ , ie Ar-G ² is an organotin reagent) or other suitable coupling partners. The cross-coupling reaction is typically carried out with a palladium catalyst to produce compound S-3, which may be followed by reduction of the nitro group to produce the compound of formula X. In some embodiments, the role of partners S-1 and S-2 in the coupling reaction may vary. For example, in some embodiments, compound S-1 may have G1 as a metal ion (Zn, Mg, etc.), boronic acid, or ester moiety (e.g., -B(OH) ₂ or etc.), tin (such as -SnBu ₃ ) or other suitable coupling partners, while compound S-2 includes G ² which is a leaving group such as a halogen or oxygen leaving group such as a tosylate , mesylate, triflate, etc. Typical conditions for the cross-coupling and reduction reaction are shown in the Examples section. The variables A, Ak, L and Cy ¹ in Scheme 1 are as defined and preferred in this application.

In some embodiments, compounds of formula X can also be prepared by the following method shown in Scheme 2. For example, in some embodiments, the method may include the combination of a compound S-4, wherein G ¹⁰ and G ¹¹ each independently represent a hydrogen or nitrogen protecting group, such as Boc and G ³ represents a metal ion (Zn, Mg, etc.), boronic acid or ester residue (for example, -B(OH) ₂ or etc.), tin (such as -SnBu ₃ ) or other suitable coupling partners, with compound S-5, where G ⁴ represents a leaving group such as a halogen or oxygen leaving group such as tosylate, mesylate , triflat, etc. Likewise, the roles of S-4 and S-5 partners may change. For example, in some embodiments, the G ⁴ in compound S-5 may be a metal ion (Zn, Mg, etc.), boronic acid, or an ester moiety (e.g., - B(OH) ₂ or etc.), tin (such as -SnBu ₃ ) or other suitable coupling partners, while G ³ in compound S-4 is a leaving group. The cross-coupling reaction is typically carried out with a palladium catalyst to yield compound S-6, which may then be followed by deprotection to yield the compound of Formula X. Typical conditions for the cross-coupling and deprotection reaction are shown in the Examples section. The variables A, Ar, L and Cy ¹ in Scheme 2 are as defined and preferred in this application.

Compounds of formula Y can be synthesized in a similar manner. For example, as shown in Scheme 3, in some embodiments, compound Y-1 can be coupled wherein G ⁶ represents hydrogen or an oxygen protecting group such as tetrahydropyranyl (THP), G 5 represents is a leaving group such as a halogen or oxygen leaving group such as tosylate, mesylate, triflate, etc., with a compound Y-2, where G ⁷ represents a metal ion (Zn, Mg, etc.), boronic acid or ester residue (for example, - B(OH) ₂ or etc.), tin (such as -SnBu ₃ ) or other suitable coupling partners, using a palladium catalyst, to give compound Y-3, which may then be followed by reduction of the nitro group and optionally deprotection, e.g. G ⁶ is an oxygen protecting group to give the compound of formula Y. Likewise, the roles of partners Y-1 and Y-2 can be reversed. For example, in some embodiments, the G ⁵ of compound Y-1 may be a metal ion (Zn, Mg, etc.), boronic acid, or an ester moiety (e.g., -B(OH) ₂ or etc.), tin (such as -SnBu ₃ ) or other suitable coupling partners, and G ⁷ in compound Y-2 may be a leaving group such as a halogen or oxygen leaving group such as tosylate, mesylate , triflat, etc. Typical conditions for cross-coupling, reduction and deprotection reactions are shown in the Examples section. The variables A, Ar, L, ring B, R ^A , R ^B , R ^C and n in Scheme 3 are as defined and preferred in this application.

In some embodiments, compounds of formula Y can also be prepared in accordance with the method presented in Scheme 4. In some embodiments, a combination of compound Y-4 can be made, wherein G ¹² and G ¹³ each independently represent a hydrogen or nitrogen protecting group such like Boc, G ⁶ represents hydrogen or an oxygen protecting group such as tetrahydropyranyl (THP), and G ⁸ represents a metal ion (Zn, Mg, etc.), boronic acid or ester moiety (eg -B( OH) ₂ or etc.), tin (such as -SnBu ₃ ) or other suitable coupling partners, with compound Y-5, where G ⁹ represents a leaving group such as a halogen or oxygen leaving group such as tosylate, mesylate , triflate, etc., using a palladium catalyst to produce compound Y-6, which may then be followed by a deprotection reaction to produce a compound of formula Y. Likewise, in some embodiments, Y-5 may be a coupling reaction partner wherein G ⁹ is a metal ion (Zn, Mg, etc.), boronic acid or ester residue (for example, -B(OH) ₂ or etc.), tin (such as -SnBu ₃ ) or other suitable coupling partner, while Y-4 is the coupling partner with the leaving group as G ⁸ . Typical conditions for cross-coupling and deprotection reactions are shown in the Examples section. The variables A, Ar, L, ring B, R ^A , R ^B , R ^C and n in Scheme 4 are as defined and preferred in this application.

Scheme 4

In some embodiments, the Cy ¹ unit in Formula Y may be introduced at a later stage in the synthesis sequence. For example, as shown in Scheme 5, in some embodiments, compound Z-1, wherein G ²⁰ is NO ₂ , NH ₂ , or protected NH ₂ , can react with a suitable Cy ¹ molecule to form a compound of formula X after optional reduction and/or removing protection. For example, in some embodiments, L ¹⁰ is OH, and the reaction of Mitsunobu with Cy ¹ -OH can provide an intermediate that can be converted to the compound of formula X after optional reduction and/or deprotection. The variables A, Ar, L and Cy ¹ in Scheme 5 are as defined and preferred in this application.

Scheme 5

As will be apparent to those skilled in the art based on the present disclosure, in some embodiments, substituents on Ar or Cy ¹ may be introduced at another step, as shown in the Schemes herein. For example, the alkynyl group in formula Y may be introduced at a later stage of the synthesis. As shown in Scheme 6, in some embodiments, compound Z-2, wherein G ²⁰ is NO ₂ , NH ₂ or protected NH ₂ , and G ²¹ is a leaving group, such as a halogen or oxygen leaving group, such as a tosylate, mesylate, triflate, etc., can be combined with a Z-3 molecule to produce compound Z-4. Typically, such a coupling reaction can be mediated by catalysis using a palladium and/or copper catalyst. Illustrative conditions are shown in the Examples section. Z-4 can then be subjected to deprotection or reduction and then deprotection to produce the compound of formula Y. The variables A, ^G6 , Ar, L, ring B, R ^A , R ^B , R ^C and n in Scheme 6 are as follows: , as defined and preferred herein.

Scheme 6

Compounds of formula Z can be synthesized similarly to compounds of formula Y. As will be apparent to those skilled in the art, conventional protecting groups may be required to prevent unwanted reactions of certain functional groups. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, various protecting groups are described in "Protective Groups in Organic Synthesis", 4 ^th ed. PGM Wuts; TW Greene, John Wiley, 2007 and references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures or obvious modifications thereof described in standard references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7th Edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999) .

In one aspect, the present invention provides a process for preparing a compound of formula (I), wherein the process steps are as follows:

(1) interaction With with education ,

where R ₁₃ represents halogen or , R ₁₄ represents -OH or -F.

(2) interaction With with education ,

where R ₁₅ represents -Br or -SnBu ₃ .

Preferably, in step (1) R ₁₃ is -Br.

Preferably, in step (2) R ₁₃ is -Br or when R ₁₃ is -Br, R ₁₅ is -SnBu ₃ , and when R ₁₃ is , R ₁₅ represents -Br.

In one aspect, the present invention provides a compound of formula (III):

where R ₁₅ represents -Br or -SnBu ₃ , the definitions of R ₀ and R ₁ are as described above.

In one aspect, the present invention provides a compound of formula (IV):

where R ₁₃ represents halogen or , the definitions of R ₂ - R ₉ are as described above. Preferably, R ₁₃ is -Br.

In one aspect, the present disclosure provides a method for preparing a compound of formula (V), wherein the process steps are as follows:

(1) interaction With with education ,

where R ₁₃ ' represents halogen or , R ₁₄ ' represents -OH or -F.

(2) interaction With with education ,

where R ₁₅ ' represents -Br or -SnBu ₃ .

Preferably, in step (1) R ₁₃ ' is -Br.

Preferably, in step (2) R ₁₃ ' is -Br or when R ₁₃ ' is -Br, R ₁₅ ' is -SnBu ₃ , and when R ₁₃ ' is , R ₁₅ ' represents -Br.

In one aspect, the present invention also provides a compound of formula (VI):

where A' represents C or N; B ₁ , B ₂ , B ₃ , B ₄ or B ₅ are independently selected from C or N.

Q' represents O or S; x' and z' are integers from 0 to 6; y' has the value 0 or 1.

R ₂ ' is selected from: -H, halogen, -NO ₂ , -CN, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F or -OC _0-10 alkyl.

When _B1 , _B2 , _B3 , _B4 or _B5 is N, _R3 ', _R4 ', _R5 ', _R6 ' or _R7 ' does not exist; When B ₁ , B ₂ , B ₃ , B ₄ or B ₅ is C, R ₃ ' is selected from: -H, halogen, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl.

R ₄ ' is selected from: -H, halogen, -OC _0-10 alkyl, -CN, C _3-10 cycloalkyl, -C'≡CR ₁₀ ', C _1-10 linear/branched alkyl, N(C _0-10 alkyl) (C _0-10 alkyl), -O heterocyclyl or -N heterocyclyl.

R ₅ ', R ₆ ', R ₇ ' are independently selected from: -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl, -C=CR ₁₀ ', -O heterocyclyl or -N heterocyclyl.

R ₈ ', R ₉ ' are independently selected from: -H, halogen or C _1-10 linear/branched alkyl.

R ₁₃ ' represents halogen or ;

R ₁₀ ' is selected from: H, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl or . Preferably, R ₁₁ ', R ₁₂ ' are independently selected from: -H, -CF ₃ , C _1-10 linear/branched alkyl, CH=C(C _0-10 alkyl) (C _0-10 alkyl), C _{3- 10} cycloalkyl, five-membered heteroaryl or six-membered heteroaryl, or R ₁₁ ' and R ₁₂ ' together with the atom(s) to which they are attached form C _3-8 cycloalkyl.

Pharmaceutical compositions and methods of use

As shown in the Examples, exemplary compounds of the present invention inhibit NRK1 activity. The structure-activity relationship presented herein also shows that compounds having either a pyridine or a pyrazine core and having different Ar, Cy ¹ and L are useful as NRK1 inhibitors. In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable formulations thereof salt) and a pharmaceutically acceptable excipient selected from: a carrier, a diluent, a binder, a lubricant and a wetting agent. Preferably, the pharmaceutical composition includes a therapeutically effective amount of a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable salts thereof) . In some embodiments, these pharmaceutical compositions are useful for treating diseases associated with HK1. The compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable salts thereof) can be formulated into pharmaceutical compositions that are useful for cancer or a disorder caused by HNK1.

The compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable salts thereof) can be prepared as pharmaceutical compositions in the form syrups, suspensions, powders, granules, tablets, capsules, aqueous solutions, creams, ointments, lotions, gels, emulsions, etc.

Preferably, the pharmaceutical composition is a unit dosage form. A unit dosage form may be a packaged preparation containing a fixed amount of a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or their pharmaceutically acceptable salts), which may be a capsule, tablet or powder packaged in a vial or ampoule. The amount of active ingredient in a unit dosage form may vary from 0.1 to 1000 mg depending on the specific application and the effectiveness of the active ingredient. If desired, the composition may also contain other suitable therapeutic agents.

The pharmaceutically acceptable carrier depends on the particular route of administration of the compound described herein. Therefore, the pharmaceutical compositions of the present invention are prepared in various dosage forms.

A compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable salts thereof) in combination with other suitable components may be formulated as aerosols (i.e. they can be "sprayed") that are administered by inhalation. The aerosol may be placed in a propellant selected from the group consisting of dichlorodifluorohexane, propane, nitrogen, etc.

A pharmaceutical composition suitable for parenteral administration, such as intravenous, intramuscular, intradermal and subcutaneous routes of administration, includes aqueous or non-aqueous isotonic sterile injections, which may contain antioxidants, buffers, bacteriostatic agents and isotonic solutes; as well as aqueous or non-aqueous sterile suspensions, which may contain suspending agents, solubilizers, thickeners, stabilizers and preservatives. In some embodiments, a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable salts thereof) can be administered by intravenous infusion, oral, local, intraperitoneal, intravesical and intrathecal. The compositions may be presented in single-dose or multi-dose sealed containers such as ampoules or vials. Injectable solutions and suspensions can be prepared from sterile powders, granules and tablets as described above.

An effective amount refers to an amount that can be effective to produce a desired biological, clinical or medical response, including an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect such treatment. The effective amount will vary depending on the compound, the disease and its severity, as well as age, body weight, etc. subject to be treated.

In one aspect, the present invention provides the use of a composition comprising a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable formulations thereof salts, stereoisomer, ester, prodrug, solvate or deuterated compound) for the prevention and/or treatment of cancer.

In one aspect, the present invention provides the use of a composition comprising a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable formulations thereof salts, stereoisomer, ester, prodrug, solvate or deuterated compound) for the preparation of a medicament for the prevention and/or treatment of cancer.

In one aspect, the present invention provides the use of a composition comprising a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable formulations thereof salts, stereoisomer, ester, prodrug, solvate or deuterated compound) in combination with PD-1, PD-L1, CTLA-4, TIM-3, TLR ₄ , TLR ₇ , TLR ₈ , TLR ₉ , TGF-β and its receptor, LAG3 antagonist or STING agonists in cancer immunotherapy.

The cancer of the present disclosure may be a carcinoma selected from: lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell cancer, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia or lymphoid malignancies, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung carcinoma, abdominal cancer, hepatocellular cancer, gastric cancer or stomach cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, anal carcinoma, penile carcinoma, Merkel cell cancer, esophageal cancer, biliary tract tumors, head cancer and neck and hematological malignancies.

In one aspect, the present invention provides the use of a composition comprising a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or pharmaceutically acceptable formulations thereof salts, stereoisomer, ester, prodrug, solvate or deuterated compound), in combination with CAR-T immunotherapy in cancer immunotherapy.

CAR-T immunotherapy refers to immunotherapy using chimeric antigen receptor T cells, which is currently one of the cell therapy treatments for malignant tumors, and the basic principle is to use the patient's own immune cells to remove cancer cells. Unlike traditional drugs, CAR-T can eradicate widespread cancer and provides long-term protection in the form of immunological memory.

In some embodiments, the present invention provides a method of inhibiting HKK1 activity. In some embodiments, the method includes administering to a subject in need thereof a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of compounds A1 to A85, or their pharmaceutically acceptable salts) or the pharmaceutical composition described in this application. In some embodiments, the subject is diagnosed with cancer. In some embodiments, the subject has a disease or disorder associated with aberrant HKK1 activity, such as cancer, metastasis, inflammation, and/or an autoimmune disease.

In some embodiments, the present invention provides a method of treating a disease or disorder associated with aberrant HNK1 activity. In some embodiments, the method includes administering to a subject in need thereof a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of Compounds A1 to A85, or their pharmaceutically acceptable salts) or the pharmaceutical composition described in this application. In some embodiments, the disease or disorder is cancer, metastasis, inflammation, and an autoimmune disease.

In some specific embodiments, the present invention provides a method for treating cancer. In some embodiments, the method includes administering to a subject in need thereof a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of compounds A1 to A85, or their pharmaceutically acceptable salts) or the pharmaceutical composition described in this application. In some embodiments, the cancer is breast cancer, colorectal cancer, hematologic malignancy, lung cancer (eg, non-small cell lung cancer), melanoma, ovarian cancer, pancreatic cancer, and/or kidney cancer (eg, renal cell carcinoma). In some embodiments, the method further includes administering to the subject one or more additional anticancer therapies. In some embodiments, the one or more additional anticancer therapies is a CAR-T cell therapy. In some embodiments, one or more additional anticancer therapies may be a cancer immune therapy, including PD-1, PD-L1, CTLA-4, TIM-3, TLR ₄ , TLR ₇ , TLR ₈ , TLR ₉ , TGF-β, and its receptor, LAG3 antagonist or STING agonists, appropriate cancer immunotherapy, which can be small molecule based, protein based (eg PD-1, PD-L1 or CTLA-4 antibodies) or cell based.

In some embodiments, the present invention also provides a method of enhancing the cytotoxicity, inhibiting depletion, and/or enhancing infiltration into spleen and/or tumors of an immune cell (e.g., a T cell), the method comprising administering to a subject receiving an immune cell (e.g., a T cell) cell, such as a Car T cell), an effective amount of a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of compounds A1 to A85, or their pharmaceutically acceptable salts) or the pharmaceutical composition described in this application. In some embodiments, the immune cell is a T cell (e.g., a CD4+ or CD8+ T cell, a CAR T cell, an NK T cell, an alpha beta T cell, or a gamma delta T cell), or NK cell. In some embodiments, the subject has cancer, wherein the cancer is lymphoma, chronic lymphocytic leukemia (CLL), B-cell acute lymphocytic leukemia (B-ALL), acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma (NHL), diffuse large cell lymphoma (DLCL), multiple myeloma, renal cell carcinoma (RCC), neuroblastoma, colorectal cancer, breast cancer, ovarian cancer, melanoma, sarcoma, prostate cancer, lung cancer, esophageal cancer, hepatocellular carcinoma, pancreatic cancer, astrocytoma , mesothelioma, head and neck cancer and/or medulloblastoma.

In some embodiments, the present invention also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention (e.g., Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any of these subformula or any of compounds A1 to A85, or pharmaceutically acceptable salts thereof) or the pharmaceutical composition described herein in combination with CAR-T cell therapy. In some embodiments, the cancer is lymphoma, chronic lymphocytic leukemia (CLL), B-cell acute lymphocytic leukemia (B-ALL), acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma (NHL), diffuse large cell lymphoma (DLCL), multiple myeloma, renal cell carcinoma (RCC), neuroblastoma, colorectal cancer, breast cancer, ovarian cancer, melanoma, sarcoma, prostate cancer, lung cancer, esophageal cancer, hepatocellular carcinoma, pancreatic cancer, astrocytoma, mesothelioma, head cancer and neck and/or medulloblastoma. In some embodiments, a compound of the present invention or pharmaceutical composition is administered in an amount effective to enhance cytotoxicity, inhibit depletion, and/or enhance infiltration into spleen and/or tumors of Car T cells.

In some embodiments, the present invention also provides a method for identifying a candidate agent for use in combination with a CAR-T cell therapy. In some embodiments, the method includes: a) incubating the test agent and the CAR-T cells with a tumor cell, wherein the tumor cell contains an antigen that can bind to and induce cytotoxicity of the CAR-T cells; b) measuring the cytotoxicity of CAR-T cells in the presence of a test agent; and optionally c) identifying a candidate agent that enhances the cytotoxicity of CAR-T cells compared to a control. Incubation conditions for test agent, CAR-T cells and tumor cells include any of those known in the art, with some conditions illustrated herein. Cytotoxicity can also be measured by any of the methods known in the art. The screening methods provided herein are also not limited to tumor cell types or any specific CAR-T cell populations. In some embodiments, the test agent is pre-screened as an NPK-1 kinase inhibitor. In some embodiments, the test agent is not prescreened in an HNK-1 kinase inhibition assay. As shown in FIG. 1 and the corresponding examples, the methods identified several compounds of the invention as effective in enhancing the cytotoxicity of the tested Car-T cells.

Definitions

It should be clear that the proper valencies are maintained for all moieties and their combinations.

It should also be understood that a particular embodiment of a variable fragment in this application may be the same or different from another particular embodiment having the same identifier.

Suitable groups for the variables in the compounds of formula I, II, III, IV, V, VI, X, Y and Z or subformula thereof, if applicable, are selected independently. It should be noted that Formula I, II, etc. in some cases may be expressed as Formula (I), Formula (II), etc. The described embodiments of the present invention can be combined. Such a combination is contemplated and is within the scope of the present invention.

As used herein, the term "compound(s) of the present disclosure" or "compound(s) of the present invention" refers to any of the compounds described herein according to Formula I, Formula II, Formula V, Formula X, Formula Y, Formula Z, any subformula thereof, or any of compounds A1-A85 or any of the specific compounds shown in Embodiment 15 (see Illustrative Embodiments section), isotopically labeled compounds thereof (such as a deuterated analogue in which one of hydrogen atoms is replaced by a deuterium atom at a content greater than its natural content), possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures), tautomers thereof, conformational isomers thereof, and/or pharmaceutically acceptable salts thereof (e.g., an acid addition salt such as HCl salt, or base addition salt such as Na salt). Hydrates and solvates of the compounds of the present invention are considered compositions of the present invention in which the compound(s) are in association with water or a solvent, respectively.

The compounds of the present invention may exist in an isotopically labeled or enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, ^2H , ^3H , 13C ^{, 14C} , ^15N , ^18O , ^32P , ^35S , ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Compounds which contain other isotopes of these and/or other atoms are within the scope of the present invention.

As used herein, the phrase “administration” of a compound or other variations thereof means delivery of a compound or a prodrug of a compound to an individual in need of treatment.

The term "subject" (alternatively referred to herein as "patient") as used herein, refers to an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experiment. In some embodiments, the subject may be a vertebrate animal such as a dog, cat, horse, or monkey.

Oxygen protecting groups and nitrogen protecting groups are well known in the art and include groups that are described in detail in "Protective Groups in Organic Synthesis", 4 ^th ed. PGM Wuts; TW Greene, John Wiley, 2007, incorporated herein by reference. Typical oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyls, silyl ethers such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl ( TIPS), tert-butyldimethylsilyl (TBDMS), etc., acetals or ketals such as tetrahydropyranyl (THP), esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., carbonates, sulfonates such as methanesulfonate (mesylate), benzylsulfonate and tosylate (Ts).

The term "leaving group" has its usual meaning in the field of organic synthesis chemistry and refers to an atom or group that can be replaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br or I (iodine atom)), alkanesulfonyloxy, arenesulfonyloxy, etc.

An "optionally substituted" group, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl groups, refers to a corresponding group that is unsubstituted or substituted. Generally, the term "substituted" means that at least one hydrogen present on a group (eg, a carbon or nitrogen atom) is replaced by an acceptable substituent, such as a substituent that, when substituted, results in a stable compound, such as a compound that does not undergoes spontaneous transformations such as rearrangement, cyclization, elimination or other reactions. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent may be the same or different at each position. Typically, upon substitution, optionally substituted groups in the present invention may be substituted with 1-5 substituents. The substituents may be a carbon substituent, a nitrogen substituent, an oxygen substituent, or a sulfur substituent, as appropriate. Two of the optional substituents may combine to form an optionally substituted cycloalkyl, heterocylyl, aryl, or heteroaryl ring. Substitution can occur at any available carbon, oxygen or nitrogen atom and can form a spirocycle. When a bicyclic or polycyclic ring structure is designated as linked to two groups, each point of attachment can be independently selected from any available positions on either ring. Typically, substitution in the present invention does not result in the formation of an OO, ON, SS, SN (other than SO ₂ -N bond), heteroatom-halogen, heteroatom-CN bond, -C(O)-S bond, or three or more consecutive heteroatoms, with with the exception of O-SO ₂ -O, O-SO ₂ -N and N-SO ₂ -N, except that some of such bonds or additions may be acceptable if they are in a stable aromatic system.

In any of the embodiments described herein, unless otherwise indicated, the "optionally substituted" non-aromatic group may be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from F, Cl, -OH, oxo (if applicable), C _1-7 alkyl (e.g. C _1-4 alkyl), C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1 or 2 ring heteroatoms, regardless selected from O, S and N, 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S and N, wherein each of alkyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl and heterocyclyl is optionally substituted 1, 2 or 3 substituents independently selected from F, -OH, oxo (if applicable), C _1-7 alkyl (eg, C _1-4 alkyl) and C _1-4 alkoxy. In any of the embodiments described herein, unless otherwise indicated, the "optionally substituted" aromatic group (including aryl and heteroaryl groups) may be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from F, Cl, -OH , -CN, C _1-7 alkyl (for example, C _1-4 alkyl), C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1 or 2 ring heteroatoms independently selected from O, S and N, 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S and N, where each of alkyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl and heterocyclyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, -OH, oxo (if applicable), C _1-7 alkyl (eg, C _1-4 alkyl) and C _1-4 alkoxy.

Unless otherwise expressly stated, combinations of substituents and/or variables are permitted only if such combinations are chemically permissible and result in a stable compound. A "stable" compound is a compound that can be prepared and isolated and whose structure and properties remain or can remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (eg, therapeutic administration to a subject).

In the context of the present application, in the term C _0-10 alkyl, C ₀ alkyl means H and thus C _0-10 alkyl includes H, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl , C ₆ alkyl, C ₇ alkyl, C ₈ alkyl, C ₉ alkyl, C ₁₀ alkyl.

C _1-10 linear/branched alkyl includes methyl, ethyl, C ₃ linear/branched alkyl, C ₄ linear/branched alkyl, C ₅ linear/branched alkyl, C ₆ linear/branched alkyl, C ₇ linear/branched alkyl, C ₈ linear/branched alkyl, C ₉ linear/branched alkyl, C ₁₀ linear/branched alkyl.

_3-10 branched alkyl includes isopropyl, isobutyl, tert-butyl, isopentyl.

C _3-10 cycloalkyl includes C ₃ cycloalkyl, C ₄ cycloalkyl _, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, C 8 cycloalkyl, C ₉ cycloalkyl, C ₁₀ cycloalkyl.

C _3-8 cycloalkyl includes C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, C ₈ cycloalkyl.

C _4-8 cycloalkyl includes C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, C ₈ cycloalkyl.

C _4-6 cycloalkyl includes C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl.

Halogen includes fluorine, chlorine, bromine and iodine.

Heterocycle refers to a non-aromatic saturated monocyclic or polycylic ring system containing 3-10 ring atoms, preferably containing 5-10 ring atoms, where one or more ring atoms is a nitrogen, oxygen or sulfur atom. Preferably, the heterocycle contains 5 or 6 ring atoms.

Heteroalkyl refers to an alkyl in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom or group of heteroatoms. Heteroatoms include, but are not limited to, N, O, S.

Heteroaryl refers to an aromatic monocyclic or polycyclic ring system containing 5-14 ring atoms, preferably containing 5-10 ring atoms, where one or more ring atoms is a nitrogen, oxygen or sulfur atom. Preferably, heteroaryl contains 5 or 6 ring atoms. Heteroaryl includes, but is not limited to, pyrazinyl, furyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, 2,3-naphthyridinyl, imidazo[1, 2-a]pyridine, imidazo[2,1-b]thiazolyl, fluorenyl, azaindole, benzimidazolyl, benzothienyl, quinolyl, imidazolyl, thienopyridinyl, quinazoline, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridinyl, isoquinolinyl, 1,2,4-triazinyl, benzothiazolyl.

Exemplary Embodiments

Embodiment 1. The compound of formula (I), its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound,

Where

A represents C or N; B represents C or N;

Ar is a five-membered heteroaryl, six-membered heteroaryl or phenyl, wherein the five-membered heteroaryl is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl or thiazolyl; six-membered heteroaryl includes pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; wherein H on a five-membered heteroaryl, six-membered heteroaryl or phenyl is optionally substituted by a group selected from -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON (C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N( C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl , -O heteroaryl or -S heteroaryl, wherein the alkyl moiety may optionally be substituted by one or more of the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), CON (C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), - N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl;

R ₂ is selected from: -H, halogen, -NO ₂ , -CN, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), - CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F or -OC _0-10 alkyl;

When B is N, R ₃ does not exist; when B is C, R ₃ is selected from: -H, halogen, -OC _0-10 alkyl, C _1-10 straight/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl) or C _3-10 cycloalkyl;

R ₄ is selected from: -H, halogen, -OC _0-10 alkyl, -CN, C _3-10 cycloalkyl, -C=CR ₁₀ , C _1-10 linear/branched alkyl, N(C _0-10 alkyl) ( C _0-10 alkyl), -O heterocyclyl or -N heterocyclyl;

R ₅ , R ₆ , R ₇ are independently selected from: -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl, -C=CR ₁₀ , -O heterocyclyl or -N heterocyclyl, or R ₆ and R ₇ together with the atom(s) to which they are attached form C _3-8 cycloalkyl, C _{3 -8} heterocyclyl containing O or S, -N heteroaryl, -O heteroaryl, -S heteroaryl or phenyl, where H on C is optionally substituted by one or more of the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl ) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _{0 -10} alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl;

R ₈ , R ₉ are independently selected from the following: -H, halogen or C _1-10 linear/branched alkyl;

R ₁₀ is selected from: H, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl or ;

R ₁₁ , R ₁₂ are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C(C _0-10 alkyl) (C _{0- 10} alkyl), -C=C(C _0-10 alkyl), C _3-10 cycloalkyl, five-membered heteroaryl or six-membered heteroaryl, or R ₁₁ and R ₁₂ together with the atom(s) to which they are attached, form a C _3-8 cycloalkyl, a C _3-8 heterocyclyl containing O or S, a C _4-9 fused cycloalkyl, a C _3-7 lactam, a C _3-7 lactone or a C _3-7 cyclic ketone, where H is optionally substituted with C alkyl or halogen;

Q represents O or S; x and z are integers from 0 to 6; y has the value 0 or 1.

Embodiment 2. The compound of Embodiment 1, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein the structure of the compound is formula (II),

Embodiment 3. The compound of Embodiment 2, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein Ar is a thiazolyl, selenothiazolyl, imidazolyl, pyrazolyl, or pyridyl, wherein at least one H is on a thiazolyl, imidazolyl , pyrazolyl or pyridyl is substituted with one group selected from -SO ₂ NH ₂ , -NHSO ₂ , -CONH(C _0-10 alkyl), halogen, -CN, -OCF ₃ , -O heterocyclyl, -N heterocyclyl, C _{1- 10} linear/branched alkyl, -OC _0-10 alkyl, C _3-10 cycloalkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -N heteroaryl, -O heteroaryl or -S heteroaryl;

R ₂ is selected from: -NO ₂ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OCF ₃ or -OC _0-10 alkyl;

When B is N, R ₃ does not exist; when B is C, R ₃ is selected from: -H, halogen, -OC _0-10 alkyl or C _1-10 linear/branched alkyl;

R ₄ is selected from: -H, halogen, -OC _0-10 alkyl, -CN, C _3-10 cycloalkyl, -C≡CR ₁₀ ;

R ₅ , R ₆ , R ₇ are independently selected from: -H, halogen, C _3-6 cycloalkyl, -OC _0-5 alkyl, C _1-5 linear/branched alkyl, C _1-5 linear/branched alkyl containing O or N, or R ₆ and R ₇ together with the atom(s) to which they are attached form a C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, where H on C is optionally replaced by an F atom;

R ₈ , R ₉ are independently selected from the following: -H or C _1-10 linear/branched alkyl;

R ₁₁ , R ₁₂ are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C(C _0-10 alkyl) (C _{0- 10} alkyl), C _3-10 cycloalkyl or six-membered heteroaryl, or R ₁₁ and R ₁₂ together with the atom(s) to which they are attached form C _3-8 cycloalkyl, C _4-7 fused cycloalkyl, C _{3- 7} lactam, C _3-7 lactone or C _3-7 cyclic ketone, where H on C is optionally replaced by alkyl or F.

Embodiment 4. A compound of any of Embodiments 1 to 3, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein at least one H on Ar is optionally substituted with -O heterocyclyl or -N heterocyclyl.

Embodiment 5. The compound of Embodiment 2, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein Ar is

R ₀ is selected from: -H, C _1-10 linear/branched alkyl, N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl or C _3-10 cycloalkyl; R ₁ is selected from: -H, -O heterocyclyl, -N heterocyclyl, C _1-10 linear/branched alkyl, C _3-10 cycloalkyl, -OC _0-10 alkyl, -N(C _0-10 alkyl) (C _{0 -10} alkyl), -SO ₂ (C _0-10 alkyl), -O (C _0-10 alkyl), -O-phenyl, -S (C _0-10 alkyl), -N heteroaryl, -O heteroaryl or - S heteroaryl, wherein the H on the C or heteroatom is optionally substituted with a group selected from C _1-3 linear alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -CF ₃ .

Embodiment 6. The compound of Embodiment 5, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein _R0 is selected from: _C1-5 linear/branched alkyl or -N( _C0-10 alkyl) (C _0-10 alkyl);

R ₁ is selected from: -O heterocyclyl, -N heterocyclyl, -SO ₂ (C _0-3 alkyl), -O-phenyl, -S (C _0-4 alkyl), C _3-6 cycloalkyl, C _3-5 linear /branched alkyl, where H on C or heteroatom is optionally substituted with -NH ₂ or -CF ₃ , -CF ₂ H, -O heterocyclyl, -N heterocyclyl, C _3-5 linear/branched alkyl, C _3-7 cycloalkyl;

R ₂ represents -NH ₂ or -NO ₂ ;

When B is N, R ₃ does not exist; when B is C, R ₃ is -H, -F or -OCH ₃ ;

R ₄ is selected from the following substituents: -H, -F, -Cl, -OSH ₃ , -CN, , -C≡CR ₁₀ ';

R ₅ , R ₆ , R ₇ are independently selected from: -H, halogen, -OC _0-3 alkyl, C _1-3 linear/branched alkyl, C _1-3 linear/branched alkyl containing N, or R ₆ and R ₇ together with the atom(s) to which they are attached form a C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O, where H on C is optionally replaced by an F atom;

R ₈ , R ₉ are independently selected from the following: -H or C _1-3 linear/branched alkyl;

R ₁₁ , R ₁₂ are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-5 linear/branched alkyl, -CH=CH(C _0-10 alkyl), C _{3- 10} cycloalkyl or six-membered heteroaryl, or R ₁₁ and R ₁₂ together with the atom(s) to which they are attached form C _3-6 cycloalkyl, C _4-6 fused cycloalkyl, C _3-7 lactam, C _3-7 lactone or C _3-7 cyclic ketone, where H on C is optionally replaced by alkyl or F.

Embodiment 7. The compound of Embodiment 6, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein R ₀ is -CH ₃ , -CH ₂ CH ₃ or -NH ₂ ;

R ₁ is selected from the following:

R ₅ , R ₆ , R ₇ are independently selected from -H, -F, -Cl, -CH ₃ , -CH ₂ NH ₂ , -CN or -OCH ₃ , or R ₆ and R ₇ together with the atom(s) to which they are attached form a five-membered cycloalkyl containing O;

R ₈ , R ₉ are independently selected from -H or -CH ₃ ;

R ₁₁ , R ₁₂ are independently selected from: -H, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , (-CH(CH ₃ ) ₂ ), (-CH ₂ CH (CH ₃ ) ₂ ), , or R ₁₁ and R ₁₂ together with the atom(s) to which they are attached form

Embodiment 8. Method for producing the compound of Embodiment 2, wherein the process steps are as follows:

(1) interaction With

with education

(2) interaction With with education

where R ₁₃ represents halogen or , R ₁₄ represents -OH or -F, R ₁₅ represents -Br or -SnBu ₃ .

Embodiment 9. The compound of formula (V), its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound,

Where

A' represents C or N; B ₁ , B ₂ , B ₃ , B ₄ or B ₅ are independently selected from C or N;

Ar' represents a five-membered heteroaryl, six-membered heteroaryl or phenyl, wherein the five-membered heteroaryl is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl or thiazolyl; six-membered heteroaryl includes pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; wherein H on a five-membered heteroaryl, six-membered heteroaryl or phenyl is optionally substituted by a group selected from -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N( C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl , -O heteroaryl or -S heteroaryl, wherein the alkyl moiety may optionally be substituted by one or more of the following groups: -SO ₂ , SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _{0 -10} alkyl) SO ₂ (C _0-10 alkyl), -CON (C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), - N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl;

R ₂ ' is selected from: -H, halogen, -NO ₂ , -CN, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F or -OC _0-10 alkyl;

When _B1 , _B2 , _B3 , _B4 or _B5 is N, _R3 ', _R4 ', _R5 ', _R6 ' or _R7 ' does not exist; When B ₁ , B ₂ , B ₃ , B ₄ or B ₅ is C, R ₃ ', R ₄ ', R ₅ ', R ₆ ' or R ₇ ' is independently selected from: -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl, -C=CR ₁₀ , -O heterocyclyl or - Heterocyclyl N, or R ₅ and R ₄ , R ₄ and R ₃ , R ₃ and R ₇ or R ₇ and R ₆ together with the atom(s) to which they are attached form C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, -N heteroaryl, -O heteroaryl, -S heteroaryl or phenyl, wherein H on C is optionally substituted by one or more of the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl) ( C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN , -OCH ₂ F, OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl;

R ₈ ', R ₉ ' are independently selected from the following: -H, halogen or C _1-10 linear/branched alkyl;

R ₁₀ ' is selected from: H, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl or ,

R ₁₁ ', R ₁₂ ' are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl, five-membered heteroaryl or six-membered heteroaryl, or R ₁₁ ' and R ₁₂ ' together with the atom(s) to which they are attached form C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, C _4-9 fused cycloalkyl, C _5-10 spiro-cycloalkyl, C _4-9 bridged cycloalkyl, C _3-7 lactam, C _3-7 lactone or C _{3- 7} cyclic ketone, where H on C is optionally replaced by a group selected from -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/ branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl, wherein the alkyl moiety may optionally be substituted with one or more of the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl;

Q' represents O or S; x' and z' are integers from 0 to 6; y' has the value 0 or 1.

Embodiment 10. The compound of Embodiment 9, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein _B1 , _B2 , _B3 , _B4 , or _B5 is C, or at least one of B ₁ , B ₂ , B ₃ , B ₄ or B ₅ is N; Ar' is thiazolyl, selenothiazolyl, imidazolyl, pyrazolyl or pyridyl, at least one H on thiazolyl, selenothiazolyl, imidazolyl, pyrazolyl or pyridyl is optionally substituted with one group selected from -SO ₂ NH ₂ , -NHSO ₂ , -CONH(C _0-10 alkyl), -O heterocyclyl, -N heterocyclyl, C _1-10 linear/branched alkyl, -OC _0-10 alkyl, C _3-10 cycloalkyl or -N(C _0-10 alkyl) (C _0-10 alkyl), -N heteroaryl, -O heteroaryl or -S heteroaryl;

R ₂ ' is selected from: -NO ₂ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OCF ₃ or -OC _0-10 alkyl;

R ₃ ' is selected from: -H, halogen, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl;

R ₄ ' is selected from: -H, halogen, -OC _0-10 alkyl, -CN, C _3-10 cycloalkyl, -C=CR ₁₀ ', C _1-10 linear/branched alkyl, N(C _0-10 alkyl ) (C _0-10 alkyl), -O heterocyclyl or -N heterocyclyl;

R ₅ ', R ₆ ', R ₇ ' are independently selected from: -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl, -C=CR ₁₀ ', -O heterocyclyl or -N heterocyclyl, or R ₆ ' and R ₇ ' together with the atom(s) to which they are attached form C _{3 -8} cycloalkyl, C _3-8 heterocyclyl containing O or S, where H on C is optionally replaced by an F atom;

R ₈ ', R ₉ ' are independently selected from: -H or C _1-10 linear/branched alkyl;

R ₁₁ ', R ₁₂ ' are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C(C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl or six-membered heteroaryl, or R ₁₁ ' and R ₁₂ ' together with the atom(s) to which they are attached form a C _3-8 cycloalkyl, C _4-9 fused cycloalkyl , C _5-10 spiro-cycloalkyl, C _4-9 bridged cycloalkyl, C _3-7 lactam, C _3-7 lactone or C _3-7 cyclic ketone, wherein H on C is optionally substituted by one group selected from - SO ₂ , -SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _{0- 10} alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _{0 -10} alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl, wherein the alkyl moiety may optionally be replaced by one or more of the following groups: -SO ₂ , SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), CON (C _0-10 alkyl ) (C _0-10 alkyl), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _{0 -10} alkyl) (C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _{0 -10} alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl;

x' and z' are integers from 0 to 2, such as 0, 1, or 2.

Embodiment 11. The compound of embodiment 9 or 10, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein at least one H on Ar' is optionally replaced by one group selected from -O heterocyclyl or -N heterocyclyl; R ₃ ' is selected from: -H, halogen, -OC _0-10 alkyl, C _1-10 linear/branched alkyl; R ₄ ' is selected from: -H, halogen, OC _0-10 alkyl, -CN, C _3-10 cycloalkyl, -C=CR ₁₀ '.

Embodiment 12. The compound of Embodiment 9, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein Ar' is

R ₀ ' is selected from: -H, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), OC _0-10 alkyl or C _3-10 cycloalkyl; R ₁ ' is selected from: -H, -O heterocyclyl, -N heterocyclyl, C _1-10 linear/branched alkyl, C _3-10 cycloalkyl, -OC _0-10 alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -SO ₂ (C _0-10 alkyl), -O (C _0-10 alkyl), -O-phenyl, -S (C _0-10 alkyl), -N heteroaryl, -O heteroaryl or -S heteroaryl, wherein the H on the C or heteroatom is optionally substituted with one group selected from C _1-3 linear alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -CF ₃ ; When R ₀ ' is adjacent to R ₁ ', R ₀ ' and R ₁ ' together with the atom(s) to which they are attached form a C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, -N heteroaryl, -O heteroaryl, -S heteroaryl or phenyl.

Embodiment 13. A compound of any of embodiments 9-12, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein _R0 ' is selected from: _C1-5 linear/branched alkyl or -N(C _0-10 alkyl) (C _0-10 alkyl);

R ₁ ' is selected from: -O heterocyclyl, -N heterocyclyl, -SO ₂ (C _0-3 alkyl), -O-phenyl, -S (C _0-4 alkyl), C _3-6 cycloalkyl, C _3-5 linear/branched alkyl, where H on C or heteroatom is optionally substituted with C _3-5 linear/branched alkyl, -NH ₂ , -CF ₂ H, -CF ₃ , C _3-7 cycloalkyl, -O heterocyclyl, -N heterocyclyl;

R ₂ ' represents -NH ₂ or -NO ₂ ;

R ₃ ' represents -H, -F or -OCH ₃ ;

R ₄ ' is selected from the following: -H, -F, -Cl, -OSH ₃ , -CN, or -C=CR ₁₀ ';

R ₅ ', R ₆ ', R ₇ ' are independently selected from: -H, halogen, -OC _0-3 alkyl, C _1-3 linear/branched alkyl, C _1-3 linear/branched alkyl containing N, or R ₆ ' and R ₇ ' together with the atom(s) to which they are attached form a C _3-8 cycloalkyl, C _3-8 heterocyclyl containing O or S, where H on C is optionally replaced by an F atom;

R ₈ ', R ₉ ' are independently selected from: -H or C _1-3 linear/branched alkyl;

R ₁₁ ', R ₁₂ ' are independently selected from: -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-5 linear/branched alkyl, -CH=CH(C _0-10 alkyl), C _3-10 cycloalkyl or six-membered heteroaryl, or R ₁₁ ' and R ₁₂ ' together with the atom(s) to which they are attached form C _3-6 cycloalkyl, C _4-6 fused cycloalkyl, C _5-8 spiro- cycloalkyl, C _4-8 cycloalkyl bridged, C _3-7 lactam, C _3-7 lactone or C _3-7 cyclic ketone, wherein H on C is optionally substituted by one group selected from -SO ₂ , -SO ₂ N (C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), -CON(C _0-10 alkyl) (C _0-10 alkyl) , -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _{0- 10} alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 linear/branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocyclyl, -N heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl, where the alkyl moiety may optionally be substituted by one or more of the following groups: -SO ₂ , SO ₂ N(C _0-10 alkyl) (C _0-10 alkyl), -N(C _0-10 alkyl) SO ₂ (C _0-10 alkyl), CON (C _0-10 alkyl) (C _0-10 alkyl ), -N(C _0-10 alkyl) CO (C _0-10 alkyl), -N(C _0-10 alkyl) COO (C _0-10 alkyl), -OCON(C _0-10 alkyl) (C _{0 -10} alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _{3- 10} cycloalkyl, -O heterocyclyl, -N heteroaryl, -O heteroaryl or -S heteroaryl.

Embodiment 14. The compound of Embodiment 12, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein R ₀ ' is -CH ₃ , -CH ₂ CH ₃ or -NH ₂ ;

R ₁ ' is selected from the following:

R ₅ ', R ₆ ', R ₇ ' are independently selected from -H, -F, -Cl, -CH ₃ , CH ₂ NH ₂ , -CN or -OCH ₃ , or R ₆ , and R ₇ ' together with an atom (atoms) to which they are attached form a five-membered cycloalkyl containing O;

R ₈ ', R ₉ ' are independently selected from -H or -CH ₃ ;

R ₁₁ ', R ₁₂ ' are independently selected from: -H, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , ,

or R ₁₁ ' and R ₁₂ ' together with the atom(s) to which they are attached form the following group:

Embodiment 15. The compound of Embodiment 9, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein the compound is selected from:

Embodiment 16: A method for producing the compound of Embodiment 9, wherein the process steps are as follows:

(1) interaction With with education ,

(2) interaction with Ar'-R ₁₅ 'with formation ,

where R ₁₃ ' represents halogen or , R ₁₄ ' represents -OH or halogen, R ₁₅ ' represents halogen or -SnBu ₃ .

Embodiment 17. A pharmaceutical composition comprising a compound of embodiment 1 or 9, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof and further comprising a pharmaceutically acceptable excipient.

Embodiment 18. Use of a compound of embodiment 1 or 9, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof for the prevention and/or treatment of cancer.

Embodiment 19. Use of a compound of embodiment 1 or 9, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof for the preparation of a medicament for the prevention and/or treatment of cancer.

Embodiment 20: Use of a compound of embodiment 1 or 9, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof in combination with PD-1, PD-L1, CTLA-4, TIM-3, TLR4, TLR7 , TLR8, TLR9, TGF-β and its receptor, LAG3 antagonist or STING agonists in cancer immunotherapy.

Embodiment 21. Use of a compound of embodiment 1 or 9, a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof in combination with CAR-T immunotherapy in cancer immunotherapy.

Embodiment 22. Use of any of embodiments 18-21, wherein the cancer is selected from the group consisting of carcinoma: lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell cancer , mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia or lymphoid malignancies, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung carcinoma , abdominal cancer, hepatocellular cancer, gastric or stomach cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, metastatic breast cancer , colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, anal canal carcinoma, penile carcinoma, Merkel cell cancer , esophageal cancer, biliary tract tumors, head and neck cancer and hematological malignancies.

Detailed description

The technical solutions in the embodiments of the present invention will be clearly and completely described below. It will be appreciated that the described embodiments are only partial embodiments of the present invention and not all of them. All other embodiments derived by one skilled in the art from the embodiments of the present invention without creative effort are within the scope of the present invention.

EXAMPLES

The various starting materials, intermediates and compounds of preferred embodiments can be isolated and purified, where necessary, using conventional methods such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Characterization of these compounds can be accomplished by conventional methods, such as melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of the steps for performing the synthesis of the products described herein are described in more detail below.

Typical chromatography conditions for LC-MS are as follows:

Device: Agilent 1200-6100

Column: HALO C-18, 4.6×50 mm, 2.7 µm

Mobile phase: ACN (0.1% FA) - water (0.1% FA)

Gradient: 5% ACN - 95% ACN for 1.0 min, hold 1.0 min, total 2.5 min

Flow rate: 1.8 ml/min.

Typical chromatography conditions for HPLC are as follows:

Shimadzu LC-2010

Column: Gemini, 4.6×150 mm, 5 µm

Mobile phase: ACN (0.05% TFA) - water (0.05% TFA)

Gradient: 0% ACN - 60% ACN for 7.5 min, 60% ACN - 100% ACN for 0.5 min, dwell time 2.0 min, total 10 min

Flow rate: 1.2ml/min

Example 1 Preparation of compound 8 (A1)

The synthesis route for the compound is as follows:

Compound 2: 4-Aminothiocarbonyltetrahydropyridine-1(2H)-carboxylic acid tert-butyl ester (25.0 g, 102.4 mmol) and chloroacetaldehyde (40% aqueous solution, 30.0 g, 153.6 mmol) were added sequentially into a round bottom flask containing 300 ml of acetone, stirred at 50°C for 16 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then separated by column chromatography (eluent: petroleum ether/ethyl acetate, 5/1, v/v), to obtain 9.0 g of a yellow oily liquid, yield: 32. 9%. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 1.47 (s, 9H), 1.73 (ddd, J=25.0, 12.1, 4.3 Hz, 2H), 2.09 (dt, J=15.5, 4.7 Hz, 2H), 2.86 (dd, J=25.4, 13.1 Hz, 2H), 3.13-3.21 (m, 1H), 4.14 (dd, J=17.4, 10, 1 Hz, 2H), 7.22 (d, J=3.3 Hz, 1H), 7.69 (d, J=3.3 Hz, 1H).

LCMS: Rt=0.45 min, MS Calculated: 268.1, MS Found: 212.9 [M+H-56]+.

Compound 3: Compound 2 (9.0 g, 33.6 mmol) was added to a round bottom flask containing 100 ml of 1,4-dioxane, and 100 ml of 4N dioxane hydrochloride solution was added and stirred at room temperature for 5 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure. After adding 200 ml of diethyl ether, the mixture was filtered with suction and the filter cake was washed with 100 ml of diethyl ether and dried without further purification to obtain 5.2 g of a gray solid, yield: 75.9%.

LCMS: Rt=0.45 min, MS Calculated: 168.1, MS Found: 169.0 [M+H]+.

Compound 4: In a 250 ml round bottom flask, compound 3 (5.2 g, 25.6 mmol) was dissolved in 80 ml tetrahydrofuran, triethylamine (2.6 g, 25.6 mmol), 37% aqueous formaldehyde (3.1 g, 38.4 mmol) and sodium triacetoxyborohydride (8.1 g, 38.4 mmol), stirred at room temperature for 16 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure, diluted with 1N sodium hydroxide solution (50 ml), extracted with dichloromethane (100 ml × 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with aqueous Na ₂ SO ₄ was concentrated under reduced pressure and then separated by column chromatography (eluent: dichloromethane/methanol, 6/1, v/v), to obtain 3.6 g of a yellow oily liquid, yield: 77.3%. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.81-1.90 (m, 2H), 2.21-2.67 (m, 4H), 2.34 (s, 3H), 2.98-3.08 (m, 3H), 7. 71 (d, J=2.6 Hz, 1H), 7.48 (d, J=3.4 Hz, 1H).

LCMS: Rt=0.42 min, MS Calculated: 182.1, MS Found: 183.0 [M+H]+.

Compound 5: In a 250 ml three-neck flask, Compound 4 (3.6 g, 19.7 mmol) was dissolved in 60 ml tetrahydrofuran, cooled to -78°C and n-butyllithium (2.4 M in tetrahydrofuran, 8.2 ml, 19.7 mmol), stirred at -78°C for 1 hour, then tributyltin chloride (6.4 g, 19.7 mmol) was added dropwise, stirred at -78°C for 1 hour . LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated ammonium chloride (50 ml), extracted with EtOAc (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure without further purification, 7.8 g of a yellow oily liquid was obtained.

LCMS: Rt=1.55 min, MS Calculated: 472.2, MS Found: 473.0 [M+H]+.

Compound 7: Compound 5 (764 mg, 1.62 mmol), 6 (500 mg, 1.62 mmol), bis(triphenylphosphine)palladium dichloride (112 mg, 0.16 mmol) and copper iodide (91 mg, 0. 48 mmol) were sequentially added to a round bottom flask containing 15 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and separated by column chromatography (eluent: methylene chloride/methanol, 6/1, v/v), to obtain 250 mg of a yellow solid, yield: 37.7%.

LCMS: Rt=1.04 min, MS Calculated: 411.1, MS Found: 411.7 [M+H]+.

Compound 8: Compound 7 (250 mg, 0.61 mmol), reduced iron powder (170 mg, 3.04 mmol) and ammonium chloride (163 mg, 3.04 mmol) were successively added to a round bottom flask containing 10 ml ethanol and 2 ml of water, stirred at 70°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA), gradient: 0-20% ACN), lyophilized to give 115 mg white solid, yield: 37.7%, ¹ H NMR (400 MHz, D ₂ O) δ ppm. 1.93-2.04 (m, 2H), 2.35 (d, J=14.7 Hz, 2H), 2.81 (s, 3H), 3.09-3.15 (m, 2H) , 3.36-3.39 (m, 1H), 3.53-3.60 (m, 2H), 5.65 (s, 2H), 7.54 (d, J=2.5 Hz, 1H ), 7.69 (d, J=2.5 Hz, 1H), 7.85 (s, 1H), 8.12 (d, J=6.5 Hz, 2H), 8.75 (d, J =6.7 Hz, 2H).

LCMS: Rt=0.34 min, MS Calculated: 381.1, MS Found: 381.9 [M+H]+.

Example 2 Preparation of compound 19 (A2)

The synthesis route for the compound is as follows:

Compound 9: Compound 3-bromo-5-hydroxypyridine (10 g, 57.8 mmol) was added to a three-neck flask containing 100 ml concentrated sulfuric acid at 0°C and 65% concentrated nitric acid (11.1 g) was added with stirring , 114.94 mmol) at 0°C, stirred at room temperature for 14 hours. LCMS monitoring was carried out, after completion of the reaction, the reaction solution was poured into 200 ml of ice water, extracted with ethyl acetate (500 ml × 2) and the combined extracts were washed with saturated aqueous sodium chloride (300 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure 11 g of yellow solid were obtained, yield: 87.4%, ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 7.85 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 12.09 (s, 1H).

LCMS: Rt=1.43 min, MS Calculated: 217.9, 219.9, MS Found: 218.7, 220.8 [M+H] ⁺

Compound 10: Compound 9 (4.4 g, 20 mmol), benzyl alcohol (2.6 g, 24 mmol), triphenylphosphine (6.4 g, 24 mmol) were added sequentially to a three-neck bottle containing 100 ml of anhydrous tetrahydrofuran, under nitrogen protective layer, diisopropyl azodicarboxylate (4.85 g, 24 mmol) was added at 0°C and stirred at 0°C for 4 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure. 100 ml of water was added, extracted with ethyl acetate (100 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate , 10/1, v/v), gave 3.2 g of white solid, yield: 49%, ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 5.41 (s, 2H), 7.37-7.45 (m, 5H), 8.31 (d, J=2.0 Hz, 1H), 8.43 (d, J=1.6 Hz , 1H).

LCMS: Rt=1.73 min, MS Calculated: 308.0, 310.0, MS Found: 308.8, 310.8 [M+H] ⁺

Compound 11: Compound 10 (3 g, 9.7 mmol), pinacolborate (4.9 g, 19.4 mmol), potassium acetate (2.9 g, 29.1 mmol), dichloride complex [1,1'- bis(diphenylphosphine)ferrocene]palladium with dichloromethane (1.6 g, 1.94 mmol) was added sequentially to a 250 ml round bottom flask containing 100 ml dioxane, under a protective layer of nitrogen, and stirred at 80°C for 12 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated under reduced pressure and then purified by column chromatography (eluent: dichloromethane/methanol, 50/1-20/1, v/v), to obtain 5 g of a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.35 (s, 12H), 5.42 (s, 2H), 7.36-7.43 (m, 5H), 8.09 (d, J=1.2 Hz, 1H), 8.28 (d, J=1.2 Hz, 1H).

LCMS: Rt=1.51 min, MS Calculated: 356.2, MS Found: 274.8 [M+H-82] ⁺

Compound 13: Compound 12 (10 g, 32.4 mmol), 2-bromothiazole (5.8 g, 35.6 mmol), sodium carbonate (10.2 g, 97.2 mmol), dichloride complex [1,1 '-bis(diphenylphosphine)ferrocene]palladium with dichloromethane (2.6 g, 3.2 mmol) was successively added to a 500 ml round bottom flask containing 200 ml dioxane and 50 ml water, under a protective layer of nitrogen, and stirred at 90° C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature and concentrated under reduced pressure. 200 ml of water was added, extracted with ethyl acetate (300 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (200 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate , 5/1, v/v), 7.8 g of yellow oily liquid were obtained, yield: 90.1%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 1.50 (s, 9H), 2.70-2.73 (m, 2H), 3.66 (t, J=5.2 Hz, 2H), 4.13-4.14 (m, 2H) , 6.59 (s, 1H), 7.24 (d, J=4.0 Hz, 1H), 7.77 (d, J=3.6 Hz, 1H).

LCMS: Rt=1.62 min, MS Calculated: 266.1, MS Found: 266.9 [M+H] ⁺

Compound 14: Compound 13 (7.8 g, 29.2 mmol), 10% palladium on carbon (10 g), acetic acid (10 ml) were added sequentially to a 1 L reactor containing 300 ml methanol/100 ml tetrahydrofuran, stirred at 50°C for 48 hours in a hydrogen atmosphere of 0.4 MPa. LCMS monitoring was carried out, after completion of the reaction and filtration, the filtrate was concentrated under reduced pressure. 100 ml of water was added, extracted with ethyl acetate (200 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to obtain 6.5 g of a yellow oily liquid, yield: 82.7%, ^1H NMR (400 MHz, CDCl ₃ ): δ ppm: 1.46 (s, 9H), 1.69-1.79 (m, 2H), 2.08-2. 11 (m, 2H), 2.88 (t, J=12.2 Hz, 2H), 3.12-3.20 (m, 1H), 4.18 (lat s, 2H), 7.21 (d, J=3.6 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H).

LCMS: Rt=1.58 min, MS Calculated: 268.1, MS Found: 212.9 [M+H-56] ⁺

Compound 15: Compound 14 (4 g, 15 mmol), N-bromosuccinimide (5.3 g, 30 mmol) was sequentially added to a 250 ml round bottom flask containing 100 ml acetonitrile and stirred at 50°C for 4 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated sodium thiosulfate (30 ml), extracted with EtOAc (100 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: ethyl acetate/petroleum ether, 1:10, v/v) to obtain 1.5 g of a yellow oily liquid, yield: 39.5%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 1.47 (s, 9H), 1.65-1.75 (m, 2H), 2.04-2.08 (m, 2H), 2.87 (t, J=12.4 Hz, 2H) , 3.06-3.14 (m, 1H), 4.19 (br s, 2H), 7.57 (s, 1H).

LCMS: Rt=1.79 min, MS Calculated: 346.0, 348.0, MS Found: 290.7, 292.7 [M+H-56] ⁺

Compound 16: Compound 15 (1.5 g, 8.6 mmol), Compound 5 (4 g (crude), 8.6 mmol), sodium carbonate (1.3 g, 12.9 mmol), dichloride complex [1 ,1'-bis(diphenylphosphine)ferrocene]palladium with dichloromethane (708 mg, 0.86 mmol) was successively added to a 250-ml round-bottom flask containing 100 ml of dioxane and 20 ml of water, under a protective layer of nitrogen, and stirred at 50° C within 14 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure. 100 ml of water was added, extracted with dichloromethane (200 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: ethyl acetate/petroleum ether , 1/3, v/v), gave 750 mg of yellow solid, yield: 34.9%, ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.42 (s, 9H), 1.55-1.61 (m, 2H), 2.07-2.10 (m, 2H), 2.94 (br. s, 2H), 4.01- 4.06 (m, 3H), 5.47 (s, 2H), 7.36-7.49 (m, 5H), 8.26 (d, J=1.6 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.45 (s, 1H).

LCMS: Rt=1.86 min, MS Calculated: 496.2, MS Found: 440.7 [M+H-56] ⁺

Compound 17: Compound 16 (750 mg, 1.5 mmol) was added to a 100 ml round bottom flask containing 10 ml dichloromethane, and 2 ml trifluoroacetic acid was added, stirred at room temperature for 14 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure. Add 20 ml saturated sodium bicarbonate solution, pH>7, extract with dichloromethane (100 ml x 4) and the combined extracts are washed with saturated aqueous sodium chloride (50 ml), dry with anhydrous Na ₂ SO ₄ , concentrate under reduced pressure to obtain 580 mg of yellow solid, yield: 97.0%, ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.70-7.76 (m, 2H), 2.05-2.08 (m, 2H), 2.68-2.77 (m, 3H), 3.10-3.13 (m, 2H ), 5.48 (s, 1H), 7.38-7.49 (m, 5H), 8.28 (s, 1H), 8.43 (d, J=1.6 Hz, 1H), 8 .46 (s, 1H).

LCMS: Rt=1.33 min, MS Calculated: 396.1, MS Found: 396.8 [M+H] ⁺

Compound 18: Compound 17 (580 mg, 1.46 mmol), 30% aqueous formaldehyde (732 mg, 7.3 mmol), sodium triacetoxyborohydride (465 mg, 2.2 mmol), acetic acid (4 ml) were added sequentially into a 100 ml round bottom flask containing 20 ml tetrahydrofuran, stirred at room temperature for 14 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure. 20 ml of water was added, extracted with dichloromethane (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride, dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to obtain 600 mg of a yellow solid, yield: 100%.

LCMS: Rt=1.33 min, MS Calculated: 410.1, MS Found: 410.8 [M+H] ⁺

Compound 19: Compound 18 (600 mg, 1.46 mmol), iron powder (408 mg, 7.3 mmol) and ammonium chloride (390 mg, 7.3 mmol) were added sequentially to a 100 ml round bottom flask containing 20 ml ethanol and 4 ml of water, stirred at 70°C for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, and the filtrate was concentrated under reduced pressure. 20 ml of water was added, extracted with dichloromethane (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride, dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then separated by high performance liquid chromatography (column: Gemini-C18 150x21, 2 mm, 5 µm, mobile phase: ACN-H ₂ O (0.1% TFA), gradient: 10-40% ACN), lyophilized, yielded 186 mg of yellow sticky substance, yield: 33.5%, ¹ H NMR (400 MHz, CD ₃ OD): δ ppm 2.06-2.16 (m, 2H), 2.41-2.45 (m, 2H), 2.95 (s, 3H), 3.21 (td, J=13.0, 2.4 Hz, 2H), 3.39-3.46 (m, 1H), 3.66-3.69 (m, 2H), 5.42 (s, 2H), 7.40-7.47 (m, 3H), 7.55-7.57 (m, 2H), 7.72 (br s, 2H), 8.04 (s, 1H). LCMS: Rt=1.14 min, MS Calculated: 380.2, MS Found: 380.8 [M+H]+.

Example 3 Preparation of compound 26 (A3)

The synthesis route for the compound is as follows:

Compound 22: Compound 20 (1 g, 4.3 mmol), Compound 21 (2.15 g, 12.8 mmol), bis(triphenylphosphine)palladium dichloride (302 mg, 0.43 mmol) and copper iodide (244 mg , 1.28 mmol) were sequentially added to a round bottom flask containing 10 ml of dioxane and 2 ml of triethylamine, and stirred at room temperature under nitrogen atmosphere for 16 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 20/1, v/v), to obtain 1 g of a yellow oily liquid, yield: 83.7%.

LCMS: Rt=1.67 min, MS Calculated: 274.2 MS Found: 296.9 [M+Na]+.

Compound 24: Compound 22 (1.0 g, 3.65 mmol), compound 23 (795 mg, 3.65 mmol) and triphenylphosphine (1.24 g, 4.74 mmol) were added sequentially to a three-neck flask containing 30 mL tetrahydrofuran, under a protective layer of nitrogen, diisopropyl azodicarboxylate (960 mg, 4.74 mmol) was added with stirring and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with water (50 ml), extracted with EtOAc (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 10/1, v/v) to obtain 1.5 g of a white solid, yield: 74.0%, ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.47-1.69 (m, 11H), 1.71-1.84 (m, 1H), 3.52-3.58 (m, 1H), 3.98-4.02 (m, 1H ), 5.15 (dd, J=5.4, 3.2 Hz, 1H), 5.22 (s, 2H), 7.33-7.51 (m, 4H), 7.68 (t, J=2.3 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H).

LCMS: Rt=1.92 min, MS Calculated: 474.1, 476.1 MS Found: 496.6, 498.6 [M+Na]+.

Compound 25: Compound 24 (1.3 g, 2.7 mmol), Compound 5 (1.3 g, 2.7 mmol), bis(triphenylphosphine)palladium dichloride (190 mg, 0.27 mmol) and copper iodide ( 154 mg, 0.81 mmol) were sequentially added to a round-bottom flask containing 30 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 5/1, v/v), to obtain 700 mg of a yellow sticky substance (crude).

LCMS: Rt=1.47 min, MS Calculated: 576.2, MS Found: 576.8 [M+H]+.

Compound 26: Compound 25 (600 mg, 1.04 mmol), zinc powder (677 mg, 10.4 mmol) and p-toluenesulfonic acid (30 mg) were successively added to a round bottom flask containing 10 ml glacial acetic acid and stirred at room temperature for 24 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated and then separated by high performance liquid chromatography (column: Gemini-C18 150x21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA) , gradient: 15-30% ACN), lyophilized to give 79.4 mg of white solid, yield: 16.3%, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 1.47 (s, 6H), 1.68-1.74 (m, 2H), 1.98-2.05 (m, 4H), 2.20 (s, 3H), 2.82-2, 95 (m, 3H), 5.22 (s, 2H), 5.47 (s, 1H), 6.07 (s, 2H), 7.34-7.42 (m, 3H), 7.54 (dd, J=3.8, 1.9 Hz, 2H), 7.77 (d, J=1.9 Hz, 1H), 7.87 (s, 1H).

LCMS: Rt=1.13 min, MS Calculated: 462.2, MS Found: 462.6 [M+H]+.

Example 4 Preparation of compound 30 (A4)

The synthesis route for the compound is as follows:

Compound 28: Compound 9 (1.0 g, 4.6 mmol), compound 27 (560 mg, 4.6 mmol) and triphenylphosphine (1.45 g, 5.5 mmol) were added sequentially to a three-neck flask containing 40 ml tetrahydrofuran, under a protective layer of nitrogen, diisopropyl azodicarboxylate (1.12 g, 5.5 mmol) was added with stirring and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with water (50 ml), extracted with EtOAc (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 1/2, v/v) to obtain 1.4 g of a white solid (crude, containing triphenylphosphine oxide).

LCMS: Rt=1.38 min, MS Calculated: 323.1, 324.1 MS Found: 323.7, 325.7 [M+H]+.

Compound 29: Compound 28 (500 mg, 1.55 mmol), Compound 5 (730 mg, 1.55 mmol), bis(triphenylphosphine)palladium dichloride (109 mg, 0.16 mmol) and copper iodide (89 mg, 0 .47 mmol) were sequentially added to a round bottom flask containing 10 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 3/1, v/v), to obtain 320 mg of a light yellow solid, yield: 48.4 %. LCMS: Rt=1.13 min, MS Calculated: 425.1, MS Found: 425.7 [M+H]+.

Compound 30: Compound 29 (320 mg, 0.75 mmol), reduced iron powder (211 mg, 3.76 mmol) and ammonium chloride (201 mg, 3.76 mmol) were successively added to a round bottom flask containing 10 ml ethanol and 2 ml of water, and stirred at 70°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA), gradient: 5-25% ACN), lyophilized to give 61 mg yellow solid, yield: 20.0%, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 1.67 (d, J=6.3 Hz, 3H), 1.86-1.95 (m, 2H), 2.26 (d, J=13.9 Hz, 2H), 2.78-2 .82 (m, 3H), 3.06-3.14 (m, 2H), 3.25-3.31 (m, 1H), 3.54 (d, J=12.0 Hz, 2H), 6.09-6.11 (m, 1H), 7.62 (s, 1H), 7.84 (s, 1H), 7.90 (s, 2H), 8.04 (s, 1H), 8 .80 (d, J=5.6 Hz, 2H), 9.72 (s, 1H). LCMS: Rt=0.92 min, MS Calculated: 395.2, MS Found: 395.7 [M+H]+.

Example 5 Preparation of compound 33 (A5)

The synthesis route for the compound is as follows:

Compound 31: Compound 9 (1.0 g, 4.6 mmol), compound 61 (580 mg, 4.6 mmol) and triphenylphosphine (1.45 g, 5.5 mmol) were added sequentially to a three-neck flask containing 40 ml tetrahydrofuran, under a protective layer of nitrogen, diisopropyl azodicarboxylate (1.12 g, 5.5 mmol) was added with stirring and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with water (50 ml), extracted with EtOAc (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 3/1, v/v) to obtain 1.3 g of yellow solid, yield: 86.7%, ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 5.23 (s, 2H), 7.06-7.20 (m, 2H), 7.33-7.52 (m, 2H), 7.71 (d, J=1.7 Hz, 1H) , 8.18 (d, J=1.8 Hz, 1H). LCMS: Rt=1.71 min, MS Calculated: 326.1, 328.1; MS Found: 326.7, 328.7 [M+H]+.

Compound 32: Compound 31 (500 mg, 1.55 mmol), Compound 5 (730 mg, 1.55 mmol), bis(triphenylphosphine)palladium dichloride (109 mg, 0.16 mmol) and copper iodide (89 mg, 0 .47 mmol) were sequentially added to a round bottom flask containing 10 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 10/1, v/v), to obtain 280 mg of a light yellow solid, yield: 41.9 %. LCMS: Rt=1.31 min, MS Calculated: 428.1, MS Found: 428.6 [M+H]+.

Compound 33: Compound 32 (280 mg, 0.65 mmol), reduced iron powder (183 mg, 3.27 mmol) and ammonium chloride (175 mg, 3.27 mmol) were successively added to a round bottom flask containing 10 ml ethanol and 2 ml of water, stirred at 70°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA), gradient: 9-20% ACN), lyophilized to give 108 mg light yellow solid, yield: 41.5%, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 1.89-1.97 (m, 2H), 2.29 (d, J=13.1 Hz, 2H), 2.80-2.83 (m, 3H), 3.07-3.16 ( m, 2H), 3.28-3.34 (m, 1H), 3.56 (d, J=12.2 Hz, 2H), 5.35 (s, 2H), 7.27 (t, J =8.8 Hz, 2H), 7.62 (dd, J=8.3, 5.7 Hz, 2H), 7.73 (s, 1H), 7.84 (s, 1H), 8.15 (s, 1H), 9.67 (s, 1H). LCMS: Rt=1.17 min, MS Calculated: 398.2, MS Found: 398.8 [M+H]+.

Example 6 Preparation of compound 40 (A6)

The synthesis route for the compound is as follows:

Compound 35: Compound 41 (3 g, 21.9 mmol) was added to a three-neck flask containing 60% sodium hydride (1 g, 26.3 mmol) and 100 ml tetrahydrofuran, stirred under nitrogen for 30 min and then compound was added 34 (3.1 g, 21.9 mmol), stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated ammonium chloride (50 ml), extracted with EtOAc (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 1/1, v/v) to obtain 2.4 g of a light yellow solid, yield: 42.5%. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.75 (s, 6H), 7.10 (dd, J=8.5, 1.1 Hz, 1H), 7.33 (dd, J=8.5, 4.6 Hz, 1H), 7 .51 (dd, J=4.7, 1.7 Hz, 2H), 7.98 (dd, J=4.6, 1.1 Hz, 1H), 8.54 (dd, J=4.7 , 1.6 Hz, 2H). LCMS: Rt=1.10 min, MS Calculated: 259.1 MS Found: 260.1 [M+H]+.

Compound 36: Compound 35 (2.4 g, 9.3 mmol), reduced iron powder (2.6 g, 46.3 mmol) and ammonium chloride (2.5 g, 46.3 mmol) were added sequentially to the round bottom flask , containing 50 ml of ethanol and 10 ml of water, was stirred at 70°C for 4 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, filtered, the filtrate was diluted with water (50 ml), extracted with ethyl acetate (100 ml × 3) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ was concentrated under reduced pressure to give 1.3 g of a white solid, yield: 61.3%. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 1.75 (s, 3H), 4.79 (s, 2H), 6.28-6.43 (m, 2H), 7.38 (dd, J=4.5, 1.6 Hz, 2H) , 7.66 (dd, J=4.1, 2.4 Hz, 1H), 8.64 (dd, J=4.5, 1.6 Hz, 2H). LCMS: Rt=0.39 min, MS Calculated: 229.1 MS Found: 229.9 [M+H]+.

Compound 37: Compound 36 (1.2 g, 5.2 mmol) was added to a round bottom flask containing 20 ml acetonitrile, then NBS (980 mg, 5.5 mmol) was added at 0°C, stirred at room temperature for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was diluted with EtOAc (150 ml) and washed with saturated sodium bicarbonate solution (50 ml × 3) and saturated aqueous sodium chloride solution (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 1/2, v/v) to obtain 1.1 g of a white solid, yield: 69.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 1.68 (s, 6H), 6.04 (s, 2H), 6.35 (d, J=2.0 Hz, 1H), 7.46 (dd, J=4.5, 1.6 Hz , 2H), 7.59 (d, J=2.0 Hz, 1H), 8.61 (dd, J=4.5, 1.6 Hz, 2H). LCMS: Rt=1.15 min, MS Calculated: 307.0, 309.0 MS Found: 307.9, 309.9 [M+H]+.

Compound 38: Compound 37 (0.5 g, 1.6 mmol), di-tert-butyl dicarbonate (1.7 g, 4.9 mmol), triethylamine (823 mg, 8.2 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) were added sequentially to a round bottom flask containing 20 mL dichloromethane and stirred at room temperature for 24 hours. LCMS monitoring was carried out, after completion of the reaction, the mixture was concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 1/1, v/v), to obtain 600 mg of a white solid, yield: 69.2%. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.47 (s, 18H), 1.81 (s, 6H), 6.96 (d, J=1.8 Hz, 1H), 7.53 (d, J=6.1 Hz, 2H), 8.14 (d, J=1.8 Hz, 1H), 8.62 (d, J=6.1 Hz, 2H). LCMS: Rt=1.15 min, MS Calculated: 507.0, 509.0 MS Found: 507.7, 509.7 [M+H]+.

Compound 39: Compound 38 (610 mg, 1.2 mmol), Compound 7 (625 mg, 1.32 mmol), bis(triphenylphosphine)palladium dichloride (84 mg, 0.12 mmol) and copper iodide (69 mg, 0 .36 mmol) were sequentially added to a round bottom flask containing 15 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 5/1, v/v), to obtain 330 mg of a yellow sticky substance, yield: 45%. LCMS: Rt=1.32 min, MS Calculated: 609.3, MS Found: 609.6 [M+H]+.

Compound 40: Compound 39 (400 mg, 0.66 mmol) and trifluoroacetic acid (3 ml) were sequentially added to a round bottom flask containing 15 ml of dichloromethane and stirred at room temperature for 5 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA), gradient: 0-20% ACN), lyophilized to give 160 mg of white solid, yield: 54.5%. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.97 (s, 6H), 1.99-2.10 (m, 2H), 2.36 (d, J=13.1 Hz, 2H), 2.93 (s, 3H), 3.15 -3.21 (m, 2H), 3.38-3.42 (m, 1H), 3.65 (d, J=12.6 Hz, 2H), 6.91 (s, 1H), 7, 72 (s, 1H), 7.79 (s, 1H), 8.07 (d, J=5.5 Hz, 2H), 8.85 (s, 2H). LCMS: Rt=0.95 min, MS Calculated: 409.2, MS Found: 409.9 [M+H]+.

Example 7 Preparation of compound 46 (A7)

The compounds were synthesized as follows:

Compound 41: Compound 9 (2 g, 9.14 mmol), 4-pyridinemethanol (1.5 g, 13.7 mmol), triphenylphosphine (3.6 g, 18.3 mmol) were added sequentially to a three-neck bottle containing 100 ml of anhydrous tetrahydrofuran, under a protective layer of nitrogen, diisopropyl azodicarboxylate (3.7 g, 18.3 mmol) was added at 0°C, stirred at room temperature for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure. 100 ml of water was added, extracted with ethyl acetate (100 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate , 10/1-3/1, v/v), yielded 2.5 g of a yellow solid (80% purity, contains triphenylphosphine oxide), yield: 71.4%. LCMS: Rt=1.21 min, MS Calculated: 309.0, 311.0, MS Found: 309.7, 311.7 [M+H] ⁺

Compound 43: In a 250 ml three-neck flask, compound 42 (1 g, 3.73 mmol) was dissolved in 30 ml anhydrous tetrahydrofuran, cooled to -78°C and n-butyllithium (2.4 M in tetrahydrofuran, 1.5 ml) was added , 3.73 mmol) under nitrogen atmosphere, stirred at -78°C for 1 hour, then tributyltin chloride (1.33 g, 4.1 mmol) was added dropwise, stirred at -78°C for 1 hour. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated ammonium chloride (50 ml), extracted with EtOAc (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: ethyl acetate/petroleum ether, 1/10, v/v), to obtain 1.4 g of a yellow oily liquid, yield: 67.3%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 0.91 (t, J=7.4 Hz, 9H), 1.11-1.15 (m, 5H), 1.26-1.38 (m, 8H), 1.49 (s, 9H) , 1.51-1.61 (m, 5H), 1.78 (dq., J=12.4, 4.0 Hz, 2H), 2.12-2.15 (m, 2H), 2, 91 (t, J=12.0 Hz, 2H), 3.19-3.27 (m, 1H), 4.11-4.20 (m, 2H), 7.64 (s, 1H).

Compound 44: Compound 43 (1.1 g, 1.97 mmol), Compound 2 (600 mg, 1.97 mmol), bis(triphenylphosphine) palladium dichloride (278 mg, 0.39 mmol), tetrabutylammonium fluoride (150 mg , 0.59 mmol) were sequentially added to a 100 ml round bottom flask containing 50 ml dioxane, under a protective layer of nitrogen, and stirred at 50°C for 14 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated under reduced pressure without further purification to obtain 2.5 g of crude material. LCMS: Rt=1.35 min, MS Calculated: 497.2, MS Found: 497.8 [M+H] ⁺

Compound 45: Compound 44 (2.5 g crude), iron powder (1.2 g, 20.1 mmol), ammonium chloride (1.1 g, 20.1 mmol) were added sequentially to a 100 mL round bottom flask containing 40 ml ethanol/10 ml water, and stirred at 50°C for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, and the filtrate was concentrated under reduced pressure. 50 ml of water was added, extracted with ethyl acetate (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride, dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 3/1 -methanol 0%-10% in dichloromethane, v/v), gave 340 mg of yellow solid, total yield over two stages: 37.0%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.42 (s, 9H), 1.58-1.60 (m, 2H), 2.01-2.05 (m, 2H), 3.18-3.21 (m, 2H), 3. 99-4.06 (m, 3H), 5.29 (s, 3H), 6.20 (s, 2H), 7.37 (s, 1H), 7.57 (d, J=5.2 Hz , 2H), 7.80 (s, 1H), 7.90 (s, 1H), 8.60 (d, J=4.8 Hz, 2H). LCMS: Rt=1.31 min, MS Calculated: 467.2, MS Found: 467.8 [M+H] ⁺

Compound 46: Compound 45 (340 mg, 0.73 mmol) was added to a 100 ml round bottom flask containing 10 ml dichloromethane, and with stirring, 2 ml trifluoroacetic acid was added and stirred at room temperature for 14 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (column: Gemini-C18 150x21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA) , gradient: 0-20% ACN), lyophilized to give 13.4 mg of yellow solid, yield: 5.0%. ¹ H NMR (400 MHz, CD ₃ OD): δ ppm. 2.04-2.14 (m, 2H), 2.36-2.39 (m, 2H), 3.21 (t, J=11.6 Hz, 2H), 3.46-3.53 ( m, 3H), 5.72 (s, 2H), 7.82 (s, 2H), 8.08 (s, 1H), 8.18 (br. s, 2H), 8.88 (s, 2H ). LCMS: Rt=0.96 min, MS Calculated: 367.1, MS Found: 367.8 [M+H]+.

Example 8 Preparation of compound 49 (A8)

The synthesis route for the compound is as follows:

Compound 47: 5-Bromo-2-nitropyridin-3-ol (1.00 g, 4.59 mmol), (2-chloropyridin-4-yl)methanol (0.66 g, 4.59 mmol) and triphenylphosphine ( 1.45 g, 5.51 mmol) was sequentially added to a three-neck flask containing 40 ml of anhydrous tetrahydrofuran, stirred in an ice bath and purged with nitrogen three times, diisopropyl azodicarboxylate (1.11 g, 5.51 mmol) was added dropwise to the mixed solution. , after which the mixture was stirred at room temperature for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure. 100 ml of water was added, extracted with ethyl acetate (100 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate , 10/1, v/v), obtained 1.4 g of a white solid, yield: 89% LCMS: Rt=1.63 min, MS Calculated: 342.9, 344.9, MS Found: 343.6, 345.6 [M+H]+.

Compound 48: Compound 47 (0.45 g, 1.31 mmol), 2-(1-piperidin-4-yl)-5(tributylstannyl)thiazole (0.62 g, 1.31 mmol), bis(triphenylphosphine) palladium chloride (0.25 g, 0.26 mmol) and iodide (0.075 g, 0.39 mmol) were added sequentially to a one-neck flask containing 20 ml of dioxane under a protective layer of nitrogen and heated to 90°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 5/1, v/v), to obtain 0.23 g of a white solid, yield: 39%. LCMS: Rt=1.34 min, MS Calculated: 445.1, MS Found: 445.7 [M+H]+.

Compound 49: Compound 48 (150 mg, 0.34 mmol) was added to a mixed solution of ethanol (5 ml) and water (1 ml), stirred at room temperature, ammonium chloride (54 mg, 1.02 mol) and powder were added successively iron (57 mg, 1.02 mmol). The reaction was carried out for 5 hours at room temperature. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated, 30 ml of methanol was added and stirred, filtered through diatomaceous earth and the filtrate was concentrated, then separated by high performance liquid chromatography (column: Gemini-C18 150x21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA, gradient: 5-20% ACN), lyophilized to give 15 mg yellow solid, yield: 11%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm 1.72-1.80 (m, 2H), 2.05 (d, J=12 Hz, 2H), 2.21 (t, J=11.6 Hz, 2H), 2.29 (s, 3H ), 3.00-2.92 (m, 3H), 5.30 (s, 2H), 6.29 (s, 2H), 7.36 (s, 1H), 7.57 (d, J= 4.8 Hz, 1H), 7.76 (s, 1H), 7.81 (s, 1H), 7.89 (s, 1H), 8.22 (s, 1H), 8.43 (d, J=5.2 Hz, 1H). LCMS: Rt=1.14 min, MS Calculated: 415.1, MS Found: 415.7[M+H]+.

Example 9 Preparation of compound 52 (A9)

The synthesis route for the compound is as follows:

Compound 50: 5-Bromo-2-nitropyridin-3-ol (3.00 g, 13.8 mmol), (2-chloropyridin-4-yl)methanol (1.91 g, 13.8 mmol) and triphenylphosphine ( 4.35 g, 16.6 mmol) were sequentially added to a three-neck flask containing 100 ml of anhydrous tetrahydrofuran, stirred in an ice bath and purged with nitrogen three times, diisopropyl azodicarboxylate (3.35 g, 16.6 mmol) was added dropwise to the mixed solution. , after which the mixture was stirred at room temperature for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure. 100 ml of water was added, extracted with dichloromethane (200 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (200 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate , 10/1, v/v), gave 1.4 g of a yellow solid, yield: 30%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 3.76 (s, 3H), 5.31 (s, 2H), 6.98 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 8.29 (d, J=1.2 Hz, 1H), 8.43 (d, J=1.6 Hz, 1H).

Compound 51: Compound 50 (1.40 g, 4.14 mmol), 2-(1-piperidin-4-yl)-5(tributylstannyl)thiazole (1.95 g, 4.14 mmol), bis(triphenylphosphine) palladium chloride (0.40 g, 0.41 mmol) and iodide (0.24 g, 1.24 mmol) were added sequentially to a one-neck flask containing 20 ml dioxane, under a protective layer of nitrogen, and heated to 90°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, filtered and the filtrate was concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 30/1, v/v), to obtain 0.70 g of a white solid, yield: 38%. LCMS: Rt=1.37 min, MS Calculated: 440.2, MS Found: 440.9 [M+H]+.

Compound 52: Compound 51 (200 mg, 0.45 mmol) was added to a mixed solution of ethanol (5 ml) and water (1 ml), stirred at room temperature, ammonium chloride (72 mg, 1.35 mol) and powder were added successively iron (76 mg, 1.35 mmol). The reaction was carried out for 5 hours at room temperature. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated, 30 ml of methanol was added and stirred, filtered through diatomaceous earth and the filtrate was concentrated, then separated by high performance liquid chromatography (column: Gemini-C18 150x21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA, gradient: 15-30% ACN), lyophilized to give 70 mg yellow solid, yield: 38%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm 1.70-1.80 (m, 2H), 2.04 (d, J=17.2 Hz, 2H), 2.27 (s, 2H), 2.90-2.98 (m, 3H) , 3.76 (s, 3H), 5.13 (s, 2H), 5.98 (s, 2H), 6.95 (d, J=8.8 Hz, 2H), 7.37 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.74 (s, 1H), 7.90 (s, 1H), 8.19 (s, 1H). LCMS: Rt=1.20 min, MS Calculated: 410.2, MS Found: 410.9 [M+H]+.

Example 10 Preparation of compound 60 (A10)

The synthesis route for the compound is as follows:

Compound 55: Compound 53 (2 g, 10.7 mmol), Compound 54 (2.7 g, 16.0 mmol), bis(triphenylphosphine)palladium dichloride (751 mg, 1.07 mmol) and copper iodide (611 mg , 3.21 mmol)) were sequentially added to a round bottom flask containing 15 ml DMF and 5 ml triethylamine, under a protective layer of nitrogen, and stirred at 70°C for 16 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 3/1, v/v), to obtain 2.3 g of a yellow oily liquid, yield: 78.1%. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 1.53-1.65 (m, 10H), 1.71-1.96 (m, 2H), 3.22 (s, 1H), 3.51-3.56 (m, 1H), 3. 95-4.01 (m, 1H), 4.74 (s, 2H), 5.15 (d, J=3.3 Hz, 1H), 7.24 (d, J=5.1 Hz, 1H ), 7.43 (s, 1H), 8.47 (d, J=5.1 Hz, 1H). LCMS: Rt=1.67 min, MS Calculated: 275.2, MS Found: 275.9 [M+H]+.

Compound 57: Compound 55 (1.3 g, 4.6 mmol), compound 56 (1 g, 4.6 mmol) and triphenylphosphine (1.45 g, 5.5 mmol) were added sequentially to a three-neck flask containing 30 mL tetrahydrofuran, under a protective layer of nitrogen, diisopropyl azodicarboxylate (1.1 g, 5.5 mmol) was added with stirring and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with water (50 ml), extracted with EtOAc (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 1/1, v/v) to obtain 1.3 g of a dark brown sticky substance (crude, containing triphenylphosphine oxide). LCMS: Rt=1.70 min, MS Calculated: 475.1/477.1, MS Found: 475.5/477.5 [M+H]+.

Compound 58: Compound 57 (1.3 g, crude), Compound 5 (1.3 g, 2.7 mmol), bis(triphenylphosphine)palladium dichloride (190 mg, 0.27 mmol) and copper iodide (154 mg, 0.81 mmol) were sequentially added to a round bottom flask containing 30 ml of dioxane under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and separated by column chromatography (eluent: dichloromethane/methanol, 5/1, v/v), to obtain 370 mg of a yellow sticky substance (crude). LCMS: Rt=1.41 min, MS Calculated: 577.2, MS Found: 577.9 [M+H]+.

Compound 59: Compound 58 (370 mg, crude), iron powder (291 mg, 5.2 mmol) and ammonium chloride (281 mg, 5.2 mmol) were successively added to a round bottom flask containing 10 ml ethanol and 2 ml water, stirred at 70°C for 4 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was diluted with water (10 ml), extracted with ethyl acetate (30 ml × 3) and the combined extracts were washed with saturated aqueous sodium chloride (10 ml), dried with anhydrous Na ₂ SO ₄ , concentrated at under reduced pressure to obtain 200 mg of a brown solid. The crude material was used directly in the next step without further purification. LCMS: Rt=1.25 min, MS Calculated: 547.3, MS Found: 547.9 [M+H]+.

Compound 60: In a 50 ml round bottom flask, compound 59 (200 mg crude) was dissolved in 15 ml tetrahydrofuran and 4N hydrochloric acid in dioxane (3 ml) was added and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure and then separated by high performance liquid chromatography (column: Gemini-C18 150x21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA) , gradient: 0-40% ACN), lyophilized to give 25 mg of white solid, total yield over four steps: 1.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 1.48 (s, 6H), 1.69-1.78 (m, 2H), 2.01-2.14 (m, 4H), 2.24 (s, 3H), 2.87-2, 97 (m, 3H), 5.28 (s, 2H), 6.24 (s, 2H), 7.33 (s, 1H), 7.54 (d, J=4.9 Hz, 1H), 7.60 (s, 1H), 7.80 (s, 1H), 7.88 (s, 1H), 8.55 (d, J=5.0 Hz, 1H). LCMS: Rt=1.07 min, MS Calculated: 463.2, MS Found: 463.6 [M+H]+.

Example 11 Preparation of compound 66 (A12)

The synthesis route for the compound is as follows:

Compound 63: Compound 62 (2 g, 12.19 mmol), N-methylpiperazine (3.66 g, 36.58 mmol) was added to a 100 ml round bottom flask and stirred at 140°C for 1 hour. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, diluted with water (50 ml), extracted with ethyl acetate (100 ml × 2) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: methanol/dichloromethane, 1/10, v/v), to obtain 1.8 g of a yellow oily liquid, yield: 81.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 2.22 (s, 3H), 2.41 (t, J=5.2 Hz, 4H), 3.37-3.39 (m, 4H), 6.84 (d, J=3.6 Hz , 1H), 7.16 (d, J=3.6 Hz, 1H). LCMS: Rt=0.39 min, MS Calculated: 183.1, MS Found: 183.9 [M+H] ⁺

Compound 64: In a 250 ml three-neck flask, compound 63 (900 mg, 4.91 mmol) was dissolved in 40 ml anhydrous tetrahydrofuran, cooled to -78°C and n-butyllithium (2.4 M solution in hexane, 2.1 ml, 4.91 mmol), stirred at -78°C for 1 hour, then added dropwise tributyltin chloride (6.4 g, 19.7 mmol), stirred at -78°C for 1 hour . LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated ammonium chloride (50 ml), extracted with EtOAc (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: methanol/dichloromethane, 1/10, v/v), to obtain 950 mg of a yellow oily liquid, yield: 40.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm 0.86 (t, J=7.2 Hz, 9H), 1.04 (t, J=8.0 Hz, 5H), 1.25-1.34 (m, 7H), 1.48-1 .59 (m, 6H), 2.22 (s, 3H), 2.39-2.42 (m, 4H), 3.37-3.40 (m, 4H), 7.06 (s, 1H ). LCMS: Rt=1.59 min, MS Calculated: 473.2, MS Found: 473.8 [M+H] ⁺

Compound 65: Compound 64 (900 mg, 1.90 mmol), Compound 41 (600 mg, 1.90 mmol), bis(triphenylphosphine) palladium dichloride (268 mg, 0.38 mmol), tetrabutylammonium fluoride (148 mg, 0 .52 mmol) were sequentially added to a 100 ml round bottom flask containing 30 ml dioxane under a protective layer of nitrogen and stirred at 90°C for 4 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature and concentrated under reduced pressure. 100 ml of water was added, extracted with ethyl acetate (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: methanol/dichloromethane, 1/5, v/v), yielded 250 mg of a yellow solid, yield: 31.9%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 2.42-2.47 (m, 5H), 3.33 (s, 3H), 3.54 (t, J=4.8 Hz, 3H), 5.52 (s, 2H), 7.46 (d, J=5.2 Hz, 2H), 7.98 (s, 1H), 8.06 (s, 1H), 8.28 (s, 1H), 8.64 (d, J=5, 2 Hz, 2H). LCMS: Rt=1.06 min, MS Calculated: 412.1, MS Found: 412.8 [M+H] ⁺

Compound 66: Compound 65 (250 mg, 0.61 mmol), iron powder (338 mg, 6.06 mmol), ammonium chloride (324 mg, 6.06 mmol) were added sequentially to a 100 mL round bottom flask containing an ethanol mixture /water (50 ml, 4/1, v/v), stirred at 50°C for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated under reduced pressure and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1 % TFA), gradient: 0-20% ACN), lyophilized to give 39.5 mg white solid, yield: 17%. 1H NMR (400 MHz, CD ₃ OD): δ ppm. 2.38 (s, 3H), 2.60 (t, J=4.8 Hz, 4H), 3.52 (t, J=4.8 Hz, 4H), 5.32 (s, 2H), 7.30 (d, J=7.2 Hz, 2H), 7.60-7.63 (m, 3H), 8.58 (d, J=4.8 Hz, 2H). LCMS: Rt=0.39 min, MS Calculated: 382.2, MS Found: 382.9 [M+H]+.

Example 12 Preparation of compound 72 (A13)

The synthesis route for the compound is as follows:

Compound 68: Compound 67 (3 g, 23.23 mmol), Lawson's reagent (4.7 g, 11.61 mmol) was added to a round bottom flask containing 50 ml anhydrous tetrahydrofuran, under a blanket of nitrogen, and stirred at 60°C. within 14 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated sodium bicarbonate (100 ml), extracted with EtOAc (200 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: dichloromethane/methanol, 10/1, v/v) to obtain 2 g of a white solid, yield: 59.3%. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 1.55-1.59 (m, 2H), 1.70-1.81 (m, 2H), 2.68-2, 76 (m, 1H), 3.30-3.34 (m, 2H), 3.86-3.90 (m, 2H), 9.10 (s, 1H), 9.40 (s, 1H) . LCMS: Rt=1.01 min, MS Calculated: 145.2, MS Found: 145.9 [M+H] ⁺

Compound 69: Compound 68 (1.4 g, 9.64 mmol), chloroacetaldehyde (40% aqueous solution, 3.8 g, 19.28 mmol) was added to a 100 ml round bottom flask containing 20 ml acetone and stirred at 60°C for 14 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was diluted with water (50 ml), extracted with ethyl acetate (100 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: methanol/dichloromethane, 1/10, v/v) to obtain 1.1 g of a brown oil, yield: 68.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.68-1.78 (m, 2H), 1.96-1.99 (m, 2H), 3.27-3.35 (m, 1H), 3.45-3.49 (m, 2H ), 3.90-3.94 (m, 2H), 7.66 (d, J=3.2 Hz, 1H), 7.78 (d, J=3.2 Hz, 1H). LCMS: Rt=1.31 min, MS Calculated: 169.2, MS Found: 169.9 [M+H] ⁺

Compound 70: In a 250 ml three-neck flask, compound 69 (700 mg, 4.14 mmol) was dissolved in 40 ml anhydrous tetrahydrofuran, cooled to -78°C and n-butyllithium (2.4 M solution in hexane, 21.8 ml, 1.14 mmol), stirred at -78°C for 1 hour, then tributyltin chloride (1.62 g, 4.96 mmol) was added dropwise, stirred at -78°C for 1 hour . LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated ammonium chloride (50 ml), extracted with EtOAc (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: methanol/dichloromethane, 1/10, v/v), to obtain 600 mg of a yellow oily liquid, yield: 31.6%. LCMS: Rt=2.82 min, MS Calculated: 459.2, MS Found: 459.6 [M+H] ⁺

Compound 71: Compound 70 (350 mg, 0.76 mmol), Compound 41 (237 mg, 0.76 mmol), tetra(triphenylphosphine)palladium (177 mg, 0.15 mmol), tetrabutylammonium fluoride (60 mg, 0. 23 mmol) were sequentially added to a 100 ml round bottom flask containing 30 ml N-methylpyrrolidone, under a protective layer of nitrogen, and stirred at 50°C for 4 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature and concentrated under reduced pressure. 100 ml of water was added, extracted with ethyl acetate (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: methanol/dichloromethane, 1/5, v/v), 900 mg of a yellow oily liquid (crude substance containing a large amount of N-methylpyrrolidone) were obtained. LCMS: Rt=1.36 min, MS Calculated: 398.1, MS Found: 398.9 [M+H] ⁺

Compound 72: Compound 71 (900 mg, crude), iron powder (420 mg, 7.53 mmol), ammonium chloride (402 mg, 7.53 mmol) were added sequentially to a 100 ml round bottom flask containing ethanol/water mixture ( 50 ml, 4/1, v/v), stirred at 50°C for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated under reduced pressure and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1 % TFA), gradient: 0-40% ACN), lyophilized to give 8 mg of yellow solid, total yield over two steps: 0.8%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 1.93-2.00 (m, 2H), 2.07-2.10 (m, 2H), 3.23-3.29 (m, 1H), 3.58 (t, J=11.6 Hz, 2H), 4.09-4.12 (m, 2H), 5.09 (s, 2H), 5.20 (s, 2H), 7.07 (s, 1H), 7.38 (d , J=4.8 Hz, 2H), 7.67 (s, 1H), 7.91 (s, 1H), 8.70 (d, J=4.8 Hz, 2H). LCMS: Rt=0.96 min, MS Calculated: 368.5, MS Found: 369.1 [M+H] ⁺ .

Example 13 Preparation of compound 75 (A11)

The synthesis route for the compound is as follows:

Compound 73: 5-Bromo-2-nitropyridin-3-ol (1.00 g, 4.59 mmol), (2-chloropyridin-4-yl)methanol (0.62 g, 4.59 mmol) and triphenylphosphine ( 1.45 g, 5.51 mmol) was sequentially added to a three-neck flask containing 40 ml of anhydrous tetrahydrofuran, stirred in an ice bath and purged with nitrogen three times, diisopropyl azodicarboxylate (1.11 g, 5.51 mmol) was added dropwise to the mixed solution. , after which the mixture was stirred at room temperature for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure. 100 ml of water was added, extracted with dichloromethane (100 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate , 5/1, v/v), yielded 0.55 g of a yellow solid, yield: 36%. LCMS: Rt=1.59 min, MS Calculated: 334.0, 336.0, MS Found: 334.7, 336.7 [M+H] ⁺ .

Compound 74: Compound 73 (0.55 g, 1.64 mmol), 2-(1-piperidin-4-yl)-5(tributylstannyl)thiazole (0.77 g, 1.64 mmol), bis(triphenylphosphine) palladium chloride (0.318 g, 0.33 mmol), iodide (0.063 g, 0.33 mmol) and tetrabutylammonium fluoride (0.64 g, 2.46 mmol) were added sequentially to a one-neck flask containing 10 ml of dioxane, under a protective layer nitrogen and heated to 90°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, filtered and the filtrate was concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 10/1, v/v), 0.5 g of a red oily liquid was obtained, yield: 70%. LCMS: Rt=1.32 min, MS Calculated: 436.1, MS Found: 436.8 [M+H]+.

Compound 75: Compound 74 (300 mg, 0.69 mmol) was added to a mixed solution of ethanol (5 ml) and water (1 ml), stirred at room temperature, ammonium chloride (74 mg, 1.38 mol) and powder were added successively iron (77 mg, 1.38 mmol). The reaction was carried out for 5 hours at room temperature. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated, 30 ml of methanol was added and stirred, filtered through diatomaceous earth and the filtrate was concentrated, then separated by preparative chromatography to obtain 13 mg of a white solid, yield: 4.6%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.71-1.79 (m, 2H), 2.04 (d, J=15.2 Hz, 2H), 2.16 (t, J=10.8 Hz, 2H), 2.26 (s , 3H), 2.90-2.96 (m, 3H), 5.34 (s, 2H), 6.36 (s, 2H), 7.38 (s, 1H), 7.82 (s, 1H), 7.87 (d, J=4.0 Hz, 1H), 7.90 (s, 1H), 8.22 (s, 1H), 8.36 (s, 1H), 8.77 ( d, J=4.8 Hz, 1H). LCMS: Rt=1.14 min, MS Calculated: 406.2, MS Found: 406.9 [M+H]+.

Example 14 Preparation of compound 85 (A40)

The synthesis route for the compound is as follows:

Compound 78: Compound 77 (5 g, 71.4 mmol) was added to a round bottom flask containing 100 ml tetrahydrofuran, ethynylmagnesium bromide (285 ml, 142.8 mmol, 0.5 M in tetrahydrofuran) was added dropwise at 0°C. under a protective layer of nitrogen, stirred at 0°C for 16 hours. TLC monitoring was carried out, after completion of the reaction the mixture was quenched with water (200 ml), extracted with ether (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and 4.8 g of yellow oily liquid were obtained. The crude material was used directly in the next step.

Compound 79: Compound 78 (4.8 g, 50.0 mmol), 4-methylbenzenesulfonic acid pyridinium salt (50 mg) was added to a round bottom flask containing 50 ml of tetrahydrofuran, followed by the addition of 3,4-dihydropyran (4.2 g , 50.0 mmol), under a protective layer of nitrogen, was stirred at room temperature for 16 hours. TLC monitoring was carried out, after completion of the reaction the mixture was concentrated and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 50/1, v/v) to obtain 2.9 g of a yellow oily liquid, the crude material was used directly in the next step.

Compound 81: Compound 79 (1 g, 5.55 mmol), Compound 80 (1.1 g, 4.63 mmol), bis(triphenylphosphine)palladium dichloride (323 mg, 0.46 mmol) and copper iodide (263 mg , 1.38 mmol) were sequentially added to a round-bottom flask containing 10 ml of dioxane and 2 ml of triethylamine, under a protective layer of nitrogen, and stirred at room temperature for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 10/1, v/v), to obtain 1.1 g of a yellow oily liquid, yield: 82.1%. LCMS: Rt=1.67 min, MS Calculated: 286.2, MS Found: 308.9 [M+Na]+.

Compound 82: Compound 81 (1.0 g, 3.5 mmol), compound 9 (762 mg, 3.5 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) were added sequentially to a three-neck flask containing 20 mL tetrahydrofuran, under a protective layer of nitrogen, diisopropyl azodicarboxylate (849 mg, 4.2 mmol) was added with stirring and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with water (50 ml), extracted with EtOAc (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 10/1, v/v) to obtain 1.0 g of a yellow sticky substance, yield: 58.6%. LCMS: Rt=1.90 min, MS Calculated: 486.1, 488.1, MS Found: 508.7, 510.8 [M+Na]+.

Compound 83: Compound 82 (950 mg, 1.95 mmol), Compound 5 (923 mg, 1.95 mmol), bis(triphenylphosphine)palladium dichloride (137 mg, 0.195 mmol) and copper iodide (111 mg, 0.585 mmol) were sequentially added to a round bottom flask containing 15 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 8/1, v/v), to obtain 260 mg of a yellow solid. The crude material was used directly in the next step. LCMS: Rt=1.58 min, MS Calculated: 588.2, MS Found: 588.9 [M+H]+.

Compound 84: Compound 83 (260 mg, crude), reduced iron powder (124 mg, 2.2 mmol) and ammonium chloride (119 mg, 2.2 mmol) were added sequentially to a round bottom flask containing 5 ml ethanol and 1 ml water , stirred at 70°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated and then 230 mg of a yellow solid was obtained. The crude material was used directly in the next step. LCMS: Rt=1.37 min, MS Calculated: 558.3, MS Found: 558.9 [M+H]+.

Compound 85: Compound 84 (230 mg, crude) was added to a round bottom flask containing 5 ml tetrahydrofuran, under a protective layer of nitrogen, a 4N solution of hydrochloric acid in dioxane (1 ml) was added and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.05% NH ₃ ), gradient: 40-90% ACN), lyophilized to give 79.2 mg of yellow solid, total yield over three steps: 8.6%. ^1H NMR (400 MHz, DMSO-d6): δ ppm 1.67-1.82 (m, 4H), 1.99-2.04 (m, 4H), 2.19-2.25 (m, 5H), 2.33-2.41 (m, 2H), 2.81-2.94 (m, 3H), 5.23 (s, 2H), 5.89 (s, 1H), 6.08 (s, 2H), 7.36-7.43 (m, 3H), 7.54-7.58 (m, 2H), 7.77 (s, 1H), 7.88 (s, 1H). LCMS: Rt=1.22 min, MS Calculated: 474.2, MS Found: 474.9 [M+H]+.

Example 15 Preparation of compound 90 (A41)

The synthesis route for the compound is as follows:

Compound 88: Compound 86 (500 mg, 1.05 mmol), 87 (528 mg, 1.26 mmol), bis(triphenylphosphine)palladium dichloride (74 mg, 0.105 mmol) and copper iodide (60 mg, 0.315 mmol) sequentially was added to a round bottom flask containing 10 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 3/1, v/v), to obtain 320 mg of a white solid, yield: 58.1%.

Compound 89: Compound 88 (320 mg, 0.61 mmol), reduced iron powder (172 mg, 3.1 mmol) and ammonium chloride (167 mg, 3.1 mmol) were sequentially added to a round bottom flask containing 5 ml ethanol and 1 ml of water, stirred at 70°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction, the mixture was then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 1/2, v/v), to obtain 240 mg of a yellow solid, yield: 80.3%.

LCMS: Rt=1.71 min, MS Calculated: 491.2, MS Found: 491.9 [M+H] ⁺ .

Compound 90: Compound 89 (240 mg, 0.49 mmol) was added to a round bottom flask containing 4 ml of tetrahydrofuran, under a protective layer of nitrogen, a 4N solution of hydrochloric acid in dioxane (1 ml) was added and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.05% NH ₃ ), gradient : 40-70% ACN), lyophilized to give 56.8 mg of white solid, yield: 28.4%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.34 (d, J=6.8 Hz, 6H), 1.47 (s, 6H), 3.22-3.33 (m, 1H), 5.22 (s, 2H), 5.47 (s, 1H), 6.08 (s, 2H), 7.34-7.42 (m, 3H), 7.54 (s, 2H), 7.77 (s, 1H), 7.86 ( s, 1H). LCMS: Rt=1.43 min, MS Calculated: 407.2, MS Found: 407.9 [M+H] ⁺ .

Example 16 Preparation of compound 94 (A38)

The synthesis route for the compound is as follows:

Compound 93: Compound 91 (300 mg, 0.56 mmol), 92 (139 mg, 1.12 mmol), bis(triphenylphosphine)palladium dichloride (39 mg, 0.056 mmol) and copper iodide (32 mg, 0.17 mmol ) were sequentially added to a round bottom flask containing 5 ml DMF and 1 ml triethylamine, under a protective layer of nitrogen, and stirred at room temperature for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 8/1, v/v), 110 mg of a yellow sticky substance was obtained, yield: 70%. LCMS: Rt=1.32 min, MS Calculated: 532.2, MS Found: 532.8 [M+H] ⁺ .

Compound 94: Compound 93 (110 mg, crude), reduced iron powder (58 mg, 1.03 mmol) and ammonium chloride (55 mg, 1.03 mmol) were added sequentially to a round bottom flask containing 5 ml ethanol and 1 ml water , stirred at 70°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature and then separated by high performance liquid chromatography (column: Gemini-C18 150x21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA) , gradient: 5-30% ACN), lyophilized to give 16 mg of white solid, total yield over two steps: 5.7%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.23-1.30 (m, 1H), 1.49-1.68 (m, 8H), 1.85-1.88 (m, 2H), 2.09-2.32 (m, 4H ), 3.04 (s, 3H), 3.24-3.30 (m, 1H), 3.44-3.61 (m, 4H), 4.63 (s, 2H), 5.82 ( s, 2H), 7.10 (s, 1H), 7.52-7.61 (m, 3H), 7.64 (s, 1H), 7.69 (s, 1H), 7.82 (s , 1H), 8.37 (s, 2H). LCMS: Rt=1.02 min, MS Calculated: 502.2, MS Found: 503.1 [M+H] ⁺ .

Example 17 Preparation of compound 104 (A39)

The synthesis route for the compound is as follows:

Compound 98: Compound 96 (1.5 g, 8.0 mmol), 97 (1.2 g, 12.0 mmol), bis(triphenylphosphine)palladium dichloride (562 mg, 0.8 mmol) and copper iodide (457 mg, 2.4 mmol) were sequentially added to a round bottom flask containing 20 ml of dioxane and 4 ml of triethylamine, under a protective layer of nitrogen, and stirred at 50°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 1/1, v/v), to obtain 1.5 g of a brown oily liquid, yield: 91.2%. ^1H NMR (400 MHz, CDCl ₃ ): δ ppm 0.27 (s, 9H), 4.75 (s, 2H), 7.25 (d, J=5.0 Hz, 1H), 7.49 (s, 1H), 8.48 (d, J=5.1 Hz, 1H). LCMS: Rt=1.51 min, MS Calculated: 205.1, MS Found: 206.0 [M+H] ⁺ .

Compound 100: Compound 98 (1.5 g, 7.3 mmol), compound 99 (1.4 g, 6.6 mmol) and triphenylphosphine (2.0 g, 7.9 mmol) were added sequentially to a three-neck flask containing 30 ml of tetrahydrofuran, under a protective layer of nitrogen, diisopropyl azodicarboxylate (1.6 g, 7.9 mmol) was added with stirring and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with water (50 ml), extracted with EtOAc (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 2/1, v/v) to obtain 1.2 g of a gray solid, yield: 45.5%. ^1H NMR (400 MHz, CDCl ₃ ): δ ppm 0.30 (s, 9H), 5.25 (s, 2H), 7.34 (d, J=4.9 Hz, 1H), 7.51 (s, 1H), 7.67 (s, 1H), 8.24 (s, 1H), 8.65 (d, J=5.0 Hz, 1H). LCMS: Rt=1.70 min, MS Calculated: 405.0, 407.0, MS Found: 405.7, 407.7 [M+H] ⁺ .

Compound 102: Compound 100 (0.8 g, 2.0 mmol), Compound 101 (932 mg, 2.0 mmol), bis(triphenylphosphine)palladium dichloride (140 mg, 0.2 mmol) and copper iodide (114 mg , 0.6 mmol) were sequentially added to a round bottom flask containing 15 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 5/1, v/v), to obtain 160 mg of a yellow sticky substance (crude). LCMS: Rt=1.46 min, MS Calculated: 507.2, MS Found: 507.9 [M+H] ⁺ .

Compound 103: Compound 102 (160 mg, crude), reduced iron powder (88 mg, 1.6 mmol) and ammonium chloride (85 mg, 1.6 mmol) were added sequentially to a round bottom flask containing 5 ml ethanol and 1 ml water , stirred at 70°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated and then 140 mg of a yellow solid was obtained. The crude material was used directly in the next step. LCMS: Rt=1.29 min, MS Calculated: 477.2, MS Found: 477.9 [M+H] ⁺ .

Compound 104: Compound 103 (140 mg, crude) and potassium carbonate (122 mg, 0.88 mmol) were added sequentially to a round bottom flask containing 300 ml methanol under a blanket of nitrogen, stirred at room temperature overnight. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1% TFA), gradient: 0-30% ACN), lyophilized to give 12 mg of gray solid, total yield over two steps: 1.5%. ¹ H NMR (400 MHz, CD ₃ OD): δ ppm. 2.05-2.16 (m, 2H), 2.37 (d, J=13.2 Hz, 2H), 2.86 (s, 3H), 3.11 (t, J=11.7 Hz , 2H), 3.36 (s, 1H), 3.54 (d, J=12.3 Hz, 2H), 3.84 (s, 1H), 5.34 (s, 2H), 7.37 (s, 1H), 7.61 (d, J=5.0 Hz, 1H), 7.76 (s, 1H), 7.80 (s, 1H), 7.87 (s, 1H), 8 .47 (s, 1H), 8.55 (d, J=5.1 Hz, 1H). LCMS: Rt=1.13 min, MS Calculated: 405.2, MS Found: 405.9 [M+H] ⁺ .

Example 18 Preparation of compound 113 (A34)

The synthesis route for the compound is as follows:

Compound 114: Compound 106 (3 g, 27.2 mmol), p-toluenesulfonic acid (50 mg) was added to a round bottom flask containing 50 ml tetrahydrofuran, followed by the addition of 3,4-dihydropyran (3 g, 27.2 mmol) , under a protective layer of nitrogen, was stirred at room temperature for 16 hours. TLC monitoring was carried out, after completion of the reaction the mixture was concentrated and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 50/1, v/v), 1.5 g of a yellow oily liquid was obtained, the crude material was used directly in the next step.

Compound 108: Compound 114 (1.3 g, 6.7 mmol), compound 107 (1.5 g, 6.7 mmol), bis(triphenylphosphine)palladium dichloride (470 mg, 0.67 mmol) and copper iodide ( 383 mg, 2.01 mmol) were sequentially added to a round bottom flask containing 20 ml dioxane and 4 ml triethylamine, under a protective layer of nitrogen, and stirred at room temperature for 16 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 10/1, v/v), to obtain 1.3 g of a yellow oily liquid, yield: 64.2%. LCMS: Rt=1.83 min, MS Calculated: 300.2, MS Found: 323.1 [M+Na] ⁺ .

Compound 110: Compound 108 (1.3 g, 4.3 mmol), compound 109 (940 mg, 4.3 mmol) and triphenylphosphine (1.35 g, 5.16 mmol) were added sequentially to a three-neck flask containing 30 mL tetrahydrofuran, under a protective layer of nitrogen, diisopropyl azodicarboxylate (1.04 g, 5.16 mmol) was added with stirring and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with water (50 ml), extracted with EtOAc (50 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 10/1, v/v) to obtain 900 mg of a yellow sticky substance, yield: 41.9%. LCMS: Rt=1.99 min, MS Calculated: 500.1, 502.1, MS Found: 522.8, 524.8 [M+Na]+.

Compound 111: Compound 110 (0.5 g, 1.0 mmol), Compound 5 (472 mg, 1.0 mmol), bis(triphenylphosphine)palladium dichloride (70 mg, 0.1 mmol) and copper iodide (57 mg , 0.3 mmol) were sequentially added to a round bottom flask containing 15 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and then purified by column chromatography (eluent: dichloromethane/methanol, 5/1, v/v), to obtain 320 mg of a yellow solid (crude). LCMS: Rt=1.55 min, MS Calculated: 602.3, MS Found: 602.9 [M+H]+.

Compound 112: Compound 111 (320 mg, crude), reduced iron powder (149 mg, 2.65 mmol) and ammonium chloride (140 mg, 2.65 mmol) were added sequentially to a round bottom flask containing 5 ml ethanol and 1 ml water , stirred at 70°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated and then 260 mg of a yellow solid was obtained. The crude material was used directly in the next step. LCMS: Rt=1.37 min, MS Calculated: 572.3, MS Found: 572.9 [M+H]+.

Compound 113: Compound 112 (260 mg, crude) was added to a round bottom flask containing 5 ml tetrahydrofuran, under a protective layer of nitrogen, a 4N solution of hydrochloric acid in dioxane (1 ml) was added and stirred at room temperature for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.05% NH ₄ OH), gradient: 30-90% ACN), lyophilized to give 50.1 mg of white solid, total yield over three steps: 10.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.68-1.76 (m, 6H), 1.84-1.91 (m, 4H), 1.98-2.04 (m, 4H), 2.19 (s, 3H), 2, 81-2.93 (m, 3H), 5.22 (s, 2H), 5.34 (s, 1H), 6.09 (s, 2H), 7.35-7.42 (m, 3H) , 7.52-7.54 (m, 2H), 7.77 (s, 1H), 7.87 (s, 1H). LCMS: Rt=1.15 min, MS Calculated: 488.2, MS Found: 488.6 [M+H]+.

Example 19 Preparation of compound 118 (A35)

The synthesis route for the compound is as follows:

Compound 116: Compound 115 (2 g, 20.17 mmol) was added to a three-neck flask containing 50 ml anhydrous tetrahydrofuran, cooled to -78°C and n-butyllithium (2.4 M solution in hexane, 8. 4 ml, 20.17 mmol), stirred at -78°C for 1 hour, then tributyltin chloride (7.2 g, 22.19 mmol) was added dropwise, stirred at -78°C for 1 hour. TLC monitoring was carried out, after completion of the reaction the mixture was quenched with saturated ammonium chloride (50 ml), extracted with EtOAc (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure without further purification, 7.8 g of a yellow oily liquid was obtained, yield: 99.2%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 0.90 (t, J=7.4 Hz, 9H), 1.09-1.13 (m, 5H), 1.29-1 .36 (m, 8H), 1.52-1.58 (m, 5H), 2.77 (s, 3H), 7.57 (s, 1H).

Compound 117: Compound 116 (1.5 g, 3.87 mmol), Compound 41 (1 g, 3.22 mmol), bis(triphenylphosphine)palladium dichloride (450 mg, 0.65 mmol), copper iodide (180 mg , 0.97 mmol) were sequentially added to a 100 ml round bottom flask containing 50 ml dioxane, under a protective layer of nitrogen, and stirred at 90°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. 100 ml of water was added, extracted with dichloromethane (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then separated using flash preparative chromatography at medium pressure (eluent : methanol/dichloromethane, 1/10, v/v), gave 830 mg of yellow solid, yield: 78.2%. LCMS: Rt=1.31 min, MS Calculated: 328.1, MS Found: 328.8 [M+H] ⁺

Compound 118: Compound 117 (730 mg, 2.22 mmol), iron powder (1.24 g, 22.23 mmol), ammonium chloride (1.19 mg, 22.23 mmol) were added sequentially to a 100 ml round bottom flask , containing an ethanol/water mixture (50 ml, 4/1, v/v), was stirred at 70°C for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated under reduced pressure and then separated using flash preparative chromatography at medium pressure (eluent: methanol/dichloromethane, 1/10, v/v), lyophilized to obtain 125 mg of a yellow solid , yield: 18.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 2.64 (s, 3H), 5.29 (s, 2H), 6.20 (s, 2H), 7.37 (s, 1H), 7.57 (d, J=4.8 Hz, 2H ), 7.76 (s, 1H), 7.85 (s, 1H), 8.60 (d, J=4.0 Hz, 2H). LCMS: Rt=0.78 min, MS Calculated: 298.1, MS Found: 299.0 [M+H]+.

Example 20 Obtaining connection 124 (A36)

The synthesis route for the compound is as follows:

Compound 120: Compound 119 (10 g, 0.11 mol), Lawson's reagent (24 g, 0.06 mol) was added to a round bottom flask containing 150 ml of anhydrous tetrahydrofuran, under a protective layer of nitrogen, and stirred at 70°C for 16 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated sodium bicarbonate, extracted with EtOAc (400 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: ethyl acetate/petroleum ether, 1/3, v/v) to obtain 5 g of a yellow solid, yield: 42.4%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 1.29 (d, J=6.8 Hz, 6H), 2.84-2.97 (m, 1H), 6.95 (s, 1H), 7.73 (s, 1H). LCMS: Rt=0.82 min, MS Calculated: 103.0, MS Found: 104.2 [M+H] ⁺

Compound 121: Compound 120 (2.5 g, 24 mmol), chloroacetaldehyde (5.7 g, 72 mmol) was added to a 100 ml round bottom flask containing 45 ml of acetone and stirred at 60°C for 16 hours. LCMS monitoring was carried out, after completion of the reaction, the mixture was concentrated under reduced pressure and then purified by column chromatography (eluent: ethyl acetate/petroleum ether, 1/2, v/v), to obtain 0.6 g of a yellow solid, yield: 19.5% . CN NMR (400 MHz, CDCl ₃ ): δ ppm 1.44 (d, J=7.2 Hz, 6H), 3.30-3.44 (m, 1H), 7.21 (d, J=3.2 Hz, 1H), 7.70 (d , J=3.2 Hz, 1H). LCMS: Rt=1.19 min, MS Calculated: 127.0, MS Found: 128.2 [M+H] ⁺

Compound 122: In a 100 ml three-neck flask, Compound 121 (600 mg, 4.72 mmol) was dissolved in 25 ml anhydrous tetrahydrofuran, cooled to -78°C and n-butyllithium (2.4 M solution in hexane, 2 .2 ml, 5.2 mmol), stirred at -78°C for 1 hour, then tributyltin chloride (1.61 g, 5.00 mmol) was added dropwise, stirred at -78°C for 1 hour. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated ammonium chloride (20 ml), extracted with EtOAc (100 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, 1.5 g of a yellow solid was obtained, yield: 76.1%. LCMS: Rt=1.94 min, MS Calculated: 417.2, MS Found: 418.0 [M+H] ⁺

Compound 123: Compound 122 (800 mg, 1.93 mmol), Compound 41 (400 mg, 1.29 mmol), bis(triphenylphosphine)palladium dichloride (180 mg, 0.26 mmol) and copper iodide (73 mg, 0 .39 mmol) were sequentially added to a round-bottom flask containing 25 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and separated using flash preparative chromatography at medium pressure (eluent: methanol/dichloromethane, 1/20, v/v), to obtain 160 mg of a gray solid, yield: 34 ,8%. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 1.39 (d, J=6.8 Hz, 6H), 3.34-3.41 (m, 1H), 5.55 (s, 2H), 7.44-7.57 (m, 2H), 8.23 (s, 1H), 8.43 (s, 1H), 8.47 (s, 1H), 8.55- 8.97 (m, 2H). LCMS: Rt=1.45 min, MS Calculated: 356.1, MS Found: 356.8 [M+H] ⁺

Compound 124: Compound 123 (160 mg, 0.45 mmol), iron powder (126 mg, 2.25 mmol), ammonium chloride (120 mg, 2.25 mmol) were added sequentially to a 100 ml round bottom flask containing an ethanol mixture /water (25 ml, 4/1, v/v), stirred at 70°C for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated under reduced pressure and then separated by flash preparative chromatography at medium pressure (eluent: methanol/dichloromethane, 1/20, v/v), to obtain 60 mg of a yellow solid, yield : 41.9%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.34 (d, J=6.8 Hz, 6H), 3.21-3.30 (m, 1H), 5.29 (s, 2H), 6.20 (s, 2H), 7.37 (s, 1H), 7.57 (d, J=4.8 Hz, 2H), 7.80 (s, 1H), 7.87 (s, 1H), 8.60 (d, J=3, 6 Hz, 2H). LCMS: Rt=0.99 min, MS Calculated: 326.1, MS Found: 327.1 [M+H] ⁺ .

Example 21 Preparation of compound 130 (A37)

The synthesis route for the compound is as follows:

Compound 126: Compound 125 (6.5 g, 51.4 mmol), Lawson's reagent (10.3 g, 25.6 mmol) was added to a round bottom flask containing 150 ml of anhydrous tetrahydrofuran, under a blanket of nitrogen, and stirred at 50 °C for 14 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated sodium bicarbonate, extracted with EtOAc (200 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: petroleum ether/ethyl acetate, 10:1-5:1, v/v) to obtain 2.9 g of a white solid, yield: 39.7%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.11-1.28 (m, 4H), 1.44-1.50 (m, 2H), 1.62-1.74 (m, 5H), 9.01 (s, 1H), 9. 27 (s, 1H). LCMS: Rt=1.44 min, MS Calculated: 143.1, MS Found: 144.0 [M+H] ⁺

Compound 127: Compound 126 (2.9 g, 20.24 mmol), chloroacetaldehyde (3.2 g, 40.49 mmol), acetic acid (4 ml) was added to a 250 ml round bottom flask containing 50 ml of acetone, and stirred at 50°C for 14 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was concentrated under reduced pressure, diluted with water (50 ml), extracted with ethyl acetate (100 ml × 2) and the combined extracts were washed with saturated aqueous sodium chloride (50 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then purified by column chromatography (eluent: ethyl acetate/petroleum ether, 1/3, v/v) to obtain 2.4 g of a yellow oily liquid, yield: 75%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 1.25-1.61 (m, 6H), 1.85-1.88 (m, 2H), 2.15-2.18 (m, 2H), 3.00-3.07 (m, 1H ), 7.20 (d, J=3.6 Hz, 1H), 7.70 (d, J=3.2 Hz, 1H). LCMS: Rt=l.67 min, MS Calculated: 167.1, MS Found: 168.0[M+H] ⁺

Compound 128: In a 250 ml three-neck flask, Compound 127 (2.3 g, 13.75 mmol) was dissolved in 100 ml anhydrous tetrahydrofuran, cooled to -78°C and n-butyllithium (2.4 M solution in hexane, 5 .7 ml, 13.75 mmol) under nitrogen, stirred at -78°C for 1 hour, then tributyltin chloride (4.9 d, 15.13 mmol) was added dropwise, stirred at -78°C for 1 hour. LCMS monitoring was carried out, after completion of the reaction the mixture was quenched with saturated ammonium chloride (50 ml), extracted with EtOAc (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, 6.2 g of a yellow oily liquid was obtained, yield: 98.4%. ^1H NMR (400 MHz, CDCl ₃ ): δ ppm 0.89-0.93 (m, 9H), 1.10-1.14 (m, 4H), 1.27-1.38 ( m, 12H), 1.53-1.59 (m, 8H), 1.85-1.88 (m, 2H), 2.16-2.19 (m, 2H), 3.03-3, 11 (m, 1H), 7.61 (s, 1H).

Compound 129: Compound 128 (1.7 g, 3.87 mmol), Compound 41 (1 g, 3.22), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride complex with dichloromethane (450 mg, 0 .64 mmol), copper iodide (184 mg, 0.97 mmol) was sequentially added to a 100 ml round bottom flask containing 50 ml dioxane, under a protective layer of nitrogen, and stirred at 90°C for 4 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature and concentrated under reduced pressure. 100 ml of water was added, extracted with ethyl acetate (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then separated using flash preparative chromatography at medium pressure (eluent : methanol/dichloromethane, 1/50-1/10, v/v), gave 580 mg of yellow solid, yield: 56.6%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.25-1.28 (m, 2H), 1.38-1.54 (m, 4H), 1.79-1.82 (m, 2H), 2.09-2.12 (m, 2H ), 3.05-3.10 (m, 1H), 5.55 (s, 2H), 7.47 (s, 2H), 8.22 (s, 1H), 8.43 (s, 1H) , 8.47 (s, 1H), 8.66 (br s, 2H). LCMS: Rt=1.62 min, MS Calculated: 396.1, MS Found: 396.9 [M+H] ⁺ .

Compound 130: Compound 129 (530 mg, 1.34 mmol), iron powder (746 mg, 13.37 mmol), ammonium chloride (715 mg, 13.37 mmol) were added sequentially to a 100 ml round bottom flask containing an ethanol mixture /water (50 ml, 4/1, v/v), stirred at 70°C for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated under reduced pressure and then separated using flash preparative chromatography at medium pressure (eluent: methanol/dichloromethane, 1/10, v/v), lyophilized to obtain 290 mg of a yellow solid , yield: 17%. ¹ H NMR (400 MHz, CD ₃ OD): δ ppm. 1.32-1.39 (m, 2H), 1.44-1.62 (m, 2H), 1.88-1.91 (m, 2H), 2.12-2.15 (m, 2H ), 2.98-3.03 (m, 1H), 5.35 (s, 2H), 7.37 (s, 1H), 7.62 (d, J=4.8 Hz, 2H), 7 .78 (s, 2H), 8.59 (br. s, 2H). LCMS: Rt=1.35 min, MS Calculated: 366.2, MS Found: 366.9 [M+H]+.

Example 22 Preparation of compound 138 (A43)

The synthesis route for the compound is as follows:

Compound 133: Compound 131 (10 g, 49.26 mmol), Compound 132 (12 g, 54.19 mmol), sodium carbonate (15.7 g, 147.79 mmol), [1,1'-bis] dichloride complex (diphenylphosphine)ferrocene]palladium with dichloromethane (4.0 g, 9.86 mmol) was added sequentially to a 500 ml round bottom flask containing 300 ml dioxane and 60 ml water, under a protective layer of nitrogen, and stirred at 90°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature and concentrated under reduced pressure. 200 ml of water was added, extracted with ethyl acetate (300 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (200 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and then separated by column chromatography (eluent: methanol/dichloromethane, 1/100, v/v), yielded 7.8 g of a brown solid, yield: 72.2%. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 2.30 (s, 3H), 2.57-2.60 (m, 4H), 3.09 (br s, 2H) , 6.59 (s, 1H), 8.21-8.29 (m, 2H), 8.77 (s, 3H). LCMS: Rt=0.54 min, MS Calculated: 219.1, MS Found: 220.0 [M+H] ⁺

Compound 134: Compound 133 (7.8 g, 35.6 mmol), 10% palladium on carbon (7 g), acetic acid (4 ml) were added sequentially to a 1 L reactor containing 300 ml methanol and 100 ml tetrahydrofuran, stirred at 40°C for 16 hours in a hydrogen atmosphere of 0.4 MPa. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, and the filtrate was concentrated under reduced pressure. 100 ml of water was added, extracted with ethyl acetate (200 ml x 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to obtain 7 g of a yellow oily liquid, yield: 97. 1%. LCMS: Rt=0.30 min, MS Calculated: 191.1, MS Found: 192.0 [M+H] ⁺

Compound 135: In a 500 ml three-neck flask, Compound 134 (7 g, 36.60 mmol) was dissolved in 80 ml hydrobromic acid solution, cooled to -10°C and sodium nitrite solution (3.8 g, 54.89 mmol) was added to nitrogen atmosphere, stirred at -10°C for 1 hour, then sodium bromide solution (5.7 g, 54.89 mmol) was added dropwise, stirred at room temperature for 16 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was adjusted to pH>7 with sodium carbonate, extracted with dichloromethane (200 ml × 2) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and separated by flash preparative chromatography at medium pressure (eluent: methanol/dichloromethane, 1/10-1/5, v/v) to obtain 700 mg of a yellow solid, yield: 7.4%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.83-1.91 (m, 2H), 2.00-2.03 (m, 2H), 2.79 (s, 3H), 2.87-2.92 (m, 1H), 3, 01-3.07 (m, 2H), 3.46-3.48 (m, 2H), 7.65 (s, 2H), 8.33 (s, 1H). LCMS: Rt=1.10 min, MS Calculated: 254.0, 256.0, MS Found: 254.9, 256.8 [M+H] ⁺

Compound 136: In a 250 ml three-neck flask, Compound 135 (440 mg, 1.7 mmol) was dissolved in 100 ml anhydrous tetrahydrofuran, cooled to -78°C and n-butyllithium (2.4 M solution in hexane, 0.86 ml), stirred at -78°C for 1 hour, then tributyltin chloride (673 mg, 2.1 mmol) was added dropwise, stirred at -78°C for 1 hour. TLC monitoring was carried out, after completion of the reaction the mixture was quenched with saturated ammonium chloride (50 ml), extracted with EtOAc (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (100 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, 800 mg of yellow oily liquid was obtained, yield: 98.2%. LCMS: Rt=1.18 min, MS Calculated: 466.2, MS Found: 467.2 [M+H] ⁺

Compound 137: Compound 136 (800 mg, 1.72 mmol), Compound 41 (300 mg, 0.97 mmol), bis(triphenylphosphine)palladium dichloride (136 mg, 0.19 mmol) and copper iodide (56 mg, 0 .29 mmol) were sequentially added to a 100 ml round bottom flask containing 50 ml dioxane under a protective layer of nitrogen and stirred at 60°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature and concentrated under reduced pressure. 100 ml of water was added, extracted with dichloromethane (100 ml x 3) and the combined extracts were washed with saturated aqueous sodium chloride (20 ml), dried with anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and separated using flash preparative chromatography at medium pressure (eluent: methanol/dichloromethane, 1/10-1/1, v/v), gave 120 mg of yellow solid, yield: 30.5%. LCMS: Rt=1.15 min, MS Calculated: 405.2, MS Found: 405.9 [M+H] ⁺

Compound 138: Compound 137 (120 mg, 0.30 mmol), iron powder (165 mg, 2.96 mmol), ammonium chloride (158 mg, 2.96 mmol) were added sequentially to a 100 ml round bottom flask containing 40 ml ethanol and 10 ml of water, and stirred at 50°C for 2 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was filtered, the filtrate was concentrated under reduced pressure and then separated by high performance liquid chromatography (column: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: ACN-H ₂ O (0.1 % TFA), gradient: 0-20% ACN), lyophilized to give 30 mg yellow oily liquid, yield: 27%. ¹ H NMR (400 MHz, CD ₃ OD): δ ppm. 1.98-2.08 (m, 2H), 2.16-2.19 (m, 2H), 2.94 (s, 3H), 2.97-3.03 (m, 1H), 3. 16-3.22 (m, 2H), 3.62-3.65 (m, 2H), 5.39 (s, 2H), 7.63 (d, J=4.4 Hz, 2H), 7 .75 (s, 1H), 7.78 (s, 2H), 8.19 (s, 1H), 8.50 (s, 1H), 8.59 (s, 2H). LCMS: Rt=0.40 min, MS Calculated: 375.2, MS Found: 375.9 [M+H]+.

Example 23 Preparation of compound 143 (A42)

The synthesis route for the compound is as follows:

Compound 141: Compound 139 (2.0 g, 4.2 mmol), 140 (2.81 g, 5.04 mmol), bis(triphenylphosphine)palladium dichloride (295 mg, 0.42 mmol) and copper iodide (240 mg, 1.26 mmol) were sequentially added to a round-bottom flask containing 40 ml of dioxane, under a protective layer of nitrogen, and stirred at 90°C for 6 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was cooled to room temperature, concentrated and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 1/1, v/v) to obtain 2.6 g of a light brown solid, yield: 92 ,8%. LCMS: Rt=2.06 min, MS Calculated: 662.3, MS Found: 685.1 [M+Na] ⁺ .

Compound 142: Compound 141 (2.5 g, 3.77 mmol), reduced iron powder (1.05 g, 18.9 mmol) and ammonium chloride (1.02 g, 18.9 mmol) were added sequentially to the round bottom flask , containing 40 ml of ethanol and 10 ml of water, was stirred at 70°C for 3 hours. LCMS monitoring was carried out, after completion of the reaction the mixture was purified by column chromatography (eluent: petroleum ether/ethyl acetate, 1/2, v/v), to obtain 1.7 g of a white solid, yield: 71.6%. LCMS: Rt=1.82 min, MS Calculated: 632.3, MS Found: 632.8 [M+H] ⁺ .

Compound 143: Compound 142 (1.0 g, 1.58 mmol) was added to a round bottom flask containing 30 ml of tetrahydrofuran, and a 4N solution of hydrochloric acid in dioxane (10 ml) was added under nitrogen atmosphere, stirred at room temperature for 3 hours . LCMS monitoring was carried out, after completion of the reaction the mixture was diluted with water (50 ml), extracted with ethyl acetate (30 ml × 3), the aqueous phase was brought to pH 10 with 2N aqueous sodium hydroxide solution, and a large amount of precipitate precipitated, it was filtered, the filter cake was washed with water and dried in vacuo to obtain 530 mg of a white solid, yield: 75.9%. ¹ H NMR (400 MHz, CD ₃ OD): δ ppm. 1.58 (s, 6H), 1.71-1.80 (m, 2H), 2.11 (d, J=12.3 Hz, 2H), 2.75 (t, J=12.3 Hz , 2H), 3.15 (d, J=12.0 Hz, 3H), 5.22 (s, 2H), 7.34 (s, 1H), 7.38-7.41 (m, 2H) , 7.48-7.51 (m, 1H), 7.56 (s, 1H), 7.76 (s, 1H), 7.79 (s, 1H). LCMS: Rt=1.20 min, MS Calculated: 448.2, MS Found: 448.9 [M+H]+.

Example 24 Preparation of compound A14

Step 1: Compound B2: To a solution of Compound B1 (6.0 g, 37.04 mmol) in DMF (200 ml) was added trimethyl orthoacetate (14.2 g, 118.53 mmol), stirred for 16 hours at 110°C . The reaction mixture was cooled to room temperature and added to water (150 ml), extracted with EtOAc (100 ml x 3). The organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: petroleum ether/ethyl acetate, 3/1, v/v), The pure fractions were evaporated to dryness to give compound B2 (4.3 g) as a yellow oil, yield: 53.7%.

^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 1.93 (s, 3H), 3.74 (s, 3H), 7.87 (s, 1H), 12.68 (s , 1H).

LCMS: Rt=1.29 min, MS Calculated: 217.0, 219.0, MS Found: 217.9, 219.9 [M+H] ⁺ .

Step 2: Compound B4: To a mixture of sodium hydride (550 mg, 13.76 mmol) in DMF (70 ml) was added compound B2 (2.5 g, 11.47 mmol), stirred for 1 hour at 0°C, then compound B3 (3.3 g, 17.2 mmol) was added and stirred for 16 hours at 80°C. The mixture was quenched with water (200 ml), extracted with EtOAc (200 ml x 3), the organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: DCM/MeOH, 10/1, v/v), the pure fractions were evaporated to dryness to give compound B4 (1.24 g) as a brown oil, yield: 34.3%.

LCMS: Rt=1.15 min, MS Calculated: 314.1, 316.1, MS Found: 314.9, 316.9[M+H] ⁺

Step 3: Compound B6: Added Compound B4 (400 mg, 1.27 mmol), Compound 5 (312 mg, 1.27 mmol), Chlorine (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1, 1'-biphenyl)

[2-(2'-amino-1,1'-biphenyl)]-palladium(II) (102 mg, 0.13 mm1), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (119 mg, 0.25 mmol), potassium carbonate (351 mg, 2.54 mmol) in a mixture of ethanol (25 ml) and water (5 ml) was stirred for 0.5 hour at 135°C under nitrogen atmosphere using microwave irradiation. The mixture was concentrated under reduced pressure, the residue was purified by chromatography on silica gel (elution gradient: DCM/MeOH, 4/1, v/v), the pure fractions were evaporated to dryness to obtain compound B6 (180 mg) as a yellow solid, yield: 32. 5%.

LCMS: Rt=1.07 min, MS Calculated: 436.2, MS Found: 437.0 [M+H] ⁺

Step 4: Compound A14: To a solution of compound B6 (260 mg, 0.6 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml, 9.0 mmol), stirred for 16 hours at rt. The mixture was concentrated under reduced pressure, adjusted to pH=8 with saturated sodium bicarbonate solution, then concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, silica gel 5 μm, diameter 21 mm, length 150 mm), using As eluents, weakly polar mixtures of water (containing 0.1% FA) and ACN (0-15%), fractions containing the desired compound were evaporated to dryness to obtain compound A14 (26.1 mg) as a yellow gum, yield: 8. 8%.

^1H NMR (400 MHz, CD ₃ OD): δ ppm 2.17-2.20 (m, 2H), 2.28-2.39 (m, 2H), 2.96 (s, 3H ), 3.21 (t, J=12.4 Hz, 2H), 3.70 (d, J=6.4 Hz, 2H), 4.43-4.49 (m, 1H), 5.96 (s, 1H), 7.73 (s, 1H), 8.26 (d, J=3.2 Hz, 2H), 8.90 (d, J=3.2 Hz, 2H).

LCMS: Rt=0.55 min, MS Calculated: 380.2, MS Found: 381.0 [M+H] ⁺ .

Example 25 Preparation of compound A16

Step 1: Compound C3: To a solution of Compound C1 (20 g, 91.33 mmol) and Compound C2 (17 g, 109.59 mmol) in DMF (300 ml) was added K ₂ CO ₃ (30 g, 91.33 mmol ). The mixture was stirred at 50°C for 14 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (200 ml), extracted with EtOAc (300 ml x 3). The organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: Hexane/EtOAc 50/1-10/1, v/v ). The pure fractions were evaporated to dryness to give compound C3 (29 g) as a yellow solid, yield: 93.5%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 3.77 (s, 3H), 5.32 (s, 2H), 6.98 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 8.29 (s, 1H), 8.43 (s, 1H).

LCMS: Rt=1.71 min, MS Calculated: 338.0, 340.0, MS Found: 360.9, 362.7 [M+Na] ⁺ .

Step 2: Compound C5: To a solution of compound C3 (3.9 g, 11.6 mmol), compound 4 (5.5 g, 11.6 mmol) and copper iodide (663 mg, 3.48 mmol) in 1, Bis(triphenylphosphine)palladium(II) chloride (814 mg, 1.16 mmol) was added to 4-dioxane (50 mL). The mixture was stirred at 90°C under N ₂ atmosphere for 6 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (elution gradient: DCM/MeOH, 10/1, v/v). The pure fractions were evaporated to dryness to give compound C5 (2.1 g) as a pale yellow solid, yield: 41.4%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 1.28-1.40 (m, 2H), 1.96-2.07 (m, 2H), 2.22 (d, J=13.6 Hz, 2H), 2.41 (s, 3H) , 3.05-3.17 (m, 3H), 3.79 (s, 3H), 5.23 (s, 2H), 6.91 (d, J=8.4 Hz, 2H), 7, 35 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.89 (s, 1H), 8.19 (s, 1H).

LCMS: Rt=1.18 min, MS Calculated: 440.2, MS Found: 441.1 [M+H] ⁺ .

Step 3: Compound C6: To a solution of Compound C5 (2.1 g, 4.8 mmol) in DCM (50 ml) was added trifluoroacetic acid (10 ml). The mixture was stirred at room temperature for 6 hours. The mixture was concentrated under vacuum. The residue was triturated with ether and the precipitate was collected by filtration, washed with ether, then air dried to give compound C6 (1.4 g) as a yellow solid, yield: 66.7%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.95 (dd, J=24.5, 11.7 Hz, 2H), 2.31 (d, J=13.3 Hz, 2H), 2.83 (s, 3H), 3.12 (t , J=12.3 Hz, 2H), 3.37 (t, J=10.5 Hz, 1H), 3.56 (d, J=12.0 Hz, 2H), 7.82 (s, 1H ), 8.38 (s, 2H), 9.61 (s, 1H).

LCMS: Rt=1.09 min, MS Calculated: 320.1, MS Found: 320.8 [M+H] ⁺ .

Step 4: Compound C8: To a solution of Compound C6 (1 g, 3.1 mmol), Compound C7 (877 mg, 3.75 mmol) and triphenylphosphine (983 mg, 3.75 mmol) in THF (30 ml) and DMF (15 ml) diisopropyl azodicarboxylate (758 mg, 3.75 mmol) was added at 0°C. The mixture was stirred at 60°C under N ₂ atmosphere for 16 hours. The mixture was quenched with water (50 ml), extracted with EtOAc (100 ml x 3). The organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: DCM/MeOH, 10/1-6/1, v/v). about). The pure fractions were evaporated to dryness to give compound C8 (370 mg, crude) as a yellow solid.

LCMS: Rt=1.28 min, MS Calculated: 536.0, MS Found: 537.0 [M+H] ⁺ .

Step 5: Compound C10: To a solution of Compound C8 (370 mg, 0.69 mmol), Compound C9 (203 mg, 2.1 mmol), bis(triphenylphosphine)palladium(II) chloride (48 mg, 0.069 mmol) and iodide copper (40 mg, 0.21 mmol) in DMF (5 ml) was added TEA (1 ml). The mixture was stirred at room temperature under N ₂ atmosphere for 16 hours. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (elution gradient: DCM/MeOH, 8/1, v/v). The pure fractions were evaporated to dryness to give compound C10 (140 mg, crude) as a yellow gum.

LCMS: Rt=1.39 min, MS Calculated: 506.2, MS Found: 506.9 [M+H]+.

Step 6: Compound A16: To a solution of compound C10 (140 mg, 0.28 mmol) and ammonium chloride (75 mg, 1.4 mmol) in EtOH (5 ml) and water (1 ml) was added iron powder (77 mg, 1.4 mmol). The mixture was stirred at 70°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (Gemini-C18 column, silica gel 5 μm, diameter 21 mm, length 150 mm), using weakly polar mixtures of water (containing 0. 1% FA) and MeCN (10-40%). Fractions containing the desired compound were evaporated to dryness to obtain compound A16 (50 mg, FA salt form) as an off-white solid. Total yield for 3 stages: 3.2%. 2H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.01 (t, J=7.4 Hz, 3H), 1.42 (s, 3H), 1.58-1.79 (m, 4H), 2.03 (d, J=11.5 Hz , 2H), 2.12 (t, J=11.4 Hz, 2H), 2.25 (s, 3H), 2.87-2.98 (m, 3H), 5.22 (s, 2H) , 6.08 (s, 2H), 7.34-7.42 (m, 3H), 7.54-7.55 (m, 2H), 7.77 (s, 1H), 7.88 (s , 1H). LCMS: Rt=1.16 min, MS Calculated: 476.2, MS Found: 476.8 [M+H] ⁺ .

Example 26 Preparation of compound A65

Step 1: Compound D3: To a solution of Compound D2 (7.6 g, 77 mmol) in THF (40 mL) was added ethyl magnesium bromide (30.8 mL, 92 mmol, 3.0 M in THF). The mixture was stirred at -5°C under N ₂ atmosphere for 0.5 hour. A solution of compound D1 (5 g, 51 mmol) in THF (15 ml) was then slowly added. The reaction mixture was stirred at -5°C under N ₂ atmosphere for 2 hours. The mixture was quenched with water (50 ml), extracted with EtOAc (100 ml x 2). The organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give D3 (5.5 g) as a brown oil, yield: 55.0%. LCMS: Rt=1.36 min, MS Calculated: 196.1, MS Found: 197.0 [M+H] ⁺ .

Step 2: Compound D4: A solution of Compound D3 (5.5 g, 28 mmol), potassium carbonate (3.87 g, 28 mmol) in methanol (100 ml) was stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water (50 ml), then extracted with EtOAc (100 ml x 2). The organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether/EtOAc, 3/1, v/v). The pure fractions were evaporated to dryness to give compound D4 (2 g) as a colorless oil, yield: 57.4%. LCMS: Rt=0.50 min, MS Calculated: 124.1, MS Found: 125.1 [M+H] ⁺ .

Step 3: Compound D6: To a solution of Compound D4 (2 g, 16 mmol), Compound D5 (3.7 g, 16 mmol) and copper iodide (0.92 g, 4.8 mmol) in 1,4-dioxane ( 15 ml) and TEA (5 ml), bis(triphenylphosphine)palladium(II) chloride (1.12 g, 1.6 mmol) was added. The mixture was stirred at 25°C under N ₂ atmosphere for 3 hours. The mixture was concentrated under reduced pressure and diluted with water (100 ml) and extracted with EA (100 ml x 3). The organic phase was washed with brine (100 ml), dried, concentrated and purified by silica gel chromatography (elution gradient: EA/PE, 1/5, v/v). The pure fractions were evaporated to dryness to give D6 (2.8 g) as a yellow solid, yield: 75.6%. ^1H NMR (400 MHz, CDCl ₃ ): 52.04-2.10 (m, 3H), 2.30-2.40 (m, 1H), 2.49-2.64 (m, 2H), 4.67 (s, 2H), 7.28-7.36 (m, 3H), 7.43 (s, 1H). LCMS: Rt=1.29 min, MS Calculated: 230.1, MS Found: 252.9 [M+Na] ⁺ .

Following procedures similar to those described in Example 3, compound D6 was converted to compound A65 as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm 1.65-1.78 (m, 2H), 1.85-2.09 (m, 7H), 2.18 (s, 3H), 2.21-2.47 (m, 3H), 2. 76-2.83 (m, 2H), 2.86-2.97 (m, 1H), 5.22 (s, 2H), 6.08 (s, 2H), 6.42 (s, 1H) , 7.31-7.47 (m, 3H), 7.72-7.80 (m, 2H), 7.76 (d, J=2.0 Hz, 1H), 7.87 (s, 1H ). LCMS: Rt=1.03 min, MS Calculated: 502.2, MS Found: 502.8 [M+H] ⁺ .

Example 27 Preparation of compound A32

Step 1: Compound E3: To a solution of Compound E1 (3 g, 20.5 mmol) in DMF (70 ml) was added NaH (1.23 g, 30.75 mmol), stirred for 0.5 hour at room temperature, then compound E2 (4.36 g, 22.6 mmol) was added and stirred for 16 hours at 50°C. The mixture was quenched with water (100 ml), extracted with EtOAc (100 ml x 3), the organic layers were washed with brine (300 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: DCM/MeOH, 10/1, v/v), the pure fractions were evaporated to dryness to give compound E3 (0.9 g) as a yellow oil, yield: 44.1%.

LCMS: Rt=1.09 min, MS Calculated: 243.0, 245.0, MS Found: 243.9, 245.9 [M+H] ⁺ .

Step 2: Compound E6: Compound E4 (1 g, 2.1 mmol), Compound 5 (587 mg, 2.31 mmol), bis(triphenylphosphine)palladium(II) chloride (140 mg, 0.2 mmol), potassium acetate (314 mg, 3.2 mmol), stirred for 4 hours at 90°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure, the residue was added to water (50 ml), extracted with EtOAc (50 ml x 3). The organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: DCM/MeOH, 3/1, v/v), pure the fractions were evaporated to dryness to obtain compound E6 (490 mg) as a yellow oil, yield: 53.0%. LCMS: Rt=1.69 min, MS Calculated: 440.18, MS Found: 462.9 [M+Na] ⁺ .

Compound E7: To a mixture of 1,4-dioxane (20 ml) and water (5 ml) was added compound E3 (220 mg, 0.9 mmol), compound E6 (400 mg, 0.9 mmol), XPhos Pd G2 (70 mg, 0.09 mmol), XPhos (43 mg, 0.09 mmol), potassium carbonate (230 mg, 1.8 mmol), stirred for 6 hours at 80°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure, the residue was added to water (30 ml), extracted with EtOAc (30 ml x 3), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (gradient elution : DCM/MeOH, 10/1, v/v), pure fractions were evaporated to dryness to give compound E7 (280 mg) as a yellow solid, yield: 55.5%. LCMS: Rt=1.50 min, MS Calculated: 559.3, MS Found: 560.2 [M+H] ⁺ .

Compound E7 was then converted to compound A32 following a reduction and deprotection procedure similar to that described herein. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.46 (s, 6H), 1.90-2.07 (m, 6H), 2.20 (s, 3H), 2.85 (d, J=5.8 Hz, 2H), 4.04 -4.10 (m, 1H), 5.18 (s, 2H), 5.47 (s, 1H), 5.65 (s, 2H), 7.33-7.42 (m, 3H), 7.52 (s, 2H), 7.75 (s, 1H), 7.79 (s, 1H), 8.10 (s, 1H). LCMS: Rt=1.19 min, MS Calculated: 445.2, MS Found: 445.9 [M+H] ⁺ .

Example 28 Preparation of compound A66

Compound F3: To a solution of Compound F1 (15 g, 66 mmol) in THF (50 ml) was added phenyltrimethylammonium tribromide (37.2 g, 99 mmol) at 0°C. The mixture was stirred at 0°C under N ₂ atmosphere for 1 hour. The mixture was quenched with water (50 ml) and extracted with EtOAc (200 ml x 2). The organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , concentrated to give a residue (7.5 g). The residue was dissolved in ethanol (200 ml), compound F2 (7.5 g, 99 mmol) was added. The mixture was stirred at 80°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified by chromatography on silica gel (elution gradient: EA/PE, 1/1, v/v). The pure fractions were evaporated to dryness to give compound F3 (10 g) as a pale yellow solid, yield: 53.5%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 1.48 (s, 9H), 1.53-1.60 (m, 2H), 1.90-1.96 (m, 2H), 2.77-2.85 (m, 3H), 4. 17 (s, 2H), 6.78 (s, 1H). LCMS: Rt=1.20 min, MS Calculated: 283.1, MS Found: 283.9 [M+H] ⁺ .

Compound F4: A solution of Compound F3 (10 g, 35 mmol), isoamyl nitrite (8.2 g, 7 mmol) and copper bromide (7.6 g, 53 mmol) in acetonitrile (200 ml) was stirred at room temperature under N ₂ atmosphere within 16 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (50 ml) and extracted with EtOAc (100 ml x 2). The organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: EA/PE, 1/5, v/v). The pure fractions were evaporated to dryness to give compound F4 (4.5 g) as a white solid, yield: 36.8%. LCMS: Rt=1.55 min, MS Calculated: 346.0, 348.0, MS Found: 368.7, 370.7 [M+Na] ⁺ .

Compound F5: A solution of Compound F4 (4.5 g, 13 mmol) in TFA (20 ml) and DCM (100 ml) was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to leave a residue, triturated with diethyl ether (200 ml), the resulting solid was filtered and dried in vacuo to give compound F5 (3.2 g) as a gray solid, yield: 68.3%. LCMS: Rt=0.64 min, MS Calculated: 246.0, 248.0, MS Found: 246.8, 248.8 [M+H] ⁺ .

Compound F6: A solution of Compound F5 (3 g, 8.3 mmol), triethylamine (2.5 g, 25 mmol) and 30% aqueous formaldehyde (8.3 g, 83 mmol) in methanol (100 ml) was stirred at room temperature temperature in N ₂ atmosphere for 1 hour. To this was added sodium cyanoborohydride (1 g, 16.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (50 ml) and extracted with EtOAc (100 ml x 2). The organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: EA/PE, 1/1, v/v). The pure fractions were evaporated to dryness to give compound F6 (1.6 g) as a white solid, yield: 74.1%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 1.71-1.82 (m, 2H), 1.95-2.10 (m, 4H), 2.32 (s, 3H), 2.76-2.84 (m, 1H), 2. 91-2.97 (m, 2H), 7.30 (d, J=0.8 Hz, 1H). LCMS: Rt=0.97 min, MS Calculated: 260.0, 262.0, MS Found: 260.8, 262.8 [M+H] ⁺ .

Compound F8: To a solution of compound F6 (890 mg, 3.41 mmol), compound 7 (1.8 g, 4.09 mmol) and potassium carbonate (722 mg, 6.82 mmol) in 1,4-dioxane (25 ml) and water (5 ml) was added bis(triphenylphosphine)palladium(II) chloride (477 mg, 0.68 mmol). The mixture was stirred at 90°C under N ₂ atmosphere for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue. The residue was diluted with water (100 ml) and extracted with EtOAc (100 ml x 3). The organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: EA/PE, 1/2, v/v). The pure fractions were evaporated to dryness to give compound F8 (500 mg) as a gray solid, yield: 25.5%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 1.52-1.60 (m, 4H), 1.61 (s, 3H), 1.65 (s, 3H), 1.94-2.06 (m, 6H), 2.18-2, 26 (m, 2H), 2.42 (s, 3H), 2.93-3.01 (m, 1H), 3.02-3.10 (m, 2H), 3.50-3.60 ( m, 1H), 3.96-4.06 (m, 1H), 5.12-5.17 (m, 1H), 5.31 (s, 2H), 7.36-7.40 (m, 1H), 7.42-7.45 (m, 2H), 7.52 (s, 1H), 7.71 (d, J=0.8 Hz, 1H), 8.14 (d, J=1 .6 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H). LCMS: Rt=1.34 min, MS Calculated: 576.2, MS Found: 576.8 [M+H] ⁺ .

Compound F8 was then converted to Compound A66 following reduction and deprotection procedures similar to those described herein. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm 1.47 (s, 6H), 1.61-1.73 (m, 2H), 1.92-1.99 (m, 2H), 2.07-2.15 (m, 2H), 2. 25 (s, 3H), 2.82-2.93 (m, 3H), 5.24 (s, 2H), 5.45 (s, 1H), 6.34 (s, 2H), 7.34 (d, J=7.7 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.51-7 .56 (m, 3H), 8.06 (d, J=1.6 Hz, 1H). LCMS: Rt=1.02 min, MS Calculated: 462.2, MS Found: 462.8 [M+H] ⁺ .

Example 29 Preparation of compound A62

Compound G3: To a solution of compound G1 (3 g, 16.8 mmol), compound G2 (4.5 g, 20.2 mmol), tetrakis(triphenylphosphine) palladium (0) (1.96 g, 1.7 mmol) Potassium acetate (3.3 g, 33.6 mmol) was added to 1,4-dioxane (120 ml) and the reaction mixture was stirred at 100° C. for 16 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 ml), extracted with EtOAc (100 ml x 3). The organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: DCM/MeOH, 8/1, v/v). The pure fractions were evaporated to dryness to give compound G3 (1.6 g) as a brown oil, yield: 40.8%. LCMS: Rt=0.64 min, MS Calculated: 194.1, MS Found: 194.9 [M+H] ⁺ .

Compound G4: To a solution of compound G3 (1.6 g, 8.2 mmol) in methanol (60 ml) was added 10% Pd/C (2 g) and the mixture was stirred at 60°C for 48 hours under a hydrogen atmosphere (0 .4 MPa). The reaction mixture was filtered and the filtrate concentrated in vacuo to give the desired product (800 mg, crude) as a yellow oil, without further purification for the next step. LCMS: Rt=0.83 min, MS Calculated: 196.1, MS Found: 197.1 [M+H] ⁺ .

Compound G5: To a solution of Compound G4 (700 mg, 3.57 mmol, crude) in tetrahydrofuran (30 ml) was added pyridinium tribromide (1.26 g, 3.93 mmol), stirred for 4 hours at room temperature. The reaction mixture was diluted with water (50 ml), extracted with EtOAc (50 ml x 3). The organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: DCM/MeOH, 10/1, v/v). The pure fractions were evaporated to dryness to give compound G5 (460 mg) as a yellow solid, yield: 47%. LCMS: Rt=1.13 min, MS Calculated: 274.0, 276.0, MS Found: 274.9, 276.9 [M+H] ⁺ .

Compound G7: To a mixture of compound G5 (0.4 g, 1.46 mmol), compound G6 (704 mg, 1.6 mmol), potassium carbonate (300 mg, 2.2 mmol) in 1,4-dioxane (20 ml) bis(triphenylphosphine)palladium(II) chloride (105 mg, 0.15 mmol) was added and the mixture was stirred for 2 hours at 90°C under N ₂ atmosphere. The mixture was cooled to room temperature and diluted with water (30 ml), extracted with EtOAc (30 ml x 3). The organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: DCM/MeOH, 5/1, v/v). The pure fractions were evaporated to dryness to give compound G7 (160 mg) as a pale yellow solid, yield: 18.5%. LCMS: Rt=1.44 min, MS Calculated: 590.3, MS Found: 590.8 [M+H] ⁺ .

Compound G7 was then converted to Compound A62 following a reduction and deprotection procedure similar to that described herein. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.47 (s, 6H), 1.66-1.74 (m, 2H), 1.98-2.08 (m, 4H), 2.22 (s, 3H), 2.25 (s, 3H), 2.84-2.90 (m, 3H), 5.20 (s, 2H), 6.06 (s, 2H), 7.10 (s, 1H), 7.33-7.39 (m, 2H), 7.51 (br s, 2H), 7.59 (s, 1H). LCMS: Rt=1.14 min, MS Calculated: 476.2, MS Found: 477.2 [M+H] ⁺ .

Example 30 Preparation of compound A28

Compound H2: A solution of Compound H1 (25 g, 143.6 mmol) in MeOH (70 ml) was stirred at room temperature for 24 hours. The solvent was carefully removed under reduced pressure at room temperature and the residue was distilled off (50 mbar, 65° C.) to obtain compound H2 (10.3 g) as a clear colorless liquid, yield: 70.3%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 0.89-0.96 (m, 4H), 1.21 (t, J=7.2 Hz, 3H), 3.76 (q, J=7.1 Hz, 2H), 4.12 (s , 1H).

Compound H4: MeMgBr in ether (3.0 M, 21 ml, 63.2 mmol) at 0°C was diluted with THF (40 ml). A solution of compound H2 (5 g, 49.0 mmol) in THF (20 ml) was added dropwise through the cannula, followed by a wash with THF (10 ml). The reaction mixture was stirred at 0°C under N ₂ atmosphere for 1 hour. In a separate flask, a solution of compound H3 (6.1 g, 56.8 mmol) in THF (40 ml) at -78°C was treated with n-BuLi in hexane (2.4 M, 22 ml, 54.9 mmol). The mixture was stirred at -78°C for 10 minutes, then added dropwise through a cannula over 10 minutes to the prepared suspension of 1-ethoxycyclopropanolate magnesium bromide. The resulting clear, colorless solution was stirred at 40°C for 16 hours, then poured into saturated aqueous NH ₄ Cl (100 ml). The phases were separated and the aqueous layer was extracted with ether (100 ml x 3). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by chromatography on silica gel (elution gradient: petroleum ether/EtOAc, 10/1, v/v). The pure fractions were evaporated to dryness to obtain compound H4 (5 g) as a clear, colorless liquid, yield: 66.1%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 0.16 (s, 9H), 0.96-1.04 (m, 2H), 1.04-1.12 (m, 2H), 2.91 (s, 1H).

Compound H5: To a solution of Compound H4 (2.0 g, 13.0 mmol) and PPTS (35 mg) in THF (25 ml) was added 3,4-dihydro-2H-pyran (1.4 g, 16.5 mmol ). The mixture was stirred at room temperature in an N ₂ atmosphere for 16 hours. The mixture was concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: petroleum ether/EtOAc, 5/1, v/v). The pure fractions were evaporated to dryness to give compound H5 (2.5 g) as a yellow oil, yield: 80.8%. ^1H NMR (400 MHz, CDCl ₃ ): δ ppm 0.16 (s, 9H), 0.94-1.12 (m, 3H), 1.21-1.31 (m, 1H) , 1.47-1.65 (m, 4H), 1.68-1.86 (m, 2H), 3.49-3.61 (m, 1H), 3.89 (t, J=9, 9 Hz, 1H).

Compound H6: To a solution of Compound H5 (2.5 g, 10.5 mmol) in MeOH (20 ml) was added K ₂ CO ₃ (146 mg, 1.05 mmol). The mixture was stirred at room temperature under N ₂ atmosphere for 3 hours. The mixture was concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: petroleum ether/EtOAc, 5/1, v/v). The pure fractions were evaporated to dryness to give compound H6 (1.5 g) as a yellow oil, yield: 85.7%. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 0.99-1.10 (m, 3H), 1.25-1.32 (m, 1H), 1.45-1.67 (m, 4H), 1.71-1.82 (m, 2H ), 2.39 (s, 1H), 3.54-3.58 (m, 1H), 3.86-3.91 (m, 1H), 5.00-5.04 (m, 1H).

Compound H8: To a solution of compound H6 (1.4 g, 8.4 mmol), compound H7 (1.9 g, 8.4 mmol), bis(triphenylphosphine) palladium(II) chloride (590 mg, 0.84 mmol ) and copper iodide (480 mg, 2.52 mmol) in 1,4-dioxane (20 ml) TEA (4 ml) was added. The mixture was stirred at room temperature under N ₂ atmosphere for 16 hours. The mixture was concentrated under reduced pressure to give the crude product, which was purified by chromatography on silica gel (elution gradient: petroleum ether/EtOAc, 8/1, v/v). The pure fractions were evaporated to dryness to give H8 (1.9 g) as a yellow oil, yield: 83.3%. LCMS: Rt=1.59 min, MS Calculated: 272.1, MS Found: 294.9 [M+Na] ⁺ .

Compound H8 was then converted to compound A28 through a series of conversions according to procedures similar to those described herein. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 0.96 (d, J=5.9 Hz, 4H), 1.64-1.75 (m, 2H), 1.97-2.05 (m, 4H), 2.18 (s, 3H) , 2.79-2.92 (m, 3H), 5.18 (s, 2H), 6.05 (s, 2H), 6.29 (s, 1H), 7.30-7.39 (m , 3H), 7.48-7.51 (m, 2H), 7.73 (s, 1H), 7.84 (s, 1H). LCMS: Rt=1.13 min, MS Calculated: 460.2, MS Found: 460.8 [M+H] ⁺ .

Example 31 Preparation of compound A68

Compound 12: To a solution of compound I1 (20 g, 222 mmol) in pyridine (200 ml) was added tosyl chloride (106 g, 555 mmol) at 0°C. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure to give the crude product, which was purified by chromatography on silica gel (elution gradient: petroleum ether/EtOAc, 3/1, v/v). The pure fractions were evaporated to dryness to give compound 12 (41 g) as a yellow oil, yield: 46.4%. ^1H NMR

(400 MHz, CDCl ₃ ): δ ppm 0.93 (d, J=6.7 Hz, 3H), 1.98-2.20 (m, 1H), 2.33 (s, 6H), 3.92 (d, J=4.0 Hz , 4H), 7.37 (d, J=4.8 Hz, 4H), 7.77 (d, J=4.6 Hz, 4H). LCMS: Rt=1.64 min, MS Calculated: 398.1, MS Found: 398.7 [M+H] ⁺ .

Compound 14: To a solution of compound 13 (20 g, 161.3 mmol) in THF (150 ml) was added n-BuLi (67.2 ml, 161.3 mmol, 2.4 Μ in hexane) dropwise at -78° C in the atmosphere N ₂ . The mixture was stirred at -30°C for 2 hours. Compound 12 (32.1 g, 80.6 mmol) in THF (150 mL) was then added dropwise at -78°C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with saturated ammonium chloride (200 ml), extracted with EtOAc (200 ml x 3). The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether/EtOAc, 5/1, v/v). The pure fractions were evaporated to dryness to give compound 14 (10 g) as a yellow oil, yield: 69.7%.

Compound 15: To a solution of compound 14 (10 g, 56.2 mmol) in DCM (30 ml) was added concentrated HCl (30 ml). The mixture was stirred at room temperature for 6 hours. The mixture was diluted with DCM (30 ml), the organic layer was separated and used in the next step without any further purification.

Compound 17: Ethynylmagnesium bromide (321 ml, 160.5 mmol, 0.5 Μ in THF) was placed in a 500 ml round bottom flask and a solution of compound 15 in DCM (60 ml) was added dropwise at -5°C. The mixture was stirred at -5°C for 3 hours. The mixture was concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: petroleum ether/EtOAc, 3/1, v/v). The pure fractions were evaporated to dryness to give compound 17 (640 mg) as a yellow oil. Total yield for 2 stages: 10.3%. ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 1.12 (d, J=6.6 Hz, 3H), 1.82-1.90 (m, 2H), 2.08-2.25 (m, 2H), 2.50 (s, 1H) , 2.57-2.64 (m, 2H).

Compound 19: To a solution of compound 17 (640 mg, 5.8 mmol) and PPTS (70 mg) in THF (20 ml) was added 3,4-dihydro-2H-pyran (978 mg, 11.6 mmol). The mixture was stirred at room temperature under N ₂ atmosphere for 16 hours. The mixture was diluted with DCM (30 ml), washed with saturated aqueous NaHCO ₃ (30 ml), water (30 ml) and brine (30 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give compound 19 (900 mg, crude) as a yellow oil. The product was used directly without any further purification.

Compound I11: To a solution of compound 9 (900 mg, 4.6 mmol), compound 110 (1.1 g, 4.6 mmol), bis(triphenylphosphine)palladium(II) chloride (323 mg, 0.46 mmol) and copper iodide (263 mg, 1.38 mmol) in 1,4-dioxane (15 ml) was added TEA (3 ml). The mixture was stirred at room temperature under N ₂ atmosphere for 6 hours. The mixture was concentrated under reduced pressure to give the crude product, which was purified by chromatography on silica gel (elution gradient: petroleum ether/EtOAc, 8/1, v/v). The pure fractions were evaporated to dryness to give compound I11 (1.3 g) as a yellow oil, yield: 93.5%. LCMS: Rt=1.71 min, MS Calculated: 300.2, MS Found: 323.1 [M+Na] ⁺ .

Compound I11 was then converted to compound A68 through a series of conversions according to procedures similar to those described herein. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.09 (d, J=6.6 Hz, 3H), 1.66-1.86 (m, 4H), 1.96-2.04 (m, 4H), 2.11-2.17 ( m, 1H), 2.18 (s, 3H), 2.53-2.58 (m, 2H), 2.80-2.92 (m, 3H), 5.23 (s, 2H), 5 .85 (s, 1H), 6.08 (s, 2H), 7.35-7.43 (m, 3H), 7.53-7.58 (m, 2H), 7.77 (d, J =1.9 Hz, 1H), 7.88 (s, 1H). LCMS: Rt=1.09 min, MS Calculated: 488.2, MS Found: 488.8 [M+H] ⁺ .

Example 32 Preparation of compound A74

Compound J2: Ethynylmagnesium bromide (0.5 Μ in THF, 20 mmol, 40 ml) was cooled to 0° C. under nitrogen atmosphere. Compound J1 (1.5 g, 20 mmol) was then added slowly and the reaction mixture was stirred at 0° C. for 1 hour. Once complete, the reaction was quenched with aqueous NH ₄ Cl and extracted with Et ₂ O (20 ml x 2). The organic layer was combined, dried over sodium sulfate and concentrated to give J2 (2.4 g, crude) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.51 (d, J=2.2 Hz, 3H), 2.51 (s, 1H), 4.28 (dd, J=48.0, 9 .0 Hz, 1H), 4.40 (dd, J=48.0, 9.0 Hz, 1H).

Compound J4: Compound J2 (2.4 g, 24 mmol) and Compound J3 (3.6 g, 15 mmol) were dissolved in 10 ml of 1,4-dioxane and 2 ml of triethylamine. Dichlorobis(triphenylphosphine) palladium(II) (2.5 g, 3.6 mmol), copper iodide (1.4 g, 7.2 mmol) were then added. The reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. Once complete, the reaction mixture was purified on a silica gel column (DCM/MeOH, 20/1, v/v) to give J4 as an orange oil, 1.7 g, 40% yield in two steps. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.46 (d, J=2.0 Hz, 3H), 4.24-4.40 (m, 2H), 4.49 (d, J =5.4 Hz, 2H), 5.26 (t, J=5.4 Hz, 1H), 5.91 (s, 1H), 7.25-7.38 (m, 4H). LCMS: Rt=1.30 min, MS Calculated: 208.1, MS Found: 190.9 [M-H ₂ O+H] ⁺ .

Compound J5: Compound J4 (1.7 g, 8.2 mmol) was dissolved in 20 ml of DCM and triethylamine (2.5 g, 25 mmol). Methanesulfonyl chloride (1.5 g, 13 mmol) was then added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction was monitored by TLC, quenched with 20 ml aqueous NaHCO ₃ solution and extracted with ethyl acetate (15 ml x 2). The organic layers were combined, dried over sodium sulfate and concentrated to give J5 as a yellow oil, 2.2 g (crude).

Compound J7: Compound J5 (2.2 g, crude) and potassium carbonate (1.9 g, 14 mmol) were dissolved in 20 ml of N,N-dimethylformamide. Compound J6 (1.8 g, 8.4 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. Once complete, the reaction mixture was purified on a silica gel column (DCM/MeOH, 100/1, v/v) to give J7 as an orange oil, 1.3 g, 39% yield in two steps. LCMS: Rt=1.62 min, MS Calculated: 408.0, 410.0, MS Found: 430.6, 432.7 [M+Na] ⁺ .

Compound J7 was then converted to compound A74 through a series of conversions according to procedures similar to those described herein. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.46 (d, J=2.0 Hz, 3H), 1.65-1.77 (m, 2H), 1.96-2.04 (m, 4H), 2.18 (s, 3H), 2.79-2.94 (m, 3H), 4.32 (dd, J=48.0, 9.0 Hz, 1H), 4, 38 (dd, J=48.0, 9.0 Hz, 1H), 5.22 (s, 2H), 5.94 (s, 1H), 6.08 (s, 2H), 7.33-7 .44 (m, 3H), 7.54-7.58 (m, 2H), 7.76 (d, J=2.0 Hz, 1H), 7.87 (s, 1H). LCMS: Rt=1.13 min, MS Calculated: 480.2, MS Found: 480.8 [M+H] ⁺ .

Example 33 Preparation of compound A77

Compound K2: To a solution of Compound K1 (3.8 g, 13.67 mmol) in tetrahydrofuran (20 ml) and water (20 ml) was added lithium hydroxide (1.7 g, 41.00 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was adjusted to pH=2 with a solution of hydrochloric acid (2N), extracted with ethyl acetate (50 ml × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give K2 (3.6 g) as a white solid, yield: 100%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 6.82 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8, 2.4 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H ).

Compound K4: To a solution of Compound K2 (2 g, 7.58 mmol) in acetonitrile (20 ml) was added Compound K3 (3 g, 18.94 mmol) and aqueous potassium hydroxide (25%, 34.09 mmol). The mixture was stirred at 50°C for 5 hours. The mixture was diluted with water (20 ml) and adjusted to pH=2 with hydrochloric acid (2N), extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: dichloromethane/methanol, 10/1, v/v) to give compound K4 (3.2 g, crude ). LCMS: Rt=1.49 min, MS Calculated: 313.9, MS Found: 312.6 [M-H] ^- .

Compound K5: To a solution of compound K4 (3.2 g, crude) in anhydrous tetrahydrofuran (20 ml) was added BH ₃ -THF (1 M in THF, 23 ml, 23 mmol) at 0°C.

The mixture was stirred at 70°C under N ₂ atmosphere for 6 hours. The mixture was quenched with MeOH (10 mL) and concentrated in vacuo to give K5 (2.9 g, crude). The product was used directly without any further purification.

Compound K5 was then used as an intermediate for the synthesis of compound A77 using similar procedures to those described herein. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.46 (s, 6H), 1.68-1.77 (m, 2H), 2.01-2.11 (m, 4H), 2.23 (s, 3H), 2.86-2, 97 (m, 3H), 5.18 (s, 2H), 6.07 (s, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.36 (d, J=1 .6 Hz, 1H), 7.48 (dd, J=8.4, 2.0 Hz, 1H), 7.33 (t, J=73.6 Hz, 1H), 7.67 (d, J =2.0 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.89 (s, 1H). LCMS: Rt=1.25 min, MS Calculated: 528.2, MS Found: 528.8 [M+H] ⁺ .

Example 34 Preparation of compound A78

Compound L3: To a solution of compound L1 (5.0 g, 22.7 mmol), compound L2 (4.6 g, 6.8 mmol), bis(triphenylphosphine) palladium(II) chloride (3.16 g, 4. 5 mmol) and copper iodide (1.3 g, 6.8 mmol) in 1,4-dioxane (100 ml), triethylamine (20 ml) was added and the mixture was stirred at room temperature for 16 hours under N ₂ atmosphere. The mixture was added to water (150 ml), extracted with EtOAc (150 ml x 3). The organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether/ethyl acetate, 6/1, v/v). The pure fractions were evaporated to dryness to give compound L3 (6.7 g) as a brown solid, yield: 96.5%.

Compound L5: A mixture of Compound L4 (2.5 g, 12.5 mmol) in thionyl chloride (40 ml) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the crude product, which was added to hexane (30 ml), stirred and filtered to give compound L5 (2.6 g) as a yellow solid, yield: 90.2%.

Compound L6: To a solution of compound L3 (2.4 g, 9.1 mmol) in THF (120 ml) was added sodium hydride (1.1 g, 27.3 mmol) at 0° C. and the reaction mixture was stirred at room temperature under for 30 minutes and then compound L5 (2.6 g, 9.1 mmol) was added and the mixture was stirred at 50°C for 6 hours. The mixture was quenched with water (100 ml), extracted with ethyl acetate (100 ml x 3), the organic layers were washed with brine (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography ( elution gradient: petroleum ether/ethyl acetate, 3/1, v/v). The pure fractions were evaporated to dryness to give compound L6 (630 mg) as a yellow solid, yield: 15.6%.

LCMS: Rt=1.84 min, MS Calculated: 444.1, 446.1, MS Found: 466.7, 468.7 [M+Na] ⁺ .

Compound L7: To a solution of Compound L6 (400 mg, 0.9 mmol), di-tert-butyl dicarbonate (490 mg, 2.25 mmol), ethyldiisopropylamine (290 mg, 2.25 mmol) in DCM (20 ml) was added 4 -dimethylaminopyridine (110 mg, 0.9 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was added to water (20 ml), extracted with DCM (20 ml x 3), the organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to obtain a crude product, which was purified by chromatography on silica gel (elution gradient: petroleum ether/ethyl acetate, 5/1, v/v). The pure fractions were evaporated to dryness to give compound L7 (510 mg) as a yellow oil, yield: 87.9%.

LCMS: Rt=2.24 min, MS Calculated: 644.2, 646.2, MS Found: 666.6, 668.6 [M+Na] ⁺ .

Compound L9: To a solution of Compound L7 (500 mg, 0.78 mmol), Compound L8 (870 mg, 1.56 mmol), bis(triphenylphosphine)palladium(II) chloride (110 mg, 0.16 mmol), TBAF ( 1M in THF, 0.78 ml, 0.78 mmol) in 1,4-dioxane (20 ml), triethylamine (240 mg, 2.4 mmol) was added and the reaction mixture was stirred at 80°C for 3 hours under nitrogen atmosphere . The mixture was concentrated under reduced pressure, the residue was added to water (30 ml), extracted with ethyl acetate (30 ml × 3). The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether/ethyl acetate, 3/1, v/v). The pure fractions were evaporated to dryness to obtain compound L9 (440 mg) as a yellow gum, yield: 66%.

Compound A78: To a solution of compound L9 (430 mg, 0.52 mmol) in THF (10 ml) was added a solution of HCl (2 ml, 4N in 1,4-dioxane) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, adjusted to pH=9 with 1N sodium hydroxide solution, extracted with ethyl acetate (20 ml x 3), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (elution gradient: DCM/MeOH, 2/1, v/v). Fractions containing the desired compound were evaporated to dryness to obtain compound A78 (58 mg) as a white solid, yield: 23.0%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 1.46 (s, 6H), 1.89-1.99 (m, 2H), 2.17-2.20 (m, 2H), 2.97-3.04 (m, 2H), 3. 30-3.31 (m, 3H), 4.99 (s, 2H), 5.48 (s, 1H), 6.32 (s, 2H), 6.99 (d, J=7.6 Hz , 1H), 7.06-7.09 (m, 2H), 7.30 (t, J=7.6 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7 .93 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 9.01 (lat s, 2H).

LCMS: Rt=1.17 min, MS Calculated: 448.2, MS Found: 448.8 [M+H] ⁺ .

Example 35 Preparation of compound A82

Compound M2: To a solution of compound M1 (5 g, 17.18 mmol) in anhydrous tetrahydrofuran (20 ml) was added BH ₃ -THF (103 ml, 103 mmol, 1 M in THF) at 0°C. The mixture was stirred at 70°C for 16 hours. The mixture was quenched with MeOH (30 mL) and concentrated in vacuo to give M2 (6.6 g, crude) as a yellow oil. The product was used directly without any further purification. LCMS: Rt=0.85 min, MS Calculated: 263.0, MS Found: 263.8[M+H] ⁺ .

Compound M3: To a solution of Compound M2 (6.6 g, crude) in MeOH (100 ml) was added formaldehyde (7 g, 85.90 mmol, 30% aqueous solution) and acetic acid (2 ml). The mixture was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (7.3 g, 34.36 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to obtain a residue. The residue was diluted with water (50 ml), extracted with dichloromethane (100 ml × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (elution gradient: dichloromethane/methanol, 10/1, v/v) to give compound M3 (3.8 g) as a yellow oil. Overall yield for 2 stages: 74%. ^1H NMR (400 MHz, CDCl ₃ ): δ ppm 2.24 (s, 6H), 3.38 (s, 2H), 4.61 (s, 2H), 7.29 (s, 1H ), 7.57 (s, 1H), 7.60-7.62 (m, 1H). LCMS: Rt=0.89 min, MS Calculated: 291.0, MS Found: 291.8 [M+H] ⁺ .

Compound M5: To a solution of compound M3 (3.7 g, 6.87 mmol), compound M4 (3.2 g, 10.3 mmol), bis(triphenylphosphine) palladium(II) chloride (692 mg, 0.69 mmol ) and copper iodide (727 mg, 2.06 mmol) in 1,4-dioxane (40 ml) was added triethylamine (8 ml). The mixture was stirred at room temperature under N ₂ atmosphere for 16 hours. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (elution gradient: petroleum dichloromethane/methanol, 10/1, v/v) to give compound M5 (2.3 g) as a brown oil. LCMS: Rt=1.10 min, MS Calculated: 331.2, MS Found: 331.9 [M+H] ⁺ .

Compound M7: To a solution of Compound M5 (1 g, 3.02 mmol), Compound M6 (793 mg, 3.62 mmol) and triphenylphosphine (950 mg, 3.62 mmol) in tetrahydrofuran (50 ml) was added diisopropyl azodicarboxylate (732 mg , 3.62 mmol) at 0°C. The mixture was stirred at 0°C under N ₂ atmosphere for 16 hours. The mixture was quenched with water (30 ml), extracted with ethyl acetate (50 ml × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: dichloromethane/methanol, 10/1, v/v) with yielding compound 7 (1.1 g) as a yellow oil. LCMS: Rt=1.29 min, MS Calculated: 531.1, 533.1, MS Found: 531.7, 533.7 [M+H] ⁺ .

Compound M9: To a solution of compound M7 (1 g, 1.88 mmol) in 1,4-dioxane (20 ml) was added bis(pinacolato)diboron (954 mg, 3.76 mmol), potassium acetate (553 mg, 5. 63 mmol) and bis(triphenylphosphine) palladium(II) chloride (264 mg, 0.38 mmol). The mixture was stirred at 80°C under N ₂ atmosphere for 12 hours. The mixture was cooled to room temperature and concentrated in vacuo to give the crude product (2.1 g). The product was used directly without any further purification. LCMS: Rt=1.34 min, MS Calculated: 497.2, MS Found: 497.8 [M+H] ⁺ .

Compound M9 was then converted to compound A82 using similar procedures to those described herein. ^1H NMR (400 MHz, DMSO-d ₆ : δ ppm 1.47 (s, 6H), 1.68-1.78 (m, 2H), 1.96-1.99 (m, 2H ), 2.29 (s, 6Η), 3.20-3.28 (m, 1Η), 3.44-3.50 (μ, 2Η), 3.64 (lat. s, 2Η), 3, 91-3.95 (m, 2H), 5.23 (s, 2H), 5.48 (s, 1H), 6.11 (s, 2H), 7.34-7.35 (m, 2H) , 7.47 (s, 1H), 7.52 (s, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.89 (s, 1H).LCMS: Rt=1, 06 min, MS Calculated: 506.2, MS Found: 506.8 [M+H] ⁺ .

Following the general synthetic schemes described herein and similar procedures described above in Examples 1-35, the following compounds were prepared and characterized:

Compound N3: To a solution of compound N1 (1.0 g, 3.2 mmol) in 1,4-dioxane (25 ml) was added compound N ₂ (1.22 g, 3.9 mmol), potassium acetate (470 mg, 4.8 mmol) and a complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride and dichloromethane (234 mg, 0.32 mmol). The mixture was stirred at 80°C under N ₂ atmosphere for 4 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo to give N3 (920 mg, crude) as a brown gum, which was used in the next step without further purification. LCMS: Rt=1.14 min, MS Calculated: 275.1, MS Found: 276.1 [M+H] ⁺ .

Compound N6: To a solution of Compound N4 (5 g, 29.2 mmol), TEA (4.42 g, 43.8 mmol) in toluene (40 ml) was added Compound N5 (7.24 g, 58.4 mmol). The mixture was stirred at 110°C under N ₂ atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (elution gradient: PE/EA, 1/1, v/v). The pure fractions were evaporated to dryness to give N6 (4.1 g) as a yellow oil, yield: 65.0%. LCMS: Rt=1.30 min, MS Calculated: 215.0, 217.0, MS Found: 215.8, 217.8 [M+H] ⁺ .

Compound N8: To a solution of Compound N6 (3 g, 13.9 mmol) in THF (60 ml) was added NaH (1.1 g, 27.8 mmol) at 0°C. The mixture was stirred at 0°C for 10 minutes. Compound N7 (3.4 g, 27.8 mmol) was added to the mixture. The resulting mixture was stirred at room temperature under N ₂ atmosphere for 3 hours. The mixture was quenched with water (50 ml), extracted with ethyl acetate (50 ml × 3). The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether/EtOAc, 1/1, v/v). The pure fractions were evaporated to dryness to give N8 (1.8 g) as a yellow solid, yield: 50.3%. LCMS: Rt=1.27 min, MS Calculated: 255.0, 257.0, MS Found: 255.8, 257.8 [M+H] ⁺ .

Compound N9: To a solution of Compound N8 (630 mg, 2.5 mmol) in DME (25 ml) and water (5 ml) was added Compound N3 (750 mg, 2.73 mmol), bis(triphenylphosphine) palladium(II) chloride (175 mg, 0.25 mmol) and sodium carbonate (400 mg, 3.75 mmol). The mixture was stirred at 80°C under N ₂ atmosphere for 2 hours. The mixture was cooled to room temperature and diluted with water (30 ml), extracted with dichloromethane (30 ml × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: dichloromethane/methane, 8/1, v/v) to give compound N9 (370 mg) as a yellow gum , yield: 36.4%. LCMS: Rt=1.11 min, MS Calculated: 406.1, MS Found: 406.8 [M+H] ⁺ .

Compound A85: To a solution of compound N9 (370 mg, 0.91 mmol) in ethanol (15 ml) and water (5 ml) was added ammonium chloride (243 mg, 4.55 mmol) and iron powder (255 mg, 4.55 mmol). The mixture was stirred at 60°C for 2 hours. The mixture was filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (elution gradient: dichloromethane/methane, 8/1, v/v) to give compound A85 (90 mg) as a white solid, yield: 26.3%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm. 3.80 (t, J=4.8 Hz, 2H), 4.01 (t, J=4.8 Hz, 2H), 4.23 (s, 2H), 5.33 (s, 2H), 6.10 (s, 2H), 7.28-7.30 (m, 1H), 7.43-7.46 (m, 2H), 7.52-7.54 (m, 1H), 7. 58-7.62 (m, 3H), 7.93 (s, 1H), 8.60-8.61 (m, 2H). LCMS: Rt=0.90 min, MS Calculated: 376.2, MS Found: 376.8 [M+H] ⁺ .

Example 37 ADP-Glo HPK1 Enzyme Assay

The buffer used in the enzyme assay contains 5 mM MOPS (pH=7.2), 2.5 mM β-glycerol phosphate, 0.4 mM EDTA, 1 mM EGTA, 0.05 mM DTT, 5 mM MgCl ₂ . The compound was dissolved in 100% DMSO at a concentration of 10 mM. The initial test concentration was 5 μM, and ten data points were diluted by a threefold gradient and each point was remeasured twice. HPK1 protein was purchased from Thermo (cat. no. PV6355) and diluted to 2X the stock solution at a concentration of 10 nM (final enzyme assay concentration was 5 nM). 2.5 μl of 2X HPK1 protein was added to each well of the plate containing the test compound, centrifuged at 1000 rpm for 30 seconds and then incubated at 25°C for 15 minutes. MBP protein was purchased from Millipore (cat. no. 13-110) and ATP was purchased from Sigma (cat. no. A7699-5G) and both were formulated in 2X working solutions at concentrations of 4 μM and 80 μM. Add 2.5 μl of a mixture of 2X MBR and ATP, centrifuge at 1000 rpm for 30 seconds, then incubate at 25°C for 90 minutes. 5 μl of ADP-GloTM (Promega, cat. no. V9102) was then added to the assay plate and incubated at 1000 rpm for 30 minutes at 25°C for 60 minutes. Finally, 10 μl of kinase assay reagent (Promega, cat. no. V9102) was added to the assay plate, centrifuged at 1000 rpm for 30 seconds at 25°C for 60 minutes, and fluorescence intensity was determined. Based on the results, the IC ₅₀ of the compound was calculated. The resulting IC ₅₀ values are shown in the following table:

Example 38. Jurkat E6-1 pSLP-76(Ser376) HTRF experiment

Jurkat E6-1 cells were purchased from ATCC (cat. no. TIB-152TM) and cultured overnight with RPMI 1640 containing 0.5% FBS, after which 20 μl (107 cells/ml) of cells were added to experimental plates. The test compounds were then diluted by a three-fold gradient into 10 different concentrations, 5 μl of each was added to the experimental plate and incubated for 4 hours in an incubator at 37°C containing 5% CO ₂ . Then 5 μl of 6X anti-human CD3 antibody (Biolegend, cat. no. 300432) was added and incubated for 20 minutes in a 37°C incubator containing 5% CO ₂ . Finally, Phospho-SLP-76 and SLP-76 results were determined using the Cisbio Phospho-SLP-76 and SLP-76 HTRF assay kits (comprising 63ADK076PEH and 63ADK077PEH, respectively). Based on the results, the IC ₅₀ of the compound was calculated. The resulting IC ₅₀ values are shown in the following table:

Example 39 Screening for Candidate Compounds That Enhance CAR-T Cell Cytotoxicity

To evaluate the ability of various compounds to enhance the cytotoxicity of CAR-T cells, the following protocol was followed: Incubate CAR-T cells with 100 nM compounds for 48 hours in a humidified incubator at 37°C and 5% CO ₂ . Transfer the compound and CAR-T combinations to a plate pre-coated with tumor cells and incubate for 12 hours at 3°C and 5% CO ₂ . Lyse the tumor cells by adding 10× lysis solution and incubate for 30 minutes at 37°C. Centrifuge the plate at 500 rpm for 3 minutes. Transfer 50 µl of the supernatant from all wells into a fresh 9b-well plate with a flat bottom. Add 50 μl of substrate mixture to each well and incubate for 30 minutes at 37°C. Protect the plate from light and incubate for 30 minutes at 37°C. Add 50 µl of stop solution to each well. Avoid bubble formation and record absorbance at 490 nm or 492 nm within 1 hour after addition of stop solution. Calculate % cytotoxicity using the formula (Experimental - Effector Spontaneous - Target Spontaneous) / (Target Maximum - Target Spontaneous). The results are shown in Fig. 1.

Finally, it should be noted that the embodiments described above are merely illustrative of the technical solutions of the present invention and are not intended to be limiting. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art will appreciate that the technical solutions described in the above embodiments may be modified, or some or all of the technical features may be equivalently replaced; and modifications or substitutions do not deviate from the technical solutions of the embodiments of the present invention.

Claims (48)

1. Compound of formula Y or a pharmaceutically acceptable salt thereof Formula Y Where: A represents CH; Ar is thiazolyl, pyrazolyl or pyridinyl; wherein the thiazolyl, pyrazolyl or pyridinyl is substituted with one or two substituents independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, 5-7 membered heterocyclyl containing 1-2 ring heteroatoms independently selected from O and N, -OR ¹⁰⁰ , and -SR ¹⁰⁷ , wherein each R ¹⁰⁰ is independently selected from phenyl; each R ¹⁰⁷ is independently selected from C _1-6 alkyl; wherein each heterocyclyl is optionally substituted with one or more substituents, each independently selected from 1) C _1-7 alkyl, optionally substituted with 1-3 substituents, each independently selected from halogen, and 10) piperazinyl; L represents -O-(C _1-4 alkylene); And ring B is selected from ; n has the value 0 or 1, each R ^A is independently selected from halogen, optionally substituted C _1-6 alkyl, wherein the substituent is selected from F, -NH ₂ , -N(CH ₃ ) ₂ , optionally substituted C _1-6 alkoxy, wherein the substituent is selected from F, R^B and R^C each independently selected from optionally substituted C_1-6 alkyl, where the substituent is selected from F, CF₃; unsubstituted C_2-6 alkenyl, or R^B And R^C together form an optionally substituted C_3-6 cycloalkyl, where the substituent is selected from oxo, -CH₃, where the triple bond in Formula Y is in the meta position relative to the linker L. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the thiazolyl, pyrazolyl or pyridinyl is substituted with one substituent which is an optionally substituted 5- or 6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N . 3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the thiazolyl, pyrazolyl or pyridinyl is substituted with one substituent which is a 5- or 6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N, optionally substituted 1-5 substituents, each of which is independently 1) C _1-7 alkyl, optionally substituted with 1-3 substituents, each of which is independently selected from halogen. 4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the thiazolyl, pyrazolyl or pyridinyl is substituted with one substituent which is a 5- or 6-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O and N, where 5 - or the 6-membered heterocyclyl is optionally substituted with 1-3 substituents, each of which is independently selected from 1) C _1-7 alkyl, optionally substituted with 1-3 fluorine atoms. 5. Connection according to any one of paragraphs. 2-4 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5- or 6-membered heterocyclic ring is a ring selected from: , which is not necessarily replaced. 6. A compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 5- or 6-membered heterocyclic ring is optionally substituted with 1-3 substituents, each of which is independently selected from C _1-7 alkyl, optionally substituted with 1-3 fluorine atoms . 7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the thiazolyl, pyrazolyl or pyridinyl is substituted with two substituents, where one substituent is defined in any of claims. 2-6, and the other substituent is selected from C _1-6 alkyl. 8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the thiazolyl, pyrazolyl or pyridinyl is substituted with one or two substituents, where one substituent is selected from and the other substituent, when present, is selected from methyl or ethyl. 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where Ar represents where R ₁ is selected from and R ₀ is selected from hydrogen, methyl or ethyl. 10. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^B and R ^C are each -CF ₃ , -CHF ₂ , -CH ₂ F , -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , , ; or represents , , , , , , , , , or . 11. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^B and R ^C are each methyl. 12. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where represents . 13. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where n is 0. 14. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1 and R ^A is CF ₃ or CH ₂ NH ₂ . 15. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L represents -O-CH ₂ - and CH ₂ is directly attached to ring B. 16. A compound selected from compound A1 to A85, or a pharmaceutically acceptable salt thereof 17. Pharmaceutical composition for inhibiting HPK1 activity, comprising an effective amount of a compound according to any one of paragraphs. 1-16 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 18. A method of inhibiting HPK1 activity, comprising administering to a subject in need thereof a compound according to any one of claims. 1-16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17.

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