WO2025161532A1 - Pde4b inhibitor, and pharmaceutical composition thereof and use thereof - Google Patents

Abstract

The present disclosure provides a compound of formula H having excellent PDE4B inhibitory activity, and a pharmaceutical composition thereof and a use thereof. The compound provided by the present disclosure can be used for effectively treating PDE4-related diseases and disorders, including but not limited to inflammatory respiratory diseases, inflammatory bowel diseases, inflammatory joint diseases, inflammatory skin diseases, inflammatory eye diseases, and diseases or cancers of the peripheral or central nervous system.

Description

PDE4B inhibitors and pharmaceutical compositions and uses thereof

This application claims priority to the following prior applications: Chinese invention patent application No. 202410144764.1, filed with the State Intellectual Property Office of China on February 1, 2024, entitled “PDE4B inhibitors, pharmaceutical compositions thereof, and uses thereof”; and Chinese invention patent application No. 202410637006.3, filed with the State Intellectual Property Office of China on May 21, 2024, entitled “PDE4B inhibitors, pharmaceutical compositions thereof, and uses thereof”. The entire contents of the above-mentioned prior applications are incorporated herein by reference.

Technical Field

The present disclosure relates to a PDE4B inhibitor and a pharmaceutical composition and use thereof, and belongs to the field of chemical medicine.

Background Art

Fibrosis is a general term for a broad range of diseases that can occur in almost all human tissues. Fibrotic tissues and organs gradually lose their normal function, severely impacting patients' quality of life and even becoming life-threatening. For example, pulmonary fibrosis, where fibrotic tissue loses its elasticity, makes it increasingly difficult for the lungs to expand and contract during breathing, reducing vital capacity and severely impairing the patient's ability to move.

Idiopathic Pulmonary Fibrosis (IPF) is a progressive pulmonary fibrosis disease. This type of pulmonary fibrosis progresses rapidly and may lead to the death of patients within a few years, which is even shorter than the survival period of many cancer patients. Due to the gradual worsening of pulmonary fibrosis and the unpredictable progression of the disease, IPF patients suffer from the "pain of being unable to breathe" that ordinary people can hardly imagine, and may die from respiratory failure and/or heart failure at any time. At the same time, because the clinical manifestations of the vast majority of IPF patients are atypical, they are easily missed and often misdiagnosed as chronic obstructive pulmonary disease, bronchial asthma or other lung diseases. The median survival time of patients after being diagnosed with IPF is only 2.5 to 5 years.

IPF is classified as a rare disease in China, the European Union, the United States, and Japan, with a combined global prevalence of approximately 3 million IPF patients. The disease primarily affects patients over 50 years of age, with men more likely to be affected than women. While there are no publicly available large-scale epidemiological studies on the incidence of IPF in China, the burden of IPF on individuals, families, society, and public health resources remains significant due to China's large population.

The PDE4 subfamily comprises four isoforms (PDE4A, PDE4B, PDE4C, and PDE4D), each with distinct tissue distributions: PDE4A is ubiquitous, with relatively high expression in adipose tissue, brain, heart, and testis; PDE4B is also widely distributed, with particularly high expression in the lung, immune cells, brain, heart, and skeletal muscle; PDE4C is primarily expressed in the testis and other tissues, with low expression in the lung and absent in blood and immune cells; and PDE4D is primarily expressed in the brain, immune cells, and skeletal muscle. Consequently, the PDE4B isoform is more highly expressed in the lung than the other isoforms. In vitro studies targeting PDE4B in pulmonary fibrosis have demonstrated the importance of PDE4B inhibition in anti-inflammatory and anti-fibrotic responses. PDE4B inhibition increases intracellular cAMP levels, subsequently activating protein kinase A (PKA) and cAMP-activated exchange protein (EPAC), reducing the synthesis and release of proinflammatory cytokines and increasing the synthesis of anti-inflammatory cytokines.

Although preclinical evidence suggests that PDE4 inhibitors are associated with anti-inflammatory and anti-fibrotic effects and have the potential to reduce inflammation and fibrotic remodeling in lung diseases, many PDE4 inhibitors have gastrointestinal side effects due to differences in selectivity, leading to the termination of clinical trials. Therefore, there is a need to develop PDE4B inhibitors that exhibit better selectivity and/or fewer gastrointestinal side effects.

SUMMARY OF THE INVENTION

In order to solve the above technical problems, the present disclosure provides a compound represented by the following formula H, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug:

in:

X ₁ represents a chemical bond, C _1-20 alkylene, O, S, NR _q , S(═O), S(═O) ₂ or C(═O);

_Rq is selected from H, halogen, OH, CN, _NO2 , oxo (=O), thioxo (=S), _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, _C3-20 cycloalkyl, C3-20 cycloalkenyl, _C3-20 cycloalkynyl, _C6-20 aryl, _5-20 membered heteroaryl, _3-20 membered heterocyclyl, C1-20 alkyloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, C3-20 cycloalkyloxy, _C3-20 cycloalkenyloxy, _C3-20 cycloalkynyloxy, _C6-20 aryloxy, _5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, _C1-20 alkylthio, _{C2-20 alkenylthio} , C -C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _{3-20 cycloalkynylthio, C 6-20 arylthio} , _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, C _1-8 -heteroalkyl-C 6-20-aryl-, C _1-8 -heteroalkyl-C _6-20 -aryl-, NH ₂ , -C(O)R ₄₁ , -C(O)OR ₄₂ , -OC(O)R ₄₃ , -S(O) ₂ R ₄₄ , -S(O) ₂ OR ₄₅ , -OS(O) _{2 R 46 ,} -P(O)(OR ₄₇ )(OR ₄₈ );

L represents a chemical bond, a C _2-20 alkynyl group or Cy; wherein L can be connected to X ₁ or R _c at any position;

Cy represents a 3-20 membered heterocyclic group, a C _6-20 aryl group, or a 5-20 membered heteroaryl group, wherein the 3-20 membered heterocyclic group, the C _6-20 aryl group, or the 5-20 membered heteroaryl group may be optionally fused with a 4-7 membered cycloalkyl group, provided that when the heterocyclic group contains a N atom, the heterocyclic group may be bonded to the carbon atom at the 2-position of the pyrimidine ring in formula H through its N atom or C atom;

W represents a chemical bond, CH, O, S, N, -S(O)-, -S(O) ₂ -, -C(O), C _1-6 alkylene, C _2-6 alkenylene, or C _2-6 alkynylene _;

R ₂ is selected from the following groups which are absent, H, unsubstituted or optionally substituted with 1, 2 or more R _d1 : C _6-20 aryl, 5-20 membered heteroaryl;

R _2′ represents absence, H, halogen, OH, CN, unsubstituted or optionally substituted by 1, 2 or more R _d2 : C _1-20 alkyl, C _2-20 alkenyl, C 2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy, 5-20 membered heteroaryloxy, _{3-20 membered heterocyclyloxy, C 1-20 alkylthio} , C _2-20 alkenylthio, C _2-20 alkynylthio, C C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20 arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH ₂ ;

Provided that R ₂ and R _2' are not "absent" at the same time;

Alternatively, R ₂ and R _2′ may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _d3 : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, 6-20 membered aryl;

_Ra represents H or -XR ₃ ;

X represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—;

R ₃ represents H, halogen, OH, CN, -CH ₂ CF ₃ , -NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 4} s: C _1-20 alkyl, -C(O)R ₆₁ , -C(O)OR ₆₂ , -OC(O)R ₆₃ , NH ₂ ;

R _b represents H or -YR ₄ ;

Y represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—;

R ₄ represents H, halogen, OH, CN, —CH ₂ CF ₃ , —NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 5} s: C _1-20 alkyl, —C(O)R ₆₁ , —C(O)OR ₆₂ , —OC(O)R ₆₃ , NH ₂ ;

The condition is that _Ra and _Rb are not H at the same time;

Alternatively, _Ra , _Rb , and the atoms to which they are attached together form the following groups which are unsubstituted or optionally substituted with 1, 2, or more _Rd6 : _C5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl;

Each of R _d1 , R _d2 , R _d3 , R _d4 , R _d5 and R _d6 is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), SO, SO ₂ , the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _e : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C -C(O)R ₃₁ , -CH 2 -C(O)R ₃₁ , -C(O)OR ₃₂ , -CH ₂ C(O)OR 32 , -C(O)NHR 32 , -CH ₂ C( _O) NHR 32 , -OC _{(O)R 33 , -S(O) 2 R 34 , -S(O) 2 OR 34 , -C(O)R 35} , -CH 2 -C(O)R ₃₅ , -C(O)OR 36 , -CH ₂ C(O)OR 37 , -C(O)NHR 38 , -CH 2 C(O)NHR 39 , -OC(O)R ₄₀ , -S(O) ₄ R 41 , -S(O) ₄ OR ₄₂ , -C(O)R 42 , -CH _{2 -C} (O)R 43 , -C(O)OR ₄₄ , -C(O)OR 45 , -C(O)NHR ₄₆ , -CH ₂ C(O)NHR ₄₇ , -OC(O)R 48 , -S(O) ₄ R ₄₉ , -S(O) ₄ R ₅₀ , -S(O) ₃₅ , -OS(O) ₂ R ₃₆ , -P(O)(OR ₃₇ )(OR ₃₈ );

Alternatively, when two or more substituents selected from R _d1 , R _d2 , R _d3 , R _d4 , R _d5 , and R _d6 exist on the same group, the two substituents Each substituent may be taken together with the atom to which it is attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _e : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

Each R _c is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _c : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl-OC _6-20 aryl-, 5-20 membered heteroaryl-NC _6-20 aryl-, 5-20 membered heteroaryl-SC _6-20 aryl-, 5-20 membered heteroaryl-CH ₂ -C _6-20 aryl-, C _4-10 cycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkyl and C C _6-20 aryl-, 4-10 membered heterocycloalkenyl and C _6-20 aryl-, C _4-10 cycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkenyl-C 6-20 aryl-, _5-20 membered heteroaryl, C _4-10 cycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl-, C _4-10 cycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl-5-20 membered heteroaryl-, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C -C(O)R ₃₁ , -C(O _{)OR 32 ,} -OC(O)R ₃₃ , -S(O _{) 2} R _{34 , -S (} O _{) 2 OR 35 , -OS ( O ) 2 R 36} , -P(O)(OR ₃₇ )(OR ₃₈ );

m is an integer selected from 1 to 10;

Each R _e is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , NH ₂ , oxo (═O), thioxo (═S), O-CONH ₂ , O-CONHR _f , the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _f : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, _{3-20 membered heterocyclyl, C 1-20 alkyloxy} , C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _{3-20 cycloalkyloxy, C 3-20} cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _-6-20 membered heteroaryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C 2-20 alkenylthio, C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, C _1-8 -heteroalkyl-C 6-20-aryl-, C _1-8 -heteroalkyl-C _6-20 -aryl-, NH ₂ , -C(O)R ₄₁ , -C(O)OR ₄₂ , -OC(O)R ₄₃ , -S(O) ₂ R _{44 ,} -S(O) ₂ OR ₄₅ , -OS(O) ₂ R ₄₆ , -P(O)(OR ₄₇ )(OR ₄₈ );

Alternatively, when two or more substituents selected from R _e are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _f : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

Each _Rf is the same or different and is independently selected from H, halogen, OH, CN, _NO2 , oxo (=O), thioxo (=S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more _Rg : _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, _C3-20 cycloalkyl, _C3-20 cycloalkenyl, _C3-20 cycloalkynyl, C6-20 aryl, _5-20 membered heteroaryl, _{3-20 membered} heterocyclyl, C1-20 alkyloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, _C3-20 cycloalkyloxy, _C3-20 cycloalkenyloxy, C3-20 cycloalkynyloxy, C6-20 aryloxy, _5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, _C1-20 alkylthio, C _-C2-20 membered alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O) _{R51 ,} -C(O) _OR52 , -OC(O) _R53 , -S(O) _2R54 , -S(O) _2OR55 , _-OS (O) _2R56 , -P(O)( _{OR57 )} ( _OR58 ) _;

Alternatively, when two or more substituents selected from R _f are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _g : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

Each R _g is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, and NH ₂ ;

R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ , R ₃₇ , R ₃₈ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ , R ₄₆ , R 47 , R ₄₈ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₆ , R ₅₇ , R ₅₈ are the same or different _and are independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 membered aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, NH ₂ ;

The 3-20 membered heterocyclic group represents a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spiro ring) or a 10-, 11-, 12-, 13-, 14- or a 15-membered tricyclic ring system, and containing at least one, for example 1, 2, 3, 4, 5 or more heteroatoms independently selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) ₂ -;

The C _6-20 aryl group represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, or spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together;

The 5-20 membered heteroaryl group represents a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1, 2, 3, 4, 5 or more heteroatoms independently selected from N, O and S.

According to a preferred embodiment in the context of the present disclosure, the compound does not comprise a compound selected from the group consisting of:

According to an embodiment of the present disclosure, the present disclosure provides a compound represented by the following formula G, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug:

in:

Cy represents a chemical bond, a 3-20 membered heterocyclic group, a C _6-20 aryl group, or a 5-20 membered heteroaryl group, provided that when the heterocyclic group contains a N atom, the heterocyclic group can be bonded to the carbon atom at the 2-position of the pyrimidine ring in formula G through its N atom or C atom;

W represents a chemical bond, CH, O, S, N, -S(O)-, -S(O) ₂ -, -C(O), C _1-6 alkylene, C _2-6 alkenylene or C _{2- 6} -alkynyl;

R ₂ is selected from the following groups which are absent, H, unsubstituted or optionally substituted with 1, 2 or more R _d1 : C _6-20 aryl, 5-20 membered heteroaryl;

R _2′ represents absence, H, halogen, OH, CN, unsubstituted or optionally substituted by 1, 2 or more R _d2 : C _1-20 alkyl, C _2-20 alkenyl, C 2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy, 5-20 membered heteroaryloxy, _{3-20 membered heterocyclyloxy, C 1-20 alkylthio} , C _2-20 alkenylthio, C _2-20 alkynylthio, C C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20 arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH ₂ ;

Provided that R ₂ and R _2' are not "absent" at the same time;

Alternatively, R ₂ and R _2′ may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _d3 : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, 6-20 membered aryl;

_Ra represents H or -XR ₃ ;

X represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—;

R ₃ represents H, halogen, OH, CN, -CH ₂ CF ₃ , -NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 4} s: C _1-20 alkyl, -C(O)R ₆₁ , -C(O)OR ₆₂ , -OC(O)R ₆₃ , NH ₂ ;

R _b represents H or -YR ₄ ;

Y represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—;

R ₄ represents H, halogen, OH, CN, —CH ₂ CF ₃ , —NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 5} s: C _1-20 alkyl, —C(O)R ₆₁ , —C(O)OR ₆₂ , —OC(O)R ₆₃ , NH ₂ ;

The condition is that _Ra and _Rb are not H at the same time;

Alternatively, _Ra , _Rb , and the atoms to which they are attached together form the following groups which are unsubstituted or optionally substituted with 1, 2, or more _Rd6 : _C5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl;

Each of R _d1 , R _d2 , R _d3 , R _d4 , R _d5 and R _d6 is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _e : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, _{3-20 membered heterocyclyl, C 1-20 alkyloxy} , C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _{3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy} , C _-C6-20 membered aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C1-20 alkylthio, _C2-20 alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, _3-20 membered heterocyclylthio, NH2, -C(O)R31, _-CH2-C (O) _R31 , -C(O)OR32, _-CH2C (O) _OR32 , -C(O) _{NHR32 , -CH2C} (O) _{NHR32 , -OC(O)R33, -S(O)2R34 , -S (} O _{) 2OR35} , -OS(O) ₂ R ₃₆ , -P(O)(OR ₃₇ )(OR ₃₈ );

Alternatively, when two or more substituents selected from R _d1 , R _d2 , R _d3 , R _d4 , R _d5 , and R _d6 are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2, or more R _e : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

Each R _c is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _c : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, _3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C _-C2-20 membered alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O) _{R31 ,} -C(O) _OR32 , -OC(O) _R33 , -S(O) _2R34 , -S(O) _2OR35 , _-OS (O) _2R36 , -P(O)( _{OR37 )} ( _OR38 ) _;

m is an integer selected from 1 to 10;

Each R _e is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _f : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C _2-20 alkenylthio, C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH ₂ , -C(O)R 41 , -C(O)OR ₄₂ , -OC(O)R ₄₃ , -S(O) ₂ R _{44 ,} -S(O) ₂ OR ₄₅ , -OS(O) ₂ R ₄₆ , -P(O)(OR ₄₇ )(OR ₄₈ );

Alternatively, when two or more substituents selected from R _e are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _f : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

Each _Rf is the same or different and is independently selected from H, halogen, OH, CN, _NO2 , oxo (=O), thioxo (=S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more _Rg : _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, _C3-20 cycloalkyl, _C3-20 cycloalkenyl, _C3-20 cycloalkynyl, C6-20 aryl, _5-20 membered heteroaryl, _{3-20 membered} heterocyclyl, C1-20 alkyloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, _C3-20 cycloalkyloxy, _C3-20 cycloalkenyloxy, C3-20 cycloalkynyloxy, C6-20 aryloxy, _5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, _C1-20 alkylthio, C _-C2-20 membered alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O) _{R51 ,} -C(O) _OR52 , -OC(O) _R53 , -S(O) _2R54 , -S(O) _2OR55 , _-OS (O) _2R56 , -P(O)( _OR57 )( _{OR58 ) ;}

Alternatively, when two or more substituents selected from R _f are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _g : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

Each R _g is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, and NH ₂ ;

R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ , R ₃₇ , R ₃₈ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ , R _{46 , R 47} , R ₄₈ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₆ , R ₅₇ , R ₅₈ are the same or different _and are independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 membered aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, NH ₂ ;

The 3-20 membered heterocyclyl represents a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, such as 1, 2, 3, 4, 5 or more heteroatoms independently selected from O, S and N, wherein N and S may be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) ₂ -;

The C _6-20 aryl group represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, or spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together;

The 5-20 membered heteroaryl group represents a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1, 2, 3, 4, 5 or more heteroatoms independently selected from N, O and S.

According to an embodiment of the present invention, the cycloalkyl group may be saturated or partially saturated.

According to an embodiment of the present invention, the compound represented by formula G, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug can be selected from the following compounds represented by formula I, II, III, IV, V, VI, VII, VIII or IX, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug:

The groups in the above formulae I to IX may independently have the definitions in the context of the present disclosure.

According to an embodiment of the present invention, the compound of formula I may have the following definition:

in:

W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl;

X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^{1.3 ,} CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-20- aryl and NR ^1.2 is substituted by a substituent in R ^1.3 ;

Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR 1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 20-} aryl and NR ^1.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

The heteroaryl ring is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10- alkyl and C _6-20- aryl substituents,

R ^1.2 and R ^1.3 independently of one another represent H or a radical selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by one, two or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 , or

R ₂ represents hydrogen, a mono- or polycyclic C _6-20- aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which may in turn be optionally substituted by 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 .

Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 20-} aryl and NR ^2.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^2.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocyclic-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C6-20 _- aryl, 5-20 membered heteroaryl and heterocyclic rings, which may be optionally substituted with OH, O-( _C1-3 -alkyl), halogen, _C1-10- alkyl and C6-20 _- aryl substituents;

R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 , or

R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _＝ CHCO _- NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C ^3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _{6- 20-} aryl and NR ^2.2 R ^2.3 ;

R ₃ represents H, C _1-6 -alkyl, F, chlorine, bromine, hydroxy, -CN, -CH ₂ CN, -CH ₂ COOR, -COOR, -CO-NH(CH ₃ )C _1-3 -fluoroalkyl, (C _1-6 -alkyl)-OH, (C _1-6 -alkyl)-OCH ₃ , (C _1-6 -alkyl)-NH ₂ , (C _1-6 -alkyl)-N(C _1-3 -alkyl) or (C _1-6 -alkyl)-NH;

R _3′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-20- aryl, C _6-20- aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, where R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more groups selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

Alternatively, R ₃ and R _3′ together represent oxo, methylene, ethylene and propylene, which may be optionally substituted by substituents selected from —CH ₃ , —OH, —F, —CF ₃ , —CHF ₂ , —CH ₂ F, —NH ₂ , —NH(C _1-3 -alkyl), —N(C _1-3 -alkyl) ₂ and O—(C _1-3 -alkyl);

R ₄ represents H, C _1-6 -alkyl, F, chlorine, bromine, hydroxy, -CN, -CH ₂ CN, -CH ₂ COOR, -COOR, -CO-NH(CH ₃ )C _1-3 -fluoroalkyl, (C _1-6 -alkyl)-OH, (C _1-6 -alkyl)-OCH ₃ , (C _1-6 -alkyl)-NH ₂ , (C _1-6 -alkyl)-N(C _1-3 -alkyl) or (C _1-6 -alkyl)-NH;

R _4′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-20- aryl, C _6-20- aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, where R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more groups selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

Alternatively, R ₄ and R _4′ together represent oxo, methylene, ethylene and propylene, which may be optionally substituted by substituents selected from —CH ₃ , —OH, —F, —CF ₃ , —CHF ₂ , —CH ₂ F, —NH ₂ , —NH(C _1-3 -alkyl), —N(C _1-3 -alkyl) ₂ and O—(C _1-3 -alkyl);

R ₅ , R ₆ independently represent H, F, C _1-6 -alkyl, C _1-3 -fluoroalkyl, C _1-6 -alkyl-OH, C _1-6 -alkenyl-OCH ₃ , C _1-6 -alkyl-NH ₂ , C _1-6 -alkynyl-NH(C _1-3 -alkyl) and C _1-6 -alkyl-N(C _1-3 -alkyl) ₂ ;

Alternatively, R ₁ and R ₃ together with the C- and N-atoms of piperidine form a saturated or partially saturated 5- or 7-membered heterocyclic group containing two or three nitrogen atoms, which may be optionally substituted by a group selected from -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 -alkyl),

Alternatively, R ₃ and R ₆ together form a bridged ring of methylene, ethylene and propylene, which may be optionally substituted with a group selected from -CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 alkyl);

Alternatively, R ₃ and R ₅ together form a bridged ring of methylene, ethylene and propylene, which may be optionally substituted with a group selected from -CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 alkyl);

Alternatively, R ₃ and R ₄ together form a bridged ring of methylene, ethylene and propylene, which may be optionally substituted with a group selected from -CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 alkyl);

Alternatively, R ₄ and R ₆ together form a bridged ring of methylene, ethylene and propylene, which may be optionally substituted with a group selected from -CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 alkyl);

Alternatively, _R4 and _R7 together with the carbon atom to which they are attached form a double bond.

According to an embodiment of the present invention, examples of R ₁ may be selected from the following groups:

According to an embodiment of the present invention, examples of -WR ₂ R _2' may be selected from the following groups:

According to an embodiment of the present invention, the compound of formula II has the following definition:

W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl;

X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ ^CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic C _6-20- aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20-membered heterocyclyl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-20- aryl and substituted by a substituent in NR ^1.2 R ^1.3 ,

Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR ^1.1 , CH ₂ COOR 1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 10-} aryl and NR ^1.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20- aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10- alkyl and C _5-10 aryl substituents;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may optionally be replaced by one, two or more groups selected from OH, substituted by halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^1.1 ;

R ₂ represents hydrogen, a mono- or polycyclic C _6-20- aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ;

Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH═CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _{1-3 -alkyl} -OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted with one, two or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20- aryl and NR ^2.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20- aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci- ₆ -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic C6-20 _- aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20- aryl substituents;

R ^2.2 and R ^2.3 independently of one another represent H or a radical selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _5-10 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, a 3-20-membered heterocycle, a heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by one, two or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 , or

R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-20- aryl, C _6-20- aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

or,

R ₂ and R _2′ together form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O,

R ₃ represents a group selected from aryl and heteroaryl, which is optionally substituted at the ortho, para or meta positions by one, two or three halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F groups, or is optionally substituted by one, two or more groups selected from the group consisting of OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^1.1 , COOR ^1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 20-} aryl and NR ^1.2 R ^2.3 ;

_R4 represents a group selected from aryl and heteroaryl, which is optionally replaced by one, two or three 1.1 , CH ₂ COOR 1.1 , CH ₂ CH ₂ COOR 1.1 , CH＝CHCOOR ^{1.1 ,} _CO - _{NR 1.1} CH 2 ^{CO -} _{NR 1.1} ^{, CH} _{2 CH 2} CO ^{- NR 1.1} _, ^CH _{＝ CHCO} ^{- NR 1.1 ,} _COR ^{1.1 , CH} _{2 COR} ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6- 20} -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20 -aryl and NR ^1.2 R ^2.3 is substituted by one, two or more substituents;

Ring A represents a chemical bond, a mono- or polycyclic C _6-20- aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three independent groups selected from fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ , or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(mono- or polycyclic-C _1.2 R 1.3, each of which may _{in turn be optionally substituted with one, two or more substituents selected from the group consisting of OH, OR 1.1 , oxo} , halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10 -aryl, _3-20 -membered heterocyclyl-C _1-6 -alkyl, 5-20 _- membered heteroaryl ^- C _{1-6 -} alkyl, C ^6-10 -aryl, SO ₂ —CH ₃ , SO _{2 —CH 2} CH ₃ and SO _{2 —NR} ^1.2 R ^1.3 _. The substituents in ^1.3 are substituted, or,

Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20- aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-20- aryl and NR ^1.2 R ^1.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20- aryl, 5-20-membered heteroaryl and heterocycle, which may optionally be selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10- alkyl and C _{6-20- aryl} ;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 .

According to an embodiment of the present invention, examples of Ring A may be selected from the following groups:

According to an embodiment of the present invention, examples of -WR ₂ R _2' may be selected from the following groups:

According to an embodiment of the present invention, examples of -XR ₃ substituents may be selected from the following groups:

According to an embodiment of the present invention, the compound of formula III has the following definition:

in:

W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl;

X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

R ₁ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20-membered heterocyclyl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-20- aryl and substituted by a substituent in NR ^1.2 R ^1.3 ,

Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR 1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 10-} aryl and NR ^1.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl substituents;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 , or

R ₂ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which in turn may be optionally substituted by 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20- aryl and NR ^2.2 R ^2.3 ,

Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 20-} aryl and NR ^2.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally associated heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^2.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10- alkyl and C _6-20 aryl substituents;

R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _— CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 , or

R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _{＝ CHCO} -NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C ^3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _{6- 20} -aryl and NR ^2.2 R ^2.3 ;

Ring A represents a chemical bond, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three independent groups selected from fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ , or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(mono- or polycyclic-C _1.2 R 1.3, each of which may _in turn be optionally substituted with one _, two or more substituents selected from OH, OR _1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _{1-6 -alkyl, C 6-20 aryl} , 3-20 membered heterocyclyl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _{1-6 - alkyl} , C ^6-10 -aryl, SO ₂ —CH ₃ , SO _{2 —CH 2 CH 3 and} SO _{2 —NR} ^1.2 R ^{1.3 .} Substitution by substituents in ^1.3 ;

Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl, C _1-6 -alkyl, C C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _6-20 aryl and NR ^1.2 R ^1.3 are substituted by 1, 2 or more substituents;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 .

Alternatively, according to an embodiment of the present invention,

According to an embodiment of the present invention, examples of Ring A may be selected from the following groups:

According to an embodiment of the present invention, examples of -WR ₂ R _2' may be selected from the following groups:

According to an embodiment of the present invention, the compound of formula IV has the following definition:

W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl;

X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

V represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ ^CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-20 aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20 aryl and NR 1.2 R 1.3. ^1.2 R is substituted by a substituent in ^1.3 ,

Alternatively, R1 represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 , ^SR1.1 , _C1-3 - _alkyl - ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl-SOR1.1 ^, _{SO2-R1.1, C1-3-alkyl-SO2R1.1 ,} ^COOR1.1 _{, CH2COOR1.1} ^{, CH2CH2COOR1.1 ,} _{CH ＝} ^CHCOOR1.1 , CO-NR1.1 ^, CH2CO _- ^NR1.1 , _CH2CH2CO -NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl, C _1-6 -alkyl, C _6-20 aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 20} aryl and NR ^1.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl substituents;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20 aryl, 3-20 membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may optionally be replaced by 1, 2 or more groups selected from OH, substituted with halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 ; or

R ₂ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted by 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ,

Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 10-} aryl and NR ^2.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 aryl-Ci _-6 -alkyl, 5-20 membered heteroaryl-Ci- ₆ -alkyl, 3-20 membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci- ₆ -alkyl, mono- or bicyclic _C6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents;

R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _— CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^2.1 , or

R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _{＝ CHCO} -NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C ^3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _{6- 20-} aryl and NR ^2.2 R ^2.3 ;

Ring A represents a chemical bond, a mono- or polycyclic C _6-20 aromatic group, which may be substituted at the ortho, para or meta positions by one, two, or three independent fluorine, chlorine, bromine, hydroxyl, CN, or NH ₂ groups, or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 ,CH＝CHCO-NR ^1.1 ,NR ^1.2 R ^1.3 ,CH ₂ -NR ^1.2 R ^1.3 ,CH ₂ CH ₂ -NR ^1.2 R ^1.3 ,C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20-membered heterocyclyl-C _6-20 aryl, 3-20-membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which may in turn be optionally substituted by 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 , or,

Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl- _{(monocyclic or polycyclic-C 6-20 aryl), 3-20 membered heterocyclyl-C 6-20 aryl ,} 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted by OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and _{C 6-20} aryl;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 .

According to an embodiment of the present invention, examples of Ring A may be selected from the following groups:

According to an embodiment of the present invention, examples of -WR ₂ R _2' may be selected from the following groups:

According to an embodiment of the present invention, the compound of formula V has the following definition:

W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl;

X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

V represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

R ₁ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR 1.2 R 1.3. ^1.2 R is substituted by a substituent in ^1.3 ;

or,

R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _{1-3 -alkyl} -SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR ^1.1 , CH ₂ COOR 1.1 , CH 2 CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

wherein R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or _bicyclic , -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and _{C 6-20} aryl substituents;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^1.1 , or

R ₂ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which in turn may be optionally substituted by 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ,

or,

R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _{1-3 -alkyl} -SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH 2 CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

wherein R ^2.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or _bicyclic , -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and _{C 6-20} aryl substituents,

R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaryl, CO—NH ₂ , CO—NH _— CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 , or

R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

or,

R ₂ and R _2′ together form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O,

A ring represents a chemical bond, a mono- or polycyclic C _6-20 -aryl group, which can be optionally replaced by one at the ortho, para or meta position, independently. 1.1 , COOR 1.1 CH 2 COOR 1.1 _, CH 2 CH ₂ COOR 1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH 2 CO-NR 1.1 , CH 2 CH ₂ CO-NR ^1.1 , ^{CH＝CHCO-NR 1.1 , NR 1.2 R 1.3 , CH 2} _-NR ^{1.2 R 1.3} , ^CH ₂ CH ₂ ^{-NR 1.2 R} _1.3 ^, C _3-10 -cycloalkyl, C _1-3 -alkyl- ₍ monocyclic or ^polycyclic _{- C 6-20} -aryl), _3-20 membered heterocyclyl, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which may in turn be optionally substituted by 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 , or,

Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _{6-20 -aryl} , 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may optionally be selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and _{C 6-20} aryl,

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 .

According to an embodiment of the present invention, examples of Ring A may be selected from the following groups:

According to an embodiment of the present invention, examples of the -WR ₂ R _2' substituent may be selected from the following groups:

According to an embodiment of the present invention, the compound of formula VI has the following definition:

W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl;

X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ ^CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-10- aryl and substituted by a substituent in NR ^1.2 R ^1.3 ,

or,

R ₁ represents a group selected from heterocyclic and heteroaryl groups, which may be optionally replaced by one, two or three halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F groups, or substituted with one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^1.1 , COOR ^1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _{1- 6} -alkyl, C _6-10 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10 -aryl and NR ^1.2 R ^2.3 is substituted by one, two or more substituents;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl substituents;

R ^1.2 and R ^1.3 independently of one another represent H or a radical selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by one, two or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 , or

R ₂ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ ^CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR 2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, a 3-20 membered heterocycle, a C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ;

Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 -aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci _-6 -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic _C6-20 aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents;

R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^2.1 ;

R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _{＝ CHCO} -NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C ^3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _{6- 20-} aryl and NR ^2.2 R ^2.3 ;

Ring A represents a chemical bond, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three independent fluorine, chlorine, bromine, hydroxyl, CN or NH ₂ groups, or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(mono- or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 is substituted by a substituent; or

Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _{6-20 -aryl} , 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and _{C 6-20} aryl;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 .

According to an embodiment of the present invention, examples of Ring A may be selected from the following groups:

According to an embodiment of the present invention, examples of the -WR ₂ R _2' substituent may be selected from the following groups:

According to an embodiment of the present invention, the compound of formula VII has the following definition:

W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl;

X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ ^CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-10- aryl and substituted by a substituent in NR ^1.2 R ^1.3 ;

Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR 1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl substituents;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^1.1 ;

R ₂ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR 2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^{2.3 ,} CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and a substituent in NR ^2.2 R ^2.3 ,

Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 ,CH＝CHCO-NR ^2.1 ,COR ^2.1 ,CH ₂ COR ^2.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6- ^2.2 R ^{2.3 ,} each of which may be optionally substituted with one, two or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _{1-6 -} alkyl, C _{6-10 -} aryl-C _1-6 -alkyl, _5-20 - _membered heteroaryl-C _1-6 alkyl, 3-20-membered heterocycle, 5-20-membered heteroarylC _1-3 -alkyl-OR 2.1 and NR ^2.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 -aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci _-6 -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic _C6-20 -aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents;

R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaryl, CO—NH ₂ , CO—NH _— CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 , or

R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _{＝ CHCO} -NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C ^3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _{6- 20-} aryl and NR ^2.2 R ^2.3 ;

Ring A represents a chemical bond, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three independent groups selected from fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ , or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(mono- or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 is substituted by a substituent; or

Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _{6-20 -aryl} , 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O. saturated, optionally fused ring or optionally bridged ring;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and _{C 6-20} aryl;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 .

According to an embodiment of the present invention, examples of Ring A may be selected from the following groups:

According to an embodiment of the present invention, examples of the -WR ₂ R _2' group may be selected from the following groups:

According to an embodiment of the present invention, the compound of formula VIII has the following definition:

W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl;

X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O);

R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ ^CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-10- aryl and substituted by a substituent in NR ^1.2 R ^1.3 ;

Alternatively, R ₁ represents a group selected from heterocyclic and heteroaryl groups, which may be optionally substituted at the ortho, para or meta positions by one, two or three halogen, OH, oxo, CF ₃ , CHF _{2 and CH 2 F groups, or by one, two or more halogen, OH, oxo, CF 3 , CHF 2} and CH ₂ F groups. ¹ , ^C _1-6 -alkyl-, ^C 1-7 -alkyl-, C ^{1-8 -alkyl-} , C _1-9 ^{-alkyl- ,} C _1-10 ^-alkyl- , C 1-11 -alkyl-, _{C 1-12} -alkyl- ^, _C 1-13 ^-alkyl- , ^C 1-14 ^-alkyl- , ^C _1-15 -alkyl-, _{C 1-16} -alkyl-, ^{C 1-17 -alkyl-, C 1-18 -alkyl-, C 1-19 -alkyl- ,} _{C 1-2 -alkyl-} ^, _C ^1-2 _-alkyl- ^, _{C 1-3 -alkyl-} ^, C _1-3 -alkyl- _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20-membered heterocyclyl-C _6-20 -aryl, 3-20-membered heterocycle, 5-20-membered heteroarylC _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted with one, two or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 -aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci _-6 -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic _C6-20 -aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^1.1 ;

R ₂ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ ^CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR 2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, a 3-20 membered heterocycle, a C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which in turn may be optionally substituted by 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ,

Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 -aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci _-6 -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic _C6-20 aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents;

R ^2.2 and R ^2.3 independently represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5- 20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3- to 20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), a radical of CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 ;

R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _6-20 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _6-20 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _＝ CHCO _- NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C ^3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _{6- 20} -aryl and NR ^2.2 R ^2.3 ;

_R4 represents a group selected from aryl and heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or is optionally substituted by one, two or more groups selected from ^OR1.1 , _C1-3 -alkyl- ^OR1.1 , ^SR1.1 , _C1-3 - ^alkyl - ^SR1.1 _, SO-R1.1, _C1-3 -alkyl- ^SOR1.1 , SO2 _- ^R1.1 , _C1-3 - _{alkyl - SO2R1.1} ^{, COOR1.1} , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH＝ ^CHCOOR1.1 , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _{CH2CH2CO -} NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 -alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^2.3 ;

Ring A represents a chemical bond, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three independent groups selected from fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ , or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(mono- or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 is substituted by a substituent; or

Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _{6-20 -aryl} , 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and _{C 6-20} aryl;

R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 .

According to an embodiment of the present invention, examples of Ring A may be selected from the following groups:

According to an embodiment of the present invention, examples of the -WR ₂ R _2' group may be selected from the following groups:

According to an embodiment of the present invention, the compound of formula IX has the following definition:

in:

X ₁ represents a chemical bond, C _1-20 alkylene, O, S, NR _q , S(═O), S(═O) ₂ or C(═O);

U represents -(CH ₂ ) _t -, O, S, NR _q , S(═O), S(═O) ₂ or C(═O), wherein t represents 0, 1, 2 or 3;

_Rq is selected from H, halogen, OH, CN, _NO2 , _NH2 , oxo (=O), thioxo (=S), C1-20 alkyl, _C2-20 alkenyl, C2-20 alkynyl, _C3-20 cycloalkyl, _C3-20 cycloalkenyl, _C3-20 cycloalkynyl, _C6-20 aryl, _5-20 membered heteroaryl, 3-20 membered heterocyclyl, _C1-20 alkyloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, _C3-20 cycloalkyloxy, _C3-20 cycloalkenyloxy, _C3-20 cycloalkynyloxy, _C6-20 aryloxy, _5-20 membered heteroaryloxy, 3-20 membered _{heterocyclyloxy} , _C1-20 alkylthio, C _-C2-20 alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, _3-20 membered heterocyclylthio, C1-8-heteroalkyl- _C6-20 -aryl-, C1-8-heteroalkyl- _C6-20- aryl-, NH2, -C( _{O) R41 ,} -C(O)OR42 _, -OC(O) _{R43 , -S(O)2R44, -S(O)2OR45 , -OS (} O) _2R46 , _-P (O)( _OR47 )( _OR48 ) _;

v represents 0, 1, 2, 3, 4, or 5;

L represents a chemical bond, a C _2-20 alkynyl group or Cy; wherein L can be connected to X ₁ or R _c at any position;

Cy represents a chemical bond, a 3-20 membered heterocyclic group, a C _6-20 aryl group, or a 5-20 membered heteroaryl group, wherein the 3-20 membered heterocyclic group, the C _6-20 aryl group, or the 5-20 membered heteroaryl group may be optionally fused with a 4-7 membered cycloalkyl group, provided that when the heterocyclic group contains a N atom, the heterocyclic group may be bonded to the carbon atom at the 2-position of the pyrimidine ring in formula IX through its N atom or C atom;

_Ra represents H or -XR ₃ ;

X represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—;

R ₃ represents H, halogen, OH, CN, -CH ₂ CF ₃ , -NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 4} s: C _1-20 alkyl, -C(O)R ₆₁ , -C(O)OR ₆₂ , -OC(O)R ₆₃ , NH ₂ ;

R _b represents H or -YR ₄ ;

Y represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—;

R ₄ represents H, halogen, OH, CN, —CH ₂ CF ₃ , —NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 5} s: C _1-20 alkyl, —C(O)R ₆₁ , —C(O)OR ₆₂ , —OC(O)R ₆₃ , NH ₂ ;

The condition is that _Ra and _Rb are not H at the same time;

Alternatively, _Ra , _Rb , and the atoms to which they are attached together form the following groups which are unsubstituted or optionally substituted with 1, 2, or more _Rd6 : _C5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl;

Each of R _d2 , R _d4 , R _d5 , and R _d6 is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), SO, SO ₂ , the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _e : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C a _5-20 -membered heteroaryloxy group, a 3-20-membered heterocyclyloxy group, a C _1-20 alkylthio group, a C _2-20 alkenylthio group, a C _2-20 alkynylthio group, a C _3-20 cycloalkylthio group, a C _3-20 cycloalkenylthio group, a C _3-20 cycloalkynylthio group, a C _6-20 arylthio group, a 5-20-membered heteroarylthio group, a 3-20-membered heterocyclylthio group, NH ₂ , -C(O)R ₃₁ , -CH ₂ -C(O)R ₃₁ , -C(O)OR ₃₂ , - CH ₂ C(O)OR ₃₂ , -C(O)NHR ₃₂ , -CH ₂ C(O)NHR ₃₂ , -OC(O)R ₃₃ , -S(O) ₂ R ₃₄ , -S(O) ₂ OR ₃₅ , -OS(O) ₂ R ₃₆ , -P(O)(OR ₃₇ )(OR ₃₈ );

Alternatively, when two or more substituents selected from R _d2 , R _d4 , R _d5 , and R _d6 are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2, or more R _e : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

Each R _c is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _c : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl-OC _6-20 aryl-, 5-20 membered heteroaryl-NC _6-20 aryl-, 5-20 membered heteroaryl-SC _6-20 aryl-, 5-20 membered heteroaryl-CH ₂ -C _6-20 aryl-, C _4-10 cycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkyl and C C _6-20 aryl-, 4-10 membered heterocycloalkenyl and C _6-20 aryl-, C _4-10 cycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkenyl-C 6-20 aryl-, _5-20 membered heteroaryl, C _4-10 cycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl-, C _4-10 cycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl-5-20 membered heteroaryl-, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C -C(O)R ₃₁ , -C(O _{)OR 32 ,} -OC(O)R ₃₃ , -S(O _{) 2} R _{34 , -S (} O _{) 2 OR 35 , -OS ( O ) 2 R 36} , -P(O)(OR ₃₇ )(OR ₃₈ );

For example, the 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl group may be: 1-methylpyrrolidinyl, 1-ethylpyrrolidinyl, 1-cyclopropylpyrrolidinyl, 1-cyclopropylmethylpyrrolidinyl, 5-methyl-4,5-dihydropyridazin-3(2H)-onyl, 1-methylazetidinyl, 1-methylpiperidinyl;

m is an integer selected from 1 to 10;

Each R _e is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , NH ₂ , oxo (═O), thioxo (═S), O-CONH ₂ , O-CONHR _f , the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _f : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, _{3-20 membered heterocyclyl, C 1-20 alkyloxy} , C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _{3-20 cycloalkyloxy, C 3-20} cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _-6-20 membered heteroaryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C 2-20 alkenylthio, C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, C _1-8 -heteroalkyl-C 6-20-aryl-, C _1-8 -heteroalkyl-C _6-20 -aryl-, NH ₂ , -C(O)R ₄₁ , -C(O)OR ₄₂ , -OC(O)R ₄₃ , -S(O) ₂ R _{44 ,} -S(O) ₂ OR ₄₅ , -OS(O) ₂ R ₄₆ , -P(O)(OR ₄₇ )(OR ₄₈ );

Alternatively, when two or more substituents selected from R _e are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _f : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

Each _Rf is the same or different and is independently selected from H, halogen, OH, CN, _NO2 , oxo (=O), thioxo (=S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more _Rg : _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, _C3-20 cycloalkyl, _C3-20 cycloalkenyl, _C3-20 cycloalkynyl, C6-20 aryl, _5-20 membered heteroaryl, _{3-20 membered} heterocyclyl, C1-20 alkyloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, _C3-20 cycloalkyloxy, _C3-20 cycloalkenyloxy, C3-20 cycloalkynyloxy, C6-20 aryloxy, _5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, _C1-20 alkylthio, C _-C2-20 membered alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O) _{R51 ,} -C(O) _OR52 , -OC(O) _R53 , -S(O) _2R54 , -S(O) _2OR55 , _-OS (O) _2R56 , -P(O)( _{OR57 )} ( _OR58 ) _;

Alternatively, when two or more substituents selected from R _f are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _g : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

Each R _g is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, and NH ₂ ;

R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ , R ₃₇ , R ₃₈ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ , R _{46 , R 47} , R ₄₈ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₆ , R ₅₇ , R ₅₈ are the same or different _and are independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 membered aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, NH ₂ ;

The 3-20 membered heterocyclyl represents a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, such as 1, 2, 3, 4, 5 or more heteroatoms independently selected from O, S and N, wherein N and S may be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) ₂ -;

The C _6-20 aryl group represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, or spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together;

The 5-20 membered heteroaryl group represents a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1, 2, 3, 4, 5 or more heteroatoms independently selected from N, O and S.

According to an embodiment of the present disclosure, L represents an alkynyl group; a mono- or polycyclic C _6-20- aryl group or a mono- or polycyclic C _6-20 -aryl and 4-7 membered cycloalkyl group, which may be optionally substituted at the ortho, para or meta position by one, two, or three independent fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ groups, or 1, 2 or more substituted groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _1-1 , 3-10-membered heterocyclic-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-10- aryl, 3-10-membered heterocyclic-C _1-6 -alkyl, C _1-3 -fluoroalkyl, C 1-3 -alkyl-CN, C _1-3 -alkyl-OH, C _1-3 -alkyl-OR ^1.1 , C _1-3 -alkyl _- NH ₂ , C _1-3 -alkyl-NHR ^1.1 , CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-10-membered heterocyclic-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^1.2 R ^1.3 , each of which may in turn be optionally substituted by one, two or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10 -aryl and NR ^1.2 R ^1.3 , or,

L represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more substituted groups selected from OR ^1.1 , _C1-3 -alkyl-CN, C1-3-alkyl-OH, _C1-3 -alkyl-OR _1.1 , _C1-3 -alkyl-NH2, C1-3-alkyl-NHR _1.1 , _{C1-3 -} alkyl-OR ^1.1 , SR ^1.1 , _C1-3 - ^{alkyl-SR 1.1, SO-R 1.1, C1-3-alkyl-SOR 1.1, SO2-R 1.1 , C1-3 -} _alkyl ^- _SO2 ^R _{1.1 ,} ^{COOR 1.1} , _CH2COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , mono- or bicyclic C _3-10 -cycloalkyl, C _6-20- aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-10 membered heterocyclyl-C _6-20- aryl, 3-10 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by one, two or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20 -aryl and NR ^1.2 R ^1.3 ;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; in some embodiments, L is selected from a 5-membered monocyclic heteroaryl, a 5-membered heteroarylacene ring, a 5-membered heteroaryl and 5-10 membered heteroaryl, a 5-membered heteroaryl and 4-7 membered cycloalkyl, a 5-membered heteroaryl and 4-7 membered heterocycloalkyl, a 6-membered heteroarylacene ring, a 6-membered heteroaryl and 5-10 membered heteroaryl, a 6-membered heteroaryl and 6-membered heteroaryl, a 6-membered heteroaryl and 4-7 membered cycloalkyl, and a 6-membered heteroaryl and 4-7 membered heterocycloalkyl;

Cycloalkyl groups may be saturated or partially saturated;

R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, C _3-11 -mono- or bicyclic heterocycle, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, 3-10-membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20- aryl, 5-20-membered heteroaryl and heterocycle, which may optionally be selected from OH, O-(C _1-3 -alkyl), halogen, C _{1-10 -} alkyl and C _6-20- aryl;

R ^1.2 and R ^1.3 independently represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20- aryl, 3-10 membered heterocycle, heteroaromatic ring, CO-NH ₂ , CO-NH _- CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 radicals, which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^1.1 .

According to an embodiment of the present disclosure, examples of L may be selected from the following groups:

According to an embodiment of the present disclosure, each R _d2 is the same or different and independently represents hydrogen, halogen, cyano, hydroxy, CF ₃ , C _1-6 -alkyl, C _1-3 -fluoroalkyl, CHF ₂ , CH ₂ F, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ , SO ₂ -NR ^1.2 R ^1.3 , C _1-3 -alkyl-CN, C _1-3 -alkyl-OH, C _1-3 -alkyl-OR ^1.1 , C _1-3 -alkyl-NH ₂ or C _1-3 -alkyl-NHR ^1.1 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20- aryl and NR ^1.2 R ^1.3 ;

According to an embodiment of the present disclosure, R _e may be selected from OH;

Each _Rd6 is the same or different and independently represents H, F, Me, _C1-3 -alkyl-CN, _C1-3 -alkyl-OH, _C1-3 -alkyl- ^OR1.1 , _C1-3 -alkyl- _NH2 , _C1-3 -alkyl- ^NHR1.1 , C1-6 _- alkyl, _C2-6- alkenyl, C2-6 _- alkynyl, a mono- or polycyclic _{C6-20- aryl} or a mono- or polycyclic _C6-20 -aryl and 4-7 membered cycloalkyl, a mono- or polycyclic C6-20-heteroaryl and 4-7 membered cycloalkyl, _C6-10 -aryl- _C1-6 -alkyl, _C5-10 -heteroaryl- _C1-6 -alkyl, _C3-10 -heterocycle and _C5-10 -heterocycle, -NR'R", fluorine, C _{C 1-6-} fluoroalkyl and C _1-6- fluoroalkoxy, wherein R' and R" are independently selected from H and C _1-6- alkyl; said groups may be optionally substituted at each occurrence with 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl; or,

Each R _d6 is the same or different and independently represents H, F, Me, C _1-3 -alkyl-CN, C _1-3 -alkyl-OH, C _1-3 -alkyl-OR ^1.1 , C _1-3 -alkyl-NH ₂ , C _1-3 -alkyl-NHR ^1.1 , C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR'R", fluorine, C _1-6- fluoroalkyl and C _{1-6 -} fluoroalkoxy, wherein R' and R" are independently selected from H and C _1-6- alkyl; said groups may be optionally substituted at each occurrence by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl.

Alternatively, the two and R _d6 together with the atoms to which they are attached form a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged cycloalkyl, or a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocycle comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocycle being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 ,COOR ^2.1 ,CH ₂ COOR ^2.1 ,CH ₂ CH ₂ COOR ^2.1 ,CH＝CHCOOR ^2.1 ,CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO—NR ^2.1 , CH═CHCO—NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6- 20-} aryl), 3-10-membered heterocyclyl-C _6-20- aryl, 3-10-membered heterocycle, 5-20-membered heteroarylC _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _{6- 20-} aryl and NR ^2.2 R ^2.3 ;

R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20- aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci- ₆ -alkyl, 3-10-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic C6-20 _- aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with substituents selected from OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and C6-20 _- aryl;

R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20- aryl, 3-10-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 .

Each R _c is the same or different and independently represents hydrogen, a mono- or polycyclic C _6-20 -aryl group or a mono- or polycyclic C _6-20 -aryl and 4-7 membered cycloalkyl group, for example C _4-10 cycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkenyl and C _6-20 aryl-, C _4-10 cycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkenyl-C _6-20 aryl-, _5-20 membered heteroaryl, C _4-10 cycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl-, C _4-10 -membered cycloalkyl-5-20-membered heteroaryl-, 4-10-membered heterocycloalkyl-5-20-membered heteroaryl-, 4-10-membered heterocycloalkenyl-5-20-membered heteroaryl-, or selected from 5-20-membered heteroaryl-OC _6-20 aryl-, 5-20-membered heteroaryl-NC _6-20 aryl-, 5-20-membered heteroaryl-SC _6-20 aryl-, 5-20-membered heteroaryl-CH ₂ -C _6-20 aryl-, the above groups may be optionally substituted at the ortho, para or meta position with one, two or three substituents of fluorine, chlorine, bromine, iodine, hydroxyl, CN, NO ₂ , NH ₂ , or with one, two or more substituents selected from OR ^4.1 , COOR ^4.1 CH ₂ COOR ^4.1 , CH ₂ CH ₂ COOR ^4.1 , CH＝CHCOOR ^4.1 ,CO-NR ^4.1 CH ₂ CO-NR ^4.1 ,CH ₂ CH ₂ CO-NR ^4.1 ,CH＝CHCO-NR ^4.1 ,NR ^4.2 R ^4.3 ,CH ₂ -NR ^4.2 R ^4.3 ,CH ₂ CH ₂ -NR ^4.2 R ^4.3 ,C _1-3 -alkyl-CN, C _1-3 -alkyl-OH, C _1-3 -alkyl-OR ^4.1 , C _1-3 -alkyl-NH ₂ , C _1-3 -alkyl-NHR ^4.1 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic C _6-20- aryl), 3-10 membered heterocyclyl-C _6-20- aryl, 3-10 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-10-membered heterocyclic-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^4.2 R ^4.3 ;

_4.1 ^{, COOR 4.1} _{, CH} ² _COOR 4.1 , CH ₂ CH ₂ COOR ^{4.1 , CH} ＝CHCOOR _4.1 ^{, CO —} _NR ^4.1 _{, CH 2 CO — NR} ^{4.1 ,} _CH ² CH ₂ CO-NR ^4.1 , CH＝CHCO-NR ^4.1 , COR ^4.1 , CH ₂ COR ^4.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20- aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-10 membered heterocyclyl-C _6-20- aryl, 3-10 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^4.1 and NR ^4.2 R ^4.3 , each of which may be optionally substituted by OH, OR ^4.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _6-10- aryl and NR ^4.2 R ^4.3 are substituted by one, two or more substituents;

Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

The heteroaryl ring is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group including 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; in some embodiments _R4 is selected from a 5-membered monocyclic heteroaryl, a 5-membered heteroarylacene ring, a 5-membered heteroaryl and 5-10 membered heteroaryl, a 5-membered heteroaryl and 4-7 membered cycloalkyl, a 5-membered heteroaryl and 4-7 membered heterocycloalkyl, a 6-membered heteroarylacene ring, a 6-membered heteroaryl and 5-10 membered heteroaryl, a 6-membered heteroaryl and 6-membered heteroaryl, a 6-membered heteroaryl and 4-7 membered cycloalkyl, and a 6-membered heteroaryl and 4-7 membered heterocycloalkyl;

Cycloalkyl groups may be saturated or partially saturated;

R ^4.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20- aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci- ₆ -alkyl, 3-10-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic C6-20 _- aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C5-10 aryl substituents;

R ^4.2 and R ^4.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-10-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^4.1 and COOR ^4.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^4.1 .

For example, the 4-10 membered heterocyclic group or 4-10 membered heterocycloalkenyl group can be: 1-methylpyrrolidinyl, 1-ethylpyrrolidinyl, 1-cyclopropylpyrrolidinyl, 1-cyclopropylmethylpyrrolidinyl, 5-methyl-4,5-dihydropyridazin-3(2H)-one, 1-methylazetidinyl, 1-methylpiperidinyl.

Alternatively, according to the compound represented by Formula H or Formula G of the present disclosure (for example, one of the compounds represented by Formulas I to IX), its racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, when present, R ₁ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two, or three fluorine, chlorine, bromine, iodine, hydroxyl, -NHOH, -C _1-3 -alkyl-NHOH, -C _1-3 -CO-NHOH, -CO-NHOH, -C _1-3 -alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, CN, NO ₂ , NH ₂ substituents, or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 ,CH＝CHCOOR ^1.1 ,CO-NR ^1.1 CH ₂ CO-NR ^1.1 ,CH ₂ CH ₂ CO-NR ^1.1 ,CH＝CHCO-NR ^1.1 ,NR ^1.2 R ^1.3 ,CH ₂ -NR ^1.2 R ^1.3 ,CH ₂ CH ₂ -NR ^1.2 R ^1.3 ,C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _{6- 20-} aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -C _1-6 -alkyl, -C _6-20 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which may in turn be optionally substituted with 1, 2 or more substituents selected from OH, CN, C _1-3 -alkyl-CN, -SH, -NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _1-3 -alkyl-CO-NHOH, -CO-NHOH, -C _1-3 -alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, C _2-6 -alkenyl, -OC _3-8 -cycloalkyl, COOR ^1.1 , C _1-3 -alkyl-COOR ^1.1 , CONHR ^1.1 , C _1-3 -alkyl-CONHR ^1.1 , ^-OR1.1 , oxo, halogen, _CF3 , _CHF2 , _CH2F , _C1-6 -alkyl, _C6-20- aryl and ^NR1.2R1.3 ; wherein ^R1.1 , ^R1.2 and ^R1.3 have the meanings described above and ^below .

Alternatively, according to the compound represented by Formula H or Formula G of the present disclosure (for example, one of the compounds represented by Formulas I to IX), its racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, when present, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta position by one, two or three halogen, OH, CN, NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _{1-3 -alkyl} -CO-NHOH, -CO-NHOH, -C _1-3 -alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, nitro, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^1.1 , COOR ^1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20- aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocyclic, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 substituents, each of which may be optionally substituted by OH, CN, C _1-3 -alkyl-CN, -SH, -NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _1-3 -alkyl-CO-NHOH, -CO-NHOH, -C _1-3 -alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, C _2-6 -alkenyl, -OC _3-8 -cycloalkyl, COOR ^1.1 , C _1-3 -alkyl-COOR ^1.1 , CONHR ^1.1 , C _1-3 -alkyl-CONHR ^1.1 , OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^2.3 ; wherein R ^1.1 , R ^1.2 and R ^1.3 have the definitions described above and below.

Alternatively, according to the compound represented by Formula H or Formula G of the present disclosure (for example, one of the compounds represented by Formulas I to IX), its racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, when present, R ₂ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two, or three fluorine, chlorine, bromine, iodine, hydroxyl, CN, NO ₂ , NH ₂ substituents, or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , C(CH ₃ ) ₂ COOR ^2.1 , CF ₂ COOR ^2.1 , CHFCOOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 , CH ₂ CO-NR ^2.1 ,CH ₂ CH ₂ CO-NR ^2.1 ,CH＝CHCO-NR ^2.1 ,NR ^2.2 R ^2.3 ,CH ₂ -NR ^2.2 R ^2.3 ,CH ₂ CH ₂ -NR ^2.2 R ^2.3 ,C _3-10 -cycloalkyl, COOR ^2.1 -C _3-8- cycloalkyl, CO-NR ^2.1 -C _3-8 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6- alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ - _2.2 R ^2.3 , each _of which may in turn be optionally substituted with one, two or more substituents selected from OH, CN, C _1-3 -alkyl-CN, -SH, -NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _1-3 -alkyl ^- CO-NHOH, -CO-NHOH, -C _1-3 -alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR _1.1 CN, -CHO, C _2-6 -alkenyl, -OC _3-8 -cycloalkyl, COOR ^1.1 , C _1-3 -COOR ^1.1 , CONHR ^1.1 , C _1-3 -alkyl-CONHR ^{1.1 ,} OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20- aryl and substituted by a substituent in NR ^2.2 R ^2.3 , CCOOR ^2.1 ; wherein R ^2.1 , R ^2.2 and R ^2.3 have the definitions described above and below.

Alternatively, according to the compound represented by Formula H or Formula G of the present disclosure (for example, one of the compounds represented by Formulas I to IX), its racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, when present, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta position by one, two or three halogen, OH, CN, NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _{1-3 -alkyl} -CO _- NHOH, -CO-NHOH, -C _1-3 -alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, nitro, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 ,SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 ,SO ₂ -R ^2.1 ,C _1-3 -alkyl-SO ₂ R ^2.1 ,COOR ^2.1 ,CH ₂ COOR ^2.1 ,COOR ^2.1 -C _3-8 -cycloalkyl, CO-NR ^2.1 -C _3-8 -cycloalkyl, CH ₂ CH ₂ COOR ^2.1 ,CH＝CHCOOR ^2.1 ,CO-NR ^2.1 CH ₂ CO-NR ^2.1 ,CH ₂ CH ₂ CO-NR ^2.1 ,CH＝CHCO-NR ^2.1 ,COR ^2.1 ,CH ₂ COR ^2.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _{3- 10} -cycloalkyl, C _2.2 R 2.3, each of which is optionally substituted by _{1, 2} or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ ^, _{CH 2 F} , C _{1-6 -} alkyl, C _{6-20 -} aryl and NR _2.2 R ^2.3 ; wherein _R ^{2.1 , R 2.2 and} _R ^2.3 have the definitions described ^above or below.

Alternatively, according to the compound represented by Formula H or Formula G of the present disclosure (e.g., one of the compounds represented by Formulas I to IX), its racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof, when present, R ₂ and R _2' , together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination, or optionally bridged heterocyclic ring comprising 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O, wherein the heterocyclic ring is unsubstituted or optionally substituted at the ortho, para, or meta position with 1, 2, or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , C _1-3 -alkyl-OC _1-3 -alkyl-COOH, C _1-3 -alkyl-OC _1-3 -alkyl-CONR ^2.1 , C _1-3 -alkyl-phosphoric acid, C _1-3 -alkyl-OC(O)-OR ^2.1 , C _1-3 -alkyl-OC(O)-NR ^2.1 , C _1-3 -alkyl-OC(═O)-C _1-3 -alkyl-(OC _1-3 -alkyl)v, C _1-3 -alkyl-OC(═O)-C _1-6 -alkyl-COOR ^2.1 , C _1-3 -alkyl-NC(═O)-C _1-6 -alkyl-COOR ^2.1 , C _1-3 -alkyl-NC(═O)-OC _1-6 -alkyl-COOR ^2.1 , C _1-3 -alkyl-NC(═O)-NC _1-6 -alkyl-COOR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 ,SO ₂ -R ^2.1 ,C _1-3 -alkyl-SO ₂ R ^2.1 ,COOR ^2.1 ,CH ₂ COOR ^2.1 ,CH ₂ CH ₂ COOR ^2.1 ,CH＝CHCOOR ^2.1 ,CO-NR ^2.1 ,CH ₂ CO-NR ^2.1 ,CH ₂ CH ₂ CO-NR ^2.1 ,CH＝CHCO-NR ^2.1 ,COR ^2.1 ,CH ₂ COR ^2.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C 3-10 _2.3 , C _6-20 -aryl; each of which may in turn be optionally replaced by one, two or more substituents selected from OH, CN, C _1-3 -alkyl-CN, C ^1-3 _{-alkyl -} NH ² , -SH, -NH ² , -NHOH, -C ^1-3 -alkyl- _NHOH , -C _1-3 -alkyl _- CO-NHOH, -CO-NHOH ^, -C _{1-3 -alkyl} -NH-CO-NR _1.2 R ^{1.3 ,} -NR ^1.1 CN, -CHO, C _2-6 -alkenyl, -OC _3-8 -cycloalkyl, COOR ^1.1 , C _1-3 -alkyl-COOR ^1.1 , CONHR ^1.1 , C _1-3 -alkyl-CONHR ^1.1 , -OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20- aryl and NR ^1.2 R ^1.3 , wherein R ^2.1 , R ^1.2 , R ^1.3 and v have the meanings given above and below herein.

Alternatively, according to the compound represented by Formula H or Formula G of the present disclosure (for example, one of the compounds represented by Formulas I to IX), its racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, when present, each R ₃₁ , R ₃₂ , R 33 , R ₃₄ , R 35 , R ₃₆ , R ₃₇ , R ₃₈ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ , R ₄₆ , R ₄₇ , R ₄₈ , R ₅₁ , R ₅₂ , R ₅₃ , R _{54 ,} R ₅₅ , R ₅₆ , R ₅₇ , R ₅₈ are the same or different and are independently selected from H _, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1.2 R 1.3 , -NR _1.1 CN, -CHO, C _2-6 -alkenyl, -OC _{3- 8} -cycloalkyl, COOR _1.1 , C _1-3 -alkyl-COOR 1.1 , CONHR 1.1 , C _1-3 -alkyl-NHOH, -C _1-3 -alkyl-CO - NHOH, -CO - NHOH _, -C _{1-3 -alkyl} -NH _- CO _- NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO ^, C _2-6 -alkenyl, -OC _{3- 8} -cycloalkyl, _{COOR 1.1 ,} C _1-3 -alkyl-COOR _1.1 ^, CONHR ^1.1 , C _1-3 -alkyl-CONHR ^1.1 , OR ^2.1 , oxo, halogen substituted by one, two or more substituents selected from halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^2.3 ; wherein R ^1.1 , R ^1.2 , R ^2.1 and R ^2.3 have the definitions described above and below.

Alternatively, according to the compound represented by Formula H or Formula G of the present disclosure (e.g., one of the compounds represented by Formulas I to IX), its racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof, when present, each R _c is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _c : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _{3-20 cycloalkynyl, C 6-20 aryl} , C _1-6 alkyl-C _4-10 heterocycloalkyl, C _1-6 alkyl-C _4-10 heterocycloalkenyl, C _1-6 alkyl-C _6-20 aryl, C _1-6 alkyl-C _5-20 membered heteroaryl, 5-20 membered heteroaryl-OC _6-20 aryl-, 5-20 membered heteroaryl-NC _6-20 aryl-, 5-20 membered heteroaryl-SC _6-20 aryl-, 5-20 membered heteroaryl-CH ₂ -C _6-20 aryl-, C _4-10 cycloalkyl and C 6-20 aryl-, 4-10 membered heterocycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkenyl and C _6-20 aryl-, C _4-10 cycloalkyl-C _6-20 aryl-, _{4-10 membered heterocycloalkyl-C 6-20 aryl-} , 4-10 membered heterocycloalkenyl-C _6-20 aryl-, 5-20 membered heteroaryl, C _4-10 -membered heteroaryl-, 4-10-membered heterocycloalkyl-5-20-membered heteroaryl-, 4-10-membered heterocycloalkenyl-5-20-membered heteroaryl-, C _4-10- membered heterocycloalkyl-5-20-membered heteroaryl-, 4-10-membered heterocycloalkenyl-5-20-membered heteroaryl-, 3-20-membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy, _5-20 -membered heteroaryloxy, 3-20 _{-membered heterocyclyloxy, C 1-20 alkylthio} , C _2-20 alkenylthio, C -C(O) _R31 , -C(O ₎ OR32, -OC(O ₎ R33, -S(O ₎ 2R34, -S(O _{) 2OR35} , -OS(O) _2R36 , -P(O)( _OR37 ) _{( OR38} ) _; wherein _{R31 ,} R32 _{, R33} , _R34 , _R35 , _R36 , _{R37 , and R38 have} the definitions described herein _above and _below .

Unless otherwise defined, in the compounds of any one of Formulas I to IX in the context of the present disclosure, when some substituents are defined as two connected groups (such as the form of "group 1-group 2", wherein group 1 and group 2 are the same or different), the position at which the substituents form a bond in the compound of any one of Formulas I to IX is not particularly limited, for example, group 1 may be bonded to the connection position in the compound of any one of Formulas I to IX, or group 2 may be bonded to the connection position in the compound of any one of Formulas I to IX, as long as the above-mentioned bonding conforms to the valence bond theory. In addition, the connection position between the two connected groups (such as group 1 and group 2) is not particularly limited, as long as the above-mentioned connection conforms to the valence bond theory.

For the purpose of illustration, for example, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 5-20-membered heteroarylC _1-3 -alkyl-OR ^1.1 , 3-20-membered heterocyclyl-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl and the like groups, which may represent C _6-20- aryl-C _1-6 -alkyl-, 5-20-membered heteroaryl-C _1-6 alkyl-, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl)-, 3-20-membered heterocyclyl-C _6-20- aryl-, 5-20-membered heteroarylC _1-3 -alkyl-OR ^1.1 -, 3-20-membered heterocyclic-C _1-6 -alkyl-, C _3-10 -cycloalkyl-C _1-6 -alkyl-, -C _6-20- aryl-C _1-6 -alkyl, -5-20-membered heteroaryl-C _1-6 alkyl, -C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), -3-20-membered heterocyclic-C _6-20- aryl, -5-20-membered heteroarylC _1-3 -alkyl-OR ^1.1 , -3-20-membered heterocyclic-C _1-6 -alkyl, -C _3-10 -cycloalkyl-C _1-6 -alkyl.

It should be understood that, for the above-mentioned "group 1-group 2" form, if a chemical bond "-" is added to the left side of group 1 or the right side of group 2, it means that its connection position in the compound described in any one of Formulas I to IX has been determined, and the position where it forms a bond in the compound described in any one of Formulas I to IX is the corresponding group to which the chemical bond is added.

The present disclosure also provides a method for preparing a compound represented by Formula H, its racemate, stereoisomer, tautomer, isotope-labeled product, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein the preparation method comprises reacting a compound of Formula A1 with a compound of Formula B1 to obtain a compound of Formula G:

Wherein, LG is a leaving group, such as Cl, Br or I;

X ₁ , L, W, _Ra , _Rb , _Rc , R ₂ , R _2′ and m are independently defined as above.

The present disclosure also provides a method for preparing a compound represented by Formula G, its racemate, stereoisomer, tautomer, isotope-labeled product, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein the preparation method comprises reacting a compound of Formula A with a compound of Formula B to obtain a compound of Formula G:

and optionally, derivatizing the compound of formula G into a stereoisomer, tautomer, isotopically labeled form, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof;

Wherein, LG is a leaving group, such as Cl, Br or I;

Cy, W, _Ra , _Rb , Rc, _R2 , R2 _{' ,} and m are independently defined above.

According to an embodiment of the present disclosure, if necessary, the reaction can be carried out under the condition that a protecting group is provided on the compound of formula A1, A2, B1 or B2. For example, the protecting group can be selected from an amino protecting group, a hydroxy protecting group or the like. Suitable protecting groups can be selected from C _1-40 alkyl, C _6-20 aryl, C _1-40 alkyl-, such as tert-butyl, isopropyl, benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl.

According to an embodiment of the present disclosure, the preparation method can be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent can be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropyl alcohol, and n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, biphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichlorodiethyl ether, and Polyethers of ethylene oxide and/or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and those possibly substituted by fluorine and chlorine atoms, such as methylene chloride, dichloromethane, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.

The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Formula H or Formula G (e.g., any one of the compounds represented by Formulas I to IX), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt, or at least one of its prodrug compounds.

According to an embodiment of the present disclosure, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

According to an embodiment of the present disclosure, the pharmaceutical composition may further contain one or more additional therapeutic agents. The additional therapeutic agent may be selected from therapeutic agents having the same or different targets as the disclosed compound, such as cancer therapeutic agents.

The present disclosure also provides the use of at least one of the compounds represented by Formula H or Formula G (e.g., one of the compounds represented by Formulas I to IX), their racemates, stereoisomers, tautomers, isotope-labeled substances, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof in the preparation of a drug.

The medicament can be used to prevent or treat a disease.

The present invention also provides a method for preventing or treating a disease, comprising administering to a patient in need thereof at least one of a compound represented by Formula H or Formula G (e.g., one of the compounds represented by Formulas I to IX), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt, or a prodrug compound thereof.

According to an embodiment of the present invention, the disease may be a PDE4B-mediated disease, or at least a disease mediated by PDE4.

For example, the disease mediated at least by PDE4 is selected from diseases mediated by PDE4, or diseases mediated by at least one (eg, 1, 2, 3, or 4) of PDE1, PDE2, PDE3, and PDE5.

For example, the medicament can be used to prevent or treat a disease mediated by PDE4 and at least one (eg, 1, 2, 3, or 4) selected from PDE1, PDE2, PDE3, and PDE5.

According to embodiments of the present disclosure, the PDE4 is selected from the group consisting of PDE4A, PDE4B (eg, PDE4B2), PDE4C, and PDE4D (eg, PDE4D2).

According to an embodiment of the present disclosure, the PDEl is selected from the group consisting of PDElA, PDElB and PDElC.

According to an embodiment of the present disclosure, the PDE2 is selected from PDE2A.

According to an embodiment of the present disclosure, the PDE3 is selected from PDE3A and PDE3B.

According to an embodiment of the present disclosure, the PDE5 is selected from PDE5A.

According to an embodiment of the present invention, the diseases include but are not limited to respiratory inflammatory diseases, inflammatory bowel diseases, arthritic diseases, skin inflammatory diseases, eye inflammatory diseases, diseases of the peripheral or central nervous system, degenerative lesions of the central nervous system, Alzheimer's disease (AD), non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF) or pulmonary hypertension associated therewith, chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), and pulmonary fibrosis. tive pulmonary disease (COPD) or its related pulmonary hypertension (Pulmonary Hypertension), hepatic fibrosis (HF), renal fibrosis (Renal fibrosis), benign prostatic hyperplasia (BPH), gastroesophageal reflux disease (Gastroesophageal Reflux disease), obstructive sleep apnea and coronary artery disease (Coronary Artery Disease) or cancer.

According to an embodiment of the present invention, the cancer includes but is not limited to one selected from the following: gastric cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, neck cancer, oral or nasal mucosal cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer and/or thyroid cancer.

According to an embodiment of the present invention, since the compounds disclosed herein have specific tissue distribution and/or low hERG inhibitory effect, the diseases are preferably selected from those diseases that are particularly advantageous when prevented or treated with compounds having specific tissue distribution and/or low hERG inhibitory effect.

For example, the focus of the disease (i.e., the part where pathological changes occur) includes the respiratory system, digestive system, excretory system and/or reproductive system, such as liver, kidney and/or prostate. For this purpose, the medicine can be a targeted drug for the respiratory system, digestive system, excretory system and/or reproductive system, such as a liver targeted drug, a kidney targeted drug and/or a prostate targeted drug.

When used as a drug, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be topical (e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. It can be administered parenterally in a single bolus form, or it can be administered by, for example, a continuous infusion pump. Topically administered pharmaceutical compositions and preparations may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, water, powders or oily bases, thickeners, etc. may be necessary or required.

In preparing the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted by the excipient, or enclosed in a carrier such as a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid substance that acts as a solvent, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may also contain: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents. The compositions of the present disclosure can be formulated using methods known in the art so as to provide immediate, sustained, or delayed release of the active ingredient after administration to the patient.

The compositions can be formulated in unit dosage form, each dose containing about 5 to 1000 mg, more usually about 100 to 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as single dosage units for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in admixture with a suitable pharmaceutical excipient.

The effective dosage of the active compound can range widely and is generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of compound administered will generally be determined by the physician based on the relevant circumstances, including the condition being treated, the route of administration chosen, the dosage of the compound administered, and the dosage of the compound administered. the actual compound used; the age, weight, and response of the individual patient; the severity of the patient's symptoms, etc.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of a compound of the present disclosure. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is generally evenly distributed throughout the composition, such that the composition can be readily divided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then divided into unit dosage forms of the type described above, containing, for example, about 0.1 to 1000 mg of the active ingredient of the present disclosure.

The tablets or pills of the present disclosure may be coated or compounded to provide dosage forms that offer the advantage of prolonged action. For example, a tablet or pill may contain an inner dosage component and an outer dosage component, the outer dosage component being in the form of a film coating the outer dosage component. The two components may be separated by an enteric layer that serves to prevent disintegration in the stomach, thereby allowing the inner component to pass intact into the duodenum or to be released later. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with such materials, such as shellac, cetyl alcohol, and cellulose acetate.

Liquid forms for oral or parenteral administration in which the disclosed compounds and compositions can be incorporated include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions; and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil; as well as elixirs and similar pharmaceutically acceptable vehicles.

Compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents, or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions may be aerosolized using an inert gas. Aerosolized solutions may be inhaled directly from a nebulizing device, or the nebulizing device may be connected to a mask curtain or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally using a device that delivers the formulation in an appropriate manner.

The amount of compound or composition administered to a patient is not fixed and depends on the agent being administered, the purpose of administration, e.g., prevention or treatment; the patient's condition; the mode of administration; and the like. In therapeutic applications, the composition may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease being treated and the judgment of the attending clinician, which will depend on factors such as the severity of the disease, the patient's age, weight, and general condition.

The compositions administered to patients can be in the form of pharmaceutical compositions as described above. These compositions can be sterilized by conventional sterilization techniques or by filtration. Aqueous solutions can be packaged for use as is or lyophilized, and the lyophilized formulation can be mixed with a sterile aqueous carrier prior to administration. The pH of the compound formulation is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of some of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

The therapeutic dose of the disclosed compounds may depend on, for example, the specific use of the treatment, the manner in which the compound is administered, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the disclosed compounds may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg/kg to about 1 g/kg body weight/day. In certain embodiments, the dosage range is about 0.01 mg/kg to about 100 mg/kg body weight/day. The dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

Beneficial effects

The present disclosure provides novel compounds comprising a novel pyrimidine-fused ring as a core, novel side chains, novel linkers, and substituents. The compounds disclosed herein exhibit excellent PDE4B inhibitory activity, even at the pmol level. The compounds disclosed herein also exhibit selective PDE4B inhibitory activity, particularly PDE4B/4D selective inhibitory activity. Some compounds also surprisingly exhibit dual- or multi-target inhibitory activity.

The compounds disclosed herein can be used to treat respiratory inflammatory diseases, inflammatory bowel disease, arthritic diseases, inflammatory skin diseases, inflammatory eye diseases, and diseases or cancers of the peripheral or central nervous system. Furthermore, the compounds disclosed herein have specific tissue distribution and/or low hERG inhibition, thus possessing promising potential as tissue-targeted drugs and improved tissue toxicity.

Definitions and Explanations of Terms

Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and/or claims.

Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to at least each specific Integer values. For example, the numerical range "1-20" is equivalent to recording each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-40", namely 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In addition, when certain numerical ranges are described as "numbers", it should be understood that the two endpoints of the range, each integer in the range, and each decimal in the range are recorded. For example, "a number from 0 to 10" should be understood as recording not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.

It should be understood that herein, when describing 1, 2 or more, "more" should refer to an integer greater than 2, for example, greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "C _1-20 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1 to 20 carbon atoms. For example, "C _1-10 alkyl" means a linear or branched alkyl radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and "C _1-6 alkyl" means a linear or branched alkyl radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like, or isomers thereof.

The term " _C2-20 alkenyl" is understood to preferably mean a linear or branched monovalent hydrocarbon group containing 1, 2 or more double bonds and having 2 to 20 carbon atoms, preferably " _C2-10 alkenyl". " _C2-10 alkenyl" is understood to preferably mean a linear or branched monovalent hydrocarbon group containing 1, 2 or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., _C2-6 alkenyl), having 2 or 3 carbon atoms (i.e., _C2-3 alkenyl). It is understood that when the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

The term "C _2-20 alkynyl" is understood to mean a straight or branched monovalent hydrocarbon radical containing 1, 2 or more triple bonds and having 2 to 20 carbon atoms, preferably a "C _2-10 alkynyl". The term "C _2-10 alkynyl" is understood to mean preferably a straight or branched monovalent hydrocarbon radical containing 1, 2 or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., "C _2-6 alkynyl"), having 2 or 3 carbon atoms ("C _2-3 alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term " _C3-20 cycloalkyl" is understood to mean a saturated or unsaturated (e.g., partially unsaturated) monovalent monocyclic, bicyclic (e.g., fused, bridged, or spiro) hydrocarbon ring or tricyclic alkane having 3 to 20 carbon atoms, preferably " _C3-10 cycloalkyl". The term " _C3-10 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (e.g., bridged, or spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The _C3-10 cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1] heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

Those skilled in the art will understand that the term "C _3-20 cycloalkyl" does not have aromatic properties. Furthermore, when the "C _3-20 cycloalkyl" is unsaturated, it may have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds. When a "C _3-20 cycloalkyl" has a carbon-carbon double bond, it may also be referred to as a "C _3-20 cycloalkenyl"; when a "C _3-20 cycloalkyl" has a carbon-carbon triple bond, it may also be referred to as a "C _3-20 cycloalkynyl."

Unless otherwise defined, the term "3-20 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) ₂ -. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic group can be connected to the rest of the molecule by any one of the carbon atoms or nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group can include but is not limited to: 4-membered rings, such as azetidinyl, oxetane; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one, two, or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. When the 3-20-membered heterocyclic group is linked to other groups to form the compounds of the present disclosure, the carbon atoms on the 3-20-membered heterocyclic group may be linked to the other groups, or heteroatoms on the 3-20-membered heterocyclic group may be linked to the other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be linked to another group. Or when the 3-20 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be linked to another group. For example, the substituted 4-10 membered heterocyclic group may be selected from: 1-methylpyrrolidinyl, 1-ethylpyrrolidinyl, 1-cyclopropylpyrrolidinyl, 1-cyclopropylmethylpyrrolidinyl, 5-methyl-4,5-dihydropyridazin-3(2H)-one, 1-methylazetidinyl, 1-methylpiperidinyl;

The term "C _6-20 aryl" should be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or multiple aromatic rings fused together, preferably _" C _6-14 aryl". The term " _C6-14 aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" _C6-14 aryl"), in particular a ring having 6 carbon atoms (" _C6 aryl"), for example phenyl or biphenyl, or a ring having 9 carbon atoms (" _C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms (" _C10 aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (" _C13 aryl"), for example fluorenyl, or a ring having 14 carbon atoms (" _C14 aryl"), for example anthracenyl. When the _C6-20 aryl is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution position, and for example, substitution can be at the ortho, para or meta position.

The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in each case, may be benzofused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one, two or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples of the term heteroaryl include, for example, pyridinyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, pyridazinyl; and 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl. , 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2- , 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbazolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-pyridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthrolinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzoisoquinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5 1-, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]thiazolyl, 2-, 4-, or 5-1H-imidazo[4,5-d]thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10-, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5- to 20-membered heteroaryl group is linked to other groups to form the compounds of the present disclosure, it can be a carbon atom on the 5- to 20-membered heteroaryl ring linked to the other groups, or it can be a heteroatom on the 5- to 20-membered heteroaryl ring linked to the other groups. When the 5- to 20-membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site. For example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.

The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

The term "fused ring" refers to a ring system in which two rings share two ring atoms.

The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

Unless otherwise specified, heterocyclyl, 5-20 membered heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include 1, 2 or more substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

The term "oxo (=O)" refers to the replacement of hydrogen or lone electron pairs on non-oxygen atoms with oxygen, for example, After being oxygenated After being oxygenated

Unless otherwise stated, the definition of a term herein also applies to the group containing the term, for example, the definition of C _1-6 alkyl also applies to C _1-6 alkyloxy, C _3-8 cycloalkyl-C _1-6 alkyl-, etc.

In the context of this disclosure, "-", "--", "---" or " All are intended to mark the chemical bonds for attachment of the substituents;

Those skilled in the art will appreciate that the compounds of Formula I may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

The compounds of the present disclosure may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present disclosure contain a polar solvent, such as water, methanol, or ethanol, as a structural element of the crystal lattice of the compound. The amount of the polar solvent, particularly water, may be present in a stoichiometric or non-stoichiometric ratio.

As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the invention and is relatively non-toxic, i.e., the substance can be administered to a subject without causing an adverse biological reaction or interacting in an adverse manner with the composition. Any components contained in the compound interact with each other.

It will be appreciated by those skilled in the art that the compounds of the present disclosure may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or the intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane/isopropanol/acetonitrile. The corresponding stable isomers can be separated according to known methods, for example, by extraction, filtration, or column chromatography.

"Isotopes" are all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to ^{, 2H} , ^3H , ^13C , ^14C , ^15N , ^18O , ^31P , ^32P , ^35S , ^18F , and ^36Cl , respectively. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents. Such compounds have various potential uses, for example, as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

The term "prodrug" refers to a compound of the present disclosure that can be converted to biologically active compounds under physiological conditions or by solvolysis. Prodrugs of the present disclosure are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present disclosure is linked to any group. When a prodrug of a compound of the present disclosure is administered to a mammalian subject, the prodrug is cleaved to form free hydroxyl groups and free amino groups, respectively.

The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.

DETAILED DESCRIPTION

The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Preparation.

Glossary of abbreviations
DMF: N,N-dimethylformamide
DCM: dichloromethane
DIEA: N,N-diisopropylethylamine
TEA: triethylamine
PE: Petroleum ether
EA: ethyl acetate
MeCN: acetonitrile
Et ₂ O: diethyl ether
DMSO: dimethyl sulfoxide
EtOAc: ethyl acetate
THF: Tetrahydrofuran
TFA: trifluoroacetic acid
MeOH: methanol
EtOH: ethanol
NaH: sodium hydride
MeI: methyl iodide
EtI: ethyl iodide
HFP:1,1,1,3,3,3-hexafluoro-2-propanol
DHP:3,4-dihydro-2H-pyran
PPTS:4-Pyridinium methylbenzenesulfonate
PPh ₃ :triphenylphosphine
DEAD: Diethyl azodicarboxylate
MsCl: Methanesulfonyl chloride
TMSOTf: trimethylsilyl trifluoromethanesulfonate
m-CPBA: meta-chloroperbenzoic acid

Analytical methods

1. Nuclear magnetic resonance (NMR) spectra were recorded on a 400 MHz Brönsted AVANCE 500 instrument. Chemical shifts are reported in ppm using tritiated residual solvent as the internal standard. Peak magnifications are indicated as follows: s, singlet; d, doublet; dd, doublet-of-doublet; t, triplet; dt, triplet-of-doublet; q, quartet; m, multiplet; br s, broad singlet.

2. Sample purity analysis was performed on a Waters HPLC/Waters MS system.

Chromatographic conditions 1:

Chromatographic column Waters X-Bridge-C1850mm*4.6mm*3.5μm

The column temperature was 40°C.

Sample temperature: room temperature

Detects UV 214nm, UV 254nm

Flow rate: 2 mL/min: 2 mL/minute.

Mobile phase A: water (0.05% TFA)

Mobile phase B: MeCN (0.05% TFA)

Gradient program: B from 5% to 100% in 1.6 min, hold at 100% for 1.4 min.

Chromatographic condition 2:

Chromatographic column: Waters X-Brdige C18 Waters X-Brdige C18: 4.6mm*50mm*3.5μm

The column temperature was 40°C.

Sample temperature: room temperature

Detects UV 214nm, UV 254nm

Flow rate: 2 mL/min.

Mobile phase A: water (0.01 mol/L NH4HCO3) B: MeCN

Mobile phase B: MeCN

Gradient program: B from 5% to 100% in 1.6 min, hold at 100% for 1.4 min.

3. Preparative HPLC was performed on a Gilson 281.

Flow rate: 20 mL/min: 20 mL/min.

Column: X-Select 10μm 19X-Select 10μm 19*250mm column

Wavelength: 254nM or 214nM

Solvent A: water (10 mM NH4HCO3) and solvent B: MeCN.

Example 1: Synthesis Example

1. Synthesis scheme:

2. Experimental part:

2.1

(S)-tert-Butyl 4-(5-chloropyrimidin-2-yl)-3-(cyanomethyl)piperazine-1-carboxylate (02010-1)

To a solution of 2,5-dichloropyrimidine (66 mg, 0.671 mmol) and DIEA (346.4 mg, 2.685 mmol) in NMP (3 mL) at room temperature was added tert-butyl 3-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.671 mmol). The mixture was then stirred at 100°C overnight, water (10 mL) was added, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/4, silica gel-CS 12 g, 30 mL/min, silica gel, UV 254) to give the product as a yellow solid (46 mg, yield 30.7%).

ESI-MS m/z calcd for[C ₁₅ H ₂₀ ClN ₅ O ₂ ][M-56+H] ⁺ :282.1; found:282.2

2.2

2-((S)-1-(5-chloropyrimidin-2-yl)-4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-2-yl)acetonitrile (MX02010)

A solution of (S)-tert-butyl 4-(5-chloropyrimidin-2-yl)-3-(cyanomethyl)piperazine-1-carboxylate (60 mg, 0.178 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (51 mg, 0.178 mmol) in HFP (3 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (16.6 mg, yield 19.1%).

ESI-MS m/z calcd for[C ₂₁ H ₂₅ ClN ₈ O ₂ S][M+H] ⁺ :489.2; found:489.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.53(s,2H),7.49(s,1H),5.11(s,1H),4.82(t,J＝5.2Hz,1H),4.61–4.47(m,3H),3.76–3.68(m,2H),3.46– 3.35(m,1H),3.30–3.16(m,2H),3.10–3.05(m,1H),2.98–2.80(m,4H),2.46–2.20(m,5H),1.82–1.71(m,2H),

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl 3-((5-chloropyrimidin-2-yl)oxy)azetidine-1-carboxylate (02019-1)

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg, 2.89 mmol) in THF (8 mL) were added 2,5-dichloropyrimidine (430 mg, 2.89 mmol) and t-BuOK (647 mg, 5.78 mmol). The mixture was stirred at 65 ° C under nitrogen protection for 2 hours. After the starting material was consumed, the reaction was quenched with water (20 mL) and extracted three times with EA (50 mL). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS20 g, 30 mL/min, silica gel, UV 254) to give a white solid product (360 mg, yield 44%).

ESI-MS m/z calcd for[C ₁₂ H ₁₆ ClN ₃ O ₃ ][M-56+H] ⁺ :230.1; found:230.1

2.2 2-(Azetidine-3-oxy)-5-chloropyrimidine (02019-2)

To a solution of tert-butyl 3-((5-chloropyrimidin-2-yl)oxy)azetidine-1-carboxylate (360 mg, 1.26 mmol) in DCM (10 mL) was added TFA (1 mL). The mixture was stirred at room temperature under nitrogen for 3 hours. After the reaction was complete, the mixture was distilled under reduced pressure to remove the solvent to give the product as a white solid (212 mg, 91% yield).

ESI-MS m/z calcd for[C ₇ H ₈ ClN ₃ O][M+H] ⁺ :186.0; found:186.3

2.3(R)-2-(3-((5-chloropyrimidin-2-yl)oxy)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02019)

To a solution of 2-(azetidine-3-oxy)-5-chloropyrimidine (100 mg, 0.54 mmol) in 1,4-dioxane (4 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (155 mg, 0.54 mmol) and DIEA (209 mg, 1.62 mmol). The mixture was stirred at 120°C in a microwave oven under nitrogen for 25 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC _[ MeCN/ _H₂O (10 mmol/ _LNH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to afford the product as a white solid (36.80 mg, 16% yield).

ESI-MS m/z calcd for[C ₁₈ H ₂₁ ClN ₆ O ₃ S][M+H] ⁺ :437.1; found:437.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.76(s,2H),7.49(s,1H),5.43–5.38(m,1H),4.86(t,J＝5.6Hz,1H),4.42(dd,J＝10.0,6.4Hz,2H),4.00(d,J＝7.2Hz,2H),3.73 –3.66(m,2H),3.45–3.37(m,1H),3.25–3.17(m,1H),2.97–2.85(m,2H),2.38–2.25(m,2H),2.14–2.10(m,2H),1.82–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 5-(5-chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (02020-1)

To a solution of tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (100 mg, 0.51 mmol) in DMF (3 mL) were added 2,5-dichloropyrimidine (76 mg, 0.51 mmol) and _{K₂CO₃ (} 211 mg, 1.53 mmol). The mixture was stirred at 100°C under nitrogen for 1 hour. Water (20 mL) was added, and the mixture was extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, 20 g silica gel-CS, 30 mL/min, silica gel, UV 254) to afford the product as a white solid (140 mg, 90% yield).

ESI-MS m/z calcd for[C ₁₄ H ₁₉ ClN ₄ O ₂ ][M-56+H] ⁺ :255.1; found:255.2

2.2

2-(5-chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane (02020-2)

To a solution of tert-butyl 5-(5-chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (140 mg, 0.45 mmol) in DCM (5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the mixture was concentrated to dryness by distillation under reduced pressure to give a white solid product (90 mg, yield 95%).

ESI-MS m/z calcd for[C ₉ H ₁₁ ClN ₄ ][M+H] ⁺ :211.1; found:211.3

2.3

(5R)-2-(5-(5-chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02020)

To a solution of 2-(5-chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane (90 mg, 0.43 mmol) in 1,4-dioxane (4 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (123 mg, 0.43 mmol) and DIEA (165 mg, 1.28 mmol). The mixture was stirred in a microwave at 120°C under nitrogen for 25 minutes. After the starting material was consumed, the mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC [MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to afford the product _as a white solid (19.09 mg, 10% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₄ ClN ₇ O ₂ S][M+H] ⁺ :462.1; found:462.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.51(s,2H),7.47–7.46(m,1H),4.84(t,J＝6.0Hz,1H),3.98–3.53(m,7H),3.45–3.41(m,2H),3.26–3.19(m,1H),3.00–2.9 6(m,1H),2.91–2.86(m,1H),2.39–2.33(m,2H),2.18–2.17(m,2H),1.83–1.70(m,2H),1.16–1.15(m,1H),0.42–0.36(m,1H),.

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl 4-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate (02021-1)

A mixture of 2,5-dichloropyrimidine (200 mg, 1.34 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate (711 mg, 3.35 mmol), and DIEA (1.1 mL, 6.7 mmol) in n-butanol (10 mL) was stirred at 150°C under argon protection in a microwave oven for 2 hours. After the mixture was cooled, the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-1/19, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give the product as a colorless oil (71 mg, yield 16.3%).

ESI-MS m/z calcd for[C ₁₅ H ₂₁ ClN ₄ O ₂ ][M-56+H] ⁺ :269.1; found:268.9

2.2

(R)-2-(4-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-7-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02021)

A solution of tert-butyl 4-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate (44 mg, 0.11 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (32 mg, 0.11 mmol) in HFP (3 mL) was stirred at 120° C. under microwave conditions for 2 hours. After the mixture was cooled, the solvent was distilled off under reduced pressure. The crude product was purified by reverse phase column purification (MeCN/ _H2O =0-12/13, C-18 column, 50 mL/min, UV 214) to give a crude product (20 mg). The crude product was then purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] _to give a white solid product (11.48 mg, yield 17.8%).

ESI-MS m/z calcd for[C ₂₁ H ₂₆ ClN ₇ O ₂ S][M+H] ⁺ :476.2; found:475.8

¹ H NMR (400MHz, DMSO-d ₆ )δ8.52(s,2H),7.41–7.38(m,1H),4.85(t,J＝5.6Hz,1H),3.95–3.93(m,2H),3.83–3.66(m,6H),3.40–3.3 7(m,1H),3.24–3.16(m,1H),2.95–2.83(m,2H),2.33–2.12(m,4H),1.77–1.73(m,2H),0.95–0.89(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-Iodo-1-(triisopropylsilyl)-1H-indole (02024-1)

A solution of 5-iodo-1H-indole (1.7 g, 6.99 mmol) in anhydrous THF (20 mL) was added dropwise to a solution of NaH (60%, 364 mg, 9.09 mmol) in THF (20 mL) at 0°C. The mixture was slowly warmed to room temperature over 30 minutes. Chlorotriisopropylsilane (1.75 g, 9.09 mmol) was then added dropwise over 5 minutes. The resulting mixture was slowly warmed to room temperature and stirred until the starting material was consumed as monitored by TLC. After completion of the reaction, the mixture was quenched with saturated aqueous _NH₄Cl (20 mL) at 0°C and extracted three times with _Et₂O (15 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-10%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product as a colorless oil (2.1 g, yield 75.17%).

ESI-MS m/z calcd for[C ₁₇ H ₂₆ INSi]

¹ H NMR(400MHz,Chloroform-d)δ7.95(d,J＝1.6Hz,1H),7.38(dd,J＝8.4,1.6Hz,1H),7.29–7.26 (m,1H),7.20(d,J＝3.2Hz,1H),6.54(d,J＝2.8Hz,1H),1.71–1.63(m,3H),1.14–1.12(m,18H).

2.2

Tert-Butyl 3-(1-(triisopropylsilyl)-1H-indol-5-yl)azetidine-1-carboxylate (02024-2)

Under nitrogen, a solution of zinc powder (327 mg, 5.01 mmol) in DMA (1.6 mL) was vigorously stirred and heated to 65 ° C. Subsequently, TMSCl (65 mg, 0.6 mmol) and dibromoethane (113 mg, 0.6 mmol) were added, and the mixture was stirred at 65 ° C for another 30 minutes. At 65 ° C, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (851 mg, 3.0 mmol) in DMA (2 mL) was added dropwise to the solution prepared above, and the reaction mixture was cooled to room temperature and a solution of 5-iodo-1-(triisopropylsilyl)-1H-indole (800 mg, 2.0 mmol) in DMA (4 mL) was added. Subsequently, 1% iodine was added to the 1% iodine-1-carboxylate solution. Pd(dppf) _Cl₂ (44 mg, 0.06 mmol) and CuI (23 mg, 0.12 mmol). The reaction mixture was heated to 80°C and stirred for 2 hours. The mixture was cooled to room temperature and quenched with water (150 mL). _NH₄Cl (2 g) was then added and the mixture was extracted twice with _Et₂O (150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-10%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product as a white solid (0.7 g, 81.52% yield).

ESI-MS m/z calcd for[C ₂₅ H ₄₀ N ₂ O ₂ Si][M+H] ⁺ :429.3; found:429.2

2.3

Tert-Butyl 3-(1H-indol-5-yl)azetidine-1-carboxylate (02024-3)

To a solution of tert-butyl 3-(1-(triisopropylsilyl)-1H-indol-5-yl)azetidine-1-carboxylate (0.7 g, 1.64 mmol) in THF (10 mL) was added TBAF (1 M in THF, 3.27 mL). The mixture was stirred at room temperature for 2 hours, quenched by the addition of water (30 mL), and then extracted twice with EA (30 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (EA/PE = 0-30%, silica gel-CS25 g, 30 mL/min, silica gel, UV 254) to give a white solid product (401 mg, yield 90.03%).

ESI-MS m/z calcd for[C ₁₆ H ₂₀ N ₂ O ₂ ][M-56+H] ⁺ :217.2; found:217.2

2.4

(R)-2-(3-(1H-indol-5-yl)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02024)

A mixture of tert-butyl 3-(1H-indol-5-yl)azetidine-1-carboxylate (100 mg, 0.37 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (104 mg, 0.37 mmol) in HFP (3 mL) was stirred at 120° C. for 2 hours under microwave conditions. After completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by preparative HPLC (MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (58 mg, 37.3% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₅ N ₅ O ₂ S][M+H] ⁺ :424.2; found:424.0

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.05(s,1H),7.50(s,1H),7.41–7.37(m,2H),7.32(t,J＝2.8Hz,1H),7.0 9(d,J＝8.4Hz,1H),6.39(s,1H),4.88(t,J＝5.6Hz,1H),4.46–4.42(m,2H),4 .03–3.94(m,3H),3.71–3.70(m,2H),3.44–3.38(m,1H),3.26–3.18(m,1H), 2.98–2.85(m,2H),2.39–2.31(m,2H),2.15–2.10(m,2H),1.80–1.70(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-tert-Butyl 3-((1H-indol-6-yl)oxy)pyrrolidine-1-carboxylate (02025-1)

CMBP (0.75 mL, 3.21 mmol) was added to a solution of 1H-indol-6-ol (171 mg, 1.284 mmol) and tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.07 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 100°C overnight under argon. After cooling, the solvent was evaporated under reduced pressure. The crude product was purified by reverse phase column chromatography (MeCN/ _H2O = 1/9 to 11/9, C-18 column, 50 mL/min, UV 214) to obtain a brown oily product (322 mg, 99.7% yield).

ESI-MS m/z calcd for[C ₁₇ H ₂₂ N ₂ O ₃ ][M-56+H] ⁺ :247.2; found:247.0

2.2

(R)-6-(Pyrrolidin-3-oxy)-1H-indole (02025-2)

A solution of (R)-tert-butyl 3-((1H-indol-6-yl)oxy)pyrrolidine-1-carboxylate (200 mg, 0.66 mmol) in HFP (5 mL) was stirred at 120° C. under argon protection in a microwave oven for 10 hours. After the mixture was cooled, the solvent was removed by distillation under reduced pressure to obtain a brown oily crude product (133 mg, 99.4% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₂ H ₁₄ N ₂ O][M+H] ⁺ :203.1; found:203.2

2.3

(R)-2-((R)-3-((1H-indol-6-yl)oxy)pyrrolidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02025)

To a solution of (R)-6-(pyrrolidin-3-oxy)-1H-indole (44 mg, 0.22 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (63 mg, 0.22 mmol) in DMF (10 mL) was added DIEA (0.18 mL, 1.1 mmol). The mixture was then stirred at 80°C overnight under argon. After cooling, the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (MeOH/DCM = 0-1/9, Silica Gel-CS 20 g, 20 mL/min, UV 254) to give a crude product (50 mg). The crude product was then purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to obtain a white solid product (33.02 mg, yield 33.5%).

ESI-MS m/z calcd for[C ₂₃ H ₂₇ N ₅ O ₃ S][M+H] ⁺ :454.2; found:454.0

¹ H NMR (400 MHz, DMSO-d ₆ )δ10.88(s,1H),7.41(d,J＝8.4Hz,1H),7.30(d,J＝7.2Hz,1H),7.20(s,1H),6 .91(s,1H),6.66(d,J＝8.8Hz,1H),6.33(s,1H),5.08(s,1H),4.89–4.84(m,1H ),3.81–3.69(m,5H),3.60–3.51(m,1H),3.46–3.37(m,1H),3.25–3.15(m,1H) ,2.98–2.80(m,2H),2.41–2.29(m,2H),2.22–2.05(m,4H),1.81–1.66(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 5-(1-(tert-Butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole-1-carboxylate (02026-1)

A reaction mixture of tert-butyl 5-bromo-1H-indole-1-carboxylate (1 g, 3.38 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1 g, 3.38 mmol), Pd(dppf) _{Cl₂ (} 247 mg, 0.338 mmol), _K₂CO₃ (1.4 g, 10.14 mmol), and water (16 mL) in 1,4-dioxane (80 mL) was stirred overnight at 100°C under argon protection. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (EA/PE = 0-1/9, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give the product as a white solid (960 mg, 73.9% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₈ N ₂ O ₄ ][M-56+H] ⁺ :329.2; found:329.2

2.2

tert-Butyl 5-(1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)-1H-indole-1-carboxylate (02026-2)

To a solution of tert-butyl 5-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole-1-carboxylate (300 mg, 0.34 mmol) in DCM (30 mL) and MeOH (75 mL) was added Pd(OH) ₂ (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 12 minutes. After completion of the reaction, the mixture was filtered under reduced pressure, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-1/9, Silica Gel-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product as a colorless oil (260 mg, 86.2% yield).

ESI-MS m/z calcd for[C ₂₂ H ₃₀ N ₂ O ₄ ][M-112+H] ⁺ :275.2; found:275.2

2.3

5-(Pyrrolidin-3-yl)-1H-indole (02026-3)

To a solution of tert-butyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-indole-1-carboxylate (248 mg, 0.64 mmol) in 1,4-dioxane (10 mL) was added a 4N (HCl)/1,4-dioxane solution (10 mL) and stirred at room temperature overnight. After completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent, and the crude product was neutralized with DIEA (10 mL) and concentrated by distillation under reduced pressure to yield a crude red solid (119 mg, 99.9% yield). This was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₂ H ₁₄ N ₂ ][M+H] ⁺ :187.1; found:187.4

2.4

(5R)-2-(3-(1H-indol-5-yl)pyrrolidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02026)

To a solution of 5-(pyrrolidin-3-yl)-1H-indole (130 mg, 0.5 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (144 mg, 0.5 mmol) in 1,4-dioxane (10 mL) was added DIEA (0.41 mL, 2.5 mmol). The mixture was stirred at 120° C. under microwave conditions for 2 hours. After cooling, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (MeOH/DCM=0-1/9, silica gel-CS 20 g, 20 mL/min, UV 254) to give a crude product (50 mg). The crude product was then purified by preparative HPLC [MeCN/ _H2O (10 mmol/ _{LNH4HCO3 )} , X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (4.69 mg, yield 2.1%).

ESI-MS m/z calcd for[C ₂₃ H ₂₇ N ₅ O ₂ S][M+H] ⁺ :438.2; found:438.0

¹ H NMR (400MHz, DMSO-d ₆ )δ11.03(s,1H),7.46(d,J＝4.0Hz,1H),7.36–7.28(m,3H),7.05(d,J＝8.4Hz,1H),6.37(s,1H),4.90–4.84(m,1H),4.05–3.95(m,1H), 3.82–3.67(m,3H),3.56–3.39(m,4H),3.24–3.17(m,1H),2.95–2.86(m,2H),2.46–2.27(m,3H),2.18–2.04(m,3H),1.79–1.66(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-Chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (02029-1)

To a solution of 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (23 mg, 0.105 mmol) in MeCN (4 mL) was added (1-aminocyclobutyl)methanol (11.7 mg, 0.115 mmol) and TEA (1 mL). The mixture was stirred at 70°C overnight and concentrated by distillation under reduced pressure. The crude product was purified by column chromatography (MeOH/DCM = 0-1/10, Silica Gel-CS 4 g, 20 mL/min, silica gel, UV 254) to give the product as a yellow solid (80% purity, 28.0 mg, 98.0% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₅ ClN ₄ O ₂ ][M+H] ⁺ :283.1; found:283.1

2.2

2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (MX02029)

A mixture of (2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (purity 80%, 28.0 mg, 0.08 mmol) and tert-butyl 4-(5-chloropyrimidin-2-yl)piperidine-1-carboxylate (45 mg, 0.15 mmol) HFP (3 mL) was stirred at 120°C for 2 hours under microwave conditions. The reaction mixture was concentrated by distillation under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select ₁₀ μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (2.0 mg, 4.55% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₆ ClN ₇ O ₂ ][M+H] ⁺ :444.2; found:444.0

¹ H NMR (400MHz, DMSO-d ₆ )δ9.07(s,1H),8.87(s,2H),7.43(s,1H),4.83(t,J＝6.0Hz,1H),4.72(d,J＝10.0Hz,2H),3.69(d,J＝5.2Hz,2H),3.33–3.26(m,2H),3.21– 3.14(m,1H),3.05–2.99(m,2H),2.62(t,J＝6.8Hz,2H),2.26–2.11(m,4H),1.96(d,J＝10.4Hz,2H),1.83–1.74(m,2H),1.67–1.59(m,2H),

1. Synthesis scheme:

2. Experimental part:

2.1

(1-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (02035-1)

To a solution of (1-aminocyclobutyl)methanol (50.5 mg, 0.5 mmol) and DIEA (0.1 mL, 0.625 mmol) in THF (5 mL) was added dropwise a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) in THF (15 mL) over 10 minutes. The resulting mixture was stirred at room temperature under argon overnight. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (EA/PE = 0-1/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product as a white solid (105 mg, 79.3% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₃ ClN ₄ O][M+H] ⁺ :265.1; found:265.1

2.2

(1-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (MX02035)

To a solution of (1-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (68 mg, 0.32 mmol) and 5-chloro-2-(piperidin-4-yl)pyrimidine (92 mg, 0.32 mmol) in DMF (20 mL) was added DIEA (0.26 mL, 1.6 mmol), and the mixture was stirred at 80°C overnight under argon protection. After cooling, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (MeOH/DCM=0-1/9, silica gel-CS 20 g, 20 mL/min, UV 254) to give a crude product (100 mg). The crude product was then purified by preparative HPLC [MeCN/ _H2O (10 mmol/ _{L NH4HCO3} ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (73.60 mg, yield 49.6%).

ESI-MS m/z calcd for[C ₂₁ H ₂₄ ClN ₇ O][M+H] ⁺ :426.2; found:426.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.86(s,2H),8.33(dd,J＝4.4,1.6Hz,1H),7.65(dd,J＝8.4,1.6Hz,1H),7.57–7.53(m,2H),4.99(t,J＝5.6Hz,1H),4.83(d,J＝12.8Hz,2H),3 .78(d,J＝5.6Hz,2H),3.22–3.16(m,1H),3.10–3.04(m,2H),2.64–2.56 (m,2H),2.18–2.11(m,2H),1.99(d,J＝10.4Hz,2H),1.88–1.65(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (02036-1)

To a solution of tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (660 mg, 2.17 mmol) in MeCN (15 mL) was added (1-aminocyclobutyl)methanol (219.5 mg, 2.17 mmol) and TEA (658.7 mg, 6.51 mmol). The mixture was heated to 70°C and stirred for 16 hours, cooled to room temperature and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, silica gel-CS 40 g, 50 mL/min, silica gel, UV light 254) to give a white solid product (441 mg, yield 55.1%).

ESI-MS m/z calcd for[C ₁₇ H ₂₅ ClN ₄ O ₃ ][M+H] ⁺ :369.2; found:369.0

2.2

tert-Butyl 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (02036-2)

To a solution of tert-butyl 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (441 mg, 1.20 mmol) in DMF (15 mL) were added 5-chloro-2-(piperidin-4-yl)pyrimidine (378 mg, 1.91 mmol) and DIEA (309 mg, 2.39 mmol). The mixture was heated to 120° C. and stirred for 16 hours, and then the mixture was cooled to room temperature. The crude product was purified by column chromatography (MeOH/DCM = 0-10%, silica gel-CS 25 g, 30 mL/min, UV 254) to give a white solid product (101 mg, yield 15.9%).

ESI-MS m/z calcd for[C ₂₆ H ₃₆ ClN ₇ O ₃ ][M+H] ⁺ :530.3; found:530.0

2.3

(1-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (MX02036)

A solution of tert-butyl 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (20 mg, 0.04 mmol) in HFP (3 mL) was stirred at 120°C for 3.5 hours under microwave conditions. The mixture was then cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as _a white solid (3.6 mg, 18.0% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₈ ClN ₇ O][M+H] ⁺ :430.2; found:430.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.85(s,2H),5.83(s,1H),4.78(t,J＝5.6Hz,1H),4.61–4.58(m,2H),3.70(d,J＝5.6Hz,2H),3.43(s,2H),3.12–3.07(m ,1H),2.90–2.85(m,4H),2.36–2.34(m,2H),2.25–2.10(m,5H),1.88–1.85(m,2H),1.77–1.74(m,2H),1.63–1.59(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

1-(2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)prop-2-en-1-one (MX02037)

Acryloyl chloride (171 mg, 1.89 mmol) was added to a solution of (1-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (0.189 mmol, crude) in MeOH (5 mL). The mixture was stirred at room temperature for 16 hours and then concentrated to dryness by distillation under reduced pressure. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as _a white solid (3.20 mg, 3.5% yield).

ESI-MS m/z calcd for[C ₂₄ H ₃₀ ClN ₇ O ₂ ][M+H] ⁺ :484.2; found:484.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.85(s,2H),6.99–6.86(m,1H),6.34(d,J＝11.6Hz,1H),6.17(dd,J＝28.0,16.0Hz,1 H),5.74(dd,J＝24.8,11.2Hz,1H),4.78–4.73(m,1H),4.61(d,J＝12.8Hz,2H),4.34(d, J＝14.4Hz,2H),3.75–3.72(m,4H),3.14–3.09(m,1H),2.90(t,J＝12.0Hz,2H),2.59–2. 57(m,1H),2.47–2.45(m,1H),2.33-2.17(m,4H),1.89–1.73(m,4H),1.64-1.56(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 2-(1-((Benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (02040-1)

A mixture of tert-butyl 2-chloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (300 mg, 1.11 mmol), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (381 mg, 1.11 mmol), Pd(dppf) _Cl2 (81 mg, 0.111 mmol ₎ , _K2CO3 (460 mg, 3.33 mmol) and water (0.8 mL) in 1,4-dioxane (4 mL) was stirred at 100°C under argon overnight. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (EA/PE=0-1/3, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a yellow oily product (501 mg, yield 99.9%).

ESI-MS m/z calcd for[C ₂₅ H ₃₀ N ₄ O ₄ ][M-56+H] ⁺ :451.2; found:451.3

2.2

tert-Butyl 2-(piperidin-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (02040-2)

To a solution of tert-butyl 2-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (393 mg, 0.87 mmol) in EA (30 mL) was added Pd/C (80 mg). The mixture was stirred overnight under a hydrogen atmosphere at room temperature. After the reaction was completed, the mixture was filtered under reduced pressure, and the solvent was removed by distillation of the filtrate under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0 to 1/3, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a colorless oily product (277 mg, yield 99.7%).

ESI-MS m/z calcd for[C ₁₇ H ₂₆ N ₄ O ₂ ][M+H] ⁺ :319.2; found:319.2

2.3

(R)-tert-Butyl 2-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (02040-3)

To a mixture of tert-butyl 2-(piperidin-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (277 mg, 0.87 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (280 mg, 0.87 mmol) in 1,4-dioxane (10 mL) was added DIEA (0.43 mL, 2.61 mmol) and stirred under argon protection at 120 °C in a microwave oven for 1 hour. After cooling, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (MeOH/DCM = 0-1/9, silica gel-CS 20 g, 20 mL/min, UV 254) to give a yellow solid product (495 mg, yield 99.9%).

ESI-MS m/z calcd for[C ₂₈ H ₃₉ N ₇ O ₄ S][M+H] ⁺ :570.3; found:569.8

2.4

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(4-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02040)

A mixture of (R)-tert-butyl 2-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (150 mg, 0.26 mmol) in HFP (10 mL) was stirred at 120°C in a microwave oven under argon protection for 2 hours. After cooling, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol _/ L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (49.00 mg, 39.6% yield).

ESI-MS m/z calcd for[C ₂₃ H ₃₁ N ₇ O ₂ S][M+H] ⁺ :470.2; found:470.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.36(s,1H),7.36(s,1H),4.85(t,J＝5.6Hz,1H),4.71(d,J＝12.4Hz,2H),3.79(s,2H),3.73–3.71(m,2H),3.45–3.37(m,1H),3.24–3.17(m, 1H),3.09–2.83(m,8H),2.69(t,J＝6.0Hz,2H),2.39–2.25(m,2H),2.18 –2.12(m,2H),1.91–1.88(m,2H),1.79–1.73(m,2H),1.65–1.61(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(1-((2-Chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (02043-1)

To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (6.641 g, 32.07 mmol) in MeCN (50 mL) were added (1-aminocyclobutyl)methanol (3.244 g, 32.07 mmol) and TEA (20 mL). The mixture was stirred at 75°C for 16 hours, then the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (EA/DCM = 0-60%, Silica Gel-CS 120 g, 50 mL/min, silica gel, UV 254) to give the product as a yellow solid (4.01 g, 46.1% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₄ ClN ₃ OS][M+H] ⁺ :272.1; found:272.1

2.2

(R)-2-Chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (02043-2)

To a solution of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (3.5 g, 12.88 mmol) and S-1,1'-bi-2-naphthol (369.0 mg, 1.288 mmol) in DCM (60 mL) were added titanium tetraisopropoxide (182.0 mg, 0.64 mmol) and water (232.0 mg, 12.88 mmol). After the mixture was stirred at room temperature for 1 hour, 70% aqueous tert-butyl hydroperoxide solution (2 g, 14.17 mmol) was added in one portion. The mixture was then stirred at room temperature for 2 hours, after which water (50 mL) was added and the mixture was extracted three times with DCM (60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM/MeOH=1/0～10/1, Silica-CS 80 g, 50 mL/min, silica gel, UV 254) to give a yellow solid product (3.50 g, yield 94.6%).

ESI-MS m/z calcd for[C ₁₁ H ₁₄ ClN ₃ O ₂ S][M+H] ⁺ :288.0; found:288.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.62(s,1H),4.89(t,J＝5.6Hz,1H),3.74–3.66(m,2H),3.61–3.52(m,1H),3.38–3.3 0(m,1H),3.16–3.12(m,1H),3.05–2.99(m,1H),2.32–2.17(m,4H),1.81–1.71(m,2H).

2.3

(R)-2-(4,5-dihydro-2H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02043)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (57 mg, 0.2 mmol) in DMF (5 mL) were added 4,5,6,7-tetrahydro-2-hydro-pyrazolo[3,4-c]pyridine hydrochloride (38 mg, 0.24 mmol) and DIEA (1.5 mL). The reaction mixture was stirred at 80° C. for 4 hours, and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (20.0 mg, yield 26.9%).

ESI-MS m/z calcd for[C ₁₇ H ₂₂ N ₆ O ₂ S][M+H] ⁺ :375.2; found:375.0

¹ H NMR (400MHz, DMSO-d ₆ )δ12.49(s,1H),7.47(s,1H),7.41(s,1H),4.88–4.83(m,3H),3.96(br,2H),3.78–3.71(m,2H),3.46–3.38(m,1H),3.24–3.16(m,1H),2 .94(dd,J＝16.8,8.0Hz,1H),2.86(dd,J＝14.4,7.2Hz,1H),2.67–2.61(m,2H),2.40–2.27(m,2H),2.21–2.17(m,2H),1.82–1.74(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 2-chloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (02044-1)

To a solution of tert-butyl 2,4-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (300 mg, 1.03 mmol) in MeOH (10 mL) and AcOH (1 mL) was added Zn powder (338 mg, 5.17 mmol). The mixture was then stirred at 50°C overnight, the solvent was distilled off under reduced pressure, water (20 mL) was added, and the mixture was extracted three times with DCM (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 40 mL/min, silica gel, UV 254) to give a yellow oily product (202.0 mg, yield 84.8%).

ESI-MS m/z calcd for[C ₁₁ H ₁₄ ClN ₃ O ₂ ][M+H] ⁺ :256.1; found:256.2

2.2

tert-Butyl 2-(1-((Benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (02044-2)

To a solution of tert-butyl 2-chloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (200 mg, 0.782 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (322 mg, 0.94 mmol), _K₂CO₃ (324 _mg , 2.35 mmol), and Pd(dppf) _Cl₂ (32 mg, 0.04 mmol). The mixture was stirred at 100°C under nitrogen overnight. After completion of the reaction, the solvent was removed by distillation under reduced pressure, water (20 mL) was added, and the mixture was extracted three times with DCM (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE=0/1-1/1, silica gel-CS 20 g, 40 mL/min, UV 254) to give an off-white solid product (255.0 mg, yield 74.6%).

ESI-MS m/z calcd for[C ₂₄ H ₂₈ N ₄ O ₄ ][M+H] ⁺ :437.2; found:437.2

2.3

tert-Butyl 2-(piperidin-4-yl)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (MX02044-3)

To a solution of tert-butyl 2-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (255 mg, 0.584 mmol) in MeOH/THF (v/v=1:1, 10 mL) was added Pd/C (50 mg, 0.256 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature overnight, filtered, and concentrated to give the product as a yellow solid (200 mg, 0.584 mmol, 100% yield).

ESI-MS m/z calcd for[C ₁₆ H ₂₄ N ₄ O ₂ ][M+H] ⁺ :305.2; found:305.2

2.4

(R)-tert-Butyl-2-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothiophene[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (02044-4)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (90 mg, 0.313 mmol) in DMF (5 mL) and DIEA (1 mL) was added tert-butyl 2-(piperidin-4-yl)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (200 mg, 0.584 mmol). The reaction mixture was stirred at 115°C for 3 hours. The reaction mixture was concentrated by distillation under reduced pressure, and the crude product was purified by column chromatography (MeOH/DCM = 0/1 to 1/10, Silica Gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give the product as a yellow solid (165.0 mg, 95.0% yield).

ESI-MS m/z calcd for[C ₂₇ H ₃₇ N ₇ O ₄ S][M+H] ⁺ :556.3; found:556.2

2.5

(R)-2-(4-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperidin-1-yl)-4-((1-

(Hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (MX02044)

A mixed solution of (R)-tert-butyl-2-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothiophene[3,2-d]pyrimidin-2-yl)piperidin-4-yl)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (50 mg, 0.09 mmol) in HFP (2 mL) was stirred at 120°C for 2 hours under microwave conditions. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (10.05 mg, 24.4% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₉ N ₇ O ₂ S][M+H] ⁺ :456.2; found:456.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.58(s,1H),7.39(s,1H),4.86(t,J＝5.6Hz,1H),4.71(d,J＝12.0Hz,2H ),4.58–4.51(m,1H),4.08(s,2H),3.98(s,2H),3.70–3.68(m,2H),3.45–3 .37(m,1H),3.24–3.12(m,2H),3.07–2.98(m,2H),2.96–2.28(m,2H),2.3 8–2.25(m,2H),2.18–2.13(m,2H),1.94–1.91(m,2H),,1.82–1.60(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

4,4-Dimethyl-2-oxocyclohexanecarboxaldehyde (02053-1)

To a solution of NaH (60%, 349 mg, 8.72 mmol) in THF (10 mL) was added 3,3-dimethylcyclohexanone (1 g, 7.92 mmol) at 30°C, and the mixture was stirred for 1 hour. Ethyl formate (1.2 g, 16.24 mol) was then added to the reaction solution at 35°C, and stirred at 40°C overnight. The mixture was acidified to pH 3 with 1N HCl aqueous solution and then extracted twice with EA (50 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily product (990 mg, yield 81.1%).

ESI-MS m/z calcd for[C ₉ H ₁₄ O ₂ ][M+H] ⁺ :155.1; found:155.4

2.2

6,6-Dimethyl-4,5,6,7-tetrahydro-1H-indazole (02053-2)

To a solution of 4,4-dimethyl-2-oxocyclohexanecarboxaldehyde (250 mg, 1.62 mmol) in MeOH (10 mL) was added dropwise a solution of hydrazine hydrate (82 mg, 1.64 mmol) in MeOH (5 mL). The mixture was heated under reflux for 15 minutes. After cooling, the solvent was distilled off under reduced pressure, water (20 mL) was added, and the mixture was extracted with EA (20 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily compound (135 mg, 55.4% yield).

ESI-MS m/z calcd for[C ₉ H ₁₄ N ₂ ][M+H] ⁺ :151.1; found:151.4

2.3

3-Iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (02053-3)

To a solution of 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (523 mg, 3.48 mmol) in DMF (10 mL) at room temperature were added _I₂ (3.68 g, 8.7 mmol) and KOH (967 mg, 17.23 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction was cooled in an ice bath, and an aqueous solution of NaHSO₃ (2 _g in 20 mL of water) was added dropwise. Further water (100 mL) was then added, resulting in a precipitate, which was filtered to afford the product as a yellow solid (400 mg, 41% yield).

ESI-MS m/z calcd for[C ₉ H ₁₃ IN ₂ ][M+H] ⁺ :277.0; found:277.1

2.4

Benzyl 4-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (02053-4)

To 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (229 mg, 0.83 mmol) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (285 mg, 0.83 mmol) was stirred in 1,4-dioxane/water (12 To a solution of 1% dppf (dppf) _Cl₂ (18 mg, 0.02 _mmol ) and _K₂CO₃ (344 mg, 2.49 mmol) in 4% dppf (4% dppf) (4% dppf) (5% dppf) (4% dppf) (5% dppf) (6% dppf) (7 ...

ESI-MS m/z calcd for[C ₂₃ H ₂₈ N ₂ O ₂ ][M+H] ⁺ :365.2; found:366.2

2.5

6,6-Dimethyl-3-(piperidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole (02053-5)

To a solution of benzyl 4-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (210 mg, 0.57 mmol) in MeOH (3 mL) was added Pd/C (20 mg). The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere, then filtered through Celite to remove the Pd/C. The filtrate was concentrated by distillation under reduced pressure to afford the product as a colorless oil (120 mg, 89.5% yield).

ESI-MS m/z calcd for[C ₁₄ H ₂₃ N ₃ ][M+H] ⁺ :234.2; found:234.4

2.6

(R)-2-(4-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02053)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.41 mmol) in DMF (7 mL) was added 6,6-dimethyl-3-(piperidin-4-yl)-4,5,6,7-tetrahydro-1H-indazole (120 mg, 0.51 mmol) and DIEA (131 mg, 1.03 mmol). The mixture was then stirred at 70°C for 3 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC _[ MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to afford the product as a white solid (20.75 mg, 8.33% yield).

ESI-MS m/z calcd for[C ₂₅ H ₃₆ N ₆ O ₂ S][M+H] ⁺ :485.3; found:485.0

¹ H NMR (400MHz, DMSO-d ₆ )δ11.95–11.82(m,1H),7.38–7.30(m,1H),4.84(t,J＝5.6Hz,1H),4.81–4.62(m,2H),3.75–3.68(m,2H),3.45–3.36(m,1H),3.24–3.16(m ,1H),3.01–2.82(m,5H),2.39–2.27(m,6H),2.19–2.10(m,2H),1.86–1.70(m,4H),1.60–1.48(m,2H),1.43(t,J＝6.4Hz,2H),0.93(s,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-(Benzyloxy)-1-(triisopropylsilyl)-1H-indole (02058-1)

To a solution of 5-(benzyloxy)-1H-indole (3 g, 13.45 mmol) in anhydrous THF (20 mL) at 0°C was added dropwise a solution of NaH (60%, 699 mg, 17.48 mmol) in THF (20 mL). The mixture was slowly warmed to room temperature over 30 minutes, followed by the dropwise addition of chlorotriisopropylsilane (3.37 g, 17.48 mmol) at 0°C over 5 minutes. The reaction solution was slowly warmed to room temperature and stirred for 4 hours. The reaction was then quenched with saturated aqueous _NH₄Cl (20 mL) at 0°C and extracted three times with _Et₂O (15 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to remove the solvent. The crude product was purified by column chromatography (EA/PE = 0-10%, Silica Gel-CS 40 g, 40 mL/min, silica gel, UV 254) to yield the product as a white solid (3.2 g, 62.69% yield).

ESI-MS m/z calcd for[C ₉ H ₁₀ FNO ₂ ],NO MS was found

2.2

1-(Triisopropylsilyl)-1H-indol-5-ol (02058-2)

To a solution of 5-(benzyloxy)-1-(triisopropylsilyl)-1H-indole (3.2 g, 8.43 mmol) in EtOH (40 mL) was added Pd/C (120 mg) at room temperature. The mixture was stirred overnight under a hydrogen atmosphere, filtered through celite, and the filtrate was distilled under reduced pressure to give the product as a colorless oil (2.3 g, 94.3%).

ESI-MS m/z calcd for[C ₁₇ H ₂₇ NOSi][M+H] ⁺ :290.2; found:290.2

2.3

Tert-Butyl 3-((1H-indol-5-yl)oxy)azetidine-1-carboxylate (02058-3)

To a solution of 1-(triisopropylsilyl)-1H-indol-5-ol (2.67 g, 9.22 mmol) and _Cs₂CO₃ (9.0 _g , 27.67 mmol) in DMF (50 mL) was added tert-butyl 3-iodoazetidine-1-carboxylate (3.1 g, 11.07 mmol). The reaction mixture was stirred at 140°C for 3 hours, after which the solvent was removed by distillation under reduced pressure. Water (150 mL) was added, and the mixture was extracted twice with EA (75 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, Silica Gel-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product as a yellow solid (480 mg, 81.5% yield).

ESI-MS m/z calcd for[C ₁₆ H ₂₀ N ₂ O ₃ ][M+H] ⁺ :289.2; found:289.1

2.4

(R)-2-(3-((1H-indol-5-yl)oxy)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02058)

A solution of tert-butyl 3-((1H-indol-5-yl)oxy)azetidine-1-carboxylate (50 mg, 0.17 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (49 mg, 0.17 mmol) in HFP (2 mL) was stirred at 120° C. under microwave conditions for 2 hours. After completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC (MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (23.54 mg, 30.89% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₅ N ₅ O ₃ S][M+H] ⁺ :440.2; found:440.0

¹ H NMR (400MHz, DMSO-d ₆ )δ10.97(s,1H),7.46(s,1H),7.32–7.30(m,2H),6.93(d,J＝2.4Hz,1H),6.72(dd,J＝8. 8,2.4Hz,1H),6.35(t,J＝2.0Hz,1H),5.11–5.06(m,1H),4.85(t,J＝5.6Hz,1H),4.45(dd ,J＝9.6,6.4Hz,2H),3.95–3.92(m,2H),3.73–3.66(m,2H),3.45–3.37(m,1H),3.25–3. 17(m,1H),2.97–2.84(m,2H),2.38–2.25(m,2H),2.14–2.10(m,2H),1.82–1.65(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 4-(5-chloropyrimidin-2-yl)piperidine-1-carboxylate (A-3)

To a solution of 4-cyanopiperidine hydrochloride (3.1 g, 21.2 mmol) in 4N HCl/1,4-dioxane (10.6 mL, 42.4 mmol) was added MeOH (2.57 mL, 63.6 mmol) while maintaining the temperature below 10°C. The mixture was cooled to 5°C, and a 25% NaOMe solution in MeOH (13.74 g, 63.6 mmol) was added while maintaining the temperature below 15°C. To this mixture was added 7N NH ₃ /MeOH (4.54 mL, 31.8 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure at 60°C to provide a solution of the crude product in 1,4-dioxane (this solution was not isolated).

A solution of the intermediate compound in 1,4-dioxane was cooled to 0°C, and a 25% NaOMe solution in MeOH (11.45 g, 53.0 mmol) was added. The mixture was then stirred for 30 minutes. Compound (Z)-N-(2-chloro-3-(dimethylamino)allylidene)-N-methylmethanium hexafluorophosphate (5.52 g, 18.02 mmol) was added to the mixture in two portions over 10 minutes at room temperature, followed by stirring at room temperature for 6 hours. The mixture was concentrated by distillation under reduced pressure, and the crude product was dispersed in DCM (100 mL). TEA (10 mL, 71.8 mmol) and (Boc) _2O (9.24 g, 42.4 mmol) were added. The mixture was then stirred at room temperature for 3 hours, followed by addition of water (100 mL), and extraction twice with DCM (150 mL). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE=0/1-1/3, silica gel-CS 80 g, 50 mL/min, silica gel, UV 254) to give a yellow oily product (2.50 g, yield 39.7%).

ESI-MS m/z calcd for[C ₁₄ H ₂₀ ClN ₃ O ₂ ][M-56+H] ⁺ :298.1; found:242.3

2.2

5-Chloro-2-(piperidin-4-yl)pyrimidine (A-4)

To a solution of tert-butyl 4-(5-chloropyrimidin-2-yl)piperidine-1-carboxylate (100 mg, 0.335 mmol) in DCM (5.0 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature overnight, and the pH of the solution was adjusted to 8 with TEA. The solvent was concentrated under reduced pressure to give a yellow oily crude product (135 mg, 100% yield) which was used directly in the next step.

ESI-MS m/z calcd for[C ₉ H ₁₂ ClN ₃ ][M+H] ⁺ :198.1; found:198.3

2.3

tert-Butyl 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (02060-1)

To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (345 mg, 1.19 mmol) in MeCN (10 mL) and TEA (3 mL) was added (1-aminocyclobutyl)methanol (120 mg, 1.19 mmol). The mixture was then stirred at 70°C for 16 hours, the solvent was removed by distillation under reduced pressure, water (20 mL) was added, and the mixture was extracted three times with DCM (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 20 g, 40 mL/min, UV 254) to give a yellow solid product (150.0 mg, yield 35.6%).

ESI-MS m/z calcd for[C ₁₆ H ₂₃ ClN ₄ O ₃ ][M+H] ⁺ :355.1; found:355.2

2.4

tert-Butyl 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (02060-2)

To a solution of tert-butyl 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (60 mg, 0.17 mmol) in DMF (4 mL) and DIEA (1 mL) was added 5-chloro-2-(piperidin-4-yl)pyrimidine (135 mg, 0.335 mmol). The mixture was then stirred at 120°C overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 20 g, 40 mL/min, silica gel, UV 254) to give the product as a yellow solid (40.0 mg, 45.6% yield).

ESI-MS m/z calcd for[C ₂₅ H ₃₄ ClN ₇ O ₃ ][M+H] ⁺ :516.2; found:516.0

2.5

(1-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (MX02060)

To a solution of tert-butyl 2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-[(1-(hydroxymethyl)cyclobutyl)amino]-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (40 mg, 0.078 mmol) in DCM (3 mL) was added TFA (0.3 mL), and the mixture was stirred at room temperature overnight. The pH of the reaction solution was adjusted to 7 with 1N _aqueous NaHCO₃. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC _[ MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (19.05 mg, 59.0% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₆ ClN ₇ O][M+H] ⁺ :416.2; found:416.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.85(s,2H),6.47(s,1H),4.79(t,J＝5.6Hz,1H),4.61(d,J＝12.8Hz,2H),4.27–4.21(m,1H),3.80–3.67(m,6H), 3.15–3.09(m,1H),2.95–2.89(m,2H),2.25–2.11(m,4H),1.89–1.86(m,2H),1.80–1.73(m,2H),1.67–1.57(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)carbamate (02063-1)

To a solution of tert-butyl piperidin-4-ylcarbamate (664 mg, 3.32 mmol) in 1,4-dioxane (8 mL) at room temperature were added 2,5-dichloropyrimidine (450 mg, 3.02 mmol) and _{Cs2CO3 (} 1.97 g, 6.04 mmol). The mixture was stirred at 100°C for 3 hours, then added with water (30 mL) and extracted three times with EA (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product as a yellow solid (800 mg, 84.6% yield).

ESI-MS m/z calcd for[C ₁₄ H ₂₁ ClN ₄ O ₂ ][M+H] ⁺ :313.1; found:313.2

2.2

1-(5-Chloropyrimidin-2-yl)piperidin-4-amine (02063-2)

To a solution of tert-butyl (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)carbamate (210 mg, 0.67 mmol) in DCM (5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature overnight, and the solvent was concentrated by distillation under reduced pressure to give a crude yellow oil (230 mg, 100% yield) which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₉ H ₁₃ ClN ₄ ][M+H] ⁺ :213.1; found:213.2

2.3

(R)-2-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)amino)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02063)

To a solution of 1-(5-chloropyrimidin-2-yl)piperidin-4-amine (230 mg, 0.67 mmol) in DMF (5 mL) and DIEA (1 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 0.347 mmol). The reaction mixture was stirred at 80°C for 16 hours. The mixture was concentrated by distillation under reduced pressure, and the crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select ₁₀ μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (12 mg, 7.5% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₆ ClN ₇ O ₂ S][M+H] ⁺ :464.2; found:464.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.41(s,2H),7.31–7.24(m,2H),4.87(t,J＝5.6Hz,1H),4.49(d,J＝13.2Hz,2H),3.94–3.90(m,1H),3.72(d,J＝5.2Hz,2H),3.39 –3.31(m,1H),3.22–3.04(m,3H),2.88–2.81(m,2H),2.41–2.30(m,2H),2.17–2.12(m,2H),1.88–1.71(m,4H),1.44–1.36(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

1-Benzyl-N-((1R,2R)-2-hydroxycyclohexyl)piperidine-4-carboxamide (02069-1)

To a solution of 1-benzylpiperidine-4-carboxylic acid (512 mg, 2.34 mmol) in DCM (8 mL) was added (COCl) ₂ (358 mg, 2.82 mmol). The mixture was stirred at room temperature for 1 hour under nitrogen protection, and the solvent was removed by distillation under reduced pressure. The resulting crude product was added with DCM (8 mL), (1R, 2R)-2-aminocyclohexanol (270 mg, 2.34 mmol) and TEA (709 mg, 7.02 mmol), and the mixture was stirred at room temperature overnight. After the reaction was complete, water (50 mL) was added and extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid product (602 mg, 81% yield).

ESI-MS m/z calcd for[C ₁₉ H ₂₈ N ₂ O ₂ ][M+H] ⁺ :317.2; found:317.3

2.2

(R)-1-Benzyl-N-(2-oxocyclohexyl)piperidine-4-carboxamide (02069-2)

To 1-benzyl-N-((1R,2R)-2-hydroxycyclohexyl)piperidine-4-carboxamide (602 mg, 1.90 mmol) in DCM (15 mL) was added 1-benzyl-N-((1R,2R)-2-hydroxycyclohexyl)piperidine-4-carboxamide (602 mg, 1.90 mmol) in DCM (15 mL) PCC (1.23 g, 5.71 mmol) was added to the solution. The resulting reaction mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, water (15 mL) was added, and the mixture was extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product as a white solid (340 mg, 56% yield).

ESI-MS m/z calcd for[C ₁₉ H ₂₆ N ₂ O ₂ ][M+H] ⁺ :315.2; found:315.2

2.3

2-(1-Benzylpiperidin-4-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole (02069-3)

To a solution of (R)-1-benzyl-N-(2-oxocyclohexyl)piperidine-4-carboxamide (140 mg, 0.44 mmol) in HOAc (5 mL) was added CH ₃ COONH ₄ (338 mg, 4.4 mmol). The mixture was stirred at 150° C. under nitrogen for 20 minutes. After the starting material was consumed, the reaction mixture was concentrated, and the crude product was purified by reverse phase column chromatography (MeCN/H ₂ O = 1/20 to 1/1, C-18 column, 20 mL/min, UV 254) to give a yellow solid product (72 mg, 55% yield).

ESI-MS m/z calcd for[C ₁₉ H ₂₅ N ₃ ][M+H] ⁺ :296.2; found:296.2

2.4

2-(Piperidin-4-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole (02069-4)

To a solution of 2-(1-benzylpiperidin-4-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole (72 mg, 0.24 mmol) in MeOH (3 mL) was added Pd/C (24 mg). The mixture was stirred at room temperature under a hydrogen atmosphere overnight. After the starting material was consumed, the mixture was filtered and the filtrate was concentrated to give the product as a colorless oil (40 mg, 80% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₉ N ₃ ][M+H] ⁺ :206.2; found:206.4

2.5

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(4-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02069)

To a solution of 2-(piperidin-4-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole (40 mg, 0.20 mmol) in 1,4-dioxane (4 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (57 mg, 0.20 mmol) and DIEA (77 mg, 0.60 mmol). The mixture was stirred at 110°C under nitrogen for 2 hours. After the starting material was consumed, the reaction mixture was concentrated. The crude product was purified by preparative HPLC ₍ MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the product as a white solid (8.55 mg, 9% yield).

ESI-MS m/z calcd for[C ₂₃ H ₃₂ N ₆ O ₂ S][M+H] ⁺ :457.2; found:457.0

¹ H NMR (400MHz, DMSO-d ₆ )δ11.19(s,1H),7.37(s,1H),4.86(t,J＝5.6Hz,1H),4.62(d,J＝11.6Hz,2H),3.72–3.69(m,2H),3.45–3.36(m,1H),3.23–3.1 6(m,1H),3.03–2.83(m,5H),2.41–2.26(m,6H),2.19–2.13(m,2H),1.85–1.73(m,4H),1.68–1.66(m,4H),1.58–1.54(m,2H),.

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (02075-1)

To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (3 g, 14.48 mmol) and DIEA (5.61 g, 43.44 mmol) in DMF (50 mL) was added methyl 2-(4-aminophenyl)acetate (2.39 g, 14.48 mmol) at room temperature. The mixture was stirred at 100°C overnight, then water (50 mL) was added to the reaction mixture and extracted twice with DCM (70 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/2, silica gel-CS 80 g, 50 mL/min, UV 254) to give an orange solid product (3.11 g, yield 63.9%).

ESI-MS m/z calcd for[C ₁₅ H ₁₄ ClN ₃ O ₂ S][M+H] ⁺ :336.1; found:336.0

2. Methyl 2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (02075-2)

To a solution of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (420 mg, 1.25 mmol) and S-1,1'-bin-2-naphthol (37.2 mg, 0.13 mmol) in DCM (10 mL) were added titanium tetraisopropoxide (17.8 mg, 0.06 mmol) and water (22.5 mg, 1.25 mmol). The mixture was stirred at room temperature under nitrogen for 16 hours, and then a 70% aqueous solution of tert-butyl hydroperoxide (123.9 mg, 1.37 mmol) was added in one portion. The mixture was then stirred at room temperature for 2 hours, and then water (20 mL) was added, and the mixture was extracted three times with DCM (60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give a white solid product (367 mg, yield 83.4%).

ESI-MS m/z calcd for[C ₁₅ H ₁₄ ClN ₃ O ₃ S][M+H]+:352.0; found:352.0

2.3

(R)-2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (02075-3)

To (R)-methyl 2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (30 mg, 0.08 mmol) and DIEA (31 mg, 0.24 mmol) in DMF (5 mL) was added 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (9.8 mg, 0.08 mmol). The mixture was then stirred at 90° C. for 1 hour. After the starting material was consumed, the reaction mixture was concentrated. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (27 mg, 72.2% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₂ FN ₆ O ₃ S][M+H] ⁺ :439.2; found:439.0

2.4

(R)-2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (MX02075)

To a solution of (R)-methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (27 mg, 0.06 mmol) in EtOH (3 mL) was added 1N aqueous LiOH solution. (0.6 mL, 0.6 mmol). The mixture was then stirred at 50°C for 1 hour, and the pH of the reaction solution was adjusted to 6 with 1N aqueous HCl. The solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm ₁₉ *250 mm, 20 mL/min, UV 254] to give a white solid product (11.57 mg, yield 35.1%).

ESI-MS m/z calcd for[C ₂₀ H ₂₀ N ₆ O ₃ S][M+H] ⁺ :425.1; found:425.0

¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O)δ7.61(d,J＝8.0Hz,2H),7.47(s,1H),7.28(d,J＝8.8Hz,2H),4.89–4.87(m,2H),4.02–4 .00(m,2H),3.59–3.54(m,3H),3.35–3.32(m,1H),3.14–3.02(m,2H),2.65–2.63(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl 4-(5-chloropyrimidin-2-yl)-1,4-diazepane-1-carboxylate (02077-1)

A mixture of 2,5-dichloropyrimidine (500 mg, 3.36 mmol), tert-butyl 1,4-diazepane-1-carboxylate (673 mg, 3.36 mmol) and DIEA (2.8 mL, 16.8 mmol) in DMF (20 mL) was stirred at 80 ° C under argon protection overnight. After cooling, the reaction mixture was evaporated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (EA/PE = 0-1/9, silica gel-CS 40 g, 40 mL/min, UV 254) to give a white solid product (981 mg, yield 93.4%).

ESI-MS m/z calcd for[C ₁₄ H ₂₁ ClN ₄ O ₂ ][M+H] ⁺ :313.1; found:313.2

2.2

1-(5-chloropyrimidin-2-yl)-1,4-diazepane(02077-2)

To a solution of tert-butyl 4-(5-chloropyrimidin-2-yl)-1,4-diazepane-1-carboxylate (200 mg, 0.64 mmol) in DCM (20 mL) was added TFA (4 mL). The mixture was stirred at 35° C. under argon protection for 2 hours, and then the reaction mixture was concentrated to dryness to give a pale yellow oily crude product (136 mg, 99.9% yield).

ESI-MS m/z calcd for[C ₉ H ₁₃ ClN ₄ ][M+H] ⁺ :213.1; found:213.2

2.3

(R)-2-(4-(5-chloropyrimidin-2-yl)-1,4-diazepan-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02077)

To a solution of 1-(5-chloropyrimidin-2-yl)-1,4-diazepane (68 mg, 0.32 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (92 mg, 0.32 mmol) in DMF (20 mL) was added DIEA (0.26 mL, 1.6 mmol). The mixture was stirred at 80° C. under argon protection overnight, and then the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (MeOH/DCM=0-1/9, silica gel-CS20 g, 20 mL/min, UV 254) to give a crude product (90 mg). The crude product was then purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give _a white solid product (73.60 mg, yield 49.6%).

ESI-MS m/z calcd for[C ₂₀ H ₂₆ ClN ₇ O ₂ S][M+H] ⁺ :464.2; found:463.9

¹ H NMR (400MHz, DMSO-d ₆ )δ8.40–8.38(m,2H),7.30(s,1H),4.85(t,J＝5.6Hz,1H),3.95–3.78(m,4H),3.74–3.57(m,6H),3.42–3.3 6(m,1H),3.23–3.15(m,1H),2.94–2.81(m,2H),2.36–2.28(m,2H),2.16–2.14(m,2H),1.86–1.72(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 3-ethoxy-2,5,6,7-tetrahydro-1H-1,4-diazepine-1-carboxylate (02078-1)

To a solution of tert-butyl 3-oxo-1,4-diazepane-1-carboxylate (500 mg, 2.34 mmol) in DCM (10 mL) was added triethoxyammonium tetrafluoroborate (613 mg, 3.50 mmol). The mixture was stirred at room temperature overnight under nitrogen protection. After the starting material was consumed, the reaction mixture was quenched with saturated NaHCO ₃ aqueous solution (50 mL) and extracted three times with EA (50 mL). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily product (525 mg, 93% yield).

ESI-MS m/z calcd for[C ₁₂ H ₂₂ N ₂ O ₃ ][M+H] ⁺ :243.2; found:243.3

2.2

tert-Butyl 3-(2-(methoxycarbonyl)hydrazino)-2,5,6,7-tetrahydro-1H-1,4-diazepine-1-carboxylate (02078-2)

To a solution of tert-butyl 3-ethoxy-2,5,6,7-tetrahydro-1H-1,4-diazepine-1-carboxylate (525 mg, 2.17 mmol) in MeOH (5 mL) was added methyl carbazate (195 mg, 2.17 mmol). The mixture was stirred at room temperature under nitrogen for 16 hours. After the starting material was consumed, the reaction mixture was concentrated. The crude product was purified by column chromatography (MeCN/ _H2O = 1/20 to 1/1, C-18 column, 30 mL/min, UV 254) to afford the product as a colorless oil (126 mg, 20% yield).

ESI-MS m/z calcd for[C ₁₂ H ₂₂ N ₄ O ₄ ][M+H] ⁺ :287.2; found:287.1

2.3

tert-Butyl 3-oxo-5,6,7,9-tetrahydro-2H-[1,2,4]triazolo[4,3-a][1,4]diazepine-8(3H)-carboxylate (02078-3)

To a solution of tert-butyl 3-(2-(methoxycarbonyl)hydrazino)-2,5,6,7-tetrahydro-1H-1,4-diazepine-1-carboxylate (126 mg, 0.44 mmol) in EtOH (3 mL) was added NaOMe (24 mg, 0.44 mmol). The mixture was stirred at 75°C under nitrogen for 4 hours. After complete consumption of the starting material, the reaction mixture was concentrated. The crude product was purified by reverse phase column chromatography (MeCN/ _H₂O = 1/20 to 1/1, C-18 column, 20 mL/min, UV 254) to afford the product as a white solid (61 mg, 55% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₈ N ₄ O ₃ ][M+H] ⁺ :255.1; found:255.2

2.4

6,7,8,9-Tetrahydro-2H-[1,2,4]triazolo[4,3-a][1,4]diazepin-3(5H)-one (02078-4)

To a solution of tert-butyl 3-oxo-5,6,7,9-tetrahydro-2H-[1,2,4]triazolo[4,3-a][1,4]diazepine-8(3H)-carboxylate (61 mg, 0.24 mmol) in DCM (2 mL) was added TFA (0.2 mL). The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the mixture was concentrated to give the product as a colorless oil (33 mg, 89% yield).

ESI-MS m/z calcd for[C ₁₂ H ₂₂ N ₄ O ₄ ][M+H] ⁺ :155.1; found:155.3

2.5

(R)-8-(4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-6,7,8,9-tetrahydro-2H-[1,2,4]triazolo[4,3-a][1,4]diazepin-3(5H)-one (MX02078)

To a solution of 6,7,8,9-tetrahydro-2H-[1,2,4]triazolo[4,3-a][1,4]diazepin-3(5H)-one (33 mg, 0.21 mmol) in DMF (3 mL) was added (R)-2-chloro-4-[(1-(hydroxymethyl)cyclobutyl)amino]-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.21 mmol) and DIEA (81 mg, 0.63 mmol). The mixture was stirred at 100°C under nitrogen for 2 hours. After the starting material was consumed, the reaction mixture was concentrated. The crude product was purified by preparative HPLC ₍ MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the product as a white solid (7.13 mg, 8% yield).

ESI-MS m/z calcd for[C ₁₇ H ₂₃ N ₇ O ₃ S][M+H] ⁺ :406.2; found:406.2

¹ H NMR (400MHz, DMSO-d ₆ )δ11.47(s,1H),7.52–7.38(m,1H),4.83–4.72(m,3H),4.04–3.94(m,2H),3.80–3.70(m,4H),3 .44–3.36(m,1H),3.23–3.16(m,1H),2.95–2.83(m,2H),2.37–2.14(m,4H),1.77–1.71(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-(2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02089)

A solution of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (40 mg, 0.148 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (40 mg, 0.138 mmol) in HFP (3 mL) was stirred at 120°C under microwave conditions for 2 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid product (16.6 mg, yield 19.1%).

ESI-MS m/z calcd for[C ₁₉ H ₂₂ ClN ₅ O ₂ S][M+H] ⁺ :420.12; found:420.0

¹ H NMR (400MHz, DMSO-d ₆ )δ7.76(d,J＝8.4Hz,1H),7.52(s,1H),7.35(d,J＝8.4Hz,1H),4.90–4.86(m,3H),4.06–4.04(m,2H),3.75–3.74(m,2H),3.43–3 .39(m,1H),3.22–3.19(m,1H),2.99–2.94(m,1H),2.90–2.86(m,3H),2.42–2.29(m,2H),2.21–2.19(m,2H),1.80–1.78(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 2-cyano-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (02090-1)

To a solution of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (230 mg, 0.86 mmol) in DMF (15 mL) were added Zn powder (562.4 mg, 8.6 mmol), Zn(CN) _₂ (1.01 g, 8.6 mmol), _Pd₂ (dba) _₃ (238.1 mg, 0.26 mmol), and dppf (144.1 mg, 0.26 mmol). The reaction mixture was then heated to 120°C and stirred for 6 hours before being cooled to room temperature and concentrated. Water (10 mL) was added, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE=0-1/2, silica gel-CS 12 g, 30 mL/min, silica gel, UV 254) to give a white solid product (167 mg, yield 75.2%).

ESI-MS m/z calcd for[C ₁₄ H ₁₇ N ₃ O ₂ ][M+H] ⁺ :260.1; found:260.2

2.2

(R)-6-(4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carbonitrile (MX02090)

A solution of tert-butyl 2-cyano-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (147 mg, 0.57 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (164 mg, 0.57 mmol) in HFP (3.0 mL) was stirred at 120°C for 2 hours under microwave conditions, then cooled to room temperature and concentrated. Water (10 mL) was added, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid product (16.0 mg, yield 6.9%).

ESI-MS m/z calcd for[C ₂₀ H ₂₂ N ₆ O ₂ S][M+H] ⁺ :411.2; found:411.0

¹ H NMR (400MHz, DMSO-d ₆ )δ7.97(d,J＝8.0Hz,1H),7.88(d,J＝7.6Hz,1H),7.55(s,1H),5.01(s,2H),4.86(t,J＝5.6Hz,1H),4.09(t,J＝5.2Hz,2H ),3.78–3.73(m,2H),3.47–3.39(m,1H),3.25–3.17(m,1H),2.99–2.85(m,4H),2.39–2.20(m,4H),1.86–1.71(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-Benzyl-1-oxa-5-azaspiro[2.4]heptane (02096-1)

To a solution of NaH (60%, 300 mg, 7.41 mmol) in DMSO (10 mL) at 0°C was added trimethylsulfonium iodide (1.38 g, 6.27 mmol) portionwise. The mixture was stirred at 25°C under argon for 1 hour, followed by the addition of a solution of 1-benzylpyrrolidin-3-one (1.0 g, 5.7 mmol) in DMSO (11 mL). The mixture was then stirred at 25°C for 2 hours. The reaction was quenched with saturated aqueous _NH4Cl (20 mL) and extracted four times with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-1/1, Silica Gel-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product as a yellow oil (326 mg, 30.2% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₅ NO][M+H] ⁺ :190.1; found:190.1

2.2

3-((1H-Benzo[d]imidazol-1-yl)methyl)-1-benzylpyrrolidin-3-ol (02096-2)

To a solution of NaH (60%, 96 mg, 2.4 mmol) in THF (6 mL) at 0°C was added 1H-benzo[d]imidazole (142 mg, 1.2 mmol) in portions and the reaction was stirred at 0°C under argon for 1 hour. A solution of 5-benzyl-1-oxa-5-azaspiro[2.4]heptane (226 mg, 1.2 mmol) in THF (4 mL) was then added and stirred at 40°C for 24 hours. The reaction was quenched with water (20 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0-1/9, silica gel-CS 40 g, 40 mL/min, UV 254) to give the product as a colorless oil (245 mg, 66.7% yield).

ESI-MS m/z calcd for[C ₁₉ H ₂₁ N ₃ O][M+H] ⁺ :308.2; found:308.2

2.3

3-((1H-Benzo[d]imidazol-1-yl)methyl)pyrrolidin-3-ol (02096-3)

To a solution of 3-((1H-benzo[d]imidazol-1-yl)methyl)-1-benzylpyrrolidin-3-ol (100 mg, 0.33 mmol) and HCOONH₄ ₍ 250 mg, 3.96 mmol) in MeOH (20 mL) was added Pd/C (30 mg), and the mixture was stirred at 70°C under a hydrogen atmosphere for 3 hours. After cooling, the reaction mixture was filtered under reduced pressure, and the filtrate was distilled off to remove the solvent under reduced pressure. The crude product was purified by reverse phase column chromatography (MeCN/H₂O = 0-3/17, C-18 column, 50 mL/min, UV 214) to afford the product as a pale yellow solid (40 mg, 56.6% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₅ N ₃ O][M+H] ⁺ :218.1; found:218.1

2.4

(5R)-2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02096)

To a solution of 3-((1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-3-ol (10 mg, 0.05 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (14 mg, 0.05 mmol) in DMF (5 mL) was added DIEA (0.04 mL, mmol). The mixture was stirred at 80° C. overnight under argon protection. After cooling, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (MeOH/DCM=0-1/4, silica gel-CS 20 g, 20 mL/min, UV 254) to give a crude product (20 mg). The crude product was then purified by preparative HPLC [MeCN/ _H2O (10 mmol/ _{L NH4HCO3} ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (7.72 mg, yield 27.3%).

ESI-MS m/z calcd for[C ₂₃ H ₂₈ N ₆ O ₃ S][M+H] ⁺ :469.2; found:469.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.20–8.14(m,1H)7.70–7.63(m,2H),7.27–7.17(m,3H),5.33–5.29(m,1H),4.87–4.76(m,1H),4.52–4.41(m,2H),3.73–3. 49(m,5H),3.44–3.35(m,2H),3.22–3.15(m,1H),2.94–2.80(m,2H),2.39–2.22(m,2H),2.16–1.92(m,3H),1.83–1.60(m,3H).

1. Synthesis scheme:

2. Experimental part:

2.1(R)-6-(4-(((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)amino)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (MX02103)

To a solution of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (100 mg, 0.49 mmol) in toluene (4 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (141 mg, 0.49 mmol), X-phos (10 mg, 0.02 mmol), BINAP (12 mg, 0.02 mmol), t-BuONa (94 mg, 0.98 mmol) and _Pd2 (dba) ₃ (18 mg, 0.02 mmol). The mixture was stirred at 120°C under nitrogen protection overnight. After the starting material was consumed, the reaction mixture was concentrated and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (6.84 mg, yield 3%).

ESI-MS m/z calcd for[C ₂₂ H ₂₆ N ₆ O ₃ S][M+H] ⁺ :455.2; found:455.0

¹ H NMR (400MHz, DMSO-d ₆ )δ10.86(s,1H),9.71(s,1H),7.78(d,J＝8.8Hz,2H),7.71(d,J＝8.8Hz,2H),7.59(s,1H),4.87(t,J＝5.2Hz,1H),3.83–3.76(m,2H ),3.53–3.47(m,1H),3.45–3.37(m,1H),3.29–3.24(m,1H),3.04–2.98(m,1H),2.95–2.90(m,1H),2.70–2.65(m,1H),2.45–2.20 (m,5H),1.83–1.74(m,2H),1.07(d,J=7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(1R,2R)-2-((Tetrahydro-2H-pyran-2-yl)oxy)cyclopentanol(02108-1)

To a solution of (1R,2R)-cyclopentane-1,2-diol (2 g, 19.61 mmol) in DCM (20 mL) was added DHP (1.65 g, 19.61 mmol) and TFA (0.6 mL). The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, water (30 mL) was added to the reaction solution, and the mixture was extracted three times with DCM (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless oily crude product (3.22 g, 88% yield), which was used directly in the next reaction.

2.2

2-Chloro-4-(((1R,2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)oxy)-6,7-dihydrothieno[3,2-d]pyrimidine (02108-2)

To a solution of (1R,2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentanol (2 g, 11.11 mmol) in THF (40 mL) was added NaH (60%, 888 mg, 22.22 mmol) under nitrogen. The mixture was stirred at 0°C for 30 minutes, followed by the addition of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (2.3 g, 11.11 mmol), and stirring was continued at 0°C for 1 hour. After the starting material was consumed, the reaction was quenched with water (20 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a colorless oily product (1.12 g, yield 29%).

ESI-MS m/z calcd for[C ₁₆ H ₂₁ ClN ₂ O ₃ S][M+H] ⁺ :357.1; found:357.2

2.3

(1R,2R)-2-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)oxy)cyclopentanol(02108-3)

To a solution of 2-chloro-4-(((1R,2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)oxy)-6,7-dihydrothieno[3,2-d]pyrimidine (1.12 g, 3.15 mmol) in EtOH (10 mL) was added PPTS (15 mg, 0.06 mmol). The mixture was stirred at 70°C under nitrogen for 1 hour. After the starting material was consumed, the reaction was quenched with water (30 mL) and extracted three times with EA (30 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a colorless oily product (640 mg, yield 75%).

ESI-MS m/z calcd for[C ₁₁ H ₁₃ ClN ₂ O ₂ S][M+H] ⁺ :273.0; found:273.1

2.4

(R)-2-Chloro-4-(((1R,2R)-2-hydroxycyclopentyl)oxy)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (02108-4)

To a solution of (1R,2R)-2-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)oxy)cyclopentanol (200 mg, 0.73 mmol) and S-1,1'-bin-2-naphthol (20 mg, 0.07 mmol) in DCM (5 mL) was added titanium tetraisopropoxide (10 mg, 0.036 mmol) and water (13 mg, 0.73 mmol). The mixture was stirred at room temperature overnight, and then a 70% aqueous solution of tert-butyl hydroperoxide (131 mg, 1.46 mmol) was added in one portion. The mixture was then stirred at room temperature for 1.5 hours, after which water (20 mL) was added and the mixture was extracted three times with DCM (50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give a white solid product (61 mg, yield 29%).

ESI-MS m/z calcd for[C ₁₁ H ₁₃ ClN ₂ O ₃ S][M+H] ⁺ :289.0; found:289.1

2.5

(R)-2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-(((1R,2R)-2-hydroxycyclopentyl)oxy)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02108)

To a solution of (R)-2-chloro-4-(((1R,2R)-2-hydroxycyclopentyl)oxy)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (61 mg, 0.21 mmol) in DMF (4 mL) was added 5-chloro-2-(piperidin-4-yl)pyrimidine (41 mg, 0.21 mmol) and DIEA (54 mg, 0.42 mmol). The mixture was stirred at 100°C under nitrogen for 3 hours. After the starting material was consumed, the reaction mixture was concentrated. The crude product was purified by preparative HPLC [MeCN/ _H₂O (10 _mmol /L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to afford the product as a white solid (22.76 mg, 24% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₄ ClN ₅ O ₃ S][M+H] ⁺ :450.1; found:450.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.88(s,2H),5.20–5.19(m,1H),5.00(d,J＝4.0Hz,1H),4.79(d,J＝13.2Hz,2H),4.14–4.10(m,1H),3.57–3.48(m,1H),3.31–3 .16(m,4H),3.10–3.04(m,1H),2.96–2.91(m,1H),2.20–2.13(m,1H),2.07–2.04(m,2H),1.88–1.81(m,1H),1.76–1.51(m,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 4-(1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (02113-1)

To tert-butyl 4-hydroxypiperidine-1-carboxylate (1.78 g, 9.26 mmol), 1H-benzo[d]imidazole (4.5 g, 18.52 mmol) To a solution of 1,3-dihydro-1,3-dihydro-1-propene (8.09 g, 18.52 mmol) and _PPh3 (8.09 g, 18.52 mmol) in anhydrous THF (375 mL) was slowly added a solution of DEAD (3.22 g, 18.52 mmol) in THF (250 mL). The mixture was stirred at room temperature overnight. After the starting material was consumed, the reaction mixture was concentrated. The crude product was purified by column chromatography (EA/PE = 0-100%, Silica-CS 80 g, 80 mL/min, silica gel, UV 254) to give the product as a white powder (266 mg, 4.77% yield).

ESI-MS m/z calcd for[C ₁₇ H ₂₃ N ₃ O ₂ ][M+H] ⁺ :302.2; found:302.2

2.2

1-(Piperidin-4-yl)-1H-benzo[d]imidazole (02113-2)

To a solution of tert-butyl 4-(1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (240 mg, 0.79 mmol) in DCM (2 mL) was added TFA (0.2 mL). The mixture was stirred at room temperature for 2 hours, the solvent was removed by distillation under reduced pressure, and the crude product was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₂ H ₁₅ N ₃ ][M+H] ⁺ :202.1; found:202.3

2.3

(R)-methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (MX02113)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (213 mg, 0.74 mmol) and DIEA (286 mg, 2.22 mmol) in DMF (3 mL) was added 1-(piperidin-4-yl)-1H-benzo[d]imidazole (50% purity, 301 mg, 0.74 mmol). The mixture was stirred at 120°C for 3 hours, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC _[ MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to afford the product as a white solid (137.64 mg, 41.1% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₈ N ₆ O ₂ S][M+H] ⁺ :453.2; found:453.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.36(s,1H),7.69(d,J＝8.0Hz,1H),7.65(d,J＝8.0Hz,1H),7.43(s,1H ),7.28–7.18(m,2H),4.89–4.67(m,4H),3.76–3.70(m,2H),3.47–3.39(m ,1H),3.26–3.18(m,1H),3.10(t,J＝12.0Hz,2H),2.98–2.85(m,2H),2.4 2–2.28(m,2H),2.20–2.07(m,4H),1.98–1.89(m,2H),1.80–1.70(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 4-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (02115-1)

To a solution of 5,6-dichloro-1H-benzo[d]imidazole (600 mg, 3.21 mmol) in MeCN (10 mL) and water (4 mL) at room temperature were added tert-butyl 4-bromopiperidine-1-carboxylate (1.27 g, 4.81 mmol) and NaOH (642 mg, 16 mmol). The mixture was stirred at 70°C overnight. The reaction mixture was distilled under reduced pressure to remove the solvent, water (30 mL) was added, and the mixture was extracted three times with DCM (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0-10%, silica gel-CS 20 g, 30 mL/min, UV 254) to afford the product as a yellow oil (128 mg, 10.75% yield).

ESI-MS m/z calcd for[C ₁₇ H ₂₁ Cl ₂ N ₃ O ₂ ][M+H] ⁺ :370.1; found:370.2

2.2

5,6-Dichloro-1-(piperidin-4-yl)-1H-benzo[d]imidazole (02115-2)

A solution of tert-butyl 4-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (128 mg, 0.347 mmol) in HFP (2 mL) was stirred at 120°C under microwave conditions for 2 hours. After the reaction was complete, the mixture was distilled under reduced pressure to remove the solvent. The crude product was obtained as a yellow oil (100 mg, 100% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₂ H ₁₃ Cl ₂ N ₃ ][M+H] ⁺ :270.1; found:270.1

2.3

(R)-2-(4-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02115)

To a solution of 5,6-dichloro-1-(piperidin-4-yl)-1H-benzo[d]imidazole (100 mg, 0.347 mmol) in MeCN (4 mL) were added DIEA (1 mL) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.208 mmol). The mixture was stirred at 70°C overnight, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select ₁₀ μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (39 mg, 45.97% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₆ Cl ₂ N ₆ O ₂ S][M+H] ⁺ :521.1; found:521.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.53(s,1H),8.18(s,1H),7.94(s,1H),7.45(s,1H),4.86–4.75(m,4H),3.76–3.69(m,2H),3.47–3.39(m,1H),3.25–3.17(m,1H),3.0 7(t,J＝12.0Hz,2H),2.98–2.85(m,2H),2.41–2.28(m,2H),2.19–2.14(m,2H),2.11–2.08(m,2H),1.94–1.86(m,2H),1.80–1.70(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-((Trimethylsilyl)ethynyl)-1H-indole (02122-1)

To a solution of 5-iodo-1H-indole (1 g, 4.11 mmol) in THF (10 mL) were added ethynyltrimethylsilane (444 mg, 4.53 mmol), CuI (78 mg, 0.41 mmol), TEA (5 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (84 mg, 0.12 mmol). The mixture was stirred at room temperature overnight under nitrogen. After the starting material was consumed, the reaction mixture was distilled under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/10, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product as a brown solid (810 mg, 93% yield).

ESI-MS m/z calcd for[C ₁₃ H ₁₅ NSi][M+H] ⁺ :214.1; found:214.3

2.2

5-Ethynyl-1H-indole (02122-2)

To a solution of 5-((trimethylsilyl)ethynyl)-1H-indole (810 mg, 3.80 mmol) in MeOH (10 mL) was added K ₂ CO ₃ (787 mg, 5.70 mmol). The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the reaction mixture was filtered and concentrated to give a brown solid product (525 mg, 98% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₀ H ₇ N][M+H] ⁺ :142.1; found:142.0

2.3

(R)-2-((1H-indol-5-yl)ethynyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02122)

To a solution of 5-ethynyl-1H-indole (100 mg, 0.71 mmol) in DMF (5 mL) were added (R)-2-chloro-4-[(1-(hydroxymethyl)cyclobutyl)amino]-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (204 mg, 0.71 mmol), CuI (13 mg, 0.07 mmol), TEA (143 mg, 1.42 mmol), and Pd(PPh ₃ ) ₂ Cl ₂ (34 mg, 0.05 mmol). The mixture was stirred at 100° C. under nitrogen overnight. After the starting material was consumed, the reaction was quenched with water (20 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] _to give a white solid product (25.61 mg, yield 9%).

ESI-MS m/z calcd for[C ₂₁ H ₂₀ N ₄ O ₂ S][M+H] ⁺ :393.1; found:393.0

¹ H NMR (400MHz, DMSO-d ₆ )δ11.45(s,1H),8.11(s,1H),7.87(s,1H),7.48–7.46(m,2H),7.29(d,J＝8.4Hz,1H),6.51(s,1H),4.93(t,J＝5.6Hz,1H),3.80– 3.72(m,2H),3.62–3.53(m,1H),3.38–3.31(m,1H),3.18–3.14(m,1H),3.04–2.99(m,1H),2.38–2.25(m,4H),1.83–1.74(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (02126-1)

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 5.0 mmol) and TEA (1.4 mL, 10 mmol) in DCM (15 mL) was slowly added dropwise a solution of MsCl (0.43 g, 5.5 mmol) in DCM (5 mL) at -10°C. The mixture was then warmed to room temperature and stirred for 2 hours, and the mixture was quenched with 1N aqueous HCl (20 mL). The organic phase was washed with 1N aqueous HCl (20 mL), saturated brine (10 mL), and 1N NaOH (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale pink solid crude product (1.38 g, yield 99.4%), which was directly used in the next reaction.

ESI-MS m/z calcd for[C ₁₁ H ₂₁ NO ₅ S][M-56+H] ⁺ :224.1; found:224.2

2.2

tert-Butyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)piperidine-1-carboxylate (02126-2)

A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (257 mg, 0.92 mmol), 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.61 mmol), and _K₂CO₃ (101 _mg , 0.73 mmol) in DMF (20 mL) was stirred at 100°C overnight under argon. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (EA/PE = 0-11/9, silica gel-CS 20 g, 20 mL/min, UV 254) to obtain a crude product (100 mg). The crude product was then purified by reverse phase column chromatography (MeCN/ _H₂O = 1/9-9/11, C-18 column, 50 mL/min, UV 214) to obtain a white solid product (41 mg, 19.3% yield).

ESI-MS m/z calcd for[C ₁₉ H ₂₆ N ₂ O ₄ ][M-56+H] ⁺ :291.2; found:291.0

2.3

6-(Piperidin-4-oxy)-3,4-dihydroquinolin-2(1H)-one (02126-3)

To a solution of tert-butyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)piperidine-1-carboxylate (20 mg, 0.058 mmol) in DCM (5 mL) was added TMSOTf (0.015 mL, 0.087 mmol), and the mixture was stirred at room temperature overnight under argon. The crude product was washed three times with _Et2O (5 mL) to remove any soluble byproducts. The crude product was then added to DCM (5 mL) to obtain a light yellow precipitate. After filtration and washing with _Et2O , the product was obtained as a light yellow solid (14 mg, 98.5% yield).

ESI-MS m/z calcd for[C ₁₄ H ₁₈ N ₂ O ₂ ][M+H] ⁺ :247.1; found:247.1

2.4

(R)-6-((1-(4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (MX02126)

To a solution of 6-(piperidin-4-oxy)-3,4-dihydroquinolin-2(1H)-one (14 mg, 0.06 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (17 mg, 0.06 mmol) in DMF (10 mL) was added DIEA (0.05 mL, 0.3 mmol). The mixture was stirred at 80° C. under argon protection overnight. After cooling, the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (MeOH/DCM=0-1/9, silica gel-CS20 g, 20 mL/min, UV 254) to give a crude product (20 mg). The crude product was then purified by preparative HPLC [MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give _a white solid product (7.72 mg, yield 27.3%).

ESI-MS m/z calcd for[C ₂₅ H ₃₁ N ₅ O ₄ S][M+H] ⁺ :498.2; found:498.0

¹ H NMR (400 MHz, DMSO-d ₆ )δ9.93(s,1H),7.41(s,1H),6.85(s,1H),6.80–6.74(m,2H),4.85(t,J＝5.6Hz ,1H),4.55–4.51(m,1H),4.16–4.12(m,2H),3.73–3.68(m,2H),3.53–3.36(m, 3H),3.23–3.16(m,1H),2.95–2.81(m,4H),2.42–2.38(m,2H),2.35–2.24(m,2 H),2.17–2.13(m,2H),191–1.83(m,2H),1.79–1.72(m,2H),1.53–1.48(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(2-fluoro-4-nitrophenyl)acetate (02128-1)

To a solution of 2-(2-fluoro-4-nitrophenyl)acetic acid (4 g, 20.101 mmol) in MeOH (40 mL) was added concentrated _H₂SO₄ ( ₂ mL) at room temperature. The mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated, and the crude product was extracted twice with saturated aqueous _NaHCO₃ (40 mL) and EA (40 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the product as a yellow solid (3.6 g, 84.1% yield).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.13–8.08 (m, 2H), 7.70 (t, J = 8.0Hz, 1H), 3.94 (s, 2H), 3.66 (s, 3H).

2.2

Methyl 2-(4-amino-2-fluorophenyl)acetate (02128-2)

To a solution of methyl 2-(2-fluoro-4-nitrophenyl)acetate (3.6 g, 16.886 mmol) in EA (40 mL) was added Pd/C (360 mg) at room temperature. The mixture was stirred overnight under a hydrogen atmosphere and filtered through celite. The filtrate was distilled off under reduced pressure, and the crude product was purified by column chromatography (EA/PE = 0-4/1, silica gel-CS 40 g, 40 mL/min, UV 254) to give the product as a yellow solid (2.9 g, 93.9% yield).

ESI-MS m/z calcd for[C ₉ H ₁₀ FNO ₂ ][M+H] ⁺ :184.1; found:184.2

2.3

Methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02128-3)

To a solution of methyl 2-(4-amino-2-fluorophenyl)acetate (3.62 g, 19.76 mmol) and DIEA (7.65 g, 59.279 mmol) in DMF (40 mL) was added 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (4.09 g, 19.76 mmol). The mixture was then stirred at 120°C for 16 hours. The reaction mixture was concentrated, water (60 mL) was added, and the mixture was extracted twice with DCM (60 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 40 g, 40 mL/min, UV 254) to give the product as a yellow solid (1.58 g, yield 22.6%).

ESI-MS m/z calcd for[C ₁₅ H ₁₃ ClFN ₃ O ₂ S][M+H] ⁺ :354.0; found:354.0

2.4

(R)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02128-4)

To a solution of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (500 mg, 1.413 mmol) and S-1,1'-binaphthol (40.5 mg, 0.141 mmol) in DCM (10 mL) was added titanium tetraisopropoxide (20.1 mg, 0.071 mmol) and water (25.4 mg, 1.413 mmol). After the mixture was stirred under nitrogen for 1 hour, 70% aqueous tert-butyl hydroperoxide (200 mg, 1.555 mmol) was added in one portion, and the mixture was then stirred at room temperature under nitrogen for 1.5 hours. Water (20 mL) was added, and the mixture was extracted three times with DCM (60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (392 mg, yield 75.1%).

ESI-MS m/z calcd for[C ₁₅ H ₁₃ ClFN ₃ O ₃ S][M+H] ⁺ :370.0; found:369.9

2.5

(R)-methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02128-5)

To a solution of (R)-methyl-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (60 mg, 0.162 mmol) in DMF (2 mL) were added 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (20 mg, 0.162 mmol) and DIEA (62.8 mg, 0.487 mmol). The mixture was then stirred at 90° C. for 1 hour. The reaction mixture was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (34 mg, 45.9% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₁ FN ₆ O ₃ S][M+H] ⁺ :457.1; found:457.0

2.6

(R)-2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02128)

To a solution of methyl (R)-2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (34 mg, 0.074 mmol) in EtOH (2 mL) was added 1N aqueous LiOH solution (0.372 mL, 0.372 mmol). The mixture was then stirred at 50°C for 1 hour, and the pH of the reaction mixture was adjusted to 6 with 1N aqueous HCl. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC _[ MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (11.57 mg, 35.1% yield).

ESI-MS m/z calcd for[C ₂₀ H ₁₉ FN ₆ O ₃ S][M+H] ⁺ :443.1; found:443.0

¹ H NMR (400MHz, Methanol-d ₄ )δ7.52–7.49(m,1H),7.40–7.36(m,2H),7.30(t,J＝8.4Hz,1H),4.97(s,2H),4.12–4.09(m,2H) ,3.70–3.62(m,1H),3.56(s,2H),3.44–3.37(m,1H),3.19–3.10(m,2H),2.71(t,J＝5.6Hz,2H).

1. Synthesis scheme:

2. Experimental part:

2.1(R)-2-(4-((2-(1-(5-chloropyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (MX02129)

To a solution of (R)-methyl 2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (332 mg, 0.898 mmol) and 5-chloro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)pyrimidine (317.6 mg, 0.988 mmol) in 1,4-dioxane/water (10 mL, v/v 5:1) were added _{K2CO3 (} 372.2 mg, 2.693 mmol), Pd(dppf) _Cl2 (65.7 mg, 0.090 mmol). The mixture was stirred at 100°C under nitrogen for 5 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to obtain a crude product. The crude product was further purified by preparative HPLC _[ MeCN/ _H2O (0.5% _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to obtain a white solid product (48 mg, yield 10.1%).

ESI-MS m/z calcd for[C ₂₄ H ₂₂ ClFN ₆ O ₃ S][M+H] ⁺ :529.1; found:529.0

¹ H NMR (400MHz, DMSO-d ₆ )δ10.09(s,1H),8.47(s,2H),7.72(dd,J＝12.4,2.0Hz,1H),7.59(dd,J＝8.4,2.0Hz,1H),7.36–7.29(m,2H),4.43-4.42(m ,2H),3.99–3.95(m,2H),3.72–3.63(m,6H),3.46–3.37(m,1H),3.29–3.25(m,1H),3.14–3.09(m,1H),2.68–2.67(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-(Ethylthio)pyrimidine-2,4(1H,3H)-dione (02137-1)

To a solution of 5-bromopyrimidine-2,4(1H,3H)-dione (1.5 g, 7.85 mmol) in DMSO (10 mL) was added NaSEt (659 mg, 7.85 mmol). The mixture was stirred at 100°C under nitrogen for 3 hours. After the starting material was consumed, water (20 mL) was added to the reaction solution, and the mixture was extracted five times with EA (50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the product as a white solid (730 mg, 56% yield).

ESI-MS m/z calcd for[C ₆ H ₈ N ₂ O ₂ S][M+H] ⁺ :173.0; found:173.2

2.2

2,4-Dichloro-5-ethylthiopyrimidine (02137-2)

A solution of 5-(ethylthio)pyrimidine-2,4(1H,3H)-dione (700 mg, 4.07 mmol) in _POCl₃ (5 mL) was stirred overnight at 100°C under nitrogen. After the starting material was consumed, water (20 mL) was added to the mixture, and the mixture was extracted three times with EA (40 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/10, 40 g of silica gel-CS, 40 mL/min, silica gel, UV 254) to afford the product as a yellow solid (152 mg, 18% yield).

ESI-MS m/z calcd for[C ₆ H ₆ Cl ₂ N ₂ S][M+H] ⁺ :209.0; found:209.0

2.3

(1-((2-Chloro-5-(ethylthio)pyrimidin-4-yl)amino)cyclobutyl)methanol (02137-3)

To a solution of 2,4-dichloro-5-(ethylthio)pyrimidine (152 mg, 0.73 mmol) in DMF (3 mL) were added (1-aminocyclobutyl)methanol (76 mg, 0.73 mmol) and DIEA (188 mg, 1.46 mmol), and the mixture was stirred at 100 ° C under nitrogen for 3 hours. After the starting material was consumed, water (20 mL) was added to the mixture and extracted three times with EA (10 mL). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (EA/PE = 0/1 to 1/10, silica gel-CS 40 g, 20 mL/min, silica gel, UV 254) to give a colorless oily product (142 mg, yield 71%).

ESI-MS m/z calcd for[C ₁₁ H ₁₆ ClN ₃ OS][M+H] ⁺ :274.1; found:274.0

2.4

(R)-(1-((2-chloro-5-(ethylsulfinyl)pyrimidin-4-yl)amino)cyclobutyl)methane(02137-4)

To a solution of (1-((2-chloro-5-(ethylthio)pyrimidin-4-yl)amino)cyclobutyl)methanol (142 mg, 0.52 mmol) and S-1,1'-bin-2-naphthol (14 mg, 0.05 mmol) in DCM (2 mL) were added titanium tetraisopropoxide (7 mg, 0.026 mmol) and water (9 mg, 0.52 mmol). The mixture was stirred at room temperature overnight, and then a 70% aqueous solution of tert-butyl hydroperoxide (94 mg, 1.04 mmol) was added in one portion. The mixture was then stirred at room temperature for 1.5 hours, and then water (20 mL) was added, followed by extraction three times with DCM (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (109 mg, yield 73%).

ESI-MS m/z calcd for[C ₁₁ H ₁₆ ClN ₃ O ₂ S][M+H] ⁺ :290.1; found:290.1

2.5

(R)-(1-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-(ethylsulfinyl)pyrimidin-4-yl)amino)cyclobutyl)methanol (MX02137)

To a solution of (R)-(1-((2-chloro-5-(ethylsulfinyl)pyrimidin-4-yl)amino)cyclobutyl)methanol (25 mg, 0.08 mmol) in DMF (2 mL) were added 5-chloro-2-(piperidin-4-yl)pyrimidine (20 mg, 0.10 mmol) and DIEA (41 mg, 0.32 mmol). The mixture was stirred at 100°C under nitrogen for 3 hours. After the starting material was consumed, the reaction mixture was concentrated by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol _/ L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (14.81 mg, 38% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₇ ClN ₆ O ₂ S][M+H] ⁺ :451.2; found:451.5

¹ H NMR (400MHz, DMSO-d ₆ )δ8.87(s,2H),7.91(s,1H),7.34(s,1H),4.90(t,J＝5.6Hz,1H),4.67(d,J＝12.8Hz,2H),3.77–3.65(m,2H),3.22–3.18(m,1H),3.12 –3.00(m,4H),2.30–2.20(m,2H),2.18–2.08(m,2H),2.02–1.94(m,2H),1.84–1.73(m,2H),1.69–1.60(m,2H),1.10(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(1-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)cyclobutyl)methanol (02138-1)

To a solution of (1-((2-chloro-5-(ethylthio)pyrimidin-4-yl)amino)cyclobutyl)methanol (100 mg, 0.37 mmol) in DCM (5 mL) was added m-CPBA (85%, 188 mg, 0.91 mmol). The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the reaction was quenched with saturated aqueous NaHCO ₃ solution (10 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/4, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product as a white solid (71 mg, 63% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₆ ClN ₃ O ₃ S][M+H] ⁺ :306.1; found:306.0

2.2

(1-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)cyclobutyl)methanol (MX02138)

To a solution of (1-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)cyclobutyl)methanol (71 mg, 0.23 mmol) in DMF (2 mL) were added 5-chloro-2-(piperidin-4-yl)pyrimidine (49 mg, 0.25 mmol) and DIEA (129 mg, 1.00 mmol). The mixture was stirred at 100°C under nitrogen for 3 hours. After the starting material was consumed, the reaction mixture was concentrated by distillation under reduced pressure. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (57.19 mg, 53% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₇ ClN ₆ O ₃ S][M+H] ⁺ :467.2; found:467.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.88(s,2H),8.17(s,1H),6.94(s,1H),4.94(t,J＝6.0Hz,1H),4.83–4.60(m,2H),3.71(d,J＝5.2Hz,2H),3.25– 3.09(m,5H),2.33–2.25(m,2H),2.15–2.08(m,2H),2.04–2.00(m,2H),1.87–1.66(m,4H),1.16(t,J＝7.6Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-(2-Fluoro-4-((5-oxo-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (MX02140)

To a solution of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (71 mg, 0.433 mmol) in dry THF (3 mL) was added NaH (60%, 26 mg, 0.649 mmol) at 0°C. The mixture was stirred at 25°C for 30 minutes, then (R)-methyl 2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (80 mg, 0.216 mmol) was added, and the mixture was stirred at 25°C overnight. Water (3 mL) was then added to the mixture, and the mixture was stirred at room temperature for a further hour. The pH of the reaction mixture was adjusted to 6 with 1N aqueous HCl. The mixture was concentrated by distillation under reduced pressure, and the crude product was purified by reverse phase column (MeCN/ _H2O = 0-20%, C-18, 40 g, 45 mL/min, UV 254) to obtain a crude product (15 mg). The crude product was further purified by preparative HPLC (MeCN/ _H2O (10 mmol/L HCOOH), X-Select 10 μm The product was purified by HPLC (19*250 mm, 20 mL/min, UV 254) to obtain a white solid product (1.92 mg, yield 1.84%).

ESI-MS m/z calcd for[C ₂₃ H ₁₉ FN ₄ O ₅ S][M+H] ⁺ :483.1; found:483.1

¹ H NMR (400MHz, DMSO-d ₆ )δ10.16–10.14(m,2H),7.35(d,J＝12.8Hz,1H),7.25–7.23(m,1H),7.11–7.07(m,2H),6.99(dd,J＝8.8,2.4Hz,1H),6.9 0(d,J＝8.8Hz,1H),3.68–3.59(m,1H),3.49–3.38(m,3H),3.22–3.07(m,2H),2.86(t,J＝7.6Hz,2H),2.45–2.38(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-(((2-chloro-5-(ethylthio)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02147-1)

To a solution of methyl 2-(4-amino-2-fluorophenyl)acetate (272 mg, 1.48 mmol) and DIEA (384 mg, 2.97 mmol) in DMF (10 mL) was added 2,4-dichloro-5-(ethylthio)pyrimidine (310 mg, 1.48 mmol). The mixture was then stirred at 90°C overnight, and the reaction mixture was concentrated by distillation under reduced pressure. Water (20 mL) was added, and the mixture was extracted twice with DCM (20 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 20 g, 20 mL/min, UV 254) to give the product as a yellow solid (177 mg, yield 33.6%).

ESI-MS m/z calcd for[C ₁₅ H ₁₅ ClFN ₃ O ₂ S][M+H] ⁺ :356.1; found:356.0

2.2

Methyl 2-(4-(((2-chloro-5-(ethylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02147-2)

To a solution of methyl 2-(4-((2-chloro-5-(ethylthio)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (87 mg, 0.245 mmol) and S-1,1'-bin-2-naphthol (7 mg, 0.0245 mmol) in DCM (1.5 mL) were added titanium tetraisopropoxide (3.5 mg, 0.0123 mmol) and water (4.4 mg, 0.245 mmol). After the mixture was stirred at room temperature for 2 hours, a 70% aqueous solution of tert-butyl hydroperoxide (44.2 mg, 0.49 mmol) was added in one portion. The mixture was then stirred at room temperature for 3.5 hours, water (5 mL) was added, and the mixture was extracted three times with DCM (10 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA=1/0~0/1, silica gel-CS12 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (49 mg, yield 53.8%).

ESI-MS m/z calcd for[C ₁₅ H ₁₅ ClFN ₃ O ₃ S][M+H] ⁺ :372.1; found:372.0

2.3

2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02147)

To a solution of methyl 2-(4-((2-chloro-5-(ethylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (20 mg, 0.054 mmol) and (3-chloro-4-methoxyphenyl)boronic acid (11 mg, 0.06 mmol) in 1,4-dioxane/water (2.5 mL, v/v 4:1) were added K ₂ CO ₃ (22.4 mg, 0.162 mmol) and Pd(dppf)Cl ₂ (4.0 mg, 0.0054 mmol). The mixture was stirred at 100° C. under nitrogen for 5 hours. The solvent was removed by distillation under reduced pressure. Water (3 mL) was then added to the crude product. The pH of the mixture was adjusted to 6 with 1N aqueous HCl solution, and then extracted three times with DCM (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (2.42 mg, yield 9.7%).

ESI-MS m/z calcd for[C ₂₁ H ₁₉ ClFN ₃ O ₄ S][M+H] ⁺ :464.1; found:464.0

¹ H NMR (400MHz, DMSO-d ₆ )δ12.47(s,1H),9.76(s,1H),8.60(s,1H),8.31(d,J＝2.0Hz,1H),8.26(dd,J＝8.8,2.0Hz,1H),7.24(d ,J＝12.8Hz,1H),7.37–7.33(m,3H),3.95(s,3H),3.64(s,2H),3.23–3.16(m,2H),1.22(t,J＝7.2Hz,3H)

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((2-(5-cyano-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(ethylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid

To a solution of methyl 2-(4-((2-chloro-5-(ethylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (20 mg, 0.054 mmol) and 6-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine-3-carbonitrile (15.4 mg, 0.06 mmol) in 1,4-dioxane/water (2.5 mL, v/v 4:4) was added 1,2-dihydropyridine-3- _carbonitrile (15.4 mg, 0.06 mmol) and _K2CO3 (22.4 mg, 0.162 mmol), Pd(dppf) _Cl2 (4 mg, 0.0054 mmol). The mixture was heated at 90°C under nitrogen protection for 5 hours. The solvent was removed by distillation under reduced pressure. Water (5 mL) was then added to the crude product. The pH of the mixture was adjusted to 6 with 1N aqueous HCl solution. The mixture was then extracted with DCM (5 mL). The aqueous layer was concentrated to dryness by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a light green solid product (5.91 mg, yield 24.0%).

ESI-MS m/z calcd for[C ₂₁ H ₁₈ FN ₅ O ₄ S][M+H] ⁺ :456.1; found:456.2

¹ H NMR (400MHz, MeOH-d ₄ )δ8.78(s,1H),8.54(s,1H),7.51(dd,J＝11.6,2.0Hz,1H),7.33(t,J＝8.0Hz,1H),7.24(d d,J＝8.0,2.0Hz,1H),3.67(s,2H),3.27–3.24(m,2H),2.68(s,3H)1.35(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 4-(5-chloropyrimidin-2-yl)piperazine-1-carboxylate (02075-1)

To a solution of 2,5-dichloropyrimidine (500.0 mg, 3.35 mmol) and DIEA (1.3 g, 10.05 mmol) in DMF (10 mL) was added tert-butyl piperazine-1-carboxylate (625 mg, 3.35 mmol). The mixture was stirred at 80°C overnight, then cooled to room temperature and concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (EA/PE = 0-30%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product as a white solid (912 mg, 91.0% yield).

ESI-MS m/z calcd for[C ₁₃ H ₁₉ ClN ₄ O ₂ ][M-56+H]+:243.1; found:243.2

2.2

5-Chloro-2-(piperazin-1-yl)pyrimidine (02149-2)

To a solution of tert-butyl 4-(5-chloropyrimidin-2-yl)piperazine-1-carboxylate (50 mg, 0.17 mmol) in DCM (2 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and the solvent was removed by distillation under reduced pressure. The crude product (33 mg, 90% yield) was used directly for the next reaction.

ESI-MS m/z calcd for[C ₈ H ₁₁ ClN ₄ ][M+H] ⁺ :199.1; found:199.2

2.3

(R)-(1-((2-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-5-(ethylsulfinyl)pyrimidin-4-yl)amino)cyclobutyl)methanol (MX02149)

To a solution of (R)-(1-((2-chloro-5-(ethylsulfinyl)pyrimidin-4-yl)amino)cyclobutyl)methanol (19 mg, 0.07 mmol) and DIEA (27.1 mg, 0.21 mmol) in DMF (3 mL) was added 5-chloro-2-(piperazin-1-yl)pyrimidine (13.9 mg, 0.08 mmol). The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/LNH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as an off-white solid (27 mg, 72.2%).

ESI-MS m/z calcd for[C ₁₉ H ₂₆ ClN ₇ O ₂ S][M+H] ⁺ :452.2; found:451.9

¹ H NMR (400MHz, DMSO-d ₆ )δ8.46(s,2H),7.93(s,1H),7.39(s,1H),4.89(s,1H),3.79–3.67(m,10H),3. 08–3.02(m,2H),2.27–2.14(m,4H),1.89–1.74(m,2H),1.09(t,J=7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02156-1)

To a solution of 5-chloro-2-(piperidin-4-yl)pyrimidine (40 mg, 0.203 mmol) in DMF (4 mL) and DIEA (1 mL) was added (R)-methyl 2-(4-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (50 mg, 0.135 mmol). The reaction mixture was stirred at 100°C for 4 hours. After completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (MeOH/DCM = 0-10%, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give a yellow ointment (67.0 mg, yield 93.0%).

ESI-MS m/z calcd for[C ₂₄ H ₂₄ ClFN ₆ O ₃ S][M+H] ⁺ :531.1; found:531.0

2.2

(R)-2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02156)

To a solution of (R)-methyl 2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (65 mg, 0.122 mmol) in MeOH (6 mL) was added 1N aqueous LiOH solution (1.22 mL, 1.22 mmol). The mixture was stirred at 50°C for 1 hour, and then the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (28.0 mg, 35.1% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₂ ClFN ₆ O ₃ S][M+H] ⁺ :517.0; found:517.0

¹ H NMR (400MHz, Methanol-d ₄ )δ9.59(s,1H),8.87(s,2H),7.46(d,J＝12.8Hz,1H),7.34(d,J＝8.8Hz,1H),7.16(t,J＝8.8Hz,1H) ,4.72–4.66(m,2H),3.56–3.47(m,1H),3.29–2.94(m,8H),2.04–2.01(m,2H),1.75–1.67(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

2,4-Dichloro-5-(ethylsulfonyl)pyrimidine (02161-1)

To a solution of 2,4-dichloro-5-(ethylthio)pyrimidine (400 mg, 1.92 mmol) in DCM (10 mL) was added m-CPBA (85%, 856 mg, 4.22 mmol). The mixture was stirred at room temperature under nitrogen for 2 hours. After the starting material was consumed, the reaction was quenched with saturated aqueous NaHCO ₃ solution (20 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/4, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a white solid product (381 mg, 83% yield).

ESI-MS m/z calcd for[C ₆ H ₆ Cl ₂ N ₂ O ₂ S][M+H] ⁺ :241.0; found:241.2

2.2

Methyl 2-(4-(((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02161-2)

To a solution of 2,4-dichloro-5-(ethylsulfonyl)pyrimidine (381 mg, 1.58 mmol) in DMF (5 mL) was added methyl 2-(4-amino-2-fluorophenyl)acetate (289 mg, 1.58 mmol) and DIEA (611 mg, 4.74 mmol). The mixture was stirred at 100°C under nitrogen for 1 hour. After the starting material was consumed, water (20 mL) was added and then extracted three times with EA (20 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/10, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (207 mg, yield 34%).

ESI-MS m/z calcd for[C ₁₅ H ₁₅ ClFN ₃ O ₄ S][M+H] ⁺ :388.1; found:388.0

2.3

Methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02161-3)

To a solution of methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (100 mg, 0.26 mmol) in 1,4-dioxane/water (2.5 mL, v/v = 5/1) were added (3-chloro-4-methoxyphenyl)boronic acid (58 mg, 0.31 mmol), _K2CO3 (72 mg, 0.52 mmol), and Pd(dppf) _Cl2 (19 mg, 0.026 mmol). _The mixture was stirred at 90°C under nitrogen for 5 hours. After the starting material was consumed, water (20 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a yellow solid product (51 mg, 40% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₁ ClFN ₃ O ₅ S][M+H] ⁺ :494.1; found:493.9

2.4

2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02161)

To a solution of methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (51 mg, 0.10 mmol) in MeOH/THF (3 mL, v/v = 1/1) was added 2N aqueous NaOH solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl solution. The mixture was then concentrated, and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (6.88 mg, 14% yield).

ESI-MS m/z calcd for[C ₂₁ H ₁₉ ClFN ₃ O ₅ S][M+H] ⁺ :480.1; found:479.6

¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O)δ8.76(s,1H),8.31(s,1H),8.27(d,J＝8.8Hz,1H),7.62(d,J＝11.6Hz,1H),7.36–7 .28(m,3H),3.96(s,3H),3.50(q,J＝7.2Hz,2H),3.35(s,2H),1.27(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-(((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02166-1)

To a solution of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (200.0 mg, 0.57 mmol) in DCM (10 mL) was added m-CPBA (85%, 216.4 mg, 1.25 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous _NaHCO₃ solution (40 mL) was added, and the mixture was extracted twice with EA (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to give the product as a yellow solid (128 mg, 58.7% yield).

ESI-MS m/z calcd for[C ₁₅ H ₁₃ ClFN ₃ O ₄ S][M+H] ⁺ :386.0; found:385.7

2.2

2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02166)

To a solution of methyl 2-(4-((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (70 mg, 0.18 mmol) and 3-chloro-4-methoxyphenyl)boronic acid (33.8 mg, 0.18 mmol) in 1,4-dioxane/water (4.0 mL, v/v 3:1) was added Pd(dppf) _Cl2 (14.2 mg, 0.0193 mmol) and _K2CO3 (74.6 _mg , 0.54 mmol). The mixture was stirred at 100°C under nitrogen for 3 hours, then water (20 mL) was added and extracted with EA (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (9.16 mg, yield 9.68%).

ESI-MS m/z calcd for[C ₂₁ H ₁₇ ClFN ₃ O ₅ S][M+H] ⁺ :478.1; found:477.6

¹ H NMR (400MHz, DMSO-d ₆ )δ8.27(d,J＝2.0Hz,1H),8.21(dd,J＝8.4,2.0Hz,1H),7.60(dd,J＝12.0,2.0Hz,1H),7.48(dd,J＝8.4 ,1.6Hz,1H),7.36–7.31(m,2H),3.94(s,3H),3.71(t,J＝6.8Hz,2H),3.58(s,2H),3.42–3.33(m,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 4-carbamoylpiperidine-1-carboxylate (02284-1)

To a solution of N-BOC-4-piperidinecarboxamide (4.6 g, 20.15 mmol) in DCM (10 mL) at room temperature was added triethyloxonium tetrafluoroborate (3.83 g, 20.15 mmol). The mixture was stirred at room temperature for 2 hours, then a methanolic ammonia solution (32 mL, 7 mol/L) was added dropwise to the reaction solution and allowed to react at room temperature for 16 hours. The mixture was concentrated by distillation under reduced pressure to obtain a crude off-white solid (5.56 g, 100% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₁ H ₂₁ N ₃ O ₂ ][M+H] ⁺ :228.2; found:228.0

2.2

tert-Butyl 4-(4-oxo-1,4,6,7-tetrahydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (02284-2)

To a solution of tert-butyl 4-carbamoylpiperidine-1-carboxylate (5.56 g, 20.15 mmol) in toluene (30 mL) were added methyl 3-oxotetrahydrothiophene-2-carboxylate (1.6 g, 10.0 mmol) and DMAP (739 mg, 6.05 mmol). The mixture was stirred at 100 ° C overnight. After the starting material was consumed, the mixture was concentrated by distillation under reduced pressure, water (50 mL) was added thereto, and extracted three times with DCM (50 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (EA/DCM = 0/1 to 1/0, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a white solid product (820 mg, yield 24.33%).

ESI-MS m/z calcd for[C ₁₆ H ₂₃ N ₃ O ₃ S][M+H] ⁺ :338.1; found:338.0

2.3

tert-Butyl 4-(4-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (02284-3)

To a solution of tert-butyl 4-(4-oxo-1,4,6,7-tetrahydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (145 mg, 0.43 mmol) in DCM (10 mL) was added _POCl₃ (198 mg, 1.29 mmol) and DIEA (56 mg, 0.43 mmol). The mixture was stirred at room temperature overnight. After the starting material was consumed, water (1 mL) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. TEA (1 mL) and (Boc) _₂O (141 mg, 0.645 mmol) were then added to the mixture, and stirring was continued at room temperature for 2 hours. The mixture was concentrated by distillation under reduced pressure, water (10 mL) was added, and the mixture was extracted three times with DCM (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give a yellow solid product (130 mg, yield 85.1%).

ESI-MS m/z calcd for[C ₁₆ H ₂₂ ClN ₃ O ₂ S][M-56+H] ⁺ :300.1; found:300.0

2.4

tert-Butyl 4-(4-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (02284-4)

To a solution of tert-butyl 4-(4-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (130 mg, 0.365 mmol) in DCM (10 mL) was added m-CPBA (85%, 371.7 mg, 2.15 mmol). The mixture was stirred at room temperature for 4 hours. After the starting material was consumed, the mixture was concentrated by distillation under reduced pressure, a saturated solution of _NaHCO₃ (10 mL) was added, and the mixture was extracted three times with DCM (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product as a yellow solid (101 mg, 71.4% yield).

ESI-MS m/z calcd for[C ₁₆ H ₂₂ ClN ₃ O ₄ S][M-56+H] ⁺ :332.1; found:332.0

2.5

tert-Butyl 4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (MX02284-5)

To a solution of tert-butyl 4-(4-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (90 mg, 0.232 mmol) in NMP (3 mL) were added 1-aminocyclobutanemethanol (23.5 mg, 0.232 mmol) and DIEA (1 mL). The mixture was stirred at 120°C overnight. After the starting material was consumed, the mixture was concentrated by distillation under reduced pressure. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a brown solid product (92 mg, purity 88%, yield 76.8%).

ESI-MS m/z calcd for[C ₂₁ H ₃₂ N ₄ O ₅ S][M+H] ⁺ :453.2; found:453.2

2.6

4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(piperidin-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (02284-6)

To a solution of tert-butyl 4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (92 mg, 88% purity, 0.179 mmol) in DCM (80 mL) was added TFA (0.4 mL). The reaction mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the reaction solution was adjusted to neutral with TEA, and the mixture was concentrated by distillation under reduced pressure to obtain a brown oily product (63.1 mg, 100% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₆ H ₂₄ N ₄ O ₃ S][M-56+H] ⁺ :353.2; found:353.2

2.7

2-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)-4-((1-hydroxymethylcyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (MX02284)

To a solution of 4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(piperidin-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (63.1 mg, 0.179 mmol) in DMF (5 mL) were added 2,5-dichloropyrimidine (39.3 mg, 0.264 mmol) and DIEA (1 mL). The mixture was stirred at 100°C under nitrogen for 4 hours. After the starting material was consumed, the reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a light yellow solid (50 mg, 75.7% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₅ ClN ₆ O ₃ S][M-56+H] ⁺ :465.1; found:465.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.42(s,2H),6.69(s,1H),5.02(t,J＝5.2Hz,1H),4.63(d,J＝12.8Hz,2H),3.66(d,J＝5.6Hz,2H),3.58(t,J＝6.8Hz,2H),3.21(t, J＝7.2Hz,2H),3.10–3.07(m,2H),3.00–2.93(m,1H),2.47–2.39(m,2H),2.12–2.05(m,2H),1.99–1.96(m,2H),1.76–1.60(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)isobutylacetamide (MX02283)

To a solution of 2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (50 mg, 0.104 mmol) in DMF (3 mL) were added isobutylamine (9.2 mg, 0.125 mmol), DIEA (23 mg, 0.18 mmol) and BOP (40 mg, 0.09 mmol). The mixture was stirred at room temperature for 2 hours. After the starting material was consumed, the reaction mixture was concentrated in vacuo to give the crude product which was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (30 mg, 53.8% yield).

ESI-MS m/z calcd for[C ₂₅ H ₂₈ ClFN ₄ O ₄ S][M+H] ⁺ :535.2; found:534.7

¹ H NMR (400MHz, DMSO-d ₆ )δ9.15(s,1H),8.78(s,1H),8.29–8.25(m,2H),8.06–8.05(m,1H),7.68(d,J＝11.2Hz,1H),7.38–7.33(m,3H),3. 96(s,3H),3.56–3.51(m,4H),2.91(t,J＝6.4Hz,2H),1.74–1.67(m,1H),1.27–1.22(m,3H),0.85(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-(((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02286-1)

To a solution of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (200 mg, 0.57 mmol) in DCM (10 mL) was added m-CPBA (85%, 216.4 mg, 1.25 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous _NaHCO₃ solution (40 mL) was added, and the mixture was extracted twice with EA (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, Silica Gel-CS 20 g, 25 mL/min, silica gel, UV 254) to give the product as a yellow solid (128 mg, 58.7% yield).

ESI-MS m/z calcd for[C ₁₅ H ₁₃ ClFN ₃ O ₄ S][M+H] ⁺ :386.0; found:385.7

2.2

2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (02286-2)

To a solution of methyl 2-(4-((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (70 mg, 0.18 mmol) and (3-chloro-4-methoxyphenyl)boronic acid (33.8 mg, 0.18 mmol) in 1,4-dioxane/water (4 mL, v/v 3:1) was added Pd(dppf) _Cl2 (14.2 mg, 0.0193 mmol) and _K2CO3 (74.6 _mg , 0.54 mmol). The mixture was stirred at 100°C under nitrogen for 3 hours, then water (20 mL) was added and extracted with EA (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (9.16 mg, yield 9.68%).

ESI-MS m/z calcd for[C ₂₁ H ₁₇ ClFN ₃ O ₅ S][M+H] ⁺ :478.1; found:477.6

2.3

2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylacetamide (MX02286)

To a solution of 2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (30 mg, 0.06 mmol) in DMF (2 mL) were added isobutylamine (5 mg, 0.07 mmol), DIEA (23 mg, 0.18 mmol) and BOP (40 mg, 0.09 mmol). The mixture was stirred at room temperature for 2 hours. After the starting material was consumed, the reaction mixture was concentrated in vacuo, and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (15 mg, 45% yield).

ESI-MS m/z calcd for[C ₂₅ H ₂₆ ClFN ₄ O ₄ S][M+H] ⁺ :533.1; found:532.6

¹ H NMR (400MHz, DMSO-d ₆ )δ9.65(s,1H),8.26(d,J＝2.0Hz,1H),8.22(dd,J＝8.8,2.0Hz,1H),8.10(t, J＝6.0Hz,1H),7.59(dd,J＝12.0,2.0Hz,1H),7.48(dd,J＝8.4,2.0Hz,1H),7.3 5–7.30(m,2H),3.94(s,3H),3.71(t,J＝6.8Hz,2H),3.50(s,2H),3.40(t,J＝ 7.2Hz,2H),2.91(t,J＝6.0Hz,2H),1.74–1.67(m,1H),0.85(d,J＝6.4Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-(((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02311-1)

To a solution of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (200.0 mg, 0.57 mmol) in dichloromethane (10 mL) was added m-CPBA (85%, 216.4 mg, 1.25 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, saturated aqueous _NaHCO₃ solution (40 mL) was added, and the mixture was extracted twice with EA (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, Silica Gel-CS 20 g, 25 mL/min, silica gel, UV 254) to give the product as a yellow solid (128 mg, 58.7% yield).

ESI-MS m/z calcd for[C ₁₅ H ₁₃ ClFN ₃ O ₄ S][M+H] ⁺ :386.0; found:385.7

2.2

Methyl 2-(4-((5,5-dioxido-2-(2-(trifluoromethyl)pyridin-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02311-2)

To a solution of methyl 2-(4-(2-chloro-5,5-dioxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenylacetate (70 mg, 0.181 mmol) in 1,4-dioxane/water (5 mL, v/v = 4/1) was added (2-(trifluoromethyl)pyridin-4-yl)boronic acid (50.2 mg, 0.272 mmol), _K₂CO₃ (100.3 _mg , 0.726 mmol), and Pd(dppf) _Cl₂ (14.8 mg, 0.018 mmol). The mixture was heated to 95°C and stirred under nitrogen for 2 hours. After cooling, the mixture was added to water (10 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM/MeOH=0-1%, silica gel CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (41 mg, yield 45.5%).

ESI-MS m/z calcd for[C ₂₁ H ₁₆ F ₄ N ₄ O ₄ S][M+H] ⁺ :497.1; found:496.9

2.3

2-(4-((5,5-dioxido-2-(2-(trifluoromethyl)pyridin-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02311)

To a solution of methyl 2-(4-(((5,5-dioxido-2-(2-(trifluoromethyl)pyridin-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (41 mg, 0.083 mmol) in methanol (3 mL) was added a solution of NaOH (19.8 mg, 0.496 mmol) in water (1 mL). The mixture was then stirred at room temperature for 2 hours. The pH of the solution was adjusted to 6 with acetic acid. The mixture was filtered and purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (25.46 mg, yield 63.6%).

ESI-MS m/z calcd for[C ₂₀ H ₁₄ F ₄ N ₄ O ₄ S][M+H] ⁺ :483.1; found:483.3

¹ H NMR (400MHz, Methanol-d ₄ )δ8.87(d,J＝5.2Hz,1H),8.66(s,1H),8.48–8.46(m,1H),7.55–7.52(m,1H) ,7.41–7.36(m,2H),3.71(t,J＝7.2Hz,2H),3.56(s,2H),3.52–3.49(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)acetate (02347-1)

A reaction mixture of tert-butyl piperidine-4-carbamate (2 g, 9.99 mmol), ethyl bromoacetate (1.83 g, 11.98 mmol), and DIPEA (1.94 g, 14.98 mmol) in DCM (25 mL) was stirred at room temperature for 3 hours. After cooling, the reaction mixture was poured into ice water (20 mL) and extracted three times with DCM (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The product was obtained as a yellow solid (1.61 g, 59% yield).

ESI-MS m/z calcd for[C ₁₃ H ₂₄ N ₂ O ₄ ][M+H] ⁺ :272.2; found:272.0

2.2

2-(4-Aminopiperidin-1-yl)acetic acid methyl ester dihydrochloride (02347-2)

To a solution of methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)acetate (1.61 g, 5.91 mmol) in DCM (30 mL) was added 4N hydrochloric acid in dioxane (10 mL) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. After the starting material was consumed, the mixture was concentrated to dryness by distillation under reduced pressure. The crude product was washed with MTBE (15 mL) to give the product as a white solid (1.44 g, 100% yield).

ESI-MS m/z calcd for[C ₈ H ₁₆ N ₂ O ₂ ][M+H] ⁺ :173.1.1; found:173.1

2.3

Methyl 2-(4-(((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)piperidin-1-yl)acetate (02347-3)

To a solution of 2,4-dichloro-5-(ethylsulfonyl)pyrimidine (80 mg, 0.33 mmol) in DMF (3 mL) was added methyl 2-(4-aminopiperidin-1-yl)acetate dihydrochloride (81 mg, 0.33 mmol) and DIEA (173 mg, 1.34 mmol). The mixture was stirred at 90°C under nitrogen for 3 hours. After the starting material was consumed, water (20 mL) was added, and then extracted three times with EA (20 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (67 mg, yield 63%).

ESI-MS m/z calcd for[C ₁₄ H ₂₁ ClN ₄ O ₄ S][M+H] ⁺ :377.1; found:377.2

2.4

Methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)piperidin-1-yl)acetate (02347-4)

To a solution of methyl 2-(4-(((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)piperidin-1-yl)acetate (67 mg, 0.18 mmol) in 1,4-dioxane/water (2.5 mL, v/v = 5/1) were added (3-chloro-4-methoxyphenyl)boronic acid (39 mg, 0.21 mmol), K ₂ CO ₃ (50 mg, 0.36 mmol) and Pd(dppf)Cl ₂ (13 mg, 0.018 mmol). The mixture was stirred at 90° C. under nitrogen for 5 hours. After the starting material was consumed, water (20 mL) was added and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV elution). 254) to give a yellow solid product (27 mg, yield 32%).

ESI-MS m/z calcd for[C ₂₁ H ₂₇ ClN ₄ O ₅ S][M+H] ⁺ :483.1; found:483.2

2.5

2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)piperidin-1-yl)acetic acid (MX02347)

To a solution of methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)piperidin-1-yl)acetate in MeOH/THF (2 mL, v/v = 1/1) was added 2N aqueous NaOH solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The mixture was then concentrated, and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (12 mg, 46% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₅ ClN ₄ O ₅ S][M+H] ⁺ :469.1; found:469.2

¹ H NMR (400MHz, Methanol-d ₄ )δ8.84–8.78(m,1H),7.69(d,J＝2.0Hz,1H),7.63(d,J＝7.2Hz,1H),7.16(d,J＝8.4Hz,1H),4.29–4.19(m,1H),3.96(s,3H), 3.63–3.59(m,4H),3.27–3.17(m,2H),2.78(q,J＝7.2Hz,2H),2.33–2.20(m,2H),2.03–1.94(m,2H),1.06(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((5,5-dioxo-2-(2-(trifluoromethyl)pyridin-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-methylacetamide (MX02358)

To a solution of 2-(4-((5,5-dioxo-2-(2-(trifluoromethyl)pyridin-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (17 mg, 0.035 mmol), BOP (23.4 mg, 0.053 mmol), and DIEA (13.6 mg, 0.105 mmol) in DMF (2 mL) was added a 2 M solution of methylamine in THF (0.05 mL, 0.105 mmol). The mixture was stirred at room temperature for 2 hours, and then the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product _as a white solid (10.8 mg, 62.3% yield).

ESI-MS m/z calcd for[C ₂₁ H ₁₇ F ₄ N ₅ O ₃ S][M+H] ⁺ :496.1; found:495.9

¹ H NMR (400MHz, Methanol-d ₄ )δ8.87(d,J＝5.2Hz,1H),8.64(s,1H),8.48(d,J＝5.2Hz,1H),7.62(dd,J＝11.6,2.0Hz,1H),7.45(dd,J＝8.4 ,2.0Hz,1H),7.39(t,J＝8.0Hz,1H),3.71(t,J＝6.8Hz,2H),3.60(s,2H),3.51(t,J＝7.2Hz,2H),2.76(s,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-butyl 4-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate (A-1)

A mixture of 2,5-dichloropyrimidine (200 mg, 1.34 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate (711 mg, 3.35 mmol), and DIEA (1.1 mL, 6.7 mmol) in n-butanol (10 mL) was stirred at 150°C under argon protection in a microwave oven for 2 hours. After the mixture was cooled, the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-1/19, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give the product as a colorless oil (71 mg, yield 16.3%).

ESI-MS m/z calcd for[C ₁₅ H ₂₁ ClN ₄ O ₂ ][M-56+H] ⁺ :269.1; found:268.9

2.2

4-(5-Chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane (A-2)

To a solution of tert-butyl 4-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate (71 mg, 0.22 mmol) in DCM (3 mL) was added TFA (0.3 mL). The reaction mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the mixture was concentrated to dryness by distillation under reduced pressure to give the product as a white solid (134.7 mg, 55% purity, 100% yield).

ESI-MS m/z calcd for[C ₁₀ H ₁₃ ClN ₄ ][M+H] ⁺ :225.1; found:225.4

2.3

(1-((2-Chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-3-fluoro-cyclobutyl)methanol (02370-1)

To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (113 mg, 0.545 mmol) in DMF (4 mL) was added (1-amino-3-fluorocyclobutyl)methanol hydrochloride (70.7 mg, 0.454 mmol) and KF (79.1 mg, 1.362 mmol). The mixture was stirred at 80°C for 16 hours, and then the solvent was removed by distillation under reduced pressure. Water (10 mL) was added, and the mixture was extracted three times with DCM (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-100%, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product as a yellow solid (100 mg, 75.9% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₃ ClFN ₃ OS][M+H] ⁺ :290.1; found:289.9

2.4

2-Chloro-4-((3-fluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (02370-2-rac)

To a solution of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-3-fluoro-cyclobutyl)methanol (100 mg, 0.345 mmol) and S-1,1'-bin-2-naphthol (9.8 mg, 0.0345 mmol) in DCM (10 mL) was added titanium tetraisopropoxide (9.8 mg, 0.0345 mmol) and water (12.4 mg, 0.69 mmol). After the mixture was stirred at room temperature for 1 hour, 70% aqueous tert-butyl hydroperoxide solution (88.7 mg, 0.69 mmol) was added in one portion. The mixture was then stirred at room temperature for 2 hours, after which water (10 mL) was added and the mixture was extracted three times with DCM (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 10/1, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give a yellow solid product (85.0 mg, yield 80.6%).

ESI-MS m/z calcd for[C ₁₁ H ₁₃ ClFN ₃ O ₂ S][M+H] ⁺ :306.0; found:305.8

2.5

2-(4,5-Dihydro-2H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-4-((1-(hydroxymethyl)-3-fluoro-cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02370-rac)

To a solution of 2-chloro-4-((1-(hydroxymethyl)-3-fluoro-cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (40 mg, 0.13 mmol) in DMF (4 mL) was added 4-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane (63.9 mg, 55% purity, 0.157 mmol) and DIEA (0.5 mL). The reaction mixture was stirred at 100°C for 4 hours, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/ _{L NH4HCO3} ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (33 mg, 51.1% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₅ ClFN ₇ O ₂ S][M+H] ⁺ :494.2; found:494..2

¹ H NMR (400MHz, DMSO-d ₆ )δ8.52(s,2H),7.89–7.60(m,1H),5.16–4.86(m,2H),3.94–3.41(m,9H) ,3.25–3.13(m,1H),2.96–2.64(m,4H),2.49–2.08(m,2H),0.96(s,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

(1-((2-Chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-3,3-difluoro-cyclobutyl)methanol (02371-1)

To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (270 mg, 1.304 mmol) in DMF (5 mL) was added (1-amino-3,3-difluorocyclobutyl)methanol hydrochloride (181.1 mg, 1.043 mmol) and KF (181.5 mg, 3.13 mmol). The mixture was stirred at 80°C for 16 hours, then the solvent was removed by distillation under reduced pressure. Water (20 mL) was added, and the mixture was extracted three times with DCM (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-100%, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product as a yellow solid (170 mg, 52.8% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₂ ClF ₂ N ₃ OS][M+H] ⁺ :308.0; found:308.2

2.2

(R)-2-Chloro-4-((1-(hydroxymethyl)-3,3-difluoro-cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (02371-2)

To a solution of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-3,3-difluoro-cyclobutyl)methanol (100 mg, 0.325 mmol) and S-1,1'-bin-2-naphthol (9.2 mg, 0.0325 mmol) in DCM (10 mL) was added titanium tetraisopropoxide (9.2 mg, 0.0325 mmol) and water (11.7 mg, 0.65 mmol). The mixture was stirred at room temperature for 1 hour, and then 70% aqueous tert-butyl hydroperoxide solution (88.7 mg, 0.69 mmol) was added in one portion. The mixture was then stirred at room temperature for 2 hours, and then water (10 mL) was added, and the mixture was extracted three times with DCM (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 10/1, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give a yellow solid product (80.0 mg, yield 76.0%).

ESI-MS m/z calcd for[C ₁₁ H ₁₂ ClF ₂ N ₃ O ₂ S][M+H] ⁺ :324.0; found:324.2

2.3

(R)-2-(4,5-dihydro-2H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-4-((1-(hydroxymethyl)-3,3-difluoro-cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02371)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)-3,3-difluoro-cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (35 mg, 0.108 mmol) in DMF (4 mL) were added 4-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane (52.8 mg, 55% purity, 0.13 mmol) and DIEA (0.5 mL). The reaction mixture was stirred at 100° C. for 4 hours, and the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to obtain a white solid product (39.0 mg, yield 70.5%).

ESI-MS m/z calcd for[C ₂₁ H ₂₄ ClF ₂ N ₇ O ₂ S][M+H] ⁺ :512.1; found:512..2

¹ H NMR (400MHz, DMSO-d ₆ )δ8.52(s,2H),7.96–7.88(m,1H),5.15(t,J＝5.6Hz,1H),3.94–3.62(m,8 H),3.45–3.41(m,1H),3.23–3.16(m,1H),2.94–2.83(m,6H),0.95(s,4H).

1. Synthesis scheme:

2. Experimental part:

2. Methyl 1,2-(2-fluoro-4-nitrophenyl)acetate (02398-1)

To a solution of 2-(2-fluoro-4-nitrophenyl)acetic acid (4 g, 20.101 mmol) in MeOH (40 mL) was added concentrated _H₂SO₄ ( ₂ mL) at room temperature. The mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated, and the crude product was extracted twice with saturated aqueous _NaHCO₃ (40 mL) and EA (40 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the product as a yellow solid (3.6 g, 84.1% yield).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.13–8.08 (m, 2H), 7.70 (t, J = 8.0Hz, 1H), 3.94 (s, 2H), 3.66 (s, 3H).

2. Methyl 2-(4-amino-2-fluorophenyl)acetate (02398-2)

To a solution of methyl 2-(2-fluoro-4-nitrophenyl)acetate (3.6 g, 16.886 mmol) in EA (40 mL) was added Pd/C (360 mg) at room temperature. The mixture was stirred overnight under a hydrogen atmosphere and filtered through celite. The filtrate was distilled off under reduced pressure, and the crude product was purified by column chromatography (EA/PE = 0-4/1, silica gel-CS 40 g, 40 mL/min, UV 254) to give the product as a yellow solid (2.9 g, 93.9% yield).

ESI-MS m/z calcd for[C ₉ H ₁₀ FNO ₂ ][M+H] ⁺ :184.1; found:184.2

2.3

Methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02398-3)

To a solution of methyl 2-(4-amino-2-fluorophenyl)acetate (3.62 g, 19.76 mmol) and DIEA (7.65 g, 59.279 mmol) in DMF (40 mL) was added 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (4.09 g, 19.76 mmol). The mixture was then stirred at 120°C for 16 hours. The reaction mixture was concentrated, water (60 mL) was added, and the mixture was extracted twice with DCM (60 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 40 g, 40 mL/min, UV 254) to give the product as a yellow solid (1.58 g, yield 22.6%).

ESI-MS m/z calcd for[C ₁₅ H ₁₃ ClFN ₃ O ₂ S][M+H] ⁺ :354.0; found:354.0

2.4

(R)-methyl 2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02398-4)

To a solution of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (500 mg, 1.413 mmol) and S-1,1'-binaphthol (40.5 mg, 0.141 mmol) in DCM (10 mL) were added titanium tetraisopropoxide (20.1 mg, 0.071 mmol) and water (25.4 mg, 1.413 mmol). After the mixture was stirred under nitrogen for 16 hours, 70% aqueous tert-butyl hydroperoxide (200 mg, 1.555 mmol) was added in one portion, and the mixture was then stirred at room temperature under nitrogen for 2 hours. Water (20 mL) was added, and the mixture was extracted three times with DCM (60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (392 mg, yield 75.1%).

ESI-MS m/z calcd for[C ₁₅ H ₁₃ ClFN ₃ O ₃ S][M+H] ⁺ :370.0; found:369.9

2.5

(R)-methyl 2-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (02398-5)

To a solution of (R)-methyl 2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (570 mg, 1.54 mmol) and 1-methyl-1H-pyrazole-4-boronic acid (233 mg, 1.85 mmol) in 1,4-dioxane/water (10 mL, v/v 5:1) were added _{K2CO3 (} 394 mg, 3.08 mmol) and Pd(dppf) _Cl2 (108 mg, 0.15 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. The solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 20/1, Silica Gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product as a yellow solid (311 mg, 49% yield).

ESI-MS m/z calcd for[C ₁₉ H ₁₈ FN ₅ O ₃ S][M+H] ⁺ :416.1; found:415.8

2.6

(R)-2-(2-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (02398-6)

To a solution of methyl ((R)-2-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (311 mg, 0.75 mmol) in MeOH/THF (6 mL, v/v=1/1) was added 2N aqueous NaOH solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature for 2 hours under nitrogen. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The mixture was then concentrated, and the crude product was purified by reverse phase column chromatography (MeCN/ _H2O =1/9 to 11/9, C-18 column, 50 mL/min, UV 214) to give a white solid product (139 mg, yield 46%).

ESI-MS m/z calcd for[C ₁₈ H ₁₆ FN ₅ O ₃ S][M+H] ⁺ :402.1; found:401.8

2.7

(R)-2-(2-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-(2,2,2-trifluoroethyl)acetamide (MX02398)

To a solution of (R)-2-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (20 mg, 0.05 mmol) in DMF (1 mL) were added 2,2,2-trifluoroethylamine (10 mg, 0.10 mmol), DIEA (13 mg, 0.10 mmol) and BOP (22 mg, 0.05 mmol). The mixture was stirred at room temperature for 1 hour. After the starting material was consumed, the reaction mixture was concentrated in vacuo to give a crude product which was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid The solid product (3.14 mg, yield 13%).

ESI-MS m/z calcd for[C ₂₀ H ₁₈ F ₄ N ₆ O ₂ S][M+H] ⁺ :483.1; found:482.5

¹ H NMR (400MHz, DMSO-d ₆ )δ10.01(s,1H),8.77(t,J＝6.0Hz,1H),8.32(s,1H),7.95(s,1H),7.71–7.63(m,2H),7.34(t,J＝8.8Hz,1H), 3.99–3.90(m,5H),3.73–3.65(m,1H),3.58(s,2H),3.44–3.37(m,1H),3.31–3.24(m,1H),3.13–3.08(m,1H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-(2,2,2-trifluoroethyl)acetamide (MX02413)

To a solution of 2-(4-(((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (20 mg, 0.044 mmol) and 2,2,2-trifluoroethylamine (13.1 mg, 0.132 mmol) in DMF (3 mL) were added BOP (38.9 mg, 0.088 mmol) and DIEA (17.1 mg, 0.132 mmol). The mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (9.69 mg, 41.1% yield).

ESI-MS m/z calcd for[C ₂₄ H ₂₁ F ₄ N ₅ O ₃ S][M+H] ⁺ :536.1; found:535.9

¹ H NMR (400MHz, DMSO-d ₆ )δ11.45(s,1H),9.12(s,1H),8.83–8.78(m,2H),8.65(s,1H),8.13(dd,J＝8.8,1.6Hz,1H),7.78(dd,J＝12.0,2.0Hz,1H ),7.51–7.38(m,4H),6.57(s,1H),3.98–3.94(m,2H),3.63(s,2H),3.56–3.51(q,J＝7.2Hz,2H),1.26(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((5-(ethylsulfonyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (02418-1)

To a solution of methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (60 mg, 0.155 mmol) in 1,4-dioxane/water (10 mL, v/v = 4/1) were added (2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)boronic acid (41.5 mg, 0.232 mmol), _K₂CO₃ (64.1 _mg , 0.464 mmol), and Pd(dppf) _Cl₂ dichloromethane complex (19 mg, 0.023 mmol). The mixture was heated to 90°C and stirred under nitrogen for 5 hours. After cooling to room temperature, the pH of the reaction solution was adjusted to 12 with 2N NaOH solution. The reaction mixture was stirred for a further 16 hours, after which the pH of the reaction solution was adjusted to neutral with 1N HCl solution. After concentration, the crude product was purified by reverse phase column (MeCN/H ₂ O=0-30%, C-18 40 g, 40 mL/min, UV 254) to obtain a yellow solid product (21 mg, yield 28.7%).

ESI-MS m/z calcd for[C ₂₁ H ₁₇ FN ₄ O ₆ S][M+H] ⁺ :473.1; found:473.0

2.2

2-(4-((5-(ethylsulfonyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylacetamide (MX02418)

To a solution of 2-(4-(((5-(ethylsulfonyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (21 mg, 0.044 mmol) and isobutylamine (9.8 mg, 0.133 mmol) in DMF (3 mL) were added BOP (39.3 mg, 0.089 mmol) and DIEA (23 mg, 0.178 mmol). The mixture was stirred at room temperature for 16 hours, then the reaction solution was filtered, and the filtrate was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _{NH4HCO3 )} , X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (2.31 mg, yield 9.9%).

ESI-MS m/z calcd for[C ₂₅ H ₂₆ FN ₅ O ₅ S][M+H] ⁺ :528.2; found:527.8

¹ H NMR (400MHz, DMSO-d ₆ )δ9.15(s,1H),8.79(s,1H),8.08–8.06(m,2H),7.93(d,J＝1.6Hz,1H),7.63(dd,J＝8.0,1.6Hz,1H),7.41–7.37 (m,3H),3.55–3.52(m,4H),2.93–2.90(m,2H),1.74–1.67(m,1H),1.25(t,J＝7.6Hz,3H),0.85(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (02434-1)

To a solution of 1-tert-butyloxycarbonyl-3-hydroxyazetidine (3.2 g, 18.5 mmol) in anhydrous DCM (50 mL) was added dropwise TsCl (5.27 g, 27.74 mmol) and DMAP (4.51 g, 37 mmol) at room temperature. The reaction was stirred overnight at room temperature, then quenched with saturated aqueous _NH4Cl (100 mL) at 0°C and extracted three times with EA (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was purified by column chromatography (EA/PE = 0-10%, Silica Gel-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product as a colorless oil (6.0 g, 99% yield).

ESI-MS m/z calcd for[C ₁₅ H ₂₁ NO ₅ S][M-56+H] ⁺ :272.1; found:272.2

2.2

Tert-Butyl 3-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)azetidine-1-carboxylate (02434-2)

To a solution of tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (1 g, 3.06 mmol) and 2,6-dihydroxyquinoline (492 mg, 3.06 mmol) in isopropanol (10 mL) was added DBU (930 mg, 6.12 mmol). The reaction mixture was stirred at 90 ° C for 3 days, and then the mixture was distilled under reduced pressure to remove the solvent. Water (30 mL) was added and extracted twice with EA (50 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give a yellow solid product (227 mg, yield 23%).

ESI-MS m/z calcd for[C ₁₇ H ₂₀ N ₂ O ₄ ][M+H] ⁺ :317.1; found:316.8

2.3

6-(Azetidin-3-oxy)quinolin-2(1H)-one (02434-3)

To a solution of tert-butyl 3-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)azetidine-1-carboxylate (20 mg, 0.06 mmol) in DCM (3 mL) was added TMSOTf (0.5 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After the starting material was consumed, the mixture was concentrated to dryness by distillation under reduced pressure to give the product as a white solid (13 mg, 95% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₂ N ₂ O ₂ ][M+H] ⁺ :217.1; found:217.0

2.4

(R)-6-((1-(4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)quinolin-2(1H)-one (MX02434)

To a solution of 6-(azetidin-3-oxy)quinolin-2(1H)-one (14 mg, 0.06 mmol) in DMF (2 mL) were added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (18 mg, 0.06 mmol) and DIEA (15 mg, 0.12 mmol). The mixture was stirred at 90°C under nitrogen for 2 hours. After the starting material was consumed, the mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (7.08 mg, 16% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₅ N ₅ O ₄ S][M+H] ⁺ :468.2; found:467.6

¹ H NMR (400MHz, DMSO-d ₆ )δ11.67(s,1H),7.86(d,J＝9.6Hz,1H),7.48(s,1H),7.27(d,J＝9.2Hz,1H),7.17–7.1 2(m,2H),6.51(d,J＝9.2Hz,1H),5.15–5.10(m,1H),4.85(t,J＝5.6Hz,1H),4.48(dd,J＝ 10.0,6.4Hz,2H),4.03–3.86(m,2H),3.74–3.66(m,2H),3.45–3.36(m,1H),3.25–3.1 8(m,1H),2.97–2.85(m,2H),2.38–2.25(m,2H),2.15–2.11(m,2H),1.82–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl 3-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)azetidine-1-carboxylate (02435-1)

To a solution of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (200 mg, 1.22 mmol) and tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (400 mg, 1.22 mmol) in DMF (10 mL) was added Cs ₂ CO ₃ (798 mg, 2.45 mmol) at room temperature. The mixture was then stirred at 60 ° C for 4 hours, followed by addition of water (20 mL) and extraction twice with EA (40 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/DCM=0/1~1/1, silica gel-CS12 g, 30 mL/min, silica gel, UV 254) to give a white solid. The obtained product was purified by HPLC (288 mg, yield 64.5%).

ESI-MS m/z calcd for[C ₁₇ H ₂₂ N ₂ O ₄ ][M-56+H] ⁺ :263.2; found:263.2

2.2

(R)-6-((1-(4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (MX02435)

To a solution of tert-butyl 3-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)azetidine-1-carboxylate (13 mg, 0.041 mmol) in DCM (2 mL) at room temperature was added TMSOTf (14 mg, 0.061 mmol). The mixture was then stirred at room temperature for 30 minutes. After completion of the reaction, the pH of the mixture was adjusted to 7 with TEA (0.02 mL). The reaction mixture was distilled under reduced pressure to obtain a crude product. To a solution of the crude product in DMF (2 mL) at room temperature were added (R)-2-chloro-4-[(1-(hydroxymethyl)cyclobutyl)amino]-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (9.4 mg, 0.033 mmol) and DIEA (11 mg, 0.082 mmol). The mixture was then stirred at 90°C for 4 hours. The solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC ₍ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give a white solid product (9 mg, 58.2%).

ESI-MS m/z calcd for[C ₂₃ H ₂₇ N ₅ O ₄ S][M+H] ⁺ :470.2; found:469.9

¹ H NMR (400MHz, DMSO-d ₆ )δ9.94(s,1H),7.47(s,1H),6.79(d,J＝8.8Hz,1H),6.74(d,J＝2.4Hz,1H),6.67(dd, J＝8.8,2.8Hz,1H),5.05–5.01(m,1H),4.85(t,J＝5.6Hz,1H),4.44–4.40(m,2H),3.8 9–3.85(m,2H),3.70–3.68(m,2H),3.43–3.35(m,1H),3.30–3.17(m,1H),2.96–2.82 (m,4H),2.46–2.39(m,2H),2.35–2.25(m,2H),2.15–2.10(m,2H),1.79–1.72(m,2H)

1. Synthesis scheme:

2. Experimental part:

2.1

6-(4-Hydroxyphenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02437-1)

To a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (500 mg, 2.461 mmol) in water (5 mL) at 0°C was added sulfuric acid (1 g, 10.20 mmol). The mixture was stirred at 0°C, and a solution of sodium nitrite (190 mg, 2.75 mmol) in water (5 mL) was slowly added dropwise to the reaction mixture. Stirring was continued for 20 minutes, and the mixture was slowly heated to 90°C over 20 minutes. The mixture was poured into water (30 mL), filtered, and dried to obtain the crude product. The crude product was purified by preparative HPLC (MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to afford the product as a dark brown solid (220 mg, 43.82% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₂ N ₂ O ₂ ][M+H] ⁺ :205.0; found:205.0

2.2

Tert-Butyl 3-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)azetidine-1-carboxylate (02437-2)

To a solution of 6-(4-hydroxyphenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (220 mg, 1.07 mmol) and tert-butyl 3-(p-toluenesulfonyloxy)azetidine _- 1-carboxylate (350 mg, 1.07 mmol) in DMF (10 mL) at 0°C was added _K2CO3 (442 mg, 3.21 mmol) and KI (35.52 mg, 0.214 mmol). The mixture was stirred at 80°C for 6 hours, then poured into water (50 mL) and extracted twice with EA (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE=0-80%, silica gel-CS 12 g, 20 mL/min, UV 254) to give a white solid product (208 mg, yield 53.74%).

ESI-MS m/z calcd for[C ₁₉ H ₂₅ N ₃ O ₄ ][M+H] ⁺ :360.2; found:360.4

2.3

6-(4-(azetidin-3-oxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02437-3)

To a solution of tert-butyl 3-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)azetidine-1-carboxylate (70 mg, 2.508 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at 25°C for 2 hours, and the solvent was removed by distillation under reduced pressure. The resulting crude white solid (87 mg) was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₄ H ₁₇ N ₃ O ₂ ][M+H] ⁺ :260.2; found:260.0

2.4

6-(4-((1-((R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (MX02437-rac)

To a solution of 6-(4-(azetidin-3-oxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (87 mg, 0.335 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (96.35 mg, 0.335 mmol) in DMF (5 mL) was added DIEA (43.29 mg, 1.340 mmol). The mixture was stirred at 90° C. for 3 hours, cooled to room temperature, and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (40.89 mg, 23.92% yield).

ESI-MS m/z calcd for[C ₂₅ H ₃₀ N ₆ O ₄ S][M+H] ⁺ :511.2; found:511.3

¹ H NMR (400MHz, DMSO-d ₆ )δ10.87(s,1H),7.75(d,J＝9.2,2H),7.47(s,1H),6.94(d,J＝8.8,2H),5.20–5.15 (m,1H),4.84(t,J＝5.6Hz,1H),4.49–4.45(m,2H),4.02–3.87(m,2H),3.70–3.67( m,2H),3.45–3.36(m,2H),3.27–3.18(m,1H),2.97–2.85(m,2H),2.70–2.64(m,1H ),2.38–2.22(m,3H),2.15–2.10(m,2H),1.82–1.67(m,2H),1.07(d,J＝7.2H,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-(Benzyloxy)-1-(triisopropylsilyl)-1H-indole (0206-1)

To a solution of 5-(benzyloxy)-1H-indole (3 g, 13.45 mmol) in anhydrous THF (20 mL) was added dropwise a solution of NaH (60%, 699 mg, 17.48 mmol) in THF (20 mL) at 0°C. The mixture was slowly warmed to room temperature over 30 minutes, and then TIPSCl (3.37 g, 17.48 mmol) was added dropwise at 0°C over 5 minutes. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction was then quenched with saturated aqueous _NH4Cl (20 mL) at 0°C and extracted with _Et2O (15 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was purified by column chromatography (EA/PE = 0-10%, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a white solid product (3.2 g, yield 62.69%).

2.2

1-(Triisopropylsilyl)-1H-indol-5-ol (02060-2)

To a solution of 5-(benzyloxy)-1-(triisopropylsilyl)-1H-indole (3.2 g, 8.43 mmol) in EtOH (40 mL) was added Pd/C (120 mg) at room temperature. The mixture was stirred overnight under a hydrogen atmosphere, filtered through celite, and the filtrate was distilled under reduced pressure to give the product as a colorless oil (2.3 g, 94.3%).

ESI-MS m/z calcd for[C ₁₇ H ₂₇ NOSi][M+H] ⁺ :290.2; found:290.2

2.3

Tert-Butyl 3-((1H-indol-5-yl)oxy)azetidine-1-carboxylate (02060-3)

To a solution of 1-(triisopropylsilyl)-1H-indol-5-ol (2.67 g, 9.22 mmol) and _Cs₂CO₃ (9.0 _g , 27.67 mmol) in DMF (50 mL) was added tert-butyl 3-iodoazetidine-1-carboxylate (3.1 g, 11.07 mmol). The reaction mixture was stirred at 140°C for 3 hours, after which the solvent was removed by distillation under reduced pressure. Water (150 mL) was added, and the mixture was extracted twice with EA (75 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, Silica Gel-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product as a yellow solid (480 mg, 81.5% yield).

ESI-MS m/z calcd for[C ₁₆ H ₂₀ N ₂ O ₃ ][M+H] ⁺ :289.2; found:289.1

2.4

Tert-Butyl 3-((1-methyl-1H-indol-5-yl)oxy)azetidine-1-carboxylate (02460-4)

To a solution of tert-butyl 3-((1H-indol-5-yl)oxy)azetidine-1-carboxylate (150 mg, 0.52 mmol) in anhydrous THF (10 mL) was added dropwise a solution of NaH (60%, 699 mg, 0.67 mmol) in THF (20 mL) at 0°C. The reaction mixture was slowly warmed to room temperature over 30 minutes, followed by the dropwise addition of MeI (88 mg, 0.62 mmol) at 0°C. The resulting mixture was slowly warmed to room temperature and stirred for 2 hours, followed by the addition of saturated _NH₄Cl (20 mL) at 0°C, and extracted three times with _Et₂O (15 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE=0-75%, silica gel-CS 20 g, 40 mL/min, silica gel, UV 254) to give a yellow solid product (480 mg, yield 81.5%).

ESI-MS m/z calcd for[C ₁₇ H ₂₂ N ₂ O ₃ ][M-56+H] ⁺ :247.2; found:247.2

2.5

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-((1-methyl-1H-indol-5-yl)oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02460)

A solution of tert-butyl 3-((1-methyl-1H-indol-5-yl)oxy)azetidine-1-carboxylate (40 mg, 0.13 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (37 mg, 0.13 mmol) in HFP (2 mL) was stirred at 120°C under microwave conditions for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC (MeCN/ _H2O ( ₁₀ mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (8.35 mg, 14.2% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₇ N ₅ O ₃ S][M+H] ⁺ :454.2; found:454.3

¹ H NMR (400MHz, DMSO-d ₆ )δ7.44(s,1H),7.36(d,J＝8.8Hz,1H),7.29(d,J＝2.8Hz,1H),6.94(d,J＝2.4Hz,1H),6.79( dd,J＝8.8,2.4Hz,1H),6.33–6.32(m,1H),5.12–5.07(m,1H),4.84(t,J＝5.6Hz,1H),4.47– 4.43(m,2H),4.02–3.85(m,2H),3.75(s,3H),3.74–3.67(m,2H),3.45–3.37(m,1H),3.25– 3.18(m,1H),2.97–2.84(m,2H),2.38–2.25(m,2H),2.14–2.10(m,2H),1.81–1.67(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(1-((2-Chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (02461-1)

To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (6.64 g, 32.07 mmol) in MeCN (50 mL) were added (1-aminocyclobutyl)methanol (3.24 g, 32.07 mmol) and TEA (20 mL). The mixture was stirred at 75°C for 16 hours, then the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (EA/DCM = 0-60%, Silica Gel-CS 120 g, 50 mL/min, silica gel, UV 254) to give the product as a yellow solid (4.01 g, 46.1% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₄ ClN ₃ OS][M+H] ⁺ :272.1; found:272.1

2.2

(R)-2-Chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (02461-2)

To a solution of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (3.5 g, 12.88 mmol) and S-1,1'-bi-2-naphthol (369.0 mg, 1.288 mmol) in DCM (60 mL) was added titanium tetraisopropoxide (182 mg, 0.64 mmol) and water (232 mg, 12.88 mmol). After the mixture was stirred at room temperature for 1 hour, 70% aqueous tert-butyl hydroperoxide solution (2 g, 14.17 mmol) was added in one portion. The mixture was then stirred at room temperature for 2 hours, after which water (50 mL) was added and the mixture was extracted three times with DCM (60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 10/1, silica gel-CS 80 g, 50 mL/min, silica gel, UV 254) to give a yellow solid product (3.50 g, yield 94.6%).

ESI-MS m/z calcd for[C ₁₁ H ₁₄ ClN ₃ O ₂ S][M+H] ⁺ :288.0; found:288.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.62(s,1H),4.89(t,J＝5.6Hz,1H),3.74–3.66(m,2H),3.61–3.52(m,1H),3.38–3.3 0(m,1H),3.16–3.12(m,1H),3.05–2.99(m,1H),2.32–2.17(m,4H),1.81–1.71(m,2H).

2.3

Tert-butyl 3-(3-methyl-1H-indol-5-yl)oxy)azetidine-1-carboxylate (02461-4)

To a solution of 3-methyl-1H-indol-5-ol (300 mg, 2.038 mmol) in DMF (5 mL) was added tert-butyl 3-iodoazetidine-1-carboxylate (577.1 mg, 2.038 mmol) and _K₂CO₃ (422.6 _mg , 3.058 mmol). The mixture was stirred at 80°C for 2 hours, water (30 mL) was added, and then extracted twice with EA (25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-20%, silica gel-CS 20 g, 25 mL/min, UV 254) to afford the product as a white solid (223 mg, 36.2% yield).

ESI-MS m/z calcd for[C ₁₇ H ₂₂ N ₂ O ₃ ][M-56+H] ⁺ :247.2; found:247.2

2.4

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-((3-methyl-1H-indol-5-yl)oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02461)

To a solution of tert-butyl 3-(3-methyl-1H-indol-5-yl)oxy)azetidine-1-carboxylate (40 mg, 0.132 mmol) in HFP (3 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (38.1 mg, 0.132 mmol). The mixture was stirred at 120°C under microwave conditions for 2 hours. After cooling to room temperature, the reaction mixture was concentrated. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol _/ L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (15.86 mg, 26.4% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₇ N ₅ O ₃ S][M+H] ⁺ :454.2; found:454.0

¹ H NMR (400MHz, DMSO-d ₆ )δ10.62–10.61(m,1H),7.45(s,1H),7.24(d,J＝8.8Hz,1H),7.08(s,1H),6.84(d,J＝2.0 Hz,1H),6.70(dd,J＝8.8,2.0Hz,1H),5.13–5.11(m,1H),4.86(t,J＝6.0Hz,1H),4.47–4.4 3(m,2H),3.95–3.93(m,2H),3.70–3.69(m,2H),3.43–3.37(m,1H),3.23–3.20(m,1H),2 .97–2.86(m,2H),2.36–2.28(m,2H),2.22(s,3H),2.15–2.09(m,2H),1.77–1.72(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-(3-((1H-indol-5-yl)oxy)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02464)

A solution of (R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (20 mg, 0.062 mmol) and tert-butyl 3-((1H-indol-5-yl)oxy)azetidine-1-carboxylate (21.3 mg, 0.074 mmol) in HFP (3 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (10.0 mg, yield 34.0%).

ESI-MS m/z calcd for[C ₂₂ H ₂₃ F ₂ N ₅ O ₃ S][M+H] ⁺ :476.2; found:476.2

¹ H NMR (400MHz, DMSO-d ₆ )δ10.97(s,1H),7.95(s,1H),7.32–7.30(m,2H),6.93(d,J＝2.4Hz,1H),6.72(dd,J＝8.8,2.4Hz,1H),6.35(t,J＝2.4Hz,1H),5.14 –5.07(m,2H),4.48–4.44(m,2H),3.96–3.95(m,2H),3.67–3.66(m,2H),3.48–3.39(m,1H),3.24–3.17(m,1H),2.99–2.83(m,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-tert-Butyl 4-(5-chloropyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (02450-1)

To a solution of (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.31 mmol) in DMF (10 mL) were added 2,5-dichloropyrimidine (341 mg, 2.31 mmol) and DIEA (894 mg, 6.93 mmol). The mixture was stirred at 100 ° C under nitrogen for 6 hours. After the starting material was consumed, water (20 mL) was added and then extracted three times with EA (20 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was obtained by Purification by column chromatography (EA/PE=0/1-2/3, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) gave the product as a yellow oil (554 mg, yield 73%).

ESI-MS m/z calcd for[C ₁₄ H ₂₁ ClN ₄ O ₃ ][M+H] ⁺ :329.1; found:329.3

2.2

(R)-2-((R)-4-(5-chloropyrimidin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02012)

A solution of tert-butyl (R)-4-(5-chloropyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (50 mg, 0.15 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (43 mg, 0.15 mmol) in HFP (2 mL) was stirred at 120°C under microwave conditions for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol _/ L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (8.16 mg, 11.0% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₆ ClN ₇ O ₃ S][M+H] ⁺ :480.2; found:480.2

¹ H NMR (400MHz, DMSO-d ₆ )δ8.44(s,2H),7.34(s,1H),4.82(t,J＝5.6Hz,1H),4.73–4.38(m,5H),3.72(d,J＝5.6,Hz,2H),3.45–3.3 7(m,3H),3.29–3.09(m,4H),2.98–2.84(m,2H),2.45–2.29(m,2H),2.20–2.15(m,2H),1.82–1.70(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-methyl 2-(4-((2-(5-chlorothien-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02159-1)

A mixture of methyl (R)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (70 mg, 0.19 mmol), (5-chlorothien-2-yl)boronic acid (30.59 mg, 0.19 mmol), RuPhosPdG₂ ₍ 13.88 mg, 0.02 mmol), _{K₃PO₄ (} 120 mg, 0.57 mmol), and water (0.5 mL) in 1,4-dioxane (4 mL) was stirred at 85°C under argon for 4 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (DCM/MeOH = 0-1/10, Silica Gel-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product as a yellow solid (45 mg, 52.9% yield).

ESI-MS m/z calcd for[C ₁₉ H ₁₅ ClFN ₃ O ₃ S ₂ ][M+H] ⁺ :452.0; found:452.2

2.2

(R)-2-(4-((2-(5-chlorothien-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02159)

To a solution of methyl (R)-2-(4-((2-(5-chlorothien-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (40 mg, 0.09 mmol) in MeOH/THF (3 mL, v/v = 1/1) was added 2N aqueous NaOH solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The mixture was then concentrated, and the crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select ₁₀ μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (17.06 mg, 44.0% yield).

ESI-MS m/z calcd for[C ₁₈ H ₁₃ ClFN ₃ O ₃ S ₂ ][M+H] ⁺ :438.0; found:437.7

¹ H NMR (400MHz, DMSO-d ₆ )δ10.02(br,1H),7.75(d,J＝4.0Hz,1H),7.67(dd,J＝12.4,2.0Hz,1H),7.53(dd,J＝8.4,2.0Hz,1H),7.34(t,J＝8.8Hz, 1H),7.27(d,J=4.0Hz,1H),3.77–3.68(m,1H),3.57(s,2H),3.47–3.40(m,1H),3.34–3.28(m,1H),3.16–3.11(m,1H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(ethylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02163-1-rac)

To a solution of methyl 2-(4-((2-chloro-5-(ethylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (47 mg, 0.13 mmol) and DIEA (65 mg, 0.51 mmol) in DMF (3 mL) was added 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine dihydrochloride (29.7 mg, 0.15 mmol). The mixture was then stirred at 90°C for 1 hour. The reaction mixture was concentrated, and the crude product was purified via reverse phase column chromatography (MeCN/ _H₂O = 0-40%, C-18 column, 50 mL/min, UV 214) to afford the product as a yellow solid (36 mg, 62.11% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₃ FN ₆ O ₃ S][M+H] ⁺ :459.2; found:458.8

2.2

2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(ethylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02163-rac)

To a solution of methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(ethylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (36 mg, 0.08 mmol) in MeOH (3 mL) was added a solution of NaOH (31.4 mg, 0.79 mmol) in water (1 mL). The mixture was then stirred at room temperature for 16 hours. The pH of the solution was adjusted to 6 with AcOH. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (23.67 mg, 67.83% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₁ FN ₆ O ₃ S][M+H] ⁺ :445.1; found:445.2

¹ H NMR (400MHz, DMSO-d ₆ )δ9.67(s,1H),8.19(s,1H),7.64–7.60(m,1H),7.46(s,1H),7.29(t,J＝8.4Hz,1H ),7.20(d,J＝8.4Hz,1H),4.88–4.84(m,2H),4.03–3.98(m,2H),3.43(s,2H),3.15 –3.06(m,2H),2.65–2.61(m,2H),1.15(t,J＝7.6Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02164-1)

To a solution of methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (50 mg, 0.13 mmol) in DMF (2 mL) were added 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine (17 mg, 0.14 mmol) and DIEA (50 mg, 0.39 mmol). The mixture was stirred at 90°C under nitrogen for 2 hours. After the starting material was consumed, it was cooled and added to water (10 mL), and extracted three times with EA (10 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS20 g, 20 mL/min, silica gel, UV 254) to give a white solid product (31 mg, yield 51%).

ESI-MS m/z calcd for[C ₂₁ H ₂₃ FN ₆ O ₄ S][M+H] ⁺ :475.2; found:474.6

2.2

2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02164)

To a solution of methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (31 mg, 0.06 mmol) in MeOH/THF (2 mL, v/v = 1/1) was added 2N aqueous NaOH solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The mixture was then concentrated, and the crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select ₁₀ μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (2.07 mg, 7% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₁ FN ₆ O ₄ S][M+H] ⁺ :461.1; found:461.2

¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O)δ8.39(s,1H),7.65–7.55(m,1H),7.48(s,1H),7.35–7.27(m,2H),4.96–4.84(m,2H),4.09 –3.96(m,2H),3.52(s,2H),3.34(q,J＝6.8Hz,2H),2.69–2.65(m,2H),1.20(t,J＝7.6Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02165-1)

To a solution of methyl 2-(4-(((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (250 mg, 0.64 mmol) and 5-indoleboronic acid (124 mg, 0.77 mmol) in 1,4-dioxane/water (10 mL, v/v 5:1) were added _K2CO3 (164 _mg , 1.28 mmol) and Pd(dppf) _Cl2 (43 mg, 0.06 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. The solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (PE/EA = 1/0 to 1/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product as a yellow solid (244 mg, 81% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₁ FN ₄ O ₄ S][M+H] ⁺ :469.1; found:468.8

2.2

2-(4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02165)

To a solution of methyl 2-(4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (244 mg, 0.52 mmol) in MeOH/THF (10 mL, v/v = 1/1) was added 2N aqueous NaOH solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The mixture was then concentrated, and the crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (123 mg, 52% yield).

ESI-MS m/z calcd for[C ₂₂ H ₁₉ FN ₄ O ₄ S][M+H] ⁺ :455.1; found:455.2

¹ H NMR (400MHz, DMSO-d ₆ )δ12.64(brs,1H),11.45(s,1H),9.12(s,1H),8.78(s,1H),8.65(s,1H),8.13(d,J＝8.8Hz,1H),7.77(d,J＝12.4Hz,1 H),7.50(d,J＝8.4Hz,1H),7.44–7.39(m,3H),6.57(s,1H),3.64(s,2H),3.53(q,J＝7.2Hz,2H),1.26(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

2,4-Dichloro-N-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide (02168-1)

To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (4.5 g, 21.29 mmol) in dry THF (50 mL) was slowly added a solution of 2,2,2-trifluoroethylamine (2.11 g, 21.29 mmol) and TEA (2.15 g, 21.29 mmol) in dry THF (25 mL) at -20 ° C. The mixture was stirred at -20 ° C for 2 hours and then stirred for 10 minutes after the temperature rose to room temperature. The precipitate was removed by filtration and the filtrate was evaporated to obtain a crude product. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/2, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give a white solid product (3.7 g, yield 63.4%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.47 (t, J = 6.0 Hz, 1H), 8.93 (s, 1H), 4.21–4.12 (m, 2H).

2.2

Methyl 2-(4-((2-chloro-5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02168-2)

To a solution of 2,4-dichloro-N-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide (1.5 g, 5.474 mmol) and DIEA (1.41 g, 10.948 mmol) in DMF (20 mL) was added methyl 2-(4-amino-2-fluorophenyl)acetate (1 g, 5.47 mmol). The mixture was stirred at 90 ° C for 3 hours. The solvent was distilled off under reduced pressure, water (10 mL) was added, and the mixture was extracted twice with DCM (30 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a yellow solid product (1.9 g, yield 82.6%).

ESI-MS m/z calcd for[C ₁₆ H ₁₃ ClF ₄ N ₄ O ₃ ][M+H] ⁺ :421.2; found:420.8

2.3

Methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02168-3)

To a solution of methyl 2-(4-((2-chloro-5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (50 mg, 0.119 mmol) and DIEA (46.1 mg, 0.356 mmol) in DMF (2 mL) was added 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (17.6 mg, 0.143 mmol). The mixture was then stirred at 90°C for 1 hour. The solvent was distilled off under reduced pressure, water (10 mL) was added, and the mixture was extracted twice with EA (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting brown crude product was used directly in the next step.

2.4

2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (02438-4)

To a solution of methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (crude, 0.110 mmol) in EtOH (2 mL) was added 1N NaOH (0.6 mL, 0.6 mmol). The mixture was stirred at 50°C for 1 hour under nitrogen. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The mixture was then concentrated, and the crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product _as a white solid (12.93 mg, 22% yield).

ESI-MS m/z calcd for[C ₂₁ H ₁₉ F ₄ N ₇ O ₃ ][M+H] ⁺ :494.2; found:494.1

¹ H NMR (400MHz, DMSO-d ₆ )δ12.48(br,1H),11.22(s,1H),9.04(t,J＝6.0Hz,1H),8.74(s,1H),7.77(d,J＝11.2Hz,1H),7.47 (s,1H),7.33–7.25(m,2H),4.92–4.88(m,2H),4.12–4.05(m,4H),3.58(s,2H),2.67–2.66(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 4-((2-methoxy-2-oxoethyl)thio)butanoate (02170-1)

To a solution of sodium methoxide (1.62 g, 29.96 mmol) in MeOH (30 mL) was added methyl 2-mercaptoacetate (2.65 g, 24.97 mmol). The mixture was stirred at room temperature for 0.5 h. NaI (37.4 mg, 0.25 mmol) and methyl 4-chlorobutyrate (4.09 g, 29.96 mmol) were then added. The mixture was stirred at 65 ° C for 20 h, cooled to room temperature and concentrated. The crude product was dissolved in DCM (100 mL), the mixture was washed with water (20 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-22%, silica gel-CS 80 g, 50 mL/min, silica gel, UV 254) to give a yellow oily product (2.8 g, yield 54.37%).

ESI-MS m/z calcd for[C ₈ H ₁₄ O ₄ S][M+H] ⁺ :207.1; found:207.2

2.2

Methyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate (02170-2)

Sodium chunks (1.09 g, 47.51 mmol) and toluene (200 mL) were added to a 500 mL flask. MeOH (20 mL) was then added. The mixture was stirred at 100° C. for 3 hours, and the MeOH was removed. A solution of methyl 4-((2-methoxy-2-oxoethyl)thio)butanoate (2.8 g, 13.58 mmol) in toluene (10 mL) was added at 100° C. The mixture was stirred at 110° C. for 1 hour and then cooled to room temperature. The mixture was poured into a mixture of concentrated hydrochloric acid (10 mL) and ice (100 g). The mixture was extracted twice with EA (100 mL), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-25%, silica gel-CS 80 g, 50 mL/min, silica gel, UV 254) to give a yellow oily product (1.5 g, yield 63.42%).

ESI-MS m/z calcd for[C ₇ H ₁₀ O ₃ S][M+H] ⁺ :175.0; found:175.4

2.3

2-(Methylthio)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (02170-3)

To a solution of KOH (1.01 g, 18.08 mmol) in MeOH (40 mL) was added methyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate (2.1 g, 12.05 mmol) and bis(S-methylthio)ammonium sulfate (1.68 g, 6.03 mmol). The mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and AcOH (3 mL) was added. A solid was formed, which was collected by filtration and rinsed with water and MTBE to give the product as a white solid (1.8 g, 69.68% yield).

ESI-MS m/z calcd for[C ₈ H ₁₀ N ₂ OS ₂ ][M+H] ⁺ :215.0; found:215.2

2.4

7,8-Dihydro-6H-thiopyrano[3,2-d]pyrimidine-2,4-diol (02170-4)

To a suspension of 2-(methylthio)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (1.8 g, 8.40 mmol) in water (20 mL) was added acetic acid (40 mL). The mixture was stirred at 130 ° C for 48 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The crude product was washed with EtOH to give a white solid product (1.1 g, yield 71.09%).

ESI-MS m/z calcd for[C ₇ H ₈ N ₂ O ₂ S][M+H] ⁺ :185.0; found:184.9

2.5

2,4-Dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (02170-5)

7,8-Dihydro-6H-thiopyrano[3,2-d]pyrimidine-2,4-diol (1.1 g, 5.97 mmol) was suspended in _POCl₃ (15 mL), followed by the addition of N,N-dimethylaniline (145 mg, 1.19 mmol). The mixture was stirred at 90°C for 16 hours, cooled to room temperature, and concentrated. The crude product was dissolved in DCM (100 mL) and washed twice with saturated aqueous _NaHCO₃ (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-30%, Silica Gel-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product as a yellow solid (1.0 g, 75.74% yield).

ESI-MS m/z calcd for[C ₇ H ₆ Cl ₂ N ₂ S][M+H] ⁺ :221.0; found:221.0

2.6

Methyl 2-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02170-6)

To a solution of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (500 mg, 2.26 mmol) and methyl 2-(4-amino-2-fluorophenyl)acetate (621 mg, 3.39 mmol) in DMF (10 mL) was added DIEA (1.17 g, 9.05 mmol). The mixture was stirred at 120°C for 16 hours, cooled to room temperature, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-25%, silica gel-CS 20 g, 25 mL/min, silica gel, UV 254) to give the product as a yellow solid (301 mg, 36.19% yield).

ESI-MS m/z calcd for[C ₁₆ H ₁₅ ClFN ₃ O ₂ S][M+H] ⁺ :368.1; found:367.9

2.7

Methyl 2-(4-(((2-chloro-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02170-7)

To a solution of methyl 2-(4-((2-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (120 mg, 0.33 mmol) in DCM (10 mL) was added m-CPBA (85%, 225 mg, 0.98 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated NaHCO ₃ solution (20 mL) and extracted with DCM (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/DCM=0-30%, silica gel-CS20 g, 20 mL/min, silica gel, UV 254) to give a white solid product (107 mg, yield 82.03%).

ESI-MS m/z calcd for[C ₁₆ H ₁₅ ClFN ₃ O ₄ S][M+H] ⁺ :400.1; found:400.0

2.8

Methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5,5-dioxo-7,8-dihydro-6H-thieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02170-8)

To a solution of methyl 2-(4-((2-chloro-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (40 mg, 0.10 mmol) and 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine dihydrochloride (23.5 mg, 0.12 mmol) in DMF (3 mL) was added DIEA (77.6 mg, 0.60 mmol). The mixture was stirred at 90°C under nitrogen for 1 hour. After cooling, the mixture was concentrated, and the crude product was purified via a reverse phase column (MeCN/ _H₂O = 0-40%, C-18 40 g, 50 mL/min, UV 254) to give the product as a white solid (40 mg, 82.18% yield).

ESI-MS m/z calcd for[C ₂₇ H ₂₇ FN ₆ O ₅ S][M+H] ⁺ :487.2; found:487.0

2.9

2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5,5-dioxo-7,8-dihydro-6H-thieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02170)

To a solution of methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (40 mg, 0.082 mmol) in MeOH (3 mL) was added A solution of NaOH (16.4 mg, 0.41 mmol) in water (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 6 with AcOH. The mixture was filtered, and the filtrate was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (33.23 mg, 85.54% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₁ FN ₆ O ₄ S][M+H] ⁺ :473.1; found:473.0

¹ H NMR (400MHz, Methanol-d ₄ )δ7.54–7.52(m,1H),7.40(s,1H),7.30(t,J＝8.4Hz,1H),7.19–7.17(m,1H),4.91–4.90(m,2H),4.07 (s,2H),3.55(s,2H),3.47–3.44(m,2H),2.88(t,J=6.4Hz,2H),2.71–2.68(m,2H),2.44–2.38(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-(Propylthio)pyrimidine-2,4(1H,3H)-dione (02175-1)

5-Bromopyrimidine-2,4(1H,3H)-dione (3.20 g, 16.76 mmol) was suspended in water (60 mL). NaOH (1.34 g, 33.51 mmol) and propane-1-thiol (2.55 g, 33.51 mmol) were added. The mixture was stirred at 90°C for 16 hours and then cooled to room temperature. The pH of the solution was adjusted to 7 with concentrated hydrochloric acid. The mixture was filtered and the solid was washed with water (10 mL), MTBE (50 mL), MeCN (20 mL) and MTBE (50 mL) to give the product as a white solid (1.0 g, crude product).

ESI-MS m/z calcd for[C ₇ H ₁₀ N ₂ O ₂ S][M+H] ⁺ :187.1; found:187.2

2.2

2,4-Dichloro-5-(propylthio)pyrimidine (02175-2)

5-(Propylthio)pyrimidine-2,4(1H,3H)-dione (1 g of the crude product from the previous step) was suspended in _POCl₃ (15 mL). The mixture was stirred at 100°C overnight, then cooled to room temperature and concentrated. Saturated _NaHCO₃ (20 mL) was added and extracted twice with EA (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA/PE = 0-30%, Silica Gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product as a white solid (202 mg, 5.40% yield over two steps).

ESI-MS m/z calcd for[C ₇ H ₈ Cl ₂ N ₂ S][M+H] ⁺ :223.0; found:222.9

2.3

Methyl 2-(4-((2-chloro-5-(propylthio)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02175-3)

To a solution of 2,4-dichloro-5-(propylthio)pyrimidine (202 mg, 0.91 mmol) and methyl 2-(4-amino-2-fluorophenyl)acetate (199 mg, 1.09 mmol) in DMF (10 mL) was added DIEA (585 mg, 4.53 mmol). The mixture was stirred at 90°C for 20 hours, cooled to room temperature, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-25%, silica gel-CS 20 g, 25 mL/min, silica gel, UV 254) to give the product as a yellow solid (171 mg, 51.07% yield).

ESI-MS m/z calcd for[C ₁₆ H ₁₇ ClFN ₃ O ₂ S][M+H] ⁺ :370.1; found:369.8

2.4

Methyl 2-(4-((2-chloro-5-(propylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02175-4-rac)

Methyl 2-(4-((2-chloro-5-(propylthio)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (50 mg, 0.14 mmol) and (S)-(-)-1,1'-bi-2-naphthol (19.2 mg, 0.068 mmol) were dissolved in DCM (5 mL), and Ti(i-PrO) ₄ (19.4 mg, 0.068 mmol) and H ₂ O (4.9 mg, 0.27 mmol) were added. The mixture was stirred at room temperature overnight. t-BuOOH (70% aqueous solution) (69.6 mg, 0.54 mmol) was then added in one portion, and the reaction was stirred at room temperature for another 2 hours. The reaction mixture was concentrated, and saturated aqueous NaHCO ₃ was added. The mixture was added to a 4% aqueous solution (40 mL) and extracted twice with EA (40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0-5%, silica gel-CS20 g, 25 mL/min, silica gel, UV 254) to give a white solid product (33 mg, yield 63.26%).

ESI-MS m/z calcd for[C ₁₆ H ₁₇ ClFN ₃ O ₃ S][M+H] ⁺ :386.1; found:386.0

2.5

Methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(propylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02175-4-rac)

To a solution of methyl 2-(4-((2-chloro-5-(propylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (45 mg, 0.12 mmol) and DIEA (60.3 mg, 0.47 mmol) in DMF (3 mL) was added 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine dihydrochloride (27.4 mg, 0.14 mmol). The mixture was then stirred at 90 ° C. for 1 hour, the reaction mixture was concentrated, saturated aqueous NaHCO ₃ solution (20 mL) was added, and the mixture was extracted twice with EA (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH/DCM=0-4%, silica gel-CS 4 g, 12 mL/min, silica gel, UV 254) to give a yellow oily product (32 mg, yield 58.06%).

ESI-MS m/z calcd for[C ₂₂ H ₂₅ FN ₆ O ₃ S][M+H] ⁺ :473.2; found:473.2

2.6

2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(propylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02175-rac)

To a solution of methyl 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(propylsulfinyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (32 mg, 0.068 mmol) in MeOH (3 mL) was added a solution of NaOH (27 mg, 0.68 mmol) in water (1 mL). The mixture was then stirred at room temperature for 2 hours. The pH of the solution was adjusted to 6 with AcOH. The mixture was filtered, and the filtrate was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (25 mg, 80.52%).

ESI-MS m/z calcd for[C ₂₁ H ₂₃ FN ₆ O ₃ S][M+H] ⁺ :459.2; found:459.2

¹ H NMR (400MHz, DMSO-d ₆ )δ9.68–9.66(m,1H),8.19(s,1H),7.64–7.61(m,1H),7.46–7.44(m,1H),7.29(t,J＝8.4Hz,1H),7.19(d,J＝8.0Hz,1H),4.91–4.85(m,2H), 4.07–3.96(m,2H),3.57–3.56(m,2H),3.25–3.13(m,1H),3.04-2.96(m,1H),2.74–2.65(m,2H),1.66-1.56(m,2H),0.99(t,J＝8.8Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((2-chloro-5-(propanesulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02181-1)

To a solution of methyl 2-(4-((2-chloro-5-(propylthio)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (60 mg, 0.16 mmol) in DCM (10 mL) was added m-CPBA (85%, 132 mg, 0.65 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated _aqueous NaHCO solution (20 mL) and extracted twice with DCM (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (EA/PE = 0-45%, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product as a white solid (44 mg, 67.49% yield).

ESI-MS m/z calcd for[C ₁₆ H ₁₇ ClFN ₃ O ₄ S][M+H] ⁺ :402.1; found:402.2

2.2

Methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(propanesulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02180-2)

To a mixed solution of methyl 2-(4-((2-chloro-5-(propanesulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (44 mg, 0.11 mmol) in 1,4-dioxane and water (5 mL, v/v = 4/1) was added (3-chloro-4-methoxyphenyl)boronic acid (28.6 mg, 0.15 mmol), _K₂CO₃ (60.5 _mg , 0.44 mmol), and Pd(dppf) _Cl₂ (8.9 mg, 0.01 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. After complete consumption of the starting material, the reaction mixture was quenched with water and extracted twice with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA/PE=0-50%, silica gel-CS 4 g, 12 mL/min, silica gel, UV 254) to give a yellow solid product (31 mg, yield 55.74%).

ESI-MS m/z calcd for[C ₂₃ H ₂₃ ClFN ₃ O ₅ S][M+H] ⁺ :508.1; found:508.2

2.3

2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(propanesulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02180)

To a solution of methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(propanesulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (31 mg, 0.061 mmol) in MeOH (3 mL) was added a solution of NaOH (12.2 mg, 0.31 mmol) in water (1 mL). The mixture was then stirred at room temperature for 2 hours. The pH of the solution was adjusted to 6 with AcOH. The mixture was filtered, and the filtrate was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (3.4 mg, 10.45% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₁ ClFN ₃ O ₅ S][M+H] ⁺ :494.1; found:493.8

¹ H NMR (400MHz, DMSO-d ₆ )δ8.78(s,1H),8.30–8.29(m,1H),8.27–8.24(m,1H),7.71–7.68(m,1H),7.38–7.34(m,3H ),3.95(s,3H),3.60(s,2H),3.54–3.50(m,2H),1.76–1.70(m,2H),0.98(t,J=7.6Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(propylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02181)

To a solution of 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-(propylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (32 mg, 0.068 mmol) in DCM (3 mL) was added m-CPBA (85%, 13.3 mg, 0.065 mmol). The mixture was then stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted twice with DCM (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (13.67 mg, yield 66.05%).

ESI-MS m/z calcd for[C ₂₁ H ₂₃ FN ₆ O ₄ S][M+H] ⁺ :475.2; found:475.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.39(s,1H),7.62–7.56(m,1H),7.47(s,1H),7.30(t,J＝8.4Hz,1H),7.24(d,J＝8.0Hz,1H),4.95–4.82(m,2H), 4.09–3.98(m,2H),3.48(s,2H),3.36–3.32(m,2H),2.67–2.63(m,2H),1.68–1.63(m,2H),0.94(t,J＝7.6Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-((Trimethylsilyl)ethynyl)-1H-indole (A-1)

To a solution of 5-iodo-1H-indole (1 g, 4.11 mmol) in THF (10 mL) were added ethynyltrimethylsilane (444 mg, 4.53 mmol), CuI (78 mg, 0.41 mmol), TEA (5 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (84 mg, 0.12 mmol). The mixture was stirred at room temperature overnight under nitrogen. After the starting material was consumed, the reaction mixture was distilled under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/10, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product as a brown solid (810 mg, 93% yield).

ESI-MS m/z calcd for[C ₁₃ H ₁₅ NSi][M+H] ⁺ :214.1; found:214.3

2.2

5-Ethynyl-1H-indole (A-2)

To a solution of 5-((trimethylsilyl)ethynyl)-1H-indole (810 mg, 3.80 mmol) in MeOH (10 mL) was added K ₂ CO ₃ (787 mg, 5.70 mmol). The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the reaction mixture was filtered and concentrated to give a brown solid product (525 mg, 98% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₀ H ₇ N][M+H] ⁺ :142.1; found:142.0

2.3

Methyl 2-(4-((2-((1H-indol-5-yl)ethynyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02188-1)

To a solution of 5-ethynyl-1H-indole (37 mg, 0.26 mmol) in DMF (5 mL) were added methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (100 mg, 0.26 mmol), CuI (5 mg, 0.026 mmol), TEA (53 mg, 0.52 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (6 mg, 0.008 mmol) were added. The mixture was stirred at 100°C under nitrogen overnight. After the starting material was consumed, the reaction was quenched with water (20 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/10, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product as a yellow solid (31 mg, 24% yield).

ESI-MS m/z calcd for[C ₂₅ H ₂₁ FN ₄ O ₄ S][M+H] ⁺ :493.1; found:492.7

2.4

2-(4-((2-((1H-indol-5-yl)ethynyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02188)

To a solution of methyl 2-(4-((2-((1H-indol-5-yl)ethynyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (31 mg, 0.06 mmol) in MeOH/THF (2 mL, v/v = 1/1) was added 2N aqueous NaOH solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The mixture was then concentrated, and the crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a pale yellow solid (2.18 mg, 7% yield).

ESI-MS m/z calcd for[C ₂₄ H ₁₉ FN ₄ O ₄ S][M+H] ⁺ :479.1; found:479.0

¹ H NMR (400MHz, DMSO-d ₆ )δ12.58(brs,1H),11.50(s,1H),9.15–9.11(m,1H),8.68(s,1H),7.92(s,1H),7.62(d,J＝11.2Hz,1H),7.5 0–7.48(m,2H),7.39–7.32(m,3H),6.53(s,1H),3.62(s,2H),3.54(q,J＝7.2Hz,2H),1.25(t,J＝7.6Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-Benzyl-1-oxa-5-azaspiro[2.4]heptane (A-0)

To a solution of NaH (60%, 300 mg, 7.41 mmol) in DMSO (10 mL) at 0°C was added trimethylsulfonium iodide (1.38 g, 6.27 mmol) portionwise. The mixture was stirred at 25°C under argon for 1 hour, followed by the addition of a solution of 1-benzylpyrrolidin-3-one (1.0 g, 5.7 mmol) in DMSO (11 mL). The mixture was then stirred at 25°C for 2 hours. The reaction was quenched with saturated aqueous _NH4Cl (20 mL) and extracted four times with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-1/1, Silica Gel-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product as a yellow oil (326 mg, 30.2% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₅ NO][M+H] ⁺ :190.1; found:190.1

2.2

3-((1H-Benzo[d]imidazol-1-yl)methyl)-1-benzylpyrrolidin-3-ol (A-2)

To a solution of NaH (60%, 96 mg, 2.4 mmol) in THF (6 mL) at 0°C was added 1H-benzo[d]imidazole (142 mg, 1.2 mmol) in portions, and the reaction was stirred at 0°C under argon for 1 hour. 5-Benzyl-1-oxa-5-azaspiro[2.4]heptane (226 mg, 1.2 mmol) in THF (4 mL) was then added and stirred at 40°C for 24 hours. The reaction was quenched with water (20 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0-1/9, silica gel-CS 40 g, 40 mL/min, UV 254) to give a colorless oily product (245 mg, yield 66.7%).

ESI-MS m/z calcd for[C ₁₉ H ₂₁ N ₃ O][M+H] ⁺ :308.2; found:308.2

2.3

3-((1H-Benzo[d]imidazol-1-yl)methyl)pyrrolidin-3-ol (A-3)

To a solution of 3-((1H-benzo[d]imidazol-1-yl)methyl)-1-benzylpyrrolidin-3-ol (100 mg, 0.33 mmol) and HCOONH₄ ₍ 250 mg, 3.96 mmol) in MeOH (20 mL) was added Pd/C (30 mg), and the mixture was stirred at 70°C under a hydrogen atmosphere for 3 hours. After cooling, the reaction mixture was filtered under reduced pressure, and the filtrate was distilled off to remove the solvent under reduced pressure. The crude product was purified by reverse phase column chromatography (MeCN/H₂O = 0-3/17, C-18 column, 50 mL/min, UV 214) to afford the product as a pale yellow solid (40 mg, 56.6% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₅ N ₃ O][M+H] ⁺ :218.1; found:218.1

2.4

Methyl 2-(4-((2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02189-2)

To a solution of 3-((1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-3-ol (22 mg, 0.10 mmol) and methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (40 mg, 0.10 mmol) in DMF (2 mL) was added DIEA (40 mg, 0.31 mmol). The mixture was stirred at 100°C under argon for 3 hours. After cooling, the mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (EA/PE=0~1/1, silica gel-CS20 g, 20 mL/min, UV 254) to give a white solid product (55 mg, yield 94%).

ESI-MS m/z calcd for[C ₂₇ H ₂₉ FN ₆ O ₅ S][M+H] ⁺ :569.2; found:568.8

2.5

2-(4-((2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-

2-Fluorophenyl)acetic acid (MX02189)

To a solution of methyl 2-(4-((2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (55 mg, 0.10 mmol) in MeOH/THF (2 mL, v/v = 1/1) was added 2N aqueous NaOH solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The mixture was then concentrated, and the crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (42.2 mg, 79% yield).

ESI-MS m/z calcd for[C ₂₆ H ₂₇ FN ₆ O ₅ S][M+H] ⁺ :555.2; found:555.2

¹ H NMR (400 MHz, DMSO-d ₆ )δ12.45(brs,1H),8.97–8.93(m,1H),8.56–8.50(m,1H),8.36–8.31(m,1 H),7.83–7.56(m,3H),7.37–7.06(m,4H),5.51(d,J＝4.4Hz,1H),4.61–4.5 1(m,2H),3.84–3.75(m,1H),3.71–3.59(m,4H),3.57(d,J＝11.2Hz,1H),3. 51–3.45(m,2H),2.22–2.10(m,1H),1.93–1.82(m,1H),1.91–1.15(m,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02191-1)

To a solution of methyl 2-(4-((2-chloro-5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (80 mg, 0.19 mmol) in DMF/water (4 mL, v/v = 3/1) were added (3-chloro-4-methoxyphenyl)boronic acid (35.4 mg, 0.19 mmol), _K2CO3 (78.8 _mg , 0.57 mmol), and Pd(dppf) _Cl2 (15.3 mg, 0.021 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. After complete consumption of the starting material, water (20 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column preparative HPLC [MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm ₁₉ *250 mm, 20 mL/min, UV 254] to give a white solid product (46 mg, yield 45.9%).

ESI-MS m/z calcd for[C ₂₃ H ₁₉ ClF ₄ N ₄ O ₄ ][M+H] ⁺ :527.1; found:527.0

2.2

2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02191)

To a solution of methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (46 mg, 0.087 mmol) in EtOH (2 mL) was added 1N NaOH (0.6 mL, 0.6 mmol). The mixture was stirred at room temperature overnight under nitrogen. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl. The mixture was then concentrated, and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (7.17 mg, 16% yield).

ESI-MS m/z calcd for[C ₂₂ H ₁₇ ClF ₄ N ₄ O ₄ ][M+H] ⁺ :513.1; found:512.5

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10(br,1H),9.59(br,1H),9.00(s,1H),8.33(d,J＝2.0Hz,1H),8.29(dd,J＝8.4,1.6Hz,1H ),7.83(d,J＝12.8Hz,1H),7.36–7.32(m,3H),4.17(q,J＝9.6Hz,2H),3.95(s,3H),3.53(s,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02206-1)

To a solution of methyl 2-(4-((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (50 mg, 0.13 mmol) and DIEA (67 mg, 0.52 mmol) in DMF (3 mL) was added 5-chloro-2-(piperidin-4-yl)pyrimidine (51 mg, 0.26 mmol). The mixture was then stirred at 90° C. for 1 hour. The reaction mixture was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a yellow solid (30 mg, 42.32% yield).

ESI-MS m/z calcd for[C ₂₄ H ₂₄ ClFN ₆ O ₄ S][M+H] ⁺ :547.1; found:547.8

2.2

2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02206)

To a solution of methyl 2-(4-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (30 mg, 0.055 mmol) in MeOH (3 mL) was added a solution of NaOH (11 mg, 0.27 mmol) in water (1 mL). The mixture was then stirred at room temperature for 2 hours. The pH of the solution was adjusted to 6 with AcOH. The mixture was filtered, and the filtrate was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (15.11 mg, 51.69% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₂ ClFN ₆ O ₄ S][M+H] ⁺ :533.1; found:532.8

¹ H NMR (400MHz, DMSO-d ₆ )δ8.87(s,2H),7.50(dd,J＝12.0,1.6Hz,1H),7.39(dd,J＝8.4,2.0Hz,1H),7.22(t,J＝8.8Hz,1H),4.74–4 .54(m,2H),3.55(t,J＝7.2Hz,2H),3.42(s,2H),3.25–3.13(m,5H),2.03–2.00(m,2H),1.74–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-Chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (02285-1)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 0.35 mmol) in TFA (1.5 mL) was added _{H₂O₂ (} 30%, 0.1 mL). The mixture was stirred at room temperature for 16 hours. The mixture was poured into a mixture of ice and aqueous ammonia. The mixture was extracted twice with DCM (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the product as a white solid (92 mg, 87.15% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₄ ClN ₃ O ₃ S][M+H] ⁺ :304.0; found:304.0

2.2

2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (MX02285)

To a solution of 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (40 mg, 0.13 mmol) in DMF (3 mL) was added 3-((1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-3-ol (40 mg, 0.18 mmol) and DIEA (68 mg, 0.53 mmol). The mixture was stirred at 90° C. for 2 hours. The mixture was concentrated, and the crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (19.35 mg, 30.33% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₈ N ₆ O ₄ S][M+H] ⁺ :485.2; found:485.0

¹ H NMR (400MHz, Methanol-d ₄ )δ8.21–8.20(m,1H),7.68–7.64(m,2H),7.34–7.26(m,2H),4.59–4.46(m,2H),3.90–3.65(m,5H),3.55–3. 35(m,3H),3.13–3.05(m,2H),2.43–2.41(m,1H),2.29–2.19(m,3H),2.03–1.93(m,3H),1.73–1.68(m,1H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02287-2)

To a solution of 3-((1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-3-ol (40.5 mg, 0.19 mmol) and methyl 2-(4-((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (60 mg, 0.16 mmol) in DMF (3 mL) was added DIEA (40 mg, 0.31 mmol), and the mixture was stirred at 90°C under argon for 1 hour. After cooling, the mixture was concentrated, and the crude product was purified by reverse phase column chromatography (MeCN/ _H2O = 0-40%, C-18 40 g, 50 mL/min, UV 254) to give the product as a white solid (31 mg, 35.18% yield).

ESI-MS m/z calcd for[C ₂₇ H ₂₇ FN ₆ O ₅ S][M+H] ⁺ :567.2; found:567.9

2.2

2-(4-((2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02287)

To a solution of methyl 2-(4-((2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (31 mg, 0.055 mmol) in MeOH (3 mL) was added a solution of NaOH (10.9 mg, 0.27 mmol) in water (1 mL). The mixture was then stirred at room temperature for 2 hours. The pH of the solution was adjusted to 6 with AcOH. The mixture was filtered, and the filtrate was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (15.03 mg, 49.71% yield).

ESI-MS m/z calcd for[C ₂₆ H ₂₅ FN ₆ O ₅ S][M+H] ⁺ :553.2; found:553.0

¹ H NMR (400MHz, Methanol-d ₄ )δ8.23(s,1H),7.78–7.62(m,2.5H),7.46–7.24(m,4H),7.02–6.98(m,0.5H),4.58–4.49(m,2H),3.90–3. 84(m,1H),3.79–3.69(m,2H),3.61–3.47(m,5H),3.23–3.13(m,2H),2.28–2.19(m,1H),2.01–1.96(m,1H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-Ethyl-3,3-dimethoxybutyrate (02295-1)

To a solution of ethyl 2-ethyl-3-oxobutanoate (3.2 g, 20.2 mmol) in toluene (40 mL) were added trimethyl orthoformate (2.58 g, 24.2 mmol) and p-toluenesulfonic acid (694 mg, 4.04 mmol). The mixture was stirred at 100° C. for 16 hours. The solvent was distilled off under reduced pressure, water (50 mL) was added, and the mixture was extracted three times with DCM (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow liquid crude product (4.2 g, yield 100%).

ESI-MS m/z calcd for[C ₁₀ H ₂₀ O ₄ ][M+H] ⁺ :205.1; found:204.3

2.2

N-Carbamoyl-2-ethyl-3,3-dimethoxybutyramide (02295-2)

To a solution of ethyl 2-ethyl-3,3-dimethoxybutyrate (4.2 g, 20.2 mmol) in toluene (40 mL) was added urea (1.21 g, 20.2 mmol) and t-BuOK (2.26 g, 20.2 mmol). The mixture was stirred at 60°C for 4 hours, then the solvent was removed by distillation under reduced pressure. Water (50 mL) was added, and the mixture was extracted three times with DCM (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude yellow liquid product (3.6 g, 81.8% yield).

ESI-MS m/z calcd for[C ₉ H ₁₈ N ₂ O ₄ ][M+H] ⁺ :219.1; found:219.0

2.3

5-Ethyl-6-methylpyrimidine-2,4(1H,3H)-dione (02295-3)

To a solution of N-carbamoyl-2-ethyl-3,3-dimethoxybutyramide (3.6 g, 16.5 mmol) in THF (40 mL) was added concentrated hydrochloric acid (8.3 mL, 100 mmol). The mixture was stirred at 60°C for 16 hours, and the solvent was removed by distillation under reduced pressure. Water (50 mL) was added, and the mixture was extracted three times with DCM (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 5/1, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product as a yellow solid (550 mg, yield 21.6%).

ESI-MS m/z calcd for[C ₇ H ₁₀ N ₂ O ₂ ][M+H] ⁺ :155.1; found:155.4

2.4

2,4-Dichloro-5-ethyl-6-methylpyrimidine (02295-4)

To a solution of 5-ethyl-6-methylpyrimidine-2,4(1H,3H)-dione (400 mg, 2.6 mmol) in _POCl₃ (4 mL) was added DIPEA (33.6 mg, 0.26 mmol). The mixture was stirred at 60°C for 5 hours, and the solvent was removed by distillation under reduced pressure. Saturated aqueous _NaHCO₃ (20 mL) was added, and the mixture was extracted three times with DCM (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-30%, silica gel-CS₃ 12 g, 30 mL/min, silica gel, UV 254) to afford the product as a yellow solid (375 mg, 76.0% yield).

ESI-MS m/z calcd for[C ₇ H ₈ Cl ₂ N ₂ ][M+H] ⁺ :191.0; found:191.2

2.5

(1-((2-Chloro-5-ethyl-6-methylpyrimidin-4-yl)amino)cyclobutyl)methanol (02295-5)

To a solution of 2,4-dichloro-5-ethyl-6-methylpyrimidine (191 mg, 1 mmol) in NMP (3 mL) and DIEA (0.5 mL) was added (1-aminocyclobutyl)methanol (101 mg, 1 mmol). The mixture was stirred at 100°C for 16 hours, and the solvent was removed by distillation under reduced pressure. Water (10 mL) was added, and the mixture was extracted three times with DCM (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-100%, silica gel-CS 12 g, 30 mL/min, silica gel, UV 254) to give the product as a yellow solid (85 mg, 33.1% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₈ ClN ₃ O][M+H] ⁺ :256.1; found:256.1

2.6

(1-((2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-5-ethyl-6-methylpyrimidin-4-yl)amino)cyclobutyl)methanol (MX02295)

To a solution of (1-((2-chloro-5-ethyl-6-methylpyrimidin-4-yl)amino)cyclobutyl)methanol (85 mg, 0.332 mmol) in NMP (3 mL) were added 5-chloro-2-(piperidin-4-yl)pyrimidine (131.0 mg, 0.664 mmol) and DIEA (1 mL). The reaction mixture was stirred at 100° C. for 16 hours, and the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (34 mg, 24.5% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₉ ClN ₆ O][M+H] ⁺ :417.2; found:417.3

¹ H NMR (400MHz, DMSO-d ₆ )δ8.86(s,2H),5.93(s,1H),4.80(t,J＝5.6Hz,1H),4.61(d,J＝12.8Hz,2H),3.69(d,J＝5.6Hz,2H),3.12–3.07(m,1H),2.89–2.83(m,2H), 2.41–2.31(m,2H),2.28–2.23(m,2H),2.15–2.08(m,5H),1.89–1.87(m,2H),1.79–1.72(m,2H),1.66–1.56(m,2H),0.97(t,J=7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (02315-1)

To a solution of methyl 2-(4-((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (120 mg, 0.31 mmol) in 1,4-dioxane/ _H₂O (10 mL, v/v = 4/1) was added (1-methyl-1H-pyrazol-4-yl)boronic acid (58.7 mg, 0.47 mmol), _{K₂CO₃ (} 172 mg, 1.24 mmol), and Pd(dppf) _Cl₂ (25.4 mg, 0.031 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. After complete consumption of the starting material, the reaction mixture was quenched with water and extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM/MeOH=0-10%, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (66 mg, yield 49.18%).

ESI-MS m/z calcd for[C ₁₉ H ₁₈ FN ₅ O ₄ S][M+H] ⁺ :432.1; found:432.0

2.2

2-(2-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (MX02315)

To a solution of methyl 2-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (66 mg, 0.15 mmol) in MeOH (3 mL) was added a solution of NaOH (31 mg, 0.77 mmol) in water (1 mL). The mixture was then stirred at room temperature for 2 hours. The pH of the solution was adjusted to 6 with AcOH. The mixture was filtered, and the filtrate was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (40 mg, 62.64% yield).

ESI-MS m/z calcd for[C ₁₈ H ₁₆ FN ₅ O ₄ S][M+H] ⁺ :418.1; found:418.0

¹ H NMR (400MHz, Methanol-d ₄ )δ8.21(s,1H),8.05(s,1H),7.62(dd,J＝11.8,2.0Hz,1H),7.43(dd,J＝11.8,2. 0Hz,1H),7.35(t,J＝8.4Hz,1H),3.95(s,3H),3.65–3.61(m,4H),3.39–3.36(m, 2H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(2-Fluoro-4-((2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (MX02317)

To a solution of methyl 2-(4-(2-chloro-5,5-dioxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenylacetate (100 mg, 0.259 mmol) in 1,4-dioxane/water (12.5 mL, v/v = 4/1) was added (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (56 mg, 0.285 mmol), K ₂ CO ₃ (108 mg, 0.777 mmol), and Pd(dppf)Cl ₂ (19 mg, 0.026 mmol). The mixture was heated to 90° C. and stirred under nitrogen for 6 hours. After cooling, the mixture was added to water (10 mL) and extracted three times with DCM (30 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (30 mg, yield 24%).

ESI-MS m/z calcd for[C ₁₉ H ₁₅ F ₄ N ₅ O ₄ S][M+H]+:486.1; found:486.0

1H NMR (400MHz, Methanol-d ₄ ) δ8.33(s,1H),7.51–7.47(m,1H),7.34–7.33(m,2H),3.99(s,3H),3.66–3.63(m,4H),3.38(t,J＝7.0Hz,2H)

2.2

2-(2-Fluoro-4-((2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-methylacetamide (MX02359)

To a solution of 2-(2-fluoro-4-((2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (21 mg, 0.044 mmol) in DMF (2 mL) was added a 2M solution of methylamine in THF (0.04 mL, 0.074 mmol), BOP (16.4 mg, 0.037 mmol), and DIEA (9.6 mg, 0.074 mmol). The mixture was stirred at room temperature for 2 hours, after which the reaction solution was concentrated to remove the solvent. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (6.8 mg, yield 55.1%).

ESI-MS m/z calcd for[C ₂₀ H ₁₈ F ₄ N ₆ O ₃ S][M+H] ⁺ :499.1; found:498.9

¹ H NMR (400MHz, Methanol-d ₄ )δ8.34(s,1H),7.52–7.49(m,1H),7.34–7.32(m,2H),3.98(s,3H),3.65(t,J＝7.2Hz,2H),3.57(s,2H),3.38(t,J＝7.2Hz,2H),2.75(s,3H)

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-nitro-1H-pyrazol-1-yl)acetate (02349-1)

To a solution of 4-nitro-1H-pyrazole (6.0 g, 53.06 mmol) in DMF (50 mL) was added NaH (60%, 2.55 g, 63.68 mmol) at 0°C. The mixture was stirred at room temperature for 0.5 hours. Methyl 2-bromoacetate (9.74 g, 63.68 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was poured into ice water and extracted twice with EA (100 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-100%, silica gel-CS 80 g, 50 mL/min, silica gel, UV 254) to give a yellow solid product (5 g, yield 50.89%).

ESI-MS m/z calcd for[C ₆ H ₇ N ₃ O ₄ ][M+H] ⁺ :186.0; found:186.2

2.2

Methyl 2-(4-amino-1H-pyrazol-1-yl)acetate (02349-2)

To a solution of methyl 2-(4-nitro-1H-pyrazol-1-yl)acetate (5.0 g, 27.0 mmol) in MeOH (50 mL) was added Pd/C (500 mg, 30% aqueous). The mixture was stirred at room temperature under hydrogen for 16 hours. The reaction mixture was filtered through Celite and rinsed with MeOH. The filtrate was concentrated to give the product as a yellow solid (4.1 g, 97.85% yield).

ESI-MS m/z calcd for[C ₆ H ₉ N ₃ O ₂ ][M+H] ⁺ :156.1; found:156.2

2.3

Methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (02349-3)

To a solution of methyl 2-(4-amino-1H-pyrazol-1-yl)acetate (450 mg, 2.90 mmol) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (901 mg, 4.35 mmol) in DMF (10 mL) was added DIEA (1.5 g, 11.6 mmol). The mixture was stirred at 90°C for 16 hours, cooled to room temperature, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, silica gel-CS 20 g, 25 mL/min, silica gel, UV 254) to give the product as a yellow solid (220 mg, 23.28% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₂ ClN ₅ O ₂ S][M+H] ⁺ :326.0; found:326.0

2.4

Methyl 2-(4-(((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (02349-4)

To a solution of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (100 mg, 0.31 mmol) in DCM (10 mL) was added m-CPBA (85%, 249.3 mg, 1.23 mmol). The mixture was stirred at room temperature for 16 hours, after which the reaction mixture was poured into saturated NaHCO ₃ solution (20 mL) and extracted with DCM (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA/DCM = 0-30%, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product as a yellow solid (55 mg, 50.08% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₂ ClN ₅ O ₄ S][M+H] ⁺ :358.0; found:358.0

2.5

Methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (02349-5)

To a solution of methyl 2-(4-((2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (55 mg, 0.15 mmol) in 1,4-dioxane/ _H₂O (5 mL, v/v = 4/1) was added (3-chloro-4-methoxyphenyl)boronic acid (43.0 mg, 0.23 mmol), _{K₂CO₃ (} 85 mg, 0.62 mmol), and Pd(dppf) _Cl₂ (12.6 mg, 0.015 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. After cooling, the reaction mixture was quenched with water and extracted twice with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM/MeOH=0-10%, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (33 mg, yield 46.27%).

ESI-MS m/z calcd for[C ₁₉ H ₁₈ ClN ₅ O ₅ S][M+H] ⁺ :464.1; found:464.0

2.6

2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetic acid (MX02349)

To a solution of methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (33 mg, 0.071 mmol) in MeOH (3 mL) was added a solution of NaOH (14.2 mg, 0.36 mmol) in water (1 mL). The mixture was then stirred at room temperature for 2 hours. The pH of the solution was adjusted to 6 with AcOH. The mixture was filtered, and the filtrate was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (21 mg, 65.62% yield).

ESI-MS m/z calcd for[C ₁₈ H ₁₆ ClN ₅ O ₅ S][M+H] ⁺ :450.1; found:450.0

¹ H NMR (400MHz, Methanol-d ₄ )δ8.39(d,J＝2.0Hz,1H),8.34(dd,J＝8.8，2.0Hz,1H),8.16(s,1H),7.82(s,1H),7.21(d ,J＝8.8Hz,1H),4.93(s,2H),3.97(s,3H),3.60(t,J＝6.8Hz,2H),3.34(t,J＝7.2Hz,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (02350-1)

To a solution of 2,4-dichloro-5-(ethylsulfonyl)pyrimidine (80 mg, 0.33 mmol) in DMF (3 mL) was added methyl 2-(4-amino-1H-pyrazol-1-yl)acetate (51 mg, 0.33 mmol) and DIEA (173 mg, 1.34 mmol). The mixture was stirred at 100°C under nitrogen for 3 hours. After the starting material was consumed, water (20 mL) was added, and then extracted three times with EA (20 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (71 mg, yield 60%).

ESI-MS m/z calcd for[C ₁₂ H ₁₄ ClN ₅ O ₄ S][M+H] ⁺ :360.1; found:360.0

2.2

Methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (02350-2)

To a solution of methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (71 mg, 0.20 mmol) in 1,4-dioxane/water (2.5 mL, v/v = 4/1) were added (3-chloro-4-methoxyphenyl)boronic acid (43 mg, 0.23 mmol), _K2CO3 (55 _mg , 0.40 mmol), and Pd(dppf) _Cl2 (14 mg, 0.02 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. After complete consumption of the starting material, water (20 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (34 mg, yield 37%).

ESI-MS m/z calcd for[C ₁₉ H ₂₀ ClN ₅ O ₅ S][M+H] ⁺ :466.1; found:466.2

2.3

2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetic acid (MX02350)

To a solution of methyl 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetate (34 mg, 0.07 mmol) in MeOH/THF (2 mL, v/v = 1/1) was added 2N aqueous NaOH solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N aqueous HCl solution. The mixture was then concentrated, and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (13 mg, 39% yield).

ESI-MS m/z calcd for[C ₁₈ H ₁₈ ClN ₅ O ₅ S][M+H] ⁺ :452.1; found:452.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.67(s,1H),8.37–8.34(m,2H),8.07(s,1H),7.75(s,1H),7.35–7.32(m, 1H), 4.62 (s, 2H), 3.96 (s, 3H), 3.50 (q, J = 7.2Hz, 2H), 1.23 (t, J = 7.2Hz, 3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-((1H-indol-5-yl)ethynyl)-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02373)

To a solution of methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (25 mg, 0.065 mmol) in 1,4-dioxane/water (2.5 mL, v/v = 5/1) were added (3-chloro-4-methoxyphenyl)boronic acid (14.5 mg, 0.08 mmol), _K2CO3 (27 _mg , 0.195 mmol), and Pd(dppf) _Cl2 (5 mg, 0.006 mmol). The mixture was stirred at 100°C under nitrogen for 3 hours. After complete consumption of the starting material, water (10 mL) was added, and the mixture was extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm ₁₉ *250 mm, 20 mL/min, UV 254] to give a white solid product (15.0 mg, yield 47.1%).

ESI-MS m/z calcd for[C ₂₂ H ₂₁ ClFN ₃ O ₅ S][M+H] ⁺ :494.1; found:493.5

¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(s,1H),8.79(s,1H),8.29–8.24(m,2H),7.73(d,J＝12.4Hz,1H),7.42–7.40(m,2H),7.35(d, J＝8.8Hz,1H),3.96(s,3H),3.78(s,2H),3.65(s,3H),3.54(q,J＝7.2Hz,2H),1.25(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(2-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-isobutylacetamide (MX02353)

To a solution of 2-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (25 mg, 0.06 mmol) and isobutylamine (13.1 mg, 0.18 mmol) in DMF (3 mL) was added BOP (53 mg, 0.12 mmol) and DIEA (31 mg, 0.24 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC [MeCN/ _H2O (10 mmol/ _{L NH4HCO3} ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (15.09 mg, 53.32% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₅ FN ₆ O ₃ S][M+H] ⁺ :473.2; found:473.0

¹ H NMR (400MHz, Methanol-d ₄ )δ8.21(s,1H),8.05(s,1H),7.64(dd,J＝12.0,2.0Hz,1H),7.46(dd,J＝8.4,2.0Hz,1H),7.36(t,J＝8.4Hz,1H),3.95(s,3H ),3.64(t,J＝6.8Hz,2H),3.59(s,2H),3.40–3.36(m,2H),3.03(d,J＝6.8Hz,2H),1.84–1.77(m,1H),0.92(d,J＝6.4Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(4-((5-(ethylsulfonyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (02354-1)

Methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (40 mg, 0.1 mmol) was added to (1-methyl-1H-pyrazol-4-yl)boronic acid (19.5 mg, 0.16 mmol), _{K₂CO₃ (} 57 mg, 0.41 mmol), and Pd(dppf) _Cl₂ (8.4 mg, 0.01 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. After the starting material was consumed, the reaction mixture was quenched with water (20 mL) and extracted twice with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM/MeOH = 0-10%, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (25 mg, yield 55.92%).

ESI-MS m/z calcd for[C ₁₉ H ₂₀ FN ₅ O ₄ S][M+H] ⁺ :434.1; found:434.0

2.2

2-(4-((5-(ethylsulfonyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (02354-2)

To a solution of methyl 2-(4-(((5-(ethylsulfonyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (25 mg, 0.058 mmol) in MeOH (3 mL) was added a solution of NaOH (11.5 mg, 0.29 mmol) in water (1 mL). The mixture was then stirred at room temperature for 2 hours. The pH value of the solution was adjusted to 6 with AcOH. The mixture was filtered, and the filtrate was purified by reverse phase chromatography [MeCN/H ₂ O, C-18 40 g, 45 mL/min, UV 254] to give the product as a yellow solid (15 mg, yield 62.01%).

ESI-MS m/z calcd for[C ₁₈ H ₁₈ FN ₅ O ₄ S][M+H] ⁺ :420.1; found:420.0

2.3

2-(4-((5-(ethylsulfonyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylacetamide (MX02354)

To a solution of 2-(4-((5-(ethylsulfonyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (15 mg, 0.036 mmol) and isobutylamine (7.8 mg, 0.11 mmol) in DMF (3 mL) were added BOP (31.6 mg, 0.072 mmol) and DIEA (18.5 mg, 0.14 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product _as a white solid (2.31 mg, 9.85% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₇ FN ₆ O ₃ S][M+H] ⁺ :475.2; found:475.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.67(s,1H),8.25(s,1H),8.06(s,1H),7.70–7.67(m,1H),7.37–7.36(m,2H),3.96(s,3H),3.59(s,2H),3 .35(q,J＝7.2Hz,2H),3.03(d,J＝6.8Hz,2H),1.84–1.77(m,1H),1.34(t,J＝7.2Hz,3H),0.92(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-(4-((2-(5-chlorothien-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylacetamide (MX02355)

To a solution of (R)-2-(4-((2-(5-chlorothien-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (10 mg, 0.02 mmol) in DMF (3 mL) were added BOP (13.26 mg, 0.03 mmol), DIEA (7.74 mg, 0.06 mmol), and isobutylamine (2.32 mg, 0.02 mmol). The mixture was stirred at room temperature under nitrogen for 2 hours. After the starting material was consumed, the reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (1.04 mg, yield 9.42%).

ESI-MS m/z calcd for[C ₂₂ H ₂₂ ClFN ₄ O ₂ S ₂ ][M+H] ⁺ :493.1; found:493.0

¹ H NMR (400MHz, DMSO-d ₆ )δ10.15(br,1H),8.06(t,J＝5.2Hz,1H),7.75(d,J＝4.0Hz,1H),7.65(dd,J ＝12.4,2.0Hz,1H),7.52(dd,J＝8.4,2.0Hz,1H),7.34(t,J＝8.4Hz,1H),7.27 (d,J＝4.0Hz,1H),3.77–3.68(m,1H),3.48(s,2H),3.45–3.40(m,1H),3.16 –3.11(m,1H),2.91(t,J＝6.4Hz,2H),1.73–1.67(m,1H),0.88–0.84(m,7H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5,5-dioxo-7,8-dihydro-6H-thieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylacetamide (MX02356)

To a solution of 2-(4-((2-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (30 mg, 0.063 mmol) and isobutylamine (14 mg, 0.19 mmol) in DMF (3 mL) was added BOP (56.2 mg, 0.13 mmol) and DIEA (32.8 mg, 0.25 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (14.65 mg, yield 43.73%).

ESI-MS m/z calcd for[C ₂₅ H ₃₀ FN ₇ O ₃ S][M+H] ⁺ :528.2; found:528.0

¹ H NMR (400MHz, Methanol-d ₄ )δ7.65–7.54(m,1H),7.46–7.38(m,1H),7.34–7.28(m,1H),7.24–7.20(m,1H),5.04–4.89(m,2H),4.08–4.02(m,2H),3.53(s,2H),3.48–3 .42(m,2H),3.02(d,J＝7.2Hz,2H),2.89(t,J＝6.4Hz,2H),2.71–2.64(m,2H),2.44–2.38(m,2H),1.84–1.74(m,1H),0.91(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-methylacetamide (MX02357)

To a solution of 2-(4-((2-(3-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxypyrrolidin-1-yl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (26 mg, 0.05 mmol) in DMF (3 mL) was added BOP (29.60 mg, 0.07 mmol) and DIEA (17.40 mg, 0.14 mmol) and dimethylamine (2M in THF) (0.07 mL, 0.14 mmol). The mixture was stirred at room temperature under nitrogen protection for 2 hours. After the starting material was consumed, the reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (11.22 mg, yield 43.0%).

ESI-MS m/z calcd for[C ₂₈ H ₃₀ FN ₇ O ₄ S][M+H] ⁺ :580.2; found:580.2

¹ H NMR (400MHz, DMSO-d ₆ )8.68(d,J＝12.0Hz,1H),8.19(d,J＝12.0Hz,1H),7.99–7.94(m,1H),7.7 9–7.54(m,3H),7.27–7.08(m,4H),5.40(d,J＝4.0Hz,1H),4.51–4.42(m,2 H),3.74–3.41(m,8H),2.81(t,J＝6.4Hz,1H),2.75(t,J＝6.8Hz,1H),2.6 8–2.55(m,3H),2.30–2.23(m,2H),2.14–2.06(m,1H),1.89–1.75(m,1H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)-N-isobutylacetamide (MX02360)

To a solution of 2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetic acid (15 mg, 0.033 mmol) and isobutylamine (7.3 mg, 0.10 mmol) in DMF (2.5 mL) were added BOP (29.5 mg, 0.067 mmol) and DIEA (10.8 mg, 0.083 mmol). The mixture was filtered and the filtrate was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product _as a white solid (8.99 mg, 53.39% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₅ ClN ₆ O ₄ S][M+H] ⁺ :505.1; found:505.0

¹ H NMR (400MHz, Methanol-d ₄ )δ8.40(d,J＝1.6Hz,1H),8.37–8.34(m,1H),8.18(s,1H),7.87(s,1H),7.20(d,J＝8.4Hz,1H),4.91(s,2H),3.98( s,3H),3.60(t,J＝6.4Hz,2H),3.40–3.35(m,2H),3.07(d,J＝7.2Hz,2H),1.83–1.78(m,1H),0.92(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)-N-isobutylacetamide (MX02361)

To a solution of 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-1H-pyrazol-1-yl)acetic acid (6 mg, 0.01 mmol) and isobutylamine (1 mg, 0.012 mmol) in DMF (1 mL) were added BOP (7 mg, 0.015 mmol) and TEA (4 mg, 0.04 mmol). The mixture was stirred at room temperature for 1 hour, then the reaction solution was filtered, and the filtrate was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (2.13 mg, 32% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₇ ClN ₆ O ₄ S][M+H] ⁺ :507.2; found:507.0

¹ H NMR (400MHz, DMSO-d ₆ )δ9.04(s,1H),8.68(s,1H),8.37–8.35(m,2H),8.14–8.12(m,2H),7.84(s,1H),7.32(d,J＝9.6Hz,1H),4.85(s,2H),3.9 6(s,3H),3.50(q,J＝7.2Hz,2H),2.95(t,J＝6.4Hz,2H),1.77–1.67(m,1H),1.23(t,J＝7.2Hz,3H),0.86(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)piperidin-1-yl)-N-isobutylacetamide (MX02363)

To a solution of 2-(4-((2-(3-chloro-4-methoxyphenyl)-5-(ethylsulfonyl)pyrimidin-4-yl)amino)piperidin-1-yl)acetic acid (5 mg, 0.01 mmol) and isobutylamine (1 mg, 0.012 mmol) in DMF (1 mL) were added BOP (7 mg, 0.015 mmol) and TEA (4 mg, 0.04 mmol). The mixture was stirred at room temperature for 1 hour, then the reaction solution was filtered, and the filtrate was purified by preparative HPLC [MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product _as a white solid (2.98 mg, 53% yield).

ESI-MS m/z calcd for[C ₂₄ H ₃₄ ClN ₅ O ₄ S][M+H] ⁺ :524.2; found:523.8

¹ H NMR (400MHz, Methanol-d ₄ )δ8.80–8.73(m,1H),7.69(s,1H),7.62(dd,J＝8.8,2.4Hz,1H),7.16(t,J＝6.8Hz,1H),4.01–3.90(m,4H),3.14–3.02(m,4H),2.92–2.8 6(m,2H),2.77(q,J＝7.2Hz,2H),2.37–2.27(m,2H),2.06–1.97(m,2H),1.83–1.65(m,3H),1.06(t,J＝7.6Hz,3H),0.92(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-tert-Butyl 3-((1H-benzo[d]imidazol-5-yl)oxy)pyrrolidine-1-carboxylate (02365-1)

To a solution of 1H-benzo[d]imidazol-5-ol (250 mg, 1.86 mmol) and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (419 mg, 2.24 mmol) in 1,4-dioxane (20 mL) was added CMBP (0.9 g, 3.73 mmol). The mixture was stirred at 100°C for 16 hours, cooled to room temperature and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give a brown oily product (481 mg, yield 85.08%).

ESI-MS m/z calcd for[C ₁₆ H ₂₁ N ₃ O ₃ ][M+H] ⁺ :304.2; found:304.1

2.2

(R)-5-(Pyrrolidin-3-oxy)-1H-benzo[d]imidazole (02365-2)

To a solution of (R)-tert-butyl 3-((1H-benzo[d]imidazol-5-yl)oxy)pyrrolidine-1-carboxylate (66 mg, 0.22 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the crude product was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₁ H ₁₃ N ₃ O][M+H] ⁺ :204.1; found:204.2

2.3

(R)-2-((R)-3-((1H-benzo[d]imidazol-5-yl)oxy)pyrrolidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02365)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (40 mg, 0.14 mmol) and (R)-5-(pyrrolidin-3-oxy)-1H-benzo[d]imidazole (42.4 mg, 0.21 mmol) in DMF (3 mL) was added TEA (98.5 mg, 0.97 mmol). The mixture was stirred at 80°C for 2 hours, cooled to room temperature, and concentrated. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select ₁₀ μm 19*250 mm, 20 mL/min, UV 254] to afford the product as a white solid (35.65 mg, 56.42% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₆ N ₆ O ₃ S][M+H] ⁺ :455.2; found:455.0

¹ H NMR (400MHz, Methanol-d ₄ )δ8.08(s,1H),7.50-7.49(m,1H),7.13(s,1H),6.93–6.91(m,1H),5.13-5.11(m,1H),4.00–3.68(m, 6H),3.58–3.52(m,1H),3.39–3.34(m,1H),3.13–3.03(m,2H),2.35–2.13(m,6H),1.93–1.76(m,2H).

1. Synthesis scheme:

2. Experimental part:

2. tert-Butyl 1(R)-3-((1H-indazol-5-yl)oxy)pyrrolidine-1-carboxylate (02366-1)

To a solution of 1H-indazol-5-ol (250 mg, 1.86 mmol) in 1,4-dioxane (10 mL) were added tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (348 mg, 1.86 mmol) and CMBP (899 mg, 3.73 mmol). The mixture was stirred at 100°C under nitrogen overnight. After cooling, water (30 mL) was added to the mixture, and the mixture was extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product as a yellow solid (550 mg, 97% yield).

ESI-MS m/z calcd for[C ₁₆ H ₂₁ N ₃ O ₃ ][M+H] ⁺ :304.2; found:304.2

2.2

(R)-5-(Pyrrolidin-3-oxy)-1H-indazole (02366-2)

To a solution of (R)-tert-butyl 3-((1H-indazol-5-yl)oxy)pyrrolidine-1-carboxylate (550 mg, 1.81 mmol) in DCM (10 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After the starting material was consumed, The mixture was concentrated to dryness under reduced pressure to give a yellow oily product (364 mg, yield 98%).

ESI-MS m/z calcd for[C ₁₁ H ₁₃ N ₃ O][M+H] ⁺ :204.1; found:204.3

2.3

(R)-2-((R)-3-((1H-indazol-5-yl)oxy)pyrrolidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02366)

To a solution of (R)-5-(pyrrolidin-3-oxy)-1H-indazole (50 mg, 0.25 mmol) in DMF (3 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (70 mg, 0.25 mmol) and DIEA (97 mg, 0.75 mmol). The mixture was stirred at 80°C under nitrogen for 16 hours. After the starting material was consumed, the mixture was cooled, added to water (10 mL), and extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] _to give a white solid product (25.47 mg, yield 23%).

ESI-MS m/z calcd for[C ₂₂ H ₂₆ N ₆ O ₃ S][M+H] ⁺ :455.2; found:454.9

¹ H NMR (400MHz, DMSO-d ₆ )δ12.93(s,1H),7.95(s,1H),7.44(d,J＝9.2Hz,1H),7.36–7.25(m,2H),7.00(dd,J＝8.8,2.0Hz,1H),5.10(s,1H),4.89–4.84(m,1H), 3.81–3.67(m,5H),3.60–3.56(m,1H),3.46–3.36(m,1H),3.25–3.15(m,1H),2.98–2.81(m,2H),2.44–2.06(m,6H),1.81–1.63(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 5-(5-chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (02367-1)

To a solution of tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (100 mg, 0.51 mmol) in DMF (3 mL) were added 2,5-dichloropyrimidine (76 mg, 0.51 mmol) and _{K₂CO₃ (} 211 mg, 1.53 mmol). The mixture was stirred at 100°C under nitrogen for 1 hour. Water (20 mL) was added, and the mixture was extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, 20 g silica gel-CS, 30 mL/min, silica gel, UV 254) to afford the product as a white solid (140 mg, 90% yield).

ESI-MS m/z calcd for[C ₁₄ H ₁₉ ClN ₄ O ₂ ][M-56+H] ⁺ :255.1; found:255.2

2.2

2-(5-Chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane (02367-2)

To a solution of tert-butyl 5-(5-chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (140 mg, 0.45 mmol) in DCM (5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the mixture was concentrated to dryness by distillation under reduced pressure to give a white solid product (90 mg, 95% yield).

ESI-MS m/z calcd for[C ₉ H ₁₁ ClN ₄ ][M+H] ⁺ :211.1; found:211.3

2.3

2-(5-(5-chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (MX02367)

To a solution of 2-(5-chloropyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane (15 mg, 0.07 mmol) in DMF (2 mL) was added 2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (21 mg, 0.07 mmol) and DIEA (27 mg, 0.21 mmol). The mixture was stirred at 100°C under nitrogen for 1 hour. After the starting material was consumed, the mixture was cooled, added to water (10 mL), and extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] _to give a white solid product (18.94 mg, yield 56%).

ESI-MS m/z calcd for[C ₂₀ H ₂₄ ClN ₇ O ₃ S][M+H] ⁺ :478.1; found:478.2

¹ H NMR (400MHz, DMSO-d ₆ )δ8.51(s,2H),6.18–6.16(m,1H),5.02(t,J＝5.2Hz,1H),4.05–3.84(m,1H),3.84–3.68(m,4H),3.58–3.42(m,4H),3.37–3.3 0(m,1H),3.13–3.07(m,2H),2.67–2.56(m,2H),2.11–2.08(m,2H),1.87–1.70(m,2H),1.22–1.14(m,1H),0.48–0.42(m,1H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-((1H-indol-5-yl)ethynyl)-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02373)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)-3,3-difluoro-cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (20 mg, 0.062 mmol) in DMF (5 mL) were added (5-ethynyl-1H-indole (10.5 mg, 0.074 mmol), CuI (1.3 mg, 0.006 mmol), TEA (14.3 mg, 0.142 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (4.5 mg, 0.006 mmol). The mixture was stirred at 100° C. under nitrogen overnight. After the starting material was consumed, the reaction was quenched with water (10 mL) and extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN/H ₂ The product was purified _by X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] _to obtain a white solid product (8.0 mg, yield 30.3%).

ESI-MS m/z calcd for[C ₂₁ H ₁₈ F ₂ N ₄ O ₂ S][M+H] ⁺ :429.1; found:428.9

¹ H NMR (400MHz, DMSO-d ₆ )δ11.45(s,1H),8.52(s,1H),7.89(s,1H),7.48–7.46(m,2H),7.31(dd,J＝8.4，1.6Hz,1H),6.51(d,J＝2.4，1H),5.2 4(t,J＝5.6Hz,1H),3.74–3.71(m,2H),3.64–3.57(m,1H),3.37–3.35(m,1H),3.22–3.16(m,1H),3.07–2.91(m,5H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-((Trimethylsilyl)ethynyl)-1H-indazole (02375-1)

To a solution of 5-iodo-1H-indazole (1 g, 4.11 mmol) in THF (10 mL) were added ethynyltrimethylsilane (444 mg, 4.53 mmol), CuI (78 mg, 0.41 mmol), TEA (5 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (84 mg, 0.12 mmol). The mixture was stirred at room temperature overnight under nitrogen. After consumption of the starting material, the reaction mixture was distilled under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/10, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product as a brown solid (670 mg, 76% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₄ N ₂ Si][M+H] ⁺ :215.1; found:215.4

2.2

5-Ethynyl-1H-indazole (02375-2)

To a solution of 5-((trimethylsilyl)ethynyl)-1H-indazole (670 mg, 3.13 mmol) in MeOH (10 mL) was added K ₂ CO ₃ (648 mg, 4.69 mmol). The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the reaction mixture was filtered and concentrated to give a brown solid product (440 mg, 95% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₉ H ₆ N ₂ ][M+H] ⁺ :143.1; found:143.4

2.3

(R)-2-((1H-indazol-5-yl)ethynyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02375)

To a solution of 5-ethynyl-1H-indazole (50 mg, 0.36 mmol) in DMF (3 mL) were added (R)-2-chloro-4-[(1-(hydroxymethyl)cyclobutyl)amino]-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (102 mg, 0.36 mmol), CuI (6 mg, 0.035 mmol), TEA (71 mg, 0.71 mmol), and Pd(PPh ₃ ) ₂ Cl ₂ (17 mg, 0.025 mmol). The mixture was stirred at 100° C. under nitrogen overnight. After the starting material was consumed, the reaction was quenched with water (20 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (2.12 mg, yield 2%).

ESI-MS m/z calcd for[C ₂₀ H ₁₉ N ₅ O ₂ S][M+H] ⁺ :394.1; found:394.2

¹ H NMR (400MHz, DMSO-d ₆ )δ13.38(s,1H),8.18–8.15(m,2H),8.13(s,1H),7.62(d,J＝8.8Hz,1H),7.52(dd,J＝8.8,1.2Hz,1H),4.92(t,J＝5.6Hz,1H),3.78 –3.72(m,2H),3.62–3.54(m,1H),3.39–3.37(m,1H),3.19–3.13(m,1H),3.05–3.00(m,1H),2.38–2.24(m,4H),1.85–1.74(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-((Trimethylsilyl)ethynyl)-1H-benzo[d]imidazole (02376-1)

To a solution of 5-bromo-1H-benzo[d]imidazole (1 g, 5.08 mmol), Pd(dppf) _Cl₂ (186 mg, 0.254 mmol), and CuI (97 mg, 0.51 mmol) in DMF (5 mL) was added TEA (5 mL) and ethynyltrimethylsilane (1 g, 10.16 mmol). The mixture was stirred at 90°C under nitrogen overnight. The solvent was removed by distillation under reduced pressure, and the crude product was purified by column chromatography (MeOH/DCM = 0/1 to 1/10, silica gel-CS 20 g, 40 mL/min, UV 254) to afford the product as a yellow solid (550 mg, 50.6% yield).

ESI-MS m/z calcd for[C12H14N2Si][M+H]+:215.1; found:215.2

2.2

5-Ethynyl-1H-benzo[d]imidazole (02376-2)

To a solution of 5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole (550 mg, 2.57 mmol) in MeOH (10 mL) was added KOH (289 mg, 5.14 mmol). The mixture was stirred at room temperature for 1 hour. The pH of the mixture was adjusted to 6 with 1N aqueous HCl, and then the solvent was removed under reduced pressure. The crude product was purified by column chromatography (MeOH/DCM = 0/1 to 1/10, silica gel-CS 20 g, 40 mL/min, UV 254) to give the product as a yellow solid (148 mg, 40.6% yield).

ESI-MS m/z calcd for[C ₉ H ₆ N ₂ ][M+H] ⁺ :143.1; found:143.3.

2.3

(R)-2-((1H-benzo[d]imidazol-5-yl)ethynyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02376)

To a solution of 5-ethynyl-1H-benzo[d]imidazole (73 mg, 0.514 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (148 mg, 0.514 mmol) in DMF (4 mL) were added TEA (156 mg, 1.542 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (35 mg, 0.05 mmol) and CuI (10 mg, 0.05 mmol). The mixture was stirred at 90° C. under nitrogen overnight. The solvent was distilled off under reduced pressure and the obtained crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (15 mg, yield 7.43%).

ESI-MS m/z calcd for[C ₂₀ H ₁₉ N ₅ O ₂ S][M+H] ⁺ :394.1; found:394.0

¹ H NMR (400MHz, DMSO-d ₆ )δ12.72(s,1H),8.36(s,1H),8.13(s,1H),7.86(s,1H),7.67–7.65(m,1H),7.42(d,J＝8.0Hz,1H),4.92(t,J＝5.6Hz,1H),3.80– 3.72(m,2H),3.62–3.54(m,1H),3.39–3.34(m,1H),3.20–3.13(m,1H),3.05–2.99(m,1H),2.38–2.25(m,4H),1.84–1.76(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

((5-Chlorothien-2-yl)ethynyl)trimethylsilane (02377-1)

To a solution of 2-bromo-5-chlorothiophene (2 g, 10.13 mmol) in THF (50 mL) were added ethynyltrimethylsilane (2.98 g, 30.38 mmol), CuI (96 mg, 0.51 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (355 mg, 0.51 mmol), and diisopropylamine (2.05 g, 20.26 mmol). The mixture was stirred at 80°C under nitrogen for 16 hours, cooled to room temperature, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-2%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product as a yellow oil (1.2 g, 55.16% yield).

2.2

2-Chloro-5-ethynylthiophene (02377-2)

To a solution of ((5-chlorothiophen-2-yl)ethynyl)trimethylsilane (1.2 g, 5.59 mmol) in MeOH (50 mL) was added _{K₂CO₃ (} 1.54 g, 11.17 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The crude product was purified by column chromatography (EA/PE = 0-25%, Silica Gel-CS 20 g, 25 mL/min, Silica Gel, UV 254) to afford the product as a brown solid (0.7 g, 87.86% yield).

¹ H NMR (400MHz, Chloroform-d) δ7.05 (d, J = 4.0 Hz, 1H), 6.79 (d, J = 3.6 Hz, 1H), 3.33 (s, 1H).

2.3

(R)-2-((5-chlorothien-2-yl)ethynyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02377)

(R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (66 mg, 0.23 mmol) and 2-chloro-5-ethynylthiophene (98 mg, 0.69 mmol) were added to DMF (5 mL) with CuI (4.4 mg, 0.023 mmol), Pd( _PPh₃ ) _{₂Cl₂ (} 16 mg, 0.023 mmol), and TEA (69.6 mg, 0.69 mmol). The mixture was stirred at 100°C for 4 hours, cooled to room temperature, and concentrated. The crude product was purified by preparative HPLC [MeCN/ _H₂O (10 mmol/L HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to afford the product as a yellow solid (1.33 mg, 1.47% yield).

ESI-MS m/z calcd for[C ₁₇ H ₁₆ ClFN ₃ O ₂ S ₂ ][M+H] ⁺ :394.0; found:394.0

¹ H NMR (400MHz, Methanol-d ₄ )δ7.35(d,J＝4.0Hz,1H),7.30(d,J＝4.0Hz,1H),3.95–3.94(m,2H),3.72–3.66(m, 1H),3.51–3.40(m,1H),3.28–3.12(m,2H),2.37–2.33(m,4H),1.94–1.88(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-((5-chloropyridin-2-yl)ethynyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02380)

To a solution of (R)-2-chloro-4-[(1-(hydroxymethyl)cyclobutyl)amino]-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 0.174 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (12.3 mg, 0.018 mmol) in DMF (5 mL) were added TEA (53 mg, 0.522 mmol), ethynyltrimethylsilane (34 mg, 0.348 mmol) and CuI (3.4 mg, 0.018 mmol). The mixture was stirred at 90° C. under nitrogen protection overnight. CsF (53 mg, 0.348 mmol), 2-bromo-5-chloropyridine (33.6 mg, 0.174 mmol), Pd( _PPh3 ) _2Cl2 (12.3 mg, 0.018 mmol), CuI (3.4 mg, 0.018 mmol), and TEA (53 mg, 0.522 mmol) were then added to the _mixture , and the mixture was stirred at 90°C under nitrogen for 3 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative HPLC [MeCN/ _H2O ( ₁₀ mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (1.5 mg, 2.2% yield).

ESI-MS m/z calcd for[C ₁₈ H ₁₇ ClN ₄ O ₂ S][M+H] ⁺ :389.1; found:389.0

¹ H NMR (400MHz, DMSO-d ₆ )δ8.73(d,J＝2.0Hz,1H),8.28(s,1H),8.05(dd,J＝8.4,2.8Hz,1H),7.78(d,J＝8.4Hz,1H),4.91(t,J＝5.6Hz,1H),3.75–3.7 2(m,2H),3.61–3.55(m,1H),3.38–3.35(m,1H),3.20–3.14(m,1H),3.06–3.01(m,1H),2.30–2.21(m,4H),1.82–1.74(m,2H)

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-(4-((2-(5-chlorothien-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-(2,2,2-trifluoroethyl)acetamide (MX02387)

To a solution of (R)-2-(4-((2-(5-chlorothien-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (20 mg, 0.046 mmol) and 2,2,2-trifluoroethylamine (13.6 mg, 0.14 mmol) in DMF (3 mL) was added BOP (40.4 mg, 0.091 mmol) and DIEA (23.6 mg, 0.18 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC [MeCN/ _H2O (10 mmol _/ L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (2.81 mg, 11.86% yield).

ESI-MS m/z calcd for[C ₂₀ H ₁₅ ClF ₄ N ₄ O ₂ S ₂ ][M+H] ⁺ :519.0; found:518.8

¹ H NMR (400MHz, DMSO-d ₆ )δ10.25–10.22(m,1H),8.78(t,J＝6.0Hz,1H),7.75(d,J＝4.0Hz,1H),7.67(dd,J＝12.4,2.0Hz,1H),7.54(dd,J＝8.4,2.0Hz,1H),7.34(t,J＝8. 4Hz,1H),7.27(d,J＝4.0Hz,1H),3.99–3.90(m,2H),3.77–3.69(m,1H), 3.59(s,2H),3.47–3.40(m,1H),3.30–3.27(m,1H),3.16–3.11(m,1H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylacetamide (02159-1)

To a solution of 2-(4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (5 mg, 0.01 mmol) in DMF (3 mL) were added BOP (7.07 mg, 0.01 mmol), DIEA (4.26 mg, 0.03 mmol) and isobutylamine (1.16 mg, 0.01 mmol). The mixture was stirred at room temperature under nitrogen for 2 hours. After the starting material was consumed, the reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (2.18 mg, 38.9% yield).

ESI-MS m/z calcd for[C ₂₆ H ₂₈ FN ₅ O ₃ S][M+H] ⁺ :510.2; found:509.6

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.44(s,1H),9.10(s,1H),8.77(s,1H),8.65(s,1H),8.13(dd,J＝8.4,1. 2Hz,1H),8.08(t,J＝5.2Hz,1H),7.76(dd,J＝12.0,2.0Hz,1H),7.50(d,J＝8.4 Hz,1H),7.46–7.37(m,3H),6.58–6.55(m,1H),3.56–3.50(m,4H),2.92(t,J＝ 6.0Hz,2H),1.75–1.68(m,1H),1.26(t,J＝7.2Hz,3H),0.86(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl 4-(5-chloropyridin-2-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate (02422-1)

To a solution of tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate (150 mg, 0.71 mmol) and 2-bromo-5-chloropyridine (149.6 mg, 0.78 mmol) in toluene (20 mL) was added _Pd (dba) (72.3 _mg , 0.071 mg), BINAP (66 mg, 0.11 mmol), t-BuOK (238 mg, 2.12 mmol), and TEA (215 mg, 2.12 mmol). The mixture was stirred at 110°C under nitrogen for 8 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-10%, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to obtain the product as a yellow syrup (60 mg, yield 26.22%).

ESI-MS m/z calcd for[C ₁₆ H ₂₂ ClN ₃ O ₂ ][M-56+H] ⁺ :324.1; found:324.2

2.2

(R)-2-(4-(5-chloropyridin-2-yl)-4,7-diazaspiro[2.5]octan-7-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02422)

To a solution of tert-butyl 4-(5-chloropyridin-2-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate (60 mg, 0.19 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the crude product was dissolved in The crude product was dissolved in DMF (3 mL). (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (40 mg, 0.14 mmol) and DIEA (89.8 mg, 0.70 mmol) were added to a solution of the crude product in DMF (3 mL). The mixture was stirred at 80°C for 2 hours. The mixture was concentrated, and the crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (26.16 mg, 39.62% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₇ ClN ₆ O ₂ S][M+H] ⁺ :475.2; found:475.0

¹ H NMR (400MHz, Methanol-d ₄ )δ8.12(d,J＝2.4Hz,1H),7.57(dd,J＝9.2,2.8Hz,1H),7.16(d,J＝6.0Hz,1H),4.01–3.81(m,8H),3.58–3.5 0(m,1H),3.39–3.34(m,1H),3.08–3.01(m,2H),2.35–2.26(m,4H),1.93–1.86(m,2H),1.01–0.92(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(4-(((5-(ethylsulfonyl)-2-(pyridin-4-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02423-1)

To methyl 2-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (40 mg, 0.104 mmol) and 4-pyridineboronic acid (15.3 mg, 0.124 mmol) in 1,4-dioxane/water (2 mL, v/v=4/1) were added K ₂ CO ₃ (43.1 mg, 0.312 mmol) and Pd(dppf)Cl ₂ (7.3 mg, 0.01 mmol). The mixture was stirred at 90° C. under nitrogen for 3 hours. Then, the mixture was added to the mixture. To the mixture were added NaOH (41.6 mg, 1.04 mmol) and MeOH (1 mL), and stirring was continued at room temperature for 2 hours. The pH of the mixture was adjusted to 6 with 1N aq. HCl, and the solvent was then removed by distillation under reduced pressure. The crude product was purified by reverse phase column chromatography (MeCN/ _H2O = 0/1 to 1/1, C-18 column, 40 mL/min, UV 254) to obtain a light yellow solid product (15 mg, 34.7% yield).

ESI-MS m/z calcd for[C ₁₉ H ₁₇ FN ₄ O ₄ S][M+H] ⁺ :417.1; found:417.

2.2

2-(4-((5-(ethylsulfonyl)-2-(pyridin-4-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylacetamide (MX02423)

To a solution of 2-(4-(((5-(ethylsulfonyl)-2-(pyridin-4-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (15 mg, 0.036 mmol) in DMF (2 mL) were added isobutylamine (6 mg, 0.072 mmol), BOP (24 mg, 0.054 mmol), and TEA (12 mg, 0.108 mmol). The mixture was stirred at room temperature for 2 hours, after which the reaction solution was concentrated to remove the solvent. The crude product was purified by preparative HPLC [MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] _to afford the product as a white solid (9 mg, 53% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₆ FN ₅ O ₃ S][M+H] ⁺ :472.2; found:472.0

¹ H NMR (400MHz, DMSO-d ₆ )δ9.24(s,1H),8.88(s,1H),8.80(d,J＝5.6Hz,2H),8.13(d,J＝5.2Hz,2H),8.09–8.05(m,1H),7.63(d,J＝11.6Hz,1H),7.43–7.39( m,2H),3.60–3.54(m,2H),3.51(s,2H),2.91(t,J＝6.0Hz,2H),1.74–1.67(m,1H),1.26(t,J＝7.2Hz,3H),0.86(s,3H),0.83(s,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 2-(2-fluoro-4-nitrophenyl)acetate (02438-1)

To a solution of 2-(2-fluoro-4-nitrophenyl)acetic acid (7.0 g, 35.15 mmol) in tert-butanol (150 mL) at room temperature were added di-tert-butyl dicarbonate (8.44 g, 38.67 mmol) and DMAP (0.43 g, 3.52 mmol). The mixture was stirred at room temperature for 24 hours, followed by the addition of saturated _NaHCO₃ solution (150 mL), stirring for 30 minutes, and then extracted twice with EA (150 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-10%, Silica Gel-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product as a colorless oil (6.0 g, 66.87% yield).

2.2

Tert-Butyl 2-(2-fluoro-4-nitrophenyl)-2-methylpropionate (02438-2)

To a solution of tert-butyl 2-(2-fluoro-4-nitrophenyl)acetate (60 g, 23.51 mmol) in DMF (50 mL) was added NaH (60%, 2.82 g, 70.52 mmol) at 0°C. The mixture was stirred at room temperature for 30 minutes and then cooled to 0°C. Iodomethane (13.35 g, 94.03 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water (150 mL) was added to the mixture, and then extracted twice with EA (150 mL). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-8%, silica gel-CS 80 g, 50 mL/min, silica gel, UV 254) to give a colorless oily product (5.4 g, yield 81.09%).

2.3

2-(2-Fluoro-4-nitrophenyl)-2-methylpropanoic acid (02438-3)

To a solution of tert-butyl 2-(2-fluoro-4-nitrophenyl)-2-methylpropanoate (1.4 g, 4.94 mmol) in DCM (25 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to give the product as a white solid (1.1 g, 97.98% yield).

2.4

2-(2-Fluoro-4-nitrophenyl)-N-isobutyl-2-methylpropionamide (02438-4)

To a solution of 2-(2-fluoro-4-nitrophenyl)-2-methylpropanoic acid (1.1 g, 4.84 mmol) in DMF (20 mL) were added 2-methylpropan-1-amine (1.06 g, 14.53 mmol), BOP (4.28 g, 9.68 mmol) and DIEA (1.88 g, 14.5 mmol). The mixture was stirred at room temperature for 16 hours and poured into water (50 mL). It was extracted twice with EA (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give a colorless oily product (1.2 g, yield 87.79%).

ESI-MS m/z calcd for[C ₁₄ H ₁₉ FN ₂ O ₃ ][M+H] ⁺ :283.1; found:283.2

2.5

2-(4-Amino-2-fluorophenyl)-N-isobutyl-2-methylpropionamide (02438-5)

To a solution of 2-(2-fluoro-4-nitrophenyl)-N-isobutyl-2-methylpropionamide (1.2 g, 4.25 mmol) in EA (40 mL) was added Pd/C (0.2 g). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction solution was filtered through celite, and the filtrate was distilled under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-70%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give a colorless oily product (1.05 g, 97.90% yield).

ESI-MS m/z calcd for[C ₁₄ H ₂₁ FN ₂ O][M+H] ⁺ :253.2; found:253.3

2.6

2-(4-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutyl-2-methylpropionamide (02438-6)

To a solution of 2-(4-amino-2-fluorophenyl)-N-isobutyl-2-methylpropionamide (250 mg, 0.99 mmol) and 2,4-dichloro-6,7-dihydrothiophene[3,2-d]pyrimidine (616 mg, 2.97 mmol) in DMF (10 mL) was added DIEA (512 mg, 3.96 mmol). The mixture was stirred at 110°C for 20 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-75%, silica gel-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product as a yellow solid (192 mg, 45.82% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₄ ClFN ₄ OS][M+H] ⁺ :423.1; found:423.1

2.7

(R)-2-(4-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutyl-2-methylpropionamide (02438-7)

To a solution of 2-(4-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutyl-2-methylpropionamide (192 mg, 0.454 mmol) and S-1,1'-binaphthol (26 mg, 0.09 mmol) in DCM (10 mL) were added tetraisopropyl titanate (26 mg, 0.09 mmol) and water (16 mg, 0.91 mmol). The mixture was stirred at room temperature for 16 hours. 70% aqueous tert-butyl hydroperoxide solution (175 mg, 1.36 mmol) was then added in one portion, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted three times with DCM (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (MeOH/DCM = 0-5%, silica gel-CS20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (103 mg, yield 51.69%).

ESI-MS m/z calcd for[C ₂₀ H ₂₄ ClFN ₄ O ₂ S][M+H] ⁺ :439.1; found:439.0

2.8

(R)-1-(4-((2-(5-chlorothien-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylcyclopropanecarboxamide (MX02438)

To a solution of (R)-2-(4-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutyl-2-methylpropanamide (40 mg, 0.09 mmol) in 1,4-dioxane/water (5 mL, v/v = 4:1) was added (5-chlorothien-2-yl)boronic acid (29 mg, 0.18 mmol), potassium phosphate (58 mg, 0.27 mmol), and RuPhosPdG2 (14 mg, 0.02 mmol). The mixture was stirred at 85°C under nitrogen for 4 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a light yellow solid (11.47 mg, yield 24.16%).

ESI-MS m/z calcd for[C ₂₄ H ₂₆ ClFN ₄ O ₂ S ₂ ][M+H] ⁺ :521.1; found:520.8

¹ H NMR (400MHz, DMSO-d ₆ )δ10.23(s,1H),7.77(d,J＝4.0Hz,1H),7.69–7.60(m,2H),7.43(t,J＝8.8Hz,1H),7.27(d,J＝4.0Hz,1H),7.22(t,J＝6.0Hz,1H),3.77–3.69 (m,1H),3.48–3.40(m,1H),3.34–3.23(m,1H),3.16–3.11(m,1H),2.88–2.82(m,2H),1.76–1.69(m,1H),1.46(s,6H),0.79(d,J＝6.8H,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-(2-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-isobutylacetamide (MX02440)

To a solution of (R)-2-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (20 mg, 0.05 mmol) in DMF (2 mL) were added isobutylamine (4 mg, 0.06 mmol), DIEA (19 mg, 0.15 mmol) and BOP (33 mg, 0.075 mmol). The mixture was stirred at room temperature for 1 hour. After the starting material was consumed, the reaction mixture was concentrated in vacuo and the crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product _as a white solid (7.12 mg, yield 31%).

ESI-MS m/z calcd for[C ₂₂ H ₂₅ FN ₆ O ₂ S][M+H] ⁺ :457.2; found:456.6

¹ H NMR (400MHz, DMSO-d ₆ )δ10.00(s,1H),8.31(s,1H),8.04(t,J＝5.6Hz,1H),7.95(s,1H),7.69–7.61(m,2H),7.33(t,J＝8.8Hz,1H),3.91(s,3H),3.73–3.65(m,1H ),3.48(s,2H),3.44–3.37(m,1H),3.30–3.24(m,1H),3.13–3.07(m,1H),2.91(t,J＝6.0Hz,2H),1.75–1.65(m,1H),0.85(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

5-(Ethylthio)pyrimidine-2,4(1H,3H)-dione (02442-1)

To a solution of 5-bromopyrimidine-2,4(1H,3H)-dione (1.5 g, 7.85 mmol) in DMSO (10 mL) was added NaSEt (659 mg, 7.85 mmol). The mixture was stirred at 100°C under nitrogen for 3 hours. After the starting material was consumed, water (20 mL) was added to the reaction solution, and the mixture was extracted five times with EA (50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the product as a white solid (730 mg, 56% yield).

ESI-MS m/z calcd for[C ₆ H ₈ N ₂ O ₂ S][M+H] ⁺ :173.0; found:173.2

2.2

2,4-Dichloro-5-ethylthiopyrimidine (02442-2)

A solution of 5-(ethylthio)pyrimidine-2,4(1H,3H)-dione (700 mg, 4.07 mmol) in _POCl₃ (5 mL) was stirred overnight at 100°C under nitrogen. After the starting material was consumed, water (20 mL) was added to the mixture, and the mixture was extracted three times with EA (40 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/10, 40 g of silica gel-CS, 40 mL/min, silica gel, UV 254) to afford the product as a yellow solid (152 mg, 18% yield).

ESI-MS m/z calcd for[C ₆ H ₆ Cl ₂ N ₂ S][M+H] ⁺ :209.0; found:209.0

2.3

Methyl 4-((2-chloro-5-(ethylthio)pyrimidin-4-yl)amino)-2-fluorobenzoate (02442-3)

To a solution of 2,4-dichloro-5-(ethylthio)pyrimidine (300 mg, 1.46 mmol) in DMF (3 mL) were added methyl 4-amino-2-fluorobenzoate (247 mg, 1.46 mmol) and NaH (117 mg, 2.92 mmol), and the mixture was stirred at 60 ° C under nitrogen protection for 1 hour. After the starting material was consumed (monitored by LCMS), the reaction mixture was quenched with water (20 mL) and then extracted three times with EA (10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 40 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (317 mg, yield 65%).

ESI-MS m/z calcd for[C ₁₄ H ₁₃ ClFN ₃ O ₂ S][M+H] ⁺ :342.0; found:342.0

2.4

Methyl 4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorobenzoate (02442-4)

To a solution of methyl 4-((2-chloro-5-(ethylthio)pyrimidin-4-yl)amino)-2-fluorobenzoate (300 mg, 0.88 mmol) in DCM (5 mL) was added m-CPBA (85%, 534 mg, 2.64 mmol). The resulting reaction mixture was stirred at room temperature overnight under nitrogen protection. After the starting material was consumed (monitored by LCMS), the mixture was quenched with 10 mL of saturated NaHCO ₃ solution and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (EA/PE=0/1～1/4, silica gel-CS20 g, 20 mL/min, silica gel, UV 254) to give a white solid product (280 mg, 85% yield).

ESI-MS m/z calcd for[C ₁₄ H ₁₃ ClFN ₃ O ₄ S][M+H] ⁺ :374.0; found:374.2

2.5

Methyl 4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorobenzoate (02442-5)

To a solution of methyl 4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorobenzoate (250 mg, 0.67 mmol) in 1,4-dioxane/water (2.5 mL, v/v = 5/1) were added (1H-indol-5-yl)boronic acid (129 mg, 0.80 mmol), _K₂CO₃ (185 _mg , 1.34 mmol), and Pd(dppf) _Cl₂ (48 mg, 0.067 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. Water (10 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE=0/1-1/1, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a yellow solid product (215 mg, yield 71%).

ESI-MS m/z calcd for[C ₂₂ H ₁₉ FN ₄ O ₄ S][M+H] ⁺ :455.1; found:455.2

2.6

4-((5-(Ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorobenzoic acid (02442-6)

To a solution of methyl 4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorobenzoate (200 mg, 0.44 mmol) in MeOH/THF (4 mL, v/v = 1/1) was added 2N NaOH aqueous solution to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the pH of the mixture was adjusted to 6 with 1N HCl aqueous solution. The mixture was then concentrated, and the crude product was purified via reverse phase column chromatography (MeCN/ _H2O = 0-3/17, C-18 column, 50 mL/min, UV 214) to afford the product as a white solid (147 mg, 76% yield).

ESI-MS m/z calcd for[C ₂₁ H ₁₇ FN ₄ O ₄ S][M+H] ⁺ :441.1; found:441.1

2.7

N-(Cyclopropylsulfonyl)-4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorobenzamide (MX02442)

To a solution of 4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorobenzoic acid (50 mg, 0.11 mmol) and cyclopropanesulfonamide (14 mg, 0.11 mmol) in DCM (4 mL) were added TEA (22 mg, 0.22 mmol) and CMPI (56 mg, 0.22 mmol). The mixture was stirred at room temperature under nitrogen for 1 hour. Water (10 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by HPLC [MeCN/ _H₂O (10 mmol/ _{L NH₄HCO₃} ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (5.03 mg, 8% yield).

ESI-MS m/z calcd for[C ₂₄ H ₂₂ FN ₅ O ₅ S ₂ ][M+H] ⁺ :544.1; found:544.2

¹ H NMR (400 MHz, DMSO-d ₆ )δ12.10(s,1H),11.46(s,1H),9.32(s,1H),8.84(s,1H),8.68(s,1H),8.16(d d,J＝8.8,1.6Hz,1H),7.95(d,J＝13.2Hz,1H),7.80(t,J＝8.4Hz,1H),7.64(d,J ＝8.4Hz,1H),7.53(d,J＝8.4Hz,1H),7.46(t,J＝2.8Hz,1H),6.61(s,1H),3.56( q,J＝7.2Hz,2H),3.14–3.07(m,1H),1.27(t,J＝7.2Hz,3H),1.16–1.08(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

N-(Cyclopropylsulfonyl)-1-(2-fluoro-4-nitrophenyl)cyclopropanecarboxamide (02443-1)

To a solution of 1-(2-fluoro-4-nitrophenyl)cyclopropanecarboxylic acid (430 mg, 1.91 mmol) and cyclopropanesulfonamide (231 mg, 1.91 mmol) in DCM (10 mL) were added TEA (386 mg, 3.82 mmol) and CMPI (974 mg, 3.82 mmol). The mixture was stirred under nitrogen at room temperature for 1 hour. Water (10 mL) was added and extracted three times with EA (20 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-70%, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a colored oily product (411 mg, yield 65%).

ESI-MS m/z calcd for[C ₁₃ H ₁₃ FN ₂ O ₅ S][M+H] ⁺ :329.1; found:329.2.

2.2

1-(4-Amino-2-fluorophenyl)-N-(cyclopropylsulfonyl)cyclopropanecarboxamide (02443-2)

To a solution of N-(cyclopropylsulfonyl)-1-(2-fluoro-4-nitrophenyl)cyclopropanecarboxamide (411 mg, 1.25 mmol) in EA (10 mL) was added Pd/C (40 mg). The mixture was stirred at room temperature under hydrogen for 16 hours. After completion of the reaction, the mixture was filtered under reduced pressure, and the solvent was removed from the filtrate by distillation under reduced pressure to obtain the product as a white solid (368 mg, 98% yield).

ESI-MS m/z calcd for[C ₁₃ H ₁₅ FN ₂ O ₃ S][M+H] ⁺ :299.1; found:299.2

2.3

1-(4-((2-chloro-5-(ethylthio)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-(cyclopropylsulfonyl)cyclopropanecarboxamide (02443-3)

To a solution of 1-(4-amino-2-fluorophenyl)-N-(cyclopropylsulfonyl)cyclopropanecarboxamide (100 mg, 0.33 mmol) and 2,4-dichloro-5-(ethylthio)pyrimidine (68 mg, 0.33 mmol) in DMF (3 mL) was added DIEA (128 mg, 1.00 mmol). The mixture was stirred at 90 ° C overnight. After the starting material was consumed (monitored by LCMS), water (10 mL) was added and extracted three times with EA (20 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE=0/1~1, silica gel-CS20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (103 mg, yield 65%).

ESI-MS m/z calcd for[C ₁₉ H ₂₀ ClFN ₄ O ₃ S ₂ ][M+H] ⁺ :471.1; found:471.1

2.4

1-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-(cyclopropylsulfonyl)cyclopropanecarboxamide (02443-4)

To a solution of 1-(4-((2-chloro-5-(ethylthio)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-(cyclopropylsulfonyl)cyclopropanecarboxamide (100 mg, 0.21 mmol) in DCM (5 mL) was added m-CPBA (85%, 127 mg, 0.63 mmol). The resulting reaction mixture was stirred at room temperature overnight under nitrogen. After the starting material was consumed (monitored by LCMS), saturated _NaHCO₃ solution (10 mL) was added, and the mixture was extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/4, Silica Gel-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product as a yellow solid (92 mg, 86% yield).

ESI-MS m/z calcd for[C ₁₉ H ₂₀ ClFN ₄ O ₅ S ₂ ][M+H] ⁺ :503.1; found:503.2

2.5

N-(Cyclopropylsulfonyl)-1-(4-((5-(ethylsulfonyl)-2-(1H-indol-5-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)cyclopropanecarboxamide (MX02443)

To 1-(4-((2-chloro-5-(ethylsulfonyl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-(cyclopropylsulfonyl)cyclopropanecarboxamide (30 mg, 0.06 mmol) in 1,4-dioxane/water (2.5 mL, v/v = 4/1) was added (1H-indol-5-yl)boronic acid (12 mg, 0.07 mmol), K ₂ CO ₃ (19 mg, 0.14 mmol), and Pd(dppf)Cl ₂ (4 mg, 0.006 mmol). The mixture was stirred at 90° C. under a nitrogen atmosphere for 5 hours. After complete consumption of the starting material (monitored by LCMS), the reaction mixture was concentrated. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (3.67 mg, yield 11%).

ESI-MS m/z calcd for[C ₂₇ H ₂₆ FN ₅ O ₅ S ₂ ][M+H] ⁺ :584.1; found:584.2

¹ H NMR (400MHz, DMSO-d ₆ )δ11.44(s,1H),11.09(s,1H),9.17(s,1H),8.80(s,1H),8.68(s,1H),8.17(dd,J＝8.4,1.6Hz,1H),7.82(d,J＝11.6Hz,1H),7.53–7. 41(m,4H),6.60(t,J＝2.0Hz,1H),3.53(q,J＝7.2Hz,2H),2.97–2.95(m,1H),1.66–1.56(m,2H),1.28–1.24(m,5H),1.12–1.02(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1

Benzyl 3-(p-Toluenesulfonyloxy)azetidine-1-carboxylate (02446-1)

To a solution of 1-benzyloxycarbonyl-3-hydroxyazetidine (2 g, 9.65 mmol) in DCM (30 mL) at 0°C, p-toluenesulfonyl chloride (3.67 g, 19.3 mmol), TEA (2.92 g, 28.95 mmol), and DMAP (117.3 mg, 0.96 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction solution was concentrated, the crude product was purified by column chromatography (EA/PE = 0-25%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give a yellow solid product (2.6 g, yield 75.57%).

ESI-MS m/z calcd for[C ₁₈ H ₁₉ NO ₅ S][M+H] ⁺ :362.1; found:362.0.

2.2

tert-Butyl 5-((1-((Benzyloxy)carbonyl)azetidin-3-yl)oxy)isoindoline-2-carboxylate (02446-2)

To benzyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (500 mg, 1.38 mmol) and

To a solution of tert-butyl 5-hydroxyisoindoline-2-carboxylate (651 mg, 1.38 mmol) in DMF (15 mL) was added _{Cs₂CO₃ (} 1.35 g, 4.14 mmol). The mixture was stirred at 140°C for 1 hour, then water (50 mL) was added and extracted twice with EA (25 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-75%, silica gel-CS 20 g, 25 mL/min, UV 254) to give the product as a white solid (370 mg, 63.24% yield).

ESI-MS m/z calcd for[C ₂₄ H ₂₈ N ₂ O ₅ ][M-100+H] ⁺ :325.2; found:325.3.

2.3

Benzyl 3-(isoindolin-5-oxy)azetidine-1-carboxylate (02446-3)

To a solution of tert-butyl 5-((1-((benzyloxy)carbonyl)azetidin-3-yl)oxy)isoindoline-2-carboxylate (170 mg, 0.400 mmol) in DCM (5 mL) was added TFA (0.5 mL) at 0°C. The mixture was gradually returned to room temperature and stirred for 2 hours. The pH value of the mixture was adjusted to 8 with saturated NaHCO ₃ solution, extracted twice with EA (20 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a colorless oily product (200 mg, 71.0% yield).

ESI-MS m/z calcd for[C ₁₉ H ₂₀ N ₂ O ₃ ][M+H] ⁺ :325.2; found:325.3.

2.4

Benzyl 3-((2-methylisoindolin-5-yl)oxy)azetidine-1-carboxylate (02446-4)

To a solution of benzyl 3-(isoindolin-5-oxy)azetidine-1-carboxylate (150 mg, 0.46 mmol) in MeOH (5 mL) at 0°C was added aqueous HCHO (37%, 37 mg, 0.46 mmol) and _NaBH₄ (26 mg, 0.69 mmol). The mixture was slowly warmed to room temperature and stirred for 2 hours until the starting material was consumed. The mixture was quenched with saturated aqueous _NH₄Cl (20 mL) at 0°C and extracted three times with EA (15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, silica gel-CS₂ 12 g, 15 mL/min, silica gel, UV 254) to afford the product as a colorless oil (132 mg, 85.16% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₂ N ₂ O ₃ ][M+H] ⁺ :339.2; found:339.3.

2.5

5-(Azetidin-3-oxy)-2-methylisoindoline (02446-5)

To a solution of benzyl 3-((2-methylisoindolin-5-yl)oxy)azetidine-1-carboxylate (132 mg, 0.39 mmol) in EtOH (20 mL) was added Pd/C (13.2 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours, then filtered through celite and the filtrate was distilled under reduced pressure. The crude product was purified by column chromatography (MeOH/DCM = 0-10%, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product as a colorless oil (54 mg, 68.34% yield).

ESI-MS m/z calcd for[C ₁₂ H ₁₆ N ₂ O][M+H] ⁺ :205.1; found:205.3

2.6

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-((2-methylisoindolin-5-yl)oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02446)

To (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (75.92 mg, 0.26 mmol) in DMF 5-(Azetidine-3-oxy)-2-methylisoindoline (54 mg, 0.26 mmol) and DIEA (100.8 mg, 0.78 mmol) were added to a solution of 4-nitro-1,2-dole-2-nitropropene (3 mL). The mixture was then stirred at 100°C for 2 hours. After the reaction was complete, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm

19*250mm, 20mL/min, UV 254] purification to obtain a white solid product (3.64mg, yield 3%).

ESI-MS m/z calcd for[C ₂₃ H ₂₉ N ₅ O ₃ S][M+H] ⁺ :456.2; found:456.4

¹ H NMR (400MHz, DMSO-d ₆ )δ7.45(s,1H),7.13(d,J＝8.4Hz,1H),6.76(d,J＝2.0Hz,1H),6.68(dd,J＝8.4,2.4Hz,1 H),5.10–5.05(m,1H),4.84(t,J＝6.0Hz,1H),4.46–4.42(m,2H),3.93–3.86(m,2H),3.7 7(s,2H),3.73(s,2H),3.69(d,J＝4.4Hz,2H),3.45–3.34(m,1H),3.25–3.17(m,1H),2. 96–2.84(m,2H),2.46(s,3H),2.38–2.25(m,2H),2.15–2.08(m,2H),1.79–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 5-(azetidin-3-oxy)isoindoline-2-carboxylate (02450-1)

To a solution of tert-butyl 5-((1-((benzyloxy)carbonyl)azetidin-3-yl)oxy)isoindoline-2-carboxylate (200 mg, 0.47 mmol) in MeOH (3 mL) was added Pd/C (20 mg). The mixture was stirred at room temperature overnight under hydrogen. After completion of the reaction, the mixture was filtered under reduced pressure, and the solvent was evaporated from the filtrate under reduced pressure to obtain the product as a colorless oil (86 mg, 64% yield).

ESI-MS m/z calcd for[C ₁₆ H ₂₂ N ₂ O ₃ ][M+H] ⁺ :291.2; found:291.4

2.2

(R)-tert-Butyl 5-((1-(4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)isoindoline-2-carboxylate (02450-2)

To a solution of tert-butyl 5-(azetidine-3-oxy)isoindoline-2-carboxylate (50 mg, 0.17 mmol) in DMF (2 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (49 mg, 0.17 mmol) and DIEA (65 mg, 0.51 mmol). The mixture was stirred at 100°C under nitrogen for 2 h. After the starting material was consumed, the mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (MeOH/DCM = 0/1 to 1/20, silica gel-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product as a yellow solid (87 mg, yield 86%).

ESI-MS m/z calcd for[C ₂₇ H ₃₅ N ₅ O ₅ S][M+H] ⁺ :542.2; found:542.4

2.3

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-(isoindolin-5-oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02450)

To a solution of (R)-tert-butyl 5-((1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)isoindoline-2-carboxylate (30 mg, 0.05 mmol) in DCM (3 mL) was added TFA (0.6 mL) at 0°C under nitrogen protection. The mixture was stirred at room temperature for 2 hours. The solvent was then evaporated under reduced pressure, and the crude product was purified by preparative HPLC ₍ MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a yellow solid (10.11 mg, 41% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₇ N ₅ O ₃ S][M+H] ⁺ :442.2; found:441.6

¹ H NMR (400MHz, DMSO-d ₆ )δ7.49(s,1H),7.26–7.18(m,1H),6.85–6.68(m,2H),5.09–5.07(m,1H) ,4.90–4.82(m,1H),4.56–4.42(m,3H),4.01(d,J＝15.2Hz,2H),3.96–3. 84(m,2H),3.73–3.66(m,2H),3.45–3.38(m,2H),3.25–3.17(m,2H),2.9 7–2.85(m,2H),2.37–2.24(m,2H),2.15–2.10(m,2H),1.79–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 2-chloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (02454-1)

To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (1 g, 3.46 mmol) and zinc powder (1.12 g, 17.30 mmol) in MeOH (10 mL) was added acetic acid (1.04 g, 17.30 mmol) at room temperature. The mixture was then stirred at 50°C for 6 hours and concentrated. DCM (30 mL) was added, the mixture was filtered and concentrated, and the crude product was purified by column chromatography (EA/PE = 0/1 to 1/4, silica gel-CS 40 g, 30 mL/min, silica gel, UV 254) to give the product as a yellow solid (385 mg, 44% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₄ ClN ₃ O ₂ ][M+H] ⁺ :256.1; found:256.3

2.2

tert-Butyl 2-((1-((benzyloxy)carbonyl)azetidin-3-yl)oxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (02454-2)

To a solution of benzyl 3-hydroxyazetidine-1-carboxylate (246 mg, 1.20 mmol) and potassium carbonate (486 mg, 3.53 mmol) in MeCN (10 mL) at room temperature were added tert-butyl 2-chloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (300 mg, 1.18 mmol) and DABCO (13.2 mg, 0.12 mmol). The mixture was then stirred at 80°C under microwave conditions for 2 hours, water (30 mL) was added, and the mixture was extracted three times with EA (40 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product as a yellow solid (309 mg, yield 62%).

ESI-MS m/z calcd for[C ₂₂ H ₂₆ N ₄ O ₅ ][M+H] ⁺ :427.2; found:426.8

2.3

Benzyl 3-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidine-1-carboxylate (02454-3)

To a solution of tert-butyl 2-((1-((benzyloxy)carbonyl)azetidin-3-yl)oxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (309 mg, 0.73 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the starting material was consumed, the mixture was concentrated by distillation under reduced pressure to give a yellow oily product (201 mg, 85% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₇ H ₁₈ N ₄ O ₃ ][M+H]+:327.1; found:327.0

2.4

Benzyl 3-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidine-1-carboxylate (02454-4)

To a solution of benzyl 3-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidine-1-carboxylate (201 mg, 0.62 mmol) and paraformaldehyde (92 mg, 3.08 mmol) in DCM (10 mL) was added sodium triacetylborohydride (394 mg, 1.86 mmol) in portions at 0°C. The mixture was stirred overnight at room temperature under nitrogen protection. After the starting material was consumed, ice water (15 mL) was added to the mixture, the pH was adjusted to 9 with sodium bicarbonate, and the mixture was extracted three times with DCM (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (EA/PE=0/1~1/0, silica gel-CS20 g, 30 mL/min, silica gel, UV 254) to give a yellow solid product (34 mg, yield 16%).

ESI-MS m/z calcd for[C ₁₈ H ₂₀ N ₄ O ₃ ][M+H] ⁺ :341.2; found:341.2

2.5

Tert-Butyl 3-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidine-1-carboxylate (02454-5)

To a solution of benzyl 3-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidine-1-carboxylate (34 mg, 0.10 mmol) in MeOH (3 mL) at room temperature were added Pd/C (10 mg) and di-tert-butyl dicarbonate (44 mg, 0.20 mmol). The mixture was then stirred under hydrogen at room temperature for 2 hours. After the starting material was consumed. Filtered and concentrated, the crude product was purified by column chromatography (EA/PE=0/1~1/0, silica gel-CS12 g, 30 mL/min, silica gel, UV 254) to give a yellow solid product (18 mg, yield 59%).

ESI-MS m/z calcd for[C ₁₅ H ₂₂ N ₄ O ₃ ][M+H] ⁺ :307.2; found:307.0

2.6

2-(Azetidin-3-yloxy)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (02454-6)

To a solution of tert-butyl 3-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidine-1-carboxylate (18 mg, 0.059 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After consuming the starting material, the mixture was concentrated by distillation under reduced pressure to give a white solid product (10 mg, 83% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₀ H ₁₄ N ₄ O][M+H] ⁺ :207.1; found:207.3

2.7

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02454)

To a solution of 2-(azetidin-3-yloxy)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (10 mg, 0.049 mmol) in DMF (2 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (14 mg, 0.049 mmol) and DIEA (8.9 mg, 0.15 mmol). The mixture was stirred at 100°C under nitrogen for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to afford the product _as a white solid (5.68 mg, 26% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₇ N ₇ O ₃ S][M+H] ⁺ :458.2; found:457.9

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.42(s,1H),7.45(s,1H),5.43–5.37(m,1H),4.85(t,J＝5.6Hz,1H),4. 41(dd,J＝10.4,6.4Hz,2H), 3.95(d,J＝7.2Hz,2H), 3.80(d,J＝14.4Hz,4H), 3.73–3.66(m,2H),3.45–3.36(m,1H),3.25–3.17(m,1H),2.97–2.84(m,2 H),2.49(s,3H),2.38–2.25(m,2H),2.15–2.09(m,2H),1.80–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Methyl 2-(2-fluoro-4-nitrophenyl)acrylate (02457-1)

To a solution of methyl 2-(2-fluoro-4-nitrophenyl)acetate (7.0 g, 32.84 mmol) in DMSO (70 mL) at 0°C was added bis(dimethylamino)methane (5.03 g, 49.26 mmol) and acetic anhydride (10.06 g, 98.52 mmol). The mixture was stirred at room temperature for 2 hours and poured into water (200 mL) and extracted twice with methyl tert-butyl ether (150 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-10%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give a colorless oily product (3.7 g, yield 50.04%).

2.2

Methyl 1-(2-fluoro-4-nitrophenyl)cyclopropanecarboxylate (02457-2)

To a solution of methyl 2-(2-fluoro-4-nitrophenyl)acrylate (3.7 g, 16.43 mmol) and trimethylsulfonium iodide (4.34 g, 19.72 mmol) in DMSO (70 mL) was added potassium tert-butoxide (2.21 g, 19.72 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours, then poured into water (200 mL) and extracted twice with methyl tert-butyl ether (150 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-8%, silica gel-CS 80 g, 50 mL/min, silica gel, UV 254) to give a colorless oily product (1.8 g, yield 45.83%).

2.3

1-(2-Fluoro-4-nitrophenyl)cyclopropanecarboxylic acid (02457-3)

To a solution of methyl 1-(2-fluoro-4-nitrophenyl)cyclopropanecarboxylate (0.6 g, 2.508 mmol) in MeOH (10 mL) was added a solution of NaOH (201 mg, 5.02 mmol) in water (5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and water (20 mL) was added. The mixture was acidified to pH = 5 with 1 M HCl. The mixture was extracted twice with EA (20 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the product as a colorless oil (401 mg, yield 71.0%).

2.4

1-(2-Fluoro-4-nitrophenyl)-N-isobutylcyclopropanecarboxamide (02457-4)

To a solution of 1-(2-fluoro-4-nitrophenyl)cyclopropanecarboxylic acid (401 mg, 1.78 mmol) in DMF (10 mL) were added 2-methylpropan-1-amine (391 mg, 5.34 mmol), BOP (1.58 mg, 3.56 mmol) and DIEA (690 mg, 5.34 mmol). The mixture was stirred at room temperature for 16 hours, then poured into water (20 mL) and extracted twice with EA (20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Crude The product was purified by column chromatography (EA/PE=0-50%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to obtain a colorless oily product (450 mg, yield 90.15%).

ESI-MS m/z calcd for[C ₁₄ H ₁₇ FN ₂ O ₃ ][M+H] ⁺ :281.1; found:281.1.

2.5

1-(4-Amino-2-fluorophenyl)-N-isobutylcyclopropanecarboxamide (02457-5)

To a solution of 1-(2-fluoro-4-nitrophenyl)-N-isobutylcyclopropanecarboxamide (450 mg, 1.604 mmol) in EA (20 mL) was added Pd/C (80 mg). The mixture was stirred at room temperature under hydrogen for 16 h, then filtered through celite. The filtrate was distilled off under reduced pressure, and the crude product was purified by column chromatography (EA/PE = 0-70%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product as a colorless oil (386 mg, 96.15% yield).

ESI-MS m/z calcd for[C ₁₄ H ₁₉ FN ₂ O][M+H] ⁺ :251.2; found:251.0

2.6

1-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylcyclopropanecarboxamide (02457-6)

To a solution of 1-(4-amino-2-fluorophenyl)-N-isobutylcyclopropanecarboxamide (200 mg, 0.79 mmol) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (492 mg, 2.38 mmol) in DMF (10 mL) was added DIEA (410 mg, 3.17 mmol). The mixture was stirred at 110°C for 20 hours, cooled to room temperature, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-75%, silica gel-CS 20 g, 25 mL/min, silica gel, UV 254) to give the product as a yellow solid (105 mg, 31.32% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₂ ClFN ₄ OS][M+H] ⁺ :421.1; found:421.0

2.7

(R)-1-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylcyclopropanecarboxamide (02457-7)

To a solution of 1-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylcyclopropanecarboxamide (105 mg, 0.25 mmol) and S-1,1'-bin-2-naphthol (14 mg, 0.05 mmol) in DCM (10 mL) was added titanium tetraisopropoxide (14 mg, 0.05 mmol) and water (9 mg, 0.50 mmol). A 70% aqueous solution of tert-butyl hydroperoxide (96 mg, 0.75 mmol) was then added in one portion, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted three times with DCM (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0-5%, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (22 mg, yield 20.19%).

ESI-MS m/z calcd for[C ₂₀ H ₂₂ ClFN ₄ O ₂ S][M+H] ⁺ :437.1; found:437.2

2.8

(R)-1-(4-((2-(5-chlorothien-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylcyclopropanecarboxamide (MX02457)

To a solution of (R)-1-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutylcyclopropanecarboxamide (22 mg, 0.05 mmol) in 1,4-dioxane/water (5 mL, v/v 4:1) was added (5-chlorothien-2-yl)boronic acid (16 mg, 0.10 mmol), K ₃ PO ₄ (32 mg, 0.15 mmol) and RuPhosPdG 2 (8 mg, 0.01 mmol). The mixture was stirred at 85° C. under nitrogen for 4 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10mmol/ _LNH4HCO3 ), X-Select 10μm 19*250mm, 20mL/min, UV 254] to give a light yellow solid product (1.40mg, yield 5.36%).

ESI-MS m/z calcd for[C ₂₄ H ₂₄ ClFN ₄ O ₂ S ₂ ][M+H] ⁺ :519.1; found:519.2

¹ H NMR (400 MHz, DMSO-d ₆ )δ10.28(s,1H),7.79–7.75(m,2H),7.63(dd,J＝8.4,1.6Hz,1H),7.40(t,J＝8 .4Hz,1H),7.28(d,J＝4.0Hz,1H),6.83(t,J＝6.0Hz,1H),3.75–3.69(m,1H),3 .49–3.41(m,1H),3.35–3.32(m,1H),3.16–3.11(m,1H),2.86–2.82(m,2H),1 .69–1.64(m,1H),1.38–1.37(m,2H),1.00–0.99(m,2H),0.76(d,J=6.4H,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

6-Fluoro-5-hydroxyindole (02458-1)

Pd/C (25 mg) was added to a solution of 2-(5-(benzyloxy)-4-fluoro-2-nitrophenyl)acetonitrile (250 mg, 0.874 mmol) in MeOH (10 mL) and acetic acid (2 mL). The mixture was stirred at room temperature under a hydrogen atmosphere at 50°C in an autoclave (3 MPa). The mixture was stirred for 10 hours, then filtered through celite and the filtrate was distilled under reduced pressure to obtain a colorless oily product (98 mg, yield 74.24%).

ESI-MS m/z calcd for[C ₁₆ H ₁₉ FN ₂ O ₃ ][MH] ⁺ :150.0; found:150.2

2.2

Tert-Butyl 3-((6-fluoro-1H-indol-5-yl)oxy)azetidine-1-carboxylate (02458-2)

To a solution _of 6-fluoro-5-hydroxyindole (80 mg, 0.529 mmol) in DMF (5 mL) and _Cs2CO3 (517 mg, 1.59 mmol) was added tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (173 mg, 0.53 mmol). The reaction mixture was stirred at 80°C for 2 hours, after which the solvent was removed by distillation under reduced pressure. Water (50 mL) was added, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, silica gel-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product as a yellow oil (60 mg, 37.0% yield).

ESI-MS m/z calcd for[C ₁₆ H ₁₉ FN ₂ O ₃ ][M-56+H] ⁺ :251.1; found:251.3

2.3

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-(isoindolin-5-oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02450)

A solution of tert-butyl 3-((6-fluoro-1H-indol-5-yl)oxy)azetidine-1-carboxylate (50 mg, 0.16 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (46 mg, 0.16 mmol) in HFP (2 mL) was stirred at 120°C under microwave conditions for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC (MeCN/ _H2O ( ₁₀ mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (14.02 mg, 18.7% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₄ FN ₅ O ₃ S][M+H] ⁺ :458.2; found:457.6

¹ H NMR (400MHz, DMSO-d ₆ )δ11.04(s,1H),7.46(s,1H),7.31(t,J＝2.8Hz,1H),7.26(d,J＝11.6Hz,1H),7.09(d ,J＝8.4Hz,1H),6.37(t,J＝2.0Hz,1H),5.15–5.10(m,1H),4.85(t,J＝6.0Hz,1H),4.4 8–4.44(m,2H),4.07–3.94(m,2H),3.74–3.66(m,2H),3.46–3.37(m,1H),3.25–3.18 (m,1H),2.98–2.65(m,2H),2.38–2.25(m,2H),2.15–2.10(m,2H),1.82–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

1-Benzyloxy-2-fluoro-4-nitrobenzene (02458-0)

To a solution of 2-fluoro-4-nitrophenol (10 g, 63.69 mmol) in DMF (50 mL) at room temperature were added K ₂ CO ₃ (17.58 g, 127.38 mmol) and benzyl bromide (16.34 g, 95.53 mmol). The mixture was stirred at 70°C overnight, cooled, and ice water (60 mL) was added. The precipitated white solid was filtered, concentrated, and evaporated to dryness to afford a white solid product (15.2 g, 97% yield).

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.19–8.12(m,2H),7.53–7.36(m,6H),5.36(s,2H).

2.2

2-(5-(Benzyloxy)-4-fluoro-2-nitrophenyl)acetonitrile (02458-2) and 2-(3-(Benzyloxy)-2-fluoro-6-nitrophenyl)acetonitrile (02459-0)

To a solution of 1-benzyloxy-2-fluoro-4-nitrobenzene (6 g, 24.29 mmol) in DMF (30 mL) were added t-BuOK (2.72 g, 24.29 mmol) and 2-(4-chlorophenoxy)acetonitrile (4.05 g, 24.29 mmol) at -10°C. The mixture was stirred at -10°C for 1 hour, and 1N dilute hydrochloric acid (50 mL) was added to the reaction solution under ice cooling, and the mixture was extracted twice with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE=0/1 to 1/0, silica gel-CS 80 g, 50 mL/min, UV 254) to give 2-(5-(benzyloxy)-4-fluoro-2-nitrophenyl)acetonitrile (1.35 g, yield 19%) as a yellow solid and 2-(3-(benzyloxy)-2-fluoro-6-nitrophenyl)acetonitrile (1.10 g, yield 16%) as a yellow solid.

ESI-MS m/z calcd for[C ₁₅ H ₁₁ FN ₂ O ₃ ][M+18] ⁺ :304.1; found:304.2(02458-2)

ESI-MS m/z calcd for[C ₁₅ H ₁₁ FN ₂ O ₃ ][M+18] ⁺ :304.1; found:304.2(02459-0)

2.3

4-Fluoro-1H-indol-5-ol (02459-1)

Pd/C (60 mg) was added to a solution of 2-(3-(benzyloxy)-2-fluoro-6-nitrophenyl)acetonitrile (600 mg, 2.09 mmol in MeOH/HOAc (v/v = 9/1, 10 mL). The reaction mixture was stirred at 50 ° C for 10 hours under 3 MPa hydrogen atmosphere. After the starting material was consumed, the mixture was filtered and the filtrate was concentrated to dryness by distillation under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 20 g, 20 mL/min, UV 254) to obtain a yellow solid product (200 mg, yield 63%).

ESI-MS m/z calcd for[C ₈ H ₆ FNO][M+H] ⁺ :152.0; found:151.2

2.4

Tert-Butyl 3-((4-fluoro-1H-indol-5-yl)oxy)azetidine-1-carboxylate (02459-2)

To _a solution of 4-fluoro-1H-indol-5-ol (100 mg, 0.66 mmol) in MeCN (4 mL) at room temperature were added tert-butyl 3-iodoazetidine-1-carboxylate (187 mg, 0.66 mmol), _CS₂CO₃ (322 mg, 0.99 mmol), and DABCO (7 mg, 0.066 mmol). The mixture was stirred at 50°C for 2 hours. After the starting material was consumed, the reaction solution was adjusted to pH 6 with 1N dilute hydrochloric acid and extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 20 g, 20 mL/min, UV 254) to afford the product as a yellow oil (41 mg, 20% yield).

ESI-MS m/z calcd for[C ₁₆ H ₁₉ FN ₂ O ₃ ][M-56+H] ⁺ :251.1; found:251.0

2.5

(R)-2-(3-((4-fluoro-1H-indol-5-yl)oxy)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02459)

A solution of tert-butyl 3-((4-fluoro-1H-indol-5-yl)oxy)azetidine-1-carboxylate (20 mg, 0.08 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (23 mg, 0.08 mmol) in HFP (2 mL) was stirred at 120°C under microwave conditions for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC (MeCN/ _H2O ( ₁₀ mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (4.31 mg, 12% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₄ FN ₅ O ₃ S][M+H] ⁺ :458.2; found:457.7

¹ H NMR (400MHz, DMSO-d ₆ )δ11.28(s,1H),7.45(s,1H),7.38(t,J＝2.8Hz,1H),7.16(d,J＝8.8Hz,1H),6.87(t ,J＝8.4Hz,1H),6.46–6.45(m,1H),5.12–5.07(m,1H),4.85(t,J＝5.6Hz,1H),4.40– 4.36(m,2H),4.02–4.00(m,2H),3.71–3.66(m,2H),3.45–3.37(m,1H),3.29–3.20( m,1H),2.97–2.85(m,2H),2.39–2.26(m,2H),2.15–2.10(m,2H),1.80–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 2-oxoindoline-1-carboxylate (02462-1)

To a solution of indolin-2-one (3 g, 22.5 mmol) in THF (50 mL) at room temperature were added _{K₂CO₃ (} 31 g, 225.0 mmol) and (Boc) _₂O (7.37 g, 33.83 mmol). The mixture was stirred at 50°C for 2 hours, cooled, filtered, and the filtrate concentrated. The crude product was extracted twice with saturated aqueous _NaHCO₃ (40 mL) and EA (40 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 80 g, 50 mL/min, UV 254) to afford the product as a colorless oil (2.67 g, 51% yield).

ESI-MS m/z calcd for[C ₁₃ H ₁₅ NO ₃ ][M-56+H] ⁺ :178.1; found:178.1

2.2

tert-Butyl 3,3-dimethyl-2-oxoindoline-1-carboxylate (02462-2)

To a solution of tert-butyl 2-oxoindoline-1-carboxylate (2.67 g, 11.46 mmol) in DMF (20 mL) were added potassium carbonate (4.74 g, 34.38 mmol) and MeI (4.07 g, 28.65 mmol) at room temperature. The mixture was stirred at 50°C for 3 hours and cooled. After cooling, water (40 mL) was added and the mixture was extracted twice with EA (40 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 40 g, 40 mL/min, UV 254) to give a yellow oily product (1.88 g, 63% yield).

ESI-MS m/z calcd for[C ₁₅ H ₁₉ NO ₃ ][M-56+H] ⁺ :206.1; found:206.4

2.3

3,3-Dimethylindolin-2-one (02462-3)

To a solution of tert-butyl 3,3-dimethyl-2-oxoindoline-1-carboxylate (1.88 g, 7.20 mmol) in DCM (10 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After the starting material was consumed, the mixture was concentrated to dryness by distillation under reduced pressure to give a yellow oily product (1.08 g, yield 94%).

ESI-MS m/z calcd for[C ₁₀ H ₁₁ NO][M+H] ⁺ :162.1; found:162.4

2.4

5-Hydroxy-3,3-dimethylindolin-2-one (02462-4)

To a solution of 3,3-dimethylindolin-2-one (1.08 g, 6.71 mmol) in _CHCl₃ (20 mL) at room temperature were added TFA (7.65 g, 67.1 mmol) and PIFA (3.46 g, 8.05 mmol). The mixture was stirred at room temperature overnight. After the starting material was consumed, the reaction solution was adjusted to pH 8 with saturated _NaHCO₃ solution and extracted three times with EA (40 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/0, silica gel-CS 40 g, 40 mL/min, UV 254) to afford the product as a yellow solid (471 mg, 39% yield).

ESI-MS m/z calcd for[C ₁₀ H ₁₁ NO ₂ ][M+H] ⁺ :178.1; found:178.2

2.5

Tert-Butyl 3-((3,3-dimethyl-2-oxoindolin-5-yl)oxy)azetidine-1-carboxylate (02462-5)

To a solution of 5-hydroxy-3,3-dimethylindolin-2-one (61 mg, 0.34 mmol) and tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (114 mg, 0.34 mmol) in DMF (3 mL) at room temperature was added _{Cs₂CO₃ (} 222 mg, 0.68 mmol). The mixture was then stirred at 70°C for 2 hours, followed by addition of water (20 mL) and extraction twice with EA (40 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/DCM = 0/1 to 1/1, Silica Gel-CS 12 g, 30 mL/min, silica gel, UV 254) to afford the product as a yellow solid (43 mg, 38% yield).

ESI-MS m/z calcd for[C ₁₈ H ₂₄ N ₂ O ₄ ][M-56+H] ⁺ :277.2; found:277.4

2.6

5-(Azetidin-3-oxy)-3,3-dimethylindolin-2-one (02462-6)

To a solution of tert-butyl 3-((3,3-dimethyl-2-oxoindolin-5-yl)oxy)azetidine-1-carboxylate (43 mg, 0.13 mmol) in DCM (2 mL) was added TFA (0.2 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the starting material was consumed, the mixture was concentrated to dryness by distillation under reduced pressure to give the product as a yellow oil (25 mg, 83% yield).

ESI-MS m/z calcd for[C ₁₃ H ₁₆ N ₂ O ₂ ][M+H] ⁺ :233.1; found:233.2

2.7

(R)-5-((1-(4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)-3,3-dimethylindolin-2-one (MX02462)

To a solution of 5-(azetidin-3-oxy)-3,3-dimethylindolin-2-one (25 mg, 0.11 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (31 mg, 0.11 mmol) in DMF (2 mL) was added DIEA (43 mg, 0.33 mmol). The mixture was stirred at 90° C. for 2 hours, cooled to room temperature, and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the product as a white solid (25.91 mg, 50% yield).

ESI-MS m/z calcd for[C ₂₄ H ₂₉ N ₅ O ₄ S][M+H] ⁺ :484.2; found:484.3

¹ H NMR (400MHz, DMSO-d ₆ )δ10.17(s,1H),7.45(s,1H),6.93(d,J＝2.4Hz,1H),6.76(d,J＝8.4Hz,1H),6.34(d d,J＝8.4,2.4Hz,1H),5.06–5.01(m,1H),4.85(t,J＝5.6Hz,1H),4.45–4.41(m,2H), 3.91–3.89(m,2H),3.73–3.59(m,2H),3.45–3.36(m,1H),3.25–3.18(m,1H),2.96– 2.84(m,2H),2.39–2.26(m,2H),2.15–2.08(m,2H),1.83–1.68(m,2H),1.24(s,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl 3-((1,3,3-trimethyl-2-oxoindolin-5-yl)oxy)azetidine-1-carboxylate (02463-1)

To a solution of tert-butyl 3-((3,3-dimethyl-2-oxoindolin-5-yl)oxy)azetidine-1-carboxylate (80 mg, 0.24 mmol) in DMF (2 mL) was added NaH (60%, 15 mg, 0.36 mmol) at 0°C. The mixture was stirred at room temperature for 30 minutes, then MeI (30 mg, 0.24 mmol) was added, and the mixture was continued to stir at room temperature for 1 hour. Water (15 mL) was added to the mixture, and then extracted twice with EA (15 mL). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-10%, silica gel-CS20 g, 20 mL/min, UV 254) to give a colorless oily product (48 mg, yield 58%).

ESI-MS m/z calcd for[C ₁₉ H ₂₆ N ₂ O ₄ ][M+H] ⁺ :347.2; found:347.4

2.2

5-(Azetidin-3-oxy)-1,3,3-trimethylindolin-2-one (02463-2)

To a solution of tert-butyl 3-((1,3,3-trimethyl-2-oxoindolin-5-yl)oxy)azetidine-1-carboxylate (48 mg, 0.13 mmol) in DCM (2 mL) was added TFA (0.2 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the starting material was consumed, the mixture was concentrated to dryness by distillation under reduced pressure to give the product as a yellow oil (23 mg, 68% yield).

ESI-MS m/z calcd for[C ₁₄ H ₁₈ N ₂ O ₂ ][M+H] ⁺ :247.1; found:247.4

2.3

(R)-5-((1-(4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)-1,3,3-trimethylindolin-2-one (MX02463)

To a solution of 5-(azetidin-3-oxy)-1,3,3-trimethylindolin-2-one (23 mg, 0.09 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (27 mg, 0.09 mmol) in DMF (2 mL) was added DIEA (37 mg, 0.27 mmol). The mixture was stirred at 90°C for 2 hours, cooled to room temperature, and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select ₁₀ μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (11.03 mg, 24% yield).

ESI-MS m/z calcd for[C ₂₅ H ₃₁ N ₅ O ₄ S][M+H] ⁺ :498.2; found:497.6

¹ H NMR (400MHz, DMSO-d ₆ )δ7.45(s,1H),7.01(d,J＝2.4Hz,1H),6.92(d,J＝8.8Hz,1H),6.74(dd,J＝8.4,2.8H z,1H),5.10–5.05(m,1H),4.85(t,J＝5.6Hz,1H),4.47–4.43(m,2H),3.91–3.89(m, 2H),3.70–3.67(m,2H),3.45–3.37(m,1H),3.25–3.18(m,1H),3.10(s,3H),2.96–2 .84(m,2H),2.50–2.26(m,2H),2.15–2.10(m,2H),1.79–1.68(m,2H),1.26(s,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-(3-((1H-indol-5-yl)oxy)azetidin-1-yl)-4-((3-fluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02465)

A solution of 2-chloro-4-((3-fluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (20 mg, 0.065 mmol) and tert-butyl 3-((1H-indol-5-yl)oxy)azetidine-1-carboxylate (18.8 mg, 0.065 mmol) in HFP (3 mL) was stirred at 120° C. for 2 hours under microwave conditions. Water (10 mL) was then added to the mixture and the mixture was washed with DCM (10 mL). The resulting mixture was extracted twice with 5% paraformaldehyde (5% NaHCO3) and 0.1% paraformaldehyde (5% NaHCO3 ₎ . The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give a white solid compound (15.0 mg, yield 50.1%).

ESI-MS m/z calcd for[C ₂₂ H ₂₄ FN ₅ O ₃ S][M+H] ⁺ :458.2; found:458.4

¹ H NMR (400MHz, DMSO-d ₆ )δ10.97(s,1H),7.89–7.54(m,1H),7.32–7.30(m,2H),6.93(s,1H),6.7 2(dd,J＝8.8,2.4Hz,1H),6.35(s,1H),5.20–4.83(m,3H),4.48–4.44(m,2 H),4.03–3.89(m,2H),3.65(d,J＝6.0Hz,1H),3.53(d,J＝5.6Hz,1H),3.4 6–3.38(m,1H),3.24–3.17(m,1H),2.98–2.73(m,4H),2.46–2.31(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(S)-tert-Butyl 4-(5-chloropyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (02466-1)

To a solution of tert-butyl (S)-3-(hydroxymethyl)piperazine-1-carboxylate (250 mg, 1.16 mmol) in DMF (10 mL) were added 2,5-dichloropyrimidine (171 mg, 1.16 mmol) and DIEA (449 mg, 3.48 mmol). The mixture was stirred at 100°C under nitrogen for 6 hours. After the starting material was consumed, water (20 mL) was added and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 2/3, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow oily product (180 mg, yield 47%).

ESI-MS m/z calcd for[C ₁₄ H ₂₁ ClN ₄ O ₃ ][M+H]+:329.1; found:329.3

2.3

(R)-2-((S)-4-(5-chloropyrimidin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02012)

A solution of (S)-tert-butyl 4-(5-chloropyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (40 mg, 0.12 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (34 mg, 0.12 mmol) in HFP (2 mL) was stirred at 120°C under microwave conditions for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was purified by preparative HPLC (MeCN/ _H₂O ( ₁₀ mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (14.41 mg, 25% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₆ ClN ₇ O ₃ S][M+H] ⁺ :480.2; found:480.2

¹ H NMR (400MHz, DMSO-d ₆ )δ8.44(s,2H),7.36(s,1H),4.82(t,J＝5.6Hz,1H),4.74(t,J＝5.2Hz,1H),4.70–4.38(m,4H),3.76–3.68(m,2H),3 .48–3.37(m,3H),3.30–3.18(m,4H),2.96–2.84(m,2H),2.41–2.30(m,2H),2.23–2.11(m,2H),1.84–1.70(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-6-(4-Hydroxyphenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02472-1)

To a solution of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (100 mg, 0.49 mmol) in water (2 mL) at 0°C was added sulfuric acid (200 mg, 2.04 mmol). The mixture was stirred at 0°C, and a solution of sodium nitrite (38 mg, 0.55 mmol) in water (1 mL) was slowly added dropwise to the reaction mixture. Stirring was continued for 20 minutes. The mixture was then slowly heated to 70°C over 20 minutes and allowed to react for 3 hours. The reaction mixture was poured into water (10 mL), filtered, and dried to obtain the crude product. The crude product was purified by preparative HPLC (MeCN/ _H₂O (10 mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to afford the product _as a dark brown solid (38 mg, 38% yield).

2.2

(5R)-6-(4-((4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)oxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (MX02472-rac)

To a solution of (R)-6-(4-hydroxyphenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (25 mg, 0.12 mmol) in MeCN (2 mL) were added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (34 mg, 0.12 mmol), Cs ₂ CO ₃ (47 mg, 0.14 mmol), and DABCO (1 mg, 0.012 mmol). The mixture was stirred at 50° C. under nitrogen for 3 hours. After the starting material was consumed, the mixture was cooled, added to water (10 mL), and extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] _to give a white solid product (6.15 mg, yield 11%).

ESI-MS m/z calcd for[C ₂₂ H ₂₅ N ₅ O ₄ S][M+H] ⁺ :456.2; found:455.6

¹ H NMR (400MHz, DMSO-d ₆ )δ10.97(s,1H),8.11(s,1H),7.84–7.82(m,2H),7.20–7.18(m,2H),4.75–4.73(m,1H),3.57–3.36(m,5H),3.10–2.96(m, 2H),2.76–2.27(m,1H),2.32–2.28(m,1H),2.24–2.01(m,2H),1.77–1.66(m,2H),1.52–1.43(m,2H),1.06(d,J＝7.2,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-6-(4-Bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02473-1)

To a solution of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (100 mg, 0.49 mmol) in MeCN (3 mL) at 0°C was added _CuBr₂ (110 mg, 0.49 mmol) and t-BuONO (75 mg, 0.74 mmol). The mixture was stirred at room temperature under nitrogen overnight. Water (20 mL) was added, and the mixture was extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, 20 g silica gel-CS, 20 mL/min, silica gel, UV 254) to afford the product as a yellow solid (87 mg, 66% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₁ BrN ₂ O][M+H] ⁺ :267.0; found:267.1

2.2

(R)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02473-2)

To a solution of (R)-6-(4-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (87 mg, 0.32 mmol) in 1,4-dioxane (2 mL) were added _B2Pin2 (813 mg, 3.2 mmol ₎ , KOAc (94 mg, 0.96 mmol), and Pd(dppf) _Cl2 (22 mg, 0.032 mmol). The mixture was stirred at 100°C under nitrogen overnight. After the starting material was consumed, the reaction solution was cooled and concentrated under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, Silica Gel-CS 40 g, 30 mL/min, silica gel, UV 254) to afford the product as a yellow solid (42 mg, 41% yield).

ESI-MS m/z calcd for[C ₁₇ H ₂₃ BN ₂ O ₃ ][M+H] ⁺ :315.2; found:315.0

2.3

(R)-6-(4-((R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (MX02473)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (29 mg, 0.10 mmol) in 1,4-dioxane/water (2.5 mL, v/v = 4/1) was added (R)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (32 mg, 0.10 mmol), _K2CO3 (41 mg, 0.30 mmol), and Pd(dppf) _Cl2 (7 mg, 0.01 mmol). The mixture was stirred at ₉₀ °C under nitrogen for 5 hours. After the starting material was consumed, water (20 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm ₁₉ *250 mm, 20 mL/min, UV 254) to give a white solid product (13.21 mg, yield 30%).

ESI-MS m/z calcd for[C ₂₂ H ₂₅ N ₅ O ₃ S][M+H] ⁺ :440.2; found:439.6

¹ H NMR (400MHz, DMSO-d ₆ )δ11.08(s,1H),8.37(d,J＝8.4Hz,2H),8.08(s,1H),7.92(d,J＝8.8Hz,2H),4.93(t,J＝6.0Hz,1H),3.87–3.81(m,2H),3.69–3.61(m,1H), 3.47–3.36(m,2H),3.26–3.20(m,1H),3.06–3.01(m,1H),2.77–2.71(m,1H),2.50–2.25(m,5H),1.88–1.82(m,2H),1.11(d,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-Chloro-4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (02474-1)

To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (50.0 mg, 0.241 mmol) in DMF (4.0 mL) was added 5-chloro-2-(piperidin-4-yl)pyrimidine (48.0 mg, 0.241 mmol) and DIEA (0.5 mL). The mixture was stirred at 100°C for 16 hours, and the solvent was removed by distillation under reduced pressure. Water (10 mL) was added, and the mixture was extracted three times with DCM (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-100%, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to afford the product as a yellow solid (45.0 mg, 50.6% yield).

ESI-MS m/z calcd for[C ₁₅ H ₁₅ Cl ₂ N ₅ S][M+H] ⁺ :368.1; found:368.2

2.2

(R)-2-Chloro-4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (02474-2)

To a solution of 2-chloro-4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (45.0 mg, 0.122 mmol) and S-1,1'-bin-2-naphthol (3.5 mg, 0.012 mmol) in DCM (5.0 mL) was added titanium tetraisopropoxide (3.5 mg, 0.012 mmol) and water (4.4 mg, 0.244 mmol). The mixture was stirred at room temperature for 1 hour, and then 70% aqueous tert-butyl hydroperoxide (31.4 mg, 0.244 mmol) was added in one portion. The mixture was then stirred at room temperature for 2 hours, and then water (10 mL) was added. The mixture was extracted three times with DCM (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM/MeOH = 1/0 to 10/1, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give a yellow solid product (35.0 mg, yield 74.7%).

ESI-MS m/z calcd for[C ₁₅ H ₁₅ Cl ₂ N ₅ OS][M+H] ⁺ :384.0; found:384.2

2.3

(R)-4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-2-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02474)

To a solution of (R)-2-chloro-4-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (35.0 mg, 0.091 mmol) in DMF (3 mL) were added (1-aminocyclobutyl)methanol (11.0 mg, 0.109 mmol) and DIEA (0.5 mL). The reaction mixture was stirred at 100°C overnight, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (6.0 mg, 14.7% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₅ ClN ₆ O ₂ S][M+H] ⁺ :449.1; found:449..3

¹ H NMR (400MHz, DMSO-d ₆ )δ8.87(s,2H),7.24(s,1H),4.78–4.69(m,3H),3.68–3.60(m,2H),3.44–3.34(m,1H),3.28 –3.16(m,4H),2.96–2.90(m,2H),2.25–2.17(m,2H),2.13–2.00(m,4H),1.80–1.68(m,4H).

1. Synthesis scheme:

2. Experimental part:

2.1 3-Hydroxybicyclo[4.2.0]octa-1,3,5-triene

The reaction mixture of 3-bromobicyclo[4.2.0]octa-1,3,5-triene (20 mg, 0.11 mmol), Pd ₂ (dba) ₃ (10 mg, 0.01 mmol), tBu-Xphos (5.6 mg, 0.01 mmol), KOH (7.3 mg, 0.1 mmol) and water (0.2 mL) in 1,4-dioxane (2 mL) was stirred at 80°C under microwave conditions for 2 hours. After the starting materials were consumed, the reaction solution was filtered, concentrated under reduced pressure and directly used in the next step.

2.2

tert-Butyl 3-(bicyclo[4.2.0]octa-1,3,5-trien-3-oxy)azetidine-1-carboxylate (02481-2)

To a solution of 3-hydroxybicyclo[4.2.0]octa-1,3,5-triene (13 mg, 0.11 mmol) and _Cs2CO3 (107 _mg , 0.33 mmol) in DMF (3.0 mL) at room temperature was added tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (49 mg, 0.13 mmol). The mixture was then stirred at 80°C overnight. After the starting material was consumed, water (10 mL) was added and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/4, 4 g silica gel-CS, 25 mL/min, silica gel, UV 254) to afford the product as a colorless oil (12 mg, 39.7% yield).

ESI-MS m/z calcd for[C ₁₆ H ₂₁ NO ₃ ][M-56+H] ⁺ :220.2; found:220.1

2.3

(R)-2-(3-(bicyclo[4.2.0]octa-1,3,5-trien-3-oxy)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02481)

A solution of tert-butyl 3-(bicyclo[4.2.0]octa-1,3,5-trien-3-oxy)azetidine-1-carboxylate (12 mg, 0.04 mmol) and (R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (12 mg, 0.04 mmol) in HFP (2 mL) was stirred at 120 °C under microwave conditions for 2 h. After the starting material was consumed, water (10 mL) was added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/ _LNH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give _a white solid compound (1.89 mg, yield 14.8%).

ESI-MS m/z calcd for[C ₂₂ H ₂₆ N ₄ O ₃ S][M+H] ⁺ :427.2; found:426.8

¹ H NMR (400MHz, DMSO-d ₆ )δ7.45(s,1H),7.00(d,J＝8.0Hz,1H),6.69–6.65(m,2H),5.05–5.04(m, 1H),4.84(t,J＝5.6Hz,1H),4.44–4.41(m,2H),3.89–3.88(m,2H),3.73–3 .69(m,2H),3.45–3.36(m,1H),3.25–3.17(m,1H),3.07–3.06(m,4H),3.0 0–2.84(m,2H),2.38–2.25(m,2H),2.15–2.10(m,2H),1.82–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

2-((S)-1-(5-chloropyrimidin-2-yl)-4-((R)-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-2-yl)acetonitrile (MX02521)

A solution of (S)-tert-butyl 4-(5-chloropyrimidin-2-yl)-3-(cyanomethyl)piperazine-1-carboxylate (10 mg, 0.03 mmol) and (R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (10 mg, 0.03 mmol) in HFP (2 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (2.80 mg, yield 17.8%).

ESI-MS m/z calcd for[C ₂₁ H ₂₃ ClF ₂ N ₈ O ₂ S][M+H] ⁺ :525.1; found:524.6

¹ H NMR (400MHz, DMSO-d ₆ )δ8.53(s,2H),8.02(s,1H),5.14–5.07(m,1H),4.59–4.67(m,3H),3.73–3.66(m,2H),3.49 –3.40(m,1H),3.25–3.17(m,2H),3.10–3.05(m,1H),3.01–2.92(m,6H),2.90–2.84(m,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-2-(3-((1-methyl-1H-indol-5-yl)oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02532)

A solution of (R)-2-chloro-4-((1-(hydroxymethyl)-3,3-difluoro-cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (20 mg, 0.062 mmol) and tert-butyl 3-((1-methyl-1H-indol-5-yl)oxy)azetidine-1-carboxylate (20.5 mg, 0.068 mmol) in HFP (3 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (15.0 mg, yield 49.5%).

ESI-MS m/z calcd for[C ₂₃ H ₂₅ F ₂ N ₅ O ₃ S][M+H] ⁺ :490.2; found:489.7

¹ H NMR (400MHz, DMSO-d ₆ )δ7.95(s,1H),7.36(d,J＝8.8Hz,1H),7.29(d,J＝3.2Hz,1H),6.94(d,J＝2.0Hz,1H),6.78(dd,J＝8.8,2.4Hz,1H),6.33(dd,J＝3.2,0.8Hz,1H),5. 14–5.09(m,2H),4.48–4.44(m,2H),3.98–3.93(m,2H),3.76(s,3H),3.6 7–3.66(m,2H),3.46–3.39(m,1H),3.22–3.17(m,1H),2.99–2.83(m,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

6-(4-((1-((R)-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (MX02538-rac)

A solution of (R)-2-chloro-4-((1-(hydroxymethyl)-3,3-difluoro-cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (20 mg, 0.062 mmol) and tert-butyl 3-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)azetidine-1-carboxylate (22 mg, 0.062 mmol) in HFP (2 mL) was stirred at 120° C. for 2 hours under microwave conditions. After completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC (MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (5.37 mg, 15.9% yield).

ESI-MS m/z calcd for[C ₂₅ H ₂₈ F ₂ N ₆ O ₄ S][M+H] ⁺ :547.2; found:547.0

¹ H NMR (400MHz, DMSO-d ₆ )δ10.89(s,1H),7.99(s,1H),7.76(d,J＝9.2Hz,2H),6.94(d,J＝8.8Hz,2H),5.18–5.12(m,2H),4.49(dd,J＝9.6,6.0Hz,2H), 3.95(br,2H),3. 71–3.63(m,2H),3.46–3.36(m,2H),3.23–3.17(m,1H),3.00–2.83(m,6H),2.70–2.64(m,1H),2.23(d,J＝16.4Hz,1H),1.07(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-(3-((1H-indol-4-yl)oxy)azetidin-1-yl)-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02578)

A solution of tert-butyl 3-((1H-indol-4-yl)oxy)azetidine-1-carboxylate (9.7 mg, 0.03 mmol) and (R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (10 mg, 0.03 mmol) in HFP (2 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (4.91 mg, yield 34.4%).

ESI-MS m/z calcd for[C ₂₂ H ₂₃ F ₂ N ₅ O ₃ S][M+H] ⁺ :476.2; found:476.1

¹ H NMR (400MHz, DMSO-d ₆ )δ11.14(s,1H),7.97(s,1H),7.25(t,J＝2.8Hz,1H),7.06–7.04(m,1H),6 .99(t,J＝8.0Hz,1H),6.49–4.42(m,1H),6.30(d,J＝7.6Hz,1H),5.23–5.1 9(m,1H),5.13(t,J＝5.6Hz,1H),4.55–4.50(m,2H),4.01–3.97(m,2H),3. 68–3.63(m,2H),3.48–3.40(m,1H),3.24–3.17(m,1H),3.00–2.81(m,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-2-(2-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-isobutyl-2-methylpropionamide (MX02591)

To a solution of (R)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-N-isobutyl-2-methylpropanamide (30 mg, 0.07 mmol) in 1,4-dioxane/water (5 mL, v/v=4:1) were added (1-methyl-1H-pyrazol-4-yl)boronic acid (17 mg, 0.14 mmol), K ₂ CO ₃ (28 mg, 0.20 mmol), and Pd(dppf)Cl ₂ (7 mg, 0.01 mmol). The mixture was stirred at 85° C. under nitrogen for 4 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a light yellow solid product (4.41 mg, yield 13.32%).

ESI-MS m/z calcd for[C ₂₄ H ₂₉ FN ₆ O ₂ S][M+H] ⁺ :485.2; found:484.6

¹ H NMR (400MHz, DMSO-d ₆ )δ8.24(s,1H),8.08(s,1H),7.66–7.58(m,2H),7.49(t,J＝8.8Hz,1H),7.30(t,J＝5.6Hz,1H),3.97(s,3H),3.85–3.76(m,1H),3.55– 3.48(m,1H),3.39–3.35(m,1H),3.26–3.12(m,1H),2.98(t,J=6.4Hz,2H),1.84–1.77(m,1H),1.57(s,6H),0.87(s,3H),0.86(s,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

N-(tert-Butyl)-2-(2-fluoro-4-nitrophenyl)-2-methylpropionamide (02594-1)

To a solution of 2-(2-fluoro-4-nitrophenyl)-2-methylpropanoic acid (1.0 g, 4.40 mmol) in DMF (20 mL) were added 2-methyl-2-propylamine (0.97 g, 13.20 mmol), HATU (3.35 g, 8.80 mmol) and DIEA (1.71 g, 13.20 mmol). The mixture was stirred at room temperature for 16 hours and poured into water (50 mL). It was extracted twice with EA (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give a colorless oily product (1.1 g, yield 88.52%).

ESI-MS m/z calcd for[C ₁₄ H ₁₉ FN ₂ O ₃ ][M+H] ⁺ :283.1; found:283.4

2.2

2-(4-Amino-2-fluorophenyl)-N-(tert-butyl)-2-methylpropionamide (02594-2)

To a solution of N-(tert-butyl)-2-(2-fluoro-4-nitrophenyl)-2-methylpropionamide (1.1 g, 3.90 mmol) in EA (40 mL) was added Pd/C (0.2 g). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h, then filtered through celite. The filtrate was evaporated under reduced pressure, and the crude product was purified by column chromatography (EA/PE = 0-70%, silica gel-CS 40 g, 50 mL/min, silica gel, UV 254) to give the product as a colorless oil (0.9 g, 91.54% yield).

ESI-MS m/z calcd for[C ₁₄ H ₂₁ FN ₂ O][M+H] ⁺ :253.2; found:253.2

2.3

N-(tert-Butyl)-2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-2-methylpropanamide (02594-3)

To a solution of 2-(4-amino-2-fluorophenyl)-N-(tert-butyl)-2-methylpropionamide (500 mg, 1.98 mmol) and 2,4-dichloro-6,7-dihydrothiophene[3,2-d]pyrimidine (1.23 g, 5.95 mmol) in DMF (20 mL) was added DIEA (1.02 g, 7.93 mmol). The mixture was stirred at 100°C for 20 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0-75%, silica gel-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product as a yellow solid (185 mg, 22.07% yield).

ESI-MS m/z calcd for[C ₂₀ H ₂₄ ClFN ₄ OS][M+H] ⁺ :423.1; found:423.1

2.4

(R)-N-(tert-Butyl)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-2-methylpropanamide (02594-5)

To a solution of N-(tert-butyl)-2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-2-methylpropanamide (185 mg, 0.44 mmol) and S-1,1'-binaphthol (25 mg, 0.09 mmol) in DCM (10 mL) were added tetraisopropyl titanate (25 mg 0.09 mmol) and water (16 mg, 0.88 mmol). The mixture was stirred at room temperature for 16 hours. 70% aqueous tert-butyl hydroperoxide solution (169 mg, 1.31 mmol) was then added in one portion, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted three times with DCM (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0-5%, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (106 mg, yield 55.21%).

ESI-MS m/z calcd for[C ₂₀ H ₂₄ ClFN ₄ O ₂ S][M+H] ⁺ :439.1; found:439.0

2.5

(R)-N-(tert-Butyl)-2-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)-2-methylpropanamide (MX02594)

To a solution of (R)-N-(tert-butyl)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)-2-methylpropanamide (35 mg, 0.08 mmol) in 1,4-dioxane/water (5 mL, v/v=4:1) were added (1-methyl-1H-pyrazol-4-yl)boronic acid (20 mg, 0.16 mmol), K ₂ CO ₃ (33 mg, 0.24 mmol), and Pd(dppf)Cl ₂ (7 mg, 0.01 mmol). The mixture was stirred at 85° C. under nitrogen for 4 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a light yellow solid product (7.67 mg, yield 19.85%).

ESI-MS m/z calcd for[C ₂₄ H ₂₉ FN ₆ O ₂ S][M+H] ⁺ :485.2; found:484.6

¹ H NMR (400MHz, DMSO-d ₆ )δ8.27(s,1H),8.11(s,1H),7.67–7.61(m,2H),7.51(t,J＝9.2Hz,1H),6.13(s,1 H),3.99(s,3H),3.85–3.80(m,1H),3.55–3.49(m,1H),3.42–3.35(m,1H),3.28– 3.21(m,1H),1.56(s,6H),1.33(s,9H).

1. Synthesis scheme:

2. Experimental part:

2.1

tert-Butyl 5-(5-chloropyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (A-1)

To a solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (72 mg, 0.36 mmol) in EtOH (2 mL) were added 2,5-dichloropyrimidine (50 mg, 0.36 mmol) and DIEA (139 mg, 1.08 mmol). The mixture was stirred at 100°C under nitrogen for 1 hour. After the starting material was consumed, water (30 mL) was added to the mixture and extracted three times with EA (30 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS12 g, 30 mL/min, silica gel, UV 254) to give a white solid product (86 mg, yield 74%).

ESI-MS m/z calcd for[C ₁₅ H ₂₁ ClN ₄ O ₂ ][M-56+H] ⁺ :269.1; found:269.1

2.2

2-(5-chloropyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (A-2)

To a solution of tert-butyl 5-(5-chloropyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (30 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.2 mL). The reaction mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the mixture was concentrated by distillation under reduced pressure to give a white solid product (19 mg, 92% yield), which was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₀ H ₁₃ ClN ₄ ][M+H] ⁺ :225.1; found:225.1

2.3

(1-(2-Chloro-5-(ethylthio)pyrimidin-4-ylamino)cyclobutyl)methanol (02596-1)

To a solution of 2,4-dichloro-5-ethylthiopyrimidine (100 mg, 0.48 mmol) in DMF (4 mL) were added (1-aminocyclobutyl)methanol hydrochloride (48.6 mg, 0.48 mmol) and DIEA (185.8 mg, 1.44 mmol). The mixture was stirred at 70°C overnight. After the starting material was consumed, water (30 mL) was added to the mixture and extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 30 mL/min, silica gel, UV 254) to give a white solid product (81 mg, yield 62%).

ESI-MS m/z calcd for[C ₁₁ H ₁₆ ClN ₃ OS][M+H] ⁺ :274.1; found:274.0

2.4

(1-(2-Chloro-5-(ethylsulfonyl)pyrimidin-4-ylamino)cyclobutyl)methanol (02596-2)

To a solution of (1-(2-chloro-5-(ethylthio)pyrimidin-4-ylamino)cyclobutyl)methanol (70 mg, 0.26 mmol) in DCM (10 mL) was added m-CPBA (85%, 154.7 mg, 0.76 mmol). The mixture was stirred at room temperature under nitrogen for 2 hours. After the starting material was consumed, the reaction was quenched with saturated aqueous NaHCO ₃ solution (20 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/2, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product as a white solid (64 mg, 79% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₆ ClN ₃ O ₃ S][M+H] ⁺ :306.1; found:306.0

2.5

(1-(2-(5-(5-chloropyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(ethylsulfonyl)pyrimidin-4-ylamino)cyclobutyl)methanol (MX02596)

To a solution of (1-(2-chloro-5-(ethylsulfonyl)pyrimidin-4-ylamino)cyclobutyl)methanol (26 mg, 0.085 mmol) and 2-(5-chloropyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (19 mg, 0.085 mmol) in DMF (2 mL) was added DIEA (33 mg, 0.255 mmol). The mixture was stirred at 100°C under nitrogen overnight. After the starting material was consumed, the mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (21.36 mg, 51% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₈ ClN ₇ O ₃ S][M+H] ⁺ :494.2; found:493.7

¹ H NMR (400MHz, DMSO-d ₆ )δ8.41(s,2H),8.13(s,1H),6.93(s,1H),4.89(t,J＝5.6Hz,1H),3.84–3.70(m,6H),3.49–3.38(m,4H),3.17(q ,J＝7.6Hz,2H),3.10(br,2H),2.34–2.29(m,2H),2.13–2.08(m,2H),1.85–1.74(m,2H),1.13(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(S)-tert-Butyl 4-(5-chloropyridin-2-yl)-3-(cyanomethyl)piperazine-1-carboxylate (02597-1)

A reaction mixture of tert-butyl 3-(cyanomethyl)piperazine-1-carboxylate (100 mg, 0.44 mmol), 2-bromo-5-chloropyridine (86 mg, 0.45 mmol), Pd(OAc) _₂ (10 mg, 0.04 mmol), _BINAP (40 mg, 0.06 mmol), and _Cs₂CO₃ (390 mg, 1.2 mmol) in toluene (8 mL) was stirred at 120°C overnight under argon. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (EA/PE = 0-1/9, silica gel-CS 20 g, 36 mL/min, silica gel, UV 254) to give the product as a colorless oil (103 mg, 69.6% yield).

ESI-MS m/z calcd for[C ₁₆ H ₂₁ ClN ₄ O ₂ ][M-56+H] ⁺ :281.1; found:281.1

2.2

2-((S)-1-(5-chloropyridin-2-yl)-4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-2-yl)acetonitrile (MX02597)

A solution of (S)-tert-butyl 4-(5-chloropyridin-2-yl)-3-(cyanomethyl)piperazine-1-carboxylate (20 mg, 0.09 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (30 mg, 0.11 mmol) in HFP (2 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (7.97 mg, yield 18.1%).

ESI-MS m/z calcd for[C ₂₂ H ₂₆ ClN ₇ O ₂ S][M+H] ⁺ :488.2; found:487.6

¹ H NMR (400MHz, DMSO-d ₆ )δ8.17(d,J＝2.8Hz,1H),7.68(dd,J＝11.2,2.4Hz,1H),7.44(s,1H),6.96(d,J＝9.6Hz ,1H),4.95–4.94(m,1H),4.81(t,J＝5.2Hz,1H),4.64–4.61(m,1H),4.52–4.50(m,1H), 4.07–4.04(m,1H),3.76–3.69(m,2H),3.46–3.35(m,2H),3.36–3.10(m,3H),2.99–2.8 5(m,2H),2.79–2.67(m,2H),2.43–2.27(m,2H),2.22–2.17(m,2H),1.85–1.71(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Benzyl 5-bromoisoindoline-2-carboxylate (02599-1)

To a solution of 5-bromoisoindoline hydrochloride (393 mg, 1.68 mmol) in THF (6 mL) was added TEA (592 mg, 5.86 mmol) and benzyl chloroformate (429 mg, 2.51 mmol) at 0°C and stirred at room temperature overnight. Water (50 mL) was added and extracted three times with EA (20 mL). The combined organic layer was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (EA/PE=0/1~1/5, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a brown solid (499 mg, yield 90%).

ESI-MS m/z calcd for[C ₁₆ H ₁₄ BrNO ₂ ][M+Na] ⁺ :354.0; found:354.1

2.2

(S)-5-(4-(tert-Butyloxycarbonyl)-2-(cyanomethyl)piperazin-1-yl)isoindoline-2-carboxylic acid benzyl ester (02599-2)

To a solution of benzyl 5-bromoisoindoline-2-carboxylate (242 mg, 1.07 mmol) and tert-butyl (S)-3-(cyanomethyl)piperazine-1-carboxylate (392 mg, 1.18 mmol) in toluene (10 mL) was added 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (67 mg, 0.11 mmol), palladium acetate (24 mg, 0.11 mmol), and cesium carbonate (1.05 g, 3.22 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at 100°C for 16 hours. After completion of the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted three times with EA (10 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA/PE=0/1~1/1, silica gel 40 g, 40 mL/min, silica gel, UV 254) to give a yellow oily product (188 mg, yield 37%).

ESI-MS m/z calcd for[C ₂₇ H ₃₂ N ₄ O ₄ ][M+H] ⁺ :477.2; found:477.3

2.3

(S)-Benzyl 5-(2-(cyanomethyl)piperazin-1-yl)isoindoline-2-carboxylate (02599-3)

Under nitrogen, benzyl (S)-5-(4-(tert-Butyloxycarbonyl)-2-(cyanomethyl)piperazin-1-yl)isoindoline-2-carboxylate (188 mg, 0.39 mmol) was dissolved in DCM (6 mL), followed by the addition of TFA (1 mL), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was drained to obtain a crude product, which was then purified via a reverse-phase column [MeCN/ _H2O (0.5% HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to afford the desired product (99 mg, 67% yield).

ESI-MS m/z calcd for[C ₂₂ H ₂₄ N ₄ O ₂ ][M+H] ⁺ :377.2; found:377.2.

2.4

Benzyl 5-((S)-2-(cyanomethyl)-4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)isoindoline-2-carboxylate (02599-4)

To a solution of (S)-benzyl 5-(2-(cyanomethyl)piperazin-1-yl)isoindoline-2-carboxylate (113 mg, 0.30 mmol) in DMF (5 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (86 mg, 0.30 mmol) and DIEA (194 mg, 1.50 mmol). The mixture was stirred at 100°C under nitrogen for 2 h. After the reaction, water (30 mL) was added, and the mixture was extracted with EA (10 mL x 3). The organic phases were combined, washed with saturated brine, dried _{over Na₂SO₄} , filtered, and concentrated to yield the crude product. The residue was purified by reverse phase column [MeCN/H ₂ O (0.5% HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the target product (120 mg, yield 67%).

ESI-MS m/z calcd for[C ₃₃ H ₃₇ N ₇ O ₄ S][M+H] ⁺ :628.3; found:628.2.

2.5

2-((S)-4-((R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxygeno-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1-(isoindolin-5-yl)piperazin-2-yl)acetonitrile (MX02599)

At 0°C, under nitrogen protection, benzyl 5-((S)-2-(cyanomethyl)-4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)isoindoline-2-carboxylate (70 mg, To a solution of HFP (6 mL) containing 1,4-dihydro-2-nitropropene (74 mg, 0.11 mmol) was added _AlCl₃ (74 mg, 0.55 mmol), and the mixture was stirred at 65°C overnight. The mixture was filtered through celite and concentrated under vacuum to obtain a crude product. The crude product was purified by preparative HPLC [MeCN/H₂O ( ₁₀ mmol/L _NH₄HCO₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to obtain a white solid product (49 mg, 89% yield).

ESI-MS m/z calcd for[C ₂₅ H ₃₁ N ₇ O ₂ S][M+H] ⁺ :494.2; found:494.2.

2.6

2-((S)-4-((R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxygeno-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1-(2-methylisoindolin-5-yl)piperazin-2-yl)acetonitrile (MX02598)

Under nitrogen protection, to a solution of 2-((S)-4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxy-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1-(isoindolin-5-yl)piperazin-2-yl)acetonitrile (30 mg, 0.06 mmol) in MeOH (3 mL) was added 35% aqueous formaldehyde (0.5 mL) and sodium borohydride (5 mg, 0.13 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the pH of the solution was adjusted to 6-7 with dilute HCl (0.5 N) and concentrated to obtain the crude product. The crude product was purified by preparative HPLC [MeCN/H ₂ O (0.5% HCOOH), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (3.45 mg, yield 10%).

ESI-MS m/z calcd for[C ₂₆ H ₃₃ N ₇ O ₂ S][M+H] ⁺ :508.2; found:508.0.

¹ H NMR (400 MHz, DMSO-d ₆ )δ7.42(s,1H),7.10(d,J＝8.0Hz,1H), 6.91(s,1H),6.85(dd,J＝8.4,2.0Hz,1H ),4.82–4.81(m,1H),4.45–4.38(m,2H),4.25–4.22(m,1H),3.77–3.70(m,6H), 3.53(dd,J＝13.2,3.2Hz,1H),3.30–3.20(m,4H),3.07–2.86(m,3H),2.67–2.60 (m,1H),2.46(s,3H),2.43–2.27(m,3H),2.22–2.17(m,2H),1.83–1.71(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-2-(3-((3-methyl-1H-indol-5-yl)oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02605)

A solution of (R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (10 mg, 0.0331 mmol) and tert-butyl 3-((3-methyl-1H-indol-5-yl)oxy)azetidine-1-carboxylate (10 mg, 0.0309 mmol) in HFP (3 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give _a white solid product (2.08 mg, yield 12.8%).

ESI-MS m/z calcd for[C ₂₃ H ₂₅ F ₂ N ₅ O ₃ S][M+H] ⁺ :490.0; found:490.0

¹ H NMR (400MHz, DMSO-d ₆ )δ10.61(d,J＝1.6Hz,1H),7.93(s,1H),7.25(d,J＝8.8Hz,1H),7.08(d,J＝1.2Hz,1H),6.86(d,J＝2.4Hz,1H),6.71(dd,J＝8.8,2.4Hz,1H),5.13(t ,J＝5.6Hz,2H),4.48–4.44(m,2H),3.97–3.95(m,2H),3.68–3.66(m,2H) ,3.48–3.39(m,1H),3.25–3.17(m,1H),3.02–2.79(m,6H),2.22(m,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-5-((1-(4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)-3,3-dimethylindolin-2-one (MX02606)

A solution of (R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (20 mg, 0.0602 mmol) and tert-butyl 3-((3-methyl-1H-indol-5-yl)oxy)azetidine-1-carboxylate (10 mg, 0.0309 mmol) in HFP (3 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm19*250 mm, 20 mL/min, UV 254) to give _a white solid product (2.27 mg, yield 14.26%).

ESI-MS m/z calcd for[C ₂₄ H ₂₇ F ₂ N ₅ O ₄ S][M+H] ⁺ :519.9; found:519.9

¹ H NMR (400MHz, DMSO-d ₆ )δ10.17(s,1H),7.95(s,1H),6.93(d,J＝2.4Hz,1H),6.76(d,J＝8.4Hz,1H),6.71(dd,J＝8.4,2.4Hz,1H),5.13(t,J＝6.0Hz,2H),5.06–5.0 1(m,1H),4.46–4.42(m,2H),3.93–3.90(m,2H),3.68–3.66(m,1H),3.47–3.39(m,1H),3.24–3.17(m,1H),2.99–2.83(m,6H),1.24(s,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl 3-((6-fluoro-1-methyl-1H-indol-5-yl)oxy)azetidine-1-carboxylate (02609-1)

To a solution of tert-butyl 3-((6-fluoro-1H-indol-5-yl)oxy)azetidine-1-carboxylate (30 mg, 0.10 mmol) in DMF (2 mL) was added NaH (60%, 5 mg, 0.12 mmol) at 0°C. The mixture was stirred at room temperature for 30 minutes, then MeI (16 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (15 mL) was added to the mixture, and then extracted twice with EA (15 mL). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0-8%, silica gel-CS20 g, 20 mL/min, UV 254) to give a colorless oily product (21 mg, yield 68%).

ESI-MS m/z calcd for[C ₁₇ H ₂₁ FN ₂ O ₃ ][M-56+H] ⁺ :265.2; found:265.1

2.2

(R)-2-(3-((6-fluoro-1-methyl-1H-indol-5-yl)oxy)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02609)

A solution of tert-butyl 3-((6-fluoro-1-methyl-1H-indol-5-yl)oxy)azetidine-1-carboxylate (21 mg, 0.06 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (19 mg, 0.06 mmol) in HFP (2 mL) was stirred at 120°C under microwave conditions for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC ₍ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (6.44 mg, 21% yield).

ESI-MS m/z calcd for[C ₂₃ H ₂₆ FN ₅ O ₃ S][M+H] ⁺ :472.2; found:471.6

¹ H NMR (400MHz, DMSO-d ₆ )δ7.46(s,1H),7.42(d,J＝12.0Hz,1H),7.29(d,J＝3.2Hz,1H),7.10(d,J＝8.0Hz,1H),6. 36(dd,J＝3.2,0.4Hz,1H),5.15–5.10(m,1H),4.84(t,J＝5.6Hz,1H),4.48–4.44(m,2H), 4.02–3.93(m,2H),3.73(s,3H),3.70(dd,J＝5.6,1.6Hz,2H),3.46–3.35(m,1H),3.25–3 .18(m,1H),2.97–2.84(m,2H),2.38–2.25(m,2H),2.15–2.10(m,2H),1.79–1.66(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl 3-(4-(1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)azetidine-1-carboxylate (02612-1)

At 0 ° C, to a solution of tert-butyl 3-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)azetidine-1-carboxylate (50 mg, 0.14 mmol) in DMF (3 mL) was added NaH (6.7 mg, 0.17 mmol). After stirring at 0 ° C for 20 minutes, MeI (22 mg, 0.15 mmol) was slowly added. The mixture was stirred at 0 ° C for 2 hours under nitrogen protection. After the starting material was consumed, ice water (15 mL) was added to the mixture and extracted three times with EA (30 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography The residue was purified by purifying (EA/PE=0/1-1/1, silica gel-CS 12 g, 30 mL/min, silica gel, UV 254) to give a white solid product (33 mg, yield 63%).

ESI-MS m/z calcd for[C ₂₀ H ₂₇ N ₃ O ₄ ][M+H] ⁺ :374.2; found:373.8

2.2

6-(4-((1-((R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)phenyl)-2,5-dimethyl-4,5-dihydropyridazin-3(2H)-one (MX02612-rac)

A solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (15 mg, 0.053 mmol) and tert-butyl 3-(4-(1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)azetidine-1-carboxylate (20 mg, 0.053 mmol) in HFP (2 mL) was stirred at 120° C. under microwave conditions for 2 hours. After completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by preparative HPLC (MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (6.99 mg, 25% yield).

ESI-MS m/z calcd for[C ₂₆ H ₃₂ N ₆ O ₄ S][M+H] ⁺ :525.2; found:524.6

¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O)δ7.79(d,J＝8.4Hz,2H),6.96(d,J＝8.4Hz,2H),5.19(br,1H),4.51–4.47(m,2H),3.95(br,2H),3.75–3.70(m,2H),3.47–3.36(m,2H),3.32(s ,3H),3.30–3.22(m,1H),3.00–2.88(m,2H),2.73–2.67(m,1H),2.34–2. 24(m,3H),2.16–2.11(m,2H),1.81–1.70(m,2H),1.07(d,J=7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

3-Bromo-4-ethoxybenzene-1-sulfonyl chloride (02618-1)

Chlorosulfonic acid (2 mL) was slowly added to a solution of 1-bromo-2-ethoxybenzene (1 g, 5.00 mmol) in DCM (10 mL) at -5°C. The mixture was then stirred at room temperature for 2 hours. After the starting material was consumed, ice water (50 mL) was added and the mixture was extracted twice with DCM (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the product as a yellow oil (1.31 g, 88% yield).

ESI-MS m/z calcd for[C ₈ H ₈ BrClO ₃ S][M+H] ⁺ :298.9; found:298.8

2.2

1-((3-Bromo-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine (02618-2)

To a solution of 3-bromo-4-ethoxybenzene-1-sulfonyl chloride (1.31 g, 4.38 mmol) and 1-methylpiperazine (438 mg, 4.38 mmol) in acetone (15 mL) was added TEA (885 mg, 8.76 mmol), and the reaction solution was stirred at room temperature for 3 hours. After the starting material was consumed, water (30 mL) was added to the mixture, and the mixture was extracted twice with EA (30 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0/1 to 1/10, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a yellow solid product (1.37 g, yield 87%).

ESI-MS m/z calcd for[C ₁₃ H ₁₉ BrN ₂ O ₃ S][M+H] ⁺ :363.0; found:362.8

2.3

2-Ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenol (02618-3)

To a solution of 1-((3-bromo-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine (200 mg, 0.55 mmol) in 1,4-dioxane/water (5 mL, v/v=4/1) were added KOH (62 mg, 1.10 mmol), tBu-Xphos (23 mg, 0.055 mmol) and _Pd2 (dba) ₃ (50 mg, 0.055 mmol). The reaction solution was stirred at 80°C under microwave conditions for 1 hour. After the starting material was consumed, water (30 mL) was added to the mixture, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0/1 to 1/10, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a white solid product (131 mg, yield 79%).

ESI-MS m/z calcd for[C ₁₃ H ₂₀ N ₂ O ₄ S][M+H] ⁺ :301.1; found:300.9

2.4

tert-Butyl 3-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)azetidine-1-carboxylate (02618-4)

To a solution of 2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenol (70 mg, 0.23 mmol) and tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (76 mg, 0.23 mmol) in DMF (3 mL) was added Cs ₂ CO ₃ at room temperature. (152 mg, 0.47 mmol). The mixture was then stirred at 80°C for 2 hours, followed by addition of water (20 mL) and extraction twice with EA (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0/1 to 1/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (98 mg, 92% yield).

ESI-MS m/z calcd for[C ₂₁ H ₃₃ N ₃ O ₆ S][M+H] ⁺ :456.2; found:455.8

2.5

(R)-2-(3-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02618)

A solution of tert-butyl 3-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)azetidine-1-carboxylate (30 mg, 0.06 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (19 mg, 0.06 mmol) in HFP (2 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (12.05 mg, yield 30%).

ESI-MS m/z calcd for[C ₂₇ H ₃₈ N ₆ O ₆ S ₂ ][M+H] ⁺ :607.2; found:606.7

¹ H NMR (400MHz, DMSO-d ₆ )δ7.48(s,1H),7.35(dd,J＝8.4,2.0Hz,1H),7.24(d,J＝8.8Hz,1H),6.95(d,J＝2.4Hz,1H),5.2 3–5.18(m,1H),4.85(t,J＝5.6Hz,1H),4.44(dd,J＝10.0,6.4Hz,2H),4.15(q,J＝6.8Hz,2H),4. 05–3.85(m,2H),3.72–3.65(m,2H),3.46–3.35(m,1H),3.25–3.18(m,1H),2.98–2.85(m,6H), 2.39–2.26(m,6H),2.15(s,3H),2.14–2.08(m,2H),1.82–1.67(m,2H),1.37(t,J=7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

4-(4-Methylpiperazin-1-yl)phenol (02627-1)

To a solution of 4-(piperazin-1-yl)phenol (150 mg, 0.84 mmol) in MeCN (2 mL) at 0°C were added acetic acid (0.5 mL), aqueous HCHO (37%, 126 mg, 4.21 mmol), and _NaBH₃CN (106 mg, 1.68 mmol). The mixture was slowly warmed to room temperature and stirred overnight until the starting material was consumed. The mixture was quenched with saturated aqueous _NH₄Cl (20 mL) at 0°C and extracted three times with EA (15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-100%, 12 g silica gel-CS, 15 mL/min, silica gel, UV 254) to afford the product as a white solid (103 mg, 64% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₆ N ₂ O][M+H] ⁺ :193.1; found:193.0

2.2

tert-Butyl 3-(4-(4-methylpiperazin-1-yl)phenoxy)azetidine-1-carboxylate (02627-2)

To a solution of 4-(4-methylpiperazin-1-yl)phenol (103 mg, 0.53 mmol) in DMF (3 _mL ) and _Cs2CO3 (345 mg, 1.06 mmol) was added tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (175 mg, 0.53 mmol). The reaction mixture was stirred at 80°C for 2 hours, after which the solvent was removed by distillation under reduced pressure. Water (50 mL) was added, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0-50%, silica gel-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product as a yellow solid (87 mg, 47% yield).

ESI-MS m/z calcd for[C ₁₉ H ₂₉ N ₃ O ₃ ][M+H] ⁺ :348.2; found:348.0

2.3

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-(4-(4-methylpiperazin-1-yl)phenoxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02627)

A solution of tert-butyl 3-(4-(4-methylpiperazin-1-yl)phenoxy)azetidine-1-carboxylate (30 mg, 0.08 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (25 mg, 0.08 mmol) in HFP (2 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (3.52 mg, yield 8%).

ESI-MS m/z calcd for[C ₂₅ H ₃₄ N ₆ O ₃ S][M+H] ⁺ :499.2; found:499.2

¹ H NMR (400MHz, DMSO-d ₆ )δ7.45(s,1H),6.91–6.87(m,2H),6.77–6.74(m,2H),5.04–5.00(m,1H),4.85(t,J＝ 5.6Hz,1H),4.41(dd,J＝9.6,6.4Hz,2H),3.95–3.84(m,2H),3.70–3.67(m,2H),3.45 –3.36(m,1H),3.25–3.17(m,1H),3.01(t,J＝5.2Hz,4H),2.96–2.84(m,2H),2.44(t, J＝4.8Hz,4H),2.38–2.25(m,2H),2.21(s,3H),2.14–2.10(m,2H),1.79–1.68(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

Benzyl 3-((2-ethylisoindolin-5-yl)oxy)azetidine-1-carboxylate (02630-1)

At 0°C, to a solution of NaH (60%, 22.0 mg, 0.54 mmol) in DMF (3.0 mL) was added benzyl 3-(isoindoline-5-oxy)azetidine-1-carboxylate (88.0 mg, 0.27 mmol), and the reaction was stirred at 0°C under argon protection for 0.5 hours. Then, a solution of EtI (92.3 mg, 0.54 mmol) in DMF (1 mL) was added and stirred at room temperature for 3 hours. The reaction was quenched with water (10 mL) and extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0-1/10, silica gel-CS 12 g, 30 mL/min, UV 254) to give a colorless oily product (28.0 mg, yield 29.3%).

ESI-MS m/z calcd for[C ₂₁ H ₂₄ N ₂ O ₃ ][M+H] ⁺ :353.2; found:353.0.

2.2

5-(Azetidin-3-oxy)-2-ethylisoindoline (02630-2)

To a solution of benzyl 3-((2-ethylisoindolin-5-yl)oxy)azetidine-1-carboxylate (28.0 mg, 0.08 mmol) in EA (5.0 mL) was added Pd/C (5.0 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours, then filtered through celite, and the filtrate was distilled under reduced pressure to give the product as a colorless oil (20.0 mg, 100.0% yield).

ESI-MS m/z calcd for[C ₁₃ H ₁₈ N ₂ O][M+H] ⁺ :219.1; found:219.2

2.3

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-((2-ethylisoindolin-5-yl)oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02630)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (26.3 mg, 0.092 mmol) in DMF (3 mL) were added 5-(azetidin-3-oxy)-2-ethylisoindoline (20.0 mg, 0.092 mmol) and DIEA (100.8 mg, 0.78 mmol). The mixture was then stirred at 100°C for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN/ _H₂O (10 mmol/L _{NH₄HCO₃ )} , X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (8.0 mg, 18.6% yield).

ESI-MS m/z calcd for[C ₂₄ H ₃₁ N ₅ O ₃ S][M+H] ⁺ :470.2; found:470.0

¹ H NMR (400MHz, DMSO-d ₆ )δ7.46(s,1H),7.15(d,J＝8.4Hz,1H),6.76(d,J＝2.0Hz,1H),6.68(dd,J＝8.4,2.4Hz,1H ),5.10–5.05(m,1H),4.88(t,J＝15.6Hz,1H),4.46–4.42(m,2H),3.90–3.89(m,2H),3.7 7(d,J＝5.6Hz,4H),3.72–3.66(m,2H),3.26–3.14(m,2H),2.97–2.85(m,2H),2.69–2.64 (m,2H),2.37–2.24(m,2H),2.15–2.10(m,2H),1.79–1.68(m,2H),1.09(t,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

4-(Pyrrolidin-1-ylmethyl)phenol (02644-1)

To a solution of pyrrolidine (200 mg, 2.82 mmol) and p-hydroxybenzaldehyde (312 mg, 2.56 mmol) in DCM (10 mL) was added sodium triacetylborohydride (814 mg, 3.84 mmol) in portions at 0°C. The mixture was stirred overnight at room temperature under nitrogen. After the starting material was consumed, ice water (15 mL) was added to the mixture, the pH was adjusted to 9 with sodium bicarbonate, and the mixture was extracted three times with DCM (30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 12 g, 30 mL/min, silica gel, UV 254) to give a white solid product (336 mg, yield 74%).

ESI-MS m/z calcd for[C ₁₁ H ₁₅ NO][M+H] ⁺ :178.1; found:178.2

2.2

tert-Butyl 3-(4-(pyrrolidin-1-ylmethyl)phenoxy)azetidine-1-carboxylate (02644-2)

To a solution of 4-(pyrrolidin-1-ylmethyl)phenol (100 mg, 0.56 mmol) and cesium carbonate (548 mg, 1.68 mmol) in DMF (3 mL) at room temperature was added tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (183 mg, 0.56 mmol). The mixture was then stirred at 80° C. overnight, water (20 mL) was added, and the mixture was extracted three times with EA (30 mL). The mixture was combined. The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (EA/PE=0/1~1/4, silica gel-CS20 g, 30 mL/min, silica gel, UV 254) to give a yellow solid product (132 mg, yield 71%).

ESI-MS m/z calcd for[C ₁₉ H ₂₈ N ₂ O ₃ ][M+H] ⁺ :333.2; found:333.2

2.3

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-(4-(pyrrolidin-1-ylmethyl)phenoxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02644)

A solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (26 mg, 0.09 mmol) and tert-butyl 3-(4-(pyrrolidin-1-ylmethyl)phenoxy)azetidine-1-carboxylate (30 mg, 0.09 mmol) in HFP (2 mL) was stirred at 120° C. under microwave conditions for 2 hours. After completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by preparative HPLC (MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) to give the product as a white solid (10.4 mg, 23.9% yield).

ESI-MS m/z calcd for[C ₂₅ H ₃₃ N ₅ O ₃ S][M+H] ⁺ :484.2; found:483.8

¹ H NMR (400 MHz, DMSO-d ₆ )δ7.46(s,1H),7.22(d,J＝8.4Hz,2H), 6.81(d,J＝8.4Hz,2H), 5.11–5.06(m ,1H),4.84(t,J＝5.6Hz,1H),4.44(dd,J＝10.0,6.4Hz,2H),3.91(br,2H),3 .69(d,J＝7.2Hz,2H),3.49(s,2H),3.43–3.37(m,1H),3.25–3.17(m,1H),2 .97–2.84(m,2H),2.39–2.25(m,6H),2.15–2.09(m,2H),1.79–1.65(m,6H).

1. Synthesis scheme:

2. Experimental part:

2.1 4-((4-Methylpiperazin-1-yl)methyl)phenol (02645-1)

To a solution of p-hydroxybenzaldehyde (200 mg, 1.64 mmol) in DCE (5 mL) at 0°C were added N-methylpiperazine (164 mg, 1.64 mmol) and sodium acetate borohydride (521 mg, 3.07 mmol). The mixture was stirred at room temperature under nitrogen for 4 hours. After the starting material was consumed, water (20 mL) was added to the mixture and extracted three times with EA (50 mL). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/EA = 0/1 to 10/1, silica gel-CS12 g, 25 mL/min, silica gel, UV 254) to give a colorless oily product (156 mg, yield 46%).

ESI-MS m/z calcd for[C ₁₂ H ₁₈ N ₂ O][M+H] ⁺ :207.1; found:207.3

2.2

tert-Butyl 3-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)azetidine-1-carboxylate (02645-2)

To a solution of 4-((4-methylpiperazin-1-yl)methyl)phenol (150 mg, 0.73 mmol) in DMF (5 mL) were added tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (238 mg, 0.73 mmol) and cesium carbonate (475 mg, 1.46 mmol). The mixture was stirred at 70°C under nitrogen for 2 hours. After the starting material was consumed, it was concentrated. The crude product was purified by reverse phase purification _[ MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to obtain The product was a light yellow oil (44 mg, 17% yield).

ESI-MS m/z calcd for[C ₂₀ H ₃₁ N ₃ O ₃ ][M+H] ⁺ :362.2; found:361.9

2.3(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(3-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02645)

To a solution of tert-butyl 3-(4-((4-methylpiperazin-1-yl)methyl)phenoxy)azetidine-1-carboxylate (44 mg, 0.21 mmol) in HFIP (3 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (35 mg, 0.21 mmol). The mixture was stirred at 120° C. for 2 hours under nitrogen protection under microwave conditions. After the starting material was consumed, the reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give the product as a white solid (3.24 mg, 3% yield).

ESI-MS m/z calcd for[C ₂₆ H ₃₆ N ₆ O ₃ S][M+H] ⁺ :513.3; found:513.0

¹ H NMR (400MHz, CD ₃ OD)δ7.27(d,J＝8.8Hz,2H),6.82(d,J＝8.8Hz,2H),5.11–5.08(m,1H),4.53–4.49(m,2H),4.05–4.03(m,2H),3.95–3.86(m ,2H),3.59–3.53(m,1H),3.48–3.47(m,2H),3.41–3.33(m,1H),3.13–3.05(m,2H),2.60–2.22(m,15H),1.92–1.84(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-6-(4-Bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02651-1)

To a solution of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (500 mg, 2.45 mmol) in MeCN (10 mL) at room temperature were added copper bromide (550 mg, 2.45 mmol) and tert-butyl nitrite (375 mg, 3.67 mmol). The mixture was then stirred at room temperature overnight, ice water (50 mL) was added, and the mixture was extracted twice with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give the product as a yellow solid (370 mg, 56% yield).

ESI-MS m/z calcd for[C ₁₁ H ₁₁ BrN ₂ O][M+H] ⁺ :267.0; found:267.1

2.2

tert-Butyl 5-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (02651-2)

To a solution of (R)-6-(4-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (100 mg, 0.37 mmol) in toluene (3 mL) were added tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (79 mg, 0.37 mmol), t-BuONa (72 mg, 0.75 mmol), BINAP (25 mg, 0.04 mmol) and Pd ₂ (dba) ₃ (36 mg, 0.04 mmol). The reaction solution was stirred at 110°C overnight under argon protection. After the starting material was consumed, water (30 mL) was added to the mixture, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The residue was purified by column chromatography (EA/PE=0/1-1/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (25 mg, yield 17%).

ESI-MS m/z calcd for[C ₂₂ H ₃₀ N ₄ O ₃ ][M+H] ⁺ :399.2; found:398.9

2.3

(5R)-6-(4-(5-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (MX02651)

A solution of tert-butyl 5-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (25 mg, 0.06 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (18 mg, 0.06 mmol) in HFP (2 mL) was stirred at 120° C. under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (2.15 mg, yield 6%).

ESI-MS m/z calcd for[C ₂₈ H ₃₅ N ₇ O ₃ S][M+H] ⁺ :550.3; found:549.7

¹ H NMR (400 MHz, DMSO-d ₆ )δ10.69(s,1H),7.61(d,J＝8.8Hz,2H),7.27(s,1H),6.58(d,J＝9.2Hz,2H),4.8 3(t,J＝5.6Hz,1H),3.82–3.76(m,2H),3.72(d,J＝5.6Hz,2H),3.60–3.51(m,2H) ,3.48–3.33(m,4H),3.06–3.38(m,5H),2.94–2.82(m,2H),2.67–2.59(m,1H),2 .42–2.28(m,2H),2.20–2.12(m,3H),1.81–1.71(m,2H),1.03(d,J＝7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

(R)-tert-Butyl 4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (02652-1)

To a solution of (R)-6-(4-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (70 mg, 0.26 mmol) in 1,4-dioxane/ _H2O (2.4 mL, v/v = 5/1) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (99 mg, 0.32 mmol), potassium carbonate (76 mg, 0.78 mmol) and Pd(dppf) _Cl2 (18 mg, 0.026 mmol). The reaction solution was stirred at 90°C for 3 hours under argon protection. After the starting material was consumed, water (30 mL) was added to the mixture, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE=0/1-1/1, silica gel-CS 20 g, 20 mL/min, silica gel, UV 254) to give a yellow solid product (89 mg, yield 92%).

ESI-MS m/z calcd for[C ₂₁ H ₂₇ N ₃ O ₃ ][M+H] ⁺ :370.2; found:369.9

2.2

(R)-6-(4-(1-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (MX02652)

A solution of (R)-tert-butyl 4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (40 mg, 0.10 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (29 mg, 0.10 mmol) in HFP (2 mL) was stirred at 120 °C under microwave conditions for 2 h. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (10.11 mg, yield 18%).

ESI-MS m/z calcd for[C ₂₇ H ₃₂ N ₆ O ₃ S][M+H] ⁺ :521.2; found:520.6

¹ H NMR (400MHz, DMSO-d ₆ )δ10.96(s,1H),7.76(d,J＝8.4Hz,2H),7.53(d,J＝8.8Hz,2H),7.39(s,1H),6.40–6. 36(m,1H),4.85(t,J＝5.6Hz,1H),4.38–4.36(m,2H),3.99(t,J＝5.2Hz,2H),3.97–3. 75(m,2H),3.47–3.35(m,2H),3.30–3.18(m,1H),2.98–2.84(m,2H),2.73–2.67(m,1 H),2.68–2.66(m,2H),2.43–2.18(m,5H),1.84–1.73(m,2H),1.07(d,J=7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

6-Chloro-1'-methyl-1',2',3',6'-tetrahydro-3,4'-bipyridine (02655-1)

To a solution of 5-bromo-2-chloropyridine (192.4 mg, 1.0 mmol) in 1,4-dioxane/water (6.0 mL, v/v = 5/1) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (223.1 mg, 1.0 mmol), K ₂ CO ₃ (414.6 mg, 3.0 mmol), and Pd(dppf)Cl ₂ (73.1 mg, 0.1 mmol). The mixture was stirred at 85° C. under nitrogen for 4 hours. After complete consumption of the starting material, water (20 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0/1 to 1/10, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a yellow solid product (128.0 mg, yield 61.5%).

ESI-MS m/z calcd for[C ₁₁ H ₁₃ ClN ₂ ][M+H] ⁺ :209.1; found:209.0

2.2

1"-Methyl-1",2",3",5,6,6"-hexahydro-[4,2':5',4"-terpyridine]-1(2H)-carboxylic acid tert-butyl ester (02655-2)

To a solution of 6-chloro-1'-methyl-1',2',3',6'-tetrahydro-3,4'-bipyridine (128.0 mg, 0.615 mmol) in 1,4-dioxane/water (6.0 mL, v/v = 5/1) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (190.3 mg, 0.615 mmol), _K2CO3 (254.0 _mg , 1.845 mmol), and Pd(dppf) _Cl2 (44.0 mg, 0.06 mmol). The mixture was stirred at 85°C under nitrogen for 16 hours. After complete consumption of the starting material, water (20 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH/DCM = 0/1 to 1/10, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a yellow solid product (85.0 mg, yield 39.0%).

ESI-MS m/z calcd for[C ₂₁ H ₂₉ ClN ₃ O ₂ ][M+H] ⁺ :356.2; found:356.0

2.3

(R)-4-((1-(Hydroxymethyl)cyclobutyl)amino)-2-(1″-methyl-1″,2″,3″,5,6,6″-hexahydro-[4,2′:5′,4″-tripyridine]-1(2H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02655)

A solution of (R)-2-chloro-4-((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (29.0 mg, 0.1 mmol) and tert-butyl 1″-methyl-1″,2″,3″,5,6,6″-hexahydro-[4,2′:5′,4″-terpyridine]-1(2H)-carboxylate (36.0 mg, 0.1 mmol) in HFP (3 mL) was stirred at 120° C. under microwave conditions for 2 hours. Water (10 mL) was then added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254) _to give a white solid compound (12.0 mg, yield 24.0%).

ESI-MS m/z calcd for[C ₂₇ H ₃₄ N ₆ O ₂ S][M+H] ⁺ :507.2; found:506.8

¹ H NMR (400MHz, DMSO-d ₆ )δ8.63(d,J＝2.4Hz,1H),7.80(dd,J＝6.0,2.4Hz,1H),7.54(d,J＝8.4Hz,1H),7.38(s,1H),6.79( s,1H),6.29(s,1H),4.86(t,J＝5.6Hz,1H),4.41(s,2H),3.97(t,J＝5.2Hz,2H),3.76–3.75(m,2H ),3.47–3.34(m,1H),3.29–3.18(m,1H),3.02(d,J＝2.8Hz,2H),3.00–2.92(m,1H),2.89–2.84(m ,1H), 2.67–2.56(m,5H), 2.40–2.32(m,3H), 2.28(s,3H), 2.22–2.17(m,2H), 1.83–1.76(m,2H).

1. Synthesis scheme:

2. Experimental part:

2.1

(4-Methoxyphenyl)hydrazine hydrochloride (02656-1)

To a solution of 4-methoxyaniline (4.0 g, 32.52 mmol) in conical HCl/H ₂ O (30 mL, v/v = 1/1) was added NaNO ₂ (2.24 g, 32.52 mmol) at -10°C. The mixture was stirred at -10°C for 45 minutes, and then an aqueous solution of SnCl ₂ .2H ₂ O (14.66 g, 65.04 mmol) was slowly added dropwise. The mixture was stirred at room temperature for another 2 hours, filtered, and the filter cake was washed with ether. It was then dried in vacuo to obtain a brown solid product (2.67 g, 47.1% yield).

ESI-MS m/z calcd for[C ₇ H ₁₀ N ₂ O][M+H] ⁺ :139.1; found:139.3

2.2

Ethyl 1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (02656-2)

To a solution of (4-methoxyphenyl)hydrazine hydrochloride (1 g, 5.75 mmol) in EtOH (20 mL) were added R-1(E)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (2 g, 8.62 mmol), TEA (1.6 mL, 11.5 mmol, HATU (564 mg, 1.49 mmol). The mixture was stirred at 80 ° C for 2 hours. After the starting material was consumed, water (20 mL) was added to the mixture and extracted three times with EA (30 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 40 g, 40 mL/min, silica gel, UV 254) to give a yellow oily product (783 mg, yield 43.4%).

ESI-MS m/z calcd for[C ₁₄ H ₁₃ F ₃ N ₂ O ₃ ][M+H] ⁺ :315.1; found:315.0

2.3

1-(4-Hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (02656-3)

To a solution of ethyl 1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (400 mg, 1.27 mmol) in DCM (10 mL) was added _BBr₃ (0.1 mL). The reaction mixture was stirred at room temperature under nitrogen for 3 hours. After the starting material was consumed, the reaction was quenched with saturated aqueous _NaHCO₃ (20 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/2, Silica Gel-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product as a white solid (304 mg, 90.1% yield).

ESI-MS m/z calcd for[C ₁₁ H ₇ F ₃ N ₂ O ₃ ][M+H] ⁺ :273.0; found:273.0

2.4

N-Ethyl-1-(4-hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (02656-4)

To a solution of 1-(4-hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (200 mg, 0.76 mmol) in DMF (6 mL) were added HATU (433 mg, 1.16 mmol), ethylamine (0.4 mL, 0.92 mmol), and TEA (0.52 mL, 3.80 mmol). The mixture was stirred at room temperature for 2 h. After the starting material was consumed, water (20 mL) was added to the mixture, and the mixture was extracted three times with EA (30 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (EA/PE=0/1~1/1, silica gel-CS20 g, 30 mL/min, silica gel, UV 254) to give a white solid product (94 mg, yield 41.4%).

ESI-MS m/z calcd for[C ₁₃ H ₁₂ F ₃ N ₃ O ₂ ][M+H] ⁺ :300.1; found:300.0

2.5

Tert-Butyl 3-(4-(4-(ethylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)azetidine-1-carboxylate (02656-5)

To a solution of N-ethyl-1-(4-hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (50 mg, 0.17 mmol) in DMF (2 mL) were added tert-butyl 3-(p-toluenesulfonyloxy)azetidine-1-carboxylate (66 mg, 0.20 mmol) and Cs ₂ CO ₃ (111 mg, 0.34 mmol). The mixture was stirred at 80°C for 2 hours. After the starting material was consumed, water (20 mL) was added to the mixture, and the mixture was extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, 20 g silica gel-CS, 30 mL/min, silica gel, UV 254) to afford the product as a white solid (16 mg, 20.7% yield).

ESI-MS m/z calcd for[C ₂₁ H ₂₅ F ₃ N ₄ O ₄ ][M-56+H] ⁺ :399.1; found:399.0

2.6

1-(4-(Azetidin-3-oxy)phenyl)-N-ethyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (02656-6)

To a solution of tert-butyl 3-(4-(4-(ethylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)azetidine-1-carboxylate (16 mg, 0.04 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the crude product was used directly in the next reaction.

ESI-MS m/z calcd for[C ₁₆ H ₁₇ F ₃ N ₄ O ₂ ][M+H] ⁺ :355.1; found:355.0

2.7

(R)-N-Ethyl-1-(4-((1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (MX02656)

To a solution of 1-(4-(azetidin-3-oxy)phenyl)-N-ethyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (10 mg, 0.03 mmol) in DMF (3 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (11 mg, 0.03 mmol) and DIEA (19 mg, 0.15 mmol). The mixture was stirred at 80°C under nitrogen for 2 hours. After the starting material was consumed, the mixture was cooled, added to water (10 mL), and extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] _to give a white solid product (6.56 mg, yield 36.1%).

ESI-MS m/z calcd for[C ₂₇ H ₃₀ F ₃ N ₇ O ₄ S][M+H] ⁺ :606.2; found:605.9

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.51(t,J＝5.2Hz,1H),8.06(s,1H),7.45–7.43(m,3H),7.07–7.03(m,2H),5 .23–5.19(m,1H),4.84(t,J＝5.6Hz,1H),4.52–4.48(m,2H),3.98–3.96(m,2H), 3.74–3.69(m,2H),3.46–3.44(m,1H),3.28–3.14(m,3H),2.98–2.84(m,2H),2 .39–2.56(m,2H),2.16–2.11(m,2H),1.83–1.64(m,2H),1.11(t,J=7.2Hz,3H).

1. Synthesis scheme:

2. Experimental part:

2.1

6-(4-Bromo-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (02660-1)

To a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (314.2 mg, 1.0 mmol) in HBr (10.0 mL, 40% v/v aqueous solution) at 0°C was added aqueous _NaNO₂ (69.0 mg, 1.0 mmol in 0.5 mL of _H₂O ). The reaction was stirred at 0°C under argon for 0.5 hours. _CuBr₂ (223.5 mg, 1.0 mmol) was then added, and the mixture was stirred at 80°C for 2 hours. The reaction was quenched with water (20 mL) and extracted three times with DCM (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA/PE=0/1-1/1, silica gel-CS 20 g, 30 mL/min, UV 254) to give a yellow oily product (340.0 mg, yield 68.0%).

ESI-MS m/z calcd for[C ₁₃ H ₁₁ BrCl ₂ N ₂ O ₂ ][M+H] ⁺ :376.9; found:377.2.

2.2

6-(2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazin-3(2H)-one (02660-2)

To a solution of 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (340.0 mg, 0.9 mmol) in 1,4-dioxane (15.0 mL) were added _{B2Pin2 (} 1143.0 mg, 4.5 mmol), KOAc (441.0 mg, 4.5 mmol), and Pd(dppf) _Cl2 (66.0 mg, 0.09 mmol). The mixture was stirred at 100°C under nitrogen overnight. After the starting material was consumed, the reaction solution was cooled and concentrated under reduced pressure. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, Silica Gel-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product as a brown solid (46.0 mg, 12.0% yield).

ESI-MS m/z calcd for[C ₁₉ H ₂₃ BCl ₂ N ₂ O ₄ ][M+H] ⁺ :425.2; found:425.3

2.3

(R)-6-(2,6-dichloro-4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenoxy)-4-isopropylpyridazin-3(2H)-one (MX02660)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (28.0 mg, 0.1 mmol) in 1,4-dioxane/water (2.5 mL, v/v = 4/1) were added 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazin-3(2H)-one (45.0 mg, 0.1 mmol), K2CO3 (28.0 mg, 0.2 mmol), and Pd(dppf _{) Cl2} (15.0 mg, 0.02 mmol). The mixture was stirred at 90°C under nitrogen for 5 hours. After the starting material was consumed, water (10 mL) was added, and _the mixture was extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/ _H2O (10 mmol/L _NH4HCO3 ), X-Select 10 μm ₁₉ *250 mm, 20 mL/min, UV 254) to give a white solid product (15.0 mg, yield 27.3%).

ESI-MS m/z calcd for[C ₂₄ H ₂₅ Cl ₂ N ₅ O ₄ S][M+H] ⁺ :550.1; found:550.2

¹ H NMR (400MHz, DMSO-d ₆ )δ12.23(s,1H),8.35(s,2H),8.27(s,1H),7.44(s,1H),4.96(t,J＝6.0Hz,1H),3.82–3.78(m,2H),3.70–3.62(m,2H), 3.42–3.35(m,1H),3.09–3.02(m,2H),2.47–2.35(m,2H),2.33–2.26(m,2H),1.89–1.81(m,2H),1.20(d,J＝6.8Hz,6H).

1. Synthesis scheme:

2. Experimental part:

2.1

Tert-Butyl 4-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (02661-1)

To a solution of 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (113.4 mg, 0.3 mmol) in 1,4-dioxane (5 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (111.3 mg, 0.36 mmol), K ₂ CO ₃ (83.0 mg, 0.6 mmol), and Pd(dppf)Cl ₂ (44.0 mg, 0.06 mmol). The mixture was stirred at 100° C. under nitrogen for 3 hours. After the starting material was consumed, water (10 mL) was added, and the mixture was extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA/PE = 0/1 to 1/1, silica gel-CS 20 g, 40 mL/min, silica gel, UV 254) to give a brown solid product (60.0 mg, yield 41.8%).

ESI-MS m/z calcd for[C ₂₃ H ₂ 7Cl ₂ N ₃ O ₄ ][M+H] ⁺ :480.1; found:479.9.

2.2

6-(2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazin-3(2H)-one (02661-2)

To a solution of tert-butyl 4-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (60.0 mg, 0.125 mmol) in DCM (5.0 mL) was added TFA (0.5 mL) and stirred under nitrogen for 5 hours. After the starting material was consumed, the reaction solution was cooled and concentrated under reduced pressure to give a brown solid product (50.0 mg, yield 100.0%).

ESI-MS m/z calcd for[C ₁₈ H ₁₉ Cl ₂ N ₃ O ₂ ][M+H] ⁺ :380.1; found:379.9

2.3

(R)-6-(2,6-dichloro-4-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenoxy)-4-isopropylpyridazin-3(2H)-one (MX02661)

To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (37.4 mg, 0.13 mmol) in DMF (5 mL) were added 6-(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-isopropylpyridazin-3(2H)-one (50.0 mg, 0.13 mmol) and DIEA (1.0 mL). The mixture was then stirred at 100° C. for 3 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN/H ₂ O (10 mmol/L NH ₄ HCO ₃ ), X-Select 10 μm 19*250 mm, 20 mL/min, UV 254] to give a white solid product (35.0 mg, yield 42.7%).

ESI-MS m/z calcd for[C ₂₉ H ₃₂ Cl ₂ N ₆ O ₄ S][M+H] ⁺ :631.2; found:631.2

¹ H NMR (400MHz, DMSO-d ₆ )δ12.19(s,1H),7.66(s,2H),7.39(d,J＝3.6Hz,2H),6.44(s,1H),4.85(t,J＝5.6Hz,1H ),4.40–4.32(m,2H),3.97(t,J＝5.2Hz,2H),3.79–3.71(m,2H),3.47–3.39(m,1H),3.2 8–3.18(m,1H),3.07–3.02(m,1H),3.00–2.92(m,1H),2.90–2.84(m,1H),2.53–2.50(m ,2H),2.45–2.30(m,2H),2.22–2.17(m,2H),1.83–1.73(m,2H),1.19(d,J＝6.8Hz,6H).

The compounds prepared according to the above method or with reference to the above method and their mass spectrometry data are summarized in the following Table 1:

Table 1: Example compounds (numbers omitting the prefix "MX02")

Example 2: PDE4B2/PDE4D2 enzyme activity inhibition experiment

Compounds were tested for inhibition of PDE4B2/4D2 enzyme activity using the FP method. PDE4B2/PDE4D2 enzyme (BPS, Cat: 60042/60040) and substrate (FAM-cyclic AMP) (BPS, Cat: 60200) solutions were prepared in reaction buffer (1× IMAP reaction buffer supplemented with 1 mM DTT, containing 0.1% BSA). Final working concentrations of PDE4B2, PDE4D2, and FAM-cyclic AMP were 0.0075 nM, 0.1 nM, and 100 nM, respectively. The positive control, MX02018 (BI1015550), was used at a starting concentration of 3 μM for PDE4B2/PDE4D2, with three-fold dilutions and a total of 10 doses. Test compounds were also used at a starting concentration of 3 μM for PDE4B2/PDE4D2, with three-fold dilutions and a total of 10 doses.

The stock solution of the test compound was heated and vortexed to mix thoroughly, and a 300 μM starting working solution was prepared. The solution was then serially diluted 3-fold to obtain 10 different final working solutions. All reactions were performed in the dilution source plate. 0.05 μL of compound diluted in 100% DMSO from the Source plate was transferred to a 384-well plate (Corning 4514) by acoustic liquid delivery technology (Echo 655), centrifuged at 1000 rpm for 1 minute, and the final DMSO concentration was 1%; 2.5 μL of PDE4B2/PDE4D2 enzyme solution was transferred to a 384-well reaction plate and centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes; 2.5 μL of substrate (FAM-cyclic adenosine monophosphate) solution was transferred to a 384-well reaction plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes; 15 μL of the binder mixture was transferred to a 384-well reaction plate and centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes; FP signals were read using BMG (PHERAstar FSX), and _IC50 values and nonlinear regression curve fitting were obtained using GraphPad Prism software.

The activity test results of some of the example compounds are summarized in Table 2 below:

Table 2: Activity test results of some example compounds

The above experimental results demonstrate that the disclosed compounds exhibit excellent PDE4B inhibitory activity, with _IC50 values for compounds such as MX02024, MX02156, MX02159, MX02166, MX02355, MX02609, MX02651, MX02652, and MX02655 reaching pmol levels. Furthermore, the above experimental results demonstrate that the novel compounds disclosed exhibit excellent PDE4B/PDE4D selectivity, as shown by the calculation of the _IC50 ratios for PDED2 and PDEB2, as follows:

Example 3: Other target enzyme activity inhibition experiments

3.1 PDE3A/3B enzyme activity inhibition assay

Compounds were tested for inhibition of PDE3A/3B enzyme activity using the FP method. PDE3A (Sino Biological, Cat: 11908-H20B1) and PDE3B (BPS, Cat: 60031) enzymes and substrate (FAM-cyclic AMP) (BPS, Cat: 60200) were prepared in reaction buffer (1× IMAP Reaction Buffer containing 0.1% BSA supplemented with 1 mM DTT). The final concentrations of PDE3A, PDE3B, and FAM-cyclic AMP were 1 nM, 0.3 nM, and 100 nM, respectively. The positive control, cilostamide, was used for PDE3A/3B starting at a concentration of 10 μM, diluted threefold, and used a total of 10 doses. Test compounds were used for PDE3A/3B starting at a concentration of 10 μM, diluted threefold, and used a total of 10 doses. The stock solution of the test compound was heated and vortexed to mix thoroughly. 6 μL of the compound was added to 54 μL of DMSO and mixed evenly to prepare a 1 mM starting working solution. This solution was then serially diluted 3-fold to produce 10 different final working solutions. This reaction was performed in a dilution source plate. Using acoustic liquid delivery technology (Echo 655), 0.05 μL of compound diluted in 100% DMSO from the Source plate was transferred to a 384-well plate (Corning 4514) and centrifuged at 1000 rpm for 1 minute to a final DMSO concentration of 1%. 2.5 μL of PDE3A/3B enzyme solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 10 minutes. 2.5 μL of Sub (FAM-cyclic AMP) solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. 15 μL of the binder mixture was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. FP signals were read using a BMG (PHERAstar FSX). _IC50 values and nonlinear regression curve fitting were obtained using GraphPad Prism software.

3.2 PDE5A1 enzyme activity inhibition assay

Compounds were tested for inhibition of PDE5A1 enzyme activity using the FP method. PDE5A1 (BPS, Cat: 60050) enzyme and substrate (FAM-cyclic GMP) (BPS, Cat: 60201) solutions were prepared in reaction buffer (1× IMAP Reaction Buffer containing 0.1% BSA supplemented with 1 mM DTT). The final concentrations of PDE5A1 and FAM-cyclic GMP were 1 nM and 100 nM, respectively. The positive control, sildenafil citrate, was used at a starting concentration of 1 μM for PDE5A1, diluted 3-fold, and used a 10-dose schedule. Test compounds were used at a starting concentration of 10 μM for PDE5A1, diluted 3-fold, and used a 10-dose schedule. The stock solution of the test compound was heated and vortexed to mix thoroughly. 6 μL of the compound was added to 54 μL of DMSO and mixed evenly to prepare a 1 mM starting working solution. This solution was then serially diluted 3-fold to produce 10 different final working solutions. This reaction was performed in a dilution source plate. Using acoustic liquid delivery technology (Echo 655), 0.05 μL of compound diluted in 100% DMSO from the Source plate was transferred to a 384-well plate (Corning 4514) and centrifuged at 1000 rpm for 1 minute to a final DMSO concentration of 1%. 2.5 μL of PDE5A1 enzyme solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 10 minutes. 2.5 μL of Sub (FAM-cyclic GMP) solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. 15 μL of the binder mixture was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. FP signals were read using a BMG (PHERAstar FSX). _IC50 values and nonlinear regression curve fitting were obtained using GraphPad Prism software.

3.3 PDE1A/2A enzyme activity inhibition assay

Compounds were tested for inhibition of PDE1A/2A enzyme activity using the FP method. PDE1A (BPS, Cat: 60010) and PDE2A (BPS, Cat: 60020) enzymes and substrate (FAM-cyclic AMP) (BPS, Cat: 60201) were prepared in reaction buffer (1× IMAP Reaction Buffer containing 0.1% BSA supplemented with 1 mM DTT). The final concentrations of PDE1A, PDE2A, and FAM-cyclic AMP were 2 nM, 0.5 nM, and 100 nM, respectively. The positive control, Bay 60-7550, was active on PDE1A. The starting concentration for all compounds was 100 μM, diluted 3-fold, and used for 10 doses. The starting concentration for the positive control Bay 60-7550 for PDE2A was 100 nM, diluted 3-fold, and used for 10 doses. The starting concentration for the test compounds for PDE1A/2A was 10 μM, diluted 3-fold, and used for 10 doses. The stock solution of the test compound was heated and vortexed to mix thoroughly. 6 μL of the compound was added to 54 μL of DMSO and mixed thoroughly to prepare a 1 mM starting working solution. This was then serially diluted 3-fold to produce 10 different final working concentrations. All reactions were performed in a dilution source plate. Using acoustic liquid delivery technology (Echo 655), 0.05 μL of compound diluted in 100% DMSO from the Source plate was transferred to a 384-well plate (Corning 4514) and centrifuged at 1000 rpm for 1 minute to a final DMSO concentration of 1%. 2.5 μL of PDE1A/2A enzyme solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 10 minutes. 2.5 μL of Sub (FAM-cyclic AMP) solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. 15 μL of the binder mixture was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. FP signals were read using a BMG (PHERAstar FSX). _IC50 values and nonlinear regression curve fitting were obtained using GraphPad Prism software.

The activity test results of the compounds of the present disclosure are as follows:

Example 4: Tissue distribution experiment

4.1 Animals

4.2 Experimental design

The mice in the fasting group were fasted for 12 hours before administration.

Free feeding was resumed 4 hours after administration.

4.3 Sample collection and analysis

(1) Plasma

Blood collection volume: 0.1mL

Blood collection method: orbital venous plexus

Anticoagulant: EDTA-K ₂

Blood collection time: 30 minutes after administration of MX02058; 30 minutes after administration of MX02473; 1 hour after administration of MX02159

The collected blood samples were transferred to microcentrifuge tubes containing EDTA- _K2 anticoagulant, centrifuged at 4°C and 4000g for 5 min, and the supernatant was collected and stored in a refrigerator at -75°C ± 15°C.

(2) Organization

Tissues collected: brain, heart, liver, lung, kidney, prostate

Tissue collection time points: 30 minutes after administration of MX02058; 30 minutes after administration of MX02473; 1 hour after administration of MX02159. Each tissue was taken out, rinsed with physiological saline, weighed, and then homogenized with 1:4 PBS and stored in a refrigerator at -75℃±15℃.

LC-MS/MS analysis was performed after pretreatment.

4.4 Animal Handling

After the experiment, all animals were euthanized using a _CO2 euthanasia device and placed in a -20°C refrigerator for unified disposal by relevant institutions.

4.5 Experimental Results

The above experimental results are detailed in Table A, which demonstrate that the compounds disclosed herein have specific tissue distribution. For example, compound MX02159 is specifically distributed in liver tissue, with a liver tissue exposure of 3710 ng/g after PO administration (10 mg/kg, mouse), 10 times the plasma concentration and 300 times the brain tissue concentration. This has potential application in the development of liver-targeted oral drugs for liver fibrosis and NASH. Compound MX02473 has significantly higher distribution in kidney and prostate tissue than in other tissues, with very little distribution in brain tissue, suggesting potential application in the development of drugs for kidney and prostate-related diseases.

Example 5: hERG activity test

Cell line: hERG-HEK293

Reagent Information

Patch clamp system instruments and software

Record the liquid used

Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl ₂ ·6H ₂ O, 2 mM CaCl ₂ ·2H ₂ O, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaH ₂ PO ₄ ·2H ₂ O; adjusted to pH 7.4 with NaOH.

Cell culture

HEK-293 cell lines stably expressing hERG potassium channel were used. hERG potassium channel cells were purchased from Creacell (Cat. No.: A-0320).

1) HEK-293 cells stably expressing hERG potassium channel were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at 37°C and 5% CO2.

2) Cell passaging: Remove the old culture medium and wash once with PBS, then add 1 mL of TrypLE ^™ Express solution and incubate at 37°C for about 0.5 min. When the cells detach from the bottom of the dish, add about 5 mL of complete culture medium preheated at 37°C. Gently pipette to dissociate aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance, seed the cells in 6 cm culture dishes at a density of 2.5 × 10 ⁵ cells per dish (final volume: 5 mL).

3) To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

4) Patch clamp assay: Before the test, cells were isolated using TrypLE ^™ Express, 4×10 ³ cells were plated on a coverslip, and cultured in a 24-well plate (final volume: 500 μL). After 18 hours, the assay was performed.

Patch clamp assay

The voltage stimulation scheme for whole-cell patch clamp recording of hERG potassium current is as follows: after the whole-cell seal is formed, the cell membrane voltage is clamped at -80mV. The clamping voltage is depolarized from -80mV to -50mV for 0.5s (as a leakage current detection), then stepped to 30mV for 2.5s, and then quickly restored to -50mV for 4s to stimulate the tail current of the hERG channel. Data collection is repeated every 10s to observe the effect of drugs on the hERG tail current. A 0.5s stimulation of -50mV is used as a leakage current detection. The experimental data are collected by an EPC-10 amplifier (Sutter Instrument) and stored in the Sutter Patch software.

The patch clamp procedure begins by pulling a recording electrode from a glass capillary using a microelectrode puller. The electrode, filled with intracellular fluid, is then placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular fluid and record the electrode resistance (Rpip). The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a GΩ high-resistance seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is performed.

When the hERG current recorded by the whole cell is stable, the drug is administered. After each drug concentration is applied for 5 minutes (or the current is stable), the next concentration is detected. One or more concentrations are detected for each test compound. The coverslip with cells is placed in the recording bath in an inverted microscope. The test compound working solution and the external solution without the compound are administered by gravity perfusion from low concentration to high concentration to flow through the recording bath to act on the cells. At the same time, a peristaltic pump is used for liquid replacement during the recording. The current detected in the external solution without the compound for each cell serves as its own control group. At least two cells are used for each concentration and the test is repeated twice independently. All electrophysiological experiments are performed at room temperature.

Data Analysis

First, the tail current after each drug concentration (Peak tail current _compound ) was normalized to the tail current of the blank solvent-treated control group (Peak tail current _Control ) (Peak tail current _compound /Peak tail current _Control ). Then, the inhibition rate corresponding to each drug concentration was calculated (1-(Peak tail current _compound /Peak tail current _Control ). The mean (Mean), standard deviation (SD), and standard error (SE) of the inhibition rate at each concentration were calculated. Data were expressed as Mean ± SE and saved in Excel. Y = 1/(1 + 10^(( _LogIC50 -X)*HillSlope)). The _IC50 value of each compound was calculated using the above equation, and the concentration-effect curve was fitted nonlinearly, where _IC50 is the half-inhibitory concentration. _IC50 calculation and curve fitting were completed using GraphPad Prism software.

Experimental results

The structure of the control compound BI1015550 is shown below:

The above experimental results show that compared with BI1015550, the compound of the present disclosure has a smaller potential risk of cardiotoxicity.

The above describes the exemplary embodiments of the present disclosure. It should be understood that the scope of protection of this application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of this disclosure shall be included in the scope of protection of this application.

Claims (15)

The compound represented by the following formula H, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug:
in: X ₁ represents a chemical bond, C _1-20 alkylene, O, S, NR _q , S(═O), S(═O) ₂ or C(═O); _Rq is selected from H, halogen, OH, CN, _NO2 , oxo (=O), thioxo (=S), _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, _C3-20 cycloalkyl, C3-20 cycloalkenyl, _C3-20 cycloalkynyl, _C6-20 aryl, _5-20 membered heteroaryl, _3-20 membered heterocyclyl, C1-20 alkyloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, C3-20 cycloalkyloxy, _C3-20 cycloalkenyloxy, _C3-20 cycloalkynyloxy, _C6-20 aryloxy, _5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, _C1-20 alkylthio, _{C2-20 alkenylthio} , C -C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20 arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, C _1-8 -heteroalkyl-C 6-20-aryl-, C _1-8 -heteroalkyl-C _{6-20 -} aryl-, NH ₂ , -C(O)R ₄₁ , -C(O)OR ₄₂ , -OC(O)R ₄₃ , -S(O) ₂ R ₄₄ , -S(O) ₂ OR ₄₅ , -OS(O) _{2 R 46 ,} -P(O)(OR ₄₇ )(OR ₄₈ ); L represents a chemical bond, a C _2-20 alkynyl group or Cy; wherein L can be connected to X ₁ or R _c at any position; Cy represents a 3-20 membered heterocyclic group, a C _6-20 aryl group, or a 5-20 membered heteroaryl group, wherein the 3-20 membered heterocyclic group, the C _6-20 aryl group, or the 5-20 membered heteroaryl group may be optionally fused with a 4-7 membered cycloalkyl group, provided that when the heterocyclic group contains a N atom, the heterocyclic group may be bonded to the carbon atom at the 2-position of the pyrimidine ring in formula H through its N atom or C atom; W represents a chemical bond, CH, O, S, N, -S(O)-, -S(O) ₂ -, -C(O), C _1-6 alkylene, C _2-6 alkenylene, or C _2-6 alkynylene _; R ₂ is selected from the following groups which are absent, H, unsubstituted or optionally substituted with 1, 2 or more R _d1 : C _6-20 aryl, 5-20 membered heteroaryl; R _2′ represents absence, H, halogen, OH, CN, unsubstituted or optionally substituted by 1, 2 or more R _d2 : C _1-20 alkyl, C _2-20 alkenyl, C 2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy, 5-20 membered heteroaryloxy, _{3-20 membered heterocyclyloxy, C 1-20 alkylthio} , C _2-20 alkenylthio, C _2-20 alkynylthio, C C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20 arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH ₂ ; Provided that R ₂ and R _2' are not "absent" at the same time; Alternatively, R ₂ and R _2′ may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _d3 : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, 6-20 membered aryl; _Ra represents H or -XR ₃ ; X represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—; R ₃ represents H, halogen, OH, CN, -CH ₂ CF ₃ , -NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 4} s: C _1-20 alkyl, -C(O)R ₆₁ , -C(O)OR ₆₂ , -OC(O)R ₆₃ , NH ₂ ; R _b represents H or -YR ₄ ; Y represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—; R ₄ represents H, halogen, OH, CN, —CH ₂ CF ₃ , —NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 5} s: C _1-20 alkyl, —C(O)R ₆₁ , —C(O)OR ₆₂ , —OC(O)R ₆₃ , NH ₂ ; The condition is that _Ra and _Rb are not H at the same time; Alternatively, _Ra , _Rb , and the atoms to which they are attached together form the following groups which are unsubstituted or optionally substituted with 1, 2, or more _Rd6 : _C5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl; Each of R _d1 , R _d2 , R _d3 , R _d4 , R _d5 and R _d6 is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), SO, SO ₂ , the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _e : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C -C(O)R ₃₁ , -CH 2 -C(O)R ₃₁ , -C(O)OR ₃₂ , -CH ₂ C(O)OR 32 , -C(O)NHR 32 , -CH ₂ C( _O) NHR 32 , -OC _{(O)R 33 , -S(O) 2 R 34 , -S(O) 2 OR 34 , -C(O)R 35} , -CH 2 -C(O)R ₃₅ , -C(O)OR 36 , -CH ₂ C(O)OR 37 , -C(O)NHR 38 , -CH 2 C(O)NHR 39 , -OC(O)R ₄₀ , -S(O) ₄ R 41 , -S(O) ₄ OR ₄₂ , -C(O)R 42 , -CH _{2 -C} (O)R 43 , -C(O)OR ₄₄ , -C(O)OR 45 , -C(O)NHR ₄₆ , -CH ₂ C(O)NHR ₄₇ , -OC(O)R 48 , -S(O) ₄ R ₄₉ , -S(O) ₄ R ₅₀ , -S(O) ₃₅ , -OS(O) ₂ R ₃₆ , -P(O)(OR ₃₇ )(OR ₃₈ ); Alternatively, when two or more substituents selected from R _d1 , R _d2 , R _d3 , R _d4 , R _d5 , and R _d6 are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2, or more R _e : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each R _c is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _c : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl-OC _6-20 aryl-, 5-20 membered heteroaryl-NC _6-20 aryl-, 5-20 membered heteroaryl-SC _6-20 aryl-, 5-20 membered heteroaryl-CH ₂ -C _6-20 aryl-, C _4-10 cycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkyl and C C _6-20 aryl-, 4-10 membered heterocycloalkenyl and C _6-20 aryl-, C _4-10 cycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkenyl-C 6-20 aryl-, _5-20 membered heteroaryl, C _4-10 cycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl-, C _4-10 cycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl-5-20 membered heteroaryl-, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C -C(O)R ₃₁ , -C(O _{)OR 32 ,} -OC(O)R ₃₃ , -S(O _{) 2} R _{34 , -S (} O _{) 2 OR 35 , -OS ( O ) 2 R 36} , -P(O)(OR ₃₇ )(OR ₃₈ ); m is an integer selected from 1 to 10; Each R _e is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , NH ₂ , oxo (═O), thioxo (═S), O-CONH ₂ , O-CONHR _f , the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _f : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, _{3-20 membered heterocyclyl, C 1-20 alkyloxy} , C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _{3-20 cycloalkyloxy, C 3-20} cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _-6-20 membered heteroaryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C 2-20 alkenylthio, C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, C _1-8 -heteroalkyl-C 6-20-aryl-, C _1-8 -heteroalkyl-C _6-20 -aryl-, NH ₂ , -C(O)R ₄₁ , -C(O)OR ₄₂ , -OC(O)R ₄₃ , -S(O) ₂ R _{44 ,} -S(O) ₂ OR ₄₅ , -OS(O) ₂ R ₄₆ , -P(O)(OR ₄₇ )(OR ₄₈ ); Alternatively, when two or more substituents selected from R _e are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 _or more R _f : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each _Rf is the same or different and is independently selected from H, halogen, OH, CN, _NO2 , oxo (=O), thioxo (=S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more _Rg : _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C _2-20 alkenylthio, C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio _, C _6-20- membered arylthio, 5-20-membered heteroarylthio, 3-20-membered heterocyclylthio, NH ₂ , -C(O)R ₅₁ , -C(O)OR ₅₂ , -OC(O)R ₅₃ , -S(O) ₂ R ₅₄ , -S(O) ₂ OR ₅₅ , -OS(O) ₂ R ₅₆ , -P(O)(OR ₅₇ )(OR ₅₈ ); Alternatively, when two or more substituents selected from R _f are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _g : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each R _g is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, and NH ₂ ; R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ , R ₃₇ , R ₃₈ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ , R ₄₆ , R 47 , R ₄₈ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₆ , R ₅₇ , R ₅₈ are the same or different _and are independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 membered aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, NH ₂ ; The 3-20 membered heterocyclyl represents a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, such as 1, 2, 3, 4, 5 or more heteroatoms independently selected from O, S and N, wherein N and S may be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) ₂ -; The C _6-20 aryl group represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, or spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together; The 5-20 membered heteroaryl group represents a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1, 2, 3, 4, 5 or more heteroatoms independently selected from N, O and S. For example, a compound represented by the following formula G, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug:
in: Cy represents a chemical bond, a 3-20 membered heterocyclic group, a C _6-20 aryl group, or a 5-20 membered heteroaryl group, provided that when the heterocyclic group contains a N atom, the heterocyclic group can be bonded to the carbon atom at the 2-position of the pyrimidine ring in formula G through its N atom or C atom; W represents a chemical bond, CH, O, S, N, -S(O)-, -S(O) ₂ -, -C(O), C _1-6 alkylene, C _2-6 alkenylene, or C _2-6 alkynylene _; R ₂ is selected from the following groups which are absent, H, unsubstituted or optionally substituted with 1, 2 or more R _d1 : C _6-20 aryl, 5-20 membered heteroaryl; R _2′ represents absence, H, halogen, OH, CN, unsubstituted or optionally substituted by 1, 2 or more R _d2 : C _1-20 alkyl, C _2-20 alkenyl, C 2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy _{, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C 1-20 alkylthio} thio group, a C _2-20 alkenylthio group, a C _2-20 alkynylthio group, a C _3-20 cycloalkylthio group, a C _3-20 cycloalkenylthio group, a C _3-20 cycloalkynylthio group, a C _6-20 arylthio group, a 5-20 membered heteroarylthio group, a 3-20 membered heterocyclylthio group, and NH ₂ ; Provided that R ₂ and R _2' are not "absent" at the same time; Alternatively, R ₂ and R _2′ may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _d3 : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, 6-20 membered aryl; _Ra represents H or -XR ₃ ; X represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—; R ₃ represents H, halogen, OH, CN, -CH ₂ CF ₃ , -NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 4} s: C _1-20 alkyl, -C(O)R ₆₁ , -C(O)OR ₆₂ , -OC(O)R ₆₃ , NH ₂ ; R _b represents H or -YR ₄ ; Y represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—; R ₄ represents H, halogen, OH, CN, —CH ₂ CF ₃ , —NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 5} s: C _1-20 alkyl, —C(O)R ₆₁ , —C(O)OR ₆₂ , —OC(O)R ₆₃ , NH ₂ ; The condition is that _Ra and _Rb are not H at the same time; Alternatively, _Ra , _Rb , and the atoms to which they are attached together form the following groups which are unsubstituted or optionally substituted with 1, 2, or more _Rd6 : _C5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl; Each of R _d1 , R _d2 , R _d3 , R _d4 , R _d5 and R _d6 is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _e : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, _{3-20 membered heterocyclyl, C 1-20 alkyloxy} , C _2-20 alkenyloxy, C _2-20 alkynyloxy, C 3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _-C6-20 membered aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C1-20 alkylthio, _C2-20 alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, _3-20 membered heterocyclylthio, NH2, -C(O)R31, _-CH2-C (O) _R31 , -C(O)OR32, _-CH2C (O) _OR32 , -C(O) _{NHR32 , -CH2C} (O) _{NHR32 , -OC(O)R33, -S(O)2R34 , -S (} O _{) 2OR35} , -OS(O) ₂ R ₃₆ , -P(O)(OR ₃₇ )(OR ₃₈ ); Alternatively, when two or more substituents selected from R _d1 , R _d2 , R _d3 , R _d4 , R _d5 , and R _d6 are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2, or more R _e : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each R _c is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _c : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, _3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C _-C2-20 membered alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O) _{R31 ,} -C(O) _OR32 , -OC(O) _R33 , -S(O) _2R34 , -S(O) _2OR35 , _-OS (O) _2R36 , -P(O)( _{OR37 )} ( _OR38 ) _; m is an integer selected from 1 to 10; Each R _e is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _f : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, _3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C _-C2-20 alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O) _R41 , -C(O) _{OR42 ,} -OC(O) _R43 , -S(O) _{2R44 ,} -S(O) _{2OR45 ,} - OS(O) ₂ R ₄₆ , -P(O)(OR ₄₇ )(OR ₄₈ ); Alternatively, when two or more substituents selected from R _e are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 _or more R _f : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each _Rf is the same or different and is independently selected from H, halogen, OH, CN, _NO2 , oxo (=O), thioxo (=S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more _Rg : _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, _C3-20 cycloalkyl, _C3-20 cycloalkenyl, _C3-20 cycloalkynyl, C6-20 aryl, _5-20 membered heteroaryl, _{3-20 membered} heterocyclyl, C1-20 alkyloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, _C3-20 cycloalkyloxy, _C3-20 cycloalkenyloxy, C3-20 cycloalkynyloxy, C6-20 aryloxy, _5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, _C1-20 alkylthio, C _-C2-20 membered alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O) _{R51 ,} -C(O) _OR52 , -OC(O) _R53 , -S(O) _2R54 , -S(O) _2OR55 , _-OS (O) _2R56 , -P(O)( _{OR57 )} ( _OR58 ) _; Alternatively, when two or more substituents selected from R _f are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _g : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each R _g is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, and NH ₂ ; R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ , R ₃₇ , R ₃₈ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ , R ₄₆ , R 47 , R ₄₈ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₆ , R ₅₇ , R ₅₈ are the same or different _and are independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 membered aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, NH ₂ ; The 3-20 membered heterocyclyl represents a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, such as 1, 2, 3, 4, 5 or more heteroatoms independently selected from O, S and N, wherein N and S may be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) ₂ -; The C _6-20 aryl group represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, or spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together; The 5-20 membered heteroaryl group represents a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1, 2, 3, 4, 5 or more heteroatoms independently selected from N, O and S; Preferably, the cycloalkyl group may be saturated or partially saturated; Preferably, the compound does not contain compounds selected from the following compounds and/or their stereoisomers and/or their racemates:

The compound represented by formula G according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound represented by formula G is selected from the compounds represented by formula I, II, III, IV, V, VI, VII or VIII:

The compound according to claim 2, its racemate, stereoisomer, tautomer, isotope-labeled product, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound of formula I has the following definition:
in: W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl; X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^{1.3 ,} CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-20- aryl and substituted by a substituent in NR ^1.2 R ^1.3 ; Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR ^1.1 , CH ₂ COOR 1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 20-} aryl and NR ^1.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; The heteroaryl ring is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10- alkyl and C _6-20- aryl substituents, R ^1.2 and R ^1.3 independently of one another represent H or a radical selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by one, two or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 , or R ₂ represents hydrogen, a mono- or polycyclic C _6-20- aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which may in turn be optionally substituted by 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 . Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 20-} aryl and NR ^2.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20- aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci- ₆ -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic C6-20 _- aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20- aryl substituents; R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 , or R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. Alternatively, R ₂ and R _2' together with the atoms to which they are attached form a 4- an 11-membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocycle, which is unsubstituted or optionally substituted in the ortho, para or meta position by one, two or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^{2.1 , SO—R 2.1 ,} C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH═CHCOOR ^2.1 , CO—NR ^2.1 CH ₂ CO—NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _{3- 10} -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _6-20- aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroarylC _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _6-20- aryl and NR ^2.2 R ^2.3 ; R ₃ represents H, C _1-6 -alkyl, F, chlorine, bromine, hydroxy, -CN, -CH ₂ CN, -CH ₂ COOR, -COOR, -CO-NH(CH ₃ )C _1-3 -fluoroalkyl, (C _1-6 -alkyl)-OH, (C _1-6 -alkyl)-OCH ₃ , (C _1-6 -alkyl)-NH ₂ , (C _1-6 -alkyl)-N(C _1-3 -alkyl) or (C _1-6 -alkyl)-NH; R _3′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-20- aryl, C _6-20- aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, where R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more groups selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. Alternatively, R ₃ and R _3′ together represent oxo, methylene, ethylene and propylene, which may be optionally substituted by substituents selected from —CH ₃ , —OH, —F, —CF ₃ , —CHF ₂ , —CH ₂ F, —NH ₂ , —NH(C _1-3 -alkyl), —N(C _1-3 -alkyl) ₂ and O—(C _1-3 -alkyl); R ₄ represents H, C _1-6 -alkyl, F, chlorine, bromine, hydroxy, -CN, -CH ₂ CN, -CH ₂ COOR, -COOR, -CO-NH(CH ₃ )C _1-3 -fluoroalkyl, (C _1-6 -alkyl)-OH, (C _1-6 -alkyl)-OCH ₃ , (C _1-6 -alkyl)-NH ₂ , (C _1-6 -alkyl)-N(C _1-3 -alkyl) or (C _1-6 -alkyl)-NH; R _4′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-20- aryl, C _6-20- aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, where R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more groups selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. Alternatively, R ₄ and R _4′ together represent oxo, methylene, ethylene and propylene, which may be optionally substituted by substituents selected from —CH ₃ , —OH, —F, —CF ₃ , —CHF ₂ , —CH ₂ F, —NH ₂ , —NH(C _1-3 -alkyl), —N(C _1-3 -alkyl) ₂ and O—(C _1-3 -alkyl); R ₅ , R ₆ independently represent H, F, C _1-6 -alkyl, C _1-3 -fluoroalkyl, C _1-6 -alkyl-OH, C _1-6 -alkenyl-OCH ₃ , C _1-6 -alkyl-NH ₂ , C _1-6 -alkynyl-NH(C _1-3 -alkyl) and C _1-6 -alkyl-N(C _1-3 -alkyl) ₂ ; Alternatively, R ₁ and R ₃ together with the C- and N-atoms of piperidine form a saturated or partially saturated 5- or 7-membered heterocyclic group containing two or three nitrogen atoms, which may be optionally substituted by a group selected from -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 -alkyl), Alternatively, R ₃ and R ₆ together form a bridged ring of methylene, ethylene and propylene, which may be optionally substituted with a group selected from -CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 alkyl); Alternatively, R ₃ and R ₅ together form a bridged ring of methylene, ethylene and propylene, which may be optionally substituted with a group selected from -CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 alkyl); Alternatively, R ₃ and R ₄ together form a bridged ring of methylene, ethylene and propylene, which may be optionally substituted with a group selected from -CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 alkyl); Alternatively, R ₄ and R ₆ together form a bridged ring of methylene, ethylene and propylene, which may be optionally substituted with a group selected from -CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₂ F, -NH ₂ , -NH(C _1-3 -alkyl), -N(C _1-3 -alkyl) ₂ and O-(C _1-3 alkyl); Alternatively, _R4 and _R7 together with the carbon atom to which they are attached form a double bond. For example, examples of R ₁ can be selected from the following groups:

For example, examples of -WR ₂ R _2' can be selected from the following groups:




The compound according to claim 2, its racemate, stereoisomer, tautomer, isotope-labeled product, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound of formula II has the following definition:
in: W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl; X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^{1.3 ,} CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic C _6-20- aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20-membered heterocyclyl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-20- aryl and substituted by a substituent in NR ^1.2 R ^1.3 , Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR 1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 10-} aryl and NR ^1.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20- aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10- alkyl and C _5-10 aryl substituents; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH—CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^1.1 ; R ₂ represents hydrogen, a mono- or polycyclic C _6-20- aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ; Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH═CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _{1-3 -alkyl} -OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted with one, two or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20- aryl and NR ^2.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20- aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci- ₆ -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic C6-20 _- aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20- aryl substituents; R ^2.2 and R ^2.3 independently of one another represent H or a radical selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _5-10 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, a 3-20-membered heterocycle, a heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by one, two or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 , or R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-20- aryl, C _6-20- aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. or, R ₂ and R _2′ together form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, R ₃ represents a group selected from aryl and heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F groups, or is optionally substituted by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR 1.1 , SO-R ^1.1 , C 1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl- ^SO _{2 R} ^1.1 , _COOR ^1.1 , CH ₂ COOR ^1.1 , CH 2 _{CH 2} COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _{6-20 -} aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _6-20- aryl and NR ^1.2 R ^2.3 substituted by one, two or more substituents; _R4 represents a group selected from aryl and heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or is optionally substituted by one, two or more groups selected from ^OR1.1 , _C1-3 -alkyl- ^OR1.1 , ^SR1.1 , _C1-3 - ^alkyl - ^SR1.1 _, SO-R1.1, _C1-3 -alkyl- ^SOR1.1 , SO2 _- ^R1.1 , _C1-3 - _{alkyl - SO2R1.1} ^{, COOR1.1 , CH2COOR1.1} , ^{CH2CH2COOR1.1} , CH＝CHCOOR1.1, CO- ^NR1.1 , _CH2CO - ^NR1.1 , _{CH2CH2CO -} NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-20- aryl and NR ^1.2 R ^2.3 ; Ring A represents a chemical bond, a mono- or polycyclic C _6-20- aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three independent groups selected from fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ , or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(mono- or polycyclic-C _1.2 R 1.3, each of which may _{in turn be optionally substituted with one, two or more substituents selected from the group consisting of OH, OR 1.1 , oxo} , halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10 -aryl, _3-20 -membered heterocyclyl-C _1-6 -alkyl, 5-20 _- membered heteroaryl ^- C _{1-6 -} alkyl, C ^6-10 -aryl, SO ₂ —CH ₃ , SO _{2 —CH 2} CH ₃ and SO _{2 —NR} ^1.2 R ^1.3 _. The substituents in ^1.3 are substituted, or, Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20- aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-20- aryl and NR ^1.2 R ^1.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20- aryl, 5-20-membered heteroaryl and heterocycle, which may optionally be selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10- alkyl and C _{6-20- aryl} ; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 . For example, examples of Ring A can be selected from the following groups:
For example, examples of -WR ₂ R _2' can be selected from the following groups:




For example, examples of -XR ₃ substituents can be selected from the following groups:

The compound according to claim 2, its racemate, stereoisomer, tautomer, isotope-labeled product, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound of formula III has the following definition:
in: W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl; X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); R ₁ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20-membered heterocyclyl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-20- aryl and substituted by a substituent in NR ^1.2 R ^1.3 , Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR 1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6-20- aryl} , C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 10-} aryl and NR ^1.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl substituents; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 , or R ₂ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , substituted by CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20- aryl and a substituent in NR ^2.2 R ^2.3 , Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 ,CH＝CHCO-NR ^2.1 ,COR ^2.1 ,CH ₂ COR ^2.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _{6- 2.1 and} NR _2.2 R _2.3 , each of which may be optionally substituted with one, two or more substituents selected from OH, OR _2.1 ^, oxo, halogen ^, CF _{3 ,} CHF ₂ , CH _{2 F} , C _{1-6 - alkyl} , ^C _6-20 ^- _aryl and NR ^2.2 R ^2.3 _; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally associated heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^2.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10- alkyl and C _6-20 aryl substituents; R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _— CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 , or R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _＝ CHCO- ^{NR 2.1} , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or ^bicyclic C _{3- 10} -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _6-20- aryl and NR ^2.2 R ^2.3 ; Ring A represents a chemical bond, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three independent groups selected from fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ , or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(mono- or polycyclic-C _1.2 R 1.3, each of which may _in turn be optionally substituted with one _, two or more substituents selected from OH, OR _1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _{1-6 -alkyl, C 6-20 aryl} , 3-20 membered heterocyclyl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _{1-6 - alkyl} , C ^6-10 -aryl, SO ₂ —CH ₃ , SO _{2 —CH 2 CH 3 and} SO _{2 —NR} ^1.2 R ^{1.3 .} Substitution by substituents in ^1.3 ; Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl, C _1-6 -alkyl, C C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclic ^1.2R1.3 , each of which may be optionally substituted with one ^, two or more substituents selected from OH, ^OR1.1 , oxo, _halogen , _CF3 , _CHF2 , ^CH2F , _{C1-6 -} alkyl, _C6-20 ^aryl and ^NR1.2R1.3 _; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 . For example, examples of Ring A may be selected from the following groups:

For example, examples of -WR ₂ R _2' can be selected from the following groups:



The compound of formula G according to claim 2, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound of formula IV has the following definition:
in: W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl; X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); V represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^{1.3 ,} CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-20 aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20 aryl and NR 1.2 R 1.3. ^1.2 R is substituted by a substituent in ^1.3 , Alternatively, R1 represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 , ^SR1.1 , _C1-3 - _alkyl - ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl-SOR1.1 ^, _{SO2-R1.1, C1-3-alkyl-SO2R1.1 ,} ^COOR1.1 _{, CH2COOR1.1} ^{, CH2CH2COOR1.1 ,} _{CH ＝} ^CHCOOR1.1 , CO-NR1.1 ^, CH2CO _- ^NR1.1 , _CH2CH2CO -NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl, C _1-6 -alkyl, C _6-20 aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _{6- 20} aryl and NR ^1.2 R ^2.3 are substituted by one, two or more substituents; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl substituents; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _— CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 ; or R ₂ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted by 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 , Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _{6- 10-} aryl and NR ^2.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 aryl-Ci _-6 -alkyl, 5-20 membered heteroaryl-Ci- ₆ -alkyl, 3-20 membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci- ₆ -alkyl, mono- or bicyclic _C6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents; R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _— CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^2.1 , or R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _＝ CHCO- ^{NR 2.1} , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or ^bicyclic C _{3- 10} -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _6-20- aryl and NR ^2.2 R ^2.3 ; Ring A represents a chemical bond, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two, or three independent fluorine, chlorine, bromine, hydroxyl, CN, or NH ₂ groups, or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(mono- or polycyclic-C _1.2 R 1.3, each of which may _in turn be optionally substituted with one _, two or more substituents selected from OH, OR _1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10 -aryl, 3-20-membered heterocyclyl-C _1-6 -alkyl, _5-20 -membered heteroaryl- _{C 1-6 -} alkyl ^, C ^6-10 -aryl, SO ₂ —CH ₃ , SO _{2 —CH 2 CH 3} and SO ₂ —NR ^1.2 R ^1.3 _. The substituents in ^1.3 are substituted, or, Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl- _{(monocyclic or polycyclic-C 6-20 aryl), 3-20 membered heterocyclyl-C 6-20 aryl ,} 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and _{C 6-20} aryl; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 . For example, examples of Ring A may be selected from the following groups:
For example, examples of -WR ₂ R _2' can be selected from the following groups:




The compound according to claim 2, its racemate, stereoisomer, tautomer, isotope-labeled product, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound of formula V has the following definition:
in: W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl; X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); V represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); R ₁ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR 1.2 R 1.3. ^1.2 R is substituted by a substituent in ^1.3 ; or, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _{1-3 -alkyl} -SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR ^1.1 , CH ₂ COOR 1.1 , CH 2 CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _{1- 1.1 and} NR _1.2 R 1.3, each of which may be optionally substituted with one, two or more substituents selected from OH, OR _2.1 ^, oxo, halogen, CF _{3 ,} CHF ₂ , ^CH ₂ F _, C _{1-6 -} alkyl, C _{6-10 - aryl} and ^{NR 1.2 R 2.3 ;} Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; wherein R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or _bicyclic , -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and _{C 6-20} aryl substituents; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^1.1 , or R ₂ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which in turn may be optionally substituted by 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 , or, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _{1-3 -alkyl} -SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH 2 CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; wherein R ^2.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or _bicyclic , -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl substituents, R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaryl, CO—NH ₂ , CO—NH _— CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 , or R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. or, R ₂ and R _2′ together form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, Ring A represents a chemical bond, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three independent groups selected from fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ , or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(mono- or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R The substituents in ^1.3 are substituted, or, Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _{6-20 -aryl} , 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may optionally be selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl, R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 . For example, examples of Ring A can be selected from the following groups:
For example, examples of -WR ₂ R _2' substituents may be selected from the following groups:




The compound according to claim 2, its racemate, stereoisomer, tautomer, isotope-labeled form, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound of formula VI has the following definition:
in: W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl; X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^{1.3 ,} CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-10- aryl and substituted by a substituent in NR ^1.2 R ^1.3 , or, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _{1-3 -alkyl} -SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR ^1.1 , CH ₂ COOR 1.1 , CH 2 CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _{1- 2.3} , each of which is optionally substituted by one, two or more substituents selected from OH _{, OR 2.1 , oxo, halogen, CF 3 , CHF 2 ,} ^CH _{2 F , C 1-6 - alkyl} , ^C _{6-10 - aryl} and ^{NR 1.2} R ^{2.3 ;} Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl substituents; R ^1.2 and R ^1.3 independently of one another represent H or a radical selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by one, two or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 , or R ₂ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ ^CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR 2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, a 3-20 membered heterocycle, a C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ; Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 -aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci _-6 -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic _C6-20 aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents; R ^2.2 and R ^2.3 independently represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5- 20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3- to 20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), a radical of CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 ; R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _＝ CHCO- ^{NR 2.1} , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or ^bicyclic C _{3- 10} -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _6-20- aryl and NR ^2.2 R ^2.3 ; Ring A represents a chemical bond, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three independent fluorine, chlorine, bromine, hydroxyl, CN or NH ₂ groups, or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(mono- or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 is substituted by a substituent; or Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _{6-20 -aryl} , 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl; R ^1.2 and R ^1.3 independently represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20 membered heterocycle, heteroaromatic ring, CO-NH ₂ , CO-NH _- CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 groups, which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 aryl and COOR ^1.1 . For example, examples of Ring A can be selected from the following groups:
For example, examples of the -WR ₂ R _2' substituent group may be selected from the following groups:



The compound according to claim 2, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs, wherein the compound of formula VII has the following definition:
in: W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl; X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^{1.3 ,} CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-10- aryl and substituted by a substituent in NR ^1.2 R ^1.3 ; Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR 1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl substituents; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^1.1 ; R ₂ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR 2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^{2.3 ,} CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and the substituents in NR ^2.2 R ^2.3 , Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH═CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R _2.3 substituents, each of which may in turn be optionally substituted with one ^, two or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 -aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci _-6 -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic _C6-20 -aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents; R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, mono- or bicyclic C _6-20- aryl, 3-20-membered heterocycle, heteroaryl, CO—NH ₂ , CO—NH _— CH ₃ , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 , or R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _＝ CHCO- ^{NR 2.1} , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or ^bicyclic C _{3- 10} -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _6-20- aryl and NR ^2.2 R ^2.3 ; A ring represents a chemical bond, a mono- or polycyclic _C6-20 -aryl group, which may be substituted at the ortho, para or meta positions by one, two, or three independent fluorine, chlorine, bromine, hydroxyl, CN, _NH2 groups, or by one, two or more selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C ^1.2 R ^1.3 ; each of which may in turn be optionally substituted by _{1, 2 or more substituents selected from OH, OR 1.1 , oxo, halogen, CF 3 , CHF 2 , CH 2 F , C 1-6 -alkyl , C 6-10 - aryl} -C 1-6 -alkyl, 3-20-membered heterocycle-C ^1-6 -alkyl, 5-20-membered heteroaryl-C _{1-6-alkyl, C 6-10 -aryl} , SO ₂ -CH ₃ , SO ₂ -CH 2 CH 3 and SO 2 -NR ^1.2 R ^1.3 ; or Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _{6-20 -aryl} , 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 . For example, examples of Ring A may be selected from the following groups:

For example, examples of -WR ₂ R _2' groups may be selected from the following groups:



The compound according to claim 2, its racemate, stereoisomer, tautomer, isotope-labeled form, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound of formula VIII has the following definition:
in: W represents CH, O, S, N, S(O), S(O) ₂ or C(O), C _1-2 -alkyl, vinyl or ethynyl; X represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Y represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); Z represents CH ₂ , O, S, NH, S(O), S(O) ₂ or C(O); R ₁ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR 1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^{1.3 ,} CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which substituents may in turn be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C 1-3 -fluoroalkyl, _6-10- aryl and substituted by a substituent in NR ^1.2 R ^1.3 ; Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^{1.1 ,} COOR 1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 -aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci _-6 -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic _C6-20 -aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^1.1 ; R ₂ represents hydrogen, a mono- or polycyclic C _6-20 -aryl group, which may be optionally replaced by one at the ortho, para or meta position, independently of each other, 2.2 R 2.3 ^{, CH 2 -NR 2.2 R 2.3 , CH 2 CH 2 -NR 2.2 R 2.3 , C 3-10 -cycloalkyl, 3-20 membered heterocycle, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CF 3 , CHF 2 , CH 2 F, C 6-10 aryl-C 2.1} _{, C} ² _CH ² _{-NR 2.1} ^, CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 , CH ₂ CH ₂ -NR ^2.2 R ^2.3 , C _3-10 -cycloalkyl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C 2.1 ^2.2 R ^2.3 , each of which may in turn be _optionally substituted by ₁ , 2 or more substituents selected from OH, OR _2.1 ^, oxo, halogen, _{CF 3 , CHF 2 , CH 2 F , C 1-6} -alkyl ^{, C} _{6-10 - aryl} and NR _{2.2 R} ^{2.3 ,} Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three groups selected from halogen, OH, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^{2.1 ,} COOR ^2.1 , CH ₂ COOR 2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, _5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted by OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^2.2 R ^2.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^2.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20 -aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci _-6 -alkyl, 3-20-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic _C6-20 aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C6-20 aryl substituents; R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 3-20-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20 -aryl and COOR ^2.1 ; R _2′ represents H, F, Me, C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10 -aryl, C _6-10 -aryl-C _1-6 -alkyl, C _6-20 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _6-20 -heterocycle, -NR′R″, fluorine, C _1-6- fluoroalkyl and C _1-6- fluoroalkoxy, wherein R′ and R″ are independently selected from H and C _1-6- alkyl; said groups may in each case be optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl. Alternatively, R ₂ and R _2′, taken together with the atoms to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocyclic ring being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO—R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ —R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH _＝ CHCO- ^{NR 2.1} , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or ^bicyclic C _{3- 10} -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _{6-20 -} aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _6-20- aryl and NR ^2.2 R ^2.3 ; R ₄ represents a group selected from aryl and heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three halogen, OH, oxo, CF ₃ , CHF ₂ and CH _{2 F groups, or optionally substituted at the ortho, para or meta position by one, two or more halogen, OH, oxo, CF 3 , CHF 2 and CH 2} F groups. ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^1.1 , COOR ^1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, _{C 6-10} -aryl, C _1-6 -alkyl, C _6-10 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6- alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20-membered heterocyclyl-C _6-20 -aryl, 3-20-membered heterocycle, 5-20-membered heteroarylC _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted with one, two or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^2.3 ; Ring A represents a chemical bond, a mono- or polycyclic C _6-20 -aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three independent groups selected from fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ , or by one, two or more groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _3-10 -cycloalkyl, C _{1- 3} -alkyl-(mono- or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _6-20 -aryl, 3-20 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-10 aryl-C _1-6 -alkyl, 3-20 membered heterocyclyl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^1.2 R ^1.3 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 is substituted by a substituent; or Ring A represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three groups selected from halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more groups selected from ^{OR1.1 ,} _C1-3 -alkyl- ^OR1.1 _, ^SR1.1 , _C1-3 -alkyl- ^SR1.1 , SO- ^R1.1 , _C1-3 -alkyl- ^SOR1.1 , _{SO2 -} ^R1.1 , _{C1-3 -} alkyl-SO2R1.1, ^COOR1.1 , ^CH2COOR1.1 , ^{CH2CH2COOR1.1} , CH _{＝ CHCOOR1.1} , CO- ^NR1.1 , _CH2CO - ^NR1.1 , _CH2CH2CO ^{- NR1.1} ,CH＝CHCO-NR ^1.1 ,COR ^1.1 ,CH ₂ COR ^1.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-10 -aryl, C _1-6 -alkyl, C _6-10 -aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 -aryl), 3-20 membered heterocyclyl-C _{6-20 -aryl} , 3-20 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by a substituent selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by one, two or more substituents selected from _1-6- alkyl, C _6-10- aryl and NR ^1.2 R ^1.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 -alkyl, 3-20 membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10 -alkyl and C _6-20 aryl; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20 aryl, 3-20-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 . For example, examples of Ring A can be selected from the following groups:

For example, examples of -WR ₂ R _2' groups may be selected from the following groups:




The compound according to claim 2, its racemate, stereoisomer, tautomer, isotope-labeled form, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound of formula IX has the following definition:
in: X ₁ represents a chemical bond, C _1-20 alkylene, O, S, NR _q , S(═O), S(═O) ₂ or C(═O); U represents -(CH ₂ ) _t -, O, S, NR _q , S(═O), S(═O) ₂ or C(═O), wherein t represents 0, 1, 2 or 3; _Rq is selected from H, halogen, OH, CN, _NO2 , _NH2 , oxo (=O), thioxo (=S), C1-20 alkyl, _C2-20 alkenyl, C2-20 alkynyl, _C3-20 cycloalkyl, _C3-20 cycloalkenyl, _C3-20 cycloalkynyl, _C6-20 aryl, _5-20 membered heteroaryl, 3-20 membered heterocyclyl, _C1-20 alkyloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, _C3-20 cycloalkyloxy, _C3-20 cycloalkenyloxy, _C3-20 cycloalkynyloxy, _C6-20 aryloxy, _5-20 membered heteroaryloxy, 3-20 membered _{heterocyclyloxy} , _C1-20 alkylthio, C _-C2-20 alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, _3-20 membered heterocyclylthio, C1-8-heteroalkyl- _C6-20 -aryl-, C1-8-heteroalkyl- _C6-20- aryl-, NH2, -C( _{O) R41 ,} -C(O)OR42 _, -OC(O) _{R43 , -S(O)2R44, -S(O)2OR45 , -OS (} O) _2R46 , _-P (O)( _OR47 )( _OR48 ) _; v represents 0, 1, 2, 3, 4, or 5; L represents a chemical bond, a C _2-20 alkynyl group or Cy; wherein L can be connected to X ₁ or R _c at any position; Cy represents a chemical bond, a 3-20 membered heterocyclic group, a C _6-20 aryl group, or a 5-20 membered heteroaryl group, wherein the 3-20 membered heterocyclic group, the C _6-20 aryl group, or the 5-20 membered heteroaryl group may be optionally fused with a 4-7 membered cycloalkyl group, provided that when the heterocyclic group contains a N atom, the heterocyclic group may be bonded to the carbon atom at the 2-position of the pyrimidine ring in formula IX through its N atom or C atom; _Ra represents H or -XR ₃ ; X represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—; R ₃ represents H, halogen, OH, CN, -CH ₂ CF ₃ , -NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 4} s: C _1-20 alkyl, -C(O)R ₆₁ , -C(O)OR ₆₂ , -OC(O)R ₆₃ , NH ₂ ; R _b represents H or -YR ₄ ; Y represents CH ₂ , O, S, NH, —S(O)—, —S(O) ₂ —, or —C(O)—; R ₄ represents H, halogen, OH, CN, —CH ₂ CF ₃ , —NHR _{d 4} , unsubstituted or optionally substituted by 1, 2 or more R _{d 5} s: C _1-20 alkyl, —C(O)R ₆₁ , —C(O)OR ₆₂ , —OC(O)R ₆₃ , NH ₂ ; The condition is that _Ra and _Rb are not H at the same time; Alternatively, _Ra , _Rb , and the atoms to which they are attached together form the following groups which are unsubstituted or optionally substituted with 1, 2, or more _Rd6 : _C5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl; Each of R _d2 , R _d4 , R _d5 , and R _d6 is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), SO, SO ₂ , the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _e : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C C _6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C _2-20 alkenylthio, C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _{3-20 cycloalkynylthio, C 6-20 arylthio} , 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH ₂ , -C(O)R ₃₁ , -CH _{2 -C} (O)R ₃₁ , -C(O)OR ₃₂ , -CH ₂ C(O)OR ₃₂ , -C(O)NHR ₃₂ , -CH ₂ C(O)NHR ₃₂ , -OC(O)R ₃₃ , -S(O) ₂ R ₃₄ , -S(O) ₂ OR ₃₅ , -OS(O) ₂ R ₃₆ , -P(O)(OR ₃₇ )(OR ₃₈ ); Alternatively, when two or more substituents selected from R _d2 , R _d4 , R _d5 , and R _d6 are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2, or more R _e : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each R _c is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _c : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl-OC _6-20 aryl-, 5-20 membered heteroaryl-NC _6-20 aryl-, 5-20 membered heteroaryl-SC _6-20 aryl-, 5-20 membered heteroaryl-CH ₂ -C _6-20 aryl-, C _4-10 cycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkyl and C C _6-20 aryl-, 4-10 membered heterocycloalkenyl and C _6-20 aryl-, C _4-10 cycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkenyl-C 6-20 aryl-, _5-20 membered heteroaryl, C _4-10 cycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl-, C _4-10 cycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl-5-20 membered heteroaryl-, 3-20 membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C -C(O)R ₃₁ , -C(O _{)OR 32 ,} -OC(O)R ₃₃ , -S(O _{) 2} R _{34 , -S (} O _{) 2 OR 35 , -OS ( O ) 2 R 36} , -P(O)(OR ₃₇ )(OR ₃₈ ); For example, the 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl group may be: 1-methylpyrrolidinyl, 1-ethylpyrrolidinyl, 1-cyclopropylpyrrolidinyl, 1-cyclopropylmethylpyrrolidinyl, 5-methyl-4,5-dihydropyridazin-3(2H)-onyl, 1-methylazetidinyl, 1-methylpiperidinyl; m is an integer selected from 1 to 10; Each R _e is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , NH ₂ , oxo (═O), thioxo (═S), O-CONH ₂ , O-CONHR _f , the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _f : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, _{3-20 membered heterocyclyl, C 1-20 alkyloxy} , C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _{3-20 cycloalkyloxy, C 3-20} cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _-6-20 membered heteroaryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C _1-20 alkylthio, C 2-20 alkenylthio, C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, C _1-8 -heteroalkyl-C 6-20-aryl-, C _1-8 -heteroalkyl-C _6-20 -aryl-, NH ₂ , -C(O)R ₄₁ , -C(O)OR ₄₂ , -OC(O)R ₄₃ , -S(O) ₂ R _{44 ,} -S(O) ₂ OR ₄₅ , -OS(O) ₂ R ₄₆ , -P(O)(OR ₄₇ )(OR ₄₈ ); Alternatively, when two or more substituents selected from R _e are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 _or more R _f : C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each _Rf is the same or different and is independently selected from H, halogen, OH, CN, _NO2 , oxo (=O), thioxo (=S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more _Rg : _C1-20 alkyl, _C2-20 alkenyl, _C2-20 alkynyl, _C3-20 cycloalkyl, _C3-20 cycloalkenyl, _C3-20 cycloalkynyl, C6-20 aryl, _5-20 membered heteroaryl, _{3-20 membered} heterocyclyl, C1-20 alkyloxy, _C2-20 alkenyloxy, _C2-20 alkynyloxy, _C3-20 cycloalkyloxy, _C3-20 cycloalkenyloxy, C3-20 cycloalkynyloxy, C6-20 aryloxy, _5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, _C1-20 alkylthio, C _-C2-20 membered alkenylthio, _C2-20 alkynylthio, _C3-20 cycloalkylthio, _C3-20 cycloalkenylthio, _C3-20 cycloalkynylthio, C6-20 arylthio, _5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O) _{R51 ,} -C(O) _OR52 , -OC(O) _R53 , -S(O) _2R54 , -S(O) _2OR55 , _-OS (O) _2R56 , -P(O)( _{OR57 )} ( _OR58 ) _; Alternatively, when two or more substituents selected from _Rf are present on the same group, the two substituents may be taken together with the atoms to which they are attached to form the following groups which are unsubstituted or optionally substituted with 1, 2 or more _Rg : _C3-20 cycloalkyl, _C3-20 cycloalkenyl, _C3-20 Cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each R _g is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, and NH ₂ ; R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ , R ₃₇ , R ₃₈ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ , R _{46 , R 47} , R ₄₈ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₆ , R ₅₇ , R ₅₈ are the same or different _and are independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 membered aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, NH ₂ ; The 3-20 membered heterocyclyl represents a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, such as 1, 2, 3, 4, 5 or more heteroatoms independently selected from O, S and N, wherein N and S may be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) ₂ -; The C _6-20 aryl group represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, or spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together; The 5-20 membered heteroaryl group represents a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1, 2, 3, 4, 5 or more heteroatoms independently selected from N, O and S. According to an embodiment of the present disclosure, L represents an alkynyl group; a mono- or polycyclic C _6-20- aryl group or a mono- or polycyclic C _6-20 -aryl and 4-7 membered cycloalkyl group, which may be optionally substituted at the ortho, para or meta position by one, two, or three independent fluorine, chlorine, bromine, hydroxyl, CN, NH ₂ groups, or 1, 2 or more substituted groups selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , NR ^1.2 R ^1.3 , CH ₂ -NR ^1.2 R ^1.3 , CH ₂ CH ₂ -NR ^1.2 R ^1.3 , C _1-1 , 3-10-membered heterocyclic-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-10- aryl, 3-10-membered heterocyclic-C _1-6 -alkyl, C _1-3 -fluoroalkyl, C 1-3 -alkyl-CN, C _1-3 -alkyl-OH, C _1-3 -alkyl-OR ^1.1 , C _1-3 -alkyl _- NH ₂ , C _1-3 -alkyl-NHR ^1.1 , CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-10-membered heterocyclic-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^1.2 R ^1.3 , each of which may in turn be optionally substituted by one, two or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10 -aryl and NR ^1.2 R ^1.3 , or, L represents a group selected from heterocycle or heteroaryl, which is optionally substituted at the ortho, para or meta position by one, two or three halogen, OH, oxo, _CF3 , _CHF2 and _CH2F , or by one, two or more substituted groups selected from OR ^1.1 , _C1-3 -alkyl-CN, C1-3-alkyl-OH, _C1-3 -alkyl-OR _1.1 , _C1-3 -alkyl-NH2, C1-3-alkyl-NHR _1.1 , _{C1-3 -} alkyl-OR ^1.1 , SR ^1.1 , _C1-3 - ^{alkyl-SR 1.1, SO-R 1.1, C1-3-alkyl-SOR 1.1, SO2-R 1.1 , C1-3 -} _alkyl ^- _SO2 ^R _{1.1 ,} ^{COOR 1.1} , _CH2COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , mono- or bicyclic C _3-10 -cycloalkyl, C _6-20- aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-10 membered heterocyclyl-C _6-20- aryl, 3-10 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by one, two or more substituents selected from OH, OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20 -aryl and NR ^1.2 R ^1.3 ; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; Heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; in some embodiments, L is selected from a 5-membered monocyclic heteroaryl, a 5-membered heteroarylacene ring, a 5-membered heteroaryl and 5-10 membered heteroaryl, a 5-membered heteroaryl and 4-7 membered cycloalkyl, a 5-membered heteroaryl and 4-7 membered heterocycloalkyl, a 6-membered heteroarylacene ring, a 6-membered heteroaryl and 5-10 membered heteroaryl, a 6-membered heteroaryl and 6-membered heteroaryl, a 6-membered heteroaryl and 4-7 membered cycloalkyl, and a 6-membered heteroaryl and 4-7 membered heterocycloalkyl; Cycloalkyl groups may be saturated or partially saturated; R ^1.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, C _3-11 -mono- or bicyclic heterocycle, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, 3-10-membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20- aryl, 5-20-membered heteroaryl and heterocycle, which may optionally be selected from OH, O-(C _1-3 -alkyl), halogen, C _{1-10 -} alkyl and C _6-20- aryl; R ^1.2 and R ^1.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20- aryl, 3-10-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^1.1 and COOR ^1.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^1.1 . According to an embodiment of the present disclosure, examples of L may be selected from the following groups:
According to an embodiment of the present disclosure, each R _d2 is the same or different and independently represents hydrogen, halogen, cyano, hydroxy, CF ₃ , C _1-6 -alkyl, C _1-3 -fluoroalkyl, CHF ₂ , CH ₂ F, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ , SO ₂ -NR ^1.2 R ^1.3 , C _1-3 -alkyl-CN, C _1-3 -alkyl-OH, C _1-3 -alkyl-OR ^1.1 , C _1-3 -alkyl-NH ₂ or C _1-3 -alkyl-NHR ^1.1 substituents, each of which in turn may be optionally substituted with 1, 2 or more substituents selected from OH, OR ^1.1 , oxo, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20- aryl and NR ^1.2 R ^1.3 ; According to an embodiment of the present disclosure, R _e may be selected from OH; Each _Rd6 is the same or different and independently represents H, F, Me, _C1-3 -alkyl-CN, _C1-3 -alkyl-OH, _C1-3 -alkyl- ^OR1.1 , _C1-3 -alkyl- _NH2 , _C1-3 -alkyl- ^NHR1.1 , C1-6 _- alkyl, _C2-6- alkenyl, C2-6 _- alkynyl, a mono- or polycyclic _{C6-20- aryl} or a mono- or polycyclic _C6-20 -aryl and 4-7 membered cycloalkyl, a mono- or polycyclic C6-20-heteroaryl and 4-7 membered cycloalkyl, _C6-10 -aryl- _C1-6 -alkyl, _C5-10 -heteroaryl- _C1-6 -alkyl, _C3-10 -heterocycle and _C5-10 -heterocycle, -NR'R", fluorine, C _{C 1-6-} fluoroalkyl and C _1-6- fluoroalkoxy, wherein R' and R" are independently selected from H and C _1-6- alkyl; said groups may be optionally substituted at each occurrence with 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6- alkyl and OC _1-6- alkyl; or, Each R _d6 is the same or different and independently represents H, F, Me, C _1-3 -alkyl-CN, C _1-3 -alkyl-OH, C _1-3 -alkyl-OR ^1.1 , C _1-3 -alkyl-NH ₂ , C _1-3 -alkyl-NHR ^1.1 , C _1-6- alkyl, C _2-6- alkenyl, C _2-6- alkynyl, C _6-10- aryl, C _6-10- Aryl-C _1-6 -alkyl, C _5-10 -heteroaryl-C _1-6 -alkyl, C _3-10 -heterocycle and C _5-10 -heterocycle, -NR'R", fluorine, C _1-6 -fluoroalkyl and C _1-6 -fluoroalkoxy, wherein R' and R" are independently selected from H and C _{1-6 -alkyl} ; said groups may in each case be optionally substituted with 1, 2 or more substituents selected from OH, oxo, halogen, C _1-6 -alkyl and OC _1-6 -alkyl. Alternatively, the two and R _d6 together with the atoms to which they are attached form a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged cycloalkyl, or a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocycle comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, said heterocycle being unsubstituted or optionally substituted in the ortho, para or meta position with 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF ₃ , CHF ₂ , CH ₂ F, OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 ,COOR ^2.1 ,CH ₂ COOR ^2.1 ,CH ₂ CH ₂ COOR ^2.1 ,CH＝CHCOOR ^2.1 ,CO-NR ^2.1 CH ₂ CO-NR ^2.1 ,CH ₂ CH ₂ CO-NR ^2.1 ,CH＝CHCO-NR ^2.1 ,COR ^2.1 ,CH ₂ COR ^2.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-10 membered heterocyclyl-C _6-20- aryl, 3-10 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^2.1 , NR ^2.2 R ^2.3 , C _6-20- aryl and NR ^2.2 R ^2.3 ; R ^2.1 is H or is selected from C _1-6- alkyl, C _1-6- alkyl alcohol, C _1-3 -haloalkyl, mono- or bicyclic, -C _3-10 -cycloalkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, 3-10-membered heterocycle-C _1-6 -alkyl, C _3-10 -cycloalkyl-C _1-6 -alkyl, mono- or bicyclic C _6-20- aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally selected from OH, O-(C _1-3 -alkyl), halogen, C _1-10- alkyl and C _6-20- aryl; R ^2.2 and R ^2.3 independently of one another represent H or a group selected from C _1-6- alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkylene, mono- or bicyclic C _6-20- aryl, 3-10-membered heterocycle, heteroaromatic ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^2.1 and COOR ^2.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^2.1 . Each R _c is the same or different and independently represents hydrogen, a mono- or polycyclic C _6-20 -aryl group or a mono- or polycyclic C _6-20 -aryl and 4-7 membered cycloalkyl group, for example C _4-10 cycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkenyl and C _6-20 aryl-, C _4-10 cycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkenyl-C _6-20 aryl-, _5-20 membered heteroaryl, C _4-10 cycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl-, C _4-10 -membered cycloalkyl-5-20-membered heteroaryl-, 4-10-membered heterocycloalkyl-5-20-membered heteroaryl-, 4-10-membered heterocycloalkenyl-5-20-membered heteroaryl-, or selected from 5-20-membered heteroaryl-OC _6-20 aryl-, 5-20-membered heteroaryl-NC _6-20 aryl-, 5-20-membered heteroaryl-SC _6-20 aryl-, 5-20-membered heteroaryl-CH ₂ -C _6-20 aryl-, the above groups may be optionally substituted at the ortho, para or meta position with one, two or three substituents of fluorine, chlorine, bromine, iodine, hydroxyl, CN, NO ₂ , NH ₂ , or with one, two or more substituents selected from OR ^4.1 , COOR ^4.1 CH ₂ COOR ^4.1 , CH ₂ CH ₂ COOR ^4.1 , CH＝CHCOOR ^4.1 ,CO-NR ^4.1 CH ₂ CO-NR ^4.1 ,CH ₂ CH ₂ CO-NR ^4.1 ,CH＝CHCO-NR ^4.1 ,NR ^4.2 R ^4.3 ,CH ₂ -NR ^4.2 R ^4.3 ,CH ₂ CH ₂ -NR ^4.2 R ^4.3 ,C _1-3 -alkyl-CN, C _1-3 -alkyl-OH, C _1-3 -alkyl-OR ^4.1 , C _1-3 -alkyl-NH ₂ , C _1-3 -alkyl-NHR ^4.1 , C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic C _6-20- aryl), 3-10 membered heterocyclyl-C _6-20- aryl, 3-10 membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-10-membered heterocyclic-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, SO ₂ —CH ₃ , SO ₂ —CH ₂ CH ₃ and SO ₂ —NR ^4.2 R ^4.3 , ^{4.1 , COOR} _4.1 ^, _{CH 2} COOR 4.1 , CH ₂ CH ₂ COOR ^{4.1 , CH} ＝ _{CHCOOR 4.1} ^, _CO ^— _NR ^4.1 _{, CH 2 CO} ^— _NR ^{4.1 ,} _CH ² CH ₂ CO-NR ^4.1 , CH＝CHCO-NR ^4.1 , COR ^4.1 , CH ₂ COR ^4.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20- aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-10 membered heterocyclyl-C _6-20- aryl, 3-10 membered heterocycle, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^4.1 and NR ^4.2 R ^4.3 , each of which may be optionally substituted by OH, OR ^4.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _6-10- aryl and NR ^4.2 R ^4.3 are substituted by one, two or more substituents; Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; The heteroaryl ring is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group including 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; in some embodiments _R4 is selected from a 5-membered monocyclic heteroaryl, a 5-membered heteroarylacene ring, a 5-membered heteroaryl and 5-10 membered heteroaryl, a 5-membered heteroaryl and 4-7 membered cycloalkyl, a 5-membered heteroaryl and 4-7 membered heterocycloalkyl, a 6-membered heteroarylacene ring, a 6-membered heteroaryl and 5-10 membered heteroaryl, a 6-membered heteroaryl and 6-membered heteroaryl, a 6-membered heteroaryl and 4-7 membered cycloalkyl, and a 6-membered heteroaryl and 4-7 membered heterocycloalkyl; Cycloalkyl groups may be saturated or partially saturated; R ^4.1 is H or is selected from Ci _-6- alkyl, Ci _-6- alkyl alcohol, Ci _-3 -haloalkyl, mono- or bicyclic, _-C3-10 -cycloalkyl, _C6-20- aryl-Ci- ₆ -alkyl, 5-20-membered heteroaryl-Ci- ₆ -alkyl, 3-10-membered heterocycle-Ci _-6 -alkyl, _C3-10 -cycloalkyl-Ci _-6 -alkyl, mono- or bicyclic C6-20 _- aryl, 5-20-membered heteroaryl and heterocycle, which may be optionally substituted with OH, O-(Ci _-3 -alkyl), halogen, Ci _-10- alkyl and _C5-10 aryl substituents; R ^4.2 and R ^4.3 independently of one another represent H or a group selected from C _1-6 -alkyl, mono- or bicyclic C _3-10- cycloalkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, mono- or bicyclic C _6-20- aryl, 3-10-membered heterocycle, heteroaryl ring, CO—NH ₂ , CO—NH _{—CH 3} , —CO—N(CH ₃ ) ₂ , SO ₂ —(C _1-3 -alkyl), CO—R ^4.1 and COOR ^4.1 , which may be optionally substituted by 1, 2 or more substituents selected from OH, halogen, C _1-6 -alkyl, C _6-20- aryl and COOR ^4.1 ; For example, the 4-10 membered heterocyclic group or 4-10 membered heterocycloalkenyl group can be: 1-methylpyrrolidinyl, 1-ethylpyrrolidinyl, 1-cyclopropylpyrrolidinyl, 1-cyclopropylmethylpyrrolidinyl, 5-methyl-4,5-dihydropyridazin-3(2H)-one, 1-methylazetidinyl, 1-methylpiperidinyl. The compound according to any one of claims 1 to 11, its racemate, stereoisomer, tautomer, isotope-labeled form, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein: R ₁ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta position by one, two or three fluorine, chlorine, bromine, iodine, hydroxyl, -NHOH, -C _1-3- alkyl-NHOH, -C _1-3- alkyl-CO _- NHOH, -CO _- NHOH, -C _1-3- alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^1.1 , COOR ^1.1 CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 ,NR ^1.2 R ^1.3 ,CH ₂ -NR ^1.2 R ^1.3 ,CH ₂ CH ₂ -NR ^1.2 R ^1.3 ,C _3-10 -cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20- aryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-20- aryl, SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^1.2 R ^1.3 , each of which may in turn be optionally substituted by one, two or more substituents selected from the group consisting of OH, CN, C _1-3 -alkyl-CN, -SH, -NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _1-3 -alkyl-CO _- NHOH, -CO _- NHOH, -C _1-3 -alkyl-NH _- CO _- NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, , C _2-6 -alkenyl, -OC _3-8 -cycloalkyl, COOR ^1.1 , C _1-3 -alkyl-COOR ^1.1 , CONHR ^1.1 , C _1-3 -alkyl-CONHR ^1.1 , -OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20- aryl and NR ^1.2 substituted by a substituent in R ^1.3 ; wherein R ^1.1 , R ^1.2 , and R ^1.3 have the definitions described above; Alternatively, R ₁ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta position by one, two or three halogen, OH, CN, NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _1-3 -alkyl-CO _- NHOH, -CO _- NHOH, -C _1-3 -alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, nitro, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^1.1 , C _1-3 -alkyl-OR ^1.1 , SR ^1.1 , C _1-3 -alkyl-SR ^1.1 , SO-R ^1.1 , C _1-3 -alkyl-SOR ^1.1 , SO ₂ -R ^1.1 , C _1-3 -alkyl-SO ₂ R ^1.1 , COOR ^1.1 , CH ₂ COOR ^1.1 , CH ₂ CH ₂ COOR ^1.1 , CH＝CHCOOR ^1.1 , CO-NR ^1.1 CH ₂ CO-NR ^1.1 , CH ₂ CH ₂ CO-NR ^1.1 , CH＝CHCO-NR ^1.1 , COR ^1.1 , CH ₂ COR ^1.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20- aryl), 3-20 membered heterocyclyl-C _6-20 membered aryl, 3-20 membered heterocyclic, 5-20 membered heteroaryl C _1-3 -alkyl-OR ^1.1 and NR ^1.2 R ^1.3 , each of which may be optionally substituted by OH, CN, C _1-3 -alkyl-CN, -SH, -NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _1-3 -alkyl-CO _{- 1.2} -alkyl-NH _- CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, C _2-6 -alkenyl, -OC _3-8 -cycloalkyl, COOR ^1.1 , C _1-3 -alkyl-COOR ^1.1 , CONHR ^1.1 , C _1-3 -alkyl-CONHR ^1.1 , OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-10 -aryl and NR ^1.2 R ^2.3 ; wherein R ^1.1 , R ^1.2 and R ^1.3 have the meanings described above; Alternatively, R ₂ represents hydrogen, a mono- or polycyclic C _6-20 aryl group, which may be optionally substituted at the ortho, para or meta positions by one, two or three substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, CN, NO ₂ , NH ₂ , or by one, two or more substituents selected from OR ^2.1 , COOR ^2.1 , CH ₂ COOR 2.1 , C(CH ₃ ) 2 COOR ^2.1 , _{CF 2} COOR ^2.1 , CHFCOOR ^2.1 , CH ₂ CH ₂ COOR ^2.1 , ^CH ＝CHCOOR ^2.1 , CO-NR ^2.1 , CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , NR ^2.2 R ^2.3 , CH ₂ -NR ^2.2 R ^2.3 ,CH ₂ CH ₂ -NR ^2.2 R ^2.3 ,C _3-10 -cycloalkyl, COOR ^2.1 -C _3-8- cycloalkyl, CO-NR ^2.1 -C _3-8- cycloalkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C _6-20 aryl), 3-20-membered heterocyclyl-C _6-20 aryl, 3-20-membered heterocycle, C _1-6 -alkyl, C _1-3 -fluoroalkyl, CF ₃ , CHF ₂ , CH ₂ F, C _6-20 aryl-C _1-6 -alkyl, 3-20-membered heterocycle-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 -alkyl, C _6-10 -aryl, C _1-3 -alkyl-SOR ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , SO ₂ -CH ₃ , SO ₂ -CH ₂ CH ₃ and SO ₂ -NR ^2.2 R ^2.3 substituents, each of which may in turn be optionally substituted with 1, 2 or more substituents selected from OH, CN, C _1-3 -alkyl-CN, -SH, -NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _1-3 -alkyl-CO-NHOH, -CO-NHOH, -C _1-3 -alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, C _2-6 -alkenyl, -OC _3-8 -cycloalkyl, COOR ^1.1 , C _1-3 -COOR ^1.1 , CONHR ^1.1 , C _1-3 -alkyl-CONHR ^1.1 , OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C substituted by a _{C 1-6} -alkyl, C _6-20 -aryl, or a substituent in NR ^2.2 R ^2.3 , CCOOR ^2.1 ; wherein R ^2.1 , R ^2.2 , and R ^2.3 have the meanings given above; Alternatively, R ₂ represents a group selected from heterocycle and heteroaryl, which may be optionally substituted at the ortho, para or meta positions by one, two or three halogen, OH, CN, NH ₂ , -NHOH, -C _1-3 -alkyl-NHOH, -C _1-3 -alkyl-CO _- NHOH, -CO-NHOH, -C _1-3 -alkyl-NH-CO-NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, nitro, oxo, CF ₃ , CHF ₂ and CH ₂ F, or by one, two or more groups selected from OR ^2.1 , C _1-3 -alkyl-OR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 , SO-R ^2.1 , C _1-3 -alkyl-SOR ^2.1 , SO ₂ -R ^2.1 , C _1-3 -alkyl-SO ₂ R ^2.1 , COOR ^2.1 , CH ₂ COOR ^2.1 , COOR ^2.1 -C _3-8 -cycloalkyl, CO-NR ^2.1 -C _3-8 -cycloalkyl, CH ₂ CH ₂ COOR ^2.1 , CH＝CHCOOR ^2.1 , CO-NR ^2.1 CH ₂ CO-NR ^2.1 , CH ₂ CH ₂ CO-NR ^2.1 , CH＝CHCO-NR ^2.1 , COR ^2.1 , CH ₂ COR ^2.1 , C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 aryl, C _1-6 -alkyl, C _6-20 -aryl-C _1-6 -alkyl, 5-20 membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(monocyclic or polycyclic-C 3-10 _{2.2 -} aryl), 3-20-membered heterocyclyl-C _1-20 aryl, 3-20-membered heterocycle, 5-20-membered heteroarylC _1-3 -alkyl-OR ^2.1 and NR ^2.2 R ^2.3 , each of which may be optionally substituted with one, two or more substituents selected from OH, OR ^2.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6- alkyl, C _6-20- aryl and NR ^2.2 R ^2.3 ; wherein R ^2.1 , R ^2.2 and R ^2.3 have the meanings as described above; or R _2.1 , C _{1-3 -alkyl-OR 2.1} , C 1-3 -alkyl-OC 1-3 -alkyl-COOH, C 1-3 -alkyl-OC 1-3 -alkyl-CONR 2.1 , C 1-3 -alkyl-phosphoric acid, C 1-3 -alkyl-OC(O)-OR _2.1 , C _1-3 -alkyl-OC ₍ O ^{)-NR 2.1} _, C _1-3 -alkyl-OC(O ₎ -OR ^{2.1 ,} C _1-3 -alkyl _- OC(O)-NR _2.1 ^, _{C 1-3} -alkyl-OC(O ₎ ^- -alkyl-OC(＝O)-C _1-3 -alkyl-(OC _1-3 -alkyl)v, C _1-3 -alkyl-OC(＝O)-C _1-6 -alkyl-COOR ^2.1 , C _1-3 -alkyl-NC(＝O)-C _1-6 -alkyl-COOR ^2.1 , C _1-3 -alkyl-NC(＝O)-OC _1-6 -alkyl-COOR ^2.1 , C _1-3 -alkyl-NC(＝O)-NC _1-6 -alkyl-COOR ^2.1 , SR ^2.1 , C _1-3 -alkyl-SR ^2.1 ,SO-R ^2.1 ,C _1-3 -alkyl-SOR ^2.1 ,SO ₂ -R ^2.1 ,C _1-3 -alkyl-SO ₂ R ^2.1 ,COOR ^2.1 ,CH ₂ COOR ^2.1 ,CH ₂ CH ₂ COOR ^2.1 ,CH＝CHCOOR ^2.1 ,CO-NR ^2.1 ,CH ₂ CO-NR ^2.1 ,CH ₂ CH ₂ CO-NR ^2.1 ,CH＝CHCO-NR ^2.1 ,COR ^2.1 ,CH ₂ COR ^2.1 ,C _1-6 -alkyl alcohol, mono- or bicyclic C _3-10 -cycloalkyl, C _6-20 -aryl, C _1-6 -alkyl, C _6-20- aryl-C _1-6 -alkyl, 5-20-membered heteroaryl-C _1-6 alkyl, C _1-3 -alkyl-(mono- or polycyclic-C _6-20- aryl), 3-20-membered heterocyclyl-C _6-20- aryl, 3-20-membered heterocycle, 5-20-membered heteroaryl C _1-3 -alkyl-OR ^2.1 ,NR ^2.2 R ^2.3 , C _6-20- aryl and NR ^2.2 R ^2.3 ; each of said substituents may in turn be optionally replaced by 1, 2 or more substituents selected from OH, CN, C _1-3 -alkyl-CN, C _1-3 -alkyl-NH ₂ , -SH, -NH ₂ , -NHOH, -C _1-3- alkyl-NHOH, -C _1-3- alkyl-CO-NHOH, -CO-NHOH, -C _1-3- alkyl-NH-CO _- NR ^1.2 R ^1.3 , -NR ^1.1 CN, -CHO, C _2-6 -alkenyl, -OC _3-8 -cycloalkyl, COOR ^1.1 , C _1-3 -alkyl-COOR ^1.1 , CONHR ^1.1 , C _1-3 -alkyl-CONHR ^1.1 , -OR ^1.1 , oxo, halogen, CF ₃ , CHF ₂ , CH ₂ F, C _1-6 -alkyl, C _6-20 -aryl and the substituents in NR ^1.2 R ^1.3 , wherein R ^2.1 , R ^1.2 , R ^1.3 and v have the meanings given above; or R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R 36 , R ₃₇ , R ₃₈ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ , R ₄₆ , R ₄₇ , R ₄₈ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₆ , R ₅₇ , R _{58 are} the same or different and are independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _1.1 , oxo, halogen, CF 3 , CHF 2 , CH ₂ F, C 1-6-alkyl, C _1-3 -alkyl-C 1-2 -alkyl-C 1-3 -alkyl-C 1-2 -alkyl-C _{1-2 -alkyl-C 1-2 -alkyl-C 1-2 -alkyl-C 1-2} -alkyl-C _1-2 -alkyl-C 1-2 -alkyl-C _1-2 -alkyl-C 1-2 -alkyl-C 1-2 -alkyl-C 1-2 -alkyl-C _1-2 -alkyl-C 1-2 -alkyl-C ^{1-2 -alkyl} -C ^1-2 -alkyl-C 1-2 -alkyl-C 1-2 -alkyl- ^C _1-2 -alkyl-C 1-2 -alkyl-C _1-2 -alkyl-C ^{1-2 -alkyl} -C 1-2 -alkyl-C _1-2 -alkyl-C _1-2 -alkyl-C ^{1-2 -alkyl} -C 1-2 ^-alkyl -C ^1-2 -alkyl-C 1-2 -alkyl-C _1-2 -alkyl-C 1-2 -alkyl-C _1-2 -alkyl-C 1-2 -alkyl-C _1-2 -alkyl-C 1-2 -alkyl-C _1-2 -alkyl-C 1-2 -alkyl- substituted by one, two or more substituents selected from _6-10- aryl and NR ^1.2 R ^2.3 ; wherein R ^1.1 , R ^1.2 , R ^2.1 and R ^2.3 have the meanings as defined above; Alternatively, each R _c is the same or different and is independently selected from H, halogen, OH, CN, NO ₂ , oxo (═O), thioxo (═S), the following groups which are unsubstituted or optionally substituted with 1, 2 or more R _c : C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _3-20 cycloalkyl, C _3-20 cycloalkenyl, C _3-20 cycloalkynyl, C _6-20 aryl, C _1-6 alkyl-C _4-10 heterocycloalkyl, C _1-6 alkyl-C _4-10 heterocycloalkenyl, C _1-6 alkyl-C _6-20 aryl, C _1-6 alkyl-C _5-20 heteroaryl, 5-20 membered heteroaryl-OC _6-20 aryl-, 5-20 membered heteroaryl-NC _6-20 aryl-, 5-20 membered heteroaryl-SC -C _6-20 aryl-, 5-20 membered heteroaryl-CH ₂ -C _6-20 aryl-, C _4-10 cycloalkyl and C _6-20 aryl-, 4-10 membered heterocycloalkyl and C 6-20 aryl-, 4-10 membered heterocycloalkenyl and C _6-20 aryl-, C _4-10 cycloalkyl-C _6-20 aryl-, _4-10 membered heterocycloalkyl-C _6-20 aryl-, 4-10 membered heterocycloalkenyl-C _6-20 aryl-, _5-20 membered heteroaryl, C 4-10 cycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl-, C _4-10 -membered cycloalkyl-5-20-membered heteroaryl-, 4-10-membered heterocycloalkyl-5-20-membered heteroaryl-, 4-10-membered heterocycloalkenyl-5-20-membered heteroaryl-, 3-20-membered heterocyclyl, C _1-20 alkyloxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, C _3-20 cycloalkyloxy, C _3-20 cycloalkenyloxy, C _3-20 cycloalkynyloxy, C _6-20 aryloxy, 5-20-membered heteroaryloxy, 3-20-membered heterocyclyloxy, C _1-20 alkylthio, C _2-20 alkenylthio, C _2-20 alkynylthio, C _3-20 cycloalkylthio, C _3-20 cycloalkenylthio, C _3-20 cycloalkynylthio, C _6-20- membered arylthio, 5-20-membered heteroarylthio, 3-20-membered heterocyclylthio, NH ₂ , -C(O)R ₃₁ , -C(O)OR ₃₂ , -OC(O)R ₃₃ , -S(O) ₂ R ₃₄ , -S(O) ₂ OR ₃₅ , -OS(O) ₂ R ₃₆ , -P(O)(OR ₃₇ )(OR ₃₈ ); wherein R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ , R ₃₆ , R ₃₇ , and R ₃₈ have the meanings described above; Alternatively, the compound is selected from the following compounds:












































A method for preparing the compound according to any one of claims 1 to 12, its racemate, stereoisomer, tautomer, isotope-labeled form, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the preparation method comprises reacting a compound of formula A1 with a compound of formula B1 to obtain a compound of formula H:
and optionally, derivatizing the compound of formula G into a stereoisomer, tautomer, isotopically labeled form, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof; Wherein, LG is a leaving group, such as Cl, Br or I; X ₁ , L, W, _Ra , _Rb , _Rc , R ₂ , R _2′ and m independently have the meanings as defined in any one of claims 1 to 11. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of any one of claims 1 to 12 (e.g., any one of the compounds of Formulas I to IX), its racemate, stereoisomer, tautomer, isotopically labeled form, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof. A method for preventing or treating a disease, comprising administering to a patient in need thereof at least one of the compound of any one of claims 1 to 12 (e.g., one of the compounds of Formulae I to IX), its racemate, stereoisomer, tautomer, isotope-labeled form, solvate, polymorph, pharmaceutically acceptable salt, or prodrug thereof; The disease may be a PDE4B-mediated disease, or a disease mediated at least by PDE4; Preferably, the disease includes but is not limited to respiratory inflammatory diseases, inflammatory bowel diseases, arthritic diseases, skin inflammatory diseases, eye inflammatory diseases and diseases of the peripheral or central nervous system, degenerative diseases of the central nervous system, Alzheimer's Disease (AD), non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF) or pulmonary hypertension associated therewith, chronic obstructive pulmonary disease (COPD) or pulmonary hypertension associated therewith, hepatic fibrosis (HF), renal fibrosis, benign prostatic hyperplasia (BPH), gastroesophageal reflux disease. Gastroesophageal Reflux disease, Obstructive Sleep apnea, and Coronary Artery Disease or Cancer; Preferably, the cancer includes but is not limited to one selected from the group consisting of: stomach cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosal cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer and/or thyroid cancer; Preferably, the lesions of the disease include the respiratory system, digestive system, excretory system and/or reproductive system, such as the lungs, liver, kidneys and/or prostate.