Compound as well as preparation method and application thereof

Abstract

Provided herein are novel compounds, for example, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. Also provided herein are methods of making the compounds and methods of using the compounds, for example, to inhibit PI3K in a cell and / or to treat various diseases, such as cancer.

Description

Cross-references to related applications

[0001] This application claims priority to International Application No. PCT / CN2023 / 117480, filed on September 7, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] In various embodiments, this disclosure generally relates to novel compounds, compositions comprising said compounds, methods for preparing said compounds, and methods for using said compounds (e.g., for inhibiting PI3K and / or for treating various diseases or conditions, such as cancer). Background Technology

[0003] Phosphoinositol 3-kinase (PI3K) is a member of the intracellular lipid kinase family, which phosphorylates the 3'-OH group on phosphatidylinositol or phosphoinositol. The PI3K family comprises more than a dozen kinases with different substrate specificities, expression patterns, and regulatory modes. PI3K-α (PI3Ka) is a heterodimeric protein complex consisting of the catalytic subunit p110α (… PIK3CA Gene encoding) and regulatory subunit p85α (by PIK3R1 Gene encoding) constitutes (Vasan N). et al., Annals of Oncology, 30(10): x3-x11 (2019)). p110α binds to p85α and catalyzes the phosphorylation of lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3).

[0004] The PI3K signaling pathway has been associated with a variety of diseases, particularly cancer. Genetic alterations in genes involved in PI3K signaling are believed to be involved in a range of diseases, including cancers such as breast cancer, endometrial cancer, gastric cancer, colorectal cancer, ovarian cancer, cervical cancer, head and neck cancer, liver cancer, lung cancer, and prostate cancer. Many cancer-associated PIK3CA mutations have been identified, such as the PI3KCA-H1047R mutation. These mutations can lead to activation of the PI3K pathway, resulting in increased cell growth and tumorigenesis. Summary of the Invention

[0005] This disclosure is based in part on compounds discovered by the applicant that can act as inhibitors of PI3K, particularly PI3K-α (“PI3Ka”), such as those with the H1047R mutation. In various embodiments, this disclosure provides novel compounds, pharmaceutical compositions, methods of preparation and use thereof. The compounds and compositions herein can be used to treat a variety of diseases or conditions, such as the cancers described herein.

[0006] In some embodiments, this disclosure provides compounds of formula I or II as defined herein, or pharmaceutically acceptable salts thereof:

[0007] In some embodiments, the compound of formula I may be characterized by having a structure according to a sub-formula selected from formulas Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4. In some embodiments, the compound of formula II may be characterized by having a structure according to a sub-formula selected from formulas II-a, II-b, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4. In some embodiments, this disclosure also provides compounds selected from the compounds shown in Table A herein, or pharmaceutically acceptable salts thereof. In some embodiments, this disclosure also provides compounds selected from the compounds shown in the Examples section herein, or pharmaceutically acceptable salts thereof.

[0008] Certain embodiments of this disclosure relate to pharmaceutical compositions comprising one or more of the compounds of this disclosure (e.g., compounds of formula I (e.g., sub-formulas such as Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), compounds of formula II (e.g., sub-formulas such as II-a, II-b, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4), any compound selected from the compounds shown in Table A herein, or pharmaceutically acceptable salts thereof), and optionally pharmaceutically acceptable excipients. The pharmaceutical compositions described herein can be formulated for various routes of administration, such as oral administration, parenteral administration, or inhalation.

[0009] Some embodiments relate to methods for treating diseases or conditions associated with PI3K activity. In some embodiments, the method includes administering to a subject in need a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of formula I (e.g., sub-formulas such as formula Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition described herein. PI3K-related diseases or conditions suitable for treatment with this method include any cancers described herein. In some implementations, PI3K-related diseases or conditions suitable for treatment with this method include CLOVES syndrome (congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

[0010] In some embodiments, a method of treating cancer is provided. In some embodiments, the method comprises administering to a subject in need a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of formula I (e.g., sub-formulas such as formula Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), a compound of formula II (e.g., sub-formulas such as II-a, II-b, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4), any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition described herein. In various embodiments, the cancer may be endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0011] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, the administration may be oral, nasal, transdermal, pulmonary, inhaled, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral.

[0012] The compounds disclosed herein can be used as a monotherapy or in combination therapy. In some embodiments, the combination therapy includes treating the subject with a targeted therapeutic agent, a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, and / or immunotherapy.

[0013] It should be understood that the foregoing description of the invention and the following detailed description are merely exemplary and illustrative, and do not limit the invention herein. Detailed Implementation

[0014] In a broader sense, this disclosure provides compounds and compositions that can be used to inhibit PI3K such as PI3Ka with the H1047R mutation and / or to treat or prevent the various diseases or conditions (e.g., cancer) described herein.

[0015] compound Formulas I and II In some embodiments, this disclosure provides compounds of formula I or II or pharmaceutically acceptable salts thereof:

[0016] in: W is CR 10 Or N, where R 10 For hydrogen, deuterium, halogen, or C atoms optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups or C groups optionally substituted with 1-3 fluorine atoms 1-4 Alkoxy; R 1 The substituted 3-12 membered ring structure is selected from monocyclic nonaromatic rings, monocyclic aromatic rings and polycyclic structures, wherein each ring in the polycyclic structure is independently aromatic or nonaromatic, and wherein the 3-12 membered ring structure optionally contains 1-4 cyclic heteroatoms independently selected from O, N and S. R X R 3 R 4 and R 5 Each is independently hydrogen, deuterium, halogen, CN, OH, G 1 Or OG 1 ; R 6 and R 7 Each can be independently hydrogen, deuterium, CN, or G. 2 ; R 8 C is hydrogen or optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl or nitrogen protecting groups; L 2 The substituted phenylene or substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl or bicyclic heteroaryl); and R 9 For OH, NH2, OG 3 NHG 3 NG 3 G3 or NHSO2G 3 ;or N, L 2 C(O), R 9 and R 8 The linkage forms an optionally substituted 6,6- or 5,6-fused bicyclic heterocyclic group or heteroaryl group; in: G 1 Each time it appears, it is independently replaced by the arbitrarily chosen C. 1-6 Alkyl groups, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne or optionally substituted 3- to 10-membered ring structures having 0 to 4 cyclic heteroatoms; G 2 Each time it appears, it is independently replaced by the arbitrarily chosen C. 1-6 Alkyl groups, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl or optionally substituted 3-6 membered rings having 0-3 heteroatoms (e.g., cyclopropyl); and G 3 Each time it appears, it is independently replaced by the arbitrarily chosen C. 1-6 Alkyl groups, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne or optionally substituted 3-8 membered nonaromatic ring structures with 0-4 ring heteroatoms, or NG 3 G 3 This represents a nitrogen-containing 4-8 membered non-aromatic ring structure that can be substituted.

[0017] R in formula I or II X Typically hydrogen, halogens, CN, or C optionally replaced by F. 1-4 Alkyl groups, C groups optionally substituted with F 2-4 Alkenyl, C substituted with F (optionally) 2-4 The alkynyl group or optionally a C group independently selected from halogens, CN, OH, or optionally substituted with F. 1-4 Alkyl groups and C groups optionally substituted with F 1-4 The 3-5 membered ring is substituted by a heteroalkyl substituent (e.g., cyclopropyl). For example, in some embodiments, R in formula I or II... X It is hydrogen.

[0018] In some implementations, R in Formula I or II X Not hydrogen. In some embodiments, R in formula I or II X C is arbitrarily replaced by F. 1-4 Alkyl groups, such as methyl groups.

[0019] In some preferred embodiments, W in Formula I is N. In some embodiments, W in Formula I is CR. 10 , where R 10 Defined herein. For example, in some implementations, R 10 It is hydrogen.

[0020] In some implementations, R in Formula I or II 1 It can be a 4-12 (e.g., 4, 5, 6, 7, 8, 9, or 10) membered heterocyclic group, which may be optionally substituted and has one or two cyclic heteroatoms, each independently selected from O, N, or S. When substituted, the 4-12 membered heterocyclic group is typically replaced by one or more, such as one or two, cyclic heteroatoms, each independently selected from deuterium, halogen, oxo, OH, NH2, COOH, CONH2, CN, G. 4 OG 4 OC(O)G 4 NHG 4 NG 4 G 4 NH-C(O)G 4 C(O)G 4 C(O)OG 4 C(O)NHG 4 C(O)NG 4 G 4 OC(O)NHG 4 OC(O)NG 4 G 4 ,NHC(O)NHG 4 or N(G) 4 )C(O)NG 4 G 4 The substituents are replaced by G, where G is the substituent. 4 It is C independently each time it appears. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., wherein C 1-4 Alkyl, the C 2-4alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A Replaced, of which G A Each time it appears, it is independently deuterium, halogen, CN, OH, or C that is optionally replaced by 1-3 F atoms. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F groups 1-4 Alkyl group. In some embodiments, G 4 The 3-12 elemental ring is a 3-7 elemental ring.

[0021] In some implementations, R in Formula I or II 1 The substituted group is a 4-7 membered monocyclic heterocyclic group having one or two independently selected cyclic heteroatoms chosen from O, N, or S. For example, in some embodiments, R 1 It can be a 4-7 membered monocyclic heterocyclic group having one cyclic heteroatom, preferably one cyclic nitrogen atom, which can be optionally substituted. In some embodiments, the monocyclic heterocyclic group is a fully saturated heterocyclic ring, such as... , or The alternative is substituted. In some embodiments, the monocyclic heterocyclic group contains one or more carbon-carbon or carbon-nitrogen double bonds in the ring, such as... Optionally, it can be substituted. The monocyclic heterocyclic group can be attached to the remainder of Formula I or II via a carbon or N-ring atom. For example, in some embodiments, R 1 It can be attached to the rest of formula I or II via a cyclic nitrogen atom, such as , or Its optionality is replaced. In some implementations, R 1 It can be attached to the rest of formula I or II via a ring carbon atom, such as or The 4-7 membered monocyclic heterocyclic group can be substituted at any available position allowed by the valence (including at the ring carbon and / or nitrogen atom). When substituted, the 4-7 membered monocyclic heterocyclic group is usually replaced by one or more, such as one or two, independently selected from deuterium, halogen, oxo, OH, NH2, COOH, CONH2, CN, G. 4 OG 4 OC(O)G 4 NHG 4 NG 4 G 4 NH-C(O)G 4 C(O)G 4 C(O)OG 4 C(O)NHG4 C(O)NG 4 G 4 OC(O)NHG 4 OC(O)NG 4 G 4 ,NHC(O)NHG 4 or N(G) 4 )C(O)NG 4 G 4 The substituents are replaced by G, where G is the substituent. 4 It is C independently each time it appears. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., wherein C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 The alkynyl or 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl) is optionally surrounded by one or more (e.g., 1, 2 or 3) G A Replaced, of which G A Each time it appears, it is independently deuterium, halogen, CN, OH, or C that is optionally replaced by 1-3 F atoms. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F groups 1-4 alkyl.

[0022] In some implementations, R in Formula I or II 1 It can be , or , where R A For G 4A C(O)G 4A C(O)OG 4A C(O)NHG 4A C(O)NG 4A G 4A SO2G 4A SO2NHG 4A or SO2NG 4A G 4AG 4A Each occurrence is independently (i)C 1-4 Alkyl, C 2-4 alkenyl or C 2-4 (ii) 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., (iii)–(C 1-4 alkylene)-3-12-membered ring, such as –(C 1-4 (iv)–(C 1-4 (heteroalkyl)-3-12-membered ring such as –(C 1-4 (heteroalkyl)-3-7-membered ring, wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A1 Replaced, of which G A1 Each time it appears, it is independently deuterium, halogen, CN, OH, NH2, or C that is optionally replaced by 1-3 F atoms. 1-4 Heteroalkyl groups, C atoms optionally substituted with 1-3 F atoms. 1-4 Alkyl or optionally a 3- to 5-membered ring substituted with one or more substituents that are independently F, CN, OH, methoxy, or methyl (e.g., cyclopropyl, cyclobutyl, oxetane, azirone, etc.); wherein R B Each time it appears, it is independently F, CN, OH, or C that is optionally replaced by 1-3 Fs. 1-4 An alkyl group or a 3- or 4-membered ring optionally substituted with 1-2 substituents, each independently of F or methyl, and j is 0, 1, or 2. (iii) C 1-4 The alkylene group can be straight-chain or branched; for example, in some embodiments, C 1-4 The alkylene group is CH2 or CH(CH3). In some embodiments, C in (iv) 1-4 Heteroalkyl groups contain one or two heteroatoms, such as one oxygen atom, one nitrogen atom, two oxygen atoms, two nitrogen atoms, or one oxygen atom and one nitrogen atom. Similarly, the C1-4 Heteroalkyl groups can be straight-chain or branched; for example, in some embodiments, the C... 1-4 The heteroalkylene group can be O-CH2 or CH(OCH3), etc. The 3-7 membered ring typically includes 0-3 cyclic heteroatoms. For example, in some embodiments, the 3-7 membered ring is C. 3-7 Cycloalkyl. In some embodiments, the 3-7 membered ring is a 4-7 membered heterocyclic group having 1-2 cyclic heteroatoms, each independently selected from O, S, or N. In some embodiments, the 3-7 membered ring is a phenyl group. In some embodiments, the 3-7 membered ring is a 5-membered heteroaryl group having 1-3 cyclic heteroatoms, each independently selected from O, S, or N. In some embodiments, the 3-7 membered ring is a 6-membered heteroaryl group having 1-2 cyclic nitrogen atoms. In some embodiments, the 3-7 membered ring is cyclopropyl, cyclobutyl, oxacyclobutane, aziranebutane, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, or phenyl. In some embodiments, j is 0. In some embodiments, j is 1 or 2, and R B Defined herein, for example, in some implementations, R B It is methyl. In some embodiments, R A It can also have the following description of variable R C Or R D The definition of the description.

[0023] In some implementations, R in Formula I or II 1 Based on: (M-1) (M-2) (M-3) (M-4) (M-5) (M-6) or The structure of (M-7), where R A Defined in this article.

[0024] In some implementations, R in Formula I or II 1 The substituted polycyclic heterocyclic group (e.g., spirocyclic, fused, or bridged bicyclic heterocyclic group) is a 6-12 member (preferably 7-11 member, such as 8, 9, or 10 member) having 1-3 independently selected cyclic heteroatoms from O, N, or S. In some embodiments, R in Formula I or II... 1The substituted 6-12 membered polycyclic heterocyclic group (e.g., spirocyclic, fused, or bridged bicyclic heterocyclic group) is a cyclic heteroatom (e.g., substituted with one or two independently selected cyclic heteroatoms from O, N, or S). For example, in some embodiments, the 6-12 membered polycyclic heterocyclic group contains one cyclic heteroatom, preferably a cyclic nitrogen, which can be present in any ring of the heterocyclic group. In some embodiments, the 6-12 membered polycyclic heterocyclic group contains two cyclic heteroatoms, such as two cyclic nitrogen atoms or one cyclic nitrogen and one epoxy group, wherein the heteroatom can be in any one or more rings of the heterocyclic group. In some embodiments, the polycyclic heterocyclic group is a fully saturated heterocyclic ring, such as... , , or Optionally, it can be replaced. In some embodiments, the polycyclic heterocyclic group contains one or more carbon-carbon or carbon-nitrogen double bonds in the ring and / or contains a carbonyl group, such as , , or The polycyclic heterocyclic group can be optionally substituted. The polycyclic heterocyclic group can be linked to the remainder of Formula I or II via carbon or N ring atoms. In some embodiments, the polycyclic heterocyclic group is a bridging heterocyclic ring, such as... or The 6-12 membered polycyclic heterocyclic group may be optionally substituted. Each ring of the 6-12 membered polycyclic heterocyclic group may be independently substituted at any available position (including at the ring carbon and / or nitrogen atom) where the valence allows. When substituted, the 6-12 membered polycyclic heterocyclic group is typically replaced by one or more, such as one or two, each independently selected from deuterium, halogen, oxo, OH, NH2, COOH, CONH2, CN, G. 4 OG 4 OC(O)G 4 NHG 4 NG 4 G 4 NH-C(O)G 4 C(O)G 4 C(O)OG 4 C(O)NHG 4 C(O)NG 4 G 4 OC(O)NHG 4 OC(O)NG 4 G 4 ,NHC(O)NHG 4 or N(G) 4 )C(O)NG 4 G 4 The substituents are replaced by G, where G is the substituent. 4 It is C independently each time it appears. 1-4 Alkyl, C 2-4alkenyl, C 2-4 Alkyne or 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., wherein C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A Replaced, of which G A Each time it appears, it is independently deuterium, halogen, CN, OH, or C that is optionally replaced by 1-3 F atoms. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F groups 1-4 Alkyl group. For example, in some embodiments, the substituents of the 6-12 membered polycyclic heterocyclic group can be independently selected from F, CN, methyl, C(O)G. 4 C(O)OG 4 C(O)NHG 4 or C(O)NG 4 G 4 G 4 As defined above.

[0025] In some implementations, R in Formula I or II 1 It may be based on: (M-8) (M-9) (M-10) (M-11) (M-12) (M-13) (M-14) or The structure of (M-15), where R A Defined in this article.

[0026] In some preferred embodiments, R in the present structure (e.g., M-1 to M-15) A It could be G 5A C(O)G 5A C(O)OG 5AC(O)NHG 5A C(O)NG 5A G 5A SO2G 5A SO2NHG 5A or SO2NG 5A G 5A G 5A Each occurrence is independently (i)C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 (ii) 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., (iii)–(C 1-4 alkylene)-3-12-membered ring, such as –(C 1-4 (iv)–(C 1-4 (heteroalkyl)-3-12-membered ring such as –(C 1-4 (heteroalkyl)-3-7-membered ring, wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. B1 Replaced, of which G B1 Each time it appears, it is independently deuterium, F, Cl, CN, OH, or C that is optionally replaced by 1-3 F. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 F atoms 1-4 Alkyl or cyclopropyl.

[0027] For example, in some preferred embodiments, R in the present structure (e.g., M-1 to M-15) A It could be G 5A C(O)G 5A C(O)OG 5A or SO2G 5A G 5A C can be arbitrarily replaced by 1-3 Fs. 1-4Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.).

[0028] In some preferred embodiments, R in the present structure (e.g., M-1 to M-15) A It could be G 5A C(O)G 5A C(O)OG 5A C(O)N(CH3)G 5A or SO2G 5A G 5A C is optionally replaced by one or two substituents, each independently selected from F or methyl. 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, , , , , wait.

[0029] In some preferred embodiments, R in the present structure (e.g., M-1 to M-15) A It could be G 5A C(O)G 5A C(O)OG 5A C(O)N(CH3)G 5A or SO2G 5A G 5A -(C) is optionally substituted by one or two substituents, each independently selected from F or methyl. 1-3 alkylene)-(C 3-6 cycloalkyl), such as , , wait.

[0030] In some preferred embodiments, R in the present structure (e.g., M-1 to M-15) A It could be G 5A C(O)G 5A C(O)OG 5A C(O)N(CH3)G 5A or SO2G 5A G 5A A 4-6 membered heterocyclic group, optionally substituted by one or two substituents each independently selected from F or methyl, such as , , , , , , Etc. Preferably, the 4-6 membered heterocyclic group is not connected to heteroatom through a cyclic heteroatom.

[0031] In some preferred embodiments, R in the present structure (e.g., M-1 to M-15) A It could be G 5A C(O)G 5A or SO2G 5A G 5A It is a phenyl or 5-10-membered heteroaryl group (e.g., pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, 9 H -purine group, imidazo[1,2-] b [[pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc.]], which are optionally substituted by one or two substituents, each independently selected from F, Cl, CN, and optionally substituted by F, such as... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , wait.

[0032] In some preferred embodiments, R in the present structure (e.g., M-1 to M-15) A It could be C(O)NHG 5A G 5A C can be arbitrarily replaced by 1-3 Fs. 1-4Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.). For example, R A It can be C(O)NH (isopropyl).

[0033] In some preferred embodiments, R in the present structure (e.g., M-1 to M-15) A It can be C(O)NG 5A G 5A In one case of G 5A C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.), and in another case, G. 5A C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.) or C groups optionally substituted with one or two substituents each independently selected from F or methyl. 3-6 Cycloalkyl groups, such as cyclopropyl groups. For example, R... A It can be C(O)N(CH3)2.

[0034] In some implementations, R in the structure (e.g., M-1 to M-15) A Selected from:

[0035]

[0036]

[0037] .

[0038] In some implementations, in the applicable formula or structural part, j is 0, or j is 1 and R B It is a methyl group.

[0039] In some implementations, R in Formula I or II 1 for or , where M is –CH2- or –CH2CH2-, and each of the rings can be substituted independently and optionally. When at least one ring is substituted, or It can usually be substituted by one or more substituents, such as a total of 1 to 3 (e.g., 1 or 2) independently selected from deuterium, F, OH, NH2, CN, G. 5 OG 5 NH-C(O)G 5 and C(O)G5 The substituents are replaced by G, where G is the substituent. 5 It is C independently each time it appears. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H- Purine group, imidazo[1,2- b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., wherein C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. B Replaced, of which G B Each time it appears, it is independently deuterium, F, Cl, CN, OH, or C that is optionally replaced by 1-3 F. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F groups 1-4 alkyl.

[0040] In some specific implementation schemes, R in Formula I or II 1 You can choose from:

[0041]

[0042]

[0043] .

[0044] In some specific implementation schemes, R in Formula I or II 1 You can choose from:

[0045]

[0046] .

[0047] In some specific implementation schemes, R in Formula I or II 1 You can choose from:

[0048]

[0049] .

[0050] In some specific implementation schemes, R in Formula I or II 1 You can choose from:

[0051]

[0052] .

[0053] In some specific implementations, R in Formula I or II 1 Selected from:

[0054]

[0055]

[0056] .

[0057] In some implementations, R in Formula I or II 1 The substituted carbon cyclic group can be optionally substituted with a 4-10, such as a 4-7 member. The 4-10 member carbon cyclic group can be monocyclic or polycyclic. In some embodiments, the 4-10 member carbon cyclic group has one or two carbon-carbon double bonds, such as... or In some implementations, the 4-10 member carbon cycloalloys can also be fully saturated, such as... Or cyclohexyl. In some embodiments, the 4-10 membered carbon cyclo group can be a bridging ring, such as... , ,or When substituted, the 4-10 membered carbon cycloalgides are usually selected independently by one or more, such as one or two, deuterium, halogen, OH, NH2, COOH, CONH2, CN, G. 4 OG 4 OC(O)G 4 NHG 4 NG 4 G 4 NH-C(O)G 4 C(O)G 4 C(O)OG4 C(O)NHG 4 C(O)NG 4 G 4 OC(O)NHG 4 OC(O)NG 4 G 4 ,NHC(O)NHG 4 and N(G 4 )C(O)NG 4 G 4 The substituents are replaced by G, where G is the substituent. 4 It is C independently each time it appears. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., wherein C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A Replaced, of which G A Each time it appears, it is independently deuterium, halogen, CN, OH, or C that is optionally replaced by 1-3 F atoms. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F groups 1-4 alkyl.

[0058] In some implementations, R in Formula I or II 1 The bridging ring can be an optionally substituted 5-12 membered ring structure, wherein the bridging ring structure optionally contains 1-4 cyclic heteroatoms independently selected from O, N, and S. As used herein, a bridging ring structure refers to any ring structure containing at least one bridge. Non-limiting bridging bicyclic ring structures include... , , , or Etc. In some implementations, R in Formula I or II 1It can be an optional 5-12 quintic bridging bicyclic carbon ring-based ring structure that can be replaced. For example, in some embodiments, R 1 The 5-8 bridging bicyclic carbon ring base ring structure can be optionally replaced. In some embodiments, R in Formula I or II... 1 It can be an optionally substituted 5-12 nucleotide (preferably 7-10 nucleotide, e.g., 7 or 8 nucleotide) bridging bicyclic heterocyclic base ring structure, wherein the bridging bicyclic heterocyclic base ring structure has one cyclic heteroatom that is an epoxy. In some embodiments, R in Formula I or II 1 It can be an optional 5-12 ternary (preferably 8-10 ternary) bridging bicyclic heterocyclic base ring structure, wherein the bridging bicyclic heterocyclic base ring structure has one or two independently selected cyclic heteroatoms chosen from S, O and N.

[0059] In some implementations, R in Formula I or II 1 It can be (M-16) (M-17) (M-18) (M-19) (M-19') or The structure of (M-19''), where R C Hydrogen, halogens (e.g., F), CN, COOH, CONH2, G 4A OG 4A C(O)G 4A C(O)OG 4A C(O)NHG 4A C(O)NG 4A G 4A ,NHC(O)G 4A 、NHC(O)OG 4A ,NHC(O)NHG 4A ,NHC(O)NG 4A G 4A NG 4A C(O)G 4A NG 4A C(O)OG 4A NG 4A C(O)NHG 4A NG 4A C(O)NG 4A G 4A SO2G 4A SO2NHG 4A or SO2NG 4A G 4A G 4A Each occurrence is independently (i)C 1-4Alkyl, C 2-4 alkenyl or C 2-4 (ii) 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., (iii)–(C 1-4 alkylene)-3-12-membered ring, such as –(C 1-4 (iv)–(C 1-4 (heteroalkyl)-3-12-membered ring such as –(C 1-4 (heteroalkyl)-3-7-membered ring, wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A1 Replaced, of which G A1 Each time it appears, it is independently deuterium, halogen, CN, OH, NH2, or C that is optionally replaced by 1-3 F atoms. 1-4 Heteroalkyl groups, C atoms optionally substituted with 1-3 F atoms. 1-4 Alkyl or optionally a 3- to 5-membered ring substituted with one or more substituents that are independently F, CN, OH, methoxy, or methyl (e.g., cyclopropyl, cyclobutyl, oxetane, azirone, etc.). C in (iii) 1-4 The alkylene group can be straight-chain or branched; for example, in some embodiments, C 1-4 The alkylene group is CH2 or CH(CH3). In some embodiments, C in (iv) 1-4 Heteroalkyl groups contain one or two heteroatoms, such as one oxygen atom, one nitrogen atom, two oxygen atoms, two nitrogen atoms, or one oxygen atom and one nitrogen atom. Similarly, the C 1-4 Heteroalkyl groups can be straight-chain or branched; for example, in some embodiments, the C... 1-4 The heteroalkylene group can be O-CH2 or CH(OCH3), etc. The 3-12 (e.g., 3-7) membered ring typically includes 0-3 cyclic heteroatoms. For example, in some embodiments, the 3-12 (e.g., 3-7) membered ring is C. 3-7Cycloalkyl. In some embodiments, the 3-12 (e.g., 3-7) membered ring is a 4-7 membered heterocyclic group having 1-2 cyclic heteroatoms, each independently selected from O, S, or N. In some embodiments, the 3-12 (e.g., 3-7) membered ring is a phenyl group. In some embodiments, the 3-12 (e.g., 3-7) membered ring is a 5-membered heteroaryl group having 1-4, such as 1-3, cyclic heteroatoms, each independently selected from O, S, or N. In some embodiments, the 3-12 (e.g., 3-7) membered ring is a 6-membered heteroaryl group having 1-2 cyclic nitrogen atoms. In some embodiments, the 3-12 membered ring is a 3-7 membered ring as defined herein. In some embodiments, the 3-12 membered ring is cyclopropyl, cyclobutyl, oxacyclobutane, aziranebutane, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, 9 H -purine group, imidazo[1,2-] b [Pyridazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, or phenyl. In some embodiments, R in formula I or II 1 It has a structure according to M-17 as defined herein. In some embodiments, R in Formula I or II 1 It has a structure according to M-18 as defined herein. In some embodiments, R in Formula I or II 1 It has a structure according to M-19 as defined herein. In some embodiments, R in Formula I or II 1 It has a structure according to M-19' as defined herein. In some embodiments, R in Formula I or II 1 It has a structure according to M-19'' as defined herein.

[0060] In some implementations, R in any of the formulas applicable herein (e.g., formulas M-16, M-17, M-18, M-19, M-19', or M-19'', etc.) C It can be CN. In some implementations, R C It can be H, a halogen (such as F, Cl, or Br), OH, NH2, CH2OH, CH(OH)CH3, CH2CH3, CH2F, CH2OCH3, CHF2, CH3, or OCH3. In some embodiments, R C For G 4A In some implementations, R C C(O)G 4A In some implementations, RC C(O)NHG 4A or C(O)NG 4A G 4A In some implementations, R C For NHC(O)G 4A 、NHC(O)OG 4A ,NHC(O)NHG 4A or NHC(O)NG 4A G 4A In some implementations, R C For G 4A C(O)G 4A C(O)NHG 4A ,NHC(O)G 4A 、NHC(O)OG 4A or NHC(O)NHG 4A G 4A C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.). In some embodiments, R C For G 4A C(O)G 4A C(O)NHG 4A ,NHC(O)G 4A 、NHC(O)OG 4A or NHC(O)NHG 4A G 4A C is optionally replaced by one or two substituents, each independently selected from F or methyl. 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, , , Etc. In some implementations, R C For G 4A C(O)G 4A C(O)NHG 4A ,NHC(O)G 4A 、NHC(O)OG 4A or NHC(O)NHG 4A G 4A –(C) can be optionally substituted by one or two substituents, each independently selected from F or methyl. 1-3 alkylene)-(C 3-6 cycloalkyl), such as , , Etc. In some implementations, R C For G 4A C(O)G4A C(O)NHG 4A ,NHC(O)G 4A 、NHC(O)OG 4A or NHC(O)NHG 4A G 4A A 4-6 membered heterocyclic group, optionally substituted by one or two substituents each independently selected from F or methyl, such as , , , , , , Generally, when 4-6 membered heterocyclic groups are linked by a cyclic nitrogen, R C C(O)G 4A For example, in some implementations, R C for , or In some implementations, R C For G 4A C(O)G 4A C(O)NHG 4A ,NHC(O)G 4A 、NHC(O)OG 4A or NHC(O)NHG 4A G 4A The aryl group is phenyl or a 5- or 6-membered heteroaryl group (e.g., pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, etc.), wherein the phenyl or the 5- or 6-membered heteroaryl group is optionally substituted by one or two substituents that are each independently F, Cl, CN, optionally substituted by 1-3 F groups, or cyclopropyl groups, such as... , , , , , , , , , , , , , , , , , , , , , , Etc. In some implementations, R C C(O)NG 4A G 4A or NHC(O)NG 4A G 4A In one case of G 4A C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.), and in another case, G. 4A C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.) or C groups optionally substituted with one or two substituents each independently selected from F or methyl. 3-6 Cycloalkyl groups, such as cyclopropyl groups.

[0061] In some specific implementations, R in Formula I or II 1 Can be selected .

[0062] In some specific implementations, R in Formula I or II 1 Having a structure according to M-16 as defined herein, for example, it can be... .

[0063] In some specific implementations, R in Formula I or II 1 Having a structure according to M-17 as defined herein, for example, it may be selected from

[0064]

[0065]

[0066]

[0067] .

[0068] In some specific implementations, R in Formula I or II 1 Having a structure according to M-17 as defined herein, for example, it can be... .

[0069] In some specific implementations, R in Formula I or II 1 Having a structure according to M-18 as defined herein, for example, it can be... , or .

[0070] In some specific implementations, R in Formula I or II 1 Having a structure according to M-19 as defined herein, for example, it may be selected from .

[0071] In some specific implementations, R in Formula I or II 1 It can also be cycloalkyl, such as .

[0072] In some specific implementations, R in Formula I or II 1 It can also be a bridging heterocyclic base, such as .

[0073] In some specific implementations, R in Formula I or II 1 You can also choose from .

[0074] In some implementations, R in Formula I or II 1 It can also be an substituted phenyl group. When substituted, the phenyl group is usually selected independently by one or more, such as one or two, deuterium, halogen, OH, NH2, COOH, CONH2, CN, G 4 OG 4 OC(O)G 4 NHG 4 NG 4 G 4 NH-C(O)G 4 C(O)G 4 C(O)OG 4 C(O)NHG 4 C(O)NG 4 G 4 OC(O)NHG 4 OC(O)NG 4 G 4 ,NHC(O)NHG 4 and N(G 4 )C(O)NG 4 G 4 The substituents are replaced by G, where G is the substituent. 4 It is C independently each time it appears. 1-4 Alkyl, C 2-4 alkenyl, C 2-4Alkyne or 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., wherein C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A Replaced, of which G A Each time it appears, it is independently deuterium, halogen, CN, OH, or C that is optionally replaced by 1-3 F atoms. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F groups 1-4 alkyl.

[0075] In some implementations, R in Formula I or II 1 It can be , where R D Halogen, CN, G 4B OG 4B NHG 4B NG 4B G 4B C(O)G 4B OC(O)G 4B ,NHC(O)G 4B NG 4B C(O)G 4B C(O)OG 4B C(O)NHG 4B C(O)NG 4B G 4B OC(O)OG 4B OC(O)NHG 4B OC(O)NG 4B G 4B 、NHC(O)OG 4B ,NHC(O)NHG 4B ,NHC(O)NG 4B G 4B NG 4B C(O)OG 4B NG4B C(O)NHG 4B NG 4B C(O)NG 4B G 4B SO2G 4B SO2NHG 4B or SO2NG 4B G 4B G 4B Each occurrence is independently (i)C 1-4 Alkyl, C 2-4 alkenyl or C 2-4 (ii) 3-12 (e.g., 3-8) membered rings (e.g., cyclopropyl, cyclobutyl, oxacyclobutane, aziranebutane, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., (iii)–C 1-4 alkylene)-3-12-membered ring such as –(C 1-4 (iv) –(C 1-4 (heteroalkyl)-3-12-membered ring such as –(C 1-4 (heteroalkyl)-3-8-membered ring, wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 (e.g., 3-8) membered ring is optionally surrounded by one or more (e.g., 1, 2, or 3) G groups. A1 Replaced, of which G A1 Each time it appears, it is independently deuterium, halogen, CN, OH, NH2, or C that is optionally replaced by 1-3 F atoms. 1-4 Heteroalkyl groups, C atoms optionally substituted with 1-3 F atoms. 1-4 Alkyl or optionally a 3- to 5-membered ring substituted with one or more substituents independently selected from F, CN, OH, methoxy, and methyl (e.g., cyclopropyl, cyclobutyl, oxetane, azirone, etc.); wherein R E Each time it appears, it is independently F, Cl, CN, OH, or C that is optionally replaced by 1-3 Fs. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 F atoms. 1-4A heteroalkyl group or a 3- or 4-membered ring optionally substituted with 1-2 substituents each independently selected from F or methyl, and k is 0, 1, or 2. (iii) C 1-4 The alkylene group can be straight-chain or branched; for example, in some embodiments, C 1-4 The alkylene group is CH2 or CH(CH3). In some embodiments, C in (iv) 1-4 Heteroalkyl groups contain one or two heteroatoms, such as one oxygen atom, one nitrogen atom, two oxygen atoms, two nitrogen atoms, or one oxygen atom and one nitrogen atom. Similarly, the C 1-4 Heteroalkyl groups can be straight-chain or branched; for example, in some embodiments, the C... 1-4 The heteroalkylene group can be O-CH2 or CH(OCH3), etc. The 3-8 membered ring typically includes 0-3 cyclic heteroatoms. For example, in some embodiments, the 3-8 membered ring is C. 3-8 Cycloalkyl. In some embodiments, the 3-8 membered ring is a 4-8 membered heterocyclic group having 1-2 cyclic heteroatoms each independently selected from O, S, or N. In some embodiments, the 3-12 (e.g., 3-8) membered ring is a phenyl group. In some embodiments, the 3-12 (e.g., 3-8) membered ring is a 5-membered heteroaryl group having 1-3 cyclic heteroatoms each independently selected from O, S, or N. In some embodiments, the 3-12 (e.g., 3-8) membered ring is a 6-membered heteroaryl group having 1-2 cyclic nitrogen atoms. In some embodiments, the 3-12 (e.g., 3-8) membered ring is cyclopropyl, cyclobutyl, oxacyclobutane, aziranebutane, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, or phenyl. In some embodiments, k is 0. In some embodiments, k is 1, and R E In this paper, is defined as F.

[0076] In some implementations, R in Formula I or II 1 It can also be an optionally substituted 5- or 6-membered heteroaryl group, such as those having one, two, or three independently selected cyclic heteroatoms chosen from N, S, and O. For example, in some embodiments, R 1 The substituted 5-membered heteroaryl group is optionally substituted with one or two cyclic heteroatoms, such as two cyclic nitrogen atoms. In some embodiments, R 1 The substituted 6-membered heteroaryl group is optionally substituted and has one or two cyclic nitrogen atoms. In some embodiments, R 1 For example, pyrazolyl group, Its optionality is replaced. In some implementations, R 1 For example, pyridyl group, or Its optionality is replaced. In some implementations, R 1 It is pyrimidinyl, for example, The 5-membered heteroaryl group can be optionally substituted. Similarly, the 5-membered heteroaryl group can be attached to the remainder of Formula I or II via a carbon or N ring atom, provided the valence allows, and when substituted, it can be substituted at any available position (including at the ring nitrogen atom). When substituted, the 5- or 6-membered heteroaryl group is typically replaced by one or more, such as one or two, independently selected from deuterium, halogens, OH, NH2, COOH, CONH2, CN, G. 4 OG 4 OC(O)G 4 NHG 4 NG 4 G 4 NH-C(O)G 4 C(O)G 4 C(O)OG 4 C(O)NHG 4 C(O)NG 4 G 4 OC(O)NHG 4 OC(O)NG 4 G 4 ,NHC(O)NHG 4 or N(G) 4 )C(O)NG 4 G 4 The substituents are replaced by G, where G is the substituent. 4 It is C independently each time it appears. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., wherein C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A Replaced, of which G A Each time it appears, it is independently deuterium, halogen, CN, OH, or C that is optionally replaced by 1-3 F atoms. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F groups 1-4 alkyl.

[0077] In some implementations, R in Formula I or II 1 It can be based on: (M-20) (M-21) (M-22) (M-23) (M-24) or The structure of (M-25), where R D Halogen, CN, G 5B NHG 5B NG 5B G 5B C(O)G 5B C(O)OG 5B C(O)NHG 5B C(O)NG 5B G 5B SO2G 5B SO2NHG 5B or SO2NG 5B G 5B G 5B Each occurrence is independently (i)C 1-4 Alkyl, C 2-4 alkenyl or C 2-4 (ii) 3-12 (e.g., 3-8) membered rings (e.g., cyclopropyl, cyclobutyl, oxacyclobutane, aziranebutane, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., (iii)–(C 1-4 alkylene)-3-12-membered ring such as –(C 1-4 (iv)–(C 1-4(heteroalkyl)-3-12-membered ring, such as –(C 1-4 (heteroalkyl)-3-8-membered ring, wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 (e.g., 3-8) membered ring is optionally surrounded by one or more (e.g., 1, 2, or 3) G groups. B1 Or one or more (e.g., 1, 2, or 3) G B2 Replaced, of which G B1 Defined in this paper, and where G B2 Each time it appears, it is independently deuterium, F, Cl, CN, OH, NH2, or C that is optionally replaced by 1-3 F atoms. 1-4 Alkyl groups, C atoms optionally substituted with 1-3 F atoms 1-4 Alkyl or optionally substituted with one or more substituents independently selected from F, CN, OH, methoxy and methyl (e.g. cyclopropyl, cyclobutyl, oxetyl, aziryl, etc.).

[0078] In some preferred embodiments, R in the present structure (e.g., M-20 to M-25) D It could be G 5B C(O)G 5B C(O)OG 5B or SO2G 5B G 5B C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.). In some preferred embodiments, R in the structures described herein (e.g., M-20 to M-25) D It can be C(O)G 5B C(O)OG 5B or SO2G 5B G 5B C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups, such as methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, or tert-butyl.

[0079] In some preferred embodiments, R in the present structure (e.g., M-20 to M-25) D It could be G 5B C(O)G 5B C(O)OG 5B or SO2G 5B G 5B C is optionally replaced by one or two substituents, each independently selected from F or methyl. 3-6Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, , , , wait.

[0080] In some preferred embodiments, R in the present structure (e.g., M-20 to M-25) D It could be G 5B C(O)G 5B C(O)OG 5B or SO2G 5B G 5B –(C) can be optionally substituted by one or two substituents, each independently selected from F or methyl. 1-3 alkylene)-(C 3-6 cycloalkyl), such as , , wait.

[0081] In some preferred embodiments, R in the present structure (e.g., M-20 to M-25) D It could be G 5B C(O)G 5B C(O)OG 5B or SO2G 5B G 5B It is a 4-7 membered heterocyclic group (e.g., having one or two cyclic heteroatoms independently selected from O and N), such as aziridine, pyrrolidinyl, piperidinyl, oxazolyl, etc., which is optionally substituted by one or two substituents independently selected from OH, OCH3, F and methyl, such as , , , , , , , , , , , , , , , , , , , , , wait.

[0082] In some preferred embodiments, R in the present structure (e.g., M-20 to M-25) D It could be G5B C(O)G 5B C(O)OG 5B or SO2G 5B G 5B It is a 5- or 6-membered heteroaryl group, such as pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, etc., optionally substituted by one or two substituents, each independently selected from F, Cl, CN, optionally substituted by F, and cyclopropyl groups, such as... , , , wait.

[0083] In some preferred embodiments, R in the present structure (e.g., M-20 to M-25) D It could be NHG 5B or C(O)NHG 5B G 5B C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.). For example, in some embodiments, R D It could be NHCH3.

[0084] In some preferred embodiments, R in the present structure (e.g., M-20 to M-25) D It can be C(O)NG 5B G 5B In one case of G 5B C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.), and in another case, G. 5B C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups (e.g., methyl, ethyl, trifluoroethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.) or C groups optionally substituted with one or two substituents each independently selected from F or methyl. 3-6 Cycloalkyl groups, such as cyclopropyl groups. For example, in some embodiments, R... D It could be CON(CH3)2.

[0085] In some implementations, R in the structure described herein (e.g., M-20 to M-25) DIt can be H, F, CN, ethynyl, methyl, ethyl, OCH3, NHCH3, or cyclopropyl. In some embodiments, R in the structures described herein (e.g., M-20 to M-25) D Selected from:

[0086]

[0087]

[0088]

[0089] .

[0090] In some implementations, in the applicable formula or structural part, k is 0, or k is 1 and R E It is F, Cl, CN, methyl, or k is 2 and R E Each can be either F or methyl.

[0091] In some implementation schemes, R 1 It can be a phenyl group, which is optionally replaced by 1-3 C atoms independently selected from deuterium, F, Cl, CN, OH, or optionally replaced by 1-3 F atoms. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

[0092] In some implementations, R in Formula I or II 1 It can be an optionally substituted phenyl group, such as those having a structure according to M-20 to M-22, for example, R. 1 You can choose from:

[0093]

[0094]

[0095] .

[0096] In some implementations, R in Formula I or II 1 You can choose from: .

[0097] In some implementation schemes, R 1 for .

[0098] In some implementations, R in Formula I or II 1It can also be an optionally substituted bicyclic heteroaryl group, such as benzoxazolyl, benzimidazolyl, or triazolylpyridinyl, for example, , or It may be selected by one or more, such as one or two, independently selected from deuterium, halogen, OH, NH2, COOH, CONH2, CN, G 4 OG 4 OC(O)G 4 NHG 4 NG 4 G 4 NH-C(O)G 4 C(O)G 4 C(O)OG 4 C(O)NHG 4 C(O)NG 4 G 4 OC(O)NHG 4 OC(O)NG 4 G 4 ,NHC(O)NHG 4 and N(G 4 )C(O)NG 4 G 4 The substituents are replaced by G, where G is the substituent. 4 It is C independently each time it appears. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., wherein C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A Replaced, of which G A Each time it appears, it is independently deuterium, halogen, CN, OH, or C that is optionally replaced by 1-3 F atoms. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F groups1-4 Alkyl group. For example, in some embodiments, R 1 for .

[0099] In some implementations, in Formula I or II, R 3 Typically hydrogen, halogens, CN, OH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 The alkyl group is substituted. In some embodiments, in formula I or II, R... 3 It is hydrogen. In some embodiments, in formula I or II, R 3 It is a methyl group.

[0100] In some implementations, R in Formula I or II 4 Hydrogen, halogen, CN, OH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

[0101] In some preferred embodiments, R in Formula I or II 4 C can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl; preferably, R 4 It is methyl, or R 4 It is either CD3 or CF3.

[0102] In some preferred embodiments, R in Formula I or II 4 It is a halogen; preferably, R 4 For F. In some implementations, R 4 It can be Cl or Br.

[0103] In some implementations, R in Formula I or II 4 It can be .

[0104] In some implementations, R in Formula I or II 5 Hydrogen, halogen, CN, OH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

[0105] In some preferred embodiments, R in Formula I or II 5 It is hydrogen.

[0106] R in formula I or II 6 and R 7 They can be the same or different. In some implementations, R 6 and R 7 Both are hydrogen. In some implementations, R 6 It is hydrogen, and R 7 For C, which is optionally replaced by one or more (e.g., 1-3) independently selected from deuterium, F, CN, OH, and C optionally replaced by 1-3 F. 1-4 The C substituent of the alkoxy group 1-4 Alkyl group. In some embodiments, R 6 It is hydrogen, and R 7 A 3- to 6-membered ring having 0, 1, or 2 heteroatoms, such as a cyclopropyl ring, optionally substituted with one or more (e.g., 1 or 2) C atoms, each independently selected from deuterium, F, CN, OH, and optionally substituted with 1 to 3 F atoms. 1-4 The alkyl group is substituted. In some preferred embodiments, R 6 It is hydrogen or deuterium, and R 7C 1-4 Alkyl; preferably, R 6 It is hydrogen or deuterium, and R 7 It is a methyl group.

[0107] It should be understood that when R 6 and R 7 At the same time, the compound has a chiral center. In some preferred embodiments, R is connected in formula I or II, or in any applicable subform, of the compound. 6 and R 7 (If R) 6 and R 7 Different carbons exhibit the following chirality: In some preferred embodiments, R is connected in formula I or II, or in any applicable subform of it. 3 and R 4 (If R) 3 and R 4 Different carbons exhibit the following chirality: For the chiral carbon, the compound may have an enantiomeric excess of greater than 50% (“ee”) (e.g., 60% ee or greater, 80% ee or greater, 90% ee or greater, 95% ee or greater, 98% ee or greater, 99% ee or greater). For example, in some embodiments, in Formula I or II, R 6 For hydrogen, R 7 It is methyl, and R 6 and R 7 All the carbon atoms are bonded to have an S-configuration. In some embodiments, in formula I or II, R 6 For hydrogen, R 7 It is methyl, and R 6 and R 7 All carbon atoms are connected to the R-configuration. This disclosure is not limited to any particular enantiomer (for those with R...). 6 and R 7 (In terms of both bonded chiral carbons), but rather encompasses two enantiomers and their mixtures in any ratio.

[0108] In equation I or II, R 8 It is typically hydrogen. In some implementations, R 8 C is optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl group. In some embodiments, R 8 It is a nitrogen protecting group as described herein.

[0109] L in formula I or II 2 Typically, it is an optionally substituted phenylene or a 5- or 6-membered heteroaryl group. For example, in some embodiments, L2 The substituted phenylene oxide is optional. For example, L 2 It can be by The 1,2-phenylene group is optionally substituted (i.e., the remaining four positions of the benzene ring can be optionally further substituted). When substituted, the phenylene group can typically be selected independently from one or more halogens, CN, OH, COOH, G... 6 and OG 6 The substituents are replaced by G, where G is the substituent. 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

[0110] In some implementations, L in Formula I or II 2 It can be an optionally substituted 6-membered heteroaryl group. Typically, the 6-membered heteroaryl group contains one or two cyclic nitrogen atoms, such as pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. For example, L... 2 It can be arbitrarily replaced In some implementations, L 2 It can be arbitrarily replaced In some implementations, L 2 It can be arbitrarily replaced When substituted, the 6-membered heteroaryl group can typically be selected independently from one or more (e.g., 1 or 2) halogens, CN, OH, COOH, G... 6 and OG 6 The substituents are replaced by G, where G is the substituent. 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

[0111] In some implementations, L in Formula I or II 2 It can be an optionally substituted 5-membered heteroaryl group. Typically, the 5-membered heteroaryl group contains one or two cyclic heteroatoms. For example, in some embodiments, L... 2 It can be arbitrarily replaced When substituted, the 5-membered heteroaryl group can typically be selected independently from one or more (e.g., 1 or 2) halogens, CN, OH, COOH, G. 6 and OG 6 The substituents are replaced by G, where G is the substituent. 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

[0112] In some preferred embodiments, L in Formula I or II 2 It can be NR is shown 8 and C(O)R 9 To show the connection direction with the rest of the molecule, and where R 20 For hydrogen, halogens, CN, OH, COOH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 The alkyl group is substituted. In some preferred embodiments, R20 It can be hydrogen, F, Cl, or C substituted with 1-3 F atoms. 1-4 Alkyl groups, such as CHF2 or CF3. In some embodiments, R 20 for .

[0113] In some preferred embodiments, L in Formula I or II 2 It can be NR is shown 8 and C(O)R 9 To show the connection direction with the rest of the molecule, and where R 20 For hydrogen, halogens, CN, OH, COOH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 The alkyl group is substituted. In some preferred embodiments, R 20 It can be hydrogen, F, Cl, or C substituted with 1-3 F atoms. 1-4 Alkyl groups, such as CHF2 or CF3. In some embodiments, R 20 for .

[0114] In some preferred embodiments, L in Formula I or II 2 It can be NR is shown 8 and C(O)R 9 To show the connection direction with the rest of the molecule, and where R 20 and R 21 Each can be independently represented by hydrogen, halogen, CN, OH, COOH, or G. 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 The alkyl group is substituted. In some preferred embodiments, R 20 and R 21 Each can be independently hydrogen, F, Cl, CN, or C substituted with 1-3 F atoms. 1-4 Alkyl groups, such as CHF2 or CF3. In some preferred embodiments, R 20 For CN and R 21 It is a halogen (e.g., Cl).

[0115] In some implementations, N and L in Formula I or II 2 C(O), R 9 and R 8 The linkage forms an optionally substituted 6,6-fused bicyclic heterocyclic group or heteroaryl group, i.e., The substituted 6,6-fused bicyclic heterocyclic group or heteroaryl group may be used. In some preferred embodiments, the substituted 6,6-fused bicyclic heterocyclic group or heteroaryl group in Formula I or II... It can be or , where R 20 For hydrogen, halogens, CN, OH, COOH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 The alkyl group is substituted. In some preferred embodiments, R 20 It can be hydrogen, F, Cl, or C substituted with 1-3 F atoms. 1-4 Alkyl groups, such as CHF2 or CF3. In some preferred embodiments, the alkyl group in formula I or II... for .

[0116] In some preferred embodiments, the compound of formula I or II may be characterized by having a structure according to formula Ia, Ib, II-a, or II-b:

[0117] in: R 20 For hydrogen, halogens, CN, OH, COOH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 The alkyl group is substituted; and Among them, variables W and R X R 1 R 3 R 4 R 5 R 6 and R 7 Defined in this article.

[0118] In some implementation schemes, R 20 It can be hydrogen, F, Cl, or C substituted with 1-3 F atoms. 1-4 Alkyl groups, such as CHF2 or CF3. For example, in some embodiments, R 20 It can be hydrogen. In some implementations, R 20 It can be F or Cl.

[0119] In some preferred embodiments, compounds of formula I or II (e.g., any applicable sub-formula, such as formula Ia, Ib, II-a, or II-b) are characterized by having a structure according to formula Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, Ib-4, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4:

[0120] in: R C Hydrogen, halogen, CN, COOH, CONH2, G 4A C(O)G 4A C(O)OG 4A C(O)NHG 4A C(O)NG 4A G 4A SO2G 4A SO2NHG 4A or SO2NG 4A G 4A G 4A Each occurrence is independently (i)C 1-4 Alkyl, C 2-4 alkenyl or C 2-4 (ii) 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., (iii)–(C 1-4 alkylene)-3-12-membered ring, such as –(C 1-4 (iv)–(C 1-4 (heteroalkyl)-3-12-membered ring such as –(C 1-4 (heteroalkyl)-3-7-membered ring, wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A1 Replaced, of which G A1 Each time it appears, it is independently deuterium, halogen, CN, OH, NH2, or C that is optionally replaced by 1-3 F atoms. 1-4 Heteroalkyl groups, C atoms optionally substituted with 1-3 F atoms. 1-4 Alkyl or optionally substituted with one or more substituents independently selected from F, CN, OH, methoxy or methyl (e.g. cyclopropyl, cyclobutyl, oxetane, azirone, etc.). Among them, variables W and R XR 3 R 4 R 5 R 6 R 7 and R 20 Defined in this article.

[0121] In some implementations, in the applicable formula or structural part (e.g., formulas Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, Ib-4, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4), R C The derivative is H, F, Cl, OH, NH2, CN, COOH, CH3, OCH3, CH2OH, CH(OH)CH3, CH2CH3, CH2OCH3, CH2F, CHF2, or CF3. In some embodiments, R is used in the applicable formula or structural part (e.g., formula Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, Ib-4, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4). C Selected from:

[0122]

[0123] In some preferred embodiments, R in the applicable formula or structural portion C It can be H, F, CN, Alternatively, a substituted 5-membered heteroaryl group may be used, for example, a triazole, thiadiazole, or oxadiazole optionally substituted with methyl, CD3, CF3, or cyclopropyl. In some embodiments, R is used in the applicable formula or structural part (e.g., formula Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, Ib-4, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4). C C(O)NHG 4A G 4A It is a 5-membered heteroaryl group containing one, two, three, or four cyclic heteroatoms each independently selected from N, O, and S, wherein the 5-membered heteroaryl group is optionally composed of one or more cyclic heteroatoms each independently selected from C. 1-4 Alkyl, fluorine-substituted C 1-4Substituents of alkyl and cyclopropyl groups; preferably, G 4A for .

[0124] Further specific definitions of the variables in Formula I or II (e.g., sub-formulas such as Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3 or Ib-4, II-a, II-b, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3 or II-b-4) include those corresponding atoms / groups / structures shown in the example compounds herein, see, for example, those shown in Table A and the Examples section.

[0125] In some embodiments, this disclosure also provides compounds selected from the compounds shown in the Example section or Compound Numbers 1-11, or pharmaceutically acceptable salts thereof.

[0126] In some embodiments, this disclosure also provides compounds selected from those shown in Table A below, or pharmaceutically acceptable salts thereof: Table A. List of compounds

[0127]

[0128] .

[0129] Exemplary synthesis and characterization of the above-described compounds are shown in the Examples section. PCT / CN2023 / 090210, filed April 24, 2023, the contents of which are incorporated herein by reference in their entirety, describes further exemplary synthesis of the compounds which may be adapted to synthesize the compounds disclosed herein. The compounds may be prepared according to this disclosure in a racemic form with respect to one or more chiral centers (the racemic form may be segregated into two enantiomers, including the enantiomers as illustrated), or may be prepared by chiral synthesis.

[0130] In some embodiments, to the extent applicable, the genus of compounds in this disclosure also excludes any compounds that have been explicitly prepared and disclosed prior to this disclosure.

[0131] The compounds disclosed herein can be readily synthesized by those skilled in the art based on this disclosure. Example synthesis is also shown in the Examples section.

[0132] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in "Protective Groups in Organic Synthesis", 4th edition, PGM Wuts; TW Greene, John Wiley, 2007, and the references cited therein. The reagents used in the reactions described herein are well-known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Other reagents may be prepared by procedures described in standard reference texts, such as Fieser and Fieser's "Reagents for Organic Synthesis" Volumes 1–15 (John Wiley and Sons, 1991), Rodd's "Chemistry of Carbon Compounds" Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989), "Organic Reactions" Volumes 1–40 (John Wiley and Sons, 1991), March's "Advanced Organic Chemistry" (Wiley, 7th edition), and Larock's "Comprehensive Organic Transformations" (Wiley-VCH, 1999), as well as any available updates up to the time of this application.

[0133] Pharmaceutical Composition Some embodiments involve pharmaceutical compositions comprising one or more compounds disclosed herein.

[0134] The pharmaceutical composition may optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of formula I (e.g., a sub-formula such as formula Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Suitable excipients, without limitation, include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's "The Science and Practice of Pharmacy," 21st edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses a variety of excipients used in the formulation of pharmaceutical compositions and known techniques for their preparation.

[0135] The pharmaceutical composition may comprise any one or more of the compounds disclosed herein. For example, in some embodiments, the pharmaceutical composition comprises (e.g., a therapeutically effective amount) a compound of formula I (e.g., sub-formulas such as formula Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from the compounds shown in the Examples section, or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the disclosed compounds used in the pharmaceutical compositions herein are selected from those compounds whose IC50 value is less than 1 μmol / L (preferably less than 100 nM or less than 50 nM) when tested in an antiproliferative assay in the T47D cell line according to Bioassay Example A herein. In some preferred embodiments, the disclosed compounds used in the pharmaceutical compositions herein are selected from those compounds whose IC50 value is greater than 1 μmol / L (preferably greater than 2 μmol / L or greater than 5 μmol / L) when tested in an antiproliferative assay in the SK-BR-3 cell line according to Bioassay Example A herein.

[0136] Pharmaceutical compositions may also be formulated for delivery via any known route of delivery, including but not limited to oral, parenteral, inhalation, etc.

[0137] In some embodiments, the pharmaceutical composition may be formulated for oral administration. Oral formulations may be presented in discrete units, such as capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of the active compound; in powder or granules; in solutions or suspensions in aqueous or non-aqueous liquids; or in oil-in-water or water-in-oil emulsions. Excipients used to prepare compositions for oral administration are known in the art. Suitable excipients that are not restrictive include, for example, agar, alginate, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butanediol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, and peanut oil. Oil), potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearate fumarate, sucrose, surfactants, talc, tragacanth gum, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof.

[0138] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral formulations can be, for example, aqueous solutions, suspensions, or emulsions. Excipients used in the preparation of parenteral formulations are known in the art. Suitable, non-limiting excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0139] In some embodiments, the pharmaceutical composition is formulated for inhalation. Inhalable formulations may be formulated, for example, as nasal sprays, dry powders, or aerosols that can be administered via a metered-dose inhaler. Excipients used to prepare inhaled formulations are known in the art. Suitable, non-limiting excipients include, for example, lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, as well as mixtures of these substances. The spray may also contain propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0140] Pharmaceutical compositions may comprise various amounts of the compounds disclosed herein, depending on various factors such as the intended use, potency, and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I (e.g., sub-formulas such as formula Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of the compounds disclosed herein is an amount effective for treating a disease or condition as described herein, which may depend on the recipient of treatment, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the efficacy of the compound (e.g., for inhibiting PI3K), its clearance rate, and whether another drug is administered concurrently.

[0141] For veterinary use, the compounds disclosed herein can be administered in appropriate and acceptable formulations according to normal veterinary practice. Veterinarians can readily determine the dosing regimen and route of administration best suited for a particular animal.

[0142] In some embodiments, all necessary components for treating PI3K-related diseases or conditions, whether used alone or in combination with another agent or intervention conventionally used to treat such diseases, may be packaged into a kit. Specifically, in some embodiments, the present invention provides a kit for a therapeutic intervention for a disease comprising a packaged drug group including the compounds disclosed herein, buffers and other components for preparing the drugs in a deliverable form, and / or a device for delivering such drugs, and / or any reagents used in combination therapies with the compounds disclosed herein, and / or instructions for treating the disease packaged with the drugs. The instructions may be affixed to any tangible medium such as printed paper, or computer-readable magnetic or optical media, or instructions referencing a remote computer data source (such as a World Wide Web accessible via the Internet).

[0143] Treatment The compounds disclosed herein can be used as therapeutically active substances for the treatment and / or prevention of diseases or conditions associated with the activity of phosphoinositol 3-kinase (PI3K), particularly PI3K-α (PI3Ka), such as those with the H1047R mutation. Such diseases or conditions include proliferative disorders (e.g., cancer).

[0144] In some embodiments, this disclosure provides a method for inhibiting the activity of phosphoinositol 3-kinase (PI3K), particularly PI3K-α (PI3Ka), such as those with the H1047R mutation, in cells, said method comprising contacting cells with an effective amount of one or more compounds of this disclosure (e.g., compounds of formula I (e.g., sub-formulas such as formula Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), compounds of formula II (e.g., sub-formulas such as II-a, II-b, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4), any compound selected from the compounds shown in Table A herein, or pharmaceutically acceptable salts thereof). As used herein, the term “cell” is intended to mean cells in vitro, ex vivo, or in vivo. In some embodiments, ex vivo cells may be a portion of a tissue sample excised from an organism such as a mammal. In some embodiments, the in vitro cells may be cells in a cell culture. In some embodiments, the in vivo cells are cells living in an organism such as a mammal. As used herein, the term "contact" means bringing the indicated portion together in an in vitro or in vivo system. For example, "contacting" PI3K with a compound of this disclosure includes administering a compound of this disclosure to a subject (e.g., a human) possessing PI3K and, for example, introducing a compound of this disclosure into a sample containing cells or a purified formulation containing the PI3K enzyme. The term "PI3K inhibitor," such as a PI3K inhibitor, refers to an agent capable of inhibiting the activity of PI3K.

[0145] In some embodiments, this disclosure provides a method of treating a disease associated with PI3K activity or expression (including aberrant activity and / or overexpression) in a subject with this need, the method comprising administering to the subject an effective amount of one or more compounds of this disclosure (e.g., compounds of formula I (e.g., sub-formulas such as formula Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), compounds of formula II (e.g., sub-formulas such as II-a, II-b, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4), any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof). Examples of disease may include any disease, symptom, or condition directly or indirectly associated with the expression or activity of the PI3K enzyme (e.g., overexpression or aberrant activity). PI3K-related diseases can also include any disease, symptom, or condition that can be prevented, improved, or cured by regulating PI3K enzyme activity. Examples of PI3K-related diseases include the various cancers described herein. In any of the embodiments described herein, unless otherwise stated or to the contrary, the PI3K enzyme can be a PI3Ka enzyme, such as those with the H1047R mutation. Examples of PI3K-related cancers include breast cancer, endometrial cancer, gastric cancer, colorectal cancer, ovarian cancer, cervical cancer, head and neck cancer, liver cancer, lung cancer, and prostate cancer. Examples of PI3K-related diseases also include CLOVES syndrome (congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS). In some implementations, PI3K-related diseases or conditions are cancers (e.g., cancers described herein, such as breast cancer, endometrial cancer, gastric cancer, colorectal cancer, ovarian cancer, cervical cancer, head and neck cancer, liver cancer, lung cancer, prostate cancer, leukemia, lymphoma, sarcoma, and melanoma). In some implementations, PI3K-related diseases or conditions include, but are not limited to, CLOVES syndrome (congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome), and PIK3CA-associated overgrowth syndrome (PROS). Endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophageal and gastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophageal and gastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, and miscellaneous.Other PI3K-related diseases or conditions are described in this article and also include those described in WO2021 / 202964, WO2023 / 060262 or WO2023 / 159155.

[0146] In some embodiments, this disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this disclosure (e.g., compounds of formula I (e.g., sub-formulas such as formula Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), compounds of formula II (e.g., sub-formulas such as II-a, II-b, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4), any compound selected from the compounds shown in Table A herein, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of the pharmaceutical composition described herein. In some embodiments, the cancer is associated with PI3K (e.g., PI3Ka, such as those having the H1047R mutation). In some implementations, the cancers include breast cancer, endometrial cancer, stomach cancer, colorectal cancer, ovarian cancer, cervical cancer, head and neck cancer, liver cancer, lung cancer, and prostate cancer. Other cancers suitable for treatment include those described herein.

[0147] In some implementation schemes, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, HIV-related cancer, HIV-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary origin, cardiac (heart) tumor, atypical teratoma-like / rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, craniopharyngioma, and skin cancer. Skin T-cell lymphoma, mycosis fungoides, Sezary syndrome, ductal carcinoma in situ (DCIS), embryonal tumor, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, gonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin's lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma Tumors, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, midline carcinoma with nut gene alteration, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumor, myelodysplastic syndrome, myelodysplastic neoplasms, myeloproliferative neoplasms, chronic myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papilloma, paraganglioma, paranasal sinus and nasal cavity Cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary adenoma, plasma cell tumor, multiple myeloma, pleural pulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, pediatric vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor.

[0148] In some implementation schemes, the cancers include endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophageal and gastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophageal and gastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumors, thyroid cancer, leukemia, or encapsulated glioma.

[0149] In some implementations, the cancer is breast cancer, prostate cancer, or brain cancer. In some implementations, the cancer is breast cancer. In some implementations, the cancer is prostate cancer. In some implementations, the cancer is brain cancer.

[0150] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is invasive ductal aneurysm. In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer is medullary carcinoma. In some embodiments, the breast cancer is tubular carcinoma. In some embodiments, the breast cancer is mucinous carcinoma. In some embodiments, the breast cancer is Paget's disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC).

[0151] In some embodiments, prostate cancer is adenocarcinoma. In some embodiments, prostate cancer is small cell carcinoma. In some embodiments, prostate cancer is a neuroendocrine tumor. In some embodiments, prostate cancer is transitional cell carcinoma. In some embodiments, prostate cancer is sarcoma.

[0152] In some embodiments, the brain cancer is an acoustic neuroma. In some embodiments, the brain cancer is an astrocytoma. In some embodiments, the brain cancer is a metastatic brain cancer. In some embodiments, the brain cancer is a choroid plexus carcinoma. In some embodiments, the brain cancer is a craniopharyngioma. In some embodiments, the brain cancer is an embryonal tumor. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a medulloblastoma. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is a pediatric brain tumor. In some embodiments, the brain cancer is a pineal cell carcinoma. In some embodiments, the brain cancer is a pituitary tumor.

[0153] In some implementations, the cancer is endometrial cancer, head and neck cancer, or sarcoma.

[0154] In some implementations, the cancer is endometrial cancer. In some implementations, the cancer is head and neck cancer. In some implementations, the cancer is sarcoma.

[0155] In some implementations, the sarcoma is a soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, amelioma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibroma.

[0156] In some implementations, the sarcoma is a soft tissue sarcoma. In some implementations, soft tissue sarcoma includes liposarcoma, atypical lipoma, dermatofibrosarcoma protuberans, malignant solitary fibroma, inflammatory myofibroblastic tumor, low-grade malignant myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade malignant fibromyxoid sarcoma, soft tissue giant cell tumor, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, soft tissue angiosarcoma, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant Triton's tumor, and malignant... Granular cell tumor, malignant ossifying fibromyxoid tumor, stromal sarcoma, myoepithelial carcinoma, malignant phosphate-urinary mesenchymal tumor, synovial sarcoma, epithelioid sarcoma, soft tissue alveolar sarcoma, soft tissue clear cell sarcoma, extraskeletal myxoid chondrosarcoma, extraskeletal Ewing's sarcoma, connective tissue proliferative small round cell tumor, extrarenal rhabdomyosarcoma, perivascular epithelioid cell tumor, endometrial sarcoma, undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, or undifferentiated sarcoma not otherwise specified.

[0157] In some embodiments, this disclosure provides a method of treating a disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of this disclosure (e.g., formula I (e.g., sub-formulas such as formula Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), formula II (e.g., sub-formulas such as II-a, II-b, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b ... The disease or condition is selected from compounds of type 3 or 12-b-4, any compound selected from those shown in Table A herein, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition described herein, wherein the disease or condition is selected from CLOVES syndrome (congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome), PIK3CA-associated overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. In some embodiments, the disease or condition is leukemia, lymphoma, or sarcoma.

[0158] In some preferred embodiments, the compounds disclosed herein used in the methods herein are selected from those compounds whose IC50 value is less than 1 μmol / L (preferably less than 100 nM, or less than 50 nM) when tested in an antiproliferative assay in a T47D breast cancer cell line with the PI3KCA-H1047R mutation according to Bioassay Example A of this article. In some preferred embodiments, the compounds disclosed herein used in the methods herein are selected from those compounds whose IC50 value is greater than 1 μmol / L (preferably greater than 2 μmol / L, or greater than 5 μmol / L) when tested in an antiproliferative assay in an SK-BR-3 breast cancer cell line without the PI3KCA mutation according to Bioassay Example A of this article.

[0159] The compounds disclosed herein can be used as a monotherapy or in combination therapy. In some embodiments, the combination therapy includes treating the subject with a targeted therapeutic agent, a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, and / or immunotherapy. In some embodiments, the compounds disclosed herein may also be administered simultaneously or sequentially with other pharmaceutically active compounds to a subject in need. In some embodiments, the combination therapy includes treating the subject with one or more additional therapies such as chemotherapeutic agents or other anticancer agents.

[0160] Combination therapy may also include further administration of the therapeutic agent as described above in combination with other bioactive ingredients and / or non-pharmacological therapies (e.g., surgery or radiation therapy).

[0161] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, the administration may be oral, nasal, transdermal, pulmonary, inhaled, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral. In some embodiments, the administration is oral.

[0162] Dosing regimens (including dosage) can vary and be adjusted depending on the recipient of treatment, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is administered concurrently.

[0163] definition It should be understood that all parts and their combinations maintain the appropriate valence.

[0164] It should also be understood that specific implementations of the variable parts in this document may be the same as or different from another specific implementation having the same identifier.

[0165] This disclosure covers all combinations of the aspects and / or embodiments disclosed herein. It should be understood that any and all embodiments of this disclosure may be combined with one or more other embodiments to describe additional embodiments. It should also be understood that each individual element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments.

[0166] Choose atoms or groups that are suitable for the variables in this paper independently. The definitions of variables can be combined. Taking Equation I as an example, in Equation I, W, L 2 R 1 R X R 3 R 4 R 5 R 6 R 7 R 8 and R 9 Any definition of one of them can be related to W and L in Equation I. 2 R 1 R X R 3 R 4 R 5 R 6 R 7 R 8 and R 9Any other combination of the definitions in the formula. Such combinations are contemplated and within the scope of this disclosure. The non-limiting use of the groups (where applicable) in compounds of formula I or II or their subforms includes any corresponding group, alone or in any combination, as shown in the specific compounds described in the Examples section or in Table A herein.

[0167] symbol When shown perpendicular to (or otherwise intersecting) the bond, it indicates the connection point between the shown portion and the rest of the molecule. It should be noted that for divalent (or multivalent) structures, one or more directly linked groups or appropriate variables shown in the formula may be indicated by the symbol. In divalent (or multivalent) structures, the direction of attachment is indicated. When neither attachment point of a divalent structure shows a directly attached group or variable, unless otherwise stated or clearly contrary to the context, it should be assumed that attachment to the rest of the molecule is permitted in either direction. The structure "XAGB" is used to indicate this, for example, if G is defined as... That is, if no directly connected groups or variables are shown, the structure "XAGB" can be or On the other hand, if G is defined as , , , or Therefore, the structure "XAGB" should be understood as .

[0168] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined according to... Handbook of Chemistry and Physics The CAS version of the periodic table is identified on the inside back cover of the 75th edition, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in the following literature: Thomas Sorrell, Organic Chemistry University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry , 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations VCHPublishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0169] The compounds disclosed herein may contain one or more asymmetric centers and / or axial chirality, and therefore may exist in a variety of isomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, transisomers, or geometric isomers, or may be in the form of mixtures of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or, preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al. , Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (Edited by EL Eliel, Univ. of Notre Dame Press, NotreDame, IN 1972). This disclosure also covers the compounds described herein as individual isomers substantially free of other isomers and alternatively as mixtures of various isomers (including racemic mixtures). In embodiments herein, unless otherwise apparent from the context, it should be understood that, when stereochemistry is specifically plotted, the compound may be present primarily as the stereoisomer as plotted, with respect to that particular chiral center or axial chirality, having less than 20 wt%, less than 10 wt%, less than 5 wt%, less than 1 wt%, or undetectable amounts of other stereoisomers, as indicated by HPLC or SFC area or both. For example, in some embodiments, for a particular chiral center or axial chirality plotted, the compound may be present primarily as a stereoisomer as plotted, having an enantiomeric excess (“ee”) greater than 50%, such as 80% ee or higher, 90% ee or higher, 95% ee or higher, 98% ee or higher, or 99% ee or higher. Those skilled in the art can determine the presence and / or amount of the stereoisomer based on this disclosure, including by using chiral HPLC or SFC.

[0170] When listing a range of values, the intention is to cover every value within that range and its subranges. For example, "C 1–6 The intention is to cover C1, C2, C3, C4, C5, C6, and C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 .

[0171] As used herein, the terms “compound of this disclosure” or “compound of the invention” mean any of the compounds described herein according to Formula I (e.g., sub-formulas such as Ia, Ib, Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, or Ib-4), Formula II (e.g., sub-formulas such as II-a, II-b, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4), selected from the formulas listed below. Any compound shown in Table A of this document, any of the compounds shown in the Examples section, its isotopically labeled compounds (such as deuterated analogs in which one or more hydrogen atoms are replaced by deuterium atoms with an abundance higher than their native abundance), its possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), its geometric isomers, its trans-isomers, its tautomers, its conformational isomers, and / or its pharmaceutically acceptable salts or esters (e.g., acid addition salts such as HCl salts, or base addition salts such as Na salts). Hydrates and solvates of the compounds of this disclosure are considered compositions of this disclosure, wherein said compounds are associated with water or a solvent, respectively. For the avoidance of doubt, compounds shown in the Examples section refer to compounds described herein designated as integers 1, 2, 3, ..., see, for example, the title compounds of the Examples. For ease of description, synthetic starting materials or intermediates may be designated by integers (compound numbers) followed by a "-" and an additional numerical value, such as 1-1, 1-2, etc., see the Examples for details. The labeling of such synthetic starting materials or intermediates should not be confused with compounds that use only integers without "-" and additional numerical designations. In some embodiments, the compounds of this disclosure may be any of those defined herein and in the claims.

[0172] The compounds disclosed herein can exist in isotopically labeled or enriched forms, wherein the isotopically labeled or enriched forms contain one or more atoms whose atomic mass or mass number differs from the most abundant atomic mass or mass number found in nature. The isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, those... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0173] As used herein, the terms “administration”, “application”, or other variations thereof, refer to the provision of the compound or a prodrug of the compound to an individual in need of treatment.

[0174] The term "aromatic" refers to a planar ring with 4n + 2 electrons in a conjugated system. As used herein, "conjugated system" refers to a connected p-orbital system with delocalized electrons, and this system may contain lone pairs of electrons.

[0175] As used herein, the term "alkyl" on its own or as part of another group refers to a straight-chain or branched aliphatic saturated hydrocarbon. In some embodiments, the alkyl group may contain one to twelve carbon atoms (i.e., C64 ... 1-12 Alkyl group or a specified number of carbon atoms (i.e., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is a straight-chain C1 alkyl group. 1-10 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-10 Alkyl group. In another embodiment, the alkyl group is a straight-chain C 1-6 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-6 Alkyl group. In another embodiment, the alkyl group is a straight-chain C 1-4 Alkyl group. In one embodiment, the alkyl group is a C18 group selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl. 1-4Alkyl groups. As used herein, the term "alkylene" on its own or as part of another group refers to a divalent group derived from an alkyl group. For example, non-limiting straight-chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, etc.

[0176] As used herein, the term "alkenyl" on its own or as part of another group refers to a straight-chain or branched aliphatic hydrocarbon containing one or more, such as one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is C 2-6 Alkenyl group. In another embodiment, the alkenyl group is C. 2-4 Alkenyl groups. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0177] As used herein, the term "alkynyl" itself, or as part of another group, refers to a straight-chain or branched aliphatic hydrocarbon containing one or more, such as one to three, carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2-6 An alkynyl group. In another embodiment, the alkynyl group is C. 2-4 Alkyne group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentylyl, and hexynyl.

[0178] As used herein, the term "alkoxy" on its own or as part of another group refers to the formula OR a1 The group, wherein R a1 It is an alkyl group. As used herein, the term "cycloalkoxy" itself or as part of another group refers to the formula OR. a1 The group, wherein R a1 It is a cycloalkyl group.

[0179] As used herein, the term "haloalkyl" itself, or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In a preferred embodiment, the haloalkyl is an alkyl group substituted with one or more fluorine atoms, alternatively referred to herein as a fluorine-substituted alkyl, such as an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is C10. 1-4 Haloalkyl group. In one embodiment, the haloalkyl group is a fluorine-substituted C14 group. 1-4 Alkyl groups.

[0180] As used herein, the term "heteroalkyl" on its own or in combination with another term, unless otherwise specified, refers to a stable straight-chain or branched alkyl group having, for example, 2 to 14 carbons, such as 2 to 10 carbons, in the chain, wherein one or more carbons have been replaced with heteroatoms selected from S, O, P, and N, and wherein nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and nitrogen heteroatoms may optionally be quaternized. Heteroatoms S, O, P, and N may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. When heteroalkyl is described as substituted, a substituent may replace one or more carbon atoms and / or hydrogen atoms attached to the heteroalkyl group. In some embodiments, the heteroalkyl is C 1-4 Heteroalkyl groups, as defined herein, refer to heteroalkyl groups having 1-4 carbon atoms. C 1-4 Examples of heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl groups such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, C2 heteroalkyl groups such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3, and C1 heteroalkyl groups such as -CH2-OH, -CH2-NH2, -O-CH3. Preferably, C... 1-4 Heteroalkyl (or C) 1-4 Heteroalkyl groups contain one or two heteroatoms, such as one oxygen atom, one nitrogen atom, two oxygen atoms, two nitrogen atoms, or one oxygen atom and one nitrogen atom. Similarly, the term "heteroalkyl" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-O-CH2-CH2- and –O-CH2-CH2-NH-CH2-. For heteroalkyl groups, the heteroatom can also occupy one or both of the chain ends. For example (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. The term "heteroalkyl" is followed by a description of a specific heteroalkyl group such as -NR'R. '' In this context, it should be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is described for clarity. Therefore, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups such as -NR'R. '' wait.

[0181] When used alone or as part of another group, "carbocyclic group" or "carbocyclic ring" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C")3–10 A carbocyclic group is a group consisting of a carbocyclic group and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. The carbocyclic group can be monocyclic (“monocyclic carbocyclic”) or contain a fused, bridged, or spirocyclic ring system, such as a bicyclic system (“bicyclic carbocyclic”), and can be saturated or partially unsaturated. Non-limiting exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decahydronaphthalene, adamantyl, cyclopentenyl, and cyclohexenyl.

[0182] In some embodiments, the "carbocyclic group" is fully saturated, and it is also referred to as a cycloalkyl group. In some embodiments, the cycloalkyl group can have 3 to 10 cyclic carbon atoms ("C..."). 3–10 (Cycloalkyl). In a preferred embodiment, the cycloalkyl group is a monocyclic ring.

[0183] When used alone or as part of another group, the term "heterocyclic group" or "heterocyclic" refers to a group having a cyclic carbon atom and one to four cyclic heteroatoms, comprising a 3- to 10-membered nonaromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10-membered heterocyclic group"). When applicable, heterocyclic groups or heterocyclic rings having ring sizes different from 3-10-membered heterocyclic groups are designated by different ring size designations. Those skilled in the art will understand that such heterocyclic groups with different ring sizes are also nonaromatic ring systems having a cyclic carbon atom and one to four cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, if the valence allows. Heterocyclic groups may be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic ring systems, such as bicyclic systems ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or two rings.

[0184] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azircyclopropane, oxacyclopropane, and thiocyclopropane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azircyclobutane, oxacyclobutane, and thiocyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tetrahydrothiaranyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolidinone, etc. Exemplary 6-membered heterocyclic groups fused with aryl rings (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0185] When used alone or as part of another group, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) ("C 6–14 The aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”; for example, phenyl). 10 Aryl group; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14”). 14 "Aryl"; for example, anthracene.

[0186] When used alone or as part of another group, "aralkyl" refers to an alkyl group that is substituted by one or more aryl groups, preferably by one aryl group. Examples of aralkyl groups include benzyl, phenethyl, etc. When aralkyl is described as optionally substituted, the alkyl or aryl portion of the aralkyl group may be optionally substituted.

[0187] When used alone or as part of another group, "heteroaryl" refers to a 5-10 membered monocyclic or bicyclic group having a cyclic carbon atom and 1-4 cyclic heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) in a 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array). When applicable, heteroaryls with different ring sizes than 5-10 membered heteroaryls are designated by different ring size designations. Those skilled in the art will understand that such heteroaryls with different ring sizes are also 4n+2 aromatic ring systems having a cyclic carbon atom and 1-4 cyclic heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) in a cyclic array (e.g., having 6 or 10 π electrons shared in a cyclic array). In heteroaryl groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, if the valence allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or two rings. One of the rings may be a bicyclic heteroaryl group (e.g., indole, quinolinyl, etc.) without heteroatoms, and the bonding point may be on either ring, i.e., on the ring with heteroatoms (e.g., 2-indole) or the ring without heteroatoms (e.g., 5-indole).

[0188] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxazirmonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0189] When used alone or as part of another group, "heteroaryl" refers to an alkyl group that is substituted by one or more heteroaryl groups, preferably by one heteroaryl group. When a heteroaryl group is described as optionally substituted, the alkyl or heteroaryl portion of the heteroaryl group may be optionally substituted.

[0190] Unless otherwise stated or contrary to context, “heteroatom” as used herein generally refers to nitrogen, oxygen, sulfur, boron, phosphorus or silicon, more preferably nitrogen, oxygen or sulfur.

[0191] As used herein, unless otherwise stated or to the contrary, the term "ring structure," "cyclic structure," or simply "ring," such as "3-10 membered ring structure," "3-12 membered ring structure," or "5- or 6-membered ring," having a specified number of ring members, shall be understood to encompass any ring structure (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.) having the specified number of ring members, which may be (1) monocyclic or polycyclic (where chemically feasible), such as monocyclic or bicyclic base rings (including fused, spirocyclic, and bridged bicyclic base rings, and two of which are monocyclic). (1) Ring systems in which the base rings are connected by single or double bonds; (2) Aromatic, partially unsaturated or fully saturated; and in the case of polycyclic structures, each ring may independently be aromatic, partially unsaturated or fully saturated; and (3) Free of heteroatoms (i.e., all ring members are carbon atoms) or containing 1-4 heteroatoms (i.e., ring members consist of carbon atoms and 1-4 heteroatoms); in the case of polycyclic structures, each ring may independently be free of cyclic heteroatoms or have 1-4 cyclic heteroatoms (e.g., O, N, S, etc.). When a ring is described as containing cyclic sulfur or nitrogen atoms, the sulfur or nitrogen atoms may optionally be oxidized. One or more cyclic carbon atoms in a ring structure may be present as C (=O). A fully saturated ring is one in which neither the cyclic carbon nor the nitrogen (if present) atoms form double or triple bonds with any other atom. A ring structure may optionally be substituted by one or more substituents described herein. Substituents in the ring structures described herein may also have cyclic structures, and in some cases, two substituents in a ring structure may be described as being connected to form a cyclic structure.

[0192] As is generally understood in the art, for clarity, when a structure can be characterized in multiple ways, a structure can be said to be a suitable definition of a variable as long as one such representation falls within the scope of the variable's definition herein. For example, when a monovalent variable is defined as an arbitrarily substituted 6-membered ring, the variable also encompasses (a) among other structures. or The structure of (a) can be considered as a 6-membered monocyclic or bicyclic ring substituted with a phenyl group; and (b) The structure can be viewed as a 6-membered ring, where two substituents are linked to form a cyclopropyl ring; however, this variable will not cover... This is because the connecting loop is not a 6-membered ring under any structural characterization. To further explain, when the variable is instead defined as an arbitrarily replaced single-ring 6-membered ring, then the variable does not cover... But covering The structure. And if the variable is defined as a 6-membered ring arbitrarily substituted with a halogen, then the variable can cover structures such as... Each of them can be considered as a 6-membered ring that is either unsubstituted or substituted by one or two fluorine atoms.

[0193] As is commonly understood in the art, alkylene, alkenylene, ynylene, heteroalkylene, carbocyclic, heterocyclic, arylene, and heteroarylene refer to the corresponding divalent groups of alkyl, alkenyl, ynylene, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, respectively.

[0194] The term "optionally substituted" refers to the corresponding group, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cyclic structures, whether unsubstituted or substituted. Generally, the term "substituted," whether or not preceded by "optionally," refers to a substituent in which at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, for example, a substituent that, upon substitution, produces a stable compound (e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position is substituted in any given structure, the substituents at each position may be the same or different. Typically, when substituted, the optionally substituted group herein may be substituted by 1 to 5 substituents. When applicable, the substituent may be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent, or a sulfur atom substituent.

[0195] Unless explicitly stated to the contrary, combinations of substituents and / or variables are permitted only if such combinations are chemically permissible and produce stable compounds. A “stable” compound is one that can be prepared and isolated, and whose structure and properties remain substantially unchanged or can remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0196] In some embodiments, the alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclic groups "optionally substituted" herein may be unsubstituted or substituted with 1, 2, 3, or 4 substituents or even 5 substituents, said substituents being independently selected from F, Cl, -OH, protected hydroxyl, oxo (where applicable), NH2, protected amino, NH(C 1-4 alkyl groups or their protected derivatives, N(C) 1-4 Alkyl ((C) 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C3-6 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, 3-7 heterocyclic group containing 1, 2, or 3 cyclic heteroatoms independently selected from O, S, and N, or independently selected from Br, -NH2, and -CN, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted by 1, 2, or 3 substituents or even 4 or 5 substituents, wherein the substituents are independently selected from F, -OH, oxo (where applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl groups (e.g., CF3), C 1-4 alkoxy and fluorine-substituted C 1-4 The alkoxy group, or independently selected from Cl, Br, -NH2, and -CN. In some embodiments, the "optionally substituted" aryl or heteroaryl group herein may be unsubstituted or substituted with 1, 2, 3, or 4 substituents, or even 5 substituents, said substituents being independently selected from F, Cl, -OH, -CN, NH2, protected amino groups, NH(C 1-4 alkyl groups or their protected derivatives, N(C) 1-4 Alkyl ((C) 1-4 Alkyl), –S(=O)(C 1-4 Alkyl), –SO2(C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 cyclic heteroatoms independently selected from O, S, and N, or 3- to 7-membered heterocyclic groups containing 1 or 2 cyclic heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted by 1, 2, or 3 substituents or even 4 or 5 substituents, wherein the substituents are independently selected from F, -OH, oxo (where applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 alkoxy and fluorine-substituted C 1-4 Alkyl groups, or independently selected from Cl, Br, -NH2 and -CN.

[0197] Exemplary carbon substituents include, but are not limited to, halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, and –OR. aa –ON(R) bb )2、–N(R bb)2、–N(R bb )3 + X – 、–N(OR cc )R bb 、–SH、–SR aa 、–SSR cc 、–C(=O)R aa 、–CO2H、–CHO、–C(OR cc )2、–CO2R aa 、–OC(=O)R aa 、–OCO2R aa 、–C(=O)N(R bb )2、–OC(=O)N(R bb )2、–NR bb C(=O)R aa 、–NR bb CO2R aa 、–NR bb C(=O)N(R bb )2、–C(=NR bb )R aa 、–C(=NR bb )OR aa 、–OC(=NR bb )R aa 、–OC(=NR bb )OR aa 、–C(=NR bb )N(R bb )2、–OC(=NR bb )N(R bb )2、–NR bb C(=NR bb )N(R bb )2、–C(=O)NR bb SO2R aa 、–NR bb SO2R aa 、–SO2N(R bb )2、–SO2R aa 、–SO2OR aa 、–OSO2R aa 、–S(=O)R aa 、–OS(=O)R aa 、–Si(R aa )3、–OSi(R aa )3、–C(=S)N(R bb )2、–C(=O)SR aa 、–C(=S)SR aa 、–SC(=S)SRaa 、 –SC(=O)SR aa 、 –OC(=O)SR aa 、 –SC(=O)OR aa 、 –SC(=O)R aa 、 –P(=O)(R aa )2、 P(=O)(OR cc )2、 –OP(=O)(R aa )2、 –OP(=O)(OR cc )2、 –P(=O)(N(R bb )2)2、 –OP(=O)(N(R bb )2)2、 NR bb P(=O)(R aa )2、 –NR bb P(=O)(OR cc )2、 –NR bb P(=O)(N(R bb )2)2、 –P(R cc )2、 P(OR cc )2、 –P(R cc )3 + X 、 P(OR cc )3 + X 、 P(R cc )4、 P(OR cc )4、 –OP(R cc )2、 –OP(R cc )3 + X 、 OP(OR cc )2、 OP(OR cc )3 + X 、 OP(R cc )4、 OP(OR cc )4、 –B(R aa ​​​​​​​​​​​​​2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 Aryl and 5–14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by a group; wherein X To counteract ions; Or, the two hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R). bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc ; R in each case aa Selected independently from C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl, or two R aa Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by groups; R in each case bb Independently selected from hydrogen, –OH, –OR aa –N(R) cc )2、–CN、–C(=O)R aa –C(=O)N(R) cc )2、–CO2R aa –SO2R aa –C(=NR) cc OR aa –C(=NR) cc )N(R cc )2、–SO2N(R cc )2、–SO2R cc –SO2OR cc –SOR aa –C(=S)N(R) cc )2、–C(=O)SR cc–C(=S)SR cc –P(=O)(R aa 2. P(=O)(OR cc )2、–P(=O)(N(R cc )2)2、C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl, or two R bb Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by a group; wherein X To counteract ions; R in each case cc Independently selected from hydrogen, C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl, or two R cc Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by groups; R in each case dd Independently selected from halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR ee –ON(R) ff )2、–N(R ff )2、–N(R ff )3 + X – –N(OR) ee )R ff –SH, –SR ee –SSR ee –C(=O)R ee –CO2H, –CO2R ee –OC(=O)R ee –OCO2R ee –C(=O)N(R) ff)2、–OC(=O)N(R ff )2、–NR ff C(=O)R ee –NR ff CO2R ee –NR ff C(=O)N(R ff )2、–C(=NR ff OR ee –OC(=NR) ff )R ee –OC(=NR) ff OR ee –C(=NR) ff )N(R ff )2、–OC(=NR ff )N(R ff )2、–NR ff C(=NR ff )N(R ff )2、–NR ff SO2R ee –SO2N(R ff )2、–SO2R ee –SO2OR ee –OSO2R ee –S(=O)R ee 、–Si(R ee )3、–OSi(R ee 3. –C(=S)N(R) ff )2、–C(=O)SR ee –C(=S)SR ee –SC(=S)SR ee –P(=O)(OR) ee )2、–P(=O)(R ee )2、–OP(=O)(R ee )2、–OP(=O)(OR ee 2. C 1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 Carbocyclic groups, 3–10-membered heterocyclic groups, C 6–10 Aryl, 5–10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Substituted by a group, or two geminal R groups dd Substituents can be linked to form =O or =S; where X To counteract ions; R in each case ee Selected independently from C 1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 carbonyl group, C 6–10 Aryl, 3–10-membered heterocyclic and 3–10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Substituted by groups; R in each case ff Independently selected from hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 Carbocyclic groups, 3–10-membered heterocyclic groups, C 6–10 aryl and 5–10 heteroaryl, or two R ff Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg The group is replaced; and R in each case gg Independently halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC 1–6 Alkyl, –ON(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)3 + X – –NH(C 1–6 Alkyl)2 + X – –NH2(C 1–6 alkyl) + X – –NH3 + X – –N(OC) 1–6 Alkyl)(C 1–6 Alkyl), –N(OH)(C 1–6 Alkyl groups, –NH(OH), –SH, –SC 1–6 Alkyl, –SS(C 1–6 Alkyl), –C(=O)(C 1–6 Alkyl group), –CO2H, –CO2(C 1–6 Alkyl), –OC (=O)(C 1–6Alkyl), –OCO2(C 1–6 Alkyl groups, –C(=O)NH2, –C(=O)N(C 1–6 Alkyl)2、–OC(=O)NH(C 1–6 Alkyl), –NHC(=O)(C 1–6 Alkyl), –N(C) 1–6 Alkyl)C(=O)(C 1–6 Alkyl), –NHCO2(C 1–6 Alkyl), –NHC(=O)N(C 1–6 Alkyl)2、–NHC(=O)NH(C 1–6 Alkyl groups), –NHC(=O)NH2, –C(=NH)O(C 1–6 Alkyl), –OC(=NH)(C 1–6 Alkyl group), –OC (=NH)OC 1–6 Alkyl group, –C(=NH)N(C 1–6 Alkyl)2、–C(=NH)NH(C 1–6 Alkyl groups, –C(=NH)NH2, –OC(=NH)N(C 1–6 Alkyl)2、–OC(NH)NH(C 1–6 Alkyl groups), –OC(NH)NH2, –NHC(NH)N(C 1–6 Alkyl)2, –NHC(=NH)NH2, –NHSO2(C 1–6 Alkyl), –SO2N(C 1–6 Alkyl)2、–SO2NH(C 1–6 Alkyl groups, –SO2NH2, –SO2C 1–6 Alkyl, –SO2OC 1–6 Alkyl, –OSO2C 1–6 Alkyl, –SOC 1–6 Alkyl, –Si(C) 1–6 Alkyl)3、–OSi(C 1–6 Alkyl)3、–C(=S)N(C 1–6 Alkyl)2、C(=S)NH(C 1–6 Alkyl), C(=S)NH2, –C(=O)S(C 1–6 Alkyl), –C(=S)SC 1–6 Alkyl, –SC(=S)SC 1–6 Alkyl group, –P(=O)(OC) 1–6 Alkyl)2、–P(=O)(C 1–6 Alkyl)2、–OP(=O)(C 1–6 Alkyl)2、–OP(=O)(OC 1–6 Alkyl)2, C 1–6 Alkyl, C1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 carbonyl group, C 6–10 aryl, 3–10 heterocyclic, 5–10 heteroaryl; or two geminal Rs gg Substituents can be linked to form =O or =S; where X – To counteract ions.

[0198] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., comprising one form of negative charge). Anionic counterions can also be polyvalent (i.e., comprising more than one form of negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., Fi). – Cl – ,Br – I – NO3 – ClO4 – OH – H2PO4 – HSO4 – Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic-5-sulfonate, ethane-1-sulfonic-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 – PF4 – PF6 – AsF6 – SbF6 – B[3,5-(CF3)2C6H3]4] – BPh4 – Al(OC(CF3)3)4 – and carborane anions (e.g., CB) 11 H 12 – or (HCB) 11 Me5Br6) – Exemplary counterions that can be multivalent include CO3. 2 HPO4 2 PO4 3 B4O7 2 SO4 2 S2O3 2 Carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipic acid, pimelic acid, succinate, azelaic acid, sebacic acid, salicylate, phthalate, aspartate, glutamate, etc.) and carborane.

[0199] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0200] "Acyl" refers to a group selected from –C(=O)R aa –CHO, –CO2R aa –C(=O)N(R) bb )2、–C(=NR bb )R aa –C(=NR) bb OR aa –C(=NR) bb )N(R bb )2、–C(=O)NR bb SO2R aa –C(=S)N(R) bb )2、–C(=O)SR aa Or –C(=S)SR aa The part where R aa and R bb As defined in this article.

[0201] When the valence allows, the nitrogen atom can be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, hydrogen, –OH, and –OR. aa –N(R) cc )2、–CN、–C(=O)R aa –C(=O)N(R) cc )2、–CO2R aa –SO2R aa –C(=NR) bb )R aa –C(=NR) cc OR aa –C(=NR) cc )N(R cc )2、–SO2N(R cc )2、–SO2R cc –SO2OR cc –SORaa –C(=S)N(R) cc )2、–C(=O)SR cc –C(=S)SR cc –P(=O)(OR) cc )2、–P(=O)(R aa )2、–P(=O)(N(R cc )2)2、C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl groups, or two R groups attached to a nitrogen atom cc Groups are linked to form 3–14-membered heterocyclic or 5–14-membered heteroaryl rings, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd The group is replaced, and R is therein. aa R bb R cc和 R dd As defined above.

[0202] In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as an amino protecting group). Nitrogen protecting groups are well known in the art and include... Protective Groups in Organic Synthesis Those described in detail in TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999 (which are incorporated herein by reference). Exemplary nitrogen-protecting groups include, but are not limited to: those that form urethane esters, such as benzyloxycarbonyl (Cbz) groups, p-methoxybenzylcarbonyl (Moz or MeOZ) groups, tert-butoxycarbonyl (BOC) groups, Troc, 9-fluorenylmethoxycarbonyl (Fmoc) groups, etc.; those that form amides, such as acetyl, benzoyl, etc.; those that form benzyl amines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc.; those that form sulfonamides, such as toluenesulfonyl, nitrobenzenesulfonyl, etc.; and others such as p-methoxyphenyl.

[0203] Exemplary oxygen substituents include, but are not limited to, –R aa –C(=O)SR aa –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2、–C(=NR bb )R aa–C(=NR) bb OR aa –C(=NR) bb )N(R bb )2、–S(=O)R aa –SO2R aa 、–Si(R aa 3. –P(R) cc )2、–P(R cc )3 + X , P(OR cc 2. P(OR cc )3 + X –P(=O)(R aa )2、–P(=O)(OR cc )2 and –P(=O)(N(R bb )2)2, where X R aa R bb and R cc As defined herein. In some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include... Protective Groups in Organic Synthesis Those described in detail in TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999 (which are incorporated herein by reference). Exemplary oxygen protecting groups include, but are not limited to: alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl (such as 4-methoxybenzyl), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc.; silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), etc.; acetals or ketals, such as tetrahydropyranyl (THP); esters, such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc.; carbonates; sulfonates, such as methanesulfonate (methanesulfonate), benzylsulfonate, and toluenesulfonate (Ts), etc.

[0204] The term "leaving group" has its general meaning in the field of synthetic organic chemistry; for example, it can refer to an atom or group that can be replaced by a nucleophile. See, for example, Smith. March Advanced Organic Chemistry6th edition (501-502). Examples of suitable leaving groups include, but are not limited to, halogens (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O -Dimethylhydroxyamino, 9-phenyloxanthyl (pixyl) and halocarboxylate.

[0205] The term "pharmaceutically acceptable salt" refers to salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0206] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one form migration of hydrogen atoms and at least one change in valence (e.g., single bond to double bond, triple bond to single bond, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerizations include ketone to enol, amide to imide, lactam to lactimide, enamine to imide, and enamine to (different enamines) tautomerization.

[0207] As used herein, the term “subject” (or, alternatively, “patient”) refers to an animal, preferably a mammal, and most preferably a human, as a subject of treatment, observation, or experimentation.

[0208] As used herein, the term "treatment" means the elimination, reduction, or improvement of a disease or condition, and / or its associated symptoms. While not excluding the possibility that treatment of a disease or condition does not require the complete elimination of the disease, condition, or its associated symptoms, the term "treatment" as used herein may include "preventive treatment," which refers to reducing the likelihood of developing or relapsing into a previously controlled disease or condition in a subject who does not have such a disease or condition but is at risk or susceptible to developing or relapsing into it. The term "treatment" and its synonyms encompass the administration of a therapeutically effective amount of the compounds described herein to a subject who requires such treatment.

[0209] As used herein, the singular forms “a”, “an”, and “the” include plural references unless explicitly stated or clearly evident from the context that this is not intended.

[0210] As used herein in expressions such as “A and / or B”, the term “and / or” is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, as used in expressions such as “A, B, and / or C”, the term “and / or” is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0211] Titles and subtitles are used for convenience and / or formal compliance only, and do not limit the subject matter technology, nor are they related to the interpretation of the subject matter technology description. In various embodiments, features described under one title or subtitle of the subject matter disclosure may be combined with features described under other titles or subtitles. Furthermore, all features under a single title or subtitle are not necessarily used together in all embodiments.

[0212] Example Various starting materials, intermediates, and compounds in the preferred embodiments can be separated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, where appropriate. Characterization of these compounds can be performed using conventional methods, such as melting point analysis, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. The examples are merely illustrative and do not limit the claimed invention in any way.

[0213] Exemplary embodiments of the steps for synthesizing the products described herein are described in more detail below. Some of the embodiments discussed herein can be prepared by separating the respective racemic mixtures. As will be understood by those skilled in the art, the compounds described in the Example Section immediately preceding the chiral separation step (e.g., by supercritical fluid chromatography (SFC)) are in the form of racemic and / or stereoisomer mixtures. It should be understood that the enantiomer excess (“ee”) and / or diastereomer excess (“de”) reported for these embodiments are merely representative of the procedures from the examples herein and not limiting; those skilled in the art will understand that such enantiomers and / or diastereomers with different ee and / or de, such as higher ee and / or de, can be obtained according to this disclosure. Generally, a “de” value is reported herein when a pair of diastereomers (different by only one chiral center) are separated from a respective diastereomer mixture. In such cases, the “de” value indicates the enrichment of one of the diastereomers.

[0214] The abbreviations used in the Embodiments section are to be understood to have their ordinary meaning in the art, unless otherwise expressly stated or obviously contrary to the context. Some abbreviations used in the Embodiments section of this document are shown below.

[0215]

[0216] The compounds disclosed herein can be synthesized by those skilled in the art according to this disclosure. Other representative compounds are synthesized by similar procedures / methods described in the Examples section herein.

[0217] Example 1 - Synthesis of Compound 1

[0218]

[0219]

[0220]

[0221]

[0222] Step 1: Under a nitrogen atmosphere at room temperature, 1H-1,2,3-triazole (2100.00 mg, 30.40 mmol) and K2CO3 (6002.6 mg, 43.43 mmol) were added to a mixture of 2-fluoro-4-methyl-1-nitrobenzene (4491.96 mg, 28.96 mmol) in DMSO (50 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE to PE / EtOAc = 3 / 1) to give 1-1 (2500 mg).

[0223] Step 2: Add Pd / C 10% (200 mg, 4.04 mmol) to the solution of 1-1 (2200 mg, 10.77 mmol) in MeOH (30 mL). Stir the mixture at 25 °C for 16 hours under a H2 atmosphere. Filter the mixture through diatomaceous earth and concentrate the filtrate to obtain 1-2 (1800 mg).

[0224] Step 3: To the solution of 1-2 (2000 mg, 11.48 mmol) in DCM (50 mL), TEA (3485.1 mg, 34.44 mmol) and DMAP (1402.6 mg, 11.48 mmol) were added, and the reaction mixture was stirred at room temperature for 5 minutes. Then, (2-methylpropyl-2-yl)carbonic anhydride (5011.19 mg, 22.96 mmol) was slowly added, and the resulting mixture was stirred at room temperature for 6 hours. The mixture was diluted with water and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE to PE / EtOAc = 1 / 1) to give 1-3 (2700 mg).

[0225] Step 4: At room temperature, K₂CO₃ (3986.1 mg, 28.84 mmol) was added to a solution of 1-3 (3600 mg, 9.61 mmol) in MeOH (50 mL). The mixture was stirred at 65 °C for 60 min. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE to PE / EtOAc = 1 / 1) to give 1-4 (2000 mg).

[0226] Step 5: Add n-BuLi (14.95 mL, 37.37 mmol, 2.5 M, in hexane) to a solution of 1-4 (5000 mg, 18.23 mmol) in THF (50 mL) at -78 °C, and stir the mixture at -78 °C for 40 min. Add a solution of methyl 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylate (3860.79 mg, 20.96 mmol) in THF (50 mL) to the above mixture and stir at -78 °C for 1 h. Quench the reaction with aqueous NH4Cl solution at -78 °C and extract with EtOAc. Combine the organic layers, wash with brine, dry to Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (PE to PE / EtOAc = 1:1) to give 1-5 (4000 mg).

[0227] Step 6: Add NaBH4 (390.3 mg, 10.32 mmol) to the mixture of 1-5 (4400 mg, 10.32 mmol) in MeOH (100 mL) at 0 °C, and stir the mixture at 0 °C for 1 hour. Quench the mixture with ammonium chloride solution at 0 °C and extract with EtOAc. Combine the organic layers, wash with brine, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography on silica gel (PE to PE / EtOAc = 1:1) to give 1-6 (3400 mg).

[0228] Step 7: Add TFA (13 mL) to a solution of 1-6 (5500 mg, 12.84 mmol) in DCM (50 mL) at 25 °C. Stir the mixture at 25 °C for 30 min. Concentrate the reaction mixture, dilute the residue with DCM and neutralize to pH 9 with aqueous NaHCO3 solution. Wash the organic layer with brine, dry over Na2SO4, and concentrate. Purify the residue by column chromatography on silica gel (PE to PE / EtOAc = 1:1) to give 1-7 (3300 mg).

[0229] Step 8: Add NBS (1707.4 mg, 9.59 mmol) to the solution of 1-7 (3000 mg, 9.14 mmol) in MeCN (130 mL), and stir the mixture at room temperature for 1 hour. Dilute the mixture with water and extract with ethyl acetate. Concentrate the organic layer and purify it by column chromatography on silica gel (PE to PE / EtOAc = 1:1) to give 1-8 (2700 mg).

[0230] Step 9: The mixture of 1-8 (2500 mg, 6.14 mmol) and manganese dioxide (5336.8 mg, 61.38 mmol) in DCM (100 mL) was stirred at room temperature for 16 hours. Another batch of manganese dioxide (5336.8 mg, 61.38 mmol) was added and stirred again at room temperature for 16 hours. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give 1-9 (2200 mg).

[0231] Step 10: Tributyl(1-ethoxyvinyl)stanane (3525.4 mg, 9.76 mmol) and bis(triphenylphosphine)palladium(II) chloride (733.1 mg, 1.05 mmol) were added to a solution of 1-9 (2700 mg, 6.97 mmol) in dioxane (80 mL). The reaction mixture was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was cooled to 0 °C, quenched with HCl (1 M, 12 mL), and stirred for 15 min. A saturated KF solution (30 mL) was added to the mixture, and the resulting mixture was stirred at room temperature for another 1 h. The mixture was filtered and the filtrate was extracted with ethyl acetate. The organic layers were combined, washed with aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE to PE / ethyl acetate = 2 / 1) to give 1-10 (1800 mg).

[0232] Step 11: To a mixture of 1-10 (1800 mg, 5.14 mmol) and (R)-2-methylpropane-2-sulfinamide (809.43 mg, 6.68 mmol) in dioxane (100 mL), tetraethanolamine (IV) (23.70 mL, 113.02 mmol) was added, and the reaction mixture was stirred at 100 °C for 8 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and ethyl acetate and filtered. The filtrate was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography, eluting with 0% to 5% methanol / dichloromethane to give 1-11 (1400 mg).

[0233] Step 12: Add NaBH4 (226.5 mg, 5.99 mmol) to a mixture of 1-11 (1400 mg, 2.99 mmol) and cerium(III) trichloride heptahydrate (2231.0 mg, 5.99 mmol) in MeOH (60 mL) at 0 °C. Stir the mixture at 0 °C for 1 hour. Neutralize the reaction mixture to pH ~5 with saturated ammonium chloride solution at 0 °C. Extract the resulting solution with ethyl acetate. Combine the organic layers, wash with brine, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography on silica gel (PE to PE / EtOAc = 1:2) to give 1-12 (1300 mg).

[0234] Step 13: In a sealed tube, the mixture of 1-12 (300 mg, 0.639 mmol) in NH3 / MeOH (7M, 5 mL) was stirred at 70°C for 16 hours. The mixture was then concentrated to obtain 1-13 (270 mg).

[0235] Step 14: HCl / EtOAc (0.68 mL, 4 M) was added to the mixture of 1-13 (270 mg, 0.61 mmol) in DCM (15 mL) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The aqueous phase was then adjusted to pH 12 with NH3·H2O and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated to give 1-14 (200 mg).

[0236] Step 15: Combine 1-14 (200 mg, 0.60 mmol), methyl 6-chloro-3-fluoropyridine-2-carboxylate (225.41 mg, 1.19 mmol), and... N,N A mixture of diisopropylethylamine (0.52 mL, 2.97 mmol) in DMAC (10 mL) was stirred at 120 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (DCM to DCM / MeOH = 10:1) to give 1-15 (210 mg).

[0237] Step 16: Add POCl3 (242.2 mg, 1.58 mmol) to a solution of 1-15 (200 mg, 0.40 mmol) in DCE (10 mL). Stir the reaction mixture at 90 °C for 1 hour under nitrogen. Quench the mixture with saturated sodium bicarbonate and extract with dichloromethane. Concentrate the organic phase, and purify the residue by column chromatography on silica gel (PE to PE / EtOAc = 1:1) to give 1-16 (140 mg).

[0238] Step 17: At room temperature, add 1-16 (140 mg, 0.29 mmol) of LiOH aqueous solution (1 M, 1.1 mL) to the mixture in THF (6 mL) and H2O (6 mL). Stir the mixture at room temperature for 2 hours. Adjust the pH of the mixture to ~3 with HCl aqueous solution (1 M) at 0 °C. Extract the resulting solution with ethyl acetate. Combine the organic layers, wash with brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by preparative HPLC (acetonitrile / 0.05% FA aqueous solution: 10%~75%) to give 1 (70 mg). LCMS (ESI, m / z ): [M+H] + =474.2; 1 H NMR (400 MHz, DMSO- d6, ppm): δ 12.90 (brs,1H), 8.92 (s, 1H), 8.69 (brs, 1H), 8.35 (s, 1H), 7.69 (d, J = 1.2Hz, 1H), 7.31(d, J = 8.8Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 5.58-5.54 (m, 1H), 2.92-2.91 (m,6H), 2.55 (s, 3H), 1.72 (d, J = 6.4 Hz, 3H).

[0239] Example 2 - Synthesis of Compound 2

[0240]

[0241]

[0242] Step 1: Add N,O-dimethylhydroxylamine hydrochloride (1266.85 mg, 12.99 mmol) to the mixture of 1-fluorobicyclo[1.1.1]pentane-3-carboxylic acid (1300 mg, 9.99 mmol) in DMF (25 mL). N,N - Diisopropylethylamine (4.95 mL, 29.97 mmol) and HATU (5698.3 mg, 14.99 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by chromatography on a silica gel column (PE to PE / ethyl acetate = 1 / 1) to give 2-1 (1000 mg).

[0243] Step 2: Add n-BuLi (2.69 mL, 6.73 mmol, 2.5 M, in hexane) to a solution of 1-4 (900 mg, 3.28 mmol) in THF (10 mL) at -78 °C, and stir the reaction mixture at -78 °C for 40 min. Add a solution of 2-1 (653.44 mg, 3.77 mmol) in THF (10 mL) to the above reaction mixture and stir the resulting mixture at -78 °C for 1 h. Then warm the mixture to room temperature and stir at room temperature for 2 h. Quench the reaction mixture with an aqueous solution of NH4Cl (50 mL) and extract with EtOAc. Combine the organic layers, wash with brine, dry over Na2SO4, filter, and concentrate. Purify the residue by chromatography on silica gel (PE to PE / ethyl acetate = 1 / 1) to give 2-2 (1200 mg).

[0244] Step 3: Add NaBH4 (205.6 mg, 5.43 mmol) to a solution of 2-2 (1000 mg, 1.81 mmol) in MeOH (30 mL) at 0 °C. Stir the mixture at 0 °C for 1 hour. Quench the reaction mixture with ammonium chloride solution (100 mL) at 0 °C and extract with EtOAc. Combine the organic layers, wash with brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by column chromatography on silica gel (PE to PE / ethyl acetate = 1:1) to give 2-3 (600 mg).

[0245] Step 4: Add 1.5 mL of TFA to a solution of 2-3 (560 mg, 1.44 mmol) in DCM (6 mL) at 25 °C. Stir the mixture at 25 °C for 30 minutes and concentrate. Dilute the residue with DCM and neutralize with aqueous NaHCO3 solution to pH 9. Wash the organic layer with brine, dry with Na2SO4, and concentrate to give 2-4 (430 mg), which is used directly.

[0246] Step 5: Add NBS (291.7 mg, 1.64 mmol) to the solution of 2-4 (450 mg, 1.56 mmol) in CH3CN (25 mL), and stir the mixture at room temperature for 1 hour. Dilute the mixture with water and extract with ethyl acetate. Concentrate the combined organic layers and purify by column chromatography on silica gel (PE to PE / ethyl acetate = 1:1) to give 2-5 (400 mg).

[0247] Step 6: The mixture of 2-5 (200 mg, 0.55 mmol) and manganese dioxide (473.5 mg, 5.45 mmol) in DCM (30 mL) was stirred at room temperature for 16 hours. Then, another batch of manganese dioxide (473.5 mg, 5.45 mmol) was added and stirred at room temperature for 16 hours. The resulting mixture was filtered through diatomaceous earth and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give 2-6 (150 mg).

[0248] Step 7: Tributyl(1-ethoxyvinyl)stanane (145.6 mg, 0.40 mmol) and bis(triphenylphosphine)palladium(II) chloride (36.3 mg, 0.05 mmol) were added to a solution of 2-6 (100 mg, 0.29 mmol) in dioxane (20 mL). The reaction mixture was stirred at 100 °C for 16 h under nitrogen. The mixture was cooled to 0 °C and adjusted to pH 3 with aqueous HCl (1 M). A saturated KF solution (2 mL) was added to the mixture and the resulting mixture was stirred at room temperature for 60 min. The mixture was filtered and the filtrate was extracted with ethyl acetate. The extracts were combined, washed with aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE to PE / ethyl acetate = 2 / 1) to give 2-7 (70 mg).

[0249] Step 8: Tetraethanolamine (IV) (1.01 mL, 4.83 mmol) was added to a mixture of 2-7 (50 mg, 0.16 mmol) and (R)-2-methylpropane-2-sulfinamide (39.06 mg, 0.32 mmol) in dioxane (4 mL), and the mixture was stirred at 100 °C for 8 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluting with 0% to 5% methanol / dichloromethane) to give 2-8 (50 mg).

[0250] Step 9: Add NaBH4 (36.6 mg, 0.97 mmol) to a mixture of 2-8 (200 mg, 0.48 mmol) and cerium(III) heptahydrate (360.4 mg, 0.97 mmol) in MeOH (25 mL) at 0 °C. Stir the mixture at 0 °C for 1 hour. Neutralize the reaction mixture to pH ~5 with saturated ammonium chloride solution at 0 °C. Extract the resulting solution with ethyl acetate. Combine the organic layers, wash with brine, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography on silica gel (PE to PE / EtOAc = 1:2) to give 2-9 (150 mg).

[0251] Step 10: Add HCl / EtOAc (4M, 0.27 mL) to the mixture of 2-9 (150 mg, 0.36 mmol) in DCM (15 mL) at 0 °C, and stir the mixture at 0 °C for 30 min. Dilute the reaction mixture with water and extract with DCM. Adjust the aqueous phase to pH=12 with NH3·H2O and extract with DCM. Combine the organic layers, wash with brine, dry over Na2SO4, and concentrate to give 2-10 (100 mg).

[0252] Step 11: Combine 2-10 (80 mg, 0.26 mmol), methyl 6-chloro-3-fluoropyridine-2-carboxylate (97.42 mg, 0.51 mmol), and... N,N A mixture of diisopropylethylamine (166.0 mg, 1.29 mmol) in DMA (10 mL) was stirred at 120 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE to PE / EtOAc = 1:1) to give 2-11 (80 mg).

[0253] Step 12: At room temperature, add 0.67 mL of LiOH aqueous solution (1M) to a mixture of 2-11 (80 mg, 0.17 mmol) in THF (6 mL) and H2O (6 mL). Stir the mixture at room temperature for 2 hours. Neutralize the reaction mixture to pH ~3 with HCl aqueous solution (1M) at 0 °C. Extract the resulting mixture with ethyl acetate. Combine the organic layers, wash with brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by preparative HPLC (acetonitrile / 0.05% FA aqueous solution: 10%~75%) to give 2 (45 mg). LCMS (ESI, m / z ): [M+H] + =467.2; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 12.92 (brs,1H), 8.92 (s, 1H), 8.82 (brs, 1H), 8.35 (s, 1H), 7.67 (s, 1H), 7.27 (d, J = 8.4Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 5.59-5.56 (m, 1H), 2.79-2.73 (m, 6H), 2.55(s, 3H), 1.72 (d,J = 6.4 Hz, 3H). 19 F NMR (376 MHz, DMSO- d 6, ppm): -146.42 (1F).

[0254] Example 3 - Synthesis of Compound 3

[0255] Step 1: At room temperature, NaOH (34.1 mg, 0.85 mmol) was added to a mixture of 1-12 (200 mg, 0.42 mmol) in THF (10 mL) and H2O (5 mL). The mixture was then stirred at room temperature for 2 hours. The reaction mixture was acidified to pH ~3 with HCl (1 M), then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to give 3-1 (180 mg, crude product).

[0256] Step 2: At room temperature, N-(1-azineethyl)hydroxylamine (43.6 mg, 0.59 mmol), PyBOP (306 mg, 0.59 mmol), and DIPEA (146.4 mg, 1.13 mmol) were added to a solution of 3-1 (200 mg, 0.45 mmol) in DMF (15 mL). The mixture was then stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to give 3-2 (200 mg, crude).

[0257] Step 3: TBAF (0.8 mL, 1 M, in THF) was added to a solution of 3-2 (200 mg, 0.40 mmol) in 15 mL of THF at 0 °C, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was acidified to pH ~5 with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether / ethyl acetate = 1 / 2) to give 3-3 (160 mg).

[0258] Step 4: Add HCl (0.38 mL, 4 M, in EtOAc) to a solution of 3-3 (180 mg, 0.38 mmol) in DCM (10 mL) at 0 °C, and then stir the mixture at 0 °C for 1 hour. Dilute the mixture with water and adjust the pH to 11 with NH3·H2O. Extract the resulting mixture with DCM. Combine the organic layers, wash with saturated brine, dry over sodium sulfate, filter and concentrate to give 3-4 (140 mg).

[0259] Step 5: To a solution of 3-4 (140 mg, 0.37 mmol) in DMA (10 mL), methyl 6-chloro-3-fluoropyridine-2-carboxylate (141.3 mg, 0.75 mmol) and DIEA (241 mg, 1.8 mmol) were added, and the mixture was stirred at 120 °C for 16 hours. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether / ethyl acetate = 1 / 2) to give 3-5 (140 mg).

[0260] Step 6: LiOH (0.7 mL, 1 M) was added to a solution of 3-5 (100 mg, 0.18 mmol) in THF (7 mL) and H2O (7 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified to pH ~3 with HCl (1 M) at 0 °C and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% FA aqueous solution: 10%~75%) to give 3 (70 mg). LCMS (ESI, m / z ):[M+H] + = 531.2; 1 H-NMR (400 MHz, DMSO- d 6, ppm): δ 12.96 (brs, 1H), 8.99 (s, 1H), 8.69 (d, J = 6.0 Hz, 1H), 8.36 (s, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.32 (d, J = 8.8Hz, 1H), 7.25 (d, J= 8.8 Hz, 1H), 5.63- 5.58 (m, 1H), 2.93- 2.86 (m, 6H), 2.67(s, 3H), 2.56 (s, 3H), 1.75 (d, J = 6.8 Hz, 3H).

[0261] Example 4 - Synthesis of Compound 4

[0262]

[0263]

[0264]

[0265]

[0266] Step 1: Under nitrogen atmosphere at 0°C, boranetetrahydrofuran (14.1 mL, 1 M, in THF) was added to a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2.0 g, 11.75 mmol) in tetrahydrofuran (35 mL). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 16 hours. The reaction mixture was quenched with methanol and concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to ethyl acetate / petroleum ether = 50%) to give 4-1 (1.4 g).

[0267] Step 2: Add Dysmart reagent (6.0 g, 14.08 mmol) to the mixture of 4-1 (2.0 g, 12.80 mmol) in dichloromethane (60 mL) at 0 °C, and stir the mixture at room temperature for 2 hours. Quench the reaction mixture with aqueous sodium thiosulfate solution at 0 °C, dilute with water, and extract with DCM. Combine the organic layers, wash with saturated aqueous sodium bicarbonate solution, dry over sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (petroleum ether to ethyl acetate / petroleum ether = 50%) to give 4-2 (1.1 g).

[0268] Step 3: 1,1-Dimethoxyprop-2-one (7.80 g, 66.04 mmol) was added to a solution of N-amino-4-methylbenzenesulfonamide (12.30 g, 66.04 mmol) in DMSO (150 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. Then, 5-methyl-2-nitroaniline (10.55 g, 69.35 mmol) was added to the above reaction mixture, and the resulting reaction mixture was stirred at 90 °C for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on a silica gel column (petroleum ether to petroleum ether / ethyl acetate = 2 / 1) and by preparative HPLC (acetonitrile / 0.05% TFA aqueous solution: 5%–50%) to give 4-3 (1.80 g).

[0269] Step 4: Add Pd / C (400 mg, 10 wt%) and ammonium hydroxide (5 drops) to a solution of 4-3 (1.80 g, 8.249 mmol) in methanol (100 mL). Stir the reaction mixture at room temperature under hydrogen atmosphere for 16 hours. Filter the mixture and concentrate to give 4-4 (1.50 g, crude product).

[0270] Step 5: Add N-bromosuccinimide (1.70 g, 9.56 mmol) to a solution of 4-4 (1.50 g, 7.96 mmol) in acetonitrile (50 mL), and stir the mixture at room temperature for 1 hour. Dilute the mixture with water and extract with dichloromethane. Combine the organic layers, dry over sodium sulfate, filter, and concentrate. Purify the residue by Combi flash (petroleum ether to ethyl acetate / petroleum ether = 70%) to give 4-5 (1.60 g).

[0271] Step 6: Add 4-2 (870 mg, 5.64 mmol) and 4-methylbenzenesulfonic acid (65 mg, 0.37 mmol) to a solution of 4-5 (500 mg, 1.87 mmol) in toluene (30 mL). Stir the reaction mixture at 120 °C for 16 hours under nitrogen. Dilute the mixture with water and extract with ethyl acetate. Combine the organic layers, wash with saturated sodium bicarbonate, dry over sodium sulfate, filter, and concentrate. Purify the residue by chromatography on a silica gel column (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 4-6 (400 mg).

[0272] Step 7: Add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (600 mg, 2.64 mmol) to a solution of 4-6 (950 mg, 2.35 mmol) in dichloromethane (50 mL). Stir the reaction mixture at room temperature for 2 hours. Dilute the mixture with water and extract with dichloromethane. Combine the organic layers, wash with saturated sodium bicarbonate, dry over sodium sulfate, filter, and concentrate. Purify the residue by chromatography on a silica gel column (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 4-7 (850 mg).

[0273] Step 8: Tributyl(1-ethoxyvinyl)stanane (2.34 g, 6.48 mmol) and Pd(PPh3)2Cl2 (387.8 mg, 0.48 mmol) were added to a solution of 4-7 (2.00 g, 4.98 mmol) in dioxane (50 mL). The reaction mixture was stirred at 105 °C for 16 hours under nitrogen. The mixture was quenched with HCl (1 M, 6 mL) and then with a saturated potassium fluoride solution (10 mL). The mixture was diluted with water and extracted with dichloromethane, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on a silica gel column (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 4-8 (1.50 g).

[0274] Step 9: The mixture of 4-8 (1.50 g, 4.11 mmol) and (R)-2-methylpropane-2-sulfinamide (598.66 mg, 4.94 mmol) in tetraethanolamine (IV) (18.78 g, 82.33 mmol) and dioxane (100 mL) was stirred at 97 °C for 8 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane to dichloromethane / methanol = 10:1) to give 4-9 (1.30 g).

[0275] Step 10: Sodium borohydride (205 mg, 5.41 mmol) was added to a mixture of 4-9 (1.30 g, 2.69 mmol) and cerium(III) heptahydrate (503 mg, 1.35 mmol) in methanol (80 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with ammonium chloride solution at 0 °C and extracted with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane to dichloromethane / methanol = 20:1) to give 4-10 (1.10 g).

[0276] Step 11: In a sealed tube, the mixture of 4-10 (380 mg, 0.78 mmol) in ammonia / methanol (10 mL, 7 M) was stirred at 70 °C for 16 hours. The mixture was then concentrated to obtain 4-11 (350 mg).

[0277] Step 12: At 0°C, add HCl / ethyl acetate (1 mL, 4M) to the mixture of 4-11 (350 mg, 0.77 mmol) in ethyl acetate (10 mL) and stir the mixture for 0.5 hours. Dilute the mixture with petroleum ether and filter. Dry the filter cake to obtain 4-12 (250 mg).

[0278] Step 13: A mixture of 4-12 (250 mg, 0.71 mmol), methyl 6-chloro-3-fluoropyridine-2-carboxylate (280 mg, 1.47 mmol), and N-ethyl-N-isopropylpropyl-2-amine (470 mg, 3.63 mmol) in N,N-dimethylacetamide (10 mL) was stirred at 120 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on a silica gel column (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 4-13 (180 mg).

[0279] Step 14: Phosphorus oxychloride (210 mg, 1.37 mmol) was added to a solution of 4-13 (180 mg, 0.34 mmol) in 1,2-dichloroethane (20 mL). The reaction mixture was stirred at 90 °C for 2 hours under nitrogen. The mixture was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether / ethyl acetate = 1 / 1) to give 4-14 (120 mg).

[0280] Step 15: At room temperature, lithium hydroxide monohydrate (30 mg, 0.71 mmol) was added to a mixture of 4-14 (120 mg, 0.23 mmol) in tetrahydrofuran (4 mL) and water (4 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched to pH ~3 with aqueous HCl (1 M) at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% FA aqueous solution: 10%~85%) to give 4 (50 mg). LCMS (ESI, m / z ): [M+H] + = 488.2; 1H-NMR (400 MHz, DMSO- d 6,ppm): δ 13.00 (s, 1H), 8.58 (d, J =7.6 Hz, 1H), 8.31 (s, 1H), 7.66 (s, 1H),7.35 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 9.2 Hz, 1H), 5.59-5.53 (m, 1H), 2.97-2.88(m, 6H), 2.85 (s, 3H), 2.54 (s, 3H), 1.74 (d, J = 6.8 Hz, 3H).

[0281] Example 5 - Synthesis of Compound 8

[0282]

[0283]

[0284]

[0285] Step 1: To a mixture of 2-iodo-4-methylaniline (10.0 g, 42.9 mmol) in EtOH (250 mL), p-anisaldehyde (7.6 g, 55.8 mmol) and cerium(III) trichloride heptahydrate (319.7 mg, 0.85 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Then, NaBH4 (3.2 g, 85.8 mmol) was added to the above reaction mixture. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, the residue was diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0% to 2.5% ethyl acetate / petroleum ether) to give 8-1 (5.66 g).

[0286] Step 2: To a solution of 8-1 (5.66 g, 16.0 mmol) in DCM (50 mL), 2-butynedic acid (1.35 g, 16.0 mmol) and DCC (3.64 g, 17.6 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated together with another batch and purified by silica gel column chromatography (eluting with 0% to 15% ethyl acetate / petroleum ether) to give 8-2 (4.18 g).

[0287] Step 3: To a solution of 8-2 (4.18 g, 9.97 mmol) in DMSO (50.0 mL), add NaN3 (972.2 mg, 14.96 mmol) and CuI (379.8 mg, 1.99 mmol). Stir the reaction mixture at 90 °C for 16 hours. Dilute the reaction mixture with another batch with water and extract with EtOAc. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (eluting with 0% to 5% ethyl acetate / dichloromethane) to give 8-3 (2.47 g).

[0288] Step 4: Add trifluoromethanesulfonic acid (2.2 g, 14.78 mmol) to a solution of 8-3 (2.47 g, 7.38 mmol) in TFA (10 mL, 129.8 mmol) and anisole (10 mL). Stir the reaction mixture at 80 °C for 4 hours. Concentrate the solution. Dilute the residue with petroleum ether and water. Collect the solid by filtration and dry to give 8-4 (1.48 g, crude product).

[0289] Step 5: Add 1,3-dibromo-5,5-dimethylhydantoin (720.7 mg, 2.52 mmol) and 3-nitrobenzenesulfonic acid (85.4 mg, 0.42 mmol) to a solution of 8-4 (900 mg, 4.2 mmol) in HFIP (15 mL). Stir the reaction mixture at 60 °C under N2 for 1 hour. Quench the reaction with water. Collect the solid by filtration and dry to obtain 8-5 (1.33 g, crude product).

[0290] Step 6: At room temperature, 4,4-difluoropiperidine hydrochloride (991.9 mg, 6.29 mmol), PyBOP (3.27 g, 6.29 mmol), and DBU (2.2 g, 14.7 mmol) were added to a solution of 8-5 (1.23 mg, 4.19 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0% to 30% ethyl acetate / petroleum ether) to give 8-6 (365 mg).

[0291] Step 7: To a solution of 8-6 (365 mg, 0.92 mmol) in dioxane (10 mL), Pd(PPh3)2Cl2 (71.7 mg, 0.09 mmol) and 1-ethoxyvinyltri-n-butyltin (432.5 mg, 1.19 mmol) were added. The reaction mixture was stirred at 105 °C for 16 hours under nitrogen. The reaction mixture was quenched with HCl (2 M, 2 mL) along with another batch, and then quenched with saturated KF solution. The resulting reaction mixture was filtered and the filtrate was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane to dichloromethane / ethyl acetate = 3 / 1) to give 8-7 (464 mg).

[0292] Step 8: To the mixture of 8-7 (290 mg, 0.80 mmol) in dioxane (4.5 mL), add (R)-2-methylpropane-2-sulfinamide (146.7 mg, 1.21 mmol) and Ti(OEt)4 (4.5 mL, 21.46 mmol), and stir the mixture at 100 °C for 6 hours. Dilute this mixture with another batch with water and extract with ethyl acetate. Combine the organic layers, dry to anhydrous Na2SO4, filter, and concentrate. Purify the residue by column chromatography on silica gel (eluting with dichloromethane to dichloromethane / ethyl acetate = 3 / 1) to give 8-8 (350 mg).

[0293] Step 9: Add NaBH4 (49.1 mg, 1.29 mmol) to a mixture of 8-8 (300 mg, 0.64 mmol) and cerium(III) heptahydrate (483.3 mg, 1.29 mmol) in MeOH (5 mL) at 0 °C. Stir the mixture at 0 °C for 1 hour. Quench the reaction with saturated ammonium chloride solution at 0 °C and extract with ethyl acetate. Combine the organic layers, dry over anhydrous Na2SO4, filter, and concentrate. Purify the residue by preparative HPLC (eluting with 5% to 95% MeCN / 0.05% FA aqueous solution) to give 8-9 (150 mg).

[0294] Step 10: Add HCl / EtOAc (3 mL, 4 M) to the mixture of 8-9 (130 mg, 0.28 mmol) in EtOAc (3 mL) and stir the reaction mixture at room temperature for 0.5 hours. Concentrate the resulting mixture, dilute the residue with HCl (2 M) and extract with EtOAc, discarding the extract. Then adjust the aqueous phase to pH 12 with ammonia solution and extract with EtOAc. Combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to give 8-10 (150 mg, crude product).

[0295] Step 11: Methyl 6-chloro-3-fluoropyridinecarboxylate (105.20 mg, 0.55 mmol) and DIEA (107.6 mg, 0.83 mmol) were added to a solution of 8-10 (100 mg, 0.27 mmol) in DMAc (5 mL). The reaction mixture was stirred at 120 °C for 6 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE to EtOAc / PE = 1 / 3) along with another batch to give 8-11 (140 mg).

[0296] Step 12: At room temperature, lithium hydroxide monohydrate (21.4 mg, 0.50 mmol) was added to a solution of 8-11 (90 mg, 0.17 mmol) in THF (2 mL) and water (2 mL). The reaction mixture was stirred at 40 °C for 1 hour. The mixture was acidified to pH ~5 with aqueous HCl (2 M) and extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile / 0.05% formic acid aqueous solution: 15%~95%) to give 8 (81.45 mg). LCMS (ESI, m / z): [M+H] + = 515.9; 1 H NMR (400 MHz, DMSO- d 6, ppm): δ 13.02 (brs,1H), 8.53 (s, 1H), 8.17 (s, 1H), 7.43 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.03(d, J = 8.0 Hz, 1H), 5.53 (t, J=6.4 Hz, 1H), 3.66-3.60 (m, 4H), 2.72 (s, 3H), 2.45 (s, 3H), 2.28 - 2.21 (m, 4H), 1.66 (d, J = 6.8 Hz, 3H). 19 F NMR (376 MHz, DMSO- d 6, ppm): δ -95.02 (2F).

[0297] Table 1 below shows the characterization of some exemplary compounds of this disclosure.

[0298] Table 1. Characterization of some exemplary compounds of this disclosure.

[0299]

[0300] Bioassay Example A: Cell proliferation assay in T47D and SK-BR-3 cell lines 1. Materials The culture media and reagents used in this study are listed in the table below.

[0301]

[0302] 2. Experimental methods and procedures T47D breast cancer cells PI3Ka_H1047R SK-BR-3 (obtained from ATCC) were cultured in an incubator at 37°C with 5% CO2 and 100% relative humidity. Cells were routinely passaged to maintain exponential growth. 1500 cells were seeded per well of each cell assay plate with 100 μL of culture medium suspension. Cells were incubated overnight, and then the compound was added to each well. The compound was prepared as a 10 mM stock solution in dimethyl sulfoxide (DMSO). Serial dilutions in DMSO were performed in 200X stock plates. 0.5 μL of the 200X compound solution was added to each well of the cell assay plate. The final DMSO concentration in each well was 0.5%. High control wells contained 0.5% DMSO with culture medium added to the cells, and low control wells contained culture medium added only to the wells in the plate. The cell assay plate was incubated for 6 days. Cell viability was measured according to the Promega CellTiter-Glo assay kit.

[0303] 3. Data Analysis The inhibition rate (IR) of the test compound was determined by the following formula: IR (%) = (mean high control – compound well) / (mean high control – mean low control) 100%. Calculation of compound IC using a nonlinear regression equation.50 Y = minimum value + (maximum value - minimum value) / (1 + 10^(LogIC)) 50 -X) HillSlope); X: Logarithm of compound concentration; Y: Inhibition rate (IR): Highest and lowest values: Plateau in the same unit as Y; logIC 50 : Same logarithmic unit as X; HillSlope: Slope coefficient or Hill slope.

[0304] Table 2 below shows the effects of representative compounds on T47D. PI3Ka_H1047R Inhibition of cancer cell growth (IC50) 50 ).

[0305] Table 2. Representative compounds and their effects on T47D PI3Ka_H1047R Inhibition of cancer cell growth (IC) 50 )

[0306] Bioassay Example B: Human Microsomal Scavenging Assay The goal of this study is to evaluate the metabolic stability of compounds in human liver microsomes using a microsomal clearance assay.

[0307] A mixture containing 100 mM potassium phosphate (pH 7.4), 0.5 mg / mL liver microsomes, 2 mM NADPH, and 1 μM of the compound was prepared and added to a 96-well plate. The plate was then incubated at 37 °C for different time points (0, 5, 15, 30, and 45 min) and the reaction was terminated with acetonitrile solution containing an internal standard. The samples were then analyzed by LC / MS / MS to determine how much compound remained at each time point. The elimination rate constant and half-life were calculated from the data as follows: elimination rate constant (k) = -slope; half-life (t1 / 2) = 0.693 / k.

[0308] The in vitro intrinsic clearance rate CLint is calculated from t1 / 2 as follows: CLint = (0.693 / t1 / 2) × (1 / (microsomal protein concentration (0.5 mg / mL))) × physiological specific radioactivity coefficient.

[0309] Table 3 below shows the in vitro intrinsic clearance values ​​of representative compounds.

[0310] Table 3. Intrinsic clearance values ​​of representative compounds in vitro

[0311] Compound A :WO2021202964, Example 326.

[0312] The summary and abstract section may set forth one or more, but not all, exemplary embodiments of the invention as conceived by the inventors, and therefore is not intended to limit the invention and the appended claims in any way.

[0313] The invention has been described above using functional building blocks that illustrate the implementation of specific functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries can be defined as long as the specified functions and their relationships are properly performed.

[0314] Regarding aspects of the invention described as belonging to a genus, all individual species are considered separately as separate aspects of the invention. If an aspect of the invention is described as "comprising" a feature, the embodiment is also contemplated as "consisting of" or "substantially consisting of" that feature.

[0315] The foregoing description of the specific embodiments will fully reveal the general nature of the invention, enabling others to readily modify and / or adapt various applications of such specific embodiments by applying knowledge of ordinary art, without excessive experimentation or departing from the general concept of the invention. Therefore, based on the teachings and guidance presented herein, such modifications and alterations are intended to be within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that the wording or terminology herein is for descriptive rather than limiting purposes, and that the terminology or terminology of this specification will be interpreted by those skilled in the art based on the teachings and guidance.

[0316] The breadth and scope of this invention should not be limited by any of the exemplary embodiments described above.

[0317] All aspects, implementation schemes, and options described herein can be combined in any and all variations.

[0318] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. If any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in any document incorporated by reference, the meaning or definition given to that term in this document shall prevail.

Claims

1. A compound of formula I or II, or a pharmaceutically acceptable salt thereof: in: W is CR 10 Or N, where R 10 For hydrogen, deuterium, halogen, or C atoms optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl groups or C groups optionally substituted with 1-3 fluorine atoms 1-4 Alkoxy; R 1 The substituted 3-12 membered ring structure is selected from monocyclic nonaromatic rings, monocyclic aromatic rings and polycyclic structures, wherein each ring in the polycyclic structure is independently aromatic or nonaromatic, and wherein the 3-12 membered ring structure optionally contains 1-4 cyclic heteroatoms independently selected from O, N and S. R X R 3 R 4 and R 5 Each is independently hydrogen, deuterium, halogen, CN, OH, G 1 Or OG 1 ; R 6 and R 7 Each can be independently hydrogen, deuterium, CN, or G. 2 ; R 8 C is hydrogen or optionally replaced by 1-3 fluorine atoms. 1-4 Alkyl or nitrogen protecting groups; L 2 The substituted phenylene or substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl or bicyclic heteroaryl); and R 9 For OH, NH2, OG 3 NHG 3 NG 3 G 3 or NHSO2G 3 ;or N, L 2 C(O), R 9 and R 8 The linkage forms an optionally substituted 6,6- or 5,6-fused bicyclic heterocyclic group or heteroaryl group; in: G 1 Each time it appears, it is independently replaced by the arbitrarily chosen C. 1-6 Alkyl groups, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne or optionally substituted 3- to 10-membered ring structures having 0-4 heteroatoms; G 2 Each time it appears, it is independently replaced by the arbitrarily chosen C. 1-6 Alkyl groups, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl or optionally substituted 3-6 membered rings having 0-3 heteroatoms (e.g., cyclopropyl); and G 3 Each time it appears, it is independently replaced by the arbitrarily chosen C. 1-6 Alkyl groups, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne or optionally substituted 3-8 membered nonaromatic ring structures with 0-4 ring heteroatoms, or NG 3 G 3 This represents a nitrogen-containing 4-8 membered non-aromatic ring structure that can be substituted.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R X Hydrogen, halogen, CN, or C optionally replaced by F 1-4 Alkyl groups, C groups optionally substituted with F 2-4 Alkenyl, C substituted with F (optionally) 2-4 The alkynyl group or optionally a C group independently selected from halogens, CN, OH, or optionally substituted with F. 1-4 Alkyl groups and C groups optionally substituted with F 1-4 Substituents of heteroalkyl groups on 3-5 membered rings (e.g., cyclopropyl).

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R X Hydrogen or C optionally replaced by F 1-4 Alkyl groups, such as methyl groups.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein W is N.

5. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein W is CH.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 for , , , , or , where R C CN, COOH, CONH2, G 4A C(O)G 4A C(O)OG 4A C(O)NHG 4A C(O)NG 4A G 4A SO2G 4A SO2NHG 4A or SO2NG 4A G 4A G 4A Each occurrence is independently (i)C 1-4 Alkyl; (ii) 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., (iii)–(C 1-4 alkylene)-3-12-membered ring such as –(C 1-4 (iv)–(C 1-4 (heteroalkyl)-3-12-membered ring such as –(C 1-4 (heteroalkyl)-3-7-membered ring, wherein the C 1-4 Alkyl or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl) is optionally surrounded by one or more (e.g., 1, 2 or 3) G A1 Replaced, of which G A1 Each time it appears, it is independently deuterium, halogen, CN, OH, NH2, or C that is optionally replaced by 1-3 F atoms. 1-4 Heteroalkyl groups, C atoms optionally substituted with 1-3 F atoms. 1-4 Alkyl or optionally substituted with one or more substituents independently selected from F, CN, OH, methoxy and methyl (e.g. cyclopropyl, cyclobutyl, oxetyl, aziryl, etc.).

7. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 for , , or , where R C Hydrogen, halogens (e.g., F), CN, COOH, CONH2, G 4A OG 4A C(O)G 4A C(O)OG 4A C(O)NHG 4A C(O)NG 4A G 4A ,NHC(O)G 4A 、NHC(O)OG 4A ,NHC(O)NHG 4A ,NHC(O)NG 4A G 4A NG 4A C(O)G 4A NG 4A C(O)OG 4A NG 4A C(O)NHG 4A NG 4A C(O)NG 4A G 4A SO2G 4A SO2NHG 4A or SO2NG 4A G 4A G 4A Each occurrence is independently (i)C 1-4 Alkyl, C 2-4 alkenyl or C 2-4 (ii) 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., (iii)–(C 1-4 alkylene)-3-12-membered ring such as –(C 1-4 (iv)–(C 1-4 (heteroalkyl)-3-12-membered ring such as –(C 1-4 (heteroalkyl)-3-7-membered ring, wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A1 Replaced, of which G A1 Each time it appears, it is independently deuterium, halogen, CN, OH, NH2, or C that is optionally replaced by 1-3 F atoms. 1-4 Heteroalkyl groups, C atoms optionally substituted with 1-3 F atoms. 1-4 Alkyl or optionally substituted with one or more substituents independently selected from F, CN, OH, methoxy and methyl (e.g. cyclopropyl, cyclobutyl, oxetyl, aziryl, etc.).

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 for .

9. The compound according to claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R C It can be H, F, Cl, CN, COOH, CH3, OCH3, CHF2, or CF3.

10. The compound according to claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R C Selected from the following: .

11. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 for or , or R 1 for or Each of them is selected independently from 1 to 3 of the following: deuterium, F, OH, NH2, CN, G. 5 OG 5 NH-C(O)G 5 and C(O)G 5 The substituents are replaced by G, where G is the substituent. 5 It is C independently each time it appears. 1-4 Alkyl or 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc.), wherein the C 1-4 Alkyl or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl) is optionally surrounded by one or more (e.g., 1, 2 or 3) G B Replaced, of which G B Each time it appears, it is independently deuterium, F, Cl, CN, OH, or C that is optionally replaced by 1-3 F. 1-4 Alkyl groups or C groups optionally substituted with 1-3 F groups 1-4 alkyl.

12. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the following: 。 13. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the following: 。 14. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: ;or R 1 Selected from: .

15. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: .

16. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: .

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein R 8 It is hydrogen.

18. The compound according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein, where applicable, L 2 For the substituted phenylene, such as It may be optionally selected by one or more elements, each independently selected from halogens, CN, OH, COOH, G 6 and OG 6 The substituents are replaced by G, where G is the substituent. 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

19. The compound according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein, where applicable, L 2 For the substituted 6-membered heteroaryl group, such as , or Each of them is optionally selected independently from one or more halogens, CN, OH, COOH, G 6 and OG 6 The substituents are replaced by G, where G is the substituent. 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

20. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein L 2 for or NR is shown 8 and C(O)R 9 To show the orientation of the connection with the rest of the molecule, and Where R 20 For hydrogen, halogens, CN, OH, COOH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl substituents are used; preferably, R 20 It can be hydrogen, F, Cl, or C substituted with 1-3 F atoms. 1-4 Alkyl groups, such as CHF2 or CF3, or R 20 for More preferably, L 2 for or ;or L 2 for NR is shown 8 and C(O)R 9 To show the connection direction with the rest of the molecule, and where R 20 and R 21 Each can be independently represented by hydrogen, halogen, CN, OH, COOH, or G. 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl substituents are used; preferably, R 20 and R 21 Each can be independently hydrogen, F, Cl, CN, or C substituted with 1-3 F atoms. 1-4 Alkyl groups, such as CHF2 or CF3; more preferably, R 20 For CN and R 21 It is a halogen (e.g., Cl).

21. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R 9 It is OH.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein... for or , where R 20 For hydrogen, halogens, CN, OH, COOH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl substituents are used; preferably, R 20 It can be hydrogen, F, Cl, or C substituted with 1-3 F atoms. 1-4 Alkyl groups, such as CHF2 or CF3; more preferably, for .

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, characterized in that... It has a structure according to formula Ia, Ib, II-a or II-b: in: R 20 For hydrogen, halogens, CN, OH, COOH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

24. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, characterized in that... Having a structure according to formulas Ia-1, Ia-2, Ia-3, Ia-4, Ib-1, Ib-2, Ib-3, Ib-4, II-a-1, II-a-2, II-a-3, II-a-4, II-b-1, II-b-2, II-b-3, or II-b-4: in: R 20 For hydrogen, halogens, CN, OH, COOH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 The alkyl group is substituted; and R C Hydrogen, halogen, CN, COOH, CONH2, G 4A C(O)G 4A C(O)OG 4A C(O)NHG 4A C(O)NG 4A G 4A SO2G 4A SO2NHG 4A or SO2NG 4A G 4A G 4A Each occurrence is independently (i)C 1-4 Alkyl, C 2-4 alkenyl or C 2-4 (ii) 3-12 membered rings, such as 3-7 membered rings or bicyclic heteroaryl groups, for example, cyclopropyl, cyclobutyl, oxadiazolyl, aziridine, tetrahydrofuranyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (e.g., 1,2,3-triazolyl, 1,3,4-triazolyl), tetrazolyl, pyrimidinyl, phenyl, 9 H -purine group, imidazo[1,2-] b ]pyrazinyl, pyrazolo[1,5-a]pyridyl, benzo[d]oxazolyl, etc., (iii)-(C 1-4 alkylene rings (-3-12-membered rings), such as -(C 1-4 (iv)-(C)-3-7-membered ring 1-4 (heteroalkyl)-3-12-membered cyclohexane-(C 1-4 (heteroalkyl)-3-7-membered ring, wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3-12 membered ring (e.g., 3-7 membered ring or bicyclic heteroaryl group) is optionally surrounded by one or more (e.g., 1, 2 or 3) G groups. A1 Replaced, of which G A1 Each time it appears, it is independently deuterium, halogen, CN, OH, NH2, or C that is optionally replaced by 1-3 F atoms. 1-4 Heteroalkyl groups, C atoms optionally substituted with 1-3 F atoms. 1-4 Alkyl or optionally substituted with one or more substituents independently selected from F, CN, OH, methoxy and methyl (e.g. cyclopropyl, cyclobutyl, oxetyl, aziryl, etc.).

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 20 It can be hydrogen, F, Cl, or C substituted with 1-3 F atoms. 1-4 Alkyl groups, such as CHF2 or CF3.

26. The compound according to claim 24 or 25, or a pharmaceutically acceptable salt thereof, wherein R C It can be H, F, Cl, CN, COOH, CH3, OCH3, CHF2 or CF3, or R. C It can be OH, NH2, CH2OH, CH(OH)CH3, CH2CH3, CH2F or CH2OCH3.

27. The compound according to claim 24 or 25, or a pharmaceutically acceptable salt thereof, wherein R C for , , , , or R C Selected from: 。 28. The compound according to claim 24 or 25, or a pharmaceutically acceptable salt thereof, wherein R C For H, F, CN, CHF2 or 5-membered heteroaryl, such as oxadiazole, which may optionally be substituted with methyl, CD3, CF3 or cyclopropyl, for example, , , , or .

29. The compound according to any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R 3 Hydrogen, halogen, CN, OH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-30, wherein R 4 Hydrogen, halogen, CN, OH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-31, wherein R 4 It is methyl, or R 4 For F, Cl, Br or , or R 4 It is either CD3 or CF3.

33. The compound according to any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R 5 Hydrogen, halogen, CN, OH, G 6 Or OG 6 G 6 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne or 3- or 4-membered ring (e.g., cyclopropyl), wherein the C 1-4 Alkyl, the C 2-4 alkenyl, the C 2-4 The alkynyl group or the 3- or 4-membered ring (e.g., cyclopropyl) is optionally replaced by one or more (e.g., 1-3) C groups, each independently selected from deuterium, F, CN, OH, or C groups optionally substituted with 1-3 F groups. 1-4 Alkyl groups and C groups optionally substituted with 1-3 F groups 1-4 Alkyl groups are substituted.

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-34, wherein R 6 and R 7 Both are hydrogen.

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-34, wherein R 6 It is either hydrogen or deuterium, and R 7 C 1-4 Alkyl groups, optionally substituted with one or more (e.g., 1-3) C atoms, each independently selected from deuterium, F, CN, OH, and C atoms optionally substituted with 1-3 F atoms. 1-4 The alkoxy group is replaced by a substituent.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-34, wherein R 6 It is either hydrogen or deuterium, and R 7 It is a methyl group.

38. A compound selected from any of the compounds shown in the Examples section or in Table A herein, or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-38.

40. A method of treating a disease or condition associated with the regulation of phosphoinositol 3-kinase (PI3K), the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1-38 or the pharmaceutical composition according to claim 39.

41. The method of claim 40, wherein PI3K is PI3Ka.

42. The method of claim 40 or 41, wherein the PI3K associated with the disease or condition has an H1047R mutation.

43. The method according to any one of claims 40-42, wherein the disease or condition is cancer.

44. The method according to claim 43, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

45. The method according to any one of claims 40-42, wherein the disease or condition is CLOVES syndrome (congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

46. ​​A method for inhibiting phosphoinositol 3-kinase (PI3K), the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1-38 or the pharmaceutical composition according to claim 39.

47. A method of treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1-38 or the pharmaceutical composition according to claim 39.

48. The method of claim 47, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

49. A method of treating a condition selected from CLOVES syndrome (congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS), the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1-38 or the pharmaceutical composition according to claim 39.

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