Modulators of TNF alpha activity and uses thereof

Abstract

Described herein are modulators of TNF [alpha] activity and pharmaceutical compositions comprising such inhibitors. These subject compounds and compositions are useful for the treatment of TNF [alpha] mediated disorders or diseases.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 519,990 filed on August 16, 2023, U.S. Provisional Application Serial No. 63 / 613,206 filed on December 21, 2023, and U.S. Provisional Application Serial No. 63 / 650,626 filed on May 22, 2024; these applications are hereby incorporated by reference in their entirety. Background Art

[0003] TNFα is the prototypical member of the tumor necrosis factor (TNF) superfamily of proteins that share the primary function of regulating cell survival and cell death. A structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to and activate specific TNF superfamily receptors. By way of example, TNFα exists in a soluble and transmembrane form and signals through two receptors, called TNFR1 and TNFR2, that differ in their functional endpoints.

[0004] TNF superfamily members, including TNFα itself, are associated with a variety of physiological and pathological functions that are believed to play a role in a range of medically significant conditions. Various products that can modulate TNFα activity are already commercially available. All currently approved products are macromolecules and work by inhibiting the binding of human TNFα to its receptors. Typical macromolecular TNFα inhibitors include anti-TNFα antibodies and soluble TNFα receptor fusion proteins. They are all approved for the treatment of inflammatory and autoimmune disorders, such as rheumatoid arthritis and Crohn's disease.

[0005] Therefore, there is a need for new, potent small molecule modulators of human TNFα activity that would be beneficial in treating a variety of disorders, including: autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and neoplastic disorders. Summary of the invention

[0006] Disclosed herein is a compound of formula (I*) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0007]

[0008] As disclosed herein, formula (I*).

[0009] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

[0010] Also disclosed herein is a method for treating a condition for which administration of a TNFα functional modulator is indicated, comprising administering to a patient in need of such treatment an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.

[0011] Also disclosed herein is a method for treating an inflammatory or autoimmune disorder, a nervous system disorder, a neurodegenerative disorder, pain, a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or a neoplastic disorder, comprising administering to a patient in need of such treatment an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 The prolongation of the pulsation period of Comparative Example 1 and Example 15 is depicted.

[0013] Figure 2 The field potential duration (Fridericia correction) for Comparative Example 1 and Example 15 is depicted.

[0014] Figure 3 The reduction in spike amplitude for Comparative Example 1 and Example 15 is depicted.

[0015] Incorporation by reference

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0017] definition

[0018] In the following description, certain specific details are set forth to provide a comprehensive understanding of the various embodiments. However, it will be understood by those skilled in the art that the present invention can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the subsequent claims, the word "comprise" and its variant forms such as "comprises" and "comprising" should be interpreted in an open, inclusive sense, i.e., "including but not limited to". In addition, the titles provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0019] References throughout the specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" that appear in different places throughout the specification do not necessarily all refer to the same embodiment. In addition, in one or more embodiments, particular features, structures, or characteristics may be combined in any suitable manner. In addition, as used in this specification and the appended claims, unless the content clearly provides otherwise, the singular forms "a", "an", and "the" include plural indicators. It should also be noted that unless the content clearly provides otherwise, the term "or" is generally used in its meaning that includes "and / or".

[0020] Unless otherwise indicated, the following terms as used herein have the following meanings:

[0021] "Oxo" refers to =0.

[0022] "Amine" refers to -NH 2 .

[0023] "Hydroxyl" refers to -OH.

[0024] "Carboxyl" refers to -COOH.

[0025] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monovalent free radical having one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever a numerical range appears in this document, such as "C 1 -C 6 In some embodiments, the term "alkyl" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the definition also includes the occurrence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C 1 -C 10 In some embodiments, the alkyl group is C 1 -C 6 In some embodiments, the alkyl group is C1 -C 5 In some embodiments, the alkyl group is C 1 -C 4 In some embodiments, the alkyl group is C 1 -C 3 Alkyl. Unless otherwise expressly stated in the specification, an alkyl group may be optionally substituted, for example, by one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. In some embodiments, an alkyl group may be optionally substituted by one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 Optionally substituted. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0026] "Alkenyl" refers to a straight or branched hydrocarbon monovalent radical having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in the cis or trans or Z or E configuration around the double bond and is understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH 2 ), 1-propenyl (-CH 2 CH=CH 2 ), isopropenyl [-C(CH 3 )=CH 2 ], butenyl, 1,3-butadienyl, etc. Whenever a numerical range appears in this document, such as "C 2 -C 6 "Alkenyl" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also includes the occurrence of the term "alkenyl" in which no numerical range is specified. Unless otherwise clearly stated in the specification, the alkenyl group can be optionally substituted, for example, by one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. In some embodiments, the alkenyl group is substituted by one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 Optionally substituted. In some embodiments, alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0027] "Alkynyl" refers to a straight or branched hydrocarbon monovalent radical having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C 2 -C 6 "Alkynyl" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also includes the occurrence of the term "alkynyl" in which no numerical range is specified. Unless otherwise clearly stated in the specification, the alkynyl group can be, for example, optionally substituted by one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. In some embodiments, the alkynyl group is substituted by one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 Optionally substituted. In some embodiments, alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0028] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise expressly stated in the specification, an alkylene group may be optionally substituted, for example, by one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, an alkylene group may be optionally substituted by one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 Optionally substituted. In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0029] "Alkoxy" refers to a radical of the formula -Oalkyl, wherein alkyl is as defined above. Unless otherwise expressly stated in the specification, an alkoxy group may be, for example, optionally substituted with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. In some embodiments, an alkoxy group may be optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2Optionally substituted. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0030] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, aryl is a 6- to 10-membered aryl. In some embodiments, aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, In some embodiments, aryl is substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -C1, -C2, -C3, -C4, -C6, -C7, -C8, -C9, -C10, -C11, -C12, -C13, -C14, -C15, -C16, -C17, -C18, -C19, -C20, -C21, -C22, -C34, -C19, -C23, -C18, -C24, -C19, -C25, -C19, -C26, -C11, -C27, -C12, -C28, -C19, -C29, -C20, -C21, -C22, -C34, -C19, -C29, -C35, -C19, -C20, -C21, -C22, -C23, -C24, -C19, -C25, -C26, -C19, -C27, -C28, -C29, -C29, -C34, -C19, -C2 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the aryl group is substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, aryl is optionally substituted with halogen.

[0031] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (e.g., C 3 -C 15 Fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl), three to ten carbon atoms (e.g., C 3 -C 10 Fully saturated alkyl or C 3 -C 10 cycloalkenyl), three to eight carbon atoms (e.g., C 3 -C 8 Fully saturated cycloalkyl or C3 -C 8 cycloalkenyl), three to six carbon atoms (e.g., C 3 -C 6 Fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl), three to five carbon atoms (e.g., C 3 -C 5 Fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) or three to four carbon atoms (e.g., C 3 -C 4 Fully saturated cycloalkyl or C 3 -C 4 In some embodiments, the cycloalkyl is a 3 to 10-membered fully saturated cycloalkyl or a 3 to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6-membered fully saturated cycloalkyl or a 3 to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6-membered fully saturated cycloalkyl or a 5 to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptane, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyl includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise expressly stated in the specification, cycloalkyl is, for example, optionally substituted by one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. In some embodiments, cycloalkyl is optionally substituted by one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the cycloalkyl group is substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0032] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0033] "Haloalkyl" refers to an alkyl radical as defined above substituted with one or more halo radicals as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0034] "Haloalkoxy" refers to an -O-haloalkyl group wherein haloalkyl is as defined above.

[0035] "Hydroxyalkyl" refers to an alkyl radical as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0036] "Aminoalkyl" refers to an alkyl radical as defined above that is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0037] "Deuterated alkyl" refers to an alkyl radical as defined above that is substituted with one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuterated alkyl includes, for example, CD 3 , CH 2 D. CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D or CH 2 CHD 2 In some embodiments, the deuterated alkyl group is CD 3 .

[0038] "Heteroalkyl" refers to an alkyl group in which one or more of the backbone atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is C 1 -C 6 A heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. 1 -C 6 Heteroalkyl, wherein the heteroalkyl contains 1 to 6 carbon atoms and one or two atoms selected from oxygen, nitrogen and sulfur, wherein the heteroalkyl is attached to the rest of the molecule at the carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH 2 OCH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 2 OCH 3 、-CH(CH 3 )OCH 3 、-CH 2 NHCH 3 、-CH 2 N(CH 3 ) 2 、-CH 2 CH 2 NHCH 3 or -CH 2 CH 2 N(CH 3 ) 2 Unless otherwise specifically stated in the specification, heteroalkyl groups are optionally substituted, for example, by one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, heteroalkyl groups are optionally substituted by one or more oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the heteroalkyl radical is replaced by one or more oxo, halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the heteroalkyl group is optionally substituted with halogen.

[0039] "Heterocycloalkyl" refers to a 3 to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and one to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon and sulfur. In some embodiments, heterocycloalkyl is fully saturated. In some embodiments, heterocycloalkyl is C-connected. In some embodiments, heterocycloalkyl is N-connected. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, heterocycloalkyl contains one to three nitrogen. In some embodiments, heterocycloalkyl contains one or two nitrogen. In some embodiments, heterocycloalkyl contains one nitrogen. In some embodiments, heterocycloalkyl contains one nitrogen and one oxygen. Unless otherwise expressly stated in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyl radicals include, but are not limited to, radicals having two to fifteen carbon atoms (e.g., C 2 -C 15 Fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), two to ten carbon atoms (e.g., C 2 -C 10 Fully saturated heterocycloalkyl or C 2 -C 10 Heterocycloalkenyl), two to eight carbon atoms (e.g., C 2 -C 8 Fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl), two to seven carbon atoms (e.g., C 2 -C 7 Fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), two to six carbon atoms (e.g., C 2 -C 6 Fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl), two to five carbon atoms (e.g., C 2 -C 5 Fully saturated heterocycloalkyl or C 2 -C 5 heterocycloalkenyl) or two to four carbon atoms (e.g., C 2 -C 4 Fully saturated heterocycloalkyl or C 2 -C 4Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl , tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes carbohydrates of all ring forms, including but not limited to monosaccharides, disaccharides and oligosaccharides. In some embodiments, heterocycloalkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) constituting heterocycloalkyl (i.e., the skeleton atoms of heterocycloalkyl ring). In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkenyl. Unless otherwise expressly stated in the specification, heterocycloalkyl is, for example, optionally substituted by one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heterocycloalkyl group is replaced by one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the heterocycloalkyl group is replaced by one or more halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0040] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-attached. In some embodiments, the heteroaryl is N-attached. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaryl is a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaryl is a 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaryl is a 5-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzophenylthio, furanyl yl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).Unless otherwise specifically stated in the specification, heteroaryl is optionally substituted, for example, by one or more halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, etc. In some embodiments, heteroaryl is substituted by one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF. 3 , -OH, -OMe, -NH 2 or-NO 2 In some embodiments, the heteroaryl group is replaced by one or more halogen, methyl, ethyl, -CN, -CF 3 In some embodiments, the heteroaryl is optionally substituted with halogen.

[0041] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, an optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at any level between full substitution and mono-substitution (e.g., -CH 2 CHF 2 、-CH 2 CF 3 , -CF 2 CH 3 ,-CFHCHF 2 wait).

[0042] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted by one, two, three or four or more substituents. In some embodiments, the subject group is optionally substituted by one, two, three or four substituents. In some embodiments, the subject group is optionally substituted by one, two or three substituents. In some embodiments, the subject group is optionally substituted by one or two substituents. In some embodiments, the subject group is optionally substituted by one substituent. In some embodiments, the subject group is optionally substituted by two substituents. In some embodiments, the subject group is optionally substituted by three substituents.

[0043] "Effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, in a single dose or as part of a series of doses, effective to produce the desired therapeutic effect.

[0044] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of an individual or cell. In some embodiments, treatment comprises administration of a pharmaceutical composition after the onset of a pathological event or exposure to a pathogen and includes stabilization of the condition (e.g., the condition does not worsen) or alleviation of the condition.

[0045] "Synergy" or "synergy" means that the effect of the combination is greater than the sum of the individual effects of each component at the same dose.

[0046] As used herein, "a disease or disorder associated with TNFα" or alternatively "a disease or disorder mediated by TNFα" means any disease or other deleterious condition in which TRPML1 or a mutant thereof is known or suspected to play a role.

[0047] Compound

[0048] Described herein are compounds useful for treating a TNFα-mediated disease or condition, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0049] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more potent than corresponding compounds having a benzimidazole core. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% more potent than corresponding compounds having a benzimidazole core.

[0050] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are less cardiotoxic than corresponding compounds having a benzimidazole core. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% less cardiotoxic than corresponding compounds having a benzimidazole core.

[0051] In some embodiments, the cell permeability of the compounds described herein or their pharmaceutically acceptable salts, solvates or stereoisomers is better than that of the corresponding compounds with a benzimidazole core. In some embodiments, the cell permeability of the compounds described herein or their pharmaceutically acceptable salts, solvates or stereoisomers is 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% higher than that of the corresponding compounds with a benzimidazole core.

[0052] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have better physical properties than corresponding compounds having a benzimidazole core.

[0053] In some embodiments, the pharmacokinetic properties of the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are better than those of the corresponding compounds having a benzimidazole core.

[0054] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have better pharmacodynamic properties than corresponding compounds having a benzimidazole core.

[0055] Compounds having a benzimidazole core contain the following ring system in their central core:

[0056] Disclosed herein is a compound of formula (I') or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0057]

[0058] in:

[0059] Ring B is phenyl or a 6-membered heteroaryl group containing one or two nitrogen atoms;

[0060] Each R 1 are independently halogen, -CN, -NO 2 、-OH、-OR a 、-NRcR d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1-C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom are optionally substituted with one or more R; 1 Together they form an oxo group;

[0061] n is 1, 2, 3 or 4;

[0062] R 2 For hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl or cycloalkyl;

[0063] X is N or CR X ;

[0064] R X Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl;

[0065] Y is N or CR Y ;

[0066] R Y Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;

[0067] Z is N or CR Z ;

[0068] R Z Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;

[0069] U is N and T is C, or U is C and T is N;

[0070] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0071] Each R 3 are independently halogen, -L-CN, -L-NO 2 , -L-OH, -L-OR a 、-L-OC(=O)R a 、-L-OC(=O)OR b 、-L-OC(=O)NR c R d 、-L-SH、-L-SR a ,-LS(=O)R a ,-LS(=O) 2 R a ,-LS(=O)(=NH)R a ,-LS(=O) 2 OR b ,-LS(=O) 2NR c R d 、-L-NR c R d 、-L-NR b C(=O)NR c R d 、-L-NR b C(=O)R a 、-L-NR b C(=O)OR b 、-L-NR b S(=O) 2 R a 、-LC(=O)R a ,-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0072] or two R on the same atom 3 Together they form an oxo group;

[0073] or two R on adjacent atoms 3 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is independently optionally substituted by one or more R;

[0074] m is 0, 1, 2, 3 or 4;

[0075] Each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0076] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0077] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0078] or Rc and R d together with the atoms to which they are attached form heterocycloalkyl which is independently optionally substituted with one or more R; and

[0079] L is absent or is C optionally substituted by one or more R 1 -C 3 Alkylene;

[0080] Each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 NH 2 、-S(=O) 2 NHC 1 -C 3 Alkyl, -S(=O) 2 N(C 1 -C 3 alkyl) 2 、-NH 2 、-NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, -P(=O)(C 1 -C 3 alkyl) 2 、-P(=O)(OC 1 -C 3 alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, C 1 -C 6 cycloalkyl or 3- to 6-membered heterocycloalkyl; or two R on the same atom together form oxo.

[0081] In some embodiments, the compound of formula (I') is:

[0082] In some embodiments, the compound of formula (I') is:

[0083] Disclosed herein is a compound of formula (I*) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0084]

[0085] in:

[0086] Ring B is phenyl or a 6-membered heteroaryl group containing one or two nitrogen atoms;

[0087] Each R 1 are independently halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom are optionally substituted with one or more R; 1 Together they form an oxo group;

[0088] n is 0, 1, 2, 3 or 4;

[0089] R 2 For hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl or cycloalkyl;

[0090] X is N or CR X ;

[0091] R X Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl;

[0092] Y is N or CR Y ;

[0093] R Y Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;

[0094] Z is N or CR Z ;

[0095] RZ Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;

[0096] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0097] Each R 3 are independently halogen, -L-CN, -L-NO 2 , -L-OH, -L-OR a 、-L-OC(=O)R a 、-L-OC(=O)OR b 、-L-OC(=O)NR c R d 、-L-SH、-L-SR a ,-LS(=O)R a ,-LS(=O) 2 R a ,-LS(=O)(=NH)R a ,-LS(=O) 2 OR b ,-LS(=O) 2 NR c R d 、-L-NR c R d 、-L-NR b C(=O)NR c R d 、-L-NR b C(=O)R a 、-L-NR b C(=O)OR b 、-L-NR b S(=O) 2 R a 、-LC(=O)R a ,-LC(=O)ORb ,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0098] or two R on the same atom 3 Together they form an oxo group;

[0099] or two R on adjacent atoms 3 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is independently optionally substituted by one or more R;

[0100] m is 0, 1, 2, 3 or 4;

[0101] Each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0102] Each Rb are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0103] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0104] or R c and R d together with the atoms to which they are attached form heterocycloalkyl which is independently optionally substituted with one or more R; and

[0105] L is absent or is C optionally substituted by one or more R 1 -C 3 Alkylene;

[0106] Each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C1 -C 3 Alkyl, -S(=O) 2 NH 2 、-S(=O) 2 NHC 1 -C 3 Alkyl, -S(=O) 2 N(C 1 -C 3 alkyl) 2 、-NH 2 、-NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, -P(=O)(C 1 -C 3 alkyl) 2 、-P(=O)(OC 1 -C 3 alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, C 1 -C 6 cycloalkyl or 3- to 6-membered heterocycloalkyl; or two R on the same atom together form oxo.

[0107] In some embodiments, the compound of formula (I*) is:

[0108] In some embodiments, the compound of formula (I*) is:

[0109] In some embodiments of compounds of formula (I') or (I*), Ring B is phenyl. In some embodiments of compounds of formula (I') or (I*), Ring B is pyridinyl. In some embodiments of compounds of formula (I') or (I*), Ring B is pyrimidinyl.

[0110] In some embodiments of the compound of formula (I') or (I*), for

[0111] In some embodiments of the compound of formula (I') or (I*), for

[0112] In some embodiments of the compound of formula (I') or (I*), for

[0113] In some embodiments of the compound of formula (I') or (I*), for

[0114] Disclosed herein is a compound of formula (I) or (I*) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0115]

[0116] in:

[0117] Each R 1 are independently halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R on the same atom are optionally substituted with one or more R; 1 Together they form an oxo group;

[0118] n is 1, 2, 3 or 4;

[0119] R 2 For hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or cycloalkyl;

[0120] X is N or CR X ;

[0121] R X Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl;

[0122] Y is N or CR Y ;

[0123] R Y Hydrogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C6 Alkynyl, cycloalkyl or heterocycloalkyl;

[0124] Z is N or CR Z ;

[0125] R Z Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;

[0126] U is N and T is C, or U is C and T is N;

[0127] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0128] Each R 3 are independently halogen, -L-CN, -L-NO 2 , -L-OH, -L-OR a 、-L-OC(=O)R a 、-L-OC(=O)OR b 、-L-OC(=O)NR c R d 、-L-SH、-L-SR a ,-LS(=O)R a ,-LS(=O) 2 R a ,-LS(=O)(=NH)R a ,-LS(=O) 2 OR b ,-LS(=O) 2 NR c R d 、-L-NR c R d 、-L-NR b C(=O)NR c R d 、-L-NR b C(=O)Ra 、-L-NR b C(=O)OR b 、-L-NR b S(=O) 2 R a 、-LC(=O)R a ,-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0129] or two R on the same atom 3 Together they form an oxo group;

[0130] or two R on adjacent atoms 3 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is independently optionally substituted by one or more R;

[0131] m is 0, 1, 2, 3 or 4;

[0132] Each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0133] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0134] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R;

[0135] or R c and R d together with the atoms to which they are attached form heterocycloalkyl which is independently optionally substituted with one or more R; and

[0136] L is absent or is C optionally substituted by one or more R 1 -C 3 Alkylene;

[0137] Each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 NH 2 、-S(=O) 2 NHC 1 -C 3 Alkyl, -S(=O) 2 N(C 1 -C 3 alkyl) 2 、-NH 2 、-NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, -P(=O)(C 1 -C 3 alkyl) 2 、-P(=O)(OC 1 -C 3 alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, C 1 -C 6 cycloalkyl or 3- to 6-membered heterocycloalkyl; or two R on the same atom together form oxo.

[0138] In some embodiments, the compound of formula (I) or (I*) is:

[0139] In some embodiments, the compound of formula (I) or (I*) is:

[0140] In some embodiments of the compound of formula (I) or (I'), It is completely aromatic.

[0141] In some embodiments of the compound of Formula (I*), It is completely aromatic.

[0142] In some embodiments of the compound of formula (I') or (I) or (I*), X is N. In some embodiments of the compound of formula (I') or (I) or (I*), X is CR X .

[0143] In some embodiments of the compound of formula (I') or (I) or (I*), Y is N. In some embodiments of the compound of formula (I') or (I) or (I*), Y is CR Y .

[0144] In some embodiments of the compound of formula (I') or (I) or (I*), Z is N. In some embodiments of the compound of formula (I') or (I) or (I*), Z is CR Z .

[0145] In some embodiments of the compound of formula (I′) or (I), U is N and T is C. In some embodiments of the compound of formula (I′) or (I), U is C and T is N.

[0146] In some embodiments of the compounds of formula (I') or (I), U is N and T is C; X is CR X , Y is CR Y And Z is CR Z In some embodiments of the compound of formula (I') or (I), U is N and T is C; X is CR X , Y is N and Z is CR Z In some embodiments of the compound of formula (I') or (I), U is N and T is C; X is CR X , Y is CR Y and Z is N. In some embodiments of the compound of formula (I') or (I), U is N and T is C; X is CR X , Y is N and Z is N.

[0147] In some embodiments of the compounds of formula (I') or (I), U is N and T is C; X is N, and Y is CR Y and Z is CR Z In some embodiments of the compound of formula (I') or (I), U is N and T is C; X is N, and Y is CR Y And Z is N.

[0148] In some embodiments of the compounds of formula (I') or (I), U is C and T is N; X is CR X , Y is CR Y And Z is CR Z In some embodiments of the compound of formula (I') or (I), U is C and T is N; X is N, and Y is CR Y and Z is CR Z In some embodiments of the compounds of formula (I') or (I), U is C and T is N; X is CR X , Y is N and Z is CR Z In some embodiments of the compounds of formula (I') or (I), U is C and T is N; X is CR X , Y is CR Y and Z is N. In some embodiments of the compound of formula (I') or (I), U is C and T is N; X is CR X , Y is N and Z is N.

[0149] In some embodiments of the compound of formula (I'), Not for

[0150] In some embodiments of the compound of formula (I') or (I) or (I*), the compound is a compound of formula (Ia):

[0151]

[0152] In some embodiments of the compound of formula (I') or (I) or (I*), the compound is a compound of formula (Ib):

[0153]

[0154] In some embodiments of the compound of formula (I') or (I) or (I*), the compound is a compound of formula (Ic):

[0155]

[0156] In some embodiments of the compound of formula (I') or (I) or (I*), the compound is a compound of formula (Id):

[0157]

[0158] In some embodiments of the compound of formula (I') or (I) or (I*), the compound is a compound of formula (Ie):

[0159]

[0160] In some embodiments of the compound of formula (I') or (I) or (I*), the compound is a compound of formula (If):

[0161]

[0162] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), n is 1, 2, or 3. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), n is 1 or 2. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), n is 1. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), n is 2. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), n is 3. In some embodiments of Formula (I*), n is 0 or 1. In some embodiments of Formula (I*), n is 0.

[0163] In some embodiments of Formulas (I'), (I), (I*), (Ia)-(If), each R 1 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 In some embodiments of Formulas (I'), (I), (I*), (Ia)-(If), each R 1 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), each R1 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 In some embodiments of Formulas (I'), (I), (I*), (Ia)-(If), each R 1 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), each R 1 Independently -OR a In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), each R 1 For-OCHF 2 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), each R 1 In some embodiments of Formulas (I'), (I), (I*), (Ia)-(If), each R 1 In some embodiments of Formulas (I'), (I), (I*), (Ia)-(If), each R 1 are independently -CN or -OCHF 2 .

[0164] In some embodiments of Formula (I'), (I), (I*), (Ia)-(Id), or (If), R X Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(Id) or (If), RX For hydrogen, halogen, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(Id) or (If), R X For hydrogen.

[0165] In some embodiments of Formula (I'), (I), (I*), (Ia)-(Ie), R Y Hydrogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(Ie), R Y For hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(Ie), R Y For hydrogen.

[0166] In some embodiments of Formula (I'), (Ia)-(Ie), R Y Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (Ia)-(Ie), R Y For hydrogen, halogen, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (Ia)-(Ie), R Y is hydrogen or halogen. In some embodiments of Formula (I'), (Ia)-(Ie), R Y In some embodiments of Formula (I'), (Ia)-(Ie), R Y It is a halogen.

[0167] In some embodiments of Formula (I'), (I), (I*), (Ia), (Ib), (Ie), or (If), R Z Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia), (Ib), (Ie) or (If), R Z For hydrogen, halogen, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia), (Ib), (Ie) or (If), R Z For hydrogen.

[0168] In some embodiments of Formula (I'), (I), (I*) or (Ia), the compound is a compound of Formula (Ia-1):

[0169]

[0170] Where R 1a is hydrogen or R 1 .

[0171] In some embodiments of Formula (I'), (I) or (Ib), the compound is a compound of Formula (Ib-1):

[0172]

[0173] Where R 1a is hydrogen or R 1 .

[0174] In some embodiments of Formula (I'), (I) or (Ic), the compound is a compound of Formula (Ic-1):

[0175]

[0176] Where R 1a is hydrogen or R 1 .

[0177] In some embodiments of the compound of Formula (I'), (I), (I*) or (Id), the compound is a compound of Formula (Id-1):

[0178]

[0179] Where R 1a is hydrogen or R 1 .

[0180] In some embodiments of the compound of Formula (I'), (I) or (Ie), the compound is a compound of Formula (Ie-1):

[0181]

[0182] Where R 1a is hydrogen or R 1 .

[0183] In some embodiments of the compound of Formula (I'), (I), (I*) or (If), the compound is a compound of Formula (If-1):

[0184]

[0185] Where R 1a is hydrogen or R 1 .

[0186] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 For hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 Halogenated alkyl.

[0187] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 For hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 A haloalkyl group or a cycloalkyl group.

[0188] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 is hydrogen or C 1- C 6 Alkyl. 2 C 1 -C 6 Alkyl, C1 -C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 C 1- C 6 Alkyl or C 1- C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 C 1- C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 C 1- C 6 Deuterated alkyl.

[0189] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 C 1- C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 C 1- C 6 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 -CH 3 or -CD 3 In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), R 2 For hydrogen.

[0190] In some embodiments of Formula (Ia-1)-(If-1), R 1a Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1- C 6 Alkyl or C 1- C 6 In some embodiments of Formula (Ia-1)-(If-1), R 1a For-OR a In some embodiments of Formula (Ia-1)-(If-1), R1a For-OCHF 2 In some embodiments of Formula (Ia-1)-(If-1), R 1a In some embodiments of Formula (Ia-1)-(If-1), R 1a In some embodiments of Formula (Ia-1)-(If-1), R 1a -CN or -OCHF 2 .

[0191] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is aryl or heteroaryl.

[0192] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is heteroaryl.

[0193] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is a 5- or 6-membered heteroaryl. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is a 6-membered heteroaryl. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is a pyridinyl or pyrimidinyl. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is a pyridinyl. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is a pyridinyl. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is a 5-membered heteroaryl.

[0194] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is cycloalkyl or heterocycloalkyl.

[0195] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is a fully saturated cycloalkyl or a fully saturated heterocycloalkyl.

[0196] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is a fully saturated cycloalkyl.

[0197] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is a fully saturated heterocycloalkyl.

[0198] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is cycloalkenyl or heterocycloalkenyl.

[0199] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is cycloalkenyl.

[0200] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is heterocycloalkenyl.

[0201] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, or tetrahydro-2H-pyranyl.

[0202] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is cyclohexenyl.

[0203] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), Ring A is cyclohexyl.

[0204] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -L-CN, -L-NO 2 , -L-OH, -L-OR a 、-L-OC(=O)R a 、-L-OC(=O)OR b 、-L-OC(=O)NR c R d 、-L-SH、-L-SR a ,-LS(=O)R a ,-LS(=O) 2 R a ,-LS(=O) 2 OR b ,-LS(=O) 2 NR c Rd 、-L-NR c R d 、-L-NR b C(=O)NR c R d 、-L-NR b C(=O)R a 、-L-NR b C(=O)OR b 、-L-NR b S(=O) 2 R a 、-LC(=O)R a ,-LC(=O)OR b ,-LC(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0205] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -L-CN, -L-NO 2 , -L-OH, -L-OR a 、-L-OC(=O)R a 、-L-OC(=O)OR b 、-L-OC(=O)NR c R d 、-L-SH、-L-SR a ,-LS(=O)R a ,-LS(=O) 2 R a ,-LS(=O)(=NH)R a ,-LS(=O) 2 OR b ,-LS(=O)2 NR c R d 、-L-NR c R d 、-L-NR b C(=O)NR c R d 、-L-NR b C(=O)R a 、-L-NR b C(=O)OR b 、-L-NR b S(=O) 2 R a 、-LC(=O)R a ,-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0206] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -LS(=O)R a ,-LS(=O) 2 R a ,-LS(=O) 2 NR c R d 、-L-NR c R d 、-LC(=O)R a ,-LC(=O)OR b,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R.

[0207] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -LS(=O) 2 R a 、-L-NR c R d 、-LC(=O)R a ,-LC(=O)OR b , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 aminoalkyl, -L-cycloalkyl or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted by one or more R.

[0208] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -L-OR a 、-L-NR c R d 、-LC(=O)R a ,-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R c R d、-LP(=O)OR c OR d , C 1- C 6 Alkyl, C 1- C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R.

[0209] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), each R 3 are independently halogen, -L-OR a 、-L-NR c R d 、-LC(=O)R a ,-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C 1- C 6 wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0210] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -L-OR a 、-L-NR c R d , C 1- C 6 Alkyl, C 1- C 6 wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0211] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -L-NR c R d , C 1- C 6wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0212] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 is independently -L-cycloalkyl or -L-heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R.

[0213] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 is independently halogen or -L-cycloalkyl optionally substituted by one or more R.

[0214] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 is independently -L-cycloalkyl optionally substituted by one or more R.

[0215] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 is independently halogen or -L-heterocycloalkyl optionally substituted by one or more R.

[0216] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 is independently -L-heterocycloalkyl optionally substituted by one or more R.

[0217] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -LS(=O)R a ,-LS(=O) 2 R a ,-LS(=O) 2 NR c R d 、-L-NR c R d 、-LC(=O)R a ,-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R cR d 、-LP(=O)OR c OR d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R.

[0218] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -LS(=O) 2 R a 、-L-NR c R d 、-LC(=O)R a ,-LC(=O)OR b , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted by one or more R.

[0219] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -L-OR a 、-L-NR c R d 、-LC(=O)R a ,-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C 1- C 6 Alkyl, C 1-C 6 wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R.

[0220] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), each R 3 are independently halogen, -L-OR a 、-L-NR c R d 、-LC(=O)R a ,-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C 1- C 6 wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0221] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -L-OR a 、-L-NR c R d , C 1- C 6 Alkyl, C 1- C 6 wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0222] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen, -L-NR c R d , C 1- C 6 wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0223] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R.

[0224] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 is independently halogen or cycloalkyl optionally substituted by one or more R.

[0225] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 is independently cycloalkyl optionally substituted by one or more R.

[0226] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 is independently halogen or heterocycloalkyl optionally substituted by one or more R.

[0227] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 is independently heterocycloalkyl optionally substituted by one or more R.

[0228] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 are independently halogen or -L-NR c R d .

[0229] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently -L-NR c R d .

[0230] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0231]

[0232] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0233] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0234] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0235] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0236]

[0237] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0238] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0239] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0240] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0241] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0242] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0243] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 for In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 for In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 for

[0244] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), each R 3 Independently

[0245]

[0246] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), two R on adjacent atoms 3 together form a cycloalkyl or heterocycloalkyl; each of which is independently optionally substituted by one or more R.

[0247] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), two R on adjacent atoms 3 Together they form a cycloalkyl group which is optionally substituted independently with one or more R.

[0248] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), two R on adjacent atoms 3 Together they form heterocycloalkyl which is optionally substituted independently with one or more R.

[0249] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), m is 0, 1, 2, or 3. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), m is 0, 1, or 2. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), m is 0 or 1. In some embodiments of Formula (I'), (I), (I*), (Ia)-(If), or (Ia-1)-(If-1), m is 1 or 2.

[0250] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0251] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0252] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for In formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-

[0253] In some embodiments of (If-1), for In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0254] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0255] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for In formula (I'),

[0256] In some embodiments of (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0257] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0258] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for In formula (I'),

[0259] In some embodiments of (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0260] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0261] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0262] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0263]

[0264] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0265]

[0266] In some embodiments of Formula (I'), (I), (I*), (Ia)-(If) or (Ia-1)-(If-1), for

[0267] In some embodiments of the compounds disclosed herein, each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R aIndependently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 In some embodiments of the compounds disclosed herein, each R a Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R a Independently for C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R a Independently for C 1 -C 6 alkyl.

[0268] In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each Rb are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R b are independently hydrogen or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R b In some embodiments of the compounds disclosed herein, each R b Independently for C 1 -C 6 alkyl.

[0269] In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each Rc and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 In some embodiments of the compounds disclosed herein, each R c and R d In some embodiments of the compounds disclosed herein, each R c and R d Independently for C 1 -C 6 alkyl.

[0270] In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached they form a heterocycloalkyl group which is independently optionally substituted with one or more R groups.

[0271] In some embodiments of the compounds disclosed herein, L is absent. In some embodiments of the compounds disclosed herein, L is C optionally substituted with one or more R 1 -C 3 In some embodiments of the compounds disclosed herein, L is C 1 -C 3 In some embodiments of the compounds disclosed herein, L is C 1 In some embodiments of the compounds disclosed herein, L is C 2In some embodiments of the compounds disclosed herein, L is C 3 In some embodiments of the compounds disclosed herein, L is -CH 2 -. In some embodiments of the compounds disclosed herein, L is -CH 2 CH 2 -. In some embodiments of the compounds disclosed herein, L is -CH 2 CH 2 CH 2 -.

[0272] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 Alkyl, -S(=O) 2 NH 2 、-S(=O) 2 NHC 1 -C 3 Alkyl, -S(=O) 2 N(C 1 -C 3 alkyl) 2 、-NH 2 、-NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1-C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, C 1 -C 6 Cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0273] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -NH 2 、-NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, C 1 -C 6 or two R on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -NH 2 、-NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl, C 1 -C 6 or two R on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -NH 2 、-NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 、-NHC(=O)OC 1 -C 3 Alkyl, -C(=O)C 1 -C 3 Alkyl, -C(=O)OH, -C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 3 alkyl) 2 、-C(=O)NHC 1 -C 3 Alkyl, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl or C 1 -C 3 or two R on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -NH 2 、-NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl or C 1 -C 3 or two R on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -NH 2 、-NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl or C 1 -C 3 or two R on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl or C 1 -C 3 or two R on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 Alkyl or C 1 -C 3 In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH 2 or C 1 -C 3 In some embodiments of the compounds disclosed herein, each R is independently halogen or C 1 -C 3 In some embodiments of the compounds disclosed herein, each R is independently halogen. In some embodiments of the compounds disclosed herein, each R is independently C 1 -C 3 alkyl.

[0274] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

[0275] In some embodiments, the compound is selected from the compounds in Table 1.

[0276] Table 1

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325] In some embodiments, the compound is selected from the compounds in Table 2.

[0326] Table 2

[0327]

[0328]

[0329]

[0330]

[0331] In some embodiments, the compound is selected from:

[0332]

[0333]

[0334]

[0335]

[0336] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0337] In some embodiments of the compounds disclosed above, for

[0338] In some embodiments, the compound is selected from:

[0339]

[0340]

[0341]

[0342]

[0343] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0344] In some embodiments of the compounds disclosed above, for

[0345] In some embodiments, the compound is selected from:

[0346]

[0347]

[0348]

[0349]

[0350] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0351] In some embodiments of the compounds disclosed above, for

[0352]

[0353] In some embodiments, the compound is selected from:

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0361] In some embodiments of the compounds disclosed above, for

[0362] In some embodiments, the compound is selected from:

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0370] In some embodiments of the compounds disclosed above, for

[0371] In some embodiments, the compound is selected from:

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments of the compounds disclosed above, for

[0379]

[0380] In some embodiments, the compound is selected from:

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0388] In some embodiments of the compounds disclosed above, for

[0389] Other forms of the compounds disclosed herein

[0390] Isomers / stereoisomers

[0391] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds proposed herein include all cis, trans, syn, anti, entgegen, E and zusammen, Z and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists independently in the form of R configuration or S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimeric forms and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and / or mixtures of diastereomers produced by a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as their respective stereoisomers by reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomer compounds, separating diastereomers and recovering optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based on solubility differences. In some embodiments, optically pure enantiomers and resolving agents are then recovered by any practical means that do not result in racemization.

[0392] Labeled compounds

[0393] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. l5 N. 18 O. 17 O.31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds described herein and pharmaceutically acceptable salts, solvates or stereoisomers thereof containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, for example, compounds incorporating radioactive isotopes (such as 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, heavy isotopes such as deuterium (i.e., 2 H) produces certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogens in the compounds disclosed herein are replaced by deuterium atoms. In some embodiments, one or more alkyl substituents in the compounds disclosed herein are replaced by deuterated alkyl substituents. In some embodiments, -CH 3 For-CD 3 .

[0394] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0395] Pharmaceutically acceptable salts

[0396] In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0397] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting the purified compound in its free form with a suitable acid or base separately and isolating the salt thus formed.

[0398] Examples of pharmaceutically acceptable salts include those prepared by reacting a compound described herein with an inorganic acid, an organic acid, or an inorganic base, such salts include, but are not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate salt, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethylsulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methyl benzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0399] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, Acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic acid, while not pharmaceutically acceptable in themselves, are employed in the preparation of salts useful as intermediates for obtaining the compounds disclosed herein, their solvates or stereoisomers, and pharmaceutically acceptable acid addition salts thereof.

[0400] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate; with ammonia; or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium and magnesium, and aluminum salts, etc. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1 -C 4 alkyl) 4 Hydroxide, etc.

[0401] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0402] Solvate

[0403] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates in pharmaceutical compositions.

[0404] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, are formed with pharmaceutically acceptable solvents (such as water, ethanol, etc.). When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. Solvates of compounds described herein can be conveniently prepared or formed in the process described herein. By way of example only, hydrates of compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures using organic solvents, including but not limited to dioxane, tetrahydrofuran or methanol. In addition, compounds described herein can exist in non-solvated and solvated forms. Generally, for the purposes of compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0405] Treatment

[0406] Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease or condition comprises: autoimmune and inflammatory conditions; nervous system and neurodegenerative conditions; pain and nociceptive conditions; cardiovascular conditions; metabolic disorders; ocular conditions; and neoplastic conditions.

[0407] Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders, and organ-specific autoimmune disorders. Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including oligoarticular and polyarticular forms thereof), anemia of chronic disease (ACD), Still's disease, and disease (juvenile and / or adult), Behcet's disease, and Sjogren's syndrome. Autoimmune endocrine disorders include thyroiditis. Organ-specific autoimmune disorders include Addison's disease, hemolytic or pernicious anemia, acute kidney injury (AKI; including cisplatin-induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin-induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis and antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis), lupus nephritis (including leukopenia), and leukopenia.LN), minimal change disease, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis, and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease disease), chondritis, cartilage degeneration and / or destruction, fibrosing disorders (including various forms of liver and lung fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease,COPD, respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatic, and axial spondylarthritis.

[0408] Nervous system and neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, ischemia, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizures and epilepsy.

[0409] Cardiovascular disorders include thrombosis, cardiac hypertrophy, hypertension, irregular contractility of the heart (e.g., during heart failure), and sexual disorders (including erectile dysfunction and female sexual dysfunction). TNFα functional modulators can also be used to treat myocardial infarction (see JJ Wu et al., JAMA, 2013, 309, 2043-2044).

[0410] Metabolic disorders include diabetes (including insulin-dependent diabetes mellitus and juvenile diabetes), dyslipidemia and metabolic syndrome.

[0411] Ocular disorders include retinopathy (including diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy, and retinopathy of prematurity), macular oedema (including diabetic macular oedema), age-related macular degeneration (ARMD), vascularization (including corneal vascularization and neovascularization), retinal vein occlusion, and various forms of uveitis (including iritis) and keratitis.

[0412] Neoplastic conditions may be acute or chronic and include proliferative disorders, particularly cancer and cancer-related complications, including skeletal complications, cachexia, and anemia. Specific categories of cancer include hematological malignancies, including leukemia and lymphoma, and non-hematological malignancies, including solid tumor cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma, and renal cell carcinoma. Chronic leukemias may be myeloid or lymphoid.Types of leukemia include lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic / lymphoid leukemia (CLL), hairy-cell leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), myelodysplastic syndrome (MS), chronic neutrophilicleukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, leukemia, multiple myeloma, acute megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, and erythroleukemia. Types of lymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALT1 lymphoma, and marginal zone lymphoma. Types of non-hematological malignancies include prostate cancer, lung cancer, breast cancer, rectal cancer, colon cancer, lymph node cancer, bladder cancer, kidney cancer, pancreatic cancer, liver cancer, ovarian cancer, uterine cancer, cervical cancer, brain cancer, skin cancer, bone cancer, stomach cancer and muscle cancer.TNFα function modulators can also be used to increase the safety of the potent anti-cancer effect of TNF (see FV Hauwermeiren et al., J Clin. Invest., 2013, 123, 2590-2603).

[0413] Drug administration

[0414] In certain embodiments, compositions containing one or more compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous therapy, the patient's health status, body weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0415] When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder or condition; previous therapy; the patient's health status and response to the drugs; and the judgment of the treating physician. In one aspect, prophylactic treatment comprises administering a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced or is at risk of at least one symptom of the disease being treated and is currently in remission to prevent recurrence of symptoms of the disease or condition.

[0416] In certain embodiments where the patient's condition does not improve, the compound is administered chronically, i.e., for an extended period of time, including for the duration of the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition, at the physician's discretion.

[0417] Once the patient's condition improves, a maintenance dose is administered (if necessary). Subsequently, in specific embodiments, depending on the symptoms, the dosage, or the frequency of administration, or both are reduced to a level that retains the improved disease, disorder, or condition. However, in certain embodiments, if there is any recurrence of symptoms, the patient requires long-term intermittent or daily treatment.

[0418] The amount of a given agent that corresponds to such an amount varies depending on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host in need of treatment (e.g., weight, sex), but is otherwise determined by the specific circumstances of the case (including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated).

[0419] Route of administration

[0420] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0421] In certain embodiments, the compounds as described herein are applied in a local manner rather than a systemic manner, for example, via direct injection of the compound into an organ, usually in the form of a depot preparation or a sustained release formulation. In a specific embodiment, the long-acting formulation is applied by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the drug is in the form of a targeted drug delivery system, for example, delivered in the form of a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to the organ and selectively absorbed by the organ. In other embodiments, the compounds as described herein are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of a medium release formulation. In some embodiments, the compounds as described herein are topically applied.

[0422] Pharmaceutical compositions / formulations

[0423] According to standard pharmaceutical practice, the compounds described herein are administered to a subject in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent, in the form of a pharmaceutical composition. In one embodiment, the compounds disclosed herein can be administered to animals. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0424] In another aspect, provided herein is a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0425] combination

[0426] Disclosed herein are methods of treating a TNFα-mediated condition or disease using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0427] In some embodiments, the additional therapeutic agent is administered simultaneously with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the frequency of administration of the additional therapeutic agent is lower than the frequency of administration of the compounds disclosed herein. In some embodiments, the frequency of administration of the additional therapeutic agent is higher than the frequency of administration of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered before the administration of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compounds disclosed herein.

[0428] Example

[0429] Intermediates 1 and 2:

[0430]

[0431] Step 1: To a stirred solution of 3-hydroxyanthranilic acid (175 g, 1.14 mol, 1.0 eq.) in MeOH (1 L) was added H 2 SO 4 (150 mL). The resulting mixture was stirred at 80 ° C for 24 h. The resulting mixture was cooled and concentrated in vacuo to remove most of the solvent. The residue was basified with NaHCO3 solution until pH = 8-9, and then extracted with DCM (500 mL x 3). The combined organic layer was washed with brine (500 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (3:1)) to give methyl 2-amino-3-hydroxybenzoate (150 g, 78.%) as a yellow solid. LC-MS: (M+H) + Actual measured value, 168.10. 1 H NMR (400 MHz, DMSO-d 6 )δ9.69(s,1H),7.22(dd,J=8.2,1.4Hz,1H),6.83(dd,J=7.6,1.5Hz,1H),6.44-6.36(m,1H),6.12(br,2H),3.78(s,3H).

[0432] Step 2: At 0°C, use NaNO 2 (68.10 g, 0.98 mol, 1.1 equiv) was treated with methyl 2-amino-3-hydroxybenzoate (150 g, 0.89 mol, 1.0 equiv) in 15% H 2 SO 4 (H 2 SO 4 (450mL) in H 2 O (2.5L) solution). The mixture was then stirred at room temperature for 1h. The resulting mixture was diluted with MeCN (1.5L), followed by the addition of KI (1.19kg, 7.18mol, 8.0 eq). The final reaction mixture was stirred at 80°C overnight. The resulting mixture was cooled and concentrated in vacuo to remove most of the solvent. The residue was washed with saturated Na 2 CO 3 The solution was basified until pH = 6-7 and extracted with EtOAc (2 L x 3). The combined organic layers were washed with Na 2 SO 3 The aqueous solution (2 L) was washed and the 2 SO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM (100%) to give methyl 3-hydroxy-2-iodobenzoate (180 g, 72%) as a brown solid. LC-MS: (M+H) + Actual measured value, 276.90. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.41 (dd, J = 7.6, 1.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.19 (dd, J = 8.0, 1.6 Hz, 1H), 5.99 (br, 1H), 3.96 (s, 3H).

[0433] Step 3: A solution of methyl 3-hydroxy-2-iodobenzoate (180 g, 0.65 mol, 1.0 eq.) in MeCN (1.8 L) was treated with 5 M KOH (KOH (182 g, 3.2 mol, 5.0 eq.) in H 2 O (500mL) solution) was treated, followed by the addition of diethyl bromodifluoromethylphosphonate (230mL, 1.3mol, 2.0 equivalents) dropwise at 0°C. The final reaction mixture was stirred at room temperature overnight. The desired product was detected by TLC (PE:EA=10:1). The resulting mixture was extracted with tert-butyl methyl ether (2L x 3). The combined organic layers were washed with brine (800mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (100:1)) to give methyl 3-(difluoromethoxy)-2-iodobenzoate (136 g, 64%) as a yellow oil. LC-MS: (M+H) + Actual measured value, 328.85. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.34-7.26 (m, 1H), 6.56 (t, J = 73.1 Hz, 1H), 3.98 (s, 3H).

[0434] Step 4: To a stirred solution of methyl 3-(difluoromethoxy)-2-iodobenzoate (137 g, 0.42 mol, 1.0 eq.) in THF (500 mL) was added MeOH (500 mL) and H 2O (500mL). NaOH (50g, 1.25mol, 3.0 equivalents) was added to the above mixture at room temperature. The resulting mixture was stirred for another 30min at 50°C. The resulting mixture was cooled and concentrated in vacuo to remove most of the solvent. The aqueous layer was acidified with 6M HCl until pH=3-4 and extracted with EtOAc (2x 1L). The combined organic layers were washed with brine (500mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. This gave 3-(difluoromethoxy)-2-iodobenzoic acid (120 g, 92%) as a pale yellow solid. LC-MS: (MH) + Actual measured value, 312.90. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.78 (dd, J = 7.7, 1.5 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.40-7.34 (m, 1H), 6.58 (t, J = 73.0 Hz, 1H).

[0435] Step 5: To a stirred solution of 3-(difluoromethoxy)-2-iodobenzoic acid (120 g, 0.38 mol, 1.00 equiv) and cyclopent-3-ene-1-amine hydrochloride (50.3 g, 0.42 mol, 1.1 equiv) in DMF (1 L) was added DIEA (148.2 g, 1.14 mmol, 3.0 equiv) at room temperature under air atmosphere. HATU (188.9 g, 496.8 mmol, 1.30 equiv) was added to the above mixture at room temperature. The resulting mixture was stirred at room temperature for 30 min. The reactants were poured into water (4 L) at room temperature. The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (2 x 1 L) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (5:1)) to give N-(cyclopent-3-en-1-yl)-3-(difluoromethoxy)-2-iodobenzamide (126 g, 87%) as a white solid. LC-MS: (M+H) + Actual measured value, 379.80. 1H NMR (400MHz, chloroform-d) δ7.39(t,J=7.9Hz,1H),7.27-7.16(m,2H),6.54(t,J=73.1Hz,1H),5.91(br, 1H), 5.79 (s, 2H), 4.81 (qt, J=7.5, 3.3Hz, 1H), 2.89 (dd, J=15.9, 7.4Hz, 2H), 2.46-2.37 (m, 2H).

[0436] Step 6: To a solution of N-(cyclopent-3-en-1-yl)-3-(difluoromethoxy)-2-iodobenzamide (126 g, 332.3 mmol, 1.0 equiv) in toluene (1.8 L) was added Et 3 N (139 mL, 997 mmol, 3.0 equiv) and PPh 3 (17.4 g, 66.5 mmol, 0.2 eq), followed by the addition of Pd(OAc) 2 (7.5 g, 33.2 mmol, 0.1 eq.). The mixture was then washed with N 2 Degas 3 times and stir overnight at 110° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (2:1)) to give 7-(difluoromethoxy)-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (81 g, 97%) as a white solid. LC-MS: (M+H) + Actual measured value, 252.05. 1 HNMR (400MHz, chloroform-d) δ8.47(dd,J=7.8,1.9Hz,1H),7.36-7.29(m,2H),6.79(s,1H),6.58(t,J=73.6Hz,1H),6.05(dd,J=5.5,3.0Hz,1H),5. 92(dd,J=5.7,2.5Hz,1H), 4.58(dd,J=7.1,3.0Hz,1H), 4.22(td,J=6.5,2.5Hz,1H), 2.52(dt,J=13.4,6.9Hz,1H), 2.02(d,J=12.8Hz,1H).

[0437] Step 7: A solution of 7-(difluoromethoxy)-3,6-dihydro-3,6-methylbenzo[c]azocine-1(2H)-one (81 g, 322.41 mmol, 1.0 eq) in THF (1 L) was treated with NaH (16.8 g, 419.13 mmol, 1.3 eq, 60%) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. MeI (30 mL, 483.62 mmol, 1.5 eq) was added dropwise to the above mixture at 0 °C under nitrogen atmosphere. The final reaction mixture was stirred at room temperature under nitrogen atmosphere for 3.5 h. The reactants were quenched with water (500 mL) at room temperature. The resulting mixture was extracted with EtOAc (1 L x2). The combined organic layers were washed with brine (1 L) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give 7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (75 g, 88%) as a white solid. LC-MS: (M+H) + Actual measured value, 266.00. 1 H NMR (400MHz, chloroform-d) δ8.53 (dd, J=8.2, 1.5Hz, 1H), 7.30 (t, J=8.1Hz, 1H), 7.22 (ddt,J=8.1,1.6,0.9Hz,1H),6.56(t,J=73.6Hz,1H),6.05(dd,J=5.5,2.9Hz, 1H),5.99-5.93(m,1H),4.47(ddd,J=7.0,2.9,1.0Hz,1H),4.33(dd,J=7.3,2 .5Hz, 1H), 3.29 (s, 3H), 2.52 (dt, J = 13.0, 7.1Hz, 1H), 2.05 (d, J = 13.0Hz, 1H).

[0438] Step 8: At 0°C, N 2 To a stirred solution of 7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (66 g, 0.25 mol, 1.0 equiv) in THF (660 mL) was added BH 3 -THF (498 mL, 0.5 mol, 2.0 equiv). The resulting mixture was heated at 0°C under N 2 At 0°C, NaOH (290 mL, 0.87 mol, 3.5 equivalents) and H 2 O 2(116 mL, 1.24 mol, 5.0 eq., 25%). The resulting mixture was stirred at 0°C for another 30 min. TLC (PE / EA=1 / 1) showed that the reaction was complete. The reaction mixture was treated with MeOH (300 mL) at 0°C, followed by Na 2 SO 3 The reaction was quenched with 4% paraformaldehyde (500 mL) and the mixture was extracted with EtOAc (3 x 800 mL). The combined organic layers were washed with brine (500 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (0 to 5%)) to give 7-(difluoromethoxy)-4-hydroxy-2-methyl-3,4,5,6-tetrahydro-3,6-methane-bridged benzo[c]azocine-1(2H)-one and 7-(difluoromethoxy)-5-hydroxy-2-methyl-3,4,5,6-tetrahydro-3,6-methane-bridged benzo[c]azocine-1(2H)-one (43 g, 58%) as pale yellow solids. The mixture was used directly in the next step without further separation. LC-MS: (M+H) + Actual measured value, 283.90.

[0439] Step 9: At 0°C, N 2 To a stirred solution of 7-(difluoromethoxy)-4-hydroxy-2-methyl-3,4,5,6-tetrahydro-3,6-methanobenzo[c]azoc-1(2H)-one and 7-(difluoromethoxy)-5-hydroxy-2-methyl-3,4,5,6-tetrahydro-3,6-methanobenzo[c]azoc-1(2H)-one (15 g, 59.25 mmol, 1.0 eq) in DCM (300 mL) was added silica gel (6.36 g, 105.90 mmol, 2 eq) followed by PCC (22.8 g, 105.90 mmol, 2.0 eq). The resulting mixture was stirred at 25 °C, N 2 Stir for 12 h under atmosphere. The reaction mixture was filtered through a celite pad. The filter cake was washed with DCM (200 mL x 3). The combined organic phases were washed with saturated NaHCO 3 solution (500 mL), brine (200 mL) and washed with Na 2 SO 4 Dry. Filter and concentrate the filtrate in vacuo to obtain a crude product. The crude product was purified by preparative Achiral SFC (column: Viridis BEH Prep 2-EP OBD column 5*15cm, 5um; mobile phase A: CO 2 , mobile phase B: IPA (1%-2M-NH 3-MeOH); flow rate: 120mL / min; gradient: isocratic 30% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220nm; RT1 (min): 3.9; RT2 (min): 5.33; sample solvent: MeOH; injection volume: 3mL) to obtain intermediate 1: 7-(difluoromethoxy)-2-methyl-2,3,5,6-tetrahydro-3,6-methanobenzo[c]azocine-1,4-dione (3.9g, 26%) as an off-white solid. LC-MS: (M+H) + Actual measured value, 282.10. 1 H NMR (400 MHz, DMSO-d 6 )δ8.26(dd,J=7.9,1.7Hz,1H),7.46-7.04(m,3H),4.16(t,J=7.2Hz,1H),4.05(d,J=8.6Hz,1H),3.20(s,3H),2.98(ddd,J=1 8.0, 8.1, 0.9Hz, 1H), 2.76 (ddd, J = 14.2, 8.7, 6.5Hz, 1H), 2.25 (ddd, J = 18.1, 3.1, 1.3Hz, 1H), 2.07 (dd, J = 14.2, 3.1Hz, 1H). Intermediate 2: 7-(difluoromethoxy)-2-methyl-3,4-dihydro-3,6-methanobenzo[c]azocine-1,5(2H,6H)-dione (5.8 g, 39%) as an off-white solid, with an overall yield of 65%. LC-MS: (M+H) + Actual measured value, 282.10. 1 H NMR (400MHz, chloroform-d) δ8.53 (dd, J=7.1, 2.5Hz, 1H), 7.41-7.31 (m, 2H), 6.64 (dd, J=79.6, 69.8Hz, 1H), 4.5 0(d,J=8.6Hz,1H),4.29(t,J=5.9Hz,1H),3.27(s,3H),2.87-2.65(m,3H),2.40(dd,J=14.2,2.7Hz,1H).

[0440] Intermediates 3 and 4

[0441]

[0442] Intermediate 1 (250 g) was purified by chiral SFC under the following conditions (column: AD; 250*40mm 10μm; Mobile phase A: supercritical CO 2, mobile phase B: IPA (+0.1% 7.0 mol / l ammonia in MEOH); flow rate: 150 mL / min; gradient: 25% B to 25% B; wavelength: 220 / 214 nm; RT1 (min): 4.30; RT2 (min): 5.60; sample solvent: IPA:DCM=1:1; injection volume: 3 mL; number of runs: 540), to obtain:

[0443] Intermediate 3: (3S,6R)-7-(difluoromethoxy)-2-methyl-2,3,5,6-tetrahydro-3,6-methanobenzo[c]azocine-1,4-dione (114.7 g, 45.9%) as a yellow oil. LCMS (ESI, m / z): 282.10 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ8.46(d,J=7.4Hz,1H),7.35(t,J=8.1Hz,1H),7.25-7.23(m,1H),6.56(t,J=73.4Hz,1H),4.33(t,J=7.6Hz,1H ), 3.81 (d, J = 8.1Hz, 1H), 3.34 (s, 3H), 2.80 (q, J = 8.4Hz, 1H), 2.68-2.61 (m, 1H), 2.49-2.43 (m, 1H), 2.25 (dd, J = 14.5, 2.7Hz, 1H).

[0444] Intermediate 4: (3R,6S)-7-(difluoromethoxy)-2-methyl-2,3,5,6-tetrahydro-3,6-methanobenzo[c]azocine-1,4-dione (115.3 mg, 46.1%) as a yellow oil. LCMS (ESI, m / z): 282.15 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ8.46(d,J=8.8Hz,1H),7.35(t,J=8.2Hz,1H),7.25-7.23(m,1H),6.56(t,J=73.3Hz,1H),4.33(t,J=7.6Hz,1H),3. 81(d,J=8.1Hz,1H),3.34(s,3H),2.80(q,J=8.5Hz,1H),2.68-2.61(m,1H),2.46(dd,J=18.9,2.5Hz,1H),2.26(dd,J=14.4,2.7Hz,1H).

[0445] Intermediates 5 and 6

[0446]

[0447] Intermediate 2 (240 g) was purified by chiral SFC under the following conditions (column: AD; 250*50mm 10μm; Mobile phase A: supercritical CO 2 , mobile phase B: IPA (+0.1% 7.0 mol / l ammonia in MeOH); flow rate: 140 mL / min; gradient: 25% B to 25% B; wavelength: 220 / 214 nm; RT1 (min): 6.70; RT2 (min): 8.60; sample solvent: IPA:DCM=1:1; injection volume: 8 mL; number of runs: 125), to obtain:

[0448] Intermediate 5: ((3S,6S)-7-(difluoromethoxy)-2-methyl-3,4-dihydro-3,6-methanobenzo[c]azocine-1,5(2H,6H)-dione (89.5 g, 43.8%) as a white solid. LCMS (ESI, m / z): 282.1 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ8.51(dd,J=5.9,2.6Hz,1H),7.34(t,J=4.9Hz,1H),6.62(dd,J =79.6,69.7Hz,1H),4.48(d,J=8.7Hz,1H),4.27(t,J=5.2Hz,1H),3.42(s,3H),2.83 -2.76(m,1H),2.72-2.65(m,2H),2.39(dd,J=14.2,2.6Hz,1H).

[0449] Intermediate 6: ((3R,6R)-7-(difluoromethoxy)-2-methyl-3,4-dihydro-3,6-methanobenzo[c]azepine-1,5(2H,6H)-dione (86.4 g, 42.3%) as a white solid. LCMS (ESI, m / z): 282.1 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (d, J = 5.8 Hz, 1H), 7.35-7.33 (m, 1H), 6.56 (dd, J = 79.4, 69.7 Hz, 1H), 4.48 (d, J = 8.5 Hz, 1H), 4.27 (s, 1H), 3.25 (s, 3H), 2.83-2.76 (m, 1H), 2.71-2.65 (m, 2H), 2.38 (d, J = 14.2 Hz, 1H).

[0450] Intermediate 7

[0451]

[0452] Step 1: A solution of intermediate 4 (750 mg, 2.7 mmol, 1 eq.) in THF (20 mL) was treated with LiHMDS (3.2 mL, 3.2 mmol, 1.2 eq.) at -78 ° C. under a nitrogen atmosphere for 10 min. The mixture was warmed to -10 ° C. The resulting mixture was stirred for 15 min at -10 ° C. under a nitrogen atmosphere. The mixture was then cooled to -78 ° C. A solution of 4-methylbenzenesulfonyl cyanide (725 mg, 4.0 mmol, 1.5 eq.) in THF (10 mL) was quickly (<1 min) added to the cold reaction mixture. The resulting mixture was stirred for 5 min at -78 ° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was purified by adding saturated NH 4 The reaction was quenched with Cl(aq) (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 60 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 1% NH 3 .H 2 O, 4:1, ref = 0.2) to give (3R, 6R) -7- (difluoromethoxy) -4-hydroxy-2-methyl-1-oxo-1,2,3,6-tetrahydro-3,6-methanobenzo [c] azacyclooctane-5-carbonitrile (300 mg, 36.7%) as a yellow oil. LCMS (ESI, m / z): 306.9 [M + H] + .

[0453] Step 2: At room temperature, under nitrogen atmosphere, use NH 2 NH 2 .H 2A solution of (3R,6R)-7-(difluoromethoxy)-4-hydroxy-2-methyl-1-oxo-1,2,3,6-tetrahydro-3,6-methanobenzo[c]azepine-5-carbonitrile (320 mg, 1.1 mmol, 1 eq) in EtOH (30 mL) was treated with 4-nitropropane-2-ol (115 mg, 2.30 mmol, 2.2 eq) for 5 min, followed by the addition of HCl (g) in dioxane (0.1 mL, 3.1 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 85 °C under nitrogen for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give (4R,11S)-1-amino-10-(difluoromethoxy)-5-methyl-2,4,5,11-tetrahydro-6H-4,11-methanobenzo[c]pyrazolo[4,3-f]azocin-6-one (120 mg, 35.9%) as a yellow solid. LCMS (ESI, m / z): 320.90 [M+H] + .

[0454] Step 3: At room temperature and under nitrogen atmosphere, use Cs 2 CO 3 A solution of (4R,11S)-1-amino-10-(difluoromethoxy)-5-methyl-2,4,5,11-tetrahydro-6H-4,11-carboxybenzo[c]pyrazolo[4,3-f]azepin-6-one (120 mg, 0.4 mmol, 1 eq) in DMF (2 mL) was treated with 4% paraformaldehyde (195 mg, 0.6 mmol, 1.6 eq) for 1 min, followed by the addition of ethyl 3-ethoxy-2-acrylate (64.8 mg, 0.5 mmol, 1.2 eq) at room temperature. The resulting mixture was stirred at 110 °C under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give (7R,14S)-1-(difluoromethoxy)-6-methyl-6,7,13,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1′,2′:1,5]pyrazolo[4,3-f]azocine-5,12-dione (98 mg, 70.3%) as a yellow solid. LCMS (ESI, m / z): 373.00 [M+H] + .

[0455] Step 4:

[0456] A solution of (7R,14S)-1-(difluoromethoxy)-6-methyl-6,7,13,14-tetrahydro-7,14-carboxybenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-5,12-dione (98 mg, 0.3 mmol, 1 eq) in DCM (4 mL) was treated with DMAP (8. mg, 0.1 mmol, 0.25 eq) and 2,6-lutidine (14.10 mg, 0.13 mmol, 0.5 eq) at 0°C under nitrogen for 1 min before the addition of (trifluoromethanesulfonyl) triflate (223 mg, 0.8 mmol, 3 eq) at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 1 h. The mixture was heated to 40°C with saturated NH 4 The mixture was acidified to pH 8 with Cl (aq.). The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (2 x 5 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:10) to give Intermediate 7: (7R, 14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-12-ester (84 mg, 63.3%) as a yellow solid. LCMS (ESI, m / z): 505.05 [M+H] + .

[0457] Intermediate 8

[0458]

[0459] Step 1: NaH (60% suspension in mineral oil, 15.6 g, 0.39 mole) was washed with ether (300 mL) and suspended therein. Ethyl formate (29.1 mL, 0.36 mole, 1.2 equivalents) was added to this suspension and the mixture was cooled in an ice bath. Ethyl fluoroacetate (29.0 mL, 0.3 mole) was slowly added over 1 h. After 2 h, the ice bath was removed and the reaction was stirred for another 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0460] Step 2: The residue was redissolved in 350 mL of anhydrous DMF and cooled in an ice bath, and iodoethane (48 mL, 0.6 mol) was added dropwise. The solution was warmed to room temperature and stirred overnight, then washed with saturated NH 4The mixture was diluted with ether and extracted with water. The separated ether layer was washed with sodium thiosulfate, brine and purified by MgSO 4 After concentration in vacuo, the residue was distilled to give ethyl 3-ethoxy-2-fluoroacrylate (6 g, 73°-85°C / 14 mmHg) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): δ1.35(t,3H),1.39(t,3H),4.10(q,2H),4.30(q,2H),6.95(d,1H).

[0461] Step 3: At room temperature and under nitrogen atmosphere, use Cs 2 CO 3 A solution of (4R,11S)-1-amino-10-(difluoromethoxy)-5-methyl-2,4,5,11-tetrahydro-6H-4,11-methanobenzo[c]pyrazolo[4,3-f]azepin-6-one (500 mg, 1.56 mmol, 1 eq) in DMF (1 mL) was treated with 4% paraformaldehyde (1.12 g, 3.43 mmol, 2.2 eq) for 1 min before the addition of (2Z)-3-ethoxy-2-fluoroprop-2-enoic acid ethyl ester (60.75 mg, 0.38 mmol, 4 eq) at room temperature. The resulting mixture was stirred at 110 °C under nitrogen for 3 h. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave (7R,14S)-1-(difluoromethoxy)-11-fluoro-6-methyl-6,7,13,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-5,12-dione (140 mg, 22.97%) as a yellow solid. LCMS (ESI, m / z): 391.10 [M+H] + .

[0462] Step 4: A solution of (7R,14S)-1-(difluoromethoxy)-11-fluoro-6-methyl-6,7,13,14-tetrahydro-7,14-carboxybenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azepine-5,12-dione (130 mg, 0.33 mmol, 1 eq) in DCM (4 mL) was treated with DMAP (20.35 mg, 0.17 mmol, 0.5 eq) at room temperature under nitrogen atmosphere for 1 min, followed by the addition of 2,6-lutidine (53.53 mg, 0.50 mmol, 1.5 eq) at room temperature. Trifluoromethanesulfonic anhydride (281.90 mg, 1.00 mmol, 3 eq) was added to the above mixture at 0°C over 1 min. The resulting mixture was stirred at 0°C for 1 h. The mixture was heated to 40°C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:2) to give Intermediate 8 (110 mg, 63.22%) as a yellow solid. LCMS (ESI, m / z): 523.15 [M+H] + .

[0463] Intermediate 9

[0464]

[0465] Step 1: To a stirred solution of intermediate 6 (2.0 g, 7.1 mmol, 1 eq) in THF (40 mL) was added LiHMDS (11.4 mL, 11.4 mmol, 1.6 eq) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h. 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (3.8 g, 10.7 mmol, 1.5 eq) in THF (40 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 78 °C to RT for 2 h. The reaction mixture was heated to 40 °C by adding saturated NH 4 The reaction was quenched with Cl(aq) (50 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100 mL) and purified by anhydrous Na 2 SO 4The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (8:1)) to give (3R,6R)-7-(difluoromethoxy)-2-methyl-1-oxo-1,2,3,6-tetrahydro-3,6-methanobenzo[c]azocine-5-yl trifluoromethanesulfonate (1.7 g, 57.8%) as a light yellow oil. LCMS (ESI, m / z): 413.90 [M+H] + .

[0466] Step 2: To a stirred mixture of (3R,6R)-7-(difluoromethoxy)-2-methyl-1-oxo-1,2,3,6-tetrahydro-3,6-methanobenzo[c]azocine-5-yl trifluoromethanesulfonate (1.7 g, 4.1 mmol, 1 eq) and 4-chloro-2-(tributylstannyl)pyridine (2.5 g, 6.2 mmol, 1.5 eq) in toluene (34 mL) was added Pd(PPh 3 ) 4 (475.3mg, 0.41mmol, 0.1 eq) and CuCl (407.2mg, 4.1mmol, 1 eq). The resulting mixture was stirred at 100 °C for 4h. The resulting mixture was filtered and the filter cake was washed with DCM (3x 20mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give (3R, 6S)-5-(4-chloropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methylbenzo[c]azocine-1(2H)-one (600mg, 38.7%) as a light yellow solid. LCMS (ESI, m / z): 376.95[M+H] + .

[0467] Step 3: To a stirred mixture of (3R,6S)-5-(4-chloropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocin-1(2H)-one (5.0 g, 13.3 mmol, 1 eq) and 2,2,6,6-tetramethylpiperidin-1-olate (0.41 g, 2.7 mmol, 0.2 eq) in DCE (100 mL) at room temperature under nitrogen atmosphere was added iron(III) nitrate nonahydrate (10.7 g, 26.5 mmol, 2.0 eq) and 4A-MS (15 g). The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with DCE (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (3:1)) to give (3R,6S)-5-(4-chloropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (2.2 g, 39.3%) as a light yellow solid. LCMS (ESI, m / z): 421.90 [M+H] + .

[0468] Step 4: A solution of (3R,6S)-5-(4-chloropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (2.2 g, 13.5 mmol, 1 eq) in toluene (44 mL) was treated with triphenyl phosphite (4.9 g, 40.5 mmol, 3 eq) at 100 °C under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give intermediate 9 (1.0 g, 50%) as a yellow solid. LCMS (ESI, m / z): 390.05 [M+H] + .

[0469] Intermediate 10

[0470]

[0471] Step 1: 2-Bromo-4-chloro-5-fluoropyridine (1 g, 4.8 mmol, 1.0 eq.), hexamethyldistanane (7.8 g, 23.8 mmol, 5.0 eq.) and Pd(PPh 3 ) 4 A solution of (549 mg, 0.48 mmol, 0.1 eq) in dioxane (15 mL) was stirred at 120 °C under nitrogen atmosphere for 1 h. 2The reaction was quenched with 1% 4% iodine (30 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. This gave 4-chloro-5-fluoro-2-(trimethylstannyl)pyridine (1 g, crude) as a black solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 293.90 [M+H] + .

[0472] Step 2: 4-Chloro-5-fluoro-2-(trimethylstannyl)pyridine (925 mg, 3.2 mmol, 2.0 eq.) and intermediate 6 (650 mg, 1.6 mmol, 1.0 eq.), CuCl (234 mg, 2.4 mmol, 1.5 eq.) and Pd(PPh 3 ) 4 (272.6 mg, 0.24 mmol, 0.15 equiv) in toluene (15 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give (3R,6S)-5-(4-chloro-5-fluoropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (300 mg, 48.32%) as a white solid. LCMS (ESI, m / z): 395.10 [M+H] + .

[0473] Step 3: A solution of molecular sieves 4A (960 mg), (3R,6S)-5-(4-chloro-5-fluoropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (320 mg, 0.8 mmol, 1.0 equiv), iron(III) nitrate nonahydrate (660 mg, 1.6 mmol, 2.0 equiv) and TEMPO (25 mg, 0.16 mmol, 0.2 equiv) in DCE (10 mL) was stirred at 80 °C under nitrogen for 2 h. The resulting mixture was filtered; the filter cake was washed with DCM (2 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give (3R,6S)-5-(4-chloro-5-fluoropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (220 mg, 61.7%) as a yellow solid. LCMS (ESI, m / z): 440.05 [M+H] + .

[0474] Step 4: A stirred solution of (3R,6S)-5-(4-chloro-5-fluoropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (500 mg, 1.1 mmol, 1 eq) and triphenyl phosphite (1.76 mg, 5.7 mmol, 5 eq) in toluene (10 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give intermediate 10 (150 mg, 32.4%) as a yellow solid. LCMS (ESI, m / z): 408.15 [M+H] + .

[0475] Intermediate 11

[0476]

[0477] Step 1: A solution of benzyl alcohol (39.9 g, 369.2 mmol, 1.1 eq.) in THF (250 mL) was treated with NaH (16.1 g, 402.8 mmol, 1.2 eq., 60%) at 0°C for 30 min, followed by the addition of 4,6-dichloropyrimidine (50 g, 335.6 mmol, 1.0 eq.) in portions at 0°C. The resulting mixture was stirred at room temperature under air atmosphere for 2 h. The mixture was stirred for 2 h at 0°C by adding saturated NH 4Cl (5 mL) was used to quench the reaction. The reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (TFA, 0.1%) in water, 50% to 90% gradient in 10 min; detector, UV 220 nm) to give 4-(benzyloxy)-6-chloropyrimidine (30 g, 40.5%) as a yellow oil. LCMS (ESI, m / z): 220.95 [M+H] + .

[0478] Step 2: At room temperature and under nitrogen atmosphere, use Pd(PPh 3 ) 4 A solution of 4-(benzyloxy)-6-chloropyrimidine (24 g, 108.8 mmol, 1 eq.), hexamethyldistanane (35.6 g, 108.8 mmol, 1 eq.) in toluene (150 mL) was treated with 4-(benzyloxy)-6-chloropyrimidine (24 g, 108.8 mmol, 1 eq.) (12.6 g, 10.9 mmol, 0.1 eq.). The resulting mixture was stirred at 120 °C under nitrogen atmosphere for 2 h. The reaction mixture was diluted with water (40 mL) and the aqueous phase was extracted with EA (3 x 60 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter, and concentrate in vacuo to give 4-(benzyloxy)-6-(trimethylstannyl)pyrimidine (23 g) as a brown semi-solid. LCMS (ESI, m / z): 349.05, 351.05 [M+H] + .

[0479] Step 3: Intermediate 6 (15 g, 12.1 mmol, 1 eq.), Pd(PPh 3 ) 4A solution of 4-(benzyloxy)-6-(trimethylstannyl)pyrimidine (4.2 g, 1.2 mmol, 0.1 eq.), CuCl (3.6 g, 12.1 mmol, 1.0 eq.) and 4-(benzyloxy)-6-(trimethylstannyl)pyrimidine (25.3 g, 24.2 mmol, 2 eq.) in toluene (300 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (500 mL). The resulting mixture was filtered and the filter cake was washed with DCM (3 x 500 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (3:2)) to give (3R,6S)-5-(6-(benzyloxy)pyrimidin-4-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (11.5 g, 32.9%) as a light yellow solid. LCMS (ESI, m / z): 350.25 [M+H] + .

[0480] Step 4: A solution of (3R,6S)-5-(6-(benzyloxy)pyrimidin-4-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocin-1(2H)-one (11.5 g, 25.6 mmol, 1 eq) in DCE (230 mL) was treated with iron(III) nitrate nonahydrate (20.7 g, 51.2 mmol, 2 eq) at room temperature under nitrogen atmosphere for 1 min, followed by the addition of 2,2,6,6-tetramethylpiperidin-1-olate (799.6 mg, 5.1 mmol, 0.2 eq) and 4A-MS (34.5 g) in portions at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was filtered and the filter cake was washed with DCM (3 x 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (13:7)) to give (3R,6S)-5-(6-(benzyloxy)pyrimidin-4-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (6.2 g, 49%) as a light yellow solid. LCMS (ESI, m / z): 495.25 [M+H] + .

[0481] Step 5: A solution of (3R,6S)-5-(6-(benzyloxy)pyrimidin-4-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocin-1(2H)-one (6.2 g, 12.5 mmol, 1 eq) in toluene (124 mL) was treated with triphenyl phosphite (11.7 g, 37.6 mmol, 3 eq) at 100° C. under nitrogen for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give (7R,14S)-12-(benzyloxy)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',6':1,5]pyrazolo[4,3-f]azocin-5(14H)-one (2.0 g, 35.5%) as a light brown solid. LCMS (ESI, m / z): 463.20 [M+H] + .

[0482] Step 6: A solution of (7R, 14S)-12-(benzyloxy)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-carboxybenzo[c]pyrimido[1',6':1,5]pyrazolo[4,3-f]azocin-5(14H)-one (2 g, 4.3 mmol, 1 eq) and Pd / C (920.5 mg, 0.87 mmol, 0.2 eq, 10%) in ethyl acetate (100 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was filtered and the filter cake was washed with MeOH:DCM=1:1 (3 x 50 mL). The filtrate was concentrated under reduced pressure to give (7R,14S)-1-(difluoromethoxy)-12-hydroxy-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',6':1,5]pyrazolo[4,3-f]azocin-5(14H)-one (1.4 g, 86.9%) as a dark yellow solid. LCMS (ESI, m / z): 373.15 [M+H] + .

[0483] Step 7: To a stirred mixture of (7R,14S)-1-(difluoromethoxy)-12-hydroxy-6-methyl-6,7-dihydro-7,14-carboxybenzo[c]pyrimido[1',6':1,5]pyrazolo[4,3-f]azocine-5(14H)-one (1.3 g, 3.5 mmol, 1 eq) and DIEA (1.4 g, 10.5 mmol, 3 eq) in DCM (26 mL) at 0°C under nitrogen atmosphere was added trifluoromethanesulfonic acid (trifluoromethane)sulfonyl ester (2.0 g, 7.0 mmol, 2 eq). The resulting mixture was stirred at room temperature for 2 h. The aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1 x 5 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give (7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',6':1,5]pyrazolo[4,3-f]azocine-12-yl trifluoromethanesulfonate (700 mg, 40%) as a light brown solid. LCMS (ESI, m / z): 505.15 [M+H] + .

[0484] Intermediates 12-23 were prepared using similar procedures.

[0485]

[0486]

[0487] Intermediates 24 and 25

[0488]

[0489] Step 1: A solution of cyclobutanone (20 g, 285.3 mmol, 1.0 eq.) and tert-butylsulfenamide (34.6 g, 285.3 mmol, 1.0 eq.) in THF (540 mL) was stirred with Ti(Oi-Pr)4 (128.1 mL, 428.0 mmol, 1.5 eq.) at 60 °C under nitrogen overnight. The resulting mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL). The residue was purified by adding saturated Na 2 CO 3 (aqueous solution) (50 mL) was used to quench the reaction. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x400 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2x 1000 mL). The combined organic layers were washed with anhydrous Na2 SO 4 The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give N-cyclobutylidene-2-methylpropane-2-sulfenamide (34.5 g, 70%) as a pale yellow liquid. LCMS (ESI, m / z): 174.10 [M+H] + .

[0490] Step 2: A solution of 5-bromo-2-iodopyrimidine (57.3 g, 201.1 mmol, 1.01 equiv) in DCM (1225 mL) was treated with n-BuLi (81.3 mL, 203.1 mmol, 1.02 equiv) in hexane at -78 °C under nitrogen atmosphere for 10 min, followed by dropwise addition of N-cyclobutylene-2-methylpropane-2-sulfinamide (34.5 g, 199.1 mmol, 1 equiv) at -78 °C. The resulting mixture was stirred overnight at -20 °C under nitrogen atmosphere. The reactants were quenched with water / ice at 0 °C. The resulting mixture was extracted with DCM (3 x 500 mL). The combined organic layers were washed and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1 / 1)) to give N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide (23.2 g, 35.1%) as a yellow solid. LCMS (ESI, m / z): 334.00 [M+H] + .

[0491] Step 3: A mixture of N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide (23 g, 69.2 mmol, 1 eq.) and HCl(g) in MeOH (230 mL) was stirred at room temperature under nitrogen atmosphere for 30 min. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification. This gave 1-(5-bromopyrimidin-2-yl)cyclobutan-1-amine (15.7 g, 99%) as a yellow oil. LCMS (ESI, m / z): 229.90 [M+H] + .

[0492] Step 4: A solution of 1-(5-bromopyrimidin-2-yl)cyclobutan-1-amine (15.7 g, 68.8 mmol, 1 eq.) and TEA (28.7 mL, 206.5 mmol, 3 eq.) in DCM (158 mL) was mixed with Boc 2O (22.5 g, 103.2 mmol, 1.5 equiv) was stirred at room temperature under air atmosphere for 1 h. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with aqueous NaHCO3 (3 x 100 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give tert-butyl N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]carbamate (14.7 g, 65.1%) as a light yellow solid. LCMS (ESI, m / z): 329.90 [M+H] + .

[0493] Step 5: To a stirred solution of tert-butyl N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]carbamate (1 g, 3.1 mmol, 1 eq) and pinacol diboron (1.2 g, 4.6 mmol, 1.5 eq) in dioxane (15 mL) at room temperature under nitrogen atmosphere was added KOAc (898 mg, 9.1 mmol, 3 eq) and Pd(dppf)Cl in portions. 2 .DCM (248 mg, 0.31 mmol, 0.1 eq). The resulting mixture was stirred at 100 °C for another 2 h. 2 The resulting mixture was diluted with 4% 4% dHO (30 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 30 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 25:1) to give tert-butyl N-{1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]cyclobutyl}carbamate (650 mg, 57%) as a light yellow solid. LCMS (ESI, m / z): 376.10 [M+H] + .

[0494] Intermediate 26-28

[0495]

[0496] Step 1: 1-Methyl-3-oxocyclobutane-1-carbonitrile (1 g, 9.2 mmol, 1 eq) was dissolved in DCM (50 mL) and cooled to -78 °C under nitrogen, and n-BuLi (4.40 mL, 11 mmol, 1.2 eq) was added dropwise. The resulting mixture was stirred at -78 °C under nitrogen for 5 min. 5-Bromo-2-iodopyrimidine (3.1 g, 11 mmol, 1.2 eq) in DCM (50 mL) was added dropwise at -78 °C to the above mixture. The resulting mixture was stirred for another 2 h at -78 °C. The resulting mixture was then stirred at room temperature under nitrogen overnight. The mixture was heated at 0 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The aqueous layer was extracted with EtOAc (3 x 20 mL). The residue was purified by preparative TLC (PE / EA 2:1) to give (3r)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile (800 mg, 32.6%) as an off-white solid. LCMS (ESI, m / z): 269.95 [M+H] + .

[0497] Step 2: 3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile (1 g) was purified by preparative chiral HPLC under the following conditions (column: JW-CHIRAL ART Cellulose-SC, 20*250 mm, 5 um; mobile phase A: EtOH, mobile phase B: Hex (0.5% 2M NH 3 -MeOH); flow rate: 20 mL / min; gradient: 70% B to 70% B in 10 min; wavelength: 220 / 254 nm; RT1 (min): 5.03; RT2 (min): 7.78; sample solvent: EtOH:DCM=1:1; injection volume: 1.4 mL; number of runs: 10), to obtain:

[0498] Intermediate 26: (1r,3r)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile (trans) (420 mg, 42.0%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.07(s,2H),6.16(s,1H),3.27-3.19(m,2H),2.42-2.34(m,2H),1.65(s,3H).

[0499] Intermediate 27: ((1s,3s)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile (cis) (220 mg, 22.0%) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6 )δ9.04(s,2H),6.19(s,1H),2.86-2.79(m,2H),2.75-2.68(m,2H),1.40(s,3H).

[0500] Step 3: A solution of intermediate 27 (100 mg, 0.37 mmol, 1 eq.), KOAc (109.8 mg, 1.1 mmol, 3 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (189.4 mg, 0.75 mmol, 2 eq.) in dioxane (3 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction was monitored by TLC. TLC (DCM:MeOH=8:1, Rf=0.3). The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave intermediate 28 (50 mg, 57.5%) as a yellow solid. LCMS (ESI, m / z): 234.20 [M+H] + .

[0501] Intermediate 29-31

[0502]

[0503] Step 1: A mixture of 3-methylenecyclobutane-1-carbonitrile (6.5 g, 69.8 mmol, 1 eq.) in THF (100 mL) was added to LDA (38.4 mL, 76.8 mmol, 1.1 eq.) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h before adding morpholine-4-carbonitrile (8.6 g, 76.8 mmol, 1.1 eq.). The mixture was stirred at -78 °C for 1 h. The reaction was diluted with water (300 mL) and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (2 x 400 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted by silica gel column chromatography with DCM / MeOH (30 / 1) to give 1-(imino(morpholino)methyl)-3-methylenecyclobutane-1-carbonitrile (5.0 g, 41%) as a light yellow oil. LCMS (ESI, m / z): 206.15 [M+H] + .

[0504] Step 2: To a mixture of 5-bromo-1,2,3-triazine (3 g, 18.8 mmol, 1.0 eq.) in a pot (100 mL) was added 1-(imino(morpholino)methyl)-3-methylenecyclobutane-1-carbonitrile (4.2 g, 20.6 mmol, 1.1 eq.) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. The above mixture was stirred at 80 °C for 6 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (30 / 1)) to give 1-(5-bromopyrimidin-2-yl)-3-methylenecyclobutane-1-carbonitrile (2.7 g, 58%) as an off-white solid. LCMS (ESI, m / z): 250.95 [M+H] + .

[0505] Step 3: A mixture of 1-(5-bromopyrimidin-2-yl)-3-methylenecyclobutane-1-carbonitrile (1.7 g, 6.8 mmol, 1 equivalent) in fluoroboric acid (20 mL) was obtained at room temperature. The resulting mixture was stirred at 70 ° C for 7 h. The reactants were quenched with saturated sodium bicarbonate solution (200 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1:1) to give 1-(5-bromopyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane-1-carbonitrile (1.3 g, 71.3%) as a yellow oil. LCMS (ESI, m / z): 270.00 [M+H] + .

[0506] Step 4: 1-(5-bromopyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane-1-carbonitrile (1 g) was purified by preparative chiral HPLC (column: JW-CHIRAL ART Cellulose-SC, 20*250 mm, 5 um; mobile phase A: IPA, mobile phase B: Hex (0.5% 2M NH 3 -MeOH); flow rate: 20 mL / min; gradient: 70% B to 70% B in 15 min; wavelength: 220 / 254 nm; RT1 (min): 6.21; RT2 (min): 12.05; sample solvent: EtOH; injection volume: 2.2 mL; number of runs: 8) to obtain

[0507] Intermediate 29: (1s,3s)-1-(5-bromopyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane-1-carbonitrile (trans) (503 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d 6 )δ9.10(s,2H),2.99-2.87(m,2H),2.82-2.72(m,2H),1.56(s,3H).

[0508] Intermediate 30: (1r,3r)-1-(5-bromopyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane-1-carbonitrile (cis) (384 mg) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.10(s,2H),2.93-2.85(m,2H),2.83-2.76(m,2H),1.21(s,3H).

[0509] Step 5: (1r,3r)-1-(5-bromopyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane-1-carbonitrile (100 mg, 0.37 mmol, 1 equivalent), Pd(dppf)Cl 2 A solution of DCM (30 mg, 0.04 mmol, 0.1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (189 mg, 0.75 mmol, 2 eq), KOAc (110 mg, 1.2 mmol, 3 eq) in dioxane (3 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This gave Intermediate 31: (1r,3r)-3-hydroxy-3-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-142ylcyclobutene-1-carbonitrile (30 mg, 26%) as a white solid. LCMS (ESI, m / z): 234.05 [M+H] + .

[0510] Intermediate 32

[0511]

[0512] Step 1: A solution of 1-aminocyclopropane-1-carbonitrile (4.5 g, 54.8 mmol, 1 eq.) in DCM (40 mL) was treated with DIEA (21.3 g, 164.42 mmol, 3 eq.) at room temperature under nitrogen atmosphere, followed by the addition of Boc 2O (23.9 g, 109.6 mmol, 2 equivalents). The resulting mixture was stirred at room temperature for 20 h. The resulting mixture was quenched with 20% citric acid (100 mL), and the organic phase was separated. The aqueous phase was extracted with DCM (60 mL x 2). The combined organic layers were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give tert-butyl N-(1-cyanocyclopropyl)carbamate (3.5 g, 31.5%) as an off-white solid.

[0513] Step 2: A solution of tert-butyl N-(1-cyanocyclopropyl)carbamate (2.0 g, 11.0 mmol, 1 eq.) in EtOH (35 mL) was treated with EtONa (7.1 g, 22.0 mmol, 2 eq., 21 wt.%) at room temperature under nitrogen for 2 h, followed by the addition of NH 4 Cl (2.35 g, 43.90 mmol, 4 equiv) and NH in MeOH 3 To the 4-thiazolinyl cyclopropyl ester (1.4 g, 57.6%) of t-butyl N-(1-carbamimidoylcyclopropyl)carbamate (1.4 g, 57.6%) of 4-thiazolinyl cyclopropyl ester (1.4 g, 57.6%) of 1 ...

[0514] Step 3: At room temperature and under nitrogen atmosphere, Br 2 (2E)-3-(dimethylamino)prop-2-enal (5 g, 50.4 mmol, 1 eq.) (16.1 g, 100.9 mmol, 2 eq.) was treated with (2E)-3-(dimethylamino)prop-2-enal (5 g, 50.4 mmol, 1 eq.) in CHCl 3 The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was diluted with DCM (20 mL). 2 S 2 O 3 Solution (50mL) was used to quench the reaction. The organic phase was separated and the aqueous phase was extracted with DCM (2x 20mL). The combined organic layers were washed with brine (20mL) and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:2)) to give (2Z)-2-bromo-3-(dimethylamino)prop-2-enal (4 g, 40.1%) as a light brown oil.

[0515] Step 4: A solution of (2Z)-2-bromo-3-(dimethylamino)prop-2-enal (500 mg, 2.8 mmol, 1 eq.) in EtOH (3 mL) was treated with tert-butyl N-(1-carbamimidoylcyclopropyl)carbamate (839.4 mg, 4.21 mmol, 1.5 eq.), dimethylamine (2 M in THF) (1.8 mL, 3.7 mmol, 1.3 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for an additional 20 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm) to give tert-butyl (1-(5-bromopyrimidin-2-yl)cyclopropyl)carbamate (400 mg, 40.8%) as a brown oil.

[0516] Step 5: A solution of tert-butyl (1-(5-bromopyrimidin-2-yl)cyclopropyl)carbamate (100 mg, 0.31 mmol, 1 eq) in dioxane (1 mL) was treated with KOAc (93.7 mg, 0.95 mmol, 3 eq) at room temperature, followed by the portionwise addition of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (161.7 mg, 0.63 mmol, 2 eq) and Pd(dppf)Cl 2 (23.3 mg, 0.032 mmol, 0.1 eq.). The resulting mixture was stirred at 100°C under nitrogen atmosphere for 1 h. 4 The resulting mixture was washed with Cl (3 x 5 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give Intermediate 32 (266 mg, crude) as a dark yellow solid. LCMS (ESI, m / z): 362.10 [M+H] +.

[0517] Intermediate 33-35

[0518]

[0519] Step 1: A solution of 1-methyl-3-oxocyclobutane-1-carbonitrile (3 g, 27.5 mmol, 1 eq.) and (R)-2-methyl-propane-2-sulfenamide (3 g, 27.5 mmol, 1 eq.) in THF (180 mL) was mixed with Ti(Oi-Pr) 4 The product was stirred overnight at 75 ° C under nitrogen atmosphere (12mL, 41.2mmol, 1.5 equivalents). The resulting mixture was concentrated in vacuo. The reactant was quenched by adding water (200mL) at room temperature. The residue was dissolved in EtOAc (250mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (5x100mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (2: 1)) to obtain (R)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (5g, 85.7%) as a white solid. LCMS (ESI, m / z): 213.10 [M+H] + .

[0520] Step 2: A solution of 5-bromo-2-iodopyrimidine (5 g, 19.8 mmol, 1.2 eq) in DCM (400 mL) was treated with butyl lithium (8 mL, 19.8 mmol, 1.2 eq) at -78 °C under nitrogen for 10 min, followed by the addition of (R)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfenamide (4 g, 16.5 mmol, 1 eq) at -78 °C for 10 min. The resulting mixture was stirred at -78 °C for 2 h. The resulting mixture was stirred at room temperature under nitrogen for 3 h. The reaction mixture was stirred at 0 °C by adding saturated NH 4 The reaction was quenched with Cl(aq) (500 mL). The resulting mixture was extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (2 x 400 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% NH 3 .H 2 O), 10% to 60% gradient in 10 min; detector, UV 254 nm. This gave (R)-N-[1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl]-2-methylpropane-2-sulfinamide) (700 mg, 8.0%) as a yellow oil. LCMS (ESI, m / z): 373.05 [M+H] + .

[0521] Step 3: The crude product (700 mg) was purified by preparative HPLC under the following conditions (column: CHIRALPAKIA3; mobile phase A: Hex (0.1% DEA): (IPA: MeOH = 1: 1) = 90: 10; flow rate: 1 mL / min; gradient: isocratic; injection volume: 2 mL) to give intermediate 33: (R) -N- ((1r, 3R) -1- (5-bromopyrimidin-2-yl) -3-cyano-3-methylcyclobutyl) -2-methylpropane-2-sulfenamide (320 mg, 45.7%) as a white solid.

[0522] Intermediate 33 (trans): 1 H NMR (400 MHz, DMSO-d 6 )δ9.08(d,J=1.6Hz,2H),6.08(s,1H),3.35-3.31(m,2H),2.74-2.55(m,2H),1.60(s,3H),1.06(s,9H). LCMS(ESI,m / z):373.05[M+H] + .

[0523] Intermediate 34 (cis): ((R)-N-((1s,3S)-1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (180 mg, 25.7%). 1 H NMR (400 MHz, DMSO-d 6 )δ9.02(s,2H),6.10(s,1H),3.02-2.99(m,1H),2.92(d,J=1.9Hz,2H),2.78(d,J=12.6Hz,1H),1.37(s,3H),1.12(s,9H).

[0524] Step 4: To a stirred solution of intermediate 34 (100 mg, 0.27 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (137 mg, 0.538 mmol, 2 eq) in dioxane (2 mL) at room temperature under nitrogen atmosphere were added KOAc (80 mg, 0.81 mmol, 3 eq) and Pd(dppf)Cl in portions. 2 .DCM (22 mg, 0.027 mmol, 0.1 eq.). The resulting mixture was stirred at 110 °C under nitrogen atmosphere for 2 h. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL) and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure to give Intermediate 35 (60 mg, 54.8%) as a black solid. LCMS (ESI, m / z): 419.22 [M+H] + .

[0525] Intermediate 36-38

[0526]

[0527] Step 1: A solution of 5-bromo-2-iodopyrimidine (1.38 g, 4.9 mmol, 1.1 eq) in toluene (30 mL) was treated with n-butyllithium (310. mg, 4.7 mmol, 1.1 eq) at -50 °C under nitrogen for 20 min. To the above mixture was added (S)-N-(3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutylidene)-2-methylpropane-2-sulfenamide (1.4 g, 4.4 mmol, 1 eq) in toluene (30 mL) at -50 °C over 5 min. The resulting mixture was stirred at room temperature for another 2 h. The mixture was heated at 0 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% FA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave (S)-N-(1-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (270 mg, 12.9%) as a yellow solid. LCMS (ESI, m / z): 476.10 [M+H] + .

[0528] Step 2: (S)-N-(1-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (270 mg) was purified by preparative HPLC under the following conditions (column: CHIRALPAKIG3; mobile phase A: Hex (0.1% DEA): IPA = 95:5; flow rate: 1 mL / min; gradient: isocratic; injection volume: 2 mL) to obtain:

[0529] Intermediate 36 (trans): ((S)-N-((1r,3S)-1-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (64 mg, 23.7%) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ8.98(s,2H),5.78(s,1H),3.03(d,J=12.7Hz,1H).

[0530] Intermediate 37 (cis): ((S)-N-((1s,3R)-1-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (110 mg, 40.7%) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ9.02(s,2H),5.83(s,1H),3.17-3.09(m,1H),2.96 -2.88(m,1H),2.65(d,J=12.2Hz,1H),2.60(d,J=12.2Hz,1H),1.04(d,J=3.5Hz,12H),0.87(s,9H),0.08(s,6H).

[0531] Step 3: A solution of intermediate 37 (60 mg, 0.13 mmol, 1 eq.) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (63.94 mg, 0.25 mmol, 2 eq.) in dioxane (1 mL) was treated with KOAc (37.07 mg, 0.38 mmol, 3 eq.) at room temperature under nitrogen atmosphere for 1 h, followed by the addition of Pd(dppf)Cl 2. DCM (20.51 mg, 0.03 mmol, 0.2 eq). The resulting mixture was stirred at 110 °C under nitrogen atmosphere for 2 h. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 5 mL). The filtrate was concentrated under reduced pressure to give Intermediate 38 (60 mg, 91.0%) as a black solid. LCMS (ESI, m / z): 524.30 [M+H] + .

[0532] Intermediate 39-41

[0533]

[0534] Step 1: A mixture of methyl 3-oxocyclobutane-1-carboxylate (25 g, 195.1 mmol, 1 eq) in methanol (60 mL) was treated dropwise at room temperature with trimethyl orthoformate (128.1 mL, 1170.7 mmol, 6 eq) and 4-methylbenzene-1-sulfonic acid (3.4 g, 19.5 mmol, 0.1 eq). The resulting mixture was heated at 70 °C, N 2 Stir for 1 h under atmosphere. Allow the mixture to cool to room temperature. Purify the crude product by vacuum distillation and collect fractions at room temperature. This afforded 3,3-dimethoxycyclobutane-1-carboxylic acid methyl ester (17 g, 51.49%) as a yellow oil.

[0535] Step 2: A solution of methyl 3,3-dimethoxycyclobutane-1-carboxylate (17.5 g, 100.5 mmol, 1 eq.) in THF (175 mL) was treated with lithium bis(propan-2-yl)amine (226 mL, 452.6 mmol, 4.5 eq.) at -78 °C under nitrogen atmosphere for 30 min, followed by the dropwise addition of MeI (19.3 mL, 310 mmol, 4.5 eq.) at -78 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was heated to 40 °C by adding saturated NH 4 The reaction was quenched with Cl solution (250 mL). The mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (100 ml) and purified by Na 2 SO 4 Dried and concentrated to give methyl 3,3-dimethoxy-1-methylcyclobutane-1-carboxylate (16 g, 82%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0536] Step 3: At 0°C, under nitrogen atmosphere, use LiAlH 4 A mixture of 3,3-dimethoxy-1-methylcyclobutane-1-carboxylic acid methyl ester (16g, 85.0mmol, 1 equivalent) in THF (250mL) was treated with (3.2g, 85.0mmol, 1 equivalent) for 1h. The resulting mixture was stirred at room temperature for 1h. The reactant was quenched by adding water (3.2mL), NaOH (10%, 6.4mL) water (3.2mL) at 0°C. The resulting mixture was filtered; the filter cake was washed with EA (500mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (8:1)) to obtain (3,3-dimethoxy-1-methylcyclobutyl)methanol (6.8g, 44%) as a yellow oil.

[0537] Step 4: (3,3-Dimethoxy-1-methylcyclobutyl)methanol (6.8 g, 42.4 mmol, 1 eq.) in propan-2-one (68 mL) and H2O was treated with p-toluenesulfonate (7.3 g, 42.4 mmol, 1 eq.) at 60 °C. 2 The mixture was stirred for 1 h at 4 ℃ for 2 hours. The mixture was stirred for 1 h at 4 ℃ for 2 hours. The mixture was cooled to room temperature. The aqueous layer was extracted with EA (25 mL). The residue was purified by silica gel column chromatography (eluted with PE:EA=3:1) to give 3-(hydroxymethyl)-3-methylcyclobutane-1-one (4.7 g, 96.6%) as a yellow liquid.

[0538] Step 5: A mixture of imidazole (0.47 g, 6.8 mmol, 0.17 eq.) in DMF (47.60 mL) was treated with 3-(hydroxymethyl)-3-methylcyclobutan-1-one (4.7 g, 41.0 mmol, 1 eq.) at room temperature under nitrogen atmosphere, followed by dropwise addition of TBSCl (18.5 g, 123.0 mmol, 3 eq.) at room temperature. The resulting mixture was stirred overnight at room temperature. Ether was added, followed by brine. The organic layer was separated and washed three times with brine. The organic layer was separated and concentrated in vacuo. This gave 3-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methylcyclobutan-1-one (7.6 g, 83.9%) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )δ3.53(s,2H),3.00-2.94(m,2H),2.58-2.52(m,2H),1.23(s,1H),0.85-0.80(m,12H).

[0539] Step 6: 3-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methylcyclobutan-1-one (7.6 g, 23.3 mmol, 1 eq., 70%), (S)-2-methylpropane-2-sulfenamide (3.4 g, 28.0 mmol, 1.2 eq.) and Ti(Oi-Pr) were reacted with 1% paraformaldehyde to obtain a 5-nitropropane-2-sulfonamide mixture. 4 A mixture of 4-(13.2 g, 46.6 mmol, 2 eq.) in THF (80 mL) was stirred at room temperature for 2 h. The mixture was quenched with water (60 mL). The mixture was stirred for 15 min. The resulting mixture was filtered; the filter cake was washed with EA (3 x 50 mL). The filtrate was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4The residue was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (15:1)) to give (S)-N-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylcyclobutylidene)-2-methylpropane-2-sulfenamide (4.6 g, 59.6%) as a yellow-green oil. LCMS (ESI, m / z): 332.25 [M+H] + .

[0540] Step 7: To a mixture of 5-bromo-2-iodopyrimidine (2.6 g, 9.0 mmol, 1.2 eq) in DCM (30 mL) was added n-BuLi (4.0 mL, 10 mmol, 1.3 eq) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h. (S)-N-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylcyclobutylidene)-2-methylpropane-2-sulfenamide (2.5 g, 7.5 mmol, 1 eq) was then added at -78 °C. The mixture was stirred at -78 °C for 2 h, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=2:1) ​​to obtain:

[0541] Intermediate 39 (trans) ((S)-N-((1r,3S)-1-(5-bromopyrimidin-2-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (300 mg, 8.1%) as an off-white solid.

[0542] Intermediate 40 (cis) (S)-N-((1s,3R)-1-(5-bromopyrimidin-2-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide as an off-white solid (250 mg, 6.8%)

[0543] Step 8: To a stirred solution of 2-methyl-N-[(1r,3s)-1-(5-bromopyrimidin-2-yl)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methylcyclobutyl]propane-2-sulfenamide (75 mg, 0.15 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (77 mg, 0.30 mmol, 2 eq) in 1,4-dioxane (1 mL) was added KOAc (45 mg, 0.46 mmol, 3 eq) and Pd(dppf)Cl in portions at room temperature under nitrogen atmosphere. 2 .DCM (12 mg, 0.01 mmol, 0.1 eq). The resulting mixture was stirred at 110 °C under nitrogen atmosphere for 2 h. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give Intermediate 41 (60 mg, 73.00%) as a black solid. LCMS (ESI, m / z): 456.30 [M+H] + .

[0544] Intermediate 42

[0545]

[0546] At 100 °C, under nitrogen atmosphere, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (234 mg, 0.92 mmol, 2 eq.), AcOK (135.6 mg, 1.4 mmol, 3 eq.), Pd(dppf)Cl 2 A solution of 2-(5-bromopyrimidin-2-yl)propan-2-ol (100 mg, 0.46 mmol, 1 eq.) in 1,4-dioxane (2 mL) was treated with 4% paraformaldehyde (33.7 mg, 0.046 mmol, 0.1 eq.) for 1 h. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD RP18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 55% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.5) to obtain intermediate 42 (80 mg, 69.4%) as a white solid. LCMS (ESI, m / z): 264.9 [M+H] + .

[0547] Intermediate 43

[0548]

[0549] Step 1: To a mixture of 5-bromo-2-iodopyrimidine (2 g, 7.0 mmol, 1.0 eq) in toluene (25 mL) was added n-BuLi (3.4 mL, 8.4 mmol, 1.2 eq) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h. Dihydrofuran-3-one (2.4 g, 28.1 mmol, 4.0 eq) was then added at -78 °C. The mixture was stirred at -78 °C for 1 h, then allowed to warm to room temperature and stirred for 1 h. The mixture was heated at 0 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 40% gradient in 10 min; detector, UV 220 nm. This gave 3-(5-bromopyrimidin-2-yl)oxacyclopentane-3-ol (600 mg, 35%) as a brownish yellow solid. LCMS (ESI, m / z): 244.95 [M+H] + .

[0550] Step 2: A solution of 3-(5-bromopyrimidin-2-yl)oxolan-3-ol (200 mg, 0.82 mmol, 1 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (414.5 mg, 1.6 mmol, 2 eq.) in dioxane (2 mL) was treated with KOAc (240.3 mg, 2.5 mmol, 3 eq.) at room temperature under nitrogen atmosphere for 2 min, followed by the addition of Pd(dppf)Cl2 (59.7 mg, 0.08 mmol, 0.1 eq.) at room temperature. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with dioxane (3 x 1 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo to afford intermediate 43 (238 mg, 99.8%) as a black oil. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 210.08 [M+H] + .

[0551] Intermediate 44-46

[0552]

[0553] Step 1: A solution of 1-(5-bromopyrimidin-2-yl)cyclobutane-1,3-diol (200 mg, 0.82 mmol, 1 eq) in DCM (5 mL) was treated with Dess-Martin (415.4 mg, 0.98 mmol, 1.20 eq) at 0°C under nitrogen for 10 min. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The mixture was heated to 40°C with saturated Na 2 SO 3 The reaction was quenched with DCM (3 x 10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give 3-(5-bromopyrimidin-2-yl)-3-hydroxycyclobutan-1-one (150 mg, 75.6%) as a yellow solid. LCMS (ESI, m / z): 243 [M+H] + .

[0554] Step 2: A solution of 3-(5-bromopyrimidin-2-yl)-3-hydroxycyclobutan-1-one (2.2 g, 9.1 mmol, 1 eq) in DMF (30 mL) was treated with imidazole (1.4 g, 19.9 mmol, 2.2 eq) at 0°C under nitrogen atmosphere, followed by the dropwise addition of TBSCl (3.0 g, 19.9 mmol, 2.2 eq) at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was heated to 40°C with saturated Na 2 SO 3 The reaction was quenched with DCM (3 x 10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give 3-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]cyclobutan-1-one (2 g, 61.8%) as a yellow oil. LCMS (ESI, m / z): 359.00 [M+H] + .

[0555] Step 3: In a 250 mL round-bottom flask, heat at -78 °C and N 2 To a solution of 3-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]cyclobutan-1-one (1.8 g, 5.0 mmol, 1 eq.) in THF (40 mL) was added methylmagnesium chloride (0.38 g, 5.0 mmol, 1 eq.) dropwise under atmosphere. The reaction mixture was stirred at -78 °C for 3 min. The mixture was stirred for another 4 h. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (4 mL) and the mixture was extracted with ether / EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL) and purified by anhydrous Na 2 SO 4 Dry and concentrate in vacuo to give the crude product, which was purified by preparative TLC (PE / EA 10:1) to give 3-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-1-methylcyclobutan-1-ol (1.7 g, 90.4%) as a yellow oil. LCMS (ESI, m / z): 375.10 [M+H] + .

[0556] Step 4: 3-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-1-methylcyclobutan-1-ol (1.7 g) was purified by preparative chiral HPLC under the following conditions (column: JW-CHIRAL ART Cellulose-SC, 20*250 mm, 5 um; mobile phase A: EtOH-HPLC, mobile phase B: Hex (0.5% 2M NH 3 -MeOH)--HPLC; flow rate: 45 mL / min; gradient: 70% B to 70% B in 11 min; wavelength: 220 / 254 nm; RT1 (min): 5.21; RT2 (min): 9.36; sample solvent: EtOH:DCM=1:1; injection volume: 2.0 mL; number of runs: 9) to give intermediate 44 (1s, 3s)-3-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-1-methylcyclobutan-1-ol (1.4 g, 82.4%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.05(s,2H),5.05(s,1H),3.03-2.92(m,2H),2.48-2.38(m,2H),0.89(s,3H),0.79(s,9H),0.19(s,6H).

[0557] Step 5: Intermediate 44 (100 mg, 0.4 mmol, 1 eq.), Pd(dppf)Cl 2 A solution of DCM (31.4 mg, 0.4 mmol, 0.1 eq.), KOAc (113.6 mg, 1.2 mmol, 3 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (196.0 mg, 0.8 mmol, 2 eq.) in dioxane (2 mL) was stirred at 80 °C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. TLC (DCM:MeOH=8:1, Rf=0.3). The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave intermediate 46 (80 mg, 92.53%) as a black solid. LCMS (ESI, m / z): 339.10 [M+H] + .

[0558] Intermediate 47

[0559]

[0560] Step 1: To a 20 mL vial, 5-bromo-2-iodopyridine (1 g, 3.5 mmol, 1 eq.) and (methylphosphoryl)methane (0.27 g, 3.5 mmol, 1 eq.) in dioxane (10 mL) were added at room temperature. To the above mixture, (methylphosphoryl)methane (0.27 g, 3.5 mmol, 1 eq.), TEA (1.07 g, 10.6 mmol, 3 eq.) were added in portions over 5 min at room temperature. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. The residue was purified by preparative TLC (DCM / MeOH=5:1) to give 5-bromo-2-(dimethylphosphoryl)pyridine (140 mg, 17%) as a white solid. LCMS (ESI-FA, m / z): 234 [M+H] + .

[0561] Step 2: At 100 °C under nitrogen atmosphere, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (173.6 mg, 0.68 mmol, 2.0 equiv), KOAc (100.64 mg, 1.03 mmol, 3.0 equiv), Pd(dppf)Cl 2 .5-bromo-2-(dimethylphosphoryl)pyridine (80 mg, 0.34 mmol, 1.0 equiv) in dioxane (1 mL) was treated with DCM (27.9 mg, 0.034 mmol, 0.10 equiv) for 2 h. The aqueous layer was extracted with EtOAc (3x10 mL). The residue was purified by silica gel column chromatography (eluted with PE / EA (5:1)) to give intermediate 47 (80 mg, 83.3%) as a white solid. The crude product was used directly in the next step without further purification.

[0562] Intermediates 48 and 49

[0563]

[0564] Step 1: To a stirred solution of 1-methyl-3-oxocyclobutane-1-carbonitrile (3.5 g, 32.07 mmol, 1 eq.) and (R)-2-methylpropane-2-sulfenamide (3.89 g, 32.07 mmol, 1 eq.) in THF (200 mL) was added Ti(OEt) dropwise at room temperature under nitrogen atmosphere.4 (13 mL, 32.07 mmol, 1 eq.) The resulting mixture was stirred at 75 °C under nitrogen overnight. The mixture was cooled to room temperature. H 2 The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with PE / EA (5:1)) to give (R)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (5.7 g, 83.7%) as an off-white solid. LCMS (ESI, m / z): 213.05 [M+H] + .

[0565] Step 2: A solution of 5-bromo-3-fluoro-2-iodopyridine (1.64 g, 5.42 mmol, 1.15 equiv) in DCM (250 mL) was treated with butyl lithium (328.86 mg, 5.13 mmol, 1.09 equiv) at -78 ° C under nitrogen atmosphere for 5 min. The resulting mixture was stirred at -78 ° C under nitrogen atmosphere for 2 min. (R)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (1 g, 4.71 mmol, 1 equiv) was added to the above mixture at -78 ° C for 2 min. The resulting mixture was stirred at -78 ° C for 2 h. The resulting mixture was stirred at 0 ° C under nitrogen atmosphere for 2 h. The desired product can be detected by LCMS. The reactants were quenched by adding saturated NH4Cl (aqueous solution) (125 mL) at 0 ° C. The resulting mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (2 x 10 mL) and purified by anhydrous Na 2 SO 4 Dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:2) to give intermediate 47 (trans): (R)-N-((1r, 3R)-1-(5-bromo-3-fluoropyridin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (200 mg, 10.9%) as a white solid and intermediate 48 (cis): (R)-N-((1s, 3S)-1-(5-bromo-3-fluoropyridin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (150 mg, 8.2%) as a white solid. LCMS (ESI, m / z): 388.05 [M+H] + .

[0566] Intermediate 48 (trans) (trans): 1H NMR (400 MHz, CHLOROFORM-d) δ 8.54-8.48 (m, 1H), 7.67-7.59 (m, 1H), 3.91 (s, 1H), 3.74 (d, J = 13.0 Hz, 1H), 3.35 (d, J = 12.8 Hz, 1H), 2.78-2.57 (m, 2H), 1.74 (d, J = 3.9 Hz, 3H), 1.20 (d, J = 2.4 Hz, 9H).

[0567] Intermediate 49 (cis): 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.46 (s, 1H), 7.63-7.56 (m, 1H), 4.04 (s, 1H), 3.15 (d, J = 13.1 Hz, 1H), 3.08-2.96 (m, 2H), 2.65 (d, J = 12.7 Hz, 1H), 1.59-1.49 (m, 3H), 1.44-1.12 (s, 9H).

[0568] Intermediates 50 and 51

[0569]

[0570] Step 1: A solution of 3-(benzyloxy)cyclobutan-1-one (10 g, 56.8 mmol, 1 eq) in THF (100 mL) was treated with MeMgBr (20.3 g, 170.3 mmol, 3 eq) at -78 °C under nitrogen for 15 min. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The mixture was heated at 0 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL) and washed with anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 50% to 100% gradient in 10 min; detector, UV 254 nm. This gave 3-(benzyloxy)-1-methylcyclobutan-1-ol (4 g, 36.7%) as a colorless oil. LCMS (ESI, m / z): 175.10 [M+H-OH]+. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.39-7.27 (m, 5H), 4.44 (s, 2H), 3.80-3.68 (m, 1H), 2.52-2.41 (m, 2H), 2.18-2.05 (m, 2H), 1.33 (t, J = 1.0 Hz, 3H).

[0571] Step 2: A solution of 3-(benzyloxy)-1-methylcyclobutan-1-ol (4 g, 20.8 mmol, 1 eq) in DCM (50 mL) was treated with imidazole (7.1 g, 104.0 mmol, 5 eq) at 0°C under nitrogen for 5 min, followed by the addition of TBSCl (9.4 g, 62.4 mmol, 3 eq) at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 5 h. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (40:1)) to give [3-(benzyloxy)-1-methylcyclobutyloxy](tert-butyl)dimethylsilane (5 g, 78.4%) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.42-7.28 (m, 5H), 4.44 (s, 2H), 3.75-3.64 (m, 1H), 2.41 (ddt, J = 11.8, 6.9, 2.5 Hz, 2H), 2.24-2.10 (m, 2H), 1.32 (t, J = 1.0 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 6H).

[0572] Step 3: Under nitrogen atmosphere, in a 250mL round-bottom flask, Pd / C (184.0mg, 1.7mmol, 0.1 equivalent) was added to a solution of [3-(benzyloxy)-1-methylcyclobutyloxy](tert-butyl)dimethylsilane (5.3g, 17.3mmol, 1 equivalent) in EtOH (60mL). The mixture was hydrogenated using a hydrogen balloon at room temperature under a nitrogen atmosphere for 1 day, filtered through a diatomaceous earth pad and concentrated under reduced pressure. The resulting mixture was filtered and the filter cake was washed with EtOH (60mL) (2x 10mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (9:1)) to obtain 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutane-1-ol (3.5g, 94.3%) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.99-3.88 (m, 1H), 2.53-2.41 (m, 2H), 2.13-2.01 (m, 2H), 1.86 (s, 1H), 1.30 (d, J=1.0 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 6H).

[0573] Step 4: A solution of 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-ol (2.5 g, 11.7 mmol, 1 eq) in DCM (26 mL) was treated with Dess-Martin reagent (6.0 g, 14.0 mmol, 1.2 eq) at 0°C under nitrogen for 10 min. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The mixture was heated to 40°C with saturated Na 2 SO 3 The reaction was quenched with DCM (3 x 10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-one (2 g, 79.8%) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.28-3.16 (m, 2H), 3.05-2.95 (m, 2H), 1.66-1.56 (m, 3H), 0.91 (s, 9H), 0.14 (s, 6H).

[0574] Step 5: A solution of 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-one (2.2 g, 10.4 mmol, 1 eq.) and (S)-2-methylpropane-2-sulfinamide (2.0 g, 16.6 mmol, 1.6 eq.) in THF (23 mL) was treated with Ti(Oi-Pr)4 (11.8 g, 41.6 mmol, 4 eq.) at room temperature for 10 min. The resulting mixture was stirred at 70 °C under nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ACN (23 mL). The reaction was quenched with water (10 mL) at 0 °C. The resulting mixture was filtered and the filter cake was washed with MeCN (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give (S)-N-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutylidene}-2-methylpropane-2-sulfenamide (2.46 g, 74.47%) as a yellow oil. 1 HNMR (400 MHz, CHLOROFORM-d) δ 3.63-3.47 (m, 1H), 3.41-3.17 (m, 2H), 3.09-2.99 (m, 1H), 1.52 (d, J = 7.4 Hz, 3H), 1.26 (d, J = 1.0 Hz, 9H), 0.90 (s, 9H), 0.12 (s, 6H).

[0575] Step 6: A solution of 5-bromo-3-fluoro-2-iodopyridine (1.9 g, 6.2 mmol, 1.1 eq.) in THF (50 mL) was treated with n-BuLi (435.7 mg, 6.8 mmol, 1.2 eq.) in hexane at -70 °C under nitrogen atmosphere for 30 min. To the above mixture was added (S)-N-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutylidene}-2-methylpropane-2-sulfenamide (1.8 g, 5.7 mmol, 1 eq.) at -66 °C over 10 min. The resulting mixture was stirred at -70 °C for 2 h. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (2:1)) to obtain:

[0576] Intermediate 50 (trans): (S)-N-((1r,3S)-1-(5-bromo-3-fluoropyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (560 mg, 20.02%) as a yellow oil. LCMS (ESI, m / z): 494.85 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.47-8.40 (m, 1H), 7.58-7.50 (m, 1H), 3.86 (s, 1H), 3.19 (d, J = 13.2 Hz, 1H), 2.76-2.52 (m, 3H), 1.58 (s, 3H), 1.18 (s, 9H), 0.79 (s, 9H), 0.04 (d, J = 7.2 Hz, 6H).

[0577] Intermediate 51 (cis): (S)-N-((1s,3R)-1-(5-bromo-3-fluoropyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (540 mg, 19.30%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.48-8.44 (m, 1H), 7.62-7.52 (m, 1H), 3.99-3.89 (m, 1H), 3.38-3.32 (m, 1H), 2.97-2.91 (m, 1H), 2.74 (d, J = 12.6 Hz, 1H), 2.56 (d, J = 12.7 Hz, 1H), 1.16 (s, 9H), 1.12 (s, 3H), 0.91 (s, 9H), 0.11 (s, 6H).

[0578] Intermediate 52

[0579]

[0580] Step 1: To an 8 mL vial at room temperature, 5-bromo-3-fluoro-2-iodopyridine (500 mg, 1.7 mmol, 1 eq.) and (methylphosphoryl)methane (193.9 mg, 2.5 mmol, 1.5 eq.) in dioxane (5 mL) were added. Pd(dppf)Cl2.DCM (134.9 mg, 0.17 mmol, 0.1 eq.), TEA (502.8 mg, 5.0 mmol, 3 eq.) were added dropwise to the above mixture at room temperature over 5 min. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered; the filter cake was washed with EtOAc (2 x 50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (10 mmol / L NH 4 HCO 3 ), gradient from 10% to 50% in 10 min; detector, UV 254 nm. This gave 5-bromo-2-(dimethylphosphoryl)-3-fluoropyridine (200 mg, 47.9%) as a yellow solid. LC-MS: (M+H) + :252.05.

[0581] Step 2: To an 8 mL vial at room temperature, 5-bromo-2-(dimethylphosphoryl)-3-fluoropyridine (200 mg, 0.8 mmol, 1 eq) and pinacol diboron (604.6 mg, 2.4 mmol, 3 eq) were added. Pd(dppf)Cl was added portionwise to the above mixture at room temperature. 2.DCM (64.6 mg, 0.08 mmol, 0.1 eq), KOAc (233.7 mg, 2.4 mmol, 3 eq) over 5 min. The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 1.5 h. The precipitated solid was collected by filtration and washed with MeOH (2 x 50 mL). The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave intermediate 52 (80 mg, 46.5%) as a reddish brown oil. LC-MS: (M+H)+: 218.10.

[0582] Intermediate 53

[0583]

[0584] Step 1: A solution of 3-oxetanones (15 g, 208.2 mmol, 1 eq.) and tert-butylsulfenamide (25.2 g, 208.2 mmol, 1.00 eq.) in THF (150 mL) was treated with tetrakis (propan-2-yloxy)titanium (88.7 g, 312.2 mmol, 1.5 eq.) at 0 ° C. under a nitrogen atmosphere for 5 min. The resulting mixture was stirred overnight at 70 ° C. under a nitrogen atmosphere. The reactants were quenched with water at 0 ° C. The resulting mixture was filtered and the filter cake was washed with EtOAc (5 x 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (2: 1)) to obtain 2-methyl-N-(oxacyclobutane-3-yl)propane-2-sulfenamide (15 g, 41.1% yield) as a yellow oil. LCMS (ESI, m / z): 176.07 [M+H] + .

[0585] Step 2: A solution of 5-bromo-2-iodopyrimidine (4.9 g, 17.3 mmol, 1.0 eq) in DCM (90 mL) was treated with n-butyllithium (2.5 M in n-hexane) (7.0 mL, 17.5 mmol, 1.0 eq) at -78 °C under nitrogen for 1 h, followed by the addition of 2-methyl-N-(oxetan-3-yl)propane-2-sulfenamide (3 g, 17.1 mmol, 1 eq) in DCM (10 mL) dropwise at -78 °C. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with DCM (2 x 20 mL) and washed with anhydrous Na 2 SO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give Intermediate 53 (1.5 g, 26.2%) as a yellow oil. LCMS (ESI, m / z): 334.01 [M+H] + .

[0586] Intermediate 54

[0587]

[0588] Step 1: A solution of 2-bromo-5-iodopyrazine (1 g, 3.5 mmol, 1 eq) in toluene (100 mL) was treated with 2.5 M n-BuLi (1.5 mL, 3.7 mmol, 1.05 eq) in hexanes at -78°C under nitrogen for 30 min, followed by the dropwise addition of 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-one (827.8 mg, 3.9 mmol, 1.1 eq) at -78°C. The resulting mixture was stirred at -78°C to 25°C under nitrogen overnight. The mixture was heated to 40°C with saturated NH 4 The reaction was quenched with Cl (aqueous solution, 50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and washed with anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 1-(5-bromopyrazin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-ol (930 mg, 71%) as a yellow oil. LCMS (ESI, m / z): 373.15 [M+H] + .

[0589] Step 2: 1-(5-bromopyrazin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-ol (900 mg) was separated by chiral HPLC under the following conditions (column: JW-CHIRALPAK IA 3.0*25 cm, 5 um; mobile phase A: IPA-HPLC, mobile phase B: Hex (0.5% 2M NH 3-MeOH)--HPLC; flow rate: 45 mL / min; gradient: 98% B to 98% B in 16 min; wavelength: 220 / 254 nm; RT1 (min): 9.06; RT2 (min): 12.21; sample solvent: IPA:Hex--HPLC; injection volume: 2.0 mL; number of runs: 6) to give intermediate 54 (300 mg, 33%) as a yellow oil. 1 HNMR (400 MHz, DMSO-d 6 )δ8.81(t,J=1.4Hz,1H),8.65(d,J=1.4Hz,1H),6.06(s,1H),2.88-2.80(m,2H),2.52-2.44(m,2H),1.24(s,3H),0.89(s,9H),0.10(s,6H).

[0590] Intermediate 55

[0591]

[0592] Step 1: A solution of 3-chloro-6-iodopyridazine (5 g, 20.8 mmol, 1 eq) in toluene (200 mL) was treated with 2.5 M n-BuLi (8.7 mL, 21.8 mmol, 1.05 eq) in hexanes at -78°C under nitrogen for 30 min, followed by the dropwise addition of 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-one (4.9 g, 22.9 mmol, 1.1 eq) at -78°C. The resulting mixture was stirred at -78°C to 25°C under nitrogen overnight. The mixture was heated to 40°C with saturated NH 4 The reaction was quenched with Cl (aqueous solution, 100 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL) and washed with anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 20% to 80% gradient in 10 min; detector, UV 254 nm. This gave intermediate 55 (290 mg, 4.0%) as a yellow oil. LCMS (ESI, m / z): 329.15 [M+H] + .

[0593] Intermediates 56-81 were prepared using similar procedures.

[0594]

[0595]

[0596]

[0597] Intermediates 82 and 83

[0598]

[0599] Step 1: To a mixture of 5-bromo-2-iodopyrimidine (2 g, 7.0 mmol, 1.0 eq.) in toluene (25 mL) was added n-BuLi (3.4 mL, 8.4 mmol, 1.2 eq.) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h. Dihydrofuran-3-one (2.42 g, 28.1 mmol, 4.0 eq.) was then added at -78 °C. The mixture was stirred at -78 °C for 1 h, then allowed to warm to room temperature and stirred for 1 h. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 40% gradient in 10 min; detector, UV 220 nm. This gave 3-(5-bromopyrimidin-2-yl)oxacyclopentane-3-ol (600 mg, 34.9%) as a brownish yellow solid. LCMS (ESI, m / z): 244.95 [M+H] + .

[0600] Step 2: 3-(5-bromopyrimidin-2-yl)oxolan-3-ol (260 mg) was further purified by preparative HPLC under the following conditions (column: JW-CHIRAL ART Cellulose-SC, 20*250 mm, 5 um; mobile phase A: IPA-HPLC, mobile phase B: Hex (0.5% 2MNH 3 -MeOH)-HPLC; Flow rate: 20 mL / min; Gradient: 85% B to 85% B in 18 min; Wavelength: 220 / 254 nm; RT1 (min): 13.51; RT2 (min): 17.32; Sample solvent: EtOH--HPLC; Injection volume: 0.2 mL; Number of runs: 15) to obtain Isomer 1 (125 mg, 48.1%) and Isomer 2 (120 mg, 46.2%) as off-white solids. LCMS (ESI, m / z): 244.95 [M+H] + .

[0601] Intermediate 84

[0602]

[0603] At room temperature, 5-bromo-2-iodopyrimidine (2.1 g, 7.5 mmol, 1.0 equivalent) and toluene (20 mL) were added to a 250 mL 3-neck round-bottom flask. At -78 ° C, n-BuLi (5.2 mL, 55.0 mmol, 7.3 equivalent) was added dropwise to the above mixture for 3 min. The resulting mixture was stirred for another 1 h at -78 ° C. Tetrahydro-pyran-4-one (3.0 g, 30.0 mmol, 4.0 equivalent) was added dropwise to the above mixture for 3 min. The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The reactant was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 x 500 mL). The combined organic layer was washed with brine (2 x 500 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% NH3.H2O) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 4-(5-bromopyrimidin-2-yl)oxacyclohexan-4-ol (500 mg, 25.7%) as a black solid. LCMS (ESI-FA, m / z): 259 [M+H] + .

[0604] Intermediate 85

[0605]

[0606] A solution of 5-bromo-2-iodopyrimidine (2.0 g, 7.0 mmol, 1.0 eq) in toluene (100 mL) was treated with n-BuLi (3.0 mL, 7.4 mmol, 1.1 eq) in hexanes at -78 °C under nitrogen for 30 min, followed by the dropwise addition of 3,3-difluorocyclobutan-1-one (819.1 mg, 7.7 mmol, 1.1 eq) at -78 °C. The resulting mixture was stirred at -78 to 25 °C under nitrogen for 1 h. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 100 mL) and washed with anhydrous Na 2 SO 4Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-ol (600 mg, 32.3%) as a brown solid. LCMS: (ESI, m / z): 266.95 [M+H] +

[0607] Intermediate 86

[0608]

[0609] To a solution of chloro(dimethylphosphoryl)methane (0.2 g, 1.6 mmol, 1.0 eq.) and 5-bromopyrimidin-2-ol (0.22 mg, 1.3 mmol, 0.8 eq.) in DMF (1 mL) was added K 2 CO 3 (0.66 g, 4.8 mmol, 3.0 equiv.). 2 The mixture was degassed 3 times. The reaction mixture was stirred at 100 ° C. under nitrogen atmosphere for 16 h. The reaction mixture was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, H2O in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 5-bromo-2-[(dimethylphosphoryl)methoxy]pyrimidine (100 mg, 23.9%) as a brown oil. LCMS (ESI, m / z): 266.90 [M+H] + .

[0610] Intermediate 87

[0611]

[0612] Step 1: At room temperature, 5-bromo-2-chloropyridine (3.0 g, 15.6 mmol, 1 equiv) and NaSH (1.3 g, 23.4 mmol, 1.5 equiv) were added to a 40 mL vial. The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 5 h. The reactant was quenched by adding water (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (2 x 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by grinding with MeOH (500 mL). The resulting mixture was concentrated in vacuo. This gave 5-bromopyridine-2-thiol (1 g) as a yellow solid. LCMS (ESI-FA, m / z): 190 [M+H] + .

[0613] Step 2: 5-Bromopyridine-2-thiol (1.0 g, 5.3 mmol, 1 eq.) and cyclopropylboronic acid (0.68 g, 7.9 mmol, 1.5 eq.) were added to a 40 mL vial at room temperature. Cu(OAc) was added to the above mixture in portions at room temperature. 2 (0.96 g, 5.3 mmol, 1 eq.), 2-(pyridin-2-yl)pyridine (0.82 g, 5.3 mmol, 1.0 eq.), Cs 2 CO 3 (1.7 g, 5.3 mmol, 1.0 equiv) for 10 min. The resulting mixture was stirred at 70 °C for another 5 h. At room temperature, water, NH 3 .H 2 The reaction was quenched with 1.5 mL of DCM (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 5-bromo-2-(cyclopropylsulfanyl)pyridine (500 mg) as a brown solid. LCMS (ESI, m / z): 230 [M+H] + .

[0614] Step 3: 5-Bromo-2-(cyclopropylsulfanyl)pyridine (500 mg, 2.2 mmol, 1.0 eq.) and ammonium carbamate (0.25 g, 3.3 mmol, 1.5 eq.), bis(acetoxy)iodobenzene (1.8 g, 5.5 mmol, 2.5 eq.) were added to a 40 mL vial at 20°C. The resulting mixture was stirred at 20°C under air atmosphere for 1 h. The resulting mixture was concentrated in vacuo. The residue was analyzed by preparative TLC (CH 2 Cl 2 / MeOH 5:1) to give (5-bromopyridin-2-yl)(cyclopropyl)imino-λ6-sulfanylketone (450 mg) as a white solid. LCMS (ESI, m / z): 261 [M+H] +

[0615] Intermediate 88

[0616]

[0617] In a 40 mL sealed tube at room temperature, 4-bromo-2-fluoro-1-iodobenzene (1.0 g, 3.3 mmol, 1.0 equiv), (methylphosphoryl)methane (0.3 g, 3.7 mmol, 1.1 equiv), Pd 2 (dba) 3 (0.15 g, 0.17 mmol, 0.05 eq), XantPhos (0.19 g, 0.33 mmol, 0.1 eq), Et 3 N (0.67 g, 6.65 mmol, 2.0 equiv) and dioxane (15 mL). The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN in water (0.1% TFA), 40% gradient in 10 min; detector, UV 254 nm. This gave 4-bromo-1-(dimethylphosphoryl)-2-fluorobenzene (600 mg, 71.9%) as a yellow solid. LCMS (ESI, m / z): 251.12 [M+H] + Intermediate 89

[0618]

[0619] A solution of chloro(dimethylphosphinoyl)methane (200 mg, 1.581 mmol, 1.00 eq.) and 4-bromopyridin-2-ol (220.04 mg, 1.265 mmol, 0.8 eq.) and K2CO3 (655.41 mg, 4.743 mmol, 3 eq.) in DMF (5 mL) was stirred at 100° C. under nitrogen atmosphere overnight. The resulting mixture was extracted with EtOAc (3×10 mL) and dried over anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 4-bromo-2-[(dimethylphosphoryl)methoxy]pyridine (38 mg, 9.10%) as a light yellow oil. LCMS (ESI, m / z): 263.95 [M+H] + .

[0620] Intermediate 90

[0621]

[0622] A solution of 5-bromo-2-iodopyrimidine (5.0 g, 17.6 mmol, 1.0 equiv) in toluene (100 mL) was treated with n-BuLi (2.3 g, 35.1 mmol, 2.0 equiv) in hexane at -78 °C under nitrogen for 3 min, followed by the dropwise addition of cyclobutanone (4.9 g, 70.2 mmol, 4.0 equiv) at -78 °C. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The mixture was purified by adding saturated NH 4 The reaction was quenched with Cl(aqueous solution) (300 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (8:1)) to give 1-(5-bromopyrimidin-2-yl)cyclobutane-1-ol (1.1 g, 64% purity) as an off-white solid. LCMS (ESI, m / z): 229.05 [M+H] +

[0623] Intermediate 91

[0624]

[0625] A solution of 5-bromo-2-iodopyrimidine (2.0 g, 7.0 mmol, 1.0 equiv) in toluene (100 mL) was treated with butyl lithium (3.0 mL, 7.7 mmol, 1.1 equiv) at -78 °C under nitrogen for 10 min. To the above mixture was added 4,4-difluorocyclohexan-1-one (4.0 g, 27.7 mmol, 4.0 equiv) in toluene (10 mL) at -78 °C over 5 min. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The mixture was purified by adding saturated NH 4 The reaction was quenched with Cl(aq) (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (3:1)) to give 1-(5-bromopyrimidin-2-yl)-4,4-difluorocyclohexan-1-ol (1.8 g, 87.5%) as a yellow solid. LCMS (ESI, m / z): 295.00 [M+H] + .

[0626] Intermediates 92 and 93

[0627]

[0628] Step 1: A solution of 5-bromo-2-iodopyrimidine (11.0 g, 38.6 mmol, 1.0 equiv) in DCM (250 mL) was treated with butyllithium (30.9 mL, 77.2 mmol, 2.0 equiv) at -78 °C under nitrogen for 5 minutes, followed by the dropwise addition of 1,1-difluoropropan-2-one (10.9 g, 115.8 mmol, 3.0 equiv) at -78 °C. The resulting mixture was stirred at 25 °C under nitrogen for 1 h. The reaction was quenched by the addition of water (200 mL) at 0 °C. The resulting mixture was extracted with DCM (3 x 80 mL). The combined organic layers were purified by anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give 2-(5-bromopyrimidin-2-yl)-1,1-difluoropropan-2-ol (4.0 g, 40.9%) as a yellow oil. LCMS (ESI, m / z): 252.95 [M+H] + .

[0629] Step 2: 2-(5-bromopyrimidin-2-yl)-1,1-difluoropropan-2-ol (4.0 g) was further purified by preparative HPLC under the following conditions (column: CHIRALPAKIG3; mobile phase A: Hex (0.1% FA): (EtOH: MeOH = 1: 1) = 90: 10; flow rate: 1 mL / min; gradient: isocratic; injection volume: 0.2 mL) to give Isomer 1 (1.4 g) and Isomer 2 (1.0 g) as yellow oils.

[0630] Intermediates 94 and 95

[0631]

[0632] Step 1: ACN (204.2 mg, 5.0 mmol, 1.0 eq.), n-BuLi (318.7 mg, 5.0 mmol, 1.0 eq.) and THF (10 mL) were added to a 10 mL 2-necked round bottom flask at -78°C. The resulting mixture was stirred at -78°C under nitrogen atmosphere for 30 min. 1-(5-bromopyrimidin-2-yl)ethanone (1.0 g, 5.0 mmol, 1.0 eq.) and THF (10 mL) were added dropwise to the above mixture at -78°C. The resulting mixture was stirred for another 30 min at -78°C. The mixture was heated at room temperature with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL) and washed with anhydrous Na 2 SO 4The residue was purified by silica gel column chromatography (eluted with PE / EA (2:1)) to give 3-(5-bromopyrimidin-2-yl)-3-hydroxybutyronitrile (35 mg, 2.9%) as a white solid. LCMS (ESI, m / z): 201.10 [M+H] + .

[0633] Step 2: 3-(5-bromopyrimidin-2-yl)-3-hydroxybutyronitrile (200 mg) was further purified by reverse phase flash chromatography under the following conditions: column: JW-CHIRALPAK IG, 20*250 mm, 5 um; mobile phase A: EtOH--HPLC, mobile phase B: Hex (0.5% 2M NH3-MeOH)--HPLC; flow rate: 20 mL / min; gradient: 70% B to 70% B in 18.5 min; wavelength: 220 / 254 nm; RT1 (min): 13.31; RT2 (min): 15.49; sample solvent: EtOH:DCM=1:1--HPLC; injection volume: 0.3 mL; number of runs: 14; detector UV 254 nm. This gave isomer 1 (60 mg) and isomer 2 (64 mg) as white solids.

[0634] Intermediate 96

[0635]

[0636] A solution of 5-bromo-2-iodopyrimidine (1.0 g, 3.5 mmol, 1.0 eq) in toluene (10 mL) was treated with n-BuLi (3 mL, 7.5 mmol, 2.1 eq) in hexane at -78 °C under nitrogen atmosphere for 0.5 h, followed by the dropwise addition of 3-oxetanone (0.45 mL, 1.1 eq) at -78 °C. The resulting mixture was stirred at -78 °C for another 30 min. The resulting mixture was stirred at room temperature for another 1 h. The mixture was purified by adding saturated NH 4 The reaction was quenched with Cl(aq) (5 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% FA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 3-(5-bromopyrimidin-2-yl)oxetan-3-ol (800 mg, 98.6%) as a yellow solid. LCMS (ESI, m / z): 230.90 [M+H]+

[0637] Intermediate 97

[0638]

[0639] Step 1: A solution of 5-bromo-2-iodopyrimidine (10 g, 35.1 mmol, 1.0 equiv) in toluene (6.7 mL) was treated with n-butyllithium (1 M in THF, 17 mL, 42.5 mmol, 1.2 equiv) at -78 °C under nitrogen for 10 min, followed by the dropwise addition of ethyl 2,2-difluoroacetate (10.9 g, 87.8 mmol, 2.5 equiv) at -78 °C. The resulting mixture was stirred at -78 °C under nitrogen for 30 min. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl(aq). 2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL) and purified by anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give 1-(5-bromopyrimidin-2-yl)-2,2-difluoroethanone (3.5 g, 41.6%) as a yellow oil. LCMS (ESI, m / z): 237 [M+H] + .

[0640] Step 2: To a stirred solution of 1-(5-bromopyrimidin-2-yl)-2,2-difluoroethanone (3.6 g, 15.2 mmol, 1.0 eq) and cyanoacetic acid (2.6 g, 30.4 mmol, 2.0 eq) in THF (72 mL) was added TEA (0.3 g, 3.0 mmol, 0.2 eq) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 6 h. The mixture was treated with CH 2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL) and purified by anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (eluted with PE / EA (3:1)) to give 3-(5-bromopyrimidin-2-yl)-4,4-difluoro-3-hydroxybutyronitrile (4 g, 94.5%) as a white solid. LCMS (ESI, m / z): 278 [M+H] + .

[0641] Intermediates 98 and 99

[0642]

[0643] Step 1: A solution of 5-bromo-2-iodopyrimidine (48.0 mL, 120.1 mmol, 1.0 equiv) in THF (450 mL) was treated with n-BuLi (75.8 mL, 121.3 mmol, 1.0 equiv) in hexanes at -78°C under nitrogen for 0.5 h, followed by the dropwise addition of cyclopropylmethyl ketone (10 g, 118.9 mmol, 1.0 equiv) at -78°C. The resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was purified by adding saturated NH 4 The reaction was quenched with Cl(aq) (200 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL) and washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography (eluted with PE / EA (3:1)) to give 1-(5-bromopyrimidin-2-yl)-1-cyclopropylethanol (6.5 g, 22.0%) as a yellow oil. LCMS (ESI, m / z): 243.01 [M+H] + .

[0644] Step 2: 1-(5-bromopyrimidin-2-yl)-1-cyclopropylethanol (5.5 g) was further purified by preparative chiral HPLC under the following conditions (column: DAICELDC pakP4VP 4.6*50 mm, 3 μm; mobile phase B: ACN:MeOH=80:20 (1% 2M NH 3 ); Gradient: isocratic % B) to give Isomer 1 and Isomer 2 as yellow solids. LCMS (ESI, m / z): 243.01 [M+H] + .

[0645] Intermediate 100 and 101

[0646]

[0647] Step 1: A solution of 5-bromo-2-iodopyrimidine (8.0 g, 29.4 mmol, 1.0 equiv) in DCM (150 mL) was treated with butyl lithium (12.0 mL, 29.4 mmol, 1.0 equiv) at -78 °C under nitrogen for 10 min, followed by the dropwise addition of 2,2-dimethylpropionic acid 3-oxocyclobutyl ester (5.0 g, 29.4 mmol, 1.0 equiv) at -78 °C. The resulting mixture was stirred at -78 °C under nitrogen for 30 min. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl(aq).2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 200 mL). The combined organic layers were washed with brine (1 x 100 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (3:1)) to give 3-(5-bromopyrimidin-2-yl)-3-hydroxycyclobutyl 2,2-dimethylpropanoate (3.9 g, 40.3%) as a light yellow solid. LCMS (ESI, m / z): 329.00 [M+H] + .

[0648] Step 2: At room temperature and under nitrogen atmosphere, use K 2 CO 3 A solution of 3-(5-bromopyrimidin-2-yl)-3-hydroxycyclobutyl 2,2-dimethylpropanoate (2.0 g, 5.5 mmol, 1.0 equiv) in MeOH (20 mL) was treated with 4-(5-bromopyrimidin-2-yl)-3-hydroxycyclobutyl (1.0 g, 5.5 mmol, 1.0 equiv). The resulting mixture was stirred at 75 ° C under nitrogen atmosphere for 30 min. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: ACN (0.1% TFA) in water, 10% to 30% gradient in 10 min; detector, UV 254 nm. This gave 1-(5-bromopyrimidin-2-yl)cyclobutane-1,3-diol (900 mg, 67.2%) as a light yellow solid. LCMS (ESI, m / z): 246.95 [M+H] + .

[0649] Step 3: 1-(5-bromopyrimidin-2-yl)cyclobutane-1,3-diol (2.0 g) was purified by preparative HPLC under the following conditions (column: GreenSep Basic 3*15 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: ACN: MeOH = 4: 1 (1% -2M-NH3-MeOH); flow rate: 75mL / min; gradient: isocratic 24% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220nm; RT1 (min): 2.88; RT2 (min): 3.82; sample solvent: MeOH; injection volume: 2mL) to obtain (1s, 3s) -1- (5-bromopyrimidin-2-yl) cyclobutane-1,3-diol (1.2g, 60.00%) as a white solid. LCMS (ESI, m / z): 246.95 [M + H] + . 1H NMR (400 MHz, DMSO-d 6 )δ8.99(d,J=1.3Hz,2H),5.65(d,J=1.0Hz,1H),5.10(d,J=6.3Hz,1H),4.08-3.92(m,1H),2.87-2.82(m,2H),2.25-2.20(m,2H).

[0650] Intermediates 102 and 103

[0651]

[0652] Step 1: Use Pd(dppf)Cl 2 .CH 2 Cl 2 (1.4 g, 1.8 mmol, 0.1 eq), Cs 2 CO 3 5-Bromo-2-iodopyrimidine (5.0 g, 17.6 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.2 g, 19.3 mmol, 1.1 equiv) were treated with dioxane (15 mL) and H 2 O (6mL). The resulting mixture was stirred at 80 ° C under nitrogen atmosphere for 12 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE: EA = 50: 1) to give 5-bromo-2-(prop-1-en-2-yl)pyrimidine (2.0 g, 57.3%) as a white solid. LCMS (ESI, m / z): 198.95 [M + H] + .

[0653] Step 2: To a stirred solution of 5-bromo-2-(prop-1-en-2-yl)pyrimidine (2.0 g, 10.0 mmol, 1.0 eq.) and NMO (1.3 g, 11.1 mmol, 1.1 eq.) in propan-2-one (6 mL), H 2 K was added to a mixture of O (2.8 mL, 38.9 mmol) and t-BuOH (2.8 mL, 20.1 mmol, 2.0 equiv). 2 O 4 .2H 2 O (0.04 g, 0.1 mmol, 0.01 equiv.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 10 mL) and washed with anhydrous Na 2 SO 4The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give 2-(5-bromopyrimidin-2-yl)propane-1,2-diol (300 mg, 12.8%) as a yellow solid. LCMS (ESI, m / z): 232.75 [M+H] + .

[0654] Step 3: 2-(5-bromopyrimidin-2-yl)propane-1,2-diol (1.3 g) was further purified by preparative chiral HPLC under the following conditions (column: CHIRALCELOD3; mobile phase A: Hex (0.1% FA): EtOH = 92:8; flow rate: 1 mL / min; gradient: isocratic; injection volume: 2 mL) to give Isomer 1 (540 mg) and Isomer 2 (500 mg) as yellow solids.

[0655] Intermediates 104 and 105

[0656]

[0657] Step 1: To a mixture of 5-bromo-2-iodopyrimidine (5.0 g, 17.6 mmol, 1.0 eq.) in THF (60 mL) was added n-butyllithium (2.5 M in n-hexane) (8.5 mL, 21.1 mmol, 1.2 eq.) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h. Oxetane-3-carbaldehyde (2.0 g, 22.8 mmol, 1.3 eq.) was then added at -78 °C. The mixture was stirred at -78 °C for 1 h, then allowed to warm to room temperature and stirred for 1 h. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3x300 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (10 mmol / L NH 4 HCO 3 ), 20% to 40% gradient in 10 min; detector, UV 220 nm. This gave (5-bromopyrimidin-2-yl)(oxetan-3-yl)methanol (720 mg) as a brownish yellow solid. LCMS (ESI, m / z): 244.95 [M+H] + .

[0658] Step 2: To a mixture of (5-bromopyrimidin-2-yl)(oxetan-3-yl)methanol (720 mg, 2.9 mmol, 1.0 eq.) in DCM (15 mL) was added chlorochromiumoylol (1.3 g, 5.9 mmol, 2.0 eq.) at 0 °C. The mixture was warmed to room temperature and stirred overnight. The resulting mixture was filtered and the filter cake was washed with DCM (15 mL) (3 x 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 20: 1) to give 5-bromo-2-(oxetane-3-carbonyl)pyrimidine (352 mg) as a colorless oil. LCMS (ESI, m / z): 243.05 [M+H] + .

[0659] Step 3: To a mixture of 5-bromo-2-(oxetane-3-carbonyl)pyrimidine (300 mg, 1.2 mmol, 1.0 eq.) in THF (6 mL) was added methylmagnesium bromide (1.0 M in THF) (147.2 mg, 1.2 mmol, 1.0 eq.) dropwise at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 1 h. The mixture was heated at 0°C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by preparative TLC (CH 2 Cl 2 / MeOH 20: 1) to give 1-(5-bromopyrimidin-2-yl)-1-(oxetan-3-yl)ethanol (170 mg) as a colorless solid. LCMS (ESI, m / z): 258.95 [M+H] + .

[0660] Step 4: 1-(5-bromopyrimidin-2-yl)-1-(oxetan-3-yl)ethanol (170 mg) was purified by preparative HPLC under the following conditions (column: JW-CHIRALPAK IG, 20*250 mm, 5 um; mobile phase A: EtOH:DCM=1:1--HPLC, mobile phase B: Hex (0.5% 2M NH 3-MeOH)--HPLC; flow rate: 20 mL / min; gradient: 40% B to 40% B in 13 min; wavelength: 220 / 254 nm; RT1 (min): 3.96; RT2 (min): 9.79; sample solvent: EtOH:DCM=1:1--HPLC; injection volume: 1.5 mL; number of runs: 4) to obtain isomer 1 (55 mg) and isomer 2 (57 mg) as colorless solids. LCMS (ESI, m / z): 259.00 [M+H] + .

[0661] Intermediate 106

[0662]

[0663] Step 1: To a 40 mL vial was added 2-bromo-5-chloropyrazine (1.0 g, 5.2 mmol, 1.0 eq) and (methylphosphoryl)methane (0.48 g, 6.2 mmol, 1.2 eq) in 1,4-dioxane (10 mL) at room temperature. Pd(OAc) was added portionwise to the above mixture at room temperature. 2 (0.12 g, 0.52 mmol, 0.1 eq.), XantPhos (0.6 g, 1.0 mmol, 0.2 eq.), DIEA (2.0 g, 15.5 mmol, 3.0 eq.) over 10 min. The resulting mixture was stirred at 100 °C for another 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm, to give 2-chloro-5-(dimethylphosphoryl)pyrazine (300 mg) as a white solid. LCMS (ESI-FA, m / z): 235 [M+H] + .

[0664] Step 2: To an 8 mL vial was added 2-chloro-5-(dimethylphosphoryl)pyrazine (300 mg, 1.6 mmol, 1.0 equiv) in 1,4-dioxane (2 mL) at room temperature. Pd(PPh 3 ) 2 Cl 2The resulting mixture was stirred at 100 ° C for 2 h. The precipitated solid was collected by filtration and washed with MeOH (2 x 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was analyzed by preparative TLC (CH 2 Cl 2 / MeOH 12:1) to give 2-(dimethylphosphoryl)-5-(tributylstannyl)pyrazine (180 mg) as a black oil. LCMS (ESI, m / z): 447 [M+H] + .

[0665] Intermediate 107

[0666]

[0667] A solution of (S)-2-methyl-N-[(1r,3s)-1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl]propane-2-sulfinamide (100 mg, 0.26 mmol, 1.00 equiv) in HCl (6N, 1 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) to give (1s,3r)-3-amino-3-(5-bromopyrimidin-2-yl)-1-methylcyclobutane-1-carboxylic acid (20 mg, 25.95% yield, 90% purity) as a colorless oil. LCMS (ESI, m / z): 285.85 [M+H] + .

[0668] Intermediates 108 and 109

[0669]

[0670] Step 1: A solution of 3-(benzyloxy)cyclobutan-1-one (20 g, 113.5 mmol, 1.0 equiv) in THF (350 mL) was treated with HMPA (101.7 g, 567.5 mmol, 5.0 equiv), CsF (5.2 g, 34.1 mmol, 0.3 equiv) at room temperature for 5 min, followed by dropwise addition of (difluoromethyl)trimethylsilane (42.3 g, 340.5 mmol, 3.0 equiv) at room temperature. TBAF (200 mL) was added dropwise to the above mixture at room temperature for 5 min. The resulting mixture was stirred at room temperature for another overnight. The mixture was acidified to pH 6 with citric acid. The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (1 x 800 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give [3-(benzyloxy)-1-(difluoromethyl)cyclobutyloxy]trimethylsilane (2.2 g, 90%) as a light yellow oil.

[0671] Step 2: A solution of 3-(benzyloxy)-1-(difluoromethyl)cyclobutan-1-ol (2.2 g, 9.6 mmol, 1.0 equiv) in DMF (20 mL) was treated with imidazole (2.2 g, 31.8 mmol, 3.3 equiv), tert-butyl(chloro)dimethylsilane*4.8 g, 31.8 mmol, 3.3 equiv) at room temperature for 1 min, followed by the addition of DMAP (0.12 g, 0.96 mmol, 0.1 equiv) dropwise at room temperature. The resulting mixture was stirred at 80° C. overnight. The residue was purified by reverse phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 15 min; detector, UV 254 nm) to give [3-(benzyloxy)-1-(difluoromethyl)cyclobutoxy](tert-butyl)dimethylsilane (2.1 g, 90% purity) as a light yellow oil.

[0672] Step 3: Under nitrogen atmosphere, in a 50 mL vial, Pd / C (1242.9 mg, 11.7 mmol, 2 eq.) was added to a solution of [3-(benzyloxy)-1-(difluoromethyl)cyclobutoxy](tert-butyl)dimethylsilane (2 g, 5.8 mmol, 1.0 eq.) in AcOH (15 mL). The mixture was hydrogenated at 50 ° C. under nitrogen atmosphere using a hydrogen balloon for 1 h, filtered through a celite pad and concentrated under reduced pressure. This gave 3-[(tert-butyldimethylsilyl)oxy]-3-(difluoromethyl)cyclobutan-1-ol (1.3 g) as an off-white oil.

[0673] Step 4: To a solution of 3-[(tert-butyldimethylsilyl)oxy]-3-(difluoromethyl)cyclobutan-1-ol (1.4 g, 5.5 mmol, 1.0 equiv) in DCM (30 mL) was added 1,1,1-tri(acetoxy)-1,1-dihydro-1,2-benzidoyl-3-(1H)-one (3.5 g, 8.3 mmol, 1.5 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for another 2 h. The reaction was monitored by TLC. The residue was purified by silica gel column chromatography (eluted with PE / EA (20:1)) to give 3-[(tert-butyldimethylsilyl)oxy]-3-(difluoromethyl)cyclobutan-1-one (1.2 g) as an off-white oil. LCMS (ESI, m / z): 251.1 [M+H] + .

[0674] Step 5: In a 500 mL round-bottom flask, heat the mixture at -78 °C and N 2 Under atmosphere, butyl lithium (1.6 M in n-hexane) (337.8 mg, 5.3 mmol, 1.1 eq.) was added dropwise to a solution of 5-bromo-2-iodopyrimidine (1.5 g, 5.3 mmol, 1.1 eq.) in toluene (35 mL). The reaction mixture was stirred at -78 °C for 30 min. A solution of 3-[(tert-butyldimethylsilyl)oxy]-3-(difluoromethyl)cyclobutan-1-one (1.2 g, 4.8 mmol, 1.0 eq.) in toluene (35 mL) was then added dropwise, and the mixture was stirred for another 2 h. The mixture was washed with water / saturated NH 4 The reaction was quenched with Cl (30 mL), and the mixture was extracted with EA (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to give the crude product, which was directly purified by reverse phase flash chromatography under the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.56) to give 1-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-3-(difluoromethyl)cyclobutan-1-ol (1.0 g) as an off-white solid.

[0675] Step 6: 1-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-3-(difluoromethyl)cyclobutan-1-ol was further purified by reverse phase flash chromatography under the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.56) to give (1s, 3s)-1-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-3-(difluoromethyl)cyclobutan-1-ol (250 mg, 95% purity) as an off-white solid.

[0676] Intermediate 110

[0677]

[0678] Step 1: Under nitrogen atmosphere, NaSH (4.4 g, 77.5 mmol, 1.5 equiv) was added to a stirred solution of 5-bromo-2-chloropyrimidine (10.0 g, 51.7 mmol, 1.0 equiv) in DMF (100 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was distributed between ethyl acetate and water and transferred to a separatory funnel. After separation of each layer, the ethyl acetate layer was washed twice with water and 5% sodium bicarbonate (2: 1). The combined water layer was acidified with 1N HCl to precipitate a yellow solid. The suspension was allowed to stand at room temperature for 2 h, and the precipitate was then collected by vacuum filtration to obtain 5-bromopyrimidine-2-thiol (11.0 g) as a yellow solid. The crude product was used directly in the next step without further purification.

[0679] Step 2: To a solution of 5-bromopyrimidine-2-thiol (5.0 g, 25.9 mmol, 1.0 eq.) in 1,2-dichloroethane (100 mL) were added cyclopropylboronic acid (3.6 g, 41.5 mmol, 1.6 eq.), Cu(OAc) 2 (4.7 g, 25.9 mmol, 1.0 equiv), 2-(pyridin-2-yl)pyridine (4.1 g, 25.9 mmol, 1.0 equiv). The reaction mixture was stirred at 70 °C for 12 h. At room temperature, water, NH 3 .H 2 The reaction was quenched with CH 2 Cl 2The resulting mixture was extracted with 4% paraformaldehyde (4:1) / MeOH (10:1) (4 x 1000 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, water in ACN, 50% to 80% gradient in 10 min; detector, UV 254 nm) to give 5-bromo-2-(cyclopropylsulfanyl)pyrimidine (1.6 g) as a light yellow oil. LCMS (ESI, m / z): 231 [M+H] + .

[0680] Step 3: A mixture of 5-bromo-2-(cyclopropylsulfanyl)pyrimidine (1.65 g, 7.1 mmol, 1.0 equiv) and (diacetoxyiodo)benzene (11.5 g, 35.7 mmol, 5.0 equiv) and ammonium carbamate (1.67 g, 21.4 mmol, 3.0 equiv) in MeOH (100 mL) was stirred at room temperature for 7 h. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 30: 1) to give (5-bromopyrimidin-2-yl)(cyclopropyl)imino-λ6-sulfanylketone (888 mg) as a light yellow solid. LCMS (ESI, m / z): 262.00 [M+H] + .

[0681] Intermediate 111

[0682]

[0683] Step 1: A solution of 5-bromo-2-iodopyrimidine (12.0 g, 42.1 mmol, 1.0 eq) in toluene (800 mL) was treated with n-BuLi (17.7 mL, 44.2 mmol, 1.1 eq) in hexane at -78 °C under nitrogen atmosphere for 30 min, followed by the dropwise addition of 3,3-difluorocyclobutan-1-one (4.9 g, 46.3 mmol, 1.1 eq) at -78 °C. The resulting mixture was stirred at -78 to 25 °C under nitrogen atmosphere for 1 h. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The aqueous layer was extracted with EtOAc (3x800 mL) and washed with anhydrous Na 2 SO 4The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This gave 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-ol (4.6 g) as a brown solid. LCMS (ESI, m / z): 266.95 [M+H] + .

[0684] Step 2: To a stirred solution of 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-ol (542 mg, 2.0 mmol, 1.0 equiv) in DCM (7 mL) at 0 °C under air atmosphere was added Et 3 N (0.6 mL, 4.1 mmol, 2.0 eq.) and TBDMSCl (580.7 mg, 2.7 mmol, 1.3 eq., 69%). The resulting mixture was stirred at room temperature under air atmosphere for 1 h. At 0 °C, saturated NaHCO 3 The reaction was quenched with EtOAc (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 2:1) to give methanesulfonic acid 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutyl ester (500 mg, 71.3%) as a light yellow solid. LCMS (ESI, m / z): 338.30 [M+H] + .

[0685] Step 3: To a stirred solution of 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutyl methanesulfonate (536 mg, 1.6 mmol, 1.0 eq.) in DMSO (7 mL) was added NaN 3 (1.1 g, 7.8 mmol, 5.0 equiv., 45%). The resulting mixture was stirred at 70 °C under air atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. This gave 2-(1-azido-3,3-difluorocyclobutyl)-5-bromopyrimidine (420 mg, 92.7% yield, 70% purity) as a light yellow oil.

[0686] Step 4: To a stirred solution of 2-(1-azido-3,3-difluorocyclobutyl)-5-bromopyrimidine (60 mg, 0.2 mmol, 1.0 equiv) in THF (2.4 mL) was added H 2 O (0.6 mL) and trimethylphosphine (1.0 M in THF) (0.31 mL, 0.3 mmol, 1.5 eq.). The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutane-1-amine (16 mg, 29.3%) as an off-white solid.

[0687] Step 5: A solution of 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutane-1-amine (50 mg, 0.18 mmol, 1.0 eq.) and di-tert-butyl dicarbonate (62 mg, 0.28 mmol, 1.5 eq.) in THF (2 mL) was stirred at 80 °C under nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3 x 5 mL) and dried over anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give tert-butyl N-[1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutyl]carbamate (50 mg) as a light yellow solid. LCMS (ESI, m / z): 366.05 [M+H] + .

[0688] Intermediates 112 and 113

[0689]

[0690] Step 1: A solution of cyclopropanecarboxaldehyde (10 g, 142.7 mmol, 1.0 equiv) and tert-butylsulfenamide (17.3 g, 142.7 mmol, .01 equiv) in THF (200 mL) was stirred with Ti(Oi-Pr)4 (106.7 mL, 356.7 mmol, 2.5 equiv) at 60 ° C under nitrogen atmosphere overnight. The resulting mixture was concentrated in vacuo. The residue was dissolved in EtOAc (60 mL). The reactants were quenched by adding sodium bicarbonate solution (aqueous solution) (30 mL) at 0 ° C. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x 20 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2x 80 mL). The combined organic layers were purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give N-[(1Z)-cyclopropylmethylene]-2-methylpropane-2-sulfenamide (15 g, 60.7%) as a light yellow liquid. LCMS (ESI, m / z): 174.1 [M+H] + .

[0691] Step 2: A solution of 5-bromo-2-iodopyrimidine (21.4 g, 75.0 mmol, 1.3 eq.) in DCM (380 mL) was treated with butyl lithium (1.6 M in n-hexane) (43.3 mL, 69.3 mmol, 1.2 eq.) at -78 °C under nitrogen atmosphere for 30 min, followed by the dropwise addition of N-[(1Z)-cyclopropylmethylene]-2-methylpropane-2-sulfenamide (10 g, 57.7 mmol, 1.0 eq.) at -78 °C. The resulting mixture was stirred at 25 °C for another 2 h. The mixture was heated to 40 °C with NH 4 The reaction was quenched with Cl. The resulting mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1 / 1)) to give N-[(5-bromopyrimidin-2-yl)(cyclopropyl)methyl]-2-methylpropane-2-sulfinamide (4.5 g, 23.4%) as a yellow oil. LCMS (ESI, m / z): 332.05 [M+H] + .

[0692] Intermediates 114 and 115

[0693]

[0694] Step 1: Methylmagnesium chloride (170.3 mL, 510.7 mmol, 1.5 eq) was added dropwise to a solution of 3-(benzyloxy)cyclobutan-1-one (60 g, 340.5 mmol, 1.0 eq) in THF (600 mL) at -78°C. The mixture was stirred at -78°C for 1 h. Then, NH 4 The reaction was quenched with aqueous Cl solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine and purified by Na 2 SO 4 The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. This gave 3-(benzyloxy)-1-methylcyclobutan-1-ol (85 g) as a yellow oil. LCMS (ESI, m / z): 192.50 [M+H] + .

[0695] Step 2: A solution of 3-(benzyloxy)-1-methylcyclobutan-1-ol (93 g, 483.7 mmol, 1.0 equiv) in DCM (1000 mL) was treated with imidazole (164.7 g, 2418.6 mmol, 5.0 equiv) at 0°C under nitrogen for 5 min, followed by the addition of TBSCl (218.7 g, 1451.2 mmol, 3.0 equiv) at 40°C. The resulting mixture was stirred at room temperature under nitrogen for 1 h. The mixture was stirred with CH 2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (40:1)) to give [3-(benzyloxy)-1-methylcyclobutyloxy](tert-butyl)dimethylsilane (100 g) as a yellow oil. LCMS (ESI, m / z): 307.10 [M+H] + .

[0696] Step 3: Under nitrogen atmosphere, in a 2L round-bottom flask, Pd / C (19.5 g, 18.3 mmol, 0.1 eq., 10%) was added to a solution of [3-(benzyloxy)-1-methylcyclobutyloxy](tert-butyl)dimethylsilane (56 g, 182.7 mmol, 1.0 eq.) in MeOH (1000 mL). The mixture was hydrogenated using a hydrogen balloon at room temperature under nitrogen atmosphere overnight, filtered through a celite pad and concentrated under reduced pressure. The resulting mixture was filtered and the filter cake was washed with MeOH (500 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 217.10 [M+H] + .

[0697] Step 4: To a stirred solution of 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-ol (29.6 g, 136.8 mmol, 1.0 equiv) in DCM (300 mL) was added 1,1-bis(acetyloxy)-3-oxo-3H-1^[5],2-benzidoyl-1-ester (87.0 g, 205.2 mmol, 1.5 equiv) dropwise at 0°C under air atmosphere. The resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched with saturated sodium thiosulfate (aqueous solution) at 0°C. The mixture was stirred with CH 2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 20 mL). The combined organic layers were washed with water (3 x 20 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (40:1)) to give 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-one (25 g) as a yellow oil. LCMS (ESI, m / z): 215.10 [M+H] + .

[0698] Step 5: A solution of 5-bromo-2-iodo-4-methylpyrimidine (2 g, 6.7 mmol, 1.0 eq) in toluene (200 mL) was treated with n-BuLi (2.8 mL, 7.0 mmol, 1.05 eq) in hexanes at -78°C under nitrogen for 30 min, followed by the dropwise addition of 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-one (1.6 g, 74 mmol, 1.1 eq) at -78°C. The resulting mixture was stirred at -78 to 25°C under nitrogen overnight. The mixture was heated to 40°C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 100 mL) and washed with anhydrous Na 2 SO4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 1-(5-bromo-4-methylpyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-ol (380 mg, 14.7%) as a yellow oil.

[0699] Step 6: 1-(5-bromo-4-methylpyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-ol (380MG) was further purified by reverse phase flash chromatography under the following conditions (column: X-Select PrepOBD C18 column, 30*150mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min; gradient: 30% B to 50% B in 7min; wavelength: 254nm / 220nm; RT1(min): 6.56) to give (1s,3s)-1-(5-bromo-4-methylpyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutan-1-ol (150mg) as an off-white solid.

[0700] Intermediates 116 and 117

[0701]

[0702] Step 1: To a stirred mixture of 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-1-one (10.0 g, 46.6 mmol, 1.0 equiv) and (S)-2-methylpropane-2-sulfinamide (5.7 g, 46.6 mmol, 1.0 equiv) in THF (100 mL) at 0°C under nitrogen atmosphere was added tetrakis(ethoxide)titanium (16.0 g, 70.0 mmol, 1.50 equiv). The resulting mixture was stirred at 60°C under nitrogen atmosphere overnight. The reaction was quenched with water at 0°C. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x 500 mL). The filtrate was extracted with EtOAc (3x 500 mL). The combined organic layers were washed with brine (2x500 mL) and purified by anhydrous Na 2 SO 4The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give (S)-N-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutylidene}-2-methylpropane-2-sulfenamide (12 g, 81.0%) as a colorless oil. LCMS (ESI, m / z): 318.15 [M+H] + .

[0703] Step 2: To a stirred solution of 5-bromo-2-iodo-4-methylpyrimidine (4.7 g, 15.7 mmol, 1.0 eq) in DCM (150 mL) was added n-BuLi (1.01 g, 15.7 mmol, 1.0 eq) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 1 h. 5-bromo-2-iodo-4-methylpyrimidine (4.7 g, 15.7 mmol, 1.0 eq) was added to the above mixture at -78 °C. The resulting mixture was stirred at -78 °C for another 1 h. The reaction mixture was heated to 40 °C by adding saturated NH 4 The reaction was quenched with Cl(aq) (150 mL). 2 Cl 2 The aqueous layer was extracted with 4-nitropropane-2-yl (3x200 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give (S)-N-[1-(5-bromo-4-methylpyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl]-2-methylpropane-2-sulfinamide (730 mg, 9.5%) as a yellow solid.

[0704] Step 3: (S)-N-(1-(5-bromo-4-methylpyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (730 mg) was further purified by preparative chiral HPLC under the following conditions (column: JW-CHIRAL ART Cellulose-SC, 20*250 mm, 5 um; mobile phase A: EtOH:DCM=1:1--HPLC, mobile phase B: Hex (0.5% 2M NH3-MeOH)--HPLC; flow rate: 20 mL / min; gradient: 98% in 10 min B to 98%; wavelength: 220 / 254nm; RT1 (min): 7.34; RT2 (min): 8.68; sample solvent: EtOH:Hex--HPLC; injection volume: 0.7mL; number of runs: 12) to obtain (S)-N-((1r,3S)-1-(5-bromo-4-methylpyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclohexane as a colorless oil. The mixture was prepared from (S)-N-((1s,3R)-1-(5-bromo-4-methylpyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (cis isomer, peak 2, Rt=8.68 min, 200 mg) as a colorless oil. LCMS (ESI, m / z): 490.10 [M+H]+.

[0705] Peak 1: 1 H NMR (400 MHz, DMSO-d 6 )δ8.86(s,1H),5.76(d,J=1.5Hz,1H),3.05(d,J=12.7Hz,1H),2.63(d,J=2.2Hz, 2H), 2.56 (s, 4H), 1.50 (s, 3H), 1.08 (s, 9H), 0.74 (s, 9H), 0.01 (d, J = 4.0Hz, 6H).

[0706] Peak 2: 1 H NMR (400 MHz, DMSO-d 6)δ8.89(s,1H),5.76(d,J=1.9Hz,1H),3.11(dd,J=12.3,4.6Hz,1H),2.94(dd,J=12.4,4.6Hz, 1H), 2.63 (d, J = 12.0Hz, 2H), 2.58 (s, 3H), 1.06 (s, 3H), 1.05 (s, 9H), 0.87 (s, 9H), 0.08 (s, 6H).

[0707] Intermediates 118 and 119

[0708]

[0709] Step 1: In a 50 mL round-bottom flask, heat the mixture at -78 °C and N 2 To a solution of 5-bromo-2-iodo-4-methylpyrimidine (3.5 g, 11.7 mmol, 1.0 eq.) in DCM (30 mL) was added n-butyllithium (2.5 M in n-hexane, 5 mL, 12.5 mmol, 1.1 eq.) under atmosphere. The resulting mixture was stirred at -78 °C for 30 min. A solution of (S)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfenamide (2.7 g, 12.9 mmol, 1.1 eq.) in DCM (30 mL) was then added dropwise, and the resulting mixture was stirred for another 1 h. The mixture was heated to 40 °C with saturated NH 4 The Cl aqueous solution quenches the reactant. The resulting mixture is quenched with water (300mL), extracted with ethyl acetate (3x 300mL). The organic extracts merged are washed with brine (2x 300mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is passed through reverse phase flash chromatography, purified using the C18 silica gel of water (0.05% TFA) / MeCN (1: 2), to obtain (S)-N-[1-(5-chloro-4-methylpyrimidine-2-yl)-3-cyano-3-methylcyclobutyl]-2-methylpropane-2-sulfinamide (500mg, 12.5%) as a yellow oil.

[0710] Step 2: To a solution of (S)-N-[1-(5-bromo-4-methylpyrimidin-2-yl)-3-cyano-3-methylcyclobutyl]-2-methylpropane-2-sulfinamide (500 mg, 1.3 mmol, 1.0 equiv) in methanol (6 mL) was added HCl (4.0 M in 1,4-dioxane, 0.6 mL). The resulting mixture was stirred at room temperature under air atmosphere for 15 min. The resulting solution was concentrated under reduced pressure to give 3-amino-3-(5-bromo-4-methylpyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile (320 mg) as a yellow solid.

[0711] Step 3: To 3-amino-3-(5-bromo-4-methylpyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile (320 mg, 1.1 mmol, 1 eq.) and Et 3 N (345mg, 3.1mmol, 3.0 equivalents) was added to a solution of di-tert-butyl dicarbonate (496mg, 2.3mmol, 2.0 equivalents) in DCM (5mL). The resulting mixture was stirred overnight at 25 ° C. The resulting mixture was quenched with water (50mL) and extracted with ethyl acetate (3x 50mL). The combined organic extracts were washed with brine (2x 50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (3: 1) to obtain tert-butyl N-[1-(5-bromo-4-methylpyrimidine-2-yl)-3-cyano-3-methylcyclobutyl]carbamate (200mg, 46.1%) as a light yellow solid.

[0712] Step 4: Tert-butyl N-[1-(5-bromo-4-methylpyrimidin-2-yl)-3-cyano-3-methylcyclobutyl]carbamate (200 mg) was separated by chiral HPLC under the following conditions (column: JW-CHIRALPAK ID, 20*250 mm, 5 μm; mobile phase A: EtOH--HPLC, mobile phase B: Hex (0.5% 2M NH3-MeOH)--HPLC; flow rate: 20 mL / min; gradient: 85% B to 85% B in 9 min; wavelength: 220 / 254 nm; RT2(min): 7.03) to give tert-butyl ((1s, 3s)-1-(5-bromo-4-methylpyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)carbamate (60 mg) as an off-white solid.

[0713] Intermediate 120

[0714]

[0715] In a 50 mL round-bottom flask, at -78 °C, N 2 Under atmosphere, n-butyllithium (2.5M in n-hexane) (3.0 mL, 7.5 mmol, 1.0 equiv) was added dropwise to a solution of 2-bromo-5-iodopyrazine (2.1 g, 7.5 mmol, 1.0 equiv) in DCM (5 mL). The reaction mixture was stirred at -78 °C for 30 min. Then a solution of tert-butyl N-(1-methyl-3-oxocyclobutyl)carbamate (1.5 g, 7.5 mmol, 1.0 equiv) was added dropwise, and the mixture was stirred for another 30 min. The mixture was heated to 40 ℃ for 1 hr with saturated NH 4The reaction was quenched with Cl (20 mL) and the mixture was extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine (10 mL) and purified by anhydrous Na 2 SO 4 Dry and concentrate in vacuo to give a crude product, which is directly purified by silica gel column chromatography (eluted with PE / EA (5:1)) to give tert-butyl ((1s, 3s)-3-(5-bromopyrazin-2-yl)-3-hydroxy-1-methylcyclobutyl)carbamate (cis isomer, peak 2, 200 mg, 7.4%) as a colorless oil and tert-butyl ((1r, 3r)-3-(5-bromopyrazin-2-yl)-3-hydroxy-1-methylcyclobutyl)carbamate (trans isomer, peak 1, 400 mg, 14.8%) as a brown oil. LC-MS: (M+H) + Found value, 360.05. Cis isomer peak 2: 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 1.4 Hz, 1H), 8.62 (d, J = 1.5 Hz, 1H), 7.16 (s, 1H), 6.04 (s, 1H), 2.64 (d, J = 13.1 Hz, 2H), 2.55 (s, 2H), 1.41 (s, 9H), 1.30 (s, 3H).

[0716] Intermediate 121

[0717]

[0718] Step 1: At 0 ° C, under a nitrogen atmosphere, tetrakis(ethoxide)titanium (23.7 g, 104.1 mmol, 1.5 equiv) was added to a stirred mixture of 3-oxetanes (5.0 g, 69.4 mmol, 1.0 equiv) and (S)-2-methylpropane-2-sulfinamide (8.4 g, 69.4 mmol, 1.0 equiv) in THF (100 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reactant was quenched by adding water (100 mL) at 0 ° C. The aqueous layer was extracted with EtOAc (3x200 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (2: 1)) to obtain (S)-2-methyl-N-(oxacyclobutane-3-yl)propane-2-sulfinamide (6 g, 49.3%) as a colorless oil. LCMS (ESI, m / z): 176.05 [M+H] + .

[0719] Step 2: To a stirred solution of 2-bromo-5-iodopyrazine (2.0 g, 6.8 mmol, 1.0 equiv) in DCM (100 mL) was added n-BuLi (2.7 mL, 6.8 mmol, 1.0 equiv) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 1 h. (S)-2-methyl-N-(oxetan-3-yl)propane-2-sulfenamide (1.2 g, 6.8 mmol, 1.0 equiv) was added dropwise to the above mixture at -78 °C. The resulting mixture was stirred for another 1 h at -78 °C. The saturated NH 4 The reaction was quenched with Cl(aq) (100 mL). 2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:2)) to give (S)-N-[3-(5-bromopyrazin-2-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (890 mg, 38.9%) as a brown solid. LCMS (ESI, m / z): 333.95 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.93(d,J=1.4Hz,1H),8.69(d,J=1.4Hz,1H),6.61(s,1H),5.05(d,J=6.4Hz,1H),4.98-4.91(m,2H),4.85(d,J=6.4Hz,1H),1.17(s,9H).

[0720] Intermediate 122

[0721]

[0722] Step 1: A solution of 5-bromopyrazine-2-carbonitrile (5.0 g, 27.2 mmol, 1.0 equiv) in THF (150 mL) was treated with tetra(propan-2-yloxy)titanium (8.7 g, 30.7 mmol, 1.1 equiv) at 0°C under nitrogen for 1 min, followed by the addition of ethylmagnesium bromide (1.0 M in THF) (7.4 g, 55.7 mmol, 2.05 equiv) at 0°C. The resulting mixture was stirred at room temperature under nitrogen overnight. The resulting mixture was stirred at 50°C under nitrogen for 4 h. The reaction mixture was purified by adding saturated NH 4Cl (aqueous solution) (100mL) was used to quench the reactant. The resulting mixture was extracted with EtOAc (1x 150mL). After filtration, the aqueous phase was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase: MeCN (0.1% FA) in water, 10% to 50% gradient in 10min; detector, UV 254nm. 1-(5-bromopyrazine-2-yl)cyclopropyl-1-amine (300mg, 5.2%) was thus obtained as a yellow oil. LCMS (ESI, m / z): 214.05[M+H] + .

[0723] Step 2: At room temperature and under nitrogen atmosphere, use Boc 2 O (611.7 mg, 2.8 mmol, 2.0 equiv) was treated with 1-(5-bromopyrazin-2-yl)cyclopropan-1-amine (300 mg, 1.4 mmol, 1.0 equiv) in THF (2 mL) and saturated Na 2 CO 3 The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The resulting mixture was extracted with EtOAc (3 x 20 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (2:1)) to give tert-butyl N-[1-(5-bromopyrazin-2-yl)cyclopropyl]carbamate (100 mg, 22.7%) as a yellow oil. LCMS (ESI, m / z): 314.05 [M+H] + .

[0724] Intermediate 123

[0725]

[0726] Step 1: To a stirred solution of 5-bromo-3-fluoro-2-iodopyridine (218.5 mg, 0.72 mmol, 1.2 eq) in DCM (5 mL) was added n-BuLi (0.32 mL, 0.8 mmol, 1.3 eq) at -78 °C under nitrogen atmosphere. The mixture was then stirred at -78 °C for 1 h. (S)-N-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylcyclobutylidene)-2-methylpropane-2-sulfenamide (200 mg, 0.6 mmol, 1.0 eq) was added dropwise to the above mixture at -78 °C. The resulting mixture was stirred at -78 °C for another 2 h. The mixture was then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was heated to 40 °C by adding saturated NH 4The reaction was quenched with Cl(aq) (5 mL). 2 Cl 2 The resulting mixture was extracted with 5 mL (3 x 5 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 2:1) to give (R)-N-(1-(5-bromo-3-fluoropyridin-2-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (180 mg, 58.8%) as a colorless oil.

[0727] Step 2: (R)-N-(1-(5-bromo-3-fluoropyridin-2-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (180 mg) was further purified by preparative chiral HPLC under the following conditions (column: JW-CHIRALPAK IH, 20*250 mm, 5 um; mobile phase A: EtOH:DCM=1:1--HPLC, mobile phase B: Hex (0.5% 2M NH 3 -MeOH)--HPLC; flow rate: 20 mL / min; gradient: 98% B to 98% B in 6.5 min; wavelength: 220 / 254 nm; RT1 (min): 3.65; RT2 (min): 5.36; sample solvent: EtOH:Hex--HPLC; injection volume: 0.4 mL; number of runs: 6) to give (R)-N-((1s, 3S)-1-(5-bromo-3-fluoropyridin-2-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (85 mg) as a colorless oil. LCMS (ESI, m / z): 507.20 [M+H] + .

[0728] Intermediate 124

[0729]

[0730] A solution of tert-butyl N-[1-(5-bromopyrimidin-2-yl)cyclopropyl]carbamate (90 mg, 0.29 mmol, 1.0 equiv) in THF (2 mL) was treated with NaH (13.8 mg, 0.34 mmol, 1.2 equiv, 60%) at 0°C under nitrogen for 1 min, followed by addition of CH 3I (48.8 mg, 0.34 mmol, 1.2 eq.). The resulting mixture was stirred at 50°C under nitrogen atmosphere for 1 h. 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (2 x 2 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 8:1) to give tert-butyl N-[1-(5-bromopyrimidin-2-yl)cyclopropyl]-N-methylcarbamate (60 mg, 63.8%) as a colorless oil. LCMS (ESI, m / z): 330.00 [M+H]+.

[0731] Intermediates 125 and 126

[0732]

[0733] Step 1: In a 500 mL round bottom flask, at -78 ° C, under N2 atmosphere, n-butyl lithium (2.5 M in n-hexane) (42 mL, 105 mmol, 1.2 eq) was added dropwise to a solution of 2,5-dibromo-3-fluoropyridine (27 g, 105 mmol, 1.2 eq) in THF (100 mL). The reaction mixture was stirred at -78 ° C for 10 min. Then a solution of 2,2-dimethylpropionic acid 3-oxocyclobutyl ester (15 g, 88 mmol, 1.0 eq) in 100 mL THF was added dropwise, and the mixture was stirred for another 10 min. Saturated NH 4 The reaction was quenched with Cl (100 mL), and the mixture was then extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude product, which was directly purified by flash chromatography (PE / EA 10:1) to give a mixture. This gave 3-(5-bromo-3-fluoropyridin-2-yl)-3-hydroxycyclobutyl pivalate (9 g, 29.5%) as a white solid. LCMS (ESI, m / z): 348.00 [M+H] + .

[0734] Step 2: To a stirred mixture of 3-(5-bromo-3-fluoropyridin-2-yl)-3-hydroxycyclobutyl pivalate (10 g, 29 mmol, 1.0 equiv) and Et 3To a solution of N (3.5 g, 35 mmol, 1.2 eq.) in DCM (100 mL) was added methanesulfonyl methanesulfonate (6 g, 35 mmol, 1.2 eq.) in portions. The resulting mixture was concentrated under reduced pressure. This afforded 3-(5-bromo-3-fluoropyridin-2-yl)-3-((methylsulfonyl)oxy)cyclobutyl pivalate (10 g) as a brown oil. LCMS (ESI, m / z): 426.00 [M+H] + .

[0735] Step 3: Pivalic acid 3-(5-bromo-3-fluoropyridin-2-yl)-3-((methylsulfonyl)oxy)cyclobutyl ester (10 g, 24 mmol, 1.0 equiv) and NaN 3 A solution of (7.7 g, 118 mmol, 5.0 equiv) in DMSO (100 mL) was stirred at 70 °C under air atmosphere for 2 h. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (5:1)) to give 3-azido-3-(5-bromo-3-fluoropyridin-2-yl)cyclobutyl pivalate (8 g, 91.4%) as a yellow oil. LCMS (ESI, m / z): 373.05 [M+H] + .

[0736] Step 4: Pivalic acid 3-azido-3-(5-bromo-3-fluoropyridin-2-yl)cyclobutyl ester (3.5 g, 9.4 mmol, 1.0 equiv) in THF (34 mL) and H2O was treated with trimethylphosphine (1.0 M in THF) (1.3 g, 16.5 mmol, 1.8 equiv) at 0 °C under nitrogen atmosphere. 2 O (3.4mL) solution for 1 min. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3x 100mL). The combined organic layers were washed with brine (2x 100mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:2)) to give 3-amino-3-(5-bromo-3-fluoropyridin-2-yl)cyclobutyl pivalate (2 g, 61.5%) as a yellow oil. LCMS (ESI, m / z): 345.05 [M+H] + .

[0737] Step 5: 3-amino-3-(5-bromo-3-fluoropyridin-2-yl)cyclobutyl pivalate (2 g) was further purified by preparative chiral HPLC under the following conditions (column: JW-CHIRALPAK IG 3.0*25 cm, 5 um; mobile phase A: IPA--HPLC, mobile phase B: Hex (0.5% 2M NH3-MeOH)--HPLC; flow rate: 20 mL / min; gradient: 85% in 13 min B to 85% B; wavelength: 220 / 254nm; RT1 (min): 7.21; RT2 (min): 9.35; sample solvent: EtOH: DCM = 1: 1--HPLC; injection volume: 0.7mL; number of runs: 19) to obtain pivalic acid (1r, 3r)-3-amino-3-(5-bromo-3-fluoropyridin-2-yl) cyclobutyl ester (918mg, Rt = 7.21min, trans isomer) as a yellow oil and pivalic acid (1s, 3s)-3-amino-3-(5-bromo-3-fluoropyridin-2-yl) cyclobutyl ester (635mg, Rt = 9.35min, cis isomer) as a yellow oil. Trans isomer: LCMS (ESI, m / z): 345.05 [M+H] + . Trans isomer: 1 H NMR (400 MHz, DMSO-d 6 )δ8.51-8.45 (m, 1H), 8.13-8.09 (m, 1.9 Hz, 1H), 5.20-5.16 (m, 1H), 2.59-2.50 (m, 2H), 2.50-2.41 (m, 2H), 2.28 (s, 2H), 1.07 (s, 9H). Cis isomer: LCMS (ESI, m / z): 345.05 [M+H] + . Cis isomer: 1H NMR (400 MHz, DMSO-d6) δ8.52 (t, J=1.5 Hz, 1H), 8.17-8.13 (m, 1H), 4.48-4.44 (m, 1H), 3.20-2.16 (m, 2H), 2.38 (s, 2H), 2.22-2.18 (m, 2H), 1.15 (s, 9H).

[0738] Intermediate 127

[0739]

[0740] Step 1: To a stirred solution of 5-bromo-2-iodopyrimidine (5.0 g, 17.5 mmol, 1.0 equiv) in DCM (170 mL) was added n-BuLi (1.1 g, 17.5 mmol, 1.0 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at -78°C under nitrogen atmosphere for 1 h. 3-Oxaazetidine-1-carboxylic acid tert-butyl ester (3.0 g, 17.5 mmol, 1.0 equiv) was added dropwise to the above mixture at -78°C. The resulting mixture was stirred for another 1 h at -78°C. The mixture was heated to 40°C by adding saturated NH 4 The reaction was quenched with Cl(aq) (150 mL). 2 Cl 2 The resulting mixture was extracted with 4% paraformaldehyde (3 x 200 mL). The combined organic layers were washed with brine (1 x 200 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give tert-butyl 3-(5-bromopyrimidin-2-yl)-3-hydroxyazetidine-1-carboxylate (3 g, 51.9%) as a yellow solid. LCMS (ESI, m / z): 276.00 [M+H-56] + .

[0741] Step 2: Trifluoroacetic acid (3 mL) was added dropwise to a stirred solution of tert-butyl 3-(5-bromopyrimidin-2-yl)-3-hydroxyazetidine-1-carboxylate (1.0 g, 3.0 mmol, 1.0 equiv) in DCM (9 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / LNH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 10% B in 9 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.56) to obtain 3-(5-bromopyrimidin-2-yl)azetidin-3-ol (620 mg, 89%) as an off-white solid. LCMS (ESI, m / z): 231.95 [M+H] + .

[0742] Step 3: A mixture of 3-(5-bromopyrimidin-2-yl)azetidin-3-ol (600 mg, 2.6 mmol, 1.0 eq.) and formaldehyde solution (234.9 mg, 7.8 mmol, 3.0 eq.) in methanol (5 mL) was stirred at room temperature under nitrogen atmosphere for 30 min. NaBH 3 CN (245.8 mg, 3.9 mmol, 1.50 equiv). The resulting mixture was stirred at room temperature for another 1 h. The residue was purified by reverse phase flash chromatography under the following conditions (column: XSelect CSH Prep C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 0% B to 10% B in 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.4), to obtain 3-(5-bromopyrimidin-2-yl)-1-methylazetidin-3-ol (400 mg, 62.8%) as a white solid. LCMS (ESI, m / z): 243.95 [M+H] + .

[0743] Intermediate 128

[0744]

[0745] Step 1: A solution of 3-bromo-5H,6H,7H-cyclopenta[b]pyridine (5 g, 25.2 mmol, 1.0 equiv) in THF (85 mL) was treated with LiHMDS (1.0 M in THF) (63 mL, 63.0 mmol, 2.5 equiv) at -78 °C under nitrogen for 1 h, followed by the dropwise addition of diethyl carbonate (9 g, 75.7 mmol, 3.0 equiv) at -78 °C. The resulting mixture was stirred at room temperature under nitrogen for 12 h. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 30 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give ethyl 3-bromo-5H,6H,7H-cyclopenta[b]pyridine-7-carboxylate (5 g, 73.3% yield) as a yellow oil. LC-MS (ESI, m / z): 271.95. 1 H NMR (400 MHz, DMSO-d 6)δ8.47-8.42(m,1H),7.95-7.93(m,1H),4.15-4.07(m,2H),4.03(dd,J=8.8,6.7Hz, 1H), 3.09-2.86 (m, 2H), 2.47-2.36 (m, 1H), 2.32-2.21 (m, 1H), 1.19 (t, J = 7.1Hz, 3H).

[0746] Step 2: A solution of ethyl 3-bromo-5H,6H,7H-cyclopenta[b]pyridine-7-carboxylate (6 g, 22.2 mmol, 1.0 equiv) in THF (80 mL) was treated with LDA (22 mL, 44.4 mmol, 2.0 equiv) at -78 °C under nitrogen for 1 h, followed by the addition of MeI (3.5 g, 24.4 mmol, 1.1 equiv) in portions at -78 °C. The resulting mixture was stirred at room temperature under nitrogen for 1 h. The mixture was heated to 40 °C with saturated NH 4 The reaction was quenched with Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 x 30 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (10:1)) to give ethyl 3-bromo-7-methyl-5H,6H-cyclopenta[b]pyridine-7-carboxylate (3.7 g, 58.6% yield) as a yellow oil. LC-MS (ESI, m / z): 285.95. 1 H NMR (400 MHz, DMSO-d 6 )δ8.46(dd,J=2.1,1.0Hz,1H),7.96-7.94(m,1H),4.13-3.94(m,2H),3.07-2.89 (m,2H),2.61-2.51(m,1H),2.09-1.99(m,1H),1.44(s,3H),1.18(t,J=7.1Hz,3H)

[0747] Step 3: At room temperature under nitrogen atmosphere, LiOH (0.51 g, 21.3 mmol, 3.0 equiv), H 2 A solution of ethyl 3-bromo-7-methyl-5H,6H-cyclopenta[b]pyridine-7-carboxylate (2 g, 7.0 mmol, 1.0 equiv) in methanol (25 mL) and THF (25 mL) was treated with 4% paraformaldehyde (2% ethanol) and 1% paraformaldehyde (2% ethanol) for 10 min. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The residue was acidified to pH 4 with citric acid. The resulting mixture was extracted with EtOAc (3 x 10 mL) and washed with anhydrous Na 2 SO 4After drying, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI, m / z): 257.95.

[0748] Step 4: A solution of 3-bromo-7-methyl-5H,6H-cyclopenta[b]pyridine-7-carboxylic acid (1 g, 3.9 mmol, 1.0 equiv) in toluene (2 mL) was treated with DPPA (1.6 g, 5.9 mmol, 1.5 equiv) at room temperature under nitrogen for 1 h. The resulting mixture was stirred at 110 °C under nitrogen for 2 h. The resulting mixture was diluted with NaOH (1 M, 20 mL). The resulting mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was extracted with EtOAc (3 x 10 mL) and purified by anhydrous Na 2 SO 4 After drying, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI, m / z): 227.00.

[0749] Step 5: At room temperature and under nitrogen atmosphere, use Boc 2 O (2.9 g, 13.2 mmol, 3.0 equiv), Na 2 CO 3 A solution of 3-bromo-7-methyl-5H,6H-cyclopenta[b]pyridin-7-amine (1 g, 4.4 mmol, 1.0 equiv) in THF (5 mL) was treated with 4% paraformaldehyde (2.3 g, 22 mmol, 5.0 equiv) for 10 min. The resulting mixture was stirred at 70 °C under nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3 x 10 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (5:1)) to give tert-butyl N-{3-bromo-7-methyl-5H,6H-cyclopenta[b]pyridin-7-yl}carbamate (600 mg, 41.6%) as a white solid. LC-MS (ESI, m / z): 327.00.

[0750] Intermediate 129

[0751]

[0752] Step 1: A solution of (7R,14S)-12-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azepin-5(14H)-one (100 mg, 0.26 mmol, 1.0 equiv) in sodium methoxide (30% in methanol) (3 mL) was stirred at 80° C. under nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 50% to 70% in 10 min; detector, UV 254 nm) to give (7R,14S)-12-chloro-1-hydroxy-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one (80 mg, 91.8%) as a yellow solid. LCMS (ESI, m / z): 340.05 [M+H] + .

[0753] Step 2: (7R,14S)-12-chloro-1-hydroxy-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one (70 mg, 0.21 mmol, 1.0 equiv) and K 2 CO 3 (142.4 mg, 0.62 mmol, 3.0 equiv., 60%), iodomethane (58.5 mg, 0.41 mmol, 2.0 equiv.) in DMF (2 mL) was stirred at 60 ° C. under nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 60% to 80% gradient in 10 min; detector, UV 254 nm) to give (7R, 14S)-12-chloro-1-methoxy-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one (60 mg, 82.3%) as a yellow solid. LCMS (ESI, m / z): 354.05 [M+H] + .

[0754] Intermediate 130

[0755]

[0756] Step 1: To a stirred solution of 2-bromo-4-chloro-5-methylpyridine (1.0 g, 4.8 mmol, 1.0 eq.) in 1,4-dioxane (20 mL) at room temperature under nitrogen atmosphere were added hexamethyldistanane (2.4 g, 7.3 mmol, 1.5 eq.) and Pd(PPh 3 ) 4 (560mg, 0.48mmol, 0.1 eq.). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 1h. The resulting mixture was diluted with brine (10mL). The resulting mixture was extracted with EA (2x 60mL). The combined organic layers were washed with brine (1x50mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 4-chloro-5-methyl-2-(trimethylstannyl)pyridine (2g) as a yellow oil. LCMS (ESI, m / z): 292[M+H] + .

[0757] Step 2: To a stirred solution of 4-chloro-5-methyl-2-(trimethylstannyl)pyridine (2.1 g, 7.2 mmol, 3.0 equiv) and (3R,6R)-7-(difluoromethoxy)-2-(methyl-d3)-1-oxo-1,2,3,6-tetrahydro-3,6-methanobenzo[c]azocine-5-yl trifluoromethanesulfonate (1.0 g, 2.4 mmol, 1.0 equiv) in toluene (15 mL) at room temperature under nitrogen atmosphere was added CuCl (237.8 mg, 2.4 mmol, 1.0 equiv) and Pd(PPh) in portions. 3 ) 4 (277.6 mg, 0.24 mmol, 0.1 eq.). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with brine (30 mL). The resulting mixture was extracted with EA (2 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give (3R,6S)-5-(4-chloro-5-methylpyridin-2-yl)-7-(difluoromethoxy)-2-(methyl-d3)-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (580 mg, 61.3%) as a yellow solid.

[0758] Step 3: A solution of (3R,6S)-5-(4-chloro-5-methylpyridin-2-yl)-7-(difluoromethoxy)-2-(methyl-d3)-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocin-1(2H)-one (580 mg, 1.5 mmol, 1.0 equiv) in DCE (20 mL) was treated with 4A-MS (1.2 g), 2,2,6,6-tetramethylpiperidin-1-olate (46.0 mg, 0.3 mmol, 0.2 equiv) and tri(nitroxide)bismuth(3+) pentahydrate (1.4 g, 3.0 mmol, 2.0 equiv) at 80° C. under nitrogen atmosphere overnight. The resulting mixture was filtered and washed with CH 2 Cl 2 (2 x 20 mL) and the filter cake was washed. The filtrate was concentrated under reduced pressure. The residue was analyzed by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give (3R,6S)-5-(4-chloro-5-methylpyridin-2-yl)-7-(difluoromethoxy)-2-(methyl-d3)-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (320 mg, 49.5%) as a light yellow solid.

[0759] Step 4: To a stirred solution of (3R,6S)-5-(4-chloro-5-methylpyridin-2-yl)-7-(difluoromethoxy)-2-(methyl-d3)-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocine-1(2H)-one (320 mg, 0.73 mmol, 1.0 equiv) in toluene (10 mL) was added dropwise triphenyl phosphite (2.3 g, 7.3 mmol, 10.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give (7R,14S)-12-chloro-1-(difluoromethoxy)-11-methyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one (160 mg, 53.9%) as a light yellow solid. LCMS (ESI, m / z): 407.10 [M+H] + .

[0760] Intermediate 131

[0761]

[0762] Step 1: A solution of (3R,6S)-7-(difluoromethoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,3,5,6-tetrahydro-3,6-methanobenzo[c]azepine-1,4-dione (1.0 g, 2.5 mmol, 1.0 equiv) in THF (3 mL) was treated at -78 °C under nitrogen atmosphere, followed by the dropwise addition of LiHMDS (1.0 M in THF) (5.0 mL, 5.0 mmol, 2 equiv) at -78 °C. The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 1 h. To the above mixture was added 4-methylbenzenesulfonyl cyanide (820.6 mg, 4.5 mmol, 1.8 equiv) portionwise at -78 °C. The resulting mixture was stirred at -78 °C ~ RT for another 2 h. The reaction mixture was diluted with water (300 mL) and the aqueous phase was extracted three times with EA (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (15:1) to give (3R,6R)-7-(difluoromethoxy)-4-hydroxy-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,6-tetrahydro-3,6-methanobenzo[c]azocine-5-carbonitrile (350 mg, 32.9%) as a light yellow oil.

[0763] Step 2: A mixture of (3R,6R)-7-(difluoromethoxy)-4-hydroxy-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,6-tetrahydro-3,6-methanobenzo[c]azepine-5-carbonitrile (2.0 g, 4.7 mmol, 1.0 equiv) and hydrazine monohydrochloride (713.4 mg, 10.4 mmol, 2.2 equiv) in EtOH (25 mL) was stirred at 85° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give (4R,11S)-1-amino-10-(difluoromethoxy)-2,4,5,11-tetrahydro-6H-4,11-methanobenzo[c]pyrazolo[4,3-f]azocin-6-one (400 mg, 27.6%) as a light yellow solid. LCMS (ESI, m / z): 306.95 [M+H] + .

[0764] Step 3: (4R,11S)-1-amino-10-(difluoromethoxy)-2,4,5,11-tetrahydro-6H-4,11-methanobenzo[c]pyrazolo[4,3-f]azocin-6-one (350 mg, 1.1 mmol, 1.0 equiv), (2Z)-3-ethoxy-2-fluoroprop-2-enoic acid ethyl ester (278 mg, 1.7 mmol, 1.5 equiv) and Cs 2 CO 3 A mixture of (820 mg, 2.5 mmol, 2.2 equiv) in DMF (5 mL) was stirred at 110 ° C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (10: 1)) to give (7R, 14S)-1-(difluoromethoxy)-11-fluoro-6,7,13,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-5,12-dione (110 mg, 25.6%) as a light yellow solid. LCMS (ESI, m / z): 377.20 [M+H] + .

[0765] Step 4: (7R,14S)-1-(difluoromethoxy)-11-fluoro-6,7,13,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azepine-5,12-dione (100 mg, 0.27 mmol, 1.0 equiv), 3-(fluorosulfonyl)-1,2-dimethylimidazol-1-ium trifluoromethanesulfonate (131 mg, 0.4 mmol, 1.5 equiv) and Et 3 A mixture of N (60 mg, 0.58 mmol, 2.2 equivalents) in MeCN (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (10: 1)) to give fluorosulfate (7R, 14S) -1- (difluoromethoxy) -11- fluoro-5-oxo-5,6,7,14-tetrahydro-7,14-methylbenzo [c] pyrimido [1', 2': 1,5] pyrazolo [4,3-f] azacyclooctane -12- ester (40 mg, 32.8% yield) as a pale yellow solid. LCMS (ESI, m / z): 459.10 [M+H] + .

[0766] Intermediate 132

[0767]

[0768] Step 1: A solution of (3R,6S)-7-(difluoromethoxy)-8-fluoro-2-(methyl-d3)-2,3,5,6-tetrahydro-3,6-methanobenzo[c]azepine-1,4-dione (1.0 g, 3.3 mmol, 1.0 equiv) in toluene (10 mL) was treated at -78 °C under nitrogen for 5 min, followed by the dropwise addition of LiHMDS (4.0 mL, 4.0 mmol, 1.2 equiv) at -78 °C. The resulting mixture was stirred at -78 °C under nitrogen for 1 h. A solution of 4-methylbenzenesulfonyl cyanide (0.72 g, 4.0 mmol, 1.2 equiv) in toluene (7 mL) was treated at -50 °C under nitrogen for 5 min, followed by the dropwise addition of the above mixture at -50 °C. The resulting mixture was stirred at -50 °C for another 1 h. The reactant was quenched by adding MeOH (1 mL) at -50 ° C. The reaction mixture was diluted with water (200 mL), and the aqueous phase was extracted three times with EA (200 mL). Water was acidified to pH 3 with 2M HCl, and the aqueous phase was extracted three times with EA (200 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with PE / EA (1: 1)) to obtain (3R, 6R) -7- (difluoromethoxy) -8- fluoro-4-hydroxy -2- (methyl -d3) -1- oxo -1,2,3,6- tetrahydro -3,6- methylbridge benzo [c] azacyclooctane -5- nitrile (500 mg, 46.2%) as a light pink solid. LCMS (ESI, m / z): 328.15 [M+H] + .

[0769] Step 2: A solution of (3R,6R)-7-(difluoromethoxy)-8-fluoro-4-hydroxy-2-(methyl-d3)-1-oxo-1,2,3,6-tetrahydro-3,6-methanobenzo[c]azocine-5-carbonitrile (480 mg, 1.5 mmol, 1.0 equiv) in EtOH (10 mL) was treated with hydrazine monohydrochloride (221 mg, 3.2 mmol, 2.2 equiv) at room temperature under nitrogen for 2 min. The resulting mixture was stirred at 80 °C under nitrogen for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using CH 2 Cl 2 / MeOH (20:1) elution) to give (4R, 11S)-1-amino-10-(difluoromethoxy)-9-fluoro-5-(methyl-d3)-2,4,5,11-tetrahydro-6H-4,11-methanobenzo[c]pyrazolo[4,3-f]azocine-6-one (260 mg) as a light green solid. LCMS (ESI, m / z): 342.10 [M+H] + .

[0770] Step 3: (4R,11S)-1-amino-10-(difluoromethoxy)-9-fluoro-5-(methyl-d3)-2,4,5,11-tetrahydro-6H-4,11-methanobenzo[c]pyrazolo[4,3-f]azocin-6-one (250 mg, 0.73 mmol, 1.0 equiv) and Cs-1-yl-2-fluoroprop-2-enoate (237.6 mg, 1.46 mmol, 2.0 equiv) were treated with (2Z)-3-ethoxy-2-fluoroprop-2-enoic acid ethyl ester (237.6 mg, 1.46 mmol, 2.0 equiv) at room temperature under nitrogen atmosphere. 2 CO 3 (501.2 mg, 1.5 mmol, 2.1 equiv) in DMF (8 mL) for 2 min. The resulting mixture was stirred at 110 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using CH 2 Cl 2 / MeOH (20:1)) to give (7R, 14S) -1- (difluoromethoxy) -2,11-difluoro-6- (methyl-d3) -6,7,13,14-tetrahydro-7,14-methanobenzo [c] pyrimido [1',2': 1,5] pyrazolo [4,3-f] azacyclooctane-5,12-dione (150 mg, 49.8%) as a yellow solid. LCMS (ESI, m / z): 412.05 [M + H] + .

[0771] Step 4: A mixture of (7R,14S)-1-(difluoromethoxy)-2,11-difluoro-6-(methyl-d3)-6,7,13,14-tetrahydro-7,14-carboxybenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azepine-5,12-dione (140 mg, 0.34 mmol, 1.0 equiv), 2,6-lutidine (145.9 mg, 1.36 mmol, 4.0 equiv) and DMAP (166.3 mg, 1.36 mmol, 4.0 equiv) in DCM (2 mL) was treated with (trifluoromethanesulfonyl) triflate (480.1 mg, 1.7 mmol, 5.0 equiv) at 0°C under nitrogen atmosphere for 2 min. The resulting mixture was stirred at room temperature for 1 h. The mixture was heated to 40°C with NH 4Cl (50mL) dilutes the reaction mixture, and extracts the aqueous phase with DCM (3x 50mL). The combined organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by preparative TLC (PE / EA 1:1) to obtain trifluoromethanesulfonic acid (7R, 14S) -1- (difluoromethoxy) -2,11- difluoro -6- (methyl -d3) -5- oxo -5,6,7,14- tetrahydro -7,14- methyl bridge benzo [c] pyrimido [1', 2': 1,5] pyrazolo [4,3-f] azacyclooctane -12- ester (100mg, 54.1%) as a pale yellow solid. LCMS (ESI, m / z): 544.10 [M+H] + .

[0772] Example 1. 12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0773]

[0774] Step 1: At room temperature and under nitrogen atmosphere, use Pd(dppf)Cl 2 .DCM (4.85 mg, 0.01 mmol, 0.1 eq) and LiOH.H 2 Intermediate 12 (30 mg, 0.06 mmol, 1 eq.) and intermediate 25 (45 mg, 0.12 mmol, 2 eq.) were treated with 2H 2 O (7.49 mg, 0.18 mmol, 3 eq.) in dioxane (5 mL) and H 2 O. 2 O (1mL) solution for 1min. The resulting mixture was stirred at 50 ° C, under a nitrogen atmosphere for 1h. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1: 10) to give tert-butyl (1- (5- (1- (difluoromethoxy) -6-methyl -5- oxo -5,6,7,14- tetrahydro -7,14- methyl bridge benzo [c] pyrimido [1 ', 2 ': 1,5] pyrazolo [4,3-f] azacyclooctane -12-yl) pyrimidin -2-yl) cyclobutyl) carbamate (30mg, 84%) as a white solid. LCMS (ESI, m / z): 604.35 [M + H] + .

[0775] Step 2: A solution of tert-butyl (1-(5-(1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-carboxybenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (40 mg, 0.07 mmol, 1 eq) in DCM (1 mL) was treated with TFA (0.25 mL) at 0°C under nitrogen for 1 min. The resulting mixture was stirred at room temperature under nitrogen for 1 h. The mixture was heated to 40°C with saturated Na 2 CO 3 The mixture was basified to pH 8 with DCM (3 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product (40 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 29% B to 49% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.3), to obtain Example 1 (2.1 mg, 6.3%). LCMS (ESI, m / z): 504.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.48(s,2H),9.26(d,J=7.4Hz,1H),8.25(d,J=7.8Hz,1H),7.77-7.47(m,2H),7.38-7.34(m,2H),5.15 -5.09(m,2H),3.29(s,3H),2.75-2.53(m,4H),2.18-2.07(m,2H),2.05-1.92(m,1H),1.86-1.82(m,1H).

[0776] Example 2. (7S,14R)-12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0777] Example 3. (7R,14S)-12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0778]

[0779] 12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one (8 mg) was separated by chiral HPLC under the following conditions (column: CHIRAL Cellulose SB; mobile phase A: Hex (0.1% DEA):(EtOH:DCM=1:1)=50:50; flow rate: 1 mL / min; gradient: isocratic; injection volume: 2 uL mL) to give Example 2 (3.0 mg, 37%), LCMS (ESI, m / z): 504.15 [M+H] + and Example 3 (3.0 mg, 37%) as a white solid, LCMS (ESI, m / z): 504.15 [M+H] + .

[0780] Example 4. (1R,3s)-3-(5-((7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile

[0781]

[0782] At room temperature and nitrogen atmosphere, Pd(dppf)Cl 2 .DCM (8.08 mg, 0.01 mmol, 0.2 eq.) and Cs 2 CO 3 Intermediate 7 (25 mg, 0.05 mmol, 1 eq.) and intermediate 28 (19 mg, 0.06 mmol, 1.1 eq.) (49 mg, 0.15 mmol, 3 eq.) were treated in dioxane (1.5 mL) and H 2O (0.3 mL) for 5 min. The resulting mixture was stirred at 50 ° C under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product (25 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD RP18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 36% B to 56% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.97), to obtain Example 4 (6 mg, 21.7%). LCMS (ESI, m / z): 544.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.53(s,2H),9.29(d,J=7.4Hz,1H),8.28-8.22(m,1H),7.75(d,J=7.5Hz,1H),7.73-7.31(m,3H),6.25(s,1H),5 .17-5.09(m,2H),3.38-3.28(m,1H),3.30(s,3H),2.95-2.87(m,2H),2.81-2.73(m,2H),2.55(s,1H),1.45(s,3H).

[0783] Example 5. (1r,3S)-1-(5-((7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-12-yl)pyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane-1-carbonitrile

[0784]

[0785] The title compound was prepared as described above in Example 4 by substitution of intermediate 31. LCMS (ESI, m / z): 544.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.56(s,2H),9.31(d,J=7.5Hz,1H),8.25(m,1H),7.90-7.66(m,1H),7.64-7.14(m,3H),5.53(s,1H),5.14( m,2H),3.35(s,1H),3.33-3.29(m,3H),3.05-2.92(m,2H),2.88-2.80(m,2H),2.54-2.49(m,1H),1.24(s,3H).

[0786] Example 6. (7R,14S)-12-(2-(1-aminocyclopropyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0787]

[0788] Step 1: At room temperature under nitrogen atmosphere, to a stirred solution of intermediate 7 (28 mg, 0.06 mmol, 1 eq.) and intermediate 32 (24.1 mg, 0.067 mmol, 1.2 eq.) in dioxane (0.5 mL) and H 2 O (0.1 mL) was added to the mixture with Pd(dppf)Cl 2 DCM (4.5 mg, 0.006 mmol, 0.1 eq.) and K 2 CO 3 (23.0 mg, 0.16 mmol, 3 eq.). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give tert-butyl (1-(5-((7R, 14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-12-yl)pyrimidin-2-yl)cyclopropyl)carbamate (15 mg, 45.8%) as a white solid. LCMS (ESI, m / z): 590.25 [M+H] + .

[0789] Step 2: To a stirred solution of (1-(5-((7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-carboxybenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azoc-12-yl)pyrimidin-2-yl)cyclopropyl)carbamate (15 mg, 0.025 mmol, 1 eq) in DCM (0.6 mL) at 0°C under nitrogen atmosphere was added TFA (0.2 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.56) to obtain Example 6 (8 mg, 61%). LCMS (ESI, m / z): 490.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.39(s,2H),9.24(d,J=8.0Hz,1H),8.25-8.23(m,1H),7.70-7.68(m,1H),7.52-7.35(m,3H),5.1 2-3.95(m,2H),3.45-3.33(m,1H),3.28(s,3H),2.54(s,1H),1.40-1.39(m,2H),1.24-1.18(m,2H).

[0790] Example 7. (1R,3s)-3-amino-3-(5-((7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile

[0791]

[0792] Step 1: At room temperature under nitrogen atmosphere, (R)-N-((1s,3S)-3-cyano-3-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfenamide (50 mg, 0.12 mmol, 1 eq) and Cs 2 CO 3The mixture was treated with (7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-12-yl trifluoromethanesulfonate (117 mg, 0.36 mmol, 3 eq) in 1,4-dioxane (1 mL) and H 2 O (0.2 mL) for 10 min, followed by the addition of Pd(dppf)Cl in portions at room temperature 2 DCM (20 mg, 0.024 mmol, 0.2 eq.). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (10: 1)) to give (R)-N-((1s, 3S)-3-cyano-1-(5-((7R, 14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-12-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (40 mg, 52.0%) as a black solid. LCMS (ESI, m / z): 647.23 [M+H] + .

[0793] Step 2: A solution of (R)-N-((1s,3S)-3-cyano-1-(5-((7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azoc-12-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (40 mg, 0.06 mmol, 1 eq) in DCM (1 mL) was treated with HCl (g) in 1,4-dioxane (0.03 mL, 0.12 mmol, 2 eq, 4 M) at 0 °C under nitrogen for 2 min. The resulting mixture was stirred at room temperature under nitrogen for 30 min. The mixture was heated to 40 °C with saturated NaHCO 3 The mixture was basified to pH 7 with 4% paraformaldehyde (5% ethanol) and 4% paraformaldehyde (5% ethanol). The resulting mixture was extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (2 x 2 mL) and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The crude product (40 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD RP18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 41% B to 61% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 8.6) to give (1R, 3s)-3-amino-3-(5-((7R, 14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile (16.3 mg, 48.5%). LCMS (ESI, m / z): 543.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.50(s,2H),9.28(d,J=7.4Hz,1H),8.26-8.23(m,1H),7.80-7.48(m,2H),7.43-7.26(m ,2H),5.14-5.11(m,2H),3.32(s,3H),2.84-2.78(m,2H),2.65-2.53(m,4H),1.45(s,3H).

[0794] Example 8. (7R,14S)-1-(difluoromethoxy)-12-(4-(2-hydroxypropan-2-yl)cyclohex-1-en-1-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0795]

[0796] Step 1: At room temperature and under nitrogen atmosphere, use Cs 2 CO 3The mixture was stirred for 2 h at 4 ℃ for 30 min. The mixture was stirred for 2 h. The mixture was stirred for 30 min. The mixture was stirred for 2 h. The mixture was stirred for 30 min. The mixture was stirred for 30 min. The mixture was stirred for 40 min. The mixture was stirred for 20 min. The mixture was stirred for 30 min. The mixture was stirred for 20 min. The mixture was stirred for 30 min. The mixture was stirred for 30 min. The mixture was stirred for 40 min. The mixture was stirred for 30 min. The mixture was stirred for 20 min. The mixture was stirred for 30 min. 2 O (1 mL) for 1 min, followed by the addition of Pd(dppf)Cl 2 .DCM (19.38 mg, 0.024 mmol, 0.2 eq). The resulting mixture was stirred at 50 ° C, under a nitrogen atmosphere for 2 h. The aqueous layer was extracted with EtOAc (3x13 mL). The residue was purified by preparative TLC (EA, RF = 0.3) to give 4-((7R, 14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methylbridge benzo [c] pyrimido [1 ', 2 ': 1,5] pyrazolo [4,3-f] azacyclooctane-12-yl) cyclohex-3-ene-1-carboxylic acid ethyl ester (50 mg, 82.66%) as a yellow solid.

[0797] Step 2: At -78 °C under nitrogen atmosphere, use CH 3 A solution of ethyl 4-((7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azoc-12-yl)cyclohex-3-ene-1-carboxylate (30 mg, 0.06 mmol, 1 eq) in THF (2 mL) was treated with MgCl (0.15 mL, 0.15 mmol, 2.5 eq) for 2 h. The reaction mixture was stirred for 2 h by adding saturated NH 4The reaction was quenched with Cl(aq) (10 mL). The crude product (50 mg) was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 54% B to 84% B in 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.6) to give (7R,14S)-1-(difluoromethoxy)-12-(4-(2-hydroxyprop-2-yl)cyclohex-1-en-1-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one (5.2 mg, 17.8%). LCMS (ESI, m / z): 495.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.91(d,J=7.6Hz,1H),8.27-8.26(m,1H),7.76-7.51(m,1H),7.41-7.32(m,2H),7 .27(dd,J=7.7,5.5Hz,1H),6.94(d,J=2.6Hz,1H),5.10-4.87(m,2H),4.19(s,1H),3 .32-3.26(m,4H),2.82-2.66(m,1H),2.47(s,1H),2.35-2.30(m,1H),2.28-2.13(m, 1H), 2.10-1.98 (m, 2H), 1.53-1.42 (m, 1H), 1.22-1.17 (m, 1H), 1.10 (d, J = 2.9Hz, 6H).

[0798] Example 9. (7R,14S)-12-(2-((1s,3R)-1-amino-3-hydroxy-3-methylcyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0799]

[0800] Step 1: At room temperature and under nitrogen atmosphere, use Cs 2 CO 3The mixture was stirred for 2 h at 4 ℃ for 30 min. (7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-12-yl trifluoromethanesulfonate (112.0 mg, 0.35 mmol, 3 eq) and (R)-N-((1s,3S)-3-((tert-butyldimethylsilyl)oxy)-3-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfenamide (57.8 mg, 0.12 mmol, 1 eq) in dioxane (1 mL) and H 2 O (0.2 mL) for 1 min, followed by the addition of Pd(dppf)Cl 2 .DCM (18.7 mg, 0.02 mmol, 0.2 eq). The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative (DCM / MeOH 10:1) to give (S)-N-((1s,3R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-((7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1′,2′:1,5]pyrazolo[4,3-f]azoc-12-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (60 mg, 69.6%) as a yellow solid. LCMS (ESI, m / z): 752.30 [M+H] + .

[0801] Step 2: A solution of (S)-N-((1s,3R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-((7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-carbazo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azoc-12-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide (60 mg, 0.08 mmol, 1 eq) in DCM (6 mL) was treated with HCl (g) in dioxane (3 mL, 0.60 mmol) at 0 °C under nitrogen for 10 min. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC under the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.56) to give (7R,14S)-12-(2-((1s,3R)-1-amino-3-hydroxy-3-methylcyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one (20.6 mg, 48.29%). LCMS (ESI, m / z): 534.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.53(s,2H),9.29(d,J=7.5Hz,1H),8.27-8.23(m,1H),7.78-7.70(m,1H),7.58-7.28(m,3H),6.07(s,2H),5.15-3. 10(m,2H),3.37-3.32(m,1H),3.30(s,3H),2.87(d,J=12.5Hz,2H),2.55(s,1H),2.37(d,J=12.4Hz,2H),1.25(s,3H).

[0802] Example 10. (7R,14S)-12-(2-((1s,3R)-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0803] The title compound was prepared as described above in Example 9 by substitution of intermediate 41. LCMS (ESI, m / z): 548.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.51(s,2H),9.28(d,J=7.5Hz,1H),8.25(dd,J=7.9,1.6Hz,1H),7.80-7.69(m,1H),7.64-7.28(m,3H),5.13(dd,J=6.8, 1.6Hz,2H),3.45(s,2H),3.37-3.32(m,1H),3.30(s,3H),2.55(s,1H),2.51-2.46(m,2H),2.22-2.09(m,2H),1.09(s,3H).

[0804] Example 11. (7R,14S)-1-(difluoromethoxy)-12-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0805]

[0806] (7R,14S)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-12-yl trifluoromethanesulfonate (40 mg, 0.08 mmol, 1.00 equiv) and 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propan-2-ol (21 mg, 0.08 mmol, 1 equiv), Pd(dppf)Cl 2 (11.6 mg, 0.016 mmol, 0.2 eq), Cs 2 CO 3 (77.5 mg, 0.24 mmol, 3 eq.) in dioxane (2 mL) and H 2 The solution / mixture in 2% O (0.4 mL) was stirred at 80° C. under nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3×10 mL) and then washed with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The crude product (40 mg) was purified by preparative HPLC under the following conditions (column: xBridge Prep Phenyl 5 μm OBD 19*250 mm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: isocratic 35% B-65% B in 20 min; wavelength: 220 / 254 nm; RT1 (min): 13) to give ((7R,14S)-1-(difluoromethoxy)-12-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one as a light green solid (12 mg, 30.4%). LCMS (ESI, m / z): 493.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.49(s,2H),9.28-9.26(m,1H),8.25-8.23(m,1H),7.77-7.49(m,2H),7.43-7.30(m,2H),5 .24(s,1H),5.13(d,J=6.7Hz,2H),3.42-3.40(m,1H),3.30(s,3H),2.54(s,1H),1.55(s,6H).

[0807] Example 12. (7R,14S)-1-(difluoromethoxy)-12-(2-(3-hydroxytetrahydrofuran-3-yl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0808] The title compound was prepared as described above in Example 9 by substitution of intermediate 43. LCMS (ESI, m / z): 521.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.52(s,2H),9.29(d,J=7.4Hz,1H),8.28-8.22(m,1H),7.77-7.55(m,2H),7.42-7.31(m,2H),5.73(s,1H),5.18-5.06(m,2H),4. 09(d,J=8.9Hz,1H),4.08-3.96(m,2H),3.92(d,J=8.9Hz,1H),3.34-3.31(m,1H),3.29(s,3H),2.57-2.52(m,2H),2.22-2.16(m,1H)

[0809] Example 13. (7R,14S)-1-(difluoromethoxy)-12-(6-(dimethylphosphoryl)pyridin-3-yl)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0810]

[0811] The title compound was prepared as described above in Example 9 by substitution of intermediate 47. LCMS (ESI, m / z): 510.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.50(d,J=2.2Hz,1H),9.27(d,J=7.4Hz,1H),8.67-8.66(m,1H),8.25(dd,J=8.0,1.6Hz,1H),8.09(dd,J=8.1,5.1Hz,1H),7.76- 7.66(m,1H),7.57-7.30(m,3H),5.14(d,J=6.8Hz,2H),3.36-3.32(m,1H),3.31(s,3H),2.66-2.53(m,1H),1.72(d,J=13.5Hz,6H).

[0812] Example 14. 12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one

[0813]

[0814] Step 1: To a stirred mixture of intermediate 13 (18 mg, 0.046 mmol, 1 eq.) and dioxane (0.4 mL) in H2 O (0.1 mL) was added to the solution 2 CO 3 (14.7 mg, 0.14 mmol, 3 eq) and tert-butyl (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)cyclobutyl)carbamate (25.0 mg, 0.07 mmol, 1.5 eq). To the above mixture was added 2nd generation XPhos precatalyst (3.6 mg, 0.005 mmol, 0.1 eq) at room temperature. The final reaction was irradiated at 140 °C for 1 h using microwave radiation. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=30:1) to give tert-butyl (1-(5-(1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[1′,2′:1,5]pyrazolo[4,3-f]azoc-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (20 mg, 71.9%) as an off-white solid. LCMS (ESI, m / z): 603.35 [M+H] + .

[0815] Step 2: A solution of tert-butyl (1-(5-(1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocin-12-yl)pyrimidin-2-yl)cyclobutyl)carbamate (15 mg, 0.025 mmol, 1 eq) and TFA (1 mL) in DCM (5 mL) was stirred at room temperature for 1 h. The mixture was heated to 40 ℃ by adding saturated NaHCO 3 The reaction was quenched with 4% paraformaldehyde (20 mL) and 4% paraformaldehyde (20 mL). The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL) and washed with anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC to give Example 14 (2.1 mg, 16.8%). LCMS (ESI, m / z): 503.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.16(s,2H),8.84(d,J=7.3Hz,1H),8.22(d,J=7.9Hz,1H),7.71(s,1H),7.60(s,1H),7.44-7.28(m,3H),5.09(d,J=6.9 Hz,1H),5.03(d,J=6.5Hz,1H),3.29(s,4H),2.64(s,2H),2.52(d,J=14.4Hz,2H),2.16(s,2H),2.01(s,1H),1.85(s,1H).

[0816] The following compounds were prepared according to similar procedures.

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842] Embodiment 301

[0843]

[0844] Step 1: A solution of (7R, 14S)-1-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocine-12-trifluoromethanesulfonate (500 mg, 1.0 mmol, 1.0 equiv) in DCM (100 mL) was obtained under nitrogen atmosphere, followed by dropwise addition of BBr3 (6 mL, 6.0 mmol, 6 equiv) at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted three times with DCM (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EA 1:2) to give (7R,14S)-12-bromo-1-hydroxy-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[c]pyrimido[1',2':1,5]pyrazolo[4,3-f]azocin-5(14H)-one (300 mg, 78.4%) as a yellow oil. LCMS (ESI, m / z): 388.14 [M+H] + ....

Claims

1. A compound of formula (I*) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: in: Ring B is phenyl or a 6-membered heteroaryl group containing one or two nitrogen atoms; Each R 1 are independently halogen, -CN, -NO2, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; or two R on the same atom 1 Together they form an oxo group; n is 0, 1, 2, 3 or 4; R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl or cycloalkyl; X is N or CR X ; R X Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl; Y is N or CR Y ; R Y Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; Z is N or CR Z ; R Z Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R 3 are independently halogen, -L-CN, -L-NO2, -L-OH, -L-OR a 、-L-OC(=O)R a 、-L-OC(=O)OR b 、-L-OC(=O)NR c R d 、-L-SH、-L-SR a ,-LS(=O)R a ,-LS(=O)2R a ,-LS(=O)(=NH)R a ,-LS(=O)2OR b ,-LS(=O)2NR c R d 、-L-NR c R d 、-L-NR b C(=O)NR c R d 、-L-NR b C(=O)R a 、-L-NR b C(=O)OR b 、-L-NR b S(=O)2R a ,-LC(=O)R a 、-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; or two R on the same atom 3 Together they form an oxo group; or two R on adjacent atoms 3 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is independently optionally substituted by one or more R; m is 0, 1, 2, 3 or 4; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; Each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; Each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; or R c and R d together with the atoms to which they are attached form heterocycloalkyl which is independently optionally substituted with one or more R; and L is absent or is C1-C3 alkylene optionally substituted by one or more R; Each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1-C3 alkyl, -C(=O)C1-C3 alkyl, - C(═O)OH, —C(═O)OC1-C3 alkyl, —C(═O)NH2, —C(═O)N(C1-C3 alkyl)2, —C(═O)NHC1-C3 alkyl, —P(═O)(C1-C3 alkyl)2, —P(═O)(OC1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C1-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Or two R on the same atom together form an oxo group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein ring B is phenyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein Ring B is pyridyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein X is N.

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein X is CR X .

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein Y is N.

7. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein Y is CR Y .

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein Z is N.

9. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein Z is CR Z .

10. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound is a compound of formula (Ia):

11. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound is a compound of formula (Id):

12. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound is a compound of formula (If):

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein n is 1.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R X It is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R X For hydrogen.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R Y Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R Y For hydrogen.

18. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R Y It is a halogen.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R Z It is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R Z For hydrogen.

21. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound is a compound of formula (Ia-1): Where R 1a is hydrogen or R 1 .

22. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound is a compound of formula (Id-1): Where R 1a is hydrogen or R 1 .

23. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound is a compound of formula (If-1): Where R 1a is hydrogen or R 1 .

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 2 It is C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl.

25. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 2 is hydrogen or C 1- C6 alkyl.

26. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 2 C 1- C6 alkyl or C 1- C6 deuterated alkyl.

27. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 2 It is -CH3 or -CD3.

28. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 2 For hydrogen.

29. The compound of any one of claims 21-28 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 1a Hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C 1- C6 alkyl or C 1- C6 haloalkyl.

30. The compound of any one of claims 21-28 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 1a For-OR a .

31. A compound according to any one of claims 21 to 28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 1a It is -CN or -OCHF2.

32. A compound according to any one of claims 21 to 28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 1a It is -OCHF2.

33. A compound according to any one of claims 21 to 28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein R 1a It is -CN.

34. The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 33; wherein ring A is a 6-membered heteroaryl group.

35. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein ring A is pyridinyl or pyrimidinyl.

36. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein Ring A is a pyrimidinyl group.

37. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 are independently halogen, -L-OR a 、-L-NR c R d ,-LC(=O)R a 、-LC(=O)OR b ,-LC(=O)NR c R d 、-LP(=O)R c R d 、-LP(=O)OR c OR d , C 1- C6 alkyl, -L-cycloalkyl or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R.

38. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 are independently halogen, -L-OR a 、-L-NR c R d ,-LC(=O)R a 、-LC(=O)OR b ,-LC(=O)NR c R d , C 1- C6 alkyl, C 1- C6 haloalkyl, -L-cycloalkyl, -L-heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R.

39. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 are independently halogen, -L-OR a 、-L-NR c R d , C 1- C6 alkyl, C 1- C6 haloalkyl, -L-cycloalkyl or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R.

40. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 are independently halogen, -L-NR c R d , C 1- C6 alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R.

41. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R.

42. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 is independently halogen or cycloalkyl optionally substituted by one or more R.

43. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 is independently cycloalkyl optionally substituted by one or more R.

44. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 are independently halogen or -L-NR c R d .

45. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 Independently -L-NR c R d .

46. ​​A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 Independently 47. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein each R 3 Independently 48. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the compounds found in Table 1, Table 2, or the specification.

49. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

50. A method for treating a condition for which administration of a TNFα functional modulator is indicated, comprising administering to a patient in need of such treatment an effective amount of a compound as claimed in any one of claims 1 to 48, or a pharmaceutically acceptable salt or solvate thereof.

51. A method for treating an inflammatory or autoimmune disorder, a nervous system disorder, a neurodegenerative disorder, pain, a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or a neoplastic disorder, comprising administering to a patient in need of such treatment an effective amount of a compound as described in any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof.

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