Heterocyclic compounds, their production methods and uses

Abstract

The present disclosure provides novel compounds, for example, compounds having formula (I), prodrugs thereof, or pharmaceutically acceptable salts thereof. The present disclosure further provides pharmaceutical compositions comprising compounds having formula (I), prodrugs thereof, or pharmaceutically acceptable salts thereof, methods for making the compounds, and methods for using the compounds (e.g., inhibiting KIF18A in cells and / or treating various cancers associated with the KIF18A protein). [Formula 1] JPEG2025538601000204.jpg31149

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to International Application No. PCT / CN2022 / 134025, filed November 24, 2022, International Application No. PCT / CN2023 / 076151, filed February 15, 2023, and International Application No. PCT / CN2023 / 123074, filed October 3, 2023, the contents of each of which are incorporated herein by reference. [Technical Field]

[0002] In various embodiments, the present invention relates generally to novel heterocyclic compounds, compositions thereof, methods for their preparation, and methods of their use, for example, to inhibit KIF18A and / or to treat a number of diseases or conditions, such as cancer, associated with the KIF18A protein. [Background technology]

[0003] KIF18A, a member of the kinesin-8 family, moves toward the positive end of microtubules in cells, driven by ATP hydrolysis. KIF18A localizes to the positive end of microtubules, regulating their dynamic instability and exerting microtubule polymerase activity, which is crucial for chromosome segregation. During mitosis, KIF18A regulates microtubule dynamics and chromosome amplitude in the spindle, potentially playing an important role in chromosome alignment, genome stability, and the successful completion of mitosis. KIF18A is also involved in many other cellular processes, including the cell cycle, cell migration, and cytoplasmic organization. Alterations in KIF18A expression and activity can lead to cell division abnormalities and promote cancer development.

[0004] Therefore, there is an unmet medical need for treatments for cancers associated with the KIF18A protein. Summary of the Invention

[0005] In various embodiments, the present disclosure provides new compounds, pharmaceutical compositions, and methods for producing and using the same. Generally, the compounds of the present disclosure are KIF18A inhibitors. The compounds and compositions of the present disclosure can be used to treat various diseases or conditions, such as cancers, associated with the KIF18A protein.

[0006] In various embodiments, the present disclosure provides compounds of Formula I, or pharmaceutically acceptable salts thereof: [ka] wherein each variable is defined in the present disclosure. In some embodiments, the compound of Formula I can have a sub-formula of I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E, as defined in the present disclosure. In some embodiments, the present disclosure provides a compound selected from the group consisting of the compounds set forth in Table A, or a pharmaceutically acceptable salt thereof. In some embodiments, where applicable, the compound can exist as a mixture of any proportional atropisomers. In some embodiments, where applicable, the compound can exist as an isolated single atropisomer essentially free of other atropisomers (e.g., containing less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts by weight or HPLC area).

[0007] Some embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E), any of the compounds set forth in Table A, or a pharmaceutically acceptable salt thereof), and any pharmaceutically acceptable excipient. Pharmaceutical compositions according to the present disclosure can be prepared for various routes of administration, such as oral administration, parenteral administration, or inhalation.

[0008] Some embodiments relate to a method for treating a disease or condition associated with the KIF18A protein. In some embodiments, the method comprises administering to a test subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E), any of the compounds set forth in Table A, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described in the present disclosure. In some embodiments, a method for treating cancer is provided. In some embodiments, the method comprises administering to a test subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a therapeutically effective amount of a pharmaceutical composition described in the present disclosure. In various embodiments, the cancer can be selected from the group consisting of breast cancer, bladder cancer, colon cancer, cervical cancer, lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. Administration is not limited to any particular route of administration. For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral. The compounds of the present disclosure can be used as a monotherapy or combination therapy. In some embodiments, the combination therapy includes treating the subject with a targeted therapeutic agent, a chemotherapeutic agent, a therapeutic antibody, radiation therapy, cell therapy, or immunotherapy.

[0009] It should be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention. [Brief explanation of the drawings]

[0010] [Figure 1] Figures 1a and 1b show the inhibition of tumor growth of exemplary compounds as measured in an OVCAR3 in vivo mouse xenograft model study. DETAILED DESCRIPTION OF THE INVENTION

[0011] In various embodiments, the present disclosure provides new compounds, pharmaceutical compositions, methods of manufacture and methods of use.

[0012] compound Some embodiments of the present disclosure relate to novel compounds. Compounds according to the present disclosure may generally be inhibitors of KIF18A.

[0013] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: R 1 may be replaced by C 3-10 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; R 2 may be substituted with hydrogen or C 1-6 Alkyl, optionally substituted C 1-6 is a heteroalkyl or nitrogen protecting group; or R 1 and R 2 are linked together with the C, C, C and N atoms therebetween to form an optionally substituted 5-14 membered heterocyclyl; R3 But R A , OR A , S.R. A , S(O)R A , S(O)2R A , C.O.R. A , COOR A , CN, NHR A ,CONHR A , S(O)2NHR A , S(O)(NH)R A , NHCOR A , NHS(O)2R A or NO2, where R A are independently hydrogen, halogen, CN, OH, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; X 1 But N or CR 4 where R 4 may be substituted with H, F, Cl, OH, NH2, CN, CD3, CF3, 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 is cycloalkyl; X 2 But N or CR 5 where R 5 may be substituted with H, F, Cl, OH, NH2, CN, CD3, CF3, 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 is cycloalkyl; X 3 But N or CR 6 where R 6may be substituted with H, F, Cl, OH, NH2, CN, CD3, CF3, 1-4 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 is cycloalkyl; or R 5 and R 6 together with the C and C atoms therebetween to form an optionally substituted 5-8 membered heteroaryl; [ka] may be replaced by C 3-10 a carbocycle, an optionally substituted 4-10 membered heterocycle, an optionally substituted aryl ring containing 0, 1, 2 or 3 heteroatoms independently selected from N, O and S; R S Each time, R T , OR T , S.R. T , NHR T , C.O.R. T , COOR T ,CONHR T , NHCOR T , CN or NO2, where R T are independently hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and n is 0, 1, 2 or 3.

[0014] In some embodiments, the present disclosure also provides a prodrug of a compound of Formula I (e.g., any of the subformulas of the present disclosure) or a pharmaceutically acceptable salt thereof. As understood in the art, a prodrug of an active ingredient generally refers to a compound that can be converted to the active ingredient after administration to a subject (e.g., a mammal, preferably a human). The prodrug is generally stable so that it can be manufactured and / or formulated for administration to a subject. In some embodiments, the prodrug is an ester prodrug, e.g., an ester prodrug derived from the OH group of a compound of Formula I and a carboxylic acid having 1-20 carbons (wherein one or more carbons may have a substituent such as OH, NH, monoalkylamine, dialkylamine, etc.). In some embodiments, the prodrug is an aminoester prodrug, e.g., a prodrug derived from the OH group of a compound of Formula I and an amino acid (e.g., a natural amino acid (e.g., L-valine) or an unnatural amino acid) or a peptide (e.g., a dipeptide, tripeptide, or tetrapeptide). Other types of prodrugs are also suitable.

[0015] In some embodiments, X 1 But N or CR 4 where R 4 is H, F, or Cl. In some embodiments, X 2 But N or CR 5 where R 5 is H, F, or Cl. In some embodiments, X 3 But N or CR 6 where R 6 is H, F, or Cl. In some embodiments, X 1 is N and X 2 and X 3 are each independently CH, CF, or CCH. In some embodiments, X 2 is N and X 1 and X 3 are each independently CH, CF, or CCH. In some embodiments, X3 is N and X 1 and X 2 are each independently CH, CF, or CCH. In some embodiments, X 1 and X 2 But both are N and X 3 is CH or CF. In some embodiments, X 2 and X 3 But both are N and X 1 is CH or CF. In some embodiments, X 1 , X 2 and X 3 are both CH. In some embodiments, X 1 , X 2 and X 3 One of them is CF and X 1 , X 2 and X 3 The other two are CH.

[0016] In some embodiments, compounds of formula I may be characterized as having formulas I-1 and I-2. [Table 1] where the variable R 1 , R 2 , R 3 , [ka] , R S and n includes any combination of any of the substituents described in this disclosure; R in Formula I-1 7a and R 7b are each independently hydrogen, halogen, CN, OH, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl or optionally substituted C1-6 haloalkyl; or R 7a and R 7b are connected together with the C atom between them to form an optionally substituted C 3-10 forming a carbocyclyl or an optionally substituted 4- to 10-membered heterocyclyl; R in Formula I-1 8a and R 8b are independently H, F, Cl, CN, OH, C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), C 1-4 haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), C 1-4 Alkoxy (e.g., methoxy, ethoxy, isopropyloxy, etc.) or C 1-4 haloalkoxy (e.g., CF3O-, CF3CH2O-, etc.); R in Formula I-2 1 and R 2 However, they do not form an optionally substituted 5-14 membered heterocyclyl without being linked.

[0017] In some embodiments, in Formula I-1, R 7a and R 7b are connected together with the C atom between them to form an optionally substituted C 3-10 Forms a carbocyclyl. For example, R 7a and R 7b are linked together with the C atom between them to form an optionally substituted C4 carbocyclyl, an optionally substituted C5 carbocyclyl, an optionally substituted C6 carbocyclyl, an optionally substituted C7 carbocyclyl or an optionally substituted C8 carbocyclyl.

[0018] In some embodiments, in Formula I-1, R 8a and R 8b are both hydrogen. In some embodiments, in Formula I-1, R 8a is hydrogen and R 8b is F or Cl.

[0019] In some embodiments, the compound of formula I-1 may be characterized as having the formula I-1-A. [ka] where the variable R 3 , [ka] , R S and n includes any combination of any of the substituents described in this disclosure; R 9a and R 9b are each independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 is heteroalkyl; or R 9a and R 9b are connected together with the C atom between them to form an optionally substituted C 3-6 forming a carbocyclyl or an optionally substituted 4- to 6-membered heterocyclyl; or R 9a and R 9b combine to form =CF2, =CCl2 or =C(CH3)2.

[0020] In some embodiments, R 9a and R 9b are each independently H, F, Cl, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, CF3O-, or CF3CHO-. 9a and R 9b are each independently H, F, Cl, methyl, ethyl, CD, trifluoromethyl, or CF0-. In some embodiments, R 9a and R 9b are linked together with the C atom between them to form an optionally substituted cyclopropyl or cyclobutyl. 9a and R9b are linked together with the C atom therebetween to form an optionally substituted cyclopropyl.

[0021] In some embodiments, [ka] is a 5- or 6-membered heteroaryl ring containing 1 or 2 ring-forming N atoms, for example, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl. [ka] is a 9-membered heteroaryl ring containing 1, 2, or 3 ring-forming N atoms, such as benzimidazolyl, pyrrolopyridyl, or imidalopyridyl. In some embodiments, R S Each time, the following R B , R C , R D , R E , R F , R G1 or R G2 In some embodiments, n is 1, 2, or 3.

[0022] In some embodiments, [ka] is selected from the following groups, which may be further substituted: [ka] During the ceremony: R B , R D , R E , R F , R G1 and R G2 are each independently hydrogen, halogen, CN, OH, NH2, optionally substituted C1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 is cycloalkyl; R C is -L1-L2, where L1 is a blank, -O-, -NH-, -N(C 1-6 alkyl)-, -CH2-, -CH(C 1-6 alkyl)-, -CH(OH)-, -C(O)-, -S-, -S(O)2- or -S(O)2NH-, and L2 is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 3-10 carbocyclyl or optionally substituted 4-10 membered heterocyclyl, preferably L2 is monocyclic or contains spirocyclic, bridged and / or fused rings, unsubstituted or substituted with F, OH and C 1-6 C substituted with one or more groups independently selected from alkyl 4-8 carbocyclyl, or monocyclic or containing spirocyclic, bridged and / or fused rings, unsubstituted or substituted with F, OH and C 1-6 C substituted with one or more groups independently selected from alkyl and containing one, two or three heteroatoms independently selected from N, O and S 4-10 It is a heterocyclyl.

[0023] In some embodiments, [ka] is selected from the following groups, which may be further substituted: [ka] During the ceremony: R B , R D , R E , R F , R G1 and R G2are each independently hydrogen, halogen, CN, OH, NH2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 is cycloalkyl; R C may be replaced by C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl or optionally substituted C 1-6 is haloalkyl; or R C is selected from the following groups, which may be further substituted: [ka]

[0024] In some embodiments, [ka] is selected from the following groups, which may be further substituted: [ka] During the ceremony: R B , R D , R E , R F , R G1 and R G2 are each independently hydrogen, halogen, CN, OH, NH2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 is cycloalkyl; R C is selected from the following groups, which may be further substituted: [ka]

[0025] In some embodiments, [ka] but, [ka] where the variable R C , R D and R F contains any combination of any of the substituents described in this disclosure. [ka] but, [ka] where the variable R C , R E and R F includes any combination of any of the substituents described in this disclosure.

[0026] In some embodiments, R B , R D , R E and R F are each independently H, F, Cl, CN, CH, CHCH, CHF, CF, CHCF, OCH, OCHCH, O-CH(CH), OCHF, OCF, OCHCF, OCHCHCF, or SCF. B is hydrogen. In some embodiments, R E and R F are both hydrogen. In some embodiments, R G1 and R G2 are both Cl or F. In some embodiments, R C is CH3, CH2CF3, CH2CH2CF3, OCF3, OCH2CF3, OCH2CH2CF3 or CF3; or R C but, [ka] is selected from the group consisting of:

[0027] In some embodiments, R C but, [ka] In some embodiments, R C is NHCH2CH2CF3, or [ka] In some embodiments, R C but, [ka] In some embodiments, R C but, [ka] is selected from the group consisting of:

[0028] In some embodiments, the compound of formula I-1-A may be characterized as having formula I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, or I-1-Ah. [Table 2]

[0029] where the variable R 3 , R 9a , R 9b , R B , R C , R D , R E and R Fincludes any combination of any of the substituents described in this disclosure.

[0030] In Formula I-1-A (e.g., Formula I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, or I-1-Ah), R 9a and R 9b may be chosen as follows: In some embodiments, R 9a and R 9b are each independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 In some embodiments, R is heteroalkyl. 9a and R 9b are each independently H, F, Cl, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, CF3O-, or CF3CHO-. 9a and R 9b are each independently H, F, Cl, methyl, ethyl, CD, trifluoromethyl, or CF0-. In some embodiments, R 9a and R 9b are both F or methyl, or R 9a is F and R 9b is methyl. In some embodiments, R 9a and R 9b are connected together with the C atom between them to form an optionally substituted C 3-6 In some embodiments, R forms a carbocyclyl or an optionally substituted 4- to 6-membered heterocyclyl. 9a and R 9b are linked together with the C atom therebetween to form an optionally substituted cyclopropyl or cyclobutyl, preferably cyclopropyl. In some embodiments, R 9a and R 9b are linked to form =CF, =CCl, or =C(CH). In some embodiments, R 9a and R 9bcombine to form =CF2.

[0031] In Formula I-1-A (e.g., Formula I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, or I-1-Ah), R 3 may be chosen as follows: In some embodiments, R 3 But -CONHR A , -S(O)2NHR A , -NHCOR A or-NHS(O)2R A where R A may be substituted with F, OH or NH 2-4 alkyl; or R 3 but, [ka] In some embodiments, R 3 but, [ka] In a more preferred embodiment, R 3 However, -NHS(O)2R A where R A is -CH2CH2OH or -CH2CH2CH2OH. In a more preferred embodiment, R 3 but, [ka] or [ka] In some embodiments, R 3 However, -NHS(O)2R A where R A is -CH2CH3. In some embodiments, R 3However, -NHS(O)2R A where R A is —CHCHN(CH). In some embodiments, R 3 However, -NHS(O)2R A where R A is —CHCHOH. In some embodiments, R 3 However, -NHS(O)2R A where R A But -CH2CH2O-G X where G X But -CH2CH2O-G X R A When the compound is administered to a subject (e.g., a mammal, preferably a human), -CH2CH2O-G X represents a group that can be converted to —CHCHOH in vivo. X is acyl as defined herein, e.g., -C(O)-G X1 where G X1 may be substituted, C 1-20 It is an aliphatic group (e.g., alkyl, alkenyl, carbocycle, etc.), an aryl ring, or a 4-14 membered heterocyclic ring structure. X is aminoacyl, which in the present disclosure broadly refers to acyl substituted with one or more amino groups (e.g., one or more groups selected from the group consisting of NH, monoalkylamino, or dialkylamino). For example, in some embodiments, -CHCHO-G X A portion of R may be an ester of —CHCHOH with an amino acid (e.g., a natural amino acid (e.g., L-valine) or an unnatural amino acid) or a peptide (e.g., a dipeptide, tripeptide, or tetrapeptide). In some embodiments, R 3 However, -NHS(O)2R A where R A is —CH2CH2OC(O)R″, where R″ is an optionally substituted C 1-6 Alkyl, optionally substituted C 2-6Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl or optionally substituted C 3-6 For example, in some embodiments, R 3 However, -NHS(O)2R A where R A is —CHCHOC(O)CH(NH)CH(CH). In some embodiments, R 3 However, -NHS(O)2R A where R A C may be replaced by F 1-4 alkyl, for example, CF or CHCF. In some preferred embodiments, R 3 but, [ka] or [ka] In some embodiments, R 3 However, -NHS(O)2R A where R A may be substituted with F and / or OH, NH-C 1-4 alkyl or 4-membered heterocyclyl, for example, NH-CH3 or [ka] In some preferred embodiments, R 3 but, [ka] or [ka] In some embodiments, R 3 But S(O)2RA where R A C, which may be substituted with F and / or OH 1-4 alkyl, for example, CH. In some preferred embodiments, R 3 but, [ka] In some embodiments, R 3 However, NHR A where R A C, which may be substituted with F and / or OH 1-6 alkyl, for example, C(CH)CHOH. In some preferred embodiments, R 3 but, [ka] is.

[0032] In formula I-1-Aa, I-1-Ac, I-1-Af or I-1-Ag, R B may be chosen as follows: In some embodiments, R B hydrogen, halogen, CN, OH, NH2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 In some embodiments, R B H, halogen, CN, C 1-3 Alkyl or C 1-3 alkoxy; preferably H, F, Cl, CN, CH3, or OCH3. In some embodiments, R B is hydrogen. In some embodiments, R B But it is F.

[0033] In formula I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag or I-1-Ah, R Cmay be chosen as follows: In some embodiments, R C is -L1-L2, where L1 is a blank, -O-, -NH-, -N(C 1-6 alkyl)-, -CH2-, -CH(C 1-6 alkyl)-, -CH(OH)-, -C(O)-, -S-, -S(O)2- or -S(O)2NH-, and L2 is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 1-6 Haloalkyl, optionally substituted C 3-10 carbocyclyl or optionally substituted 4-10 membered heterocyclyl, preferably L2 is monocyclic or contains spirocyclic, bridged and / or fused rings, unsubstituted or substituted with F, OH and C 1-6 C substituted with one or more groups independently selected from alkyl 4-8 carbocyclyl, or monocyclic or containing spirocyclic, bridged and / or fused rings, unsubstituted or substituted with F, OH and C 1-6 C substituted with one or more groups independently selected from alkyl and containing one, two or three heteroatoms independently selected from N, O and S 4-10 In some embodiments, R is heterocyclyl. C may be replaced by C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl or optionally substituted C 1-6 In some embodiments, R C is selected from the following groups, which may be further substituted: [ka] In some embodiments, R C is selected from the following groups, which may be further substituted: [ka] In some embodiments, R Cis CH3, CH2CF3, CH2CH2CF3, OCF3, OCH2CF3, OCH2CH2CF3, or CF3. In some embodiments, R C is selected from the following groups, which may be further substituted: [ka] In some embodiments, R C is selected from the following groups, which may be further substituted: [ka] In some embodiments, R C is NHCH2CH2CF3 or is selected from the following groups, which may be further substituted: [ka] In some embodiments, R C is selected from the following groups, which may be further substituted: [ka] In some embodiments, R C is selected from the following groups, which may be further substituted: [ka] In some embodiments, R C but, [ka] is.

[0034] In formula I-1-Aa, I-1-Ab, I-1-Ae, I-1-Af, I-1-Ag, or I-1-Ah, R D may be chosen as follows: In some embodiments, R DHowever, hydrogen, halogens, CN, OH, NH2, C 1-6 Alkyl, O(C 1-6 alkyl), O(CH2) 1-3 O(C 1-6 alkyl), O(CH2) 1-3 NH(C 1-6 alkyl), O(CH2) 1-3 N(C 1-6 Alkyl)(C 1-6 alkyl), NH(C 1-6 alkyl), N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)NH2, C(O)NH(C 1-6 alkyl), C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), optionally substituted C 3-6 cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl, wherein C 1-6 The alkyl may be substituted. In some embodiments, R D However, hydrogen, F, Cl, CN, OH, NH2, C 1-6 Alkyl, O(C 1-6 alkyl), O(CH2) 1-3 O(C 1-6 alkyl), O(CH2) 1-3 NH(C 1-6 alkyl), O(CH2) 1-3 N(C 1-6 Alkyl)(C 1-6 alkyl), NH(C 1-6 alkyl), N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)NH2, C(O)NH(C 1-6 alkyl), C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), C 3-5 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl, or heteroaryl is unsubstituted or substituted with halogen (e.g., F or Cl) and C 1-6substituted with one or more groups independently selected from the group consisting of alkyl, and C 1-6 The alkyl is unsubstituted or substituted with F. In some embodiments, R D However, hydrogen, F, Cl, CN, OH, NH2, C 1-6 Alkyl, O(C 1-6 alkyl), O(CH2) 1-3 O(C 1-6 alkyl), O(CH2) 1-3 NH(C 1-6 alkyl), O(CH2) 1-3 N(C 1-6 Alkyl)(C 1-6 alkyl), NH(C 1-6 alkyl), N(C 1-6 Alkyl)(C 1-6 alkyl), C(O)NH2, C(O)NH(C 1-6 alkyl), C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), C 3-5 cycloalkyl or 5-6 membered heteroaryl containing 1, 2 or 3 ring-forming nitrogen atoms, where the cycloalkyl or heteroaryl is unsubstituted or substituted with halogen (e.g., F or Cl) and C 1-6 substituted with one or more groups independently selected from the group consisting of alkyl, and C 1-6 The alkyl is unsubstituted or substituted with F. In some embodiments, R D hydrogen, halogen, CN, OH, NH2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 In some embodiments, R D H, halogen, CN, C 1-3 Alkyl or C 1-3 alkoxy; preferably H, F, Cl, CN, CH3, or OCH3. In some preferred embodiments, R Dis H, F, Cl, OH, CN, CH3, OCH3, CHF2, CF3, OCHF2, CH2CH3, N(CH3)2, C(O)NH2, C(O)NHCH3, C(O)NHCH2CH3, OCH2CH2OCH3, OCH2CH2N(CH3)2, or cyclopropyl. D contains 1, 2 or 3 ring-forming nitrogen atoms, C 1-2 In some preferred embodiments, R is a 5-membered heteroaryl optionally substituted with alkyl, such as pyrazolyl optionally substituted with methyl, imidazolyl optionally substituted with methyl, or triazolyl optionally substituted with methyl. D but, [ka] In some embodiments, R D contains one or two ring-forming nitrogen atoms, C 1-2 In some preferred embodiments, R is a 6-membered heteroaryl optionally substituted with alkyl, such as pyridyl optionally substituted with methyl or pyrimidyl optionally substituted with methyl. D but, [ka] In some embodiments, R D contains one or two ring-forming nitrogen atoms and is oxo and / or C 1-2 and optionally alkyl-substituted 5- or 6-membered heterocyclyl, such as optionally oxo-substituted pyrrolidinyl, optionally methyl-substituted piperidinyl, optionally oxo- and methyl-substituted piperazinyl, or optionally methyl-substituted tetrahydropyridyl. D but, [ka] In some embodiments, RD is C(O)-(5-6 membered heterocyclyl), wherein the heterocyclyl contains 1 or 2 ring-forming nitrogen atoms, and C 1-2 C(O)-piperazinyl, which may be substituted with alkyl, for example, methyl. In some preferred embodiments, R D but, [ka] is.

[0035] In formula I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af or I-1-Ag, R E may be chosen as follows: In some embodiments, R E hydrogen, halogen, CN, OH, NH2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 In some embodiments, R E is hydrogen.

[0036] In formula I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Af, I-1-Ag or I-1-Ah, R F may be chosen as follows: In some embodiments, R F hydrogen, halogen, CN, OH, NH2, optionally substituted C 1-6 Alkyl, optionally substituted C 1-4 Heteroalkyl or optionally substituted C 3-6 In some embodiments, R F is hydrogen.

[0037] In some embodiments, the compound of formula I-2 may be characterized as having formula I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E: [Table 3] where the variable R 1 , R 3 , R B , R C , R D , R E , R F , R G1 and R G2 includes any combination of any of the substituents described in this disclosure.

[0038] In some embodiments, in Formula I, specifically in Formula I-2 (e.g., in Formula I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E), R 1 is selected from the following groups, which may be further substituted: [ka]

[0039] In some preferred embodiments, R 1 but, [ka] is selected from the group consisting of:

[0040] In some embodiments, R 3 But -CONHR A , -S(O)2NHR A , -NHCOR A or-NHS(O)2R A where R A may be substituted with F, OH or NH 2-4 alkyl; or R 3 but, [ka] is selected from the group consisting of:

[0041] In a more preferred embodiment, R 3 However, -NHS(O)2RA where R A is -CH2CH2OH or -CH2CH2CH2OH. In a more preferred embodiment, R 3 but, [ka] or [ka] In some embodiments, R 3 However, -NHS(O)2R A where R A is -CH2CH3. In some embodiments, R 3 However, -NHS(O)2R A where R A is —CHCHN(CH). In some embodiments, R 3 However, -NHS(O)2R A where R A is —CHCHOH. In some embodiments, R 3 However, -NHS(O)2R A where R A But -CH2CH2O-G X where G X But -CH2CH2O-G X R A When the compound is administered to a subject (e.g., a mammal, preferably a human), -CH2CH2O-G X represents a group that can be converted to —CHCHOH in vivo. X is acyl as defined herein, e.g., -C(O)-G X1 where G X1 may be substituted, C 1-20 It is an aliphatic group (e.g., alkyl, alkenyl, carbocycle, etc.), an aryl ring, or a 4-14 membered heterocyclic ring structure. Xis aminoacyl, which in the present disclosure broadly refers to acyl substituted with one or more amino groups (e.g., one or more groups selected from the group consisting of NH, monoalkylamino, or dialkylamino). For example, in some embodiments, -CHCHO-G X may be an ester of —CHCHOH with an amino acid (e.g., a natural amino acid (e.g., L-valine) or an unnatural amino acid) or a peptide (e.g., a dipeptide, tripeptide, or tetrapeptide). 3 However, -NHS(O)2R A where R A is —CH2CH2OC(O)R″, where R″ is an optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl or optionally substituted C 3-6 For example, in some embodiments, R 3 However, -NHS(O)2R A where R A is -CH2CH2OC(O)CH(NH2)CH(CH3)2.

[0042] In some embodiments, in formula I-1-Aa, I-1-Ac, I-1-Ag, I-2-C, or I-2-D, R B H, halogen, CN, C 1-3 Alkyl or C 1-3 alkoxy; preferably H, F, Cl, CN, CH3 or OCH3.

[0043] In some embodiments, in formula I-1-Aa, I-1-Ab, I-1-Ag, or I-1-Ah, R D H, halogen, CN, C 1-3 Alkyl or C 1-3 alkoxy; preferably H, F, Cl, CN, CH3 or OCH3.

[0044] In some embodiments, the present disclosure further provides a compound selected from the group consisting of the compounds set forth in Table A, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure further provides a prodrug of a compound selected from the group consisting of the compounds set forth in Table A, or a pharmaceutically acceptable salt thereof, such as an ester prodrug or aminoester prodrug described in this disclosure. [Table 4] JPEG2025538601000059.jpg233159 JPEG2025538601000060.jpg237159 JPEG2025538601000061.jpg237149 JPEG2025538601000062.jpg144159

[0045] Synthesis method The compounds of the present disclosure can be readily synthesized by one skilled in the art following the teachings of the present disclosure, and exemplary syntheses are also shown in the Examples section.

[0046] As will be apparent to those skilled in the art, some functional groups may require common protecting groups to prevent undesired reactions. Suitable protecting groups for each functional group and suitable conditions for protecting and deprotecting specific functional groups are known in the art. For example, numerous protecting groups are described in "Protective Groups in Organic Synthesis" (4th ed., P.G.M.Wuts, T.W. Greene, John Wiley, 2007) and the references cited therein. Reagents for the reactions of the present invention are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, some reagents are commercially available, such as those sold by Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (Wiley, 7th Edition) and Larock's Comprehensive Organic Transformations (Wiley VCH, 1999) and available updated versions of any of these publications, or obvious modifications thereof.

[0047] Pharmaceutical Composition Some embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0048] The pharmaceutical composition can optionally include a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition includes a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E), any compound shown in Table A of the present disclosure, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmacologically acceptable excipients are well known in the art. Non-limiting examples of suitable excipients include, for example, encapsulants or additives such as absorption enhancers, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, swelling agents, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. Further, various excipients for preparing pharmaceutical compositions and the prior art for their manufacture are disclosed in Remington's The Science and Practice of Pharmacy, 21 st Edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005, which is incorporated herein by reference).

[0049] The pharmaceutical composition can include any one or more compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition includes, for example, a therapeutically effective amount of a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E), any compound shown in Table A, or a pharmaceutically acceptable salt thereof. In any embodiment according to the present disclosure, the pharmaceutical composition can include a therapeutically effective amount of any compound selected from the group consisting of the compounds shown in Table A or the Examples section of this disclosure, or a pharmaceutically acceptable salt thereof.

[0050] Pharmaceutical compositions can further be prepared to be administered by any known route of administration, including, but not limited to, oral administration, parenteral administration, inhalation administration, and the like.

[0051] In some embodiments, pharmaceutical compositions can be prepared for oral administration. Oral formulations can be presented as discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of active compound; as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for preparing oral administration compositions are well known in the art. Non-limiting examples of suitable excipients include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethylcellulose, isopropanol, saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, and the like. oil), potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium laurate sulfate, sodium sorbitol, soybean oil, stearic acid, stearic fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofuryl alcohol, triglycerides, water and mixtures thereof.

[0052] In some embodiments, the pharmaceutical composition is prepared in a dosage form for parenteral administration (e.g., intravenous injection or infusion, subcutaneous injection, or intramuscular injection). Parenteral formulations may be, for example, aqueous solutions, suspensions, or emulsions. Excipients for the manufacture of parenteral formulations are well known in the art. Non-limiting examples of suitable excipients include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, glucose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0053] In some embodiments, the pharmaceutical composition is prepared into an inhalable formulation. The inhalable formulation is prepared into a nasal spray, dry powder, or aerosol that can be administered, for example, by a metered-dose inhaler. Excipients for the manufacture of inhalable formulations are well known in the art. Non-limiting examples of suitable excipients include lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, and mixtures thereof. Sprays can further contain propellants such as chlorofluorocarbons and unsubstituted volatile hydrocarbon compounds such as butane and propane.

[0054] Pharmaceutical compositions can contain varying amounts of a compound of the present disclosure, depending on various factors, such as the intended use, potency, and selectivity of the compound. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E), any compound shown in Table A, or a pharmaceutically acceptable salt thereof). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. As used in this disclosure, a therapeutically effective amount of a compound of the present disclosure means an amount effective to treat a disease or condition according to the present disclosure, which depends on the subject being treated, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency (e.g., inhibition of KIF18A), its clearance rate, and whether it is used in combination with other drugs.

[0055] For veterinary use, the compounds of the present disclosure can be administered in an appropriately acceptable formulation in accordance with normal veterinary practice, and a veterinarian can readily determine the most appropriate dosing regimen and route of administration for a particular animal.

[0056] In some embodiments, all components necessary for the treatment of a KIF18A-associated disease can be packaged into a kit, using a compound of the present disclosure, either alone or in combination with another therapeutic or interventional agent conventionally used to treat such disease. Specifically, in some embodiments, the present invention provides kits for therapeutic intervention of a disease, comprising a compound of the present disclosure, a packaged drug set, including buffers and other components for preparing the drug in a usable format, and / or a device for delivering such a drug, and / or any other agent for co-treatment with the compound of the present disclosure, and / or instructions for treating the disease in the drug package. These instructions may be affixed to any tangible medium, such as a printed sheet, or to a computer-readable magnetic or optical medium, or instructions referencing a remote computer data source (e.g., a World Wide Web page accessible via the Internet).

[0057] Treatment method The compounds of the present disclosure are used as therapeutically active substances to treat and / or prevent diseases or conditions associated with the KIF18A protein.

[0058] In some embodiments, the disclosure provides a method of inhibiting KIF18A in a cell, the method comprising contacting the cell with a therapeutically effective amount of one or more compounds of the disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D or I-2-E), any compound shown in Table A, or a pharmaceutically acceptable salt thereof).

[0059] In some embodiments, the present disclosure provides a method for treating a disease or condition (e.g., a cancer associated with a KIF18A protein) in a subject in need thereof. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E), any compound shown in Table A, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described in the present disclosure.

[0060] In some embodiments, a method of treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E), any compound set forth in Table A, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound of the present disclosure. In some embodiments, the cancer involves KIF18A protein. In various embodiments, the cancer may be a solid tumor or a blood-borne tumor selected from the group consisting of bladder cancer, endometrial cancer, lung squamous cell carcinoma, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer. In some embodiments, the cancer is a lymphoid hematopoietic tumor selected from the group consisting of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkett lymphoma. In some embodiments, the cancer is a myeloid hematopoietic tumor selected from the group consisting of acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia. In some embodiments, the cancer is a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma. In some embodiments, the cancer is a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma, hi some embodiments, the cancer is melanoma, seminoma, teratocarcinoma, osteosarcoma, pigmented dysplasia, keratosis keratosis mucosa, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0061] In some embodiments, the present disclosure provides a method of treating a disease or condition (e.g., a cancer described in the present disclosure) in a test subject in need thereof, the method comprising: determining whether the test subject has a KIF18A protein; and, if the test subject is determined to have a KIF18A protein, administering to the test subject a therapeutically effective amount of at least one compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E), any compound set forth in Table A, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising at least one compound of the present disclosure.

[0062] The compounds of the present disclosure are used as monotherapy or combination therapy. In some embodiments, the combination therapy includes treating a subject with a chemotherapeutic agent, a therapeutic antibody, radiation therapy, cell therapy, or immunotherapy. In some embodiments, the compounds of the present disclosure can be co-administered simultaneously or sequentially in any order with an additional pharmaceutically active compound to a subject in need thereof (e.g., a subject having a cancer associated with a KIF18A protein according to the present disclosure). In some embodiments, the additional pharmaceutically active compound can be a chemotherapeutic agent, a therapeutic antibody, or the like. Any known chemotherapeutic agent can be used in combination with the compounds of the present disclosure. In some embodiments, the compounds of the present disclosure are used in combination with radiation therapy, hormone therapy, cell therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0063] The administration of the present disclosure is not limited to a particular route of administration. For example, in some embodiments, the mode of administration may be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, the mode of administration is oral.

[0064] Dosage regimens, including dosage, can vary and be adjusted depending on the patient being treated, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether it is used in combination with other drugs.

[0065] definition It should be understood that all moieties and combinations thereof maintain the appropriate chemical value.

[0066] It should be understood that a specific embodiment of a variable portion according to the present disclosure may be the same as or different from another specific embodiment having the same reference number.

[0067] Suitable atoms or groups for the variables in this disclosure are independently selected. The definitions of the variables may be combined. For example, in Formula I, R 1 , R 2 , R 3 , [ka] , X 1 , X 2 , X 3 , R 4 , R 5 , R 6 , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R A , R B , R C , R D , R E , R F , R G1 , R G2 , R S , R T and any definition of n is R in Formula I 1 , R 2 , R 3 , [ka] , X 1 , X 2 , X 3 , R 4 , R 5 , R 6 , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R A , R B , R C , R D , R E , R F , R G1 , R G2 , R S , R T and any other definition of n. Such combinations are contemplated and are within the scope of the present disclosure.

[0068] Definitions of specific functional groups and chemical terms are discussed in more detail below. Chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover), and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rdEdition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents set forth herein.

[0069] The compounds of the present disclosure can contain one or more asymmetric centers and / or axial chirality and can therefore exist in various isomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds of the present disclosure can be in the form of a single enantiomer, diastereomer, atropisomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); and Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds of the present disclosure as single isomers essentially free of other isomers or as mixtures of various isomers, including racemic mixtures. In embodiments of the present disclosure, unless otherwise stated, when stereochemistry is specifically depicted for that particular chiral center or axial asymmetry, it is to be understood that the compound exists predominantly as the depicted stereoisomer, with less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of other stereoisomers, e.g., by weight, by HPLC area, or both. In accordance with the present disclosure, one of ordinary skill in the art can determine the presence and / or amount of stereoisomers by methods including determination by chiral HPLC.

[0070] The compounds of the present disclosure may have atropisomers. In any embodiment according to the present disclosure, if applicable, the compounds of the present disclosure can exist as a mixture of atropisomers in any ratio. In some embodiments, if applicable, the compounds can exist as isolated individual atropisomers that are substantially free of other atropisomers (e.g., the amount of other atropisomers is less than 20%, less than 10%, less than 5%, less than 1%, or undetectable by weight, HPLC area, or both). The Examples section shows exemplary isolated atropisomers of the compounds of the present disclosure. As will be understood by those skilled in the art, when rotation is restricted around a single bond, such as a biaryl single bond, the compound can exist as a mixture of atropisomers in which each individual atropisomer can be isolated.

[0071] When a range of values ​​is stated, it is intended to encompass each value and subrange within that range. For example, "C 1~6 " refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 is intended to encompass.

[0072] As used herein, the term "one or more compounds of the present disclosure" or "one or more compounds of the invention" refers to a compound according to Formula I (e.g., Formula I-1, I-1-A, I-1-Aa, I-1-Ab, I-1-Ac, I-1-Ad, I-1-Ae, I-1-Af, I-1-Ag, I-1-Ah, I-2, I-2-A, I-2-B, I-2-C, I-2-D, or I-2-E) described in this disclosure, any of the compounds shown in Table A and in the Examples section of this disclosure, It refers to a compound, its isotopically labeled compounds (e.g., deuterium analogs in which one hydrogen atom is replaced with a deuterium atom, where the abundance of the deuterium atom is higher than its natural abundance), its possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), geometric isomers, atropisomers, tautomers, conformers, and / or pharmacologically acceptable salts thereof (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). Hydrates and solvates of the compounds of the present disclosure are considered to be compositions of the present disclosure in which the compounds are combined with water or solvent, respectively.

[0073] The compounds of the present disclosure can exist in isotopically labeled or isotopically enriched forms containing one or more atoms having an atomic mass or mass number different from that most abundantly found in nature. Isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18 F, 36 Cl and 125 Compounds that contain other isotopes of these and / or other atoms are within the scope of this invention, including, but not limited to, I.

[0074] As used in this disclosure, the term "alkyl," when used alone or as part of another group, refers to a straight-chain or branched-chain aliphatic saturated hydrocarbon. In some embodiments, an alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C 1~12 alkyl group) or a specified number of carbon atoms (i.e., a C alkyl group, e.g., a methyl group; a C alkyl group, e.g., an ethyl group; a C alkyl group, e.g., a propyl group or an isopropyl group, etc.). In one embodiment, the alkyl group is a straight-chain C 1~10 In another embodiment, the alkyl group is a branched C 3~10 In another embodiment, the alkyl group is a straight-chain C 1~6 In another embodiment, the alkyl group is a branched C 3~6 In another embodiment, the alkyl group is a straight-chain C 1~4 In one embodiment, the alkyl group is a C 11 group selected from the group consisting of methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl. 1~4 It is an alkyl group. As used in this disclosure, the term "alkylene group," when used alone or as part of another group, means a divalent group derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH-CH-CH-CH-, -CH-CH-CH-, -CH-CH-, and the like.

[0075] As used in this disclosure, the term "heteroalkyl" refers to an alkyl, as defined above, in which one or more carbons have been replaced with a heteroatom, such as O or N. Heteroalkyls are designated by the number of carbons. For example, C 1-4 Heteroalkyl means a heteroalkyl containing 1-4 carbons. If optionally substituted, any heteroatom or carbon atom of a heteroalkyl may be substituted with an acceptable substituent. As used in this disclosure, the term "heteroalkylene," when used alone or as part of another group, refers to a divalent radical derived from heteroalkyl.

[0076] As used in this disclosure, the term "alkenyl," when used alone or as part of another group, refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, e.g., one, two, or three, carbon-carbon double bonds. In one embodiment, an alkenyl group is 2~6 In another embodiment, the alkenyl group is C 2~4 Alkenyl groups. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl groups.

[0077] As used herein, the term "alkynyl," when used alone or as part of another group, refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, e.g., one to three, carbon-carbon triple bonds. In one embodiment, an alkynyl group has one carbon-carbon triple bond. In one embodiment, an alkynyl group is a C 2~6 In another embodiment, the alkynyl group is C 2~4 Alkynyl groups. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0078] As used in this disclosure, the term "alkoxy" when used alone or as part of another group refers to a group of the formula OR a1 where R a1 is an alkyl group as defined herein.

[0079] As used herein, the term "haloalkyl," when used alone or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In preferred embodiments, a haloalkyl group is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, a haloalkyl group is a C 1~4 It is a haloalkyl group.

[0080] "Carbocyclyl" or "carbocycle", when used alone or as part of another group, refers to a ring system having 3 to 10 ring-forming carbon atoms ("C 3-10 "Carbocyclyl" refers to a non-aromatic cyclic hydrocarbon group having 0 heteroatoms and 0 heteroatoms. A carbocyclyl group can be monocyclic ("monocyclic carbocyclyl"), or it can be a bicyclic ring system ("bicyclic carbocyclyl"), including fused, bridged, or spiro ring systems, and can be saturated or partially unsaturated. A "carbocyclyl" also includes ring systems in which a carbocycle, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is at the carbocycle, and in this case the number of carbons still represents the number of carbons in the carbocyclic ring system. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamantyl, cyclopentenyl, and cyclohexenyl.

[0081] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl having 3 to 10 ring-forming carbon atoms ("C 3-10 In some embodiments, a "carbocyclyl" has 3 to 8 ring-forming carbon atoms ("C 3-8 In some embodiments, a "carbocyclyl" has 3 to 6 ring-forming carbon atoms ("C 3-6 In some embodiments, a "carbocyclyl" has 5 to 6 ring-forming carbon atoms ("C 5-6 In some embodiments, a "carbocyclyl" has 5 to 10 ring-forming carbon atoms ("C 5-10 cycloalkyl").

[0082] "Heterocyclyl" or "heterocycle," when used alone or as part of another group, refers to a 3- to 10-membered non-aromatic ring system having ring-forming carbon atoms and 1 to 4 ring-forming heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "3- to 10-membered heterocyclyl group"). Where applicable, heterocyclyl groups or heterocycles having a different ring size from a 3- to 10-membered heterocyclyl group are designated by the designation of the different ring size. One skilled in the art would recognize that such heterocyclyl groups having a different ring size are also non-aromatic ring systems having ring-forming carbon atoms and 1 to 4 ring-forming heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, for example, the point of attachment may be at a carbon or nitrogen atom, where valency is permitted. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl groups"), fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl groups"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl groups" also include ring systems comprising a heterocycle, as defined above, fused with one or more carbocyclic groups, where the point of attachment is at the carbocyclic or heterocyclic ring, and ring systems comprising a heterocycle, as defined above, fused with one or more aryl or heteroaryl groups, where the point of attachment is at the heterocycle, and in which case the number of ring members still refers to the number of ring members in the heterocyclic ring system.

[0083] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl groups. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrole-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolane, oxathiolane, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl groups. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tetrahydrothianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, 1,4-dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to in the present disclosure as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolyl groups, isoindolyl groups, dihydrobenzofuryl groups, dihydrobenzothienyl groups, benzoxazolinonyl groups, etc. Exemplary 6-membered heterocyclyl groups (also referred to in the present disclosure as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl groups, tetrahydroisoquinolinyl groups, etc.

[0084] "Aryl," when used alone or as part of another group, refers to a group having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared by the cyclic ring array) of 6 to 14 carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring-forming carbon atoms (a "C aryl group"; e.g., a phenyl group). In some embodiments, an aryl group has 10 ring-forming carbon atoms (a "C 10 aryl groups"; e.g., naphthyl groups, e.g., 1-naphthyl and 2-naphthyl groups. In some embodiments, aryl groups have 14 ring-forming carbon atoms ("C 14 "Aryl group" includes, for example, an anthryl group. "Aryl group" further includes ring systems comprising an aryl ring, as defined above, fused with one or more carbocyclic or heterocyclic groups, where the radical or point of attachment is on the aryl ring, and in this case the number of carbon atoms still represents the number of carbon atoms in the aromatic ring system.

[0085] "Aralkyl," when used alone or as part of another group, refers to an alkyl group substituted with one or more aryl groups, preferably one aryl group. Examples of aralkyl groups include benzyl, phenethyl, and the like. When an aralkyl group is described as being optionally substituted, either the alkyl portion or the aryl portion of the aralkyl group may be substituted.

[0086] "Heteroaryl," when used alone or as part of another group, refers to a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 or 10 π-electrons shared by the cycloarray) ("5-10-membered heteroaryl group") having ring-forming carbon atoms and 1 to 4 ring-forming heteroatoms (where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur) provided in the aromatic ring system. In heteroaryl groups containing one or more nitrogen atoms, for example, the point of attachment may be at a carbon or nitrogen atom, where valency allows. Bicyclic heteroaryl ring systems contain one or more heteroatoms in one or both rings. "Heteroaryl group" includes ring systems comprising a heteroaryl ring, as defined above, fused with one or more carbocyclic or heterocyclic groups, where the point of attachment is at the heteroaryl ring, and in this case the number of ring members still represents the number of ring members in the heteroaryl ring system. The term "heteroaryl" also includes ring systems comprising a heteroaryl ring, as defined above, fused to one or more aryl groups, where the point of attachment is at the aryl or heteroaryl ring, and in this case the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In dicycloheteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbozolyl, etc.), the point of attachment can be at either ring, i.e., at a heteroatom ring (e.g., 2-indolyl) or at a ring without a heteroatom (e.g., 5-indolyl).

[0087] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl groups. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl groups. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl groups. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl groups. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl groups. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, piperazinyl, pyrimidinyl, and pyrazinyl groups. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl groups, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl groups. Exemplary 5,6-dicycloheteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzoisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl groups. Exemplary 6,6-dicycloheteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, 2,3-phthalazinyl, and quinazolinyl groups.

[0088] A "heteroaralkyl group," when used alone or as part of another group, is an alkyl group substituted with one or more heteroaryl groups, preferably one heteroaryl group. Where a heteroaralkyl group is described as being optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl group may be substituted.

[0089] As generally understood by those skilled in the art, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene are the corresponding divalent radicals of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, respectively.

[0090] "Optionally substituted" groups, such as optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted carbocyclic groups, optionally substituted heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups, refer to the respective unsubstituted or substituted groups. Typically, the term "substituted," despite the preceding term "optionally," refers to a group in which at least one hydrogen atom present in the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent whose substitution produces a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions in any given structure are substituted, the substituent may be the same or different at each position. The substituent may be a carbon atom, nitrogen atom, oxygen atom, or sulfur atom substituent, as appropriate.

[0091] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permissible and result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain unchanged, or essentially unchanged, for a period of time sufficient to permit use of the compound for the purposes described in this disclosure (e.g., therapeutic administration to a subject).

[0092] In some embodiments, an "optionally substituted" non-aromatic group in the present disclosure can be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, the substituents being independently F, Cl, -OH, oxo group (where applicable), C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, C 1~4 Alkoxy group, C 3~6 Cycloalkyl groups, C 3~6 a cycloalkoxy group, a phenyl group, a 5- or 6-membered heteroaryl group containing 1, 2, 3, or 4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, a 4- to 7-membered heterocyclic group containing 1, 2, 3, or 4 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, or independently selected from the group consisting of Br, I, -NH2, and -CN, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted with 1, 2, 3, 4, or 5 substituents, which are independently selected from F, -OH, oxo (if applicable), C, 1~4 Alkyl group, fluorine-substituted C 1~4 Alkyl groups (e.g., CF3), C 1~4 Alkoxy and fluorine-substituted C 1~4In some embodiments, aromatic groups, including "optionally substituted" aryl or heteroaryl groups, in the present disclosure may be unsubstituted or substituted with 1, 2, 3, or 4 substituents, wherein the substituents are independently selected from the group consisting of F, Cl, -OH, -CN, -C ... 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkoxy, phenyl, a 5- or 6-membered heteroaryl group containing 1, 2, or 3, or 4 or 5 ring-forming heteroatoms independently selected from the group consisting of O, S, and N, a 4- to 7-membered heterocyclyl group containing 1, 2, or 3, or 4, independently selected from the group consisting of O, S, and N, or independently selected from the group consisting of Br, I, and -NH, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, or 3, or 4 or 5, substituents, said substituents being independently selected from F, -OH, oxo (if applicable), C 1~4 Alkyl group, fluorine-substituted C 1~4 Alkyl group, C 1~4 Alkoxy and fluorine-substituted C 1~4 alkoxy groups, or independently selected from the group consisting of Br, I, -NH2, and -CN.

[0093] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSRcc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa ,-P(=O)(Raa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Carbocyclyl group, 3-14 membered heterocyclyl group, C 6-14 and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; -is a counterion; or, two gem hydrogens on a carbon atom are bonded to groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc is replaced by; R aa Each instance of is independently C 1~10 Alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6~14 aryl groups and 5- to 14-membered heteroaryl groups, or two R aa groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa)2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6~14 aryl groups and 5- to 14-membered heteroaryl groups, or two R bb groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; - is the counterion; R cc Each instance of is independently hydrogen, C 1~10 Alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6~14 aryl groups and 5- to 14-membered heteroaryl groups, or two R cc groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each example of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3+X - , -N(OR ee )R ff , -SH, -SR ee , -SSRee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2,-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)(OR) ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. C 1~6 Arukaraki, C 1~6 Haruka Raki, C 2-6 アルケニbase, C 2-6 アルキニbased, C 3~10 Carbon ring group, 3~10 member complex ring group, C 6~10aryl, and 5-10 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg or two gem R dd The substituents may be linked to form =O or =S; where X - is the counterion; R ee Each instance of is independently C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3~10 carbocyclic group, C 6~10 aryl groups, 3- to 10-membered heterocyclic groups, and 3- to 10-membered heteroaryl groups, wherein each alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of is independently hydrogen, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3~10 Carbocyclic group, 3- to 10-membered heterocyclic group, C 6~10 aryl groups and 5-10 membered heteroaryl groups, or two R ff groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; and R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl group, -ON(C 1-6alkyl group)2, -N(C 1-6 alkyl group)2, -N(C 1-6 Alkyl group)3+X - , -NH(C 1-6 Alkyl group)2+X - , -NH2(C 1-6 alkyl group) + X - , -NH3+X - , -N(OC 1-6 alkyl group)(C 1-6 alkyl group), -N(OH)(C 1-6 alkyl group), -NH(OH), -SH, -SC 1-6 Alkyl group, -SS(C 1-6 alkyl group), -C(=O)(C 1-6 alkyl group), -CO2H, -CO2(C 1-6 alkyl group), -OC(=O)(C 1-6 alkyl group), -OCO2(C 1-6 alkyl group), -C(=O)NH2, -C(=O)N(C 1-6 alkyl group)2, -OC(=O)NH(C 1-6 alkyl group), -NHC(=O)(C 1-6 alkyl group), -N(C 1-6 alkyl group)C(=O)(C 1-6 alkyl group), -NHCO2(C 1-6 alkyl group), -NHC(=O)N(C 1-6 alkyl group)2, -NHC(=O)NH(C 1-6 alkyl group), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl group), -OC(=NH)(C 1-6 alkyl group), -OC(=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 alkyl group)2, -C(=NH)NH(C 1-6 alkyl group), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl group)2, -OC(NH)NH(C 1-6 alkyl group), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl group), -NHC(=NH)NH, -NHSO(C 1-6alkyl group), -SO2N(C 1-6 alkyl group)2, -SO2NH(C 1-6 alkyl group), -SO2NH2, -SO2C 1-6 Alkyl group, -SO2OC 1-6 Alkyl group, -OSO2C 1-6 Alkyl group, -SOC 1-6 Alkyl group, -Si(C 1-6 alkyl group)3, -OSi(C 1-6 alkyl group)3-C(=S)N(C 1-6 alkyl group), C(=S)NH(C 1-6 alkyl group), C(=S)NH2, -C(=O)S(C 1-6 alkyl group), -C(=S)SC 1-6 Alkyl group, -SC(=S)SC 1-6 Alkyl group, -P(=O)(OC 1-6 alkyl group)2, -P(=O)(C 1-6 alkyl group)2, -OP(=O)(C 1-6 alkyl group)2, -OP(=O)(OC 1-6 Alkyl group)2, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3~10 carbocyclic group, C 6~10 an aryl group, a 3- to 10-membered heterocyclic group, or a 5- to 10-membered heteroaryl group; or two geminal R gg The substituents may be linked to form =O or =S; where X - is the counter ion.

[0094] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain charge neutrality. Anionic counterions can be monovalent (i.e., contain one form of negative charge). Anionic counterions can also be multivalent (i.e., contain more than one form of negative charge), such as divalent or trivalent. Exemplary counterions are halogen ions (e.g., F - , Cl - , Br - , I- ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonic acid-5-sulfonate ion, ethane-1-sulfonic acid-2-sulfonate ion, etc.), carborate ions (e.g., acetate ion, propionate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, gluconate ion, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , BPh4 - , Al(OC(CF3)3)4 - and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - ) Exemplary multivalent counterions include CO 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, glucosate, succinate, glutarate, adipate, pimelate, suberate, azelaate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0095] "Halo" or "halogen" means fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0096] An "acyl group" is -C(=O)R aa , -CHO, -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2, -C(=O)SR aa , or -C(=S)SR aa where R aa and R bb as defined in this disclosure.

[0097] Where valency allows, nitrogen atoms may be substituted or unsubstituted, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(ORcc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl group, C 1~10 Haloalkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6~14 aryl groups, and 5- to 14-membered heteroaryl groups, or two R groups linked to a nitrogen atom. cc groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd group, and wherein R aa , R bb , R cc and R dd is defined above.

[0098] In some embodiments, the substituent at the nitrogen atom is a nitrogen protecting group (also called an amino protecting group). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl, aryl C 1-10 Alkyl, heteroaryl C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group and R aa , R bb , R cc , and R dd Nitrogen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0099] Exemplary oxygen atom substituents are -R aa , -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3+X - , -P(OR cc )2, -P(OR cc )3+X - , -P(=O)(R aa )2, -P(=O)(OR cc )2 and -P(=O)(N(R bb)2)2, including but not limited to, where X - , R aa , R bb and R cc is as defined in the present disclosure. In some embodiments, the oxygen atom substituent on the oxygen atom is an oxygen protecting group (also referred to as a hydroxy protecting group). Oxygen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999. Exemplary oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyl groups (e.g., 4-methoxybenzyl), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), and the like; silyl ethers such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), and the like; acetals or ketals such as tetrahydropyranyl (THP); esters such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, and the like; carbonates; sulfonates such as methanesulfonates (methanesulfonate), benzylsulfonates, and toluenesulfonates (Ts), and the like.

[0100] The term "leaving group" has its usual meaning in the art of synthetic organic chemistry, e.g., an atom or group displaceable by a nucleophile. See, e.g., Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogens (e.g., F, Cl, Br, or I (iodine)), alkoxycarbonyl groups, aryloxycarbonyl groups, alkylsulfonyloxy groups, arylsulfonyloxy groups, alkyl-carbonyl groups (e.g., acetoxy groups), arylcarbonyl groups, aryloxy groups, methoxy groups, N,O-dimethylhydroxyamino groups, 9-phenylpixyl, and haloformate groups.

[0101] The term "pharmacologically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0102] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds by the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers varies depending on several factors, such as temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include ketone to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0103] As used in this disclosure, the term "subject" (alternatively referred to in this disclosure as "patient") refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0104] As used in this disclosure, the terms "treatment," "treating," and the like refer to the elimination, alleviation, or amelioration of a disease or condition and / or its associated symptoms. Although not excluded, treatment of a disease or condition does not necessarily result in the complete elimination of the disease, condition, or its associated symptoms. As used in this disclosure, the terms "treatment," "treating," and the like can include "prophylactic treatment," which refers to reducing the likelihood of a disease or condition redeveloping or recurring in a subject who does not have a disease or condition redeveloping or recurring, but who is at risk of having a disease or condition redeveloping or recurring, or who has a propensity to have a disease or condition redeveloping or recurring. The term "treatment" and synonyms refer to the administration of a therapeutically effective amount of a compound according to the present disclosure to a subject in need of such treatment.

[0105] As used in this disclosure, the phrase "administration" of a compound, "administering" a compound, or other variations thereof, means providing a compound or a prodrug of a compound to an individual in need of treatment. [Example]

[0106] The various starting materials, intermediates, and compounds of the preferred examples can be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be carried out using conventional methods such as melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of processes for synthesizing the products described in this disclosure are described in more detail below.

[0107] Abbreviations used in this disclosure are as follows:

[0108] [Table 5] JPEG2025538601000066.jpg72149

[0109] Example 1 Synthesis of Compound 1 [ka]

[0110] Step 1: At 0 °C, a solution of PPh3 (32.1 g, 122.4 mmol) and 1H-imidazole (16.7 g, 244.8 mmol) in DCM (150 mL) was treated with iodine (31.1 g, 122.4 mmol). After the iodine was completely dissolved, a solution of 1-1 (5 g, 49.0 mmol) was added to the reaction mixture. The mixture was stirred at 0 °C for 1 h and then at 25 °C overnight. The reaction mixture was decanted into water and extracted with DCM. The combined organic layers were washed with NaSO3, dried over Na2SO4, filtered, and concentrated in vacuo at 25 °C. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to give 1-2.

[0111] Step 2: At 0 °C, TBAF (56.8 mL, 56.8 mmol) was added to a solution of 1-2 (8.7 g, 27.0 mmol) and TMSCN (7.10 mL, 56.8 mmol) in THF (150 mL). The mixture was stirred at room temperature overnight. H2O was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 1-3.

[0112] Step 3: To a solution of 1-3 (2.0 g, 16.6 mmol) in HO (20 mL) was added KOH (4.67 g, 83.2 mmol) at room temperature. The mixture was then stirred at 100 °C for 12 h. The mixture was cooled to room temperature and acidified with concentrated HCl to a pH of 2. The mixture was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated to give 1-4, which was used directly in the next step without further purification.

[0113] Step 4: To a solution of 1-4 (2.47 g, crude) in EtOH (20 mL) was added concentrated HSO (2 mL) at room temperature. Then, this mixture was stirred at 80 °C for 3 h. The mixture was cooled to room temperature, and H0 was added. The mixture was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give 1-5, which was used directly in the next step without further purification.

[0114] Step 5: At 0 °C, LiAlH (12.3 mL, 30.8 mmol) was slowly added to a solution of 1-5 (3.3 g, crude) in THF (30 mL). The mixture was then stirred at 0 °C for 1 h. The reaction was quenched with NaSO 10H O, and the mixture was stirred at room temperature for 15 min. The mixture was filtered, and the filtrate was concentrated in vacuo to give 1-6, which was used directly in the next step without further purification.

[0115] Step 6: Iodine (17.2 g, 67.6 mmol) was added to a mixture of imidazole (9.2 g, 135.2 mmol) and PPh3 (17.7 g, 67.6 mmol) in DCM (300 mL) at 0 °C. After stirring the mixture at 0 °C for 15 min, a solution of 1-6 (2.2, crude) in DCM (10 mL) was added to the mixture. This mixture was then stirred at room temperature for 1 h. H2O was added to the mixture, and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (100% petroleum ether) to give 1-7.

[0116] Step 7: At 0 °C, TBAF (35.7 mL, 35.7 mmol) was added to a solution of 1-8 (10 g, 32.45 ml) and TMSCN (4.53 mL, 35.7 mmol) in THF (100 mL). The mixture was stirred at room temperature overnight. H2O was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to give 1-9.

[0117] Step 8: At 0 °C, NaH (661.2 mg, 16.5 mmol) was added to a solution of 1-9 (1.4 g, 5.5 mmol) in DMF (25 mL). After the mixture was stirred at 0 °C for 0.5 h, 1-7 (2.12 g, 6.1 mmol) was added to the mixture. The mixture was then stirred at room temperature for 1 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give 1-10, which was used directly in the next step without further purification.

[0118] Step 9: To a solution of 1-10 (1.8 g, crude) in DMF (25 mL) was added KCO (1.52 g, 11.0 mmol) and CHCl (0.7 mL, 11.0 mmol) at room temperature. The mixture was then stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to give 1-11.

[0119] Step 10: Tetrabutylammonium borohydride (2.88 g, 11.2 mmol) was added to a solution of 1-11 (1.3 g, 3.7 mmol) in DCM (20 mL) at room temperature, and the mixture was then stirred at 50 °C for 4 h. The reaction was quenched with HCl (1 N) and H2O and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 1-12.

[0120] Step 11: At 0 °C, KHMDS (0.47 mL, 0.47 mmol) was added to a suspension of 1-12 (100 mg, 0.31 mmol) in THF (3 mL). After stirring the mixture at 0 °C for 10 min, 2,4-dichloropyrimidine (69.8 mg, 0.47 mmol) was added. The mixture was then stirred at 60 °C for 5 h. The reaction was quenched with H2O. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 1-13 and 1-14.

[0121] Step 12: A mixture of 1-13 (40 mg, 0.092 mmol), 4,4-difluorohexahydropyridine (22.3 mg, 0.18 mmol), and DIPEA (0.06 mL, 0.37 mmol) in DMF (2 mL) was heated at 100° C. for 3 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to give 1-15.

[0122] Step 13: A mixture of 1-15 (32 mg, 0.062 mmol), 2-hydroxyethane-1-sulfonamide (11.6 mg, 0.093 mmol), CuI (11.8 mg, 0.062 mmol), KPO (39.4 mg, 0.19 mmol), and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (4.4 mg, 0.031 mmol) in DMF (1 mL) was heated at 90 °C for 2 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 20 / 1) to give: 1. LCMS (ESI, m / z): [M+H] + =562.2; 1H NMR(400MHz,CDCl3,ppm) δ 8.32-8.30(d,J=5.7Hz,1H),8.19-8.17(d,J=8.4Hz,1H),7.72-7.71(d,J=5.7H z,1H),7.39(s,1H),7.24-7.19(m,1H),6.94(s,1H),4.46(s,2H),4.21-4.14(m ,2H),4.08-3.97(m,4H),3.42-3.34(m,2H),2.46-2.40(m,1H),2.12-2.01(m,6 H),1.98-1.87(m,2H),1.79-1.70(m,2H),0.93-0.84(m,2H),0.42-0.28(m,4H). 19 F NMR (376MHz, CDCl3, ppm) δ-96.72 (2F).

[0123] Example 2 Synthesis of Compounds 2 and 3 [ka]

[0124] Step 1: To a solution of 2-1 (10 g, 37.59 mmol) in DMSO (65 mL) at 20 °C, 6-azaspiro[2.5]octane hydrochloride (7.22 g, 48.9 mmol) was added. Then, K2CO3 (15.6 g, 112.8 mmol) was added, and the reaction mixture was stirred under N2 at 140 °C for 48 h. The reaction mixture was slowly decanted into ice water and then extracted with hexane. The aqueous phase was adjusted to pH = 6 with HCl (2 N). The solid was filtered and washed with water, collected, and dried to give 2-2.

[0125] Step 2: To a mixture of 2-3 (1 g, 6.13 mmol) and CsCO (4.0 g, 12.26 mmol) in DMF (10 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.56 g, 6.74 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the following: a mixture of 2-4A and 2-4B.

[0126] Step 3: To a mixture of 2-4A and 2-4B (1 g, 4.08 mmol) in EtOH (10 mL) and HO (mL) was added Fe (0.7 g, 12.24 mmol) and NHCl (1.1 g, 20.4 mmol). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated to give a mixture of 2-5A and 2-5B, which was used directly in the next step without further purification.

[0127] Step 4: A mixture of 2-2 (415.1 mg, 1.16 mmol), HATU (485.9 mg, 1.28 mmol), and DIEA (0.19 mL, 1.16 mmol) in DMF (5 mL) was stirred at room temperature for 15 minutes. Then, a mixture of 2-5A and 2-5B (250 mg, crude) was added to the mixture. This mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the following: a mixture of 2-6A and 2-6B.

[0128] Step 5: A mixture of 2-hydroxyethane-1-sulfonamide (169.3 mg, 1.35 mmol), CuI (103.0 mg, 0.54 mmol), sarcosine (96.4 mg, 1.08 mmol), and KPO (344.6 mg, 1.62 mmol) in DMF (10 mL) was heated to 50 °C under N and stirred for 5 minutes. After that, a mixture of 2-6A and 2-6B (300 mg, 0.54 mmol) was added, and the resulting mixture was stirred under N at 100 °C for 4 hours. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give compounds 2 and 3. 2: LCMS (ESI, m / z): [M+H] + =552.2; 1 H NMR(400MHz,DMSO-d6,ppm) δ 11.74(s,1H),10.19-10.02(m,1H),8.61-8.22(m,2H),7.88-7.86(m, 1H),7.81-7.69(m,1H),7.47-7.38(m,1H),7.19-7.18(m,1H),7.06-7 .04(m,1H),5.35-5.33(m,2H),5.02-4.90(m,1H),3.79-3.73(m,2H), 3.37-3.33(m,2H),3.01-2.98(m,4H),1.61-1.44(m,4H),0.35(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm) δ-69.98 (3F). 3:LCMS(ESI,m / z):[M+H] + =552.2; 1 H NMR(400MHz,DMSO-d6,ppm) δ 11.74(s,1H),10.10(s,1H),8.29-8.23(m,2H),7.85-7.82(m,1H),7.72-7.70(m,1H),7.63-7.61(m,1H),7.17-7.16(m,1H),7.04-7.02 (m,1H),5.37-5.31(m,2H),4.98-4.95(m,1H),3.79-3.74(m,2H),3.37-3.33(m,2H),3.00-2.98(m,4H),1.58-1.45(m,4H),0.35(s,4H). 19F NMR (376MHz, DMSO-d6, ppm) δ-70.28 (3F).

[0129] Example 3 Synthesis of Compounds 4 and 5 [ka]

[0130] Step 1: To a solution of 4-1 (6.0 g, 27.12 mmol) in THF (300 mL) at −78 °C under N2, N,N,N',N'-tetramethylethylenediamine (5.67 g, 48.81 mmol) was added, followed by S-BuLi (39.64 mL, 51.53 mmol) over 15 min, and the reaction mixture was stirred at −78 °C for 1.5 h. Dry ice (11.9 g, 271.19 mmol) was added to the reaction mixture and stirred at −78 °C for 10 min. The reaction was quenched with aqueous NH4Cl, and then HCl (1 N) was added to adjust the mixture to pH 5. The mixture was extracted with EtOAc, and the organic layer was dried over Na2SO4, filtered, and concentrated to give 4-2, which was used directly in the next step without further purification.

[0131] Step 2: A solution of 4-2 (4.0 g, crude) in HCl / MeOH (40.00 mL) was stirred at 60 °C for 36 h. The reaction mixture was concentrated in vacuo. EtOAc and NaHCO were added to the residue. The organic layer was separated and washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give 4-3, which was used directly in the next step without further purification.

[0132] Step 3: To a solution of 4-3 (1.46 g, 8.14 mmol) in MeCN (20 mL) was added Na2CO3 (1.73 g, 16.29 mmol) and benzyl bromide (1.45 mL, 12.22 mmol), and the reaction mixture was stirred at 80 °C for 3 h. The mixture was concentrated in vacuo, and the residue was diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 4-4.

[0133] Step 4: At 0 °C, a solution of 4-4 (1.37 g, 5.09 mL) in THF (5 mL) was added with a solution of LiAlH (2.04 mL, 5.1 mmol) in THF (15 mL), and the reaction was stirred at 0 °C for 10 min. The reaction was quenched with NaSO 10H O and diluted with EtOAc. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 4-5.

[0134] Step 5: At 0 °C, 6-bromo-2-fluoropyridin-3-ol, PPh3 (614.8 mg, 2.34 mmol), and DEAD (614.8 mg, 2.34 mmol) were added to a solution of 4-5 (226.2 mg, 0.94 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 4-6.

[0135] Step 6: To a solution of 4-6 (322 mg, 0.78 mmol) in 1,2-dichloroethane (6 mL) was added 1-chloroethyl chloroformate (443.4 mg, 3.10 mmol), and the mixture was stirred at 110 °C for 18 h. The mixture was concentrated in vacuo, and MeOH (8 mL) was added to the residue, and the mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated in vacuo to give 4-7, which was used directly in the next step without further purification.

[0136] Step 7: To a solution of 4-7 (280 mg, crude) in EtOH (10 mL) was added K2CO3 (428.1 mg, 3.1 mmol), and the mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 4-8.

[0137] Step 8: To a solution of 4-8 (142 mg, 0.47 mmol) in toluene (5 mL) under N2, BINAP (58.0 mg, 0.093 mmol), NaOBu t (89.4 mg, 0.93 mmol), diphenylmethanimine (97.0 mg, 0.54 mmol), and Pd(dba) (85.2 mg, 0.093 mmol) were added, and the mixture was stirred at 100 °C for 18 h. The mixture was diluted with EtOAc and water, and the organic layer was separated and washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give 4-9, which was used directly in the next step without further purification.

[0138] Step 9: To a solution of 4-9 (186.5 mg, crude) in MeOH (5 mL) was added hydroxylamine hydrochloride (159.8 mg, 2.30 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo. The residue was diluted with EtOAc and water, and the organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 4-10.

[0139] Step 10: To a solution of 2-2 (139.7 mg, 0.39 mmol) in DMF (3 mL) was added 4-10 (78.6 mg, 0.33 mmol), DIPEA (0.14 mL, 0.82 mmol), and HATU (185.8 mg, 0.49 mmol). The mixture was stirred at 0 °C for 30 min. The mixture was diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 4-11.

[0140] Step 11: To a solution of 2-hydroxyethane-1-sulfamide (53.9 mg, 0.43 mmol) in DMF (2 mL), CuI (20.5 mg, 0.11 mmol), N-methylglycine (19.2 mg, 0.22 mmol), and KPO (228.6 mg, 1.08 mmol) were added, and the reaction was stirred under N at 50 °C for 5 min. After this, a solution of 4-11 (125 mg, 0.22 mmol) in DMF (0.5 mL) was added, and the reaction mixture was heated at 100 °C for 3 h. The mixture was diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 5 / 1) to give 4-12.

[0141] Step 12: 4-12 (100 mg) were purified by SFC (Column: ChiralCel OJ, 250 × 30 mm ID, 10 μm (0.1% NH₃·H₂O in methanol) / supercritical CO₂ = 25 / 75) to give 4 (48 mg) and 5 (33 mg), respectively. 4: SFC analysis: 98.88% ee; Retention time: 4.358 min; Column: ChiralCel OJ, 150 × 4.6 mm ID, 3 μm, methanol (0.05% DEA) with CO₂ from 5% to 40%; Pressure: 100 bar; Flow rate: 2.5 mL / min. LCMS (ESI, m / z): [M+H] + =578.4; 1 H NMR(400MHz, CDCl3, ppm):δ 12.99(s,1H),8.22-8.19(m,1H),7.71-7.69(m,1H),7.32(s,1H),7.20 (s,1H),7.06-7.04(m,2H),4.90-4.73(m,1H),4.34-4.23(m,1H),4.18 -4.09(m,2H),4.05-3.97(m,1H),3.62-3.51(m,1H),3.39-3.29(m,2H) ,3.13-3.00(m,4H),2.99-2.84(m,2H),2.23-1.62(m,8H),0.39(s,4H). 19 F NMR (376 MHz, CDCl3, ppm) δ -89.49 (1F), -102.64 (1F). 5: SFC analysis: 99.5% ee; retention time: 4.571 min; column: ChiralCel OJ, 150 × 4.6 mm ID, 3 μm, methanol (0.05% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 2.5 mL / min. LCMS (ESI, m / z): [M+H] + =578.4; 1H NMR(400MHz, CDCl3, ppm):δ 12.92(s,1H),8.15-8.13(m,1H),7.64-7.62(m,1H),7.25(s,1H),7.09 (s,1H),6.99-6.97(m,2H),4.83-4.71(m,1H),4.27-4.19(m,1H),4.11 -4.02(m,2H),3.98-3.90(m,1H),3.54-3.45(m,1H),3.32-3.23(m,2H) ,3.06-2.92(m,4H),2.92-2.73(m,2H),2.15-1.55(m,8H),0.33(s,4H). 19 F NMR (376MHz, CDCl3, ppm) δ-89.48(1F),-102.63(1F).

[0142] Example 4 Synthesis of Compound 6 [ka]

[0143] Step 1: A mixture of 6-1 (2.0 g, 13.93 mmol), 4,4-difluorohexahydropyridine (2.53 g, 20.9 mmol), and DIPEA (6.91 mL, 41.79 mmol) in NMP (20 mL) was stirred at 170 °C for 28 h. The mixture was diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 6-2.

[0144] Step 2: To a suspension of methyltriphenylphosphonium bromide (54.9 g, 153.67 mmol) in THF (60 mL) at −78 °C, n-butyllithium (2.5 M, 61.47 mL, 153.67 mmol) was slowly added. After addition, the mixture was stirred at −78 °C for 15 min and then at 0 °C for 1 h. The mixture was cooled to −78 °C, and a solution of 6-3 (20 g, 128.06 mmol) in THF (60 mL) was slowly added. The mixture was then stirred at room temperature for 1 h. The reaction was quenched with saturated NH₄Cl. The mixture was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 6-4.

[0145] Step 3: To a solution of 6-4 (11 g, 71.33 mmol) in toluene (110 mL) was added diethylzinc (1 M, 178.33 mL, 178.33 mmol) at -60 °C. The mixture was stirred at this temperature for 15 min. Diiodomethane (28.73 mL, 356.66 mmol) was added dropwise to the mixture over 30 min. The solution was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl ether. The organic phase was washed with water and dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 6-5.

[0146] Step 4: To a solution of 6-5 (9.2 g, 54.68 mmol) in THF (40 mL) at room temperature, HCl (1 M, 40 mL, 40.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with EtOAc. The organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 6-6.

[0147] Step 5: To a stirred solution of 6-6 (4.5 g, 36.24 mmol) in anhydrous THF (60 mL) was added LiHMDS (1 M, 39.86 mL, 39.86 mmol) dropwise at −78 °C and stirred with N for 1 h. To the mixture was added a solution of N,N-bis(trifluoromethanesulfonyl)aniline (15.5 g, 43.49 mmol) in THF (40 mL) dropwise at −78 °C. The mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 6-7.

[0148] Step 6: A mixture of 6-8 (4.2 g, 16.15 mmol), bis(pinaconato)diboron (6.2 g, 24.23 mmol), KOAc (3.2 g, 32.30 mmol), and Pd(dppf)Cl.CHCl (1.3 g, 1.62 mmol) in dioxane (50 mL) was stirred under N at 90 °C for 16 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give 6-9.

[0149] Step 7: A mixture of 6-7 (1.88 g, 7.33 mmol), 6-9 (2.70 g, 8.79 mmol), K2CO3 (3.0 g, 21.98 mmol), and Pd(dppf)Cl2.CHCl2 (0.6 g, 0.73 mmol) in dioxane (35 mL) and H2O (7 mL) was stirred under N2 at 90 °C for 2 h. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give 6-10.

[0150] Step 8: To a solution of 6-10 (1.85 g, 6.44 mmol) in THF (15 mL) and MeOH (5 mL) at room temperature, LiOH (1 M, 30 mL, 30 mmol) was added, and the mixture was stirred at room temperature for 3 h. HCl was added to the mixture to adjust the pH to 7, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 6-11, which was used directly in the next step without further purification.

[0151] Step 9: To a solution of 6-11 (1.68 g, crude) in DMF (20 mL) at room temperature, DIPEA (3.55 mL, 21.47 mmol) and TCFH (2.1 g, 7.36 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Then, 6-2 (1.4 g, 6.13 mmol) was added to the reaction mixture, and the mixture was stirred at 100 °C for 16 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 6-12.

[0152] Step 10: To a solution of 6-12 (520 mg, 1.08 mmol) in EtOH (15 mL) and HO (15 mL) at room temperature, HCl (0.5 mL), NHCl (460.2 mg, 8.60 mmol), and Fe (240 mg, 4.30 mmol) were added, and the mixture was stirred at 70 °C for 2 h. The mixture was extracted with EtOAc, and the organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 6-13, which was used directly in the next step without further purification.

[0153] Step 11: To a solution of 6-13 (200 mg, 0.44 mmol) in THF (8 mL), triethylamine (0.18 mL, 1.32 mmol) and DMAP (16.2 mg, 0.13 mmol) were added, and the mixture was cooled to 0 °C. Then, 6-14 (310.5 mg, crude) in THF (5 mL) was added to the reaction mixture and stirred for 30 min. The mixture was concentrated in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 6-15.

[0154] Step 12: To a solution of 6-15 (100 mg, 0.15 mmol) in DCM (2 mL) was added BCl at −78° C. under N. The reaction mixture was stirred at −78° C. for 1 h. The reaction was quenched with MeOH (3 mL) and concentrated in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 5 / 1) followed by reverse-phase HPLC (MeCN / water: 0-70%) to give: 6. LCMS (ESI, m / z): [M+H] + =562.2; 1 H NMR(400MHz,DMSO-d6,ppm) δ 10.21-9.77(m,2H),7.56-7.44(m,1H),7.28-7.11(m,2H),7.10-7.02(m,1H),5.79-5.67(m,1H),5.28-4.60(m,1H) ,3.97-3.66(m,6H),3.32-3.27(m,2H),2.34-2.23(m,5H),2.04-1.84(m,6H),1.48-1.35(m,2H),0.32-0.17(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm) δ-94.87 (2F).

[0155] Example 5 Synthesis of Compound 7 [ka]

[0156] Step 1: To a solution of 7-1 (1 g, 6.66 mmol) in concentrated HSO (3.5 mL) was added a mixture of concentrated HSO (1.5 mL) and concentrated nitric acid (1.5 mL, 6.66 mmol) over 5 min at 0 °C, and the reaction was stirred at room temperature for 1 h. The reaction solution was decanted into ice. The precipitated particles were filtered, washed with water, and then dried to give 7-2.

[0157] Step 2: To a solution of 7-2 (1 g, 5.13 mmol) in DMF (10 mL), MeI (1.5 g, 10.25 mmol) and K2CO3 (2.1 g, 15.37 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with ice water. The precipitated particles were filtered, washed with water, and then dried to give 7-3.

[0158] Step 3: To a solution of 7-3 (1 g, 4.78) in THF (10 mL), BH3.THF (9.56 mL, 9.56 mmol) was added and the reaction mixture was stirred at 80 °C for 2 h. The reaction was quenched with MeOH at 70 °C. The mixture was concentrated in vacuo to give 7-4.

[0159] Step 4: To a solution of 7-4 (120 mg, 0.62 mmol) in HO (0.3 mL) and EtOH (2 mL), Fe (171.7 mg, 3.08 mmol) and NHCl (164.5 mg, 3.08 mmol) were added, and the mixture was stirred at 75 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 7-5, which was used directly in the next step without further purification.

[0160] Step 5: Following the procedure for synthesizing compound 4-12 in Example 3, the following was prepared from compound 7-5: Compound 7. LCMS (ESI, m / z): [M+H] + =502.4; 1H NMR(400MHz,DMSO-d6,ppm) δ12.88(s,1H),10.18(s,1H),8.07-8.05(m,1H),7.43-7.41(m,1H),7. 27-7.26(m,1H),7.15-7.05(m,1H),6.98-6.96(m,1H),5.10-4.85(m,1H) ),4.26-4.14(m,2H),3.78-3.75(m,2H),3.50-3.40(m,2H),3.40-3.31( m,2H),3.06(s,3H),3.10-2.85(m,4H),2.05-1.50(m,4H),0.38(s,4H).

[0161] Example 6 Synthesis of Compound 9 [ka]

[0162] Step 1: To a solution of methyltriphenylphosphonium bromide (15.9 g, 44.39 mmol) in THF (50 mL) at 15°C, t OK (5.0 g, 44.39 mmol) was added. The mixture was stirred under N2 at 55 °C for 2 hours. Then, 9-1 (5.0 g, 22.19 mmol) was added to the mixture and stirred at 55 °C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 9-2.

[0163] Step 2: At -60 to -50 °C, diethylzinc (34.70 mL, 34.70 mmol) was added to a solution of 9-2 (3.1 g, 13.88 mmol) in toluene (10 mL). The mixture was stirred for 15 min, and then diiodomethane (5.59 mL, 69.41 mmol) was added dropwise to the mixture over 30 min. The mixture was warmed to room temperature and stirred at room temperature for 16 h. The reaction mixture was poured into ice-cooled saturated aqueous NH4Cl solution. The reaction mixture was extracted with ethyl ether. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 9-3.

[0164] Step 3: To a solution of 9-3 (600 mg, 2.53 mmol) in DCM (10 mL) was added TFA (2.88 g, 25.28 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give 9-4.

[0165] Step 4: Following the procedure for synthesizing compound 2-2 in Example 2, the following was prepared from compound 9-4: compound 9-5.

[0166] Step 5: Following the procedure for synthesizing compound 4-12 in Example 3, the following was prepared from compound 9-5: Compound 9. LCMS (ESI, m / z): [M+H] + =591.2; 1 H NMR(400MHz,DMSO-d6,ppm) δ 11.66(s,1H),7.72-7.70(m,1H),7.28(s,1H),6.93(s,1H),6.82-6.79(m,1H),3.76-3.72(m,4H),3.61-3.58(m,4H),3.21- 3.16(m,2H),2.41-2.37(m,2H),2.17(s,3H),1.86-1.78(m,8H),0.87-0.84(m,2H),0.55-0.38(m,2H),0.09--0.08(m,2H). 19 F NMR (376MHz, DMSO-d6, ppm) δ-95.17 (2F).

[0167] Example 7 Synthesis of Compound 11 [ka]

[0168] Step 1: A mixture of 1-14 (40 mg, 0.092 mmol), 3,3,3-trifluoropropan-1-ol (21.1 mg, 0.19 mmol), DABCO (5.2 mg, 0.046 mmol), and CsCO (90.3 mg, 0.28 mmol) in THF (1 mL) and DMF (1 mL) was stirred at room temperature for 12 h. H2O was added to the mixture. The mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 25 / 1) to give 11-1.

[0169] Step 2: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 11-1: compound 11. LCMS (ESI, m / z): [M+H] + =555.4; 1 H NMR(400MHz,CDCl3,ppm) δ 8.36(s,1H),8.16-7.94(m,2H),7.31(s,1H),7.19-7.13(m,1H),6.85(s,1H),5.31-5.21(m,1H),4.63-4.53(m,2H),4.37(s,2H),4. 14-4.04(m,2H),3.34-3.24(m,2H),2.74-2.58(m,2H),2.01-1.81(m,4H),1.71-1.63(m,2H),0.84-0.78(m,2H),0.34-0.19(m,4H). 19 F NMR (376MHz, CDCl3, ppm) δ-64.77 (3F).

[0170] Example 8 Synthesis of Compound 13 [ka]

[0171] Step 1: A mixture of 13-1 (1.5 g, 6.23 mmol), 4,4-difluorohexahydropyridine (0.75 g, 6.23 mmol), and K2CO3 (1.3 g, 9.34 mmol) in DMSO (10 ml) was stirred at 100 °C for 5 h. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 13-2.

[0172] Step 2: A mixture of 1-12 (110 mg, 0.34 mmol), 13-2 (176.27 mg, 0.52 mmol), CuI (65.4 mg, 0.34 mmol), KCO (189.9 mg, 1.37 mmol), and N,N'-dimethyl-1,2-ethylenediamine (30.3 mg, 0.34 mmol) in dioxane (8 mL) was stirred at 105 °C for 10 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 2) to give 13-3.

[0173] Step 3: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 13-3: compound 13. LCMS (ESI, m / z): [M+H] + =579.6; 1 H NMR(400MHz,DMSO-d6,ppm) δ 8.12-8.03(m,1H),7.94-7.84(m,1H),7.40-7.28(m,1H),7.24-7.16(m,1H),7.04-6.96(m,1H),3.91(s,2H),3.81-3.71( m,2H),3.61-3.46(m,4H),3.33-3.27(m,2H),2.19-2.02(m,4H),1.89-1.74(m,6H),0.96-0.80(m,2H),0.36-0.22(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm) δ-94.78(2F),-135.17(1F).

[0174] Example 9 Synthesis of Compound 14 [ka]

[0175] Step 1: A solution of 14-1 (1 g, 7.52 mmol), 4,4-difluorohexahydropyridine (0.91 g, 7.52 mmol), and K2CO3 (1.6 g, 11.27 mmol) in DMSO (10 mL) was stirred at 100 °C for 5 h. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 14-2.

[0176] Step 2: A solution of 1-12 (80 mg, 0.25 mmol), 14-2 (87.8 mg, 0.38 mmol), and CsCO (162.8 mg, 0.50 mmol) in DMSO (6 mL) was stirred at 110 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 14-3.

[0177] Step 3: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 14-3: compound 14. LCMS (ESI, m / z): [M+H] + =579.6; 1 H NMR(400MHz,DMSO-d6,ppm) δ 10.80-9.60(m,1H),8.04-7.92(m,1H),7.68-7.56(m,2H),7.38-7.31( m,1H),7.28-7.19(m,1H),5.45-4.65(m,1H),4.28(s,2H),3.82-3.72( m,2H),3.70-3.55(m,4H),3.40-3.34(m,2H),2.18-2.04(m,4H),2.03- 1.90(m,2H),1.85-1.64(m,4H),0.96-0.80(m,2H),0.40-0.22(m,4H).19 F NMR (376MHz, DMSO-d6, ppm) δ-94.52(2F),-133.68(1F).

[0178] Example 10 Synthesis of Compound 15 [ka]

[0179] Step 1: To a suspension of 1-12 (77 mg, 0.24 mmol) in THF (5 mL) at 0 °C, KHMDS (1 M, 0.36 mL) was added. After the mixture was stirred at 0 °C for 10 min, 15-1 (60.2 mg, 0.36 mmol) was added. The mixture was then stirred at 60 °C for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 15-2.

[0180] Step 2: Following the procedure for synthesizing Compound 1 in Example 1, the following was prepared from Compound 15-2: Compound 15. LCMS (ESI, m / z): [M+H] + =580.2; 1 H NMR(400MHz,DMSO-d6,ppm) δ 10.29(s,1H),8.49-8.46(m,1H),7.99-7.89(m,1H),7.36(s,1H),7.27-7.18(m,1H),5.00(s,1H),4.04(s,2H),3 .89-3.86(m,4H),3.81-3.72(m,2H),2.14-1.94(m,5H),1.94-1.67(m,7H),0.94-0.81(m,2H),0.39-0.21(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm) δ-95.02(2F),-149.81(1F).

[0181] Example 11 Synthesis of Compound 16 [ka]

[0182] Step 1: To a solution of 16-1 (2 g, 9.09 mmol) in DMF (20 mL), 2,2,2-trifluoroethan-1-amine (0.99 g, 10.0 mmol) and DIPEA (3.01 mL, 18.18 mmol) were added, and the mixture was stirred at 80 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 16-2.

[0183] Step 2: To a solution of 16-2 (1 g, 3.34 mmol) in EtOH (10 mL) and HO (2 mL), Fe (0.9 g, 16.72 mmol) and NHCl (0.9 g, 16.72 mmol) were added, and the mixture was stirred at 70 °C for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give 16-3, which was used directly in the next step without further purification.

[0184] Step 3: To a solution of 16-3 (400 mg, crude) in DMF (2.5 mL), HCl (0.1 mL, 1.5 mmol) and trimethoxymethane (2.5 mL, 1.49 mmol) were added, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with saturated NaHCO and brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 16-4.

[0185] Step 4: To a solution of 1-12 (100 mg, 0.31 mmol) in DMF (3 mL), 16-4 (130.7 mg, 0.47 mmol), CuI (59.5 mg, 0.31 mmol), KPO (198.9 mg, 0.94 mmol), and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (22.2 mg, 0.16 mmol) were added, and the mixture was stirred at 90 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 16-5.

[0186] Step 5: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 16-5: compound 16. LCMS (ESI, m / z): [M+H] + =563.2; 1 H NMR(400MHz,CD3OD,ppm) δ 8.40-8.25(m,1H),8.02-8.00(m,1H),7.85-7.70(m,1H),7.46-7.45(m,1H),7.36-7.35(m,1H),7.28-7.27(m,1H),7.26-7.25(m,1 H),5.25-5.18(m,2H),4.06(s,2H),3.97-3.94(m,2H),3.45-3.30(m,2H),2.14-1.82(m,6H),1.05-0.84(m,2H),0.40-0.25(m,4H). 19 F NMR(376MHz,CD3OD,ppm) δ-73.00(3F).

[0187] Example 12 Synthesis of Compound 17 [ka]

[0188] Step 1: To a solution of 17-1 (2 g, 8.3 mmol) and ethynyltrimethylsilane (1.6 g, 16.6 mmol) in THF (20 mL), CuI (0.2 g, 0.83 mmol), triethylamine (3.46 mL, 24.9 mmol), and bis(triphenylphosphino)dichloropalladium (0.6 g, 0.854 mmol) were added. The reaction mixture was stirred at 90 °C for 2 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 17-2.

[0189] Step 2: To a solution of 17-2 (2 g, 7.74 mmol) in MeOH (20 mL), KCO (1.6 g, 11.61 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 3) to give 17-3.

[0190] Step 3: To a solution of 17-3 (1.1 g, 5.91 mmol) in NMP (10 mL) was added potassium tert-butoxide (1.3 g, 11.82 mmol), and the reaction mixture was stirred at room temperature for 16 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 17-4.

[0191] Step 4: To a solution of 17-4 (100 mg, 0.54 mmol) in DMF (2 mL), NaH (32.2 mg, 0.81 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min. Then, iodomethane (114.4 mg, 0.81 mmol) was added to the mixture. The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and ice water. The combined organic layer was separated and washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to give 17-5.

[0192] Step 5: To a solution of 17-5 (100 mg, 0.5 mmol) in THF (1 mL), NIS (168.6 mg, 0.75 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 3) to give 17-6.

[0193] Step 6: To a solution of 1-12 (100 mg, 0.31 mmol) in DMF (3 mL), 17-6 (152.7 mg, 0.47 mmol), CuI (59.5 mg, 0.31 mmol), KPO (198.9 mg, 0.94 mmol), and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (22.2 mg, 0.16 mmol) were added, and the reaction mixture was stirred at 90 °C for 3 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 17-7.

[0194] Step 7: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 17-7: compound 17. LCMS (ESI, m / z): [M+H] + =563.2; 1H NMR(400MHz,CD3OD,ppm) δ 8.16(s,1H),8.10-8.00(m,2H),7.64-7.62(m,1H),7.44(s,1H),7.28-7.24(m,1H),4.49(s,2H),3.99- 3.91(m,5H),3.41-3.32(m,2H),2.36-2.17(m,2H),2.10-1.90(m,4H),0.89-0.86(m,2H),0.32(s,4H). 19 F NMR(376MHz,CD3OD,ppm) δ-66.84(3F).

[0195] Example 13 Synthesis of Compound 18 [ka]

[0196] Step 1: To a solution of 18-1 (500 mg, 2.69 mmol) and 3,3-difluoroazetidine (275.2 mg, 2.96 mmol) in DCM (10 mL) was added sodium triacetylborohydride (854.5 mg, 4.03 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 3) to give 18-2.

[0197] Step 2: Following the procedure for synthesizing compound 16 in Example 11, the following was prepared from compound 18-2: compound 18. LCMS (ESI, m / z): [M+H] + =547.2; 1 H NMR(400MHz,DMSO-d6,ppm) δ 10.21(s,1H),8.00-7.93(m,2H),7.82-7.78(m,1H),7.37(s,1H),7.26-7.16(m,2H),5.01-4.92(m,1H),4.30( s,2H),3.85(s,2H),3.79-3.73(m,6H),3.36-3.33(m,2H),2.01-1.69(m,6H),0.89-0.81(m,2H),0.29(s,4H).19 F NMR (376MHz, DMSO-d6, ppm) δ-97.75 (2F).

[0198] Example 14 Synthesis of Compound 20 [ka]

[0199] Step 1: To a solution of 20-1 (1 g, 3.14 mmol) in THF (30 mL) at room temperature under N2, ethylmagnesium bromide (3.76 mL, 3.76 mmol) was added over 5 minutes, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with NH4Cl solution, and the mixture was concentrated in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 20-2.

[0200] Step 2: To a solution of 20-2 (400 mg, 1.67 mmol) in toluene (12 mL) under N was added 4,4-difluorohexahydropyridine (242.4 mg, 2.0 mmol), sodium tert-butoxide (560.8 mg, 5.84 mmol), RuPhos (116.7 mg, 0.25 mmol), and Pd(OAc) (56.2 mg, 0.25 mmol), and the reaction was stirred at 110 °C under N for 18 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated and washed with brine. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC (0–60% MeCN in water) to give 20-3.

[0201] Step 3: Following the procedure for synthesizing compound 16 in Example 11, the following was prepared from compound 20-3: compound 20. LCMS (ESI, m / z): [M+H] + =564.2; 1H NMR(400MHz,DMSO-d6,ppm):δ 7.92-7.86(m,1H),7.34-7.27(m,2H),7.23-7.16(m,1H),4.28(s,2H),3.79-3.71(m,2H),3.49(s,3H),3.32-3.27(m,2H),3.19- 3.12(m,4H),2.21-2.09(m,4H),2.09-2.00(m,2H),1.82-1.70(m,2H),1.67-1.57(m,2H),0.89-0.78(m,2H),0.38-0.23(m,4H). 19 F NMR (376 MHz, DMSO-d 6, ppm) δ-94.77(2 F).

[0202] Example 15 Synthesis of Compound 23 [ka]

[0203] Step 1: A solution of 23-1 (1.81 g, 13.22 mmol) and ethyl (2-oxocyclopentyl)acetate (1.5 g, 8.81 mmol) in toluene (12 ml) was stirred at 110 °C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 2) to give 23-2.

[0204] Step 2: To a solution of 23-2 (1 g, 4.11 mmol) in THF (10 mL) was added BH THF (12.33 mL, 12.33 mmol) at −68 °C. The mixture was stirred at −68 °C for 1 h. The reaction mixture was then stirred at 60 °C for 2 h. HCl (2 M) was added to the mixture at 0 °C to quench the reaction, and the mixture was then stirred at 60 °C for 1 h. NaHCO solution was added to adjust the pH to 8, and the resulting mixture was extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give 23-3, which was used directly in the next step without further purification.

[0205] Step 3: To a solution of 23-3 (820 mg, crude) in isopropanol (10 mL) at 20 °C, Pd(OH) (248.9 mg, 1.77 mmol) was added. The mixture was stirred under a H balloon at 55 °C for 6 h. The mixture was filtered. HCl (8 mL, 4 M in dioxane) was added to the filtrate, and the mixture was concentrated in vacuo to give 23-4, which was used directly in the next step without further purification.

[0206] Step 4: A solution of 2,6-dibromopyridine (200 mg, 0.84 mmol), 23-4 (103.3 mg, crude), and KPO (716.8 mg, 3.38 mmol) in dioxane (8 mL) was stirred at 100 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 23-5.

[0207] Step 5: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 23-5: compound 23. LCMS (ESI, m / z): [M+H] + =551.3; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.65-9.70(m,1H),8.01-7.92(m,1H),7.56-7.46(m,1H),7.42-7.28(m,2H),7.2 6-7.18(m,1H),6.32-6.22(m,1H),5.25-4.75(m,1H),4.46-4.28(m,2H),4.27-4.1 9(m,1H),3.82-3.70(m,2H),3.55-3.38(m,2H),3.37-3.34(m,2H),2.83-2.72(m, 1H), 2.19-1.93(m, 4H), 1.83-1.43(m, 10H), 0.90-0.78(m, 2H), 0.35-0.22(m, 4H).

[0208] Example 16 Synthesis of Compound 24 [ka]

[0209] Step 1: To a solution of 3,3-difluorocyclobutan-1-ol (117.9 mg, 1.09 mmol) in THF (2 mL) was added NaH (54.5 mg, 1.36 mmol) at 0 °C. After stirring the mixture at 0 °C for 10 min, 24-1 (160 mg, 0.91 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (100% petroleum ether) to give 24-2.

[0210] Step 2: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 24-2: compound 24. LCMS (ESI, m / z): [M+H] + =548.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.38-10.12(m,1H),8.00-7.98(m,1H),7.83-7.76(m,2H),7.36(s,1H),7.27- 7.22(m,1H),6.71-6.64(m,1H),5.21-5.10(m,1H),5.07-4.80(m,1H),4.30(s, 2H),3.80-3.72(m,2H),3.38-3.35(m,2H),3.26-3.14(m,2H),2.90-2.74(m,2H ),2.05-1.92(m,2H),1.86-1.67(m,4H),0.95-0.84(m,2H),0.38-0.22(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm) δ-83.04(1F),-94.22(1F).

[0211] Example 17 Synthesis of Compound 26 [ka]

[0212] Step 1: To a solution of 26-1 (1 g, 4.55 mmol) in THF (15 mL) was added TMEDA (0.82 mL, 5.46 mmol) and S-BuLi (4.20 mL, 5.46 mmol) at −78° C. The mixture was stirred at −78° C. for 2 h. The mixture was quenched with NH4Cl solution and extracted with EtOAc. The organic layer was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 4 / 1) to give 26-2.

[0213] Step 2: To a solution of 26-2 (610 mg, 3 mmol) in DCM (8 mL) was added TFA (2 mL, 3.33 mmol) at 20° C. The mixture was stirred at 20° C. for 2 hours. The mixture was concentrated to give the TFA salt 26-3.

[0214] Step 3: Following the procedure for synthesizing compound 23 in Example 15, the following was prepared from compound 26-3: Compound 26, which was a TFA salt. LCMS (ESI, m / z): [M+H] + =523.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.19(s,1H),7.98-7.96(m,1H),7.59-7.51(m,1H),7.49-7.43(m,1H),7.36-7.31(m,1H),7.26-7.20(m ,1H),6.53-6.45(m,1H),5.20-4.75(m,1H),4.63-4.54(m,1H),4.24-4.15(m,1H),3.77-3.74(m,2H),3. 58-3.53(m,2H),3.38-3.31(m,2H),3.01-2.90(m,1H),2.28-2.17(m,1H),2.13-2.00(m,3H),1.88-1.77 (m,1H),1.77-1.63(m,4H),0.89-0.76(m,2H),0.75-0.67(m,1H),0.51-0.45(m,1H),0.34-0.22(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-73.74 (3F).

[0215] Example 18 Synthesis of Compound 27 [ka]

[0216] Step 1: To a solution of 27-1 (1 g, 5.24 mmol) in NMP (20 mL) at room temperature, 4,4-difluorohexahydropyridine (0.95 g, 7.85 mmol) and DIPEA (2.6 mL, 15.71 mmol) were added. The mixture was then stirred at 130 °C for 12 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 1 / 1) to give 27-2.

[0217] Step 2: At 0 °C, trifluoroacetic anhydride (228.6 mg, 1.09 mmol) was slowly added to a reaction mixture of 27-2 (200 mg, 0.73 mmol) and TEA (0.15 mL, 1.09 mmol) in DCM (5 mL). The reaction mixture was stirred at 0 °C for 15 min. The reaction was quenched with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 1 / 1) to give 27-3.

[0218] Step 3: To a suspension of 1-12 (50 mg, 0.16 mmol) in DMA (2 mL) was added CsCO 3( 27-3 (80.5 mg, 0.31 mmol) was added. The mixture was then stirred at 120 °C for 12 h. The mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 9 / 1) to give 27-4.

[0219] Step 4: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 27-4: compound 27. LCMS (ESI, m / z): [M+H] + =586.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.10-8.01(m,1H),7.94-7.88(m,1H),7.88-7.82(m,1H),7.19(s,1H),7.13-7.05(m,1H),4.39(s,2H),3.88-3.79(m,4H),3.77-3.69( m,2H),3.22-3.20(m,2H),2.22-2.08(m,4H),2.00-1.86(m,2H),1.85-1.74(m,2H),1.71-1.58(m,2H),0.91-0.77(m,2H),0.29(s,4H); 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.66 (2F).

[0220] Example 19 Synthesis of Compounds 28 and 29 [ka]

[0221] Step 1: At 0 °C, NaBH (1.1 g, 30 mmol) was added to a solution of 28-1 (3 g, 15 mmol) in MeOH (50 mL). The mixture was then stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous NH Cl and extracted with EtOAc. The combined organic layers were dried over Na SO , filtered, and the filtrate was concentrated in vacuo to give 28-2, which was used directly in the next step without further purification.

[0222] Step 2: To a solution of 28-2 (3 g, 14.85 mmol) in DCM (50 mL) was added toluenesulfonyl chloride (3.68 g, 19.30 mmol) and DMAP (0.2 g, 1.49 mmol). The reaction mixture was stirred at room temperature for 16 hours. H2O was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 6 / 1) to give 28-3.

[0223] Step 3: To a solution of 28-3 (1.5 g, 4.21 mmol) in MeCN (10 mL) was added 3,3-difluoroazetidine hydrochloride (0.71 g, 5.47 mmol) and K2CO3 (2.9 g, 21.05 mmol). The reaction mixture was stirred at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 8 / 1) to give 28-4.

[0224] Step 4: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 28-4: compound 28-5.

[0225] Step 5: Purification by SFC (chromatographic column: ChiralCel OJ, 250 × 30 mm ID, 10 μm (0.1% NHOH in MeOH) / supercritical CO = 20 / 80) gave 28-5 and 29, respectively. 28: SFC analysis: 99.66% ee; retention time: 2.636 min; column: ChiralCel OJ, 150 × 4.6 mm ID, 5 μm; MeOH (0.05% DEA), 5%–40% in CO; pressure: 100 bar; flow rate: 2.5 mL / min; LCMS (ESI, m / z): [M+H] + =561.3; 1H NMR (400MHz, CDCl3, ppm) δ 8.09-8.07(m,1H),7.94-7.92(m,1H),7.66-7.62(m,1H),7.32(s,1H) ,7.11-7.09(m,2H),4.32-4.23(m,2H),4.11-4.03(m,2H),3.65-3.48( m,5H),3.32-3.25(m,2H),2.01-1.90(m,2H),1.89-1.78(m,2H),1.75- 1.68(m,2H),1.29-1.27(m,3H),0.82-0.74(m,2H),0.30-0.17(m,4H). 19 F NMR (376MHz, CDCl3, ppm) δ -99.34 (2F). 29: SFC analysis: 97.52% ee; holding time: 2.769 min; color: ChiralCel OJ, 150×4.6mm ID, 5μm; MeOH (0.05% DEA) in CO2, 5% to 40%; pressure: 100 bar; flow rate: 2.5 mL / min; LCMS (ESI, m / z): [M+H] + =561.3; 1 H NMR (400MHz, CDCl3, ppm) δ 8.09-8.07(m,1H),7.94-7.92(m,1H),7.66-7.61(m,1H),7.32(s,1H) ,7.14-7.07(m,2H),4.33-4.23(m,2H),4.11-4.01(m,2H),3.65-3.50( m,5H),3.35-3.25(m,2H),1.99-1.91(m,2H),1.88-1.79(m,2H),1.74- 1.69(m,2H),1.29-1.27(m,3H),0.79-0.75(m,2H),0.30-0.17(m,4H). 19 F NMR (376MHz, CDCl3, ppm) δ-99.34 (2F).

[0226] Example 20 Synthesis of Compound 35

change

[0227] Step 1: A mixture of 35-1 (500 mg, 3.20 mmol), 4,4-difluorohexahydropyridine (387.7 mg, 3.20 mmol), and DIPEA (2.65 mL, 16.01 mmol) was heated at 100° C. for 12 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (DCM / MeOH=1 / 0 to 10 / 1) to give 35-2.

[0228] Step 2: To an ice-cold solution of 35-2 (428 mg, 1.87 mmol) in DMF (10 mL) at 0 °C, POBr (695.8 mg, 2.43 mmol) was added. This mixture was heated at 70 °C for 1 h. The mixture was then concentrated in vacuo. Saturated NaHCO solution was added to the residue, and the mixture was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 5 / 1) to give 35-3.

[0229] Step 3: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 35-3: compound 35. LCMS (ESI, m / z): [M+H] + =576.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 7.69-7.61(m,1H),7.55(s,1H),6.84-6.78(m,1H),6.77-6.70(m,1H),4.35(s,2H),3.98-3.85(m,4H),3.72-3.63(m,2H), 2.96-2.83(m,2H),2.28(s,3H),2.01-1.95(m,4H),1.80-1.74(m,2H),1.57-1.53(m,4H),0.83-0.74(m,2H),0.27(s,4H); 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.60 (2F).

[0230] Example 21 Synthesis of Compound 36 [ka]

[0231] Step 1: A mixture of 36-1 (10 g, 41.17 mmol) and 4,4-difluorohexahydropyridine (2.52 g, 20.79 mmol) in DIPEA (50 ml) was stirred at 55 °C for 16 hours. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 1 / 1) to give 36-2.

[0232] Step 2: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 36-2: compound 36. LCMS (ESI, m / z): [M+H] + =567.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 7.66-7.53(m,1H),7.11(s,1H),6.79(s,1H),6.76-6.69(m,1H),5.09-5.03(m,1H),4.23(s,2H),3.68-3.66(m,2H),3.63-3. 55(m,4H),2.94-2.84(m,2H),2.17-2.01(m,6H),1.85-1.70(m,2H),1.65-1.52(m,2H),0.87-0.74(m,2H),0.36-0.23(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-95.67 (2F).

[0233] Example 22 Synthesis of Compound 41 [ka]

[0234] Step 1: To a solution of 41-1 (5.0 g, 21.46 mmol) in DMF (60 mL) at room temperature, K2CO3 (5.9 g, 42.91 mmol) and CHCl (2.67 mL, 42.91 mmol) were added. The mixture was then stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 5 / 1) to give 41-2.

[0235] Step 2: To a solution of 41-2 (4.60 g, 18.62 mmol) in CCl (60 mL), dibenzoyl peroxide (0.9 g, 3.72 mmol) was added, and the reaction mixture was stirred under N at 70 °C for 15 min. NBS (4.0 g, 22.34 mmol) was then added, and the mixture was stirred under N at 85 °C for 16 h. The reaction was quenched with water and extracted with DCM. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 2 / 1) to give 41-3.

[0236] Step 3: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 41-3: compound 41. LCMS (ESI, m / z): [M+H] + =580.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.54-9.57(m,1H),8.36-8.34(m,1H),7.79-7.76(m,1H),7.65-7.57(m,2H),5.34-4.71(m,1H),4.47(s,2H),3.99-3.89(m,4H) ,3.83-3.75(m,2H),3.40-3.35(m,2H),2.07-1.94(m,6H),1.85-1.75(m,2H),1.68-1.60(m,2H),0.88-0.82(m,2H),0.30(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.67(2F),-126.55(1F).

[0237] Example 23 Synthesis of Compound 43 [ka]

[0238] Step 1: To a mixture of 43-1 (2.5 g, 18.36 mmol) in DCM (30 mL), TEA (3.31 mL, 23.87 mmol) was added, and the mixture was cooled to 0 °C. Then, methanesulfonyl chloride (1.85 mL, 23.87 mmol) was added dropwise to the mixture, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and saturated NaHCO solution. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to give 43-2. ​​This was used directly in the next step without further purification.

[0239] Step 2: To a mixture of 43-2 (1.04 g, 4.86 mmol), 3-bromo-1H-pyrazole (650 mg, 4.42 mmol) in DMF (10 mL) was added CsCO (1.87 g, 5.75 mmol). The mixture was then stirred at 100 °C for 5 h. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 2 / 3) to give 43-3.

[0240] Step 3: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 43-3: compound 43. LCMS (ESI, m / z): [M+H] + =549.2; 1H NMR (400 MHz, DMSO-d, ppm): δ 10.15-10.10(m,1H),7.95-7.93(m,1H),7.77(s,1H),7.34-7.33(m,1H),7 .23-7.20(m,1H),6.80(s,1H),5.21-4.82(m,1H),4.46-4.33(m,1H),4.25 (s,2H),3.77-3.74(m,2H),3.35-3.29(m,2H),2.23-1.88(m,10H),1.84-1 .71(m,2H),1.71-1.59(m,2H),0.86(d,J=13.5Hz,2H),0.40-0.19(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm) δ-92.79(1F),-98.40(1F).

[0241] Example 24 Synthesis of Compound 44 [ka]

[0242] Step 1: To an ice-cold solution of 44-1 (5 g, 31.22 mmol) in THF (50 mL) was added LiAlH (62.43 mL, 62.43 mmol) at 0 °C over 10 min. The reaction mixture was stirred at 80 °C for 2 h. The reaction was quenched with water and 10% NaOH. The mixture was filtered, and the filtrate was concentrated in vacuo to give 44-2, which was used directly in the next step without further purification.

[0243] Step 2: Following the procedure for synthesizing compound 1-7 in Example 1, the following was prepared from compound 44-2: compound 44-3.

[0244] Step 3: To an ice-cold solution of 2-(3-bromophenyl)acetonitrile (1.84 g, 9.38 mmol) and 44-3 (3.0 g, 8.52 mmol) in DMF (50 mL) at 0 °C, NaH (1.13 g, 28.13 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 44-4.

[0245] Step 4: To an ice-cold solution of 44-4 (1.0 g, 3.42 mmol) in THF (20 mL) at 0 °C, tetrahydrofuranborolane (8.55 mL, 8.55 mmol) was added. The reaction mixture was stirred at 75 °C for 2 h. The mixture was cooled to 0 °C and quenched by slowly adding EtOH. Then, HCl (4 M in MeOH) was added to the mixture, and the mixture was stirred at room temperature for an additional 30 min. The mixture was concentrated in vacuo to give the HCl salt 44-5, which was used directly in the next step without further purification.

[0246] Step 5: At 0 °C, to an ice-cold solution of 44-5 (1.1 g, crude) and triethylamine (1.55 mL, 11.14 mmol) in DCM (20 mL) was added ethyl chloroformate (483.5 mg, 4.46 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give 44-6, which was used directly in the next step without further purification.

[0247] Step 6: Trifluoromethanesulfonic acid (26.5 g, 176.48 mmol) was slowly added to 44-6 (1.3 g, crude) at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The reaction mixture was poured into ice water. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 44-7.

[0248] Step 7: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 44-7: compound 44. LCMS (ESI, m / z): [M+H] + =564.3; 1 H NMR (400 MHz, CDCl3, ppm): δ 8.22-8.21(m,1H),8.11-8.08(m,1H),7.66-7.65(m,1H),7.29-7.28(m,1H) ,7.13-7.10(m,1H),6.79(s,1H),4.30(s,2H),4.09-4.05(m,2H),3.95-3.9 2(m,4H),3.29-3.27(m,2H),2.29-2.27(m,1H),2.01-1.91(m,4H),1.88-1. 80(m,2H),1.51-1.41(m,4H),1.33-1.29(m,2H),1.19(s,3H),0.95(s,3H). 19 F NMR (376MHz, CDCl3, ppm): δ-96.91 (2F).

[0249] Example 25 Synthesis of Compound 52 [ka]

[0250] Step 1: At −78° C., a solution of 52-1 (1.0 g, 5.68 mmol) in 10 mL of THF was added dropwise to a solution of LDA (3.41 mL, 6.82 mmol) in 10 mL of THF. The mixture was stirred at −78° C. for 4 hours. Then, iodomethane (0.39 mL, 6.25 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 0 / 1) to give 52-2.

[0251] Step 2: To a solution of 52-2 (200 mg, 0.95 mmol) and 4,4-difluorohexahydropyridine (182.5 mg, 1.51 mmol) in DMSO (3 mL) at room temperature was added DIPEA (0.52 mL, 3.16 mmol). The mixture was stirred at 130 °C for 16 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 1 / 1) to give 52-3.

[0252] Step 3: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 52-3: Compound 52. LCMS (ESI, m / z): [M+H] + =575.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.25-10.11(m,1H),7.97(s,1H),7.75-7.73(m,1H),7.58-7.56(m,1H ),7.33-7.23(m,2H),5.09-4.88(m,1H),4.33(s,2H),3.79-3.71(m,2H) ,3.34-3.28(m,6H),2.25(s,3H),2.17-2.08(m,4H),2.03-1.97(m,2H) ,1.81-1.75(m,2H),1.69-1.66(m,2H),0.86-0.82(m,2H),0.29(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.99 (2F).

[0253] Example 26 Synthesis of Compound 55 [ka]

[0254] Step 1: A solution of 55-1 (10 g, 121.79 mmol) and ethyl propan-2-ynoate (12.34 mL, 121.79 mmol) in DMF (15 mL) was stirred at 110° C. for 72 hours. The mixture was filtered. The filter cake was washed with MeOH and petroleum ether and dried to give 55-2.

[0255] Step 2: At 0 °C, TEA (7.21 mL, 51.89 mmol) was added to a solution of 55-2 (2.90 g, 21.62 mmol) and tert-butyldimethylchlorosilane (7.2 g, 47.56 mmol) in DMF (45 mL). The mixture was stirred at 0 °C under N for 16 h. The mixture was diluted with H O and extracted with EtOAc. The combined organic phase was washed with H O and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 20 / 1) to give 55-3.

[0256] Step 3: To a solution of 55-3 (3.19 g, 12.84 mmol) in THF (18 mL) at −78° C., LDA (7.71 mL, 15.41 mmol) was added. The mixture was stirred at −78° C. for 25 min. Then, CHI (0.96 mL, 15.41 mmol) was added, and the mixture was stirred at −78° C. for 25 min. The mixture was quenched with acetic acid (5 mL) and stirred at 50° C. for 1 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 55-4.

[0257] Step 4: A solution of 55-4 (1.71 g, 11.54 mmol) in POCl (10 mL) was stirred at 100 °C for 2 h. The mixture was concentrated, and then saturated NaHCO solution was added to the residue, and the mixture was extracted with EtOAc. The combined organic phase was washed with H O and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 6 / 1) to give 55-5. Step 5: A solution of 55-5 (400 mg, 2.40 mmol), NBS (683.7 mg, 3.84 mmol), and AIBN (157.7 mg, 0.96 mmol) in CCl (6 mL) was stirred at 70 °C for 4 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 10 / 1) to give 55-6.

[0258] Step 6: A solution of 55-6 (200 mg, 0.82 mmol), 3,3-difluoroazetidine hydrochloride (116.1 mg, 0.90 mmol), and DIPEA (0.20 mL, 1.22 mmol) in DMF (6 mL) was stirred at 70 °C for 3 h. The mixture was diluted with HO and extracted with EtOAc. The organic phase was washed with HO and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 4 / 1) to give 55-7.

[0259] Step 7: Following the procedure for synthesizing compound 14 in Example 9, the following was prepared from compound 55-7: Compound 55. LCMS (ESI, m / z): [M+H] + =586.2; 1H NMR(400MHz,DMSO-d6,ppm):δ 10.09(s,1H),8.00-7.93(m,1H),7.91-7.85(m,1H),7.29(s,1H),7.21-7.14(m,1H),6 .66-6.59(m,1H),6.12-6.06(m,1H),4.94(s,1H),4.62-4.45(m,4H),3.77-3.69(m,2H) ,3.60-3.44(m,2H),3.32-3.27(m,2H),1.84-1.74(m,2H),1.66-1.59(m,1H),1.56-1. 47(m,5H),1.08-0.96(m,1H),0.90-0.81(m,1H),0.57-0.48(m,1H),0.30-0.16(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-98.94 (2F).

[0260] Example 27 Synthesis of Compound 56 [ka]

[0261] Step 1: Following the procedure for synthesizing compound 27-3 in Example 18, the following was prepared from compound 27-1: compound 56-1.

[0262] Step 2: To a solution of 56-1 (180 mg, 0.74 mmol) in DCM (2 mL), di-tert-butyl dicarbonate (0.34 mL, 1.45 mmol) and DMAP (9.0 mg, 0.074 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 4 / 1) to give 56-2.

[0263] Step 3: Following the procedure for synthesizing compound 27 in Example 18, the following was prepared from compound 56-2: compound 56-3.

[0264] Step 4: A solution of 56-3 (50 mg, 0.074 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (3 mL) was stirred at 80 °C for 72 h. The mixture was concentrated in vacuo. The residue was purified by reverse-phase HPLC (MeCN in HO (0-100%)) to give 56. LCMS (ESI, m / z): [M+H] + =572.2; 1 H NMR(400MHz,CD3OD,ppm):δ 8.07-8.05(m,1H),7.83-7.80(m,1H),7.69-7.69(m,1H),7.40(s,1H),7.30-7.20(m,1H),5.35-5.31(m,1H),4.47(s,2H),3.96-3.93(m,2) H),3.38-3.30(m,2H),3.12-3.02(m,2H),2.80-2.69(m,2H),2.16-1.99(m,4H),1.77-1.74(m,2H),0.93-0.88(m,2H),0.39-0.32(m,4H). 19 F NMR (376MHz, CD3OD, ppm): δ-84.88(1F),-100.21(1F).

[0265] Example 28 Synthesis of Compound 58 [ka]

[0266] Step 1: To a solution of 58-1 (0.5 g, 3.36 mmol) and 3,3-difluorocyclobutan-1-amine (395.4 mg, 3.69 mmol) in NMP (5 mL) was added DIPEA (1.11 mL, 6.71 mmol). The mixture was stirred at 110 °C for 3 h. Water and EtOAc were added to the mixture, and the mixture was extracted with EtOAc. The combined organic layer was dried over Na SO , filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 2 / 1) to give 58-2.

[0267] Step 2: To a solution of 58-2 (627 mg, 2.86 mmol) and BocO (0.72 mL, 3.14 mmol) in DCM (20 mL) was added TEA (0.6 mL, 4.28 mmol) and DMAP (34.9 mg, 0.29 mmol). The mixture was stirred at 35 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 6 / 1) to give 58-3.

[0268] Step 3: To a suspension of 1-12 (50 mg, 0.16 mL) in dioxane (5 mg) at 0 °C, KHMDS (0.31 mL, 0.31 mmol) was added. After stirring the mixture at room temperature for 10 min, 58-3 (79.88 mg, 0.25 mmol) was added, and the mixture was stirred at 90 °C for 6 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 2 / 1) to give 58-4.

[0269] Step 4: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 58-4: compound 58-5.

[0270] Step 5: To the reaction mixture of 58-5 (20 mg, 0.031 mmol) in DCM (2 mL) at room temperature, TFA (0.6 mL, 7.84 mmol) was slowly added. The reaction mixture was stirred at 35 °C for 2 hours. The reaction mixture was concentrated. The residue was purified by reverse-phase HPLC (MeCN / water (0.05% NH3H2O ​​in water): 5%-35%) to give 58. LCMS (ESI, m / z): [M+H] + =548.2; 1H NMR(400MHz,DMSO-d6,ppm):δ 8.65(s,1H),7.99-7.96(m,1H),7.77-7.68(m,2H),7.33(s,1H),7.25-7 .17(m,1H),4.30(s,2H),4.22-4.11(m,1H),3.77-3.74(m,2H),3.33-3. 27(m,2H),3.13-2.98(m,2H),2.71-2.53(m,2H),2.10-1.96(m,2H),1.8 5-1.72(m,2H),1.72-1.59(m,2H),0.87-0.81(m,2H),0.36-0.23(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm) δ-81.59(1F),-95.66(1F).

[0271] Example 29 Synthesis of Compound 59 [ka]

[0272] Step 1: Following the procedure for synthesizing compound 41-3 in Example 22, the following was prepared from compound 59-1: compound 59-2.

[0273] Step 2: Following the procedure for synthesizing compound 1-11 in Example 1, the following was prepared from compound 59-2: compound 59-3.

[0274] Step 3: A mixture of 59-3 (2.00 g, 5.73 mmol), tert-butyl carbamate (1.34 g, 11.45 mmol), XantPhos Pd G (381.3 mg, 0.43 mmol), and CsCO (5.6 g, 17.18 mmol) in dioxane (40 mL) was heated under N at 100 °C for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 3 / 1) to give 59-4.

[0275] Step 4: To a solution of 59-4 (1.20 g, 3.11 mmol) in MeOH (40 mL), Raney Ni (1.0 g) and HCl / dioxane (3 mL) were added. The reaction mixture was heated to 60 °C and stirred with H for 72 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 5 / 1) to give 59-5.

[0276] Step 5: To a solution of 59-5 (100 mg, 0.2 mmol) in dioxane (2 mL), 29-3 (75.7 mg, 0.29 mmol), CsCO 3( To the reaction mixture were added Xantphos (159.5 mg, 0.49 mmol), Xantphos (22.7 mg, 0.039 mmol), and Pd(dba) (35.9 mg, 0.039 mmol). The reaction mixture was stirred under N at 105 °C for 9 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 59-6.

[0277] Step 6: To a solution of 59-6 (80 mg, 0.14 mmol) in DCM (5 mL) was added TFA (2 mL, 0.14 mmol), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was diluted with EtOAc and NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 20 / 1) to give 59-7.

[0278] Step 7: Following the procedure for synthesizing compound 6 in Example 4, the following was prepared from compound 59-7: compound 59. LCMS (ESI, m / z): [M+H] + =587.4; 1H NMR(400MHz,DMSO-d6,ppm):δ 8.06-8.00(m,1H),7.94-7.91(m,1H),7.89-7.84(m,1H),7.30-7.23(m,1H),4.38(s,2H),3.85-3.81(m,4H),3.72-3.69(m,2H), 2.96-2.93(m,2H),2.20-2.09(m,4H),1.96-1.87(m,2H),1.82-1.72(m,2H),1.64-1.58(m,2H),0.87-0.78(m,2H),0.28(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.66 (2F).

[0279] Example 30 Synthesis of Compound 60 [ka]

[0280] Step 1: To a solution of 60-1 (500 mg, 2.54 mmol) and CsCO (1.65 g, 5.08 mmol) in DMF (10 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (647.90 mg, 2.79 mmol). The reaction mixture was stirred at 25 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 0 / 1) to give 60-2.

[0281] Step 2: Following the procedure for synthesizing compound 16 in Example 11, the following was prepared from compound 60-2: compound 60. LCMS (ESI, m / z): [M+H] + =564.4; 1H NMR(400MHz,DMSO-d6,ppm):δ 8.52-8.51(m,1H),8.20-8.18(m,1H),8.05-7.86(m,2H),7.35-7.22(m,1H),7.22-7.14(m,1H),5.35-5.16(m,2H),4.45-4.2 6(m,2H),3.63-3.81(m,2H),2.81-2.62(m,2H),2.13-1.94(m,2H),1.91-1.60(m,4H),0.95-0.68(m,2H),0.41-0.18(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-70.25 (3F).

[0282] Example 31 Synthesis of Compound 67 [ka]

[0283] Step 1: Following the procedure for synthesizing compound 35-2 in Example 20, the following was prepared from compound 67-1: compound 67-2.

[0284] Step 2: Following the procedure for synthesizing compound 55-5 in Example 26, the following was prepared from compound 67-2: compound 67-3.

[0285] Step 3: To a solution of 67-4 (10 g, 57.42 mmol) in DCM (200 mL), ethylene glycol (3.52 mL, 63.16 mmol) and chlorotrimethylsilane (14.56 mL, 114.84 mmol) were added, and the reaction mixture was stirred at 50 °C for 16 h. The mixture was diluted with DCM and saturated NaHCO . The organic layer was separated, washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to give 67-5.

[0286] Step 4: Following the procedure for synthesizing compound 1-7 in Example 1, the following was prepared from compound 67-5: compound 67-6.

[0287] Step 5: Following the procedure for synthesizing compound 1-12 in Example 1, the following was prepared from compound 67-6: compound 67-7.

[0288] Step 6: Following the procedure for synthesizing compound 6-6 in Example 4, the following was prepared from compound 67-7: compound 67-8.

[0289] Step 7: At 0 °C, diethylaminosulfur trifluoride (1.11 mL, 8.37 mmol) was added to a solution of 67-8 (430 mg, 1.40 mmol) in DCM (10 mL). The mixture was then stirred at 0 °C for 3 h. The reaction was quenched with aqueous NH4Cl and extracted with DCM. The combined organic layer was concentrated and purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 67-9.

[0290] Step 8: To a suspension of 67-9 (100 mg, 0.30 mmol) in DMA (3 mL) at 0 °C, NaH (36.3 mg, 0.91 mmol) was added. After stirring the mixture at 0 °C for 10 min, 67-3 (92.0 mg, 0.39 mmol) was added. The mixture was then stirred at 60 °C for 2 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 67-10.

[0291] Step 9: To a solution of 67-10 (80 mg, 0.15 mL) in DMF (3 mmol) at room temperature, HATU (111.6 mg, 0.29 mmol) and DIPEA (0.24 mL, 1.47 mmol) were added. The mixture was then heated at 60 °C for 1 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 10 / 1) to give 67-11.

[0292] Step 10: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 67-11: compound 67. The crude product 67 was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 2 / 3) and SFC (column: ChiralCel OJ, 150 × 4.6 mm ID, 3 μm (0.05% DEA in MeOH), supercritical CO = 5-40%) to remove impurities and obtain the following: pure 67. LCMS (ESI, m / z): [M+H] + =572.3; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.34-8.33(m,1H),7.98-7.96(m,1H),7.68-7.67(m,1H),7.24-7.16(m,2H),4.46(s,2H),3.97-3.84(m,4H),3. 76-3.73(m,2H),3.31-3.26(m,2H),2.16-2.10(m,2H),2.10-1.93(m,6H),1.93-1.83(m,2H),1.83-1.73(m,2H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-89.49(1F),-94.83(2F),-99.09(1F).

[0293] Example 32 Synthesis of Compound 68 [ka]

[0294] Step 1: Following the procedure for synthesizing compound 35-3 in Example 20, the following was prepared from compound 67-2: compound 68-1.

[0295] Step 2: To a solution of 68-2 (25 g, 121.35 mmol) and 2-methylpropan-2-yl cyanoacetate (20.56 g, 145.62 mmol) in DMF (200 mL) at room temperature, K2CO3 (16.8 g, 121.35 mmol) was added. The reaction mixture was stirred at 100 °C for 6 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 6 / 1) to give 68-3.

[0296] Step 3: To a solution of 68-3 (5.20 g, 16.74 mmol) in toluene (50 mL) at room temperature, 4-toluenesulfonic acid (0.3 g, 1.67 mmol) was added. The reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 2 / 1) to give 68-4.

[0297] Step 4: To a solution of methyl 68-4 (1.50 g, 7.12 mmol) and 1-7 (2.74 g, 7.83 mmol) in DMA (20 mL) at room temperature, K2CO3 (3.0 g, 21.37 mmol) was added. The reaction mixture was stirred at 100 °C for 30 min. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give 68-5, which was used directly in the next step without further purification.

[0298] Step 5: Following the procedure for synthesizing compound 59 in Example 29, the following was prepared from compound 68-5: Compound 68. The product was obtained as a 0.3 FA salt. LCMS (ESI, m / z): [M+H] + =563.2; 1H NMR(400MHz,DMSO-d6,ppm):δ 8.32-8.31(m,1H),8.21(s,0.3 H),8.14-8.12(m,1H),7.58-7.57(m,1H),6.83-6.81(m,1H),4.46(s,2H),3.97-3.90(m,4H),3.83-3.75(m,2H),3 .69-3.61(m,2H),2.14-1.94(m,6H),1.94-1.82(m,2H),1.59-1.51(m,2H),0.98-0.89(m,2H),0.34-0.21(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.69 (2F).

[0299] Example 33 Synthesis of Compound 73 [ka]

[0300] Step 1: To a solution of 73-1 (1 g, 6.14 mmol) in DMF (30 mL), 4,4-difluorohexahydropyridine (2.23 g, 18.41 mmol) and CsCO (10.0 g, 30.68 mmol) were added, and the reaction mixture was stirred at 100 °C for 6 h. Water was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 2 / 1) to give 73-2.

[0301] Step 2: To a solution of 1-12 (100 mg, 0.31 mmol) in DMA (3 mL), 73-2 (154.7 mg, 0.63 mmol) and CsCO (305.2 mg, 0.94 mmol) were added, and the reaction mixture was stirred at 150 °C for 18 h. Water was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 0 / 1) to give 73-3.

[0302] Step 3: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 73-3: Compound 73. LCMS (ESI, m / z): [M+H] + =576.2; 1 H NMR(400MHz,CD3OD,ppm):δ 8.90(s,1H),7.94-7.92(m,1H),7.27(s,1H),7.14-7.11(m,1H),4.33(s,2H),3.96-3.93(m,2H),3.4 8-3.42(m,4H),2.53(s,3H),2.18-2.00(m,10H),1.77-1.74(m,2H),0.89-0.80(m,2H),0.33(s,4H). 19 F NMR (376MHz, CD3OD, ppm): δ-98.55 (2F).

[0303] Example 34 Synthesis of Compound 77 [ka]

[0304] Step 1: A solution of 67-7 (250 mg, 0.71 mmol), 68-1 (296.1 mg, 1.06 mmol), CsF (323.4 mg, 2.13 mmol), CuI (135.2 mg, 0.71 mmol), and N,N′-dimethylethylenediamine (31.3 mg, 0.36 mmol) in DMA (2 mL) was heated and stirred at 90 °C for 16 h. The solvent was removed, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 77-1.

[0305] Step 2: A solution of 77-1 (130 mg, 0.24 mmol) in TFA (2 mL), THF (1 mL), and water (1.5 mL) was stirred at room temperature for 16 hours. The mixture was poured into saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 77-2.

[0306] Step 3: At -50°C, Bu t To a solution of OK (31.1 mg, 0.28 mmol) in DMF (0.5 mL) was added a solution of 77-2 (70 mg, 0.14 mmol) and difluoromethyl 2-pyridyl sulfone (29.4 mg, 0.15 mmol) in DMF (0.5 mL). The mixture was then stirred at 0 °C for 1 h. The reaction was quenched with water. The mixture was then extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 77-3.

[0307] Step 4: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 77-3: compound 77. LCMS (ESI, m / z): [M+H] + =584.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.32(d,J=5.7Hz,1H),7.94(d,J=8.4Hz,1H),7.62(d,J=5.7Hz,1H),7.20-7.13(m,2H),4.42(s,2H),3.94-3.86(m,4H) ),3.76-3.73(m,2H),3.30-3.27(m,2H),2.40-2.37(m,2H),2.13-2.08(m,2H),2.03-1.96(m,4H),1.82-1.65(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.77(2F),-97.46(2F).

[0308] Example 35 Synthesis of Compound 78 [ka]

[0309] Step 1: At −78° C., LDA (21.53 mL, 43.06 mmol) was added to a solution of 4,4-difluorocyclohexane-1-nitrile (2.5 g, 17.22 mmol) in THF (30 mL). The mixture was stirred at −78° C. for 3 hours, and then 78-1 (3.01 g, 17.22 mmol) in THF (30 mL) was added dropwise to the mixture at −78° C. The resulting mixture was stirred at room temperature for 16 hours. HCl (1N, 200 mL) was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated and dried over Na2SO4, filtered, and concentrated in vacuo to give 78-2, which was used directly in the next step without further purification.

[0310] Step 2: To a solution of 78-2 (3.9 g, crude) in DMF (50 mL), CHCl (1.62 mL, 26.03 mmol) and KCO (5.4 g, 39.04 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 78-3.

[0311] Step 3: To a solution of 78-3 (4 g, 12.75 mmol) in MeOH (60 mL) was added Raney Ni (3 g) at room temperature. The mixture was then stirred at 50 °C under H (1 atm, maintained by a balloon) for 8 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 20 / 1) to give 78-4.

[0312] Step 4: Following the procedure for synthesizing compound 27 in Example 18, the following was prepared from compound 78-4: Compound 78. LCMS (ESI, m / z): [M+H] + =596.2; 1H NMR(400MHz,DMSO-d6,ppm):δ 8.08(d,J=8.6Hz,1H),7.90(d,J=8.6Hz,1H),7.84(d,J=8.6Hz,1H),7.16-7.05(m,2H),4.36(s,2H) ,3.81-3.70(m,6H),3.20(t,J=6.5Hz,2H),2.20-1.94(m,8H),1.94-1.84(m,2H),1.83-1.74(m,2H). 19 F NMR: ( 376MHz, DMSO-d6, ppm): δ-89.95(1F),-94.96(2F),-99.24(1F).

[0313] Example 36 Synthesis of Compound 83 [ka]

[0314] Step 1: A solution of 83-1 (400 mg, 1.21 mmol) and NaOH (48.2 mg, 1.21 mmol) in HO (10 mL) was stirred at 110 °C in a microwave for 1 h. HO was added to the mixture, and the mixture was acidified with HCl (2N) to pH = 5, followed by extraction with EtOAc. The combined organic layer was washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 3) to give 83-2.

[0315] Step 2: To a solution of 83-2 (300 mg, 1.35 mmol) in DMA (6 mL) at 20 °C, 3-(bromomethyl)-1,1-difluorocyclobutane (250.0 mg, 1.35 mmol) was added, followed by K2CO3 (373.5 mg, 2.70 mmol), and the reaction mixture was stirred at 50 °C for 16 h. H2O was added to the mixture, and the mixture was extracted with EtOAc. The organic fractions were combined, washed with brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 83-3.

[0316] Step 3: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 83-3: Compound 83. LCMS (ESI, m / z): [M+H] + =563.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 7.93(d,J=8.4Hz,1H),7.85(d,J=9.8Hz,1H),7.34(s,1H),7.22(d,J=8.6Hz,1H),6.99(d,J=9.9Hz,1H),4.20(d,J=6.8Hz,2H),4 .04(s,2H),3.75(t,J=6.4Hz,2H),2.75-2.61(m,6H),2.55-2.51(m,1H),1.98-1.66(m,6H),0.87(d,J=13.0Hz,2H),0.30(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-81.56(1F),-91.77(1F).

[0317] Example 37 Synthesis of Compound 85 [ka]

[0318] Step 1: At 0 °C, LDA (23.09 mL, 46.19 mmol) was added to a solution of 85-1 (3.8 g, 32.99 mmol) in THF (40 mL). After stirring the mixture at 0 °C for 0.5 h, 1-bromo-4,4,5,5-tetramethyl-3-oxa-4-silanehexane (11.84 g, 49.49 mmol) was added to the mixture. The mixture was then stirred at room temperature for 12 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 85-2.

[0319] Step 2: At −78° C., n-butyllithium (7.62 mL, 19.04 mmol) was added to a solution of 2,6-dibromopyridine (4.1 g, 17.31 mmol) in THF (80 mL). After stirring the mixture at −78° C. for 0.5 h, 85-2 (5.21 g, 19.04 mmol) was added to the mixture. The mixture was then stirred at room temperature for 1 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 85-3.

[0320] Step 3: To a mixture of 85-3 (4.2 g, 10.87 mmol), (S,S)—N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine(p-methylisopropylphenyl)chlororuthenium(II) (325.1 mg, 0.51 mmol), a mixture of TEA (3.78 mL, 27.17 mmol) and formic acid (222.3 mg, 1.16 mmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give 85-4.

[0321] Step 4: To a solution of 85-4 (1.6 g, 4.12 mmol) in THF (20 mL) was added TBAF (4.53 mL, 4.53 mmol). The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to give 85-5.

[0322] Step 5: To a mixture of 85-5 (820 mg, 2.99 mmol) in DCM (40 mL), DMAP (401.9 mg, 3.29 mmol), TEA (0.83 mL, 5.98 mmol), and 4-toluenesulfonyl chloride (627.2 mg, 3.29 mmol) were added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 85-6.

[0323] Step 6: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 85-6: Compound 85. LCMS (ESI, m / z): [M+H] + =540.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.02-7.96(m,2H),7.81(t,J=7.9Hz,1H),7.34(s,1H),7.27-7.18(m,2H ),4.51-4.40(m,2H),4.27(d,J=13.4Hz,1H),4.12-4.08(m,1H),3.99-3 .90(m,1H),3.76(t,J=6.5Hz,2H),2.14-2.03(m,1H),2.02-1.62(m,8H) ,1.38-1.19(m,4H),0.91-0.73(m,2H),0.61(s,3H),0.34-0.22(m,4H).

[0324] Example 38 Synthesis of Compound 91 [ka]

[0325] Step 1: To a colorless solution of 91-1 (1.5 g, 14.98 mmol) in saturated NaCO (15 mL) was added NHOH HCl (1145.2 mg, 16.48 mmol). The reaction mixture was stirred at 40 °C for 2 h. The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to give 91-2, which was used directly in the next step without further purification.

[0326] Step 2: Raney Ni (1184.5 mg, 20.18 mmol) was added to 91-2 (1.55 g, crude) in MeOH (20 mL), and the mixture was stirred under a H balloon at 60 °C for 16 h. The mixture was filtered and concentrated to give 91-3, which was used directly in the next step without further purification.

[0327] Step 3: Following the procedure for synthesizing Compound 1 in Example 1, the following was prepared from Compound 91-3: Compound 91. LCMS (ESI, m / z): [M+H] + =542.4; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.12(d,J=5.5Hz,1H),7.71(d,J=8.6Hz,1H),7.58-7.41(m,1H),7.35-7.15(m,1H), 6.93-6.78(m,2H),5.65(s,1H),4.70-4.25(m,2H),4.23-3.98(m,1H),3.95-3.52(m ,5H),2.98(t,J=6.6Hz,2H),2.32-2.17(m,1H),2.08-1.65(m,5H),1.58(d,J=12.9H z,2H),1.21(d,J=6.1Hz,2H),1.01(d,J=6.2Hz,1H),0.88-0.70(m,2H),0.27(s,4H).

[0328] Example 39 Synthesis of Compound 92 [ka]

[0329] Step 1: Diethylzinc (34.52 mL, 34.52 mmol) was added to a solution of 92-1 (1 g, 5.46 mmol) in toluene (50 mL) at -60 °C. The mixture was stirred at this temperature for 15 min, and then diiodomethane (18.5 g, 69.04 mmol) was added dropwise to the mixture over 30 min. The mixture was stirred at room temperature for 16 h. The mixture was poured into an ice-cooled saturated aqueous NH4Cl solution and extracted with ethyl ether. The organic phase was washed with water and dried over NaSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 92-2.

[0330] Step 2: A mixture of 92-2 (180 mg, 0.78 mmol) and Pd / C (10%, 18 mg) in MeOH (3 mL) was stirred at room temperature with H for 16 h. The mixture was filtered, and the filtrate was concentrated to give 92-3, which was used directly in the next step without further purification.

[0331] Step 3: Following the procedure for synthesizing Compound 1 in Example 1, the following was prepared from Compound 92-3: Compound 92. LCMS (ESI, m / z): [M+H] + =538.4; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.24(d,J=5.8Hz,1H),7.95(d,J=8.6Hz,1H),7.53(d,J=5.8Hz,1H),7.27-7.17(m,2 H),4.47-4.43(m,2H),4.20-4.17(m,1H),3.98-3.88(m,1H),3.77-3.70(m,2H),3.4 5-3.35(m,4H),2.08-1.99(m,4H),1.79-1.72(m,2H),1.64-1.61(m,2H),1.13-1.02 (m,2H),0.85-0.83(m,2H),0.62-0.59(m,1H),0.35-0.28(m,4H),0.15-0.10(m,1H).

[0332] Example 40 Synthesis of Compound 93 [ka]

[0333] Step 1: A mixture of 93-1 (150 mg, 0.69 mmol), 3,3,3-trifluoropropan-1-amine (116.2 mg, 1.03 mmol), and KCO (284.0 mg, 2.06 mmol) in CHCN (3 mL) was heated at 80 °C for 1 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 93-2.

[0334] Step 2: To a mixture of 93-2 (100 mg, 0.32 mmol) and TEA (0.07 mL, 0.48 mmol) in DCM (3 mL), TFAA (100.9 mg, 0.48 mmol) was added. The mixture was then stirred at room temperature for 15 minutes. The pH of the mixture was adjusted to 8 with TEA. The mixture was then concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 93-3.

[0335] Step 3: Following the procedure for synthesizing compound 18 in Example 13, the following was prepared from compound 93-3: Compound 93. LCMS (ESI, m / z): [M+H] + =578.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 7.89-7.85(m,2H),7.60(d,J=8.6Hz,1H),7.40(t,J=5.6Hz,1H),6.93-7.18(m,2H),4.36(s,2H),3.75-3.66(m,4H),3. 18(t,J=5.8Hz,2H),2.71-2.59(m,2H),1.92-1.75(m,4H),1.62(d,J=12.4Hz,2H),0.83(d,J=13.0Hz,2H),0.27(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-63.73 (3F).

[0336] Example 41 Synthesis of Compounds 99 and 100 [ka]

[0337] Step 1: To a solution of 27-1 (300 mg, 1.57 mmol) and KCO (325.6 mg, 2.36 mmol) in CHCN (6 mL) at 20 °C, cyclopentyl mercaptan (0.15 mL, 1.41 mmol) was added. The mixture was stirred at 20 °C for 2 h. The mixture was diluted with H O and extracted with EtOAc. The organic phase was washed with H O and concentrated to give 99-1, which was used directly in the next step without further purification.

[0338] Step 2: Following the procedure for synthesizing compound 27 in Example 18, the following was prepared from compound 99-1: compound 99. LCMS (ESI, m / z): [M+H] + =567.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.35(s,1H),8.21-8.07(m,2H),7.93(d,J=8.6Hz,1H),7.21(s,1H),7.12(d,J=8.4Hz,1H),4.47(s,2H),4.28-4.15(m,1H),3.74(t, J=6.6Hz,2H),3.23(t,J=6.6Hz,2H),2.36-2.20(m,2H),1.96-1.75(m,6H),1.73-1.61(m,6H),0.92-0.81(m,2H),0.33-0.25(m,4H).

[0339] Step 3: A solution of 99 (110 mg, 0.19 mmol) and potassium monopersulfate(oxone) (1.19 g, 1.94 mmol) in CHCN (18 mL) and HO (10 mL) was stirred at 20 °C for 16 h. The mixture was diluted with HO and extracted with EtOAc. The combined organic phase was washed with HO and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 100-1.

[0340] Step 4: A solution of 100-1 (51 mg, 0.088 mmol) and 3-chloroperbenzoic acid (30.2 mg, 0.18 mmol) in DCM (5 mL) was stirred at 20 °C for 4 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) and reverse-phase HPLC (MeCN / water (0.05% FA)): 5%-70% to give 100, 0.3% FA salt. LCMS (ESI, m / z): [M+H] + =599.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.65-8.55(m,2H),8.28(s,0.3 H),7.88(d,J=8.6Hz,1H),7.27(s,1H),7.18(d,J=8.5Hz,1H),4.42(s,2H),4.32-4.21(m,1H),3.75(t,J=6.4 Hz,2H),3.29(t,J=6.4Hz,2H),2.09-2.00(m,4H),1.92-1.60(m,10H),0.90-0.80(m,2H),0.33-0.24(s,4H).

[0341] Example 42 Synthesis of Compound 103 [ka]

[0342] Step 1: LDA (74.76 mL, 149.51 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (10 g, 59.81 mmol) in THF (80 mL) at −78 °C over 30 min, and the reaction mixture was stirred at −78 °C for 1 h. 103-1 (13.10 g, 59.81 mmol) was added dropwise to the mixture at −78 °C. The mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated NH4Cl solution, and the mixture was acidified with HCl (2 M) to pH = 4. The mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 103-2, which was used directly in the next step without further purification.

[0343] Step 2: To a solution of 103-2 (23 g, crude) in DCE (250 mL) at room temperature, tetrabutylammonium borohydride (31.8 g, 125.61 mmol) was added. The mixture was then stirred at 60 °C for 1 h. The reaction was quenched with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 103-3.

[0344] Step 3: To a solution of 103-3 (2.2 g, 6.25 mmol) in THF (10 mL), TFA (20 mL) and water (10 mL) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into NaHCO solution and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 103-4.

[0345] Step 4: To a solution of 103-4 (1.7 g, 5.52 mmol) in THF (50 mL) at −78 °C, methylmagnesium bromide (5.52 mL, 16.55 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NH₄Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 103-5.

[0346] Step 5: To a solution of 103-5 (750 mg, 2.31 mmol) in DCM (20 mL) at −78 °C, DAST (1.12 g, 6.94 mmol) was added, and the reaction mixture was stirred at −78 °C for 1 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 103-6.

[0347] Step 6: Following the procedure for synthesizing compound 1 in Example 1, the following was prepared from compound 103-6: compound 103. LCMS (ESI, m / z): [M+H] + =568.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.28(s,1H),8.33(d,J=5.7Hz,1H),8.01(d,J=8.6Hz,1H),7.66(d,J=5.7Hz,1H),7.32-7.26(m,2H),4.96(s,1H),4.38(s,2 H),3.90-3.89(m,4H),3.77-3.74(m,2H),3.38-3.34(m,2H),2.08-1.69(m,10H),1.58-1.55(m,2H),1.35(d,J=21.1Hz,3H). 19 F NMR (376MHz, DMSO-d6, ppm): δ -94.91 (2F), -150.36 (1F).

[0348] Example 43 Synthesis of Compound 114 [ka]

[0349] Step 1: To a solution of methyltriphenylphosphonium bromide (944.4 g, 2643.79 mmol) in THF (7000 mL) was added potassium tert-butoxide (296.7 g, 2643.79 mmol) in portions at −20° C., and the mixture was then stirred at 0° C. for 1 hour. A solution of 114-1 (300 g, 1762.53 mmol) in THF (500 mL) was added at 0° C., and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture with stirring over 10 minutes. The mixture was concentrated, and the residue was extracted with tert-butyl methyl ether / heptane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was precipitated in heptane and filtered through silica gel. The filtrate was concentrated to give 114-2.

[0350] Step 2: To a solution of diethylzinc (1682 mL, 2.0 M, 3364.24 mmol) in DCM (4000 mL) was added trifluoroacetic acid (383.6 g, 3364.24 mmol) dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 h. Then, a solution of diiodomethane (901.1 g, 3364.24 mmol) in DCM (600 mL) was added to the mixture at 0 °C. The reaction mixture was stirred for 40 min. Then, a solution of 114-2 (283 g, 1682.12 mmol) in DCM (400 mL) was added, and the mixture was stirred at 0 °C for 2 h. The mixture was quenched with NH Cl solution. The organic layer was separated, washed with brine, dried over Na SO , filtered, and concentrated to give 114-3.

[0351] Step 3: To a solution of 114-3 (280 g, 1536.27 mmol) in methanol (1400 mL) and water (700 mL) was added lithium hydroxide monohydrate (193.4 g, 4608.80 mmol), and the reaction mixture was stirred at 60 °C for 1 h. The mixture was then concentrated, and the residue was washed with tert-butyl methyl ether. The aqueous layer was adjusted to pH 5 with 2 M aqueous hydrochloric acid and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 114-4.

[0352] Step 4: To a solution of 114-4 (190 g, 1232.09 mmol) in DCM (1500 mL) and DMF (0.5 mL) at 0 °C, oxalyl chloride (187.7 g, 1478.50 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated. The residue was dissolved in THF (100 mL), and ammonium hydroxide (920 mL, 25%) was added dropwise at 0 °C. The mixture was filtered, and the filter cake was dried to obtain 114-5.

[0353] Step 5: To a mixture of 114-5 (167 g, 1089.94 mmol) and TEA (441.2 g, 4359.74 mmol) in THF (1200 mL) at 0 °C, a solution of trifluoroacetic anhydride (343.4 g, 1634.90 mmol) in THF (300 mL) was added dropwise, and the mixture was stirred for 0.5 h. The reaction mixture was added to 0.5 N aqueous hydrochloric acid (1000 mL) and extracted with tert-butyl methyl ether. The combined organic layer was washed with 0.5 N aqueous hydrochloric acid, Na2CO3, and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by distillation under reduced pressure to give 114-6.

[0354] Step 6: To a mixture of 4-chloro-2-fluorobenzoic acid (50 g, 286.43 mmol) and 114-6 (65.84 g, 486.940 mmol) in THF (500 mL) at −40° C., LiHMDS (974 mL, 1.0 M in THF, 974 mmol) was added dropwise, and the mixture was stirred at 40° C. for 16 h. The mixture was quenched with water, adjusted to pH ∼5 with 2 N hydrochloric acid, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was slurried with acetonitrile and filtered to give 114-7.

[0355] Step 7: To a solution of 114-7 (60 g, 207.07 mmol) in methanol (600 mL), ammonium hydroxide (211.2 g, 25%, 3106.02 mmol) and Raney-Ni (120 g) were added, and the mixture was stirred under a hydrogen atmosphere at 30 °C for 24 h. After that, the mixture was filtered, and the filtrate was concentrated. The crude product was slurried with acetonitrile and filtered to give 114-8.

[0356] Step 8: To a solution of 114-9 (1.0 g, 3.91 mmol) in DCM (10 mL) at 0 °C, 2-methylpropan-2-amine (1.32 mL, 12.52 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with water and brine. The collected organic layer was dried over Na SO , filtered, and concentrated to give 114-10.

[0357] Step 9: To a solution of 114-8 (270 mg, 0.98 mmol) in dioxane (4 mL) under N was added 114-10 (400.5 mg, 1.37 mmol), CsCO (797.5 mg, 2.45 mmol), and XantPhos Pd G (87.0 mg, 0.098 mmol), and the reaction mixture was stirred at 85 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 114-11.

[0358] Step 10: To a solution of 114-11 (100 mg, 0.21 mmol) in DMSO (2.5 mL) under N2, ethanesulfamide (64.2 mg, 0.59 mmol), copper(I) oxide (14.9 mg, 0.10 mmol), 4-hydroxy-N-(2-methyl-1-naphthyl)pyridine-2-formamide (28.6 mg, 0.10 mmol), and potassium tert-butoxide (69.1 mg, 0.62 mmol) were added, and the reaction mixture was stirred at 130 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase HPLC (MeCN in water (0-100%)) to give 114. LCMS (ESI, m / z): [M+H] + =560.4; 1H NMR(400MHz,DMSO-d6,ppm):δ 10.25(s,1H),7.98-7.87(m,2H),7.71-7.57(m,4H),7.38(s,1H),7.24(d,J=8.1Hz,1H),3.99(s,2H),3.24 -3.19(m,2H),1.80-1.77(m,6H),1.22(t,J=7.3Hz,3H),1.10(s,9H),0.85(d,J=10.1Hz,2H),0.26(s,4H).

[0359] Example 44 Synthesis of Compound 117 [ka]

[0360] Step 1: To a solution of 117-1 (8 g, 40.0 mmol) in DMF (20 mL), benzyl mercaptan (4.97 g, 40.0 mmol) and CsCO (19.5 g, 60.0 mmol) were added, and the reaction mixture was stirred at 25 °C for 1.5 h. Water was added to the mixture and stirred for 10 min. The mixture was filtered and dried to give 117-2, which was used directly in the next step without further purification.

[0361] Step 2: To a solution of 117-2 (14 g, 36.82 mmol) in MeCN (250 mL), AcOH (9.8 mL, 171.19 mmol) and HO (5 mL) were added, and the mixture was cooled to 0 °C. Then, 1,3-dichloro-5,5-dimethyl-2-oxotetrahydro-1H-imidazol-4-one (14.51 g, 73.64 mmol) was added, and the mixture was stirred for 1 h. The mixture was concentrated in vacuo. The residue was diluted with EtOAc and water. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 117-3.

[0362] Step 3: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 117-3: compound 117. LCMS (ESI, m / z): [M+H] + =621.0; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.28(s,1H),8.29(d,J=8.5Hz,2H),8.01-7.94(m,2H),7.40(s,1H),7.27-7.24(m,1H),4.99(s,1H),4.50(t,J=12. 5Hz,4H),4.10(s,2H),3.77(t,J=6.4Hz,2H),3.40-3.36(m,2H),1.84-1.82(m,6H),0.88-0.86(m,2H),0.28(s,4H).

[0363] Example 45 Synthesis of Compound 122 [ka]

[0364] Step 1: A mixture of 122-1 (4 g, 16.92 mmol), tetrahydropyrrole (1.67 mL, 20.30 mmol), HATU (7.7 g, 20.30 mmol), and DIPEA (5.59 mL, 33.83 mmol) in DCM (20 mL) was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 122-2.

[0365] Step 2: To a solution of 114-8 (600 mg, 2.17 mmol) in dioxane (5 mL), 122-2 (693 mg, 2.39 mmol), Pd(dba) (199.2 mg, 0.22 mmol), CsCO (2127.8 mg, 6.53 mmol), and Xantphos (251.8 mg, 0.44 mmol) were added. The reaction mixture was stirred at 90 °C for 2 h under a N atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 122-3.

[0366] Step 3: A mixture of 122-3 (300 mg, 0.57 mmol), Zn(CN) (66.6 mg, 0.57 mmol), and Pd(PPh) (65.5 mg, 0.057 mmol) in DMF (5 mL) was stirred at 100 °C under N atmosphere and microwave conditions for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 122-4.

[0367] Step 4: To a solution of 122-4 (80 mg, 0.17 mmol) in DMSO (3 mL), 2-hydroxyethane-1-sulfonamide (21.08 mg, 0.168 mmol), CuI (32.1 mg, 0.17 mmol), KPO (107.2 mg, 0.51 mmol), and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (12.0 mg, 0.084 mmol) were added. The mixture was stirred at 130 °C for 2 h under a N atmosphere. The mixture was filtered, and the filtrate was concentrated. The residue was purified by reverse-phase HPLC (0.05% FA in water / MeCN, 10%-60%) to give 122, 0.3% FA salt. LCMS (ESI, m / z): [M+H] + =564.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.40-8.33(m,2H),8.28(s,0.3H),7.98(d,J=8.5Hz,1H),7.28(s,1H),7.22-7.15(m,1H),4.36(s,2H),3.7 9-3.71(m,2H),3.64-3.52(m,4H),3.31-3.26(m,2H),1.97-1.63(m,10H),0.88-0.81(m,2H),0.28(s,4H).

[0368] Example 46 Synthesis of Compound 125 [ka]

[0369] Step 1: A solution of 125-1 (5.0 g, 36.74 mmol), N,O-dimethylhydroxyamine hydrochloride (4.3 g, 44.09 mmol), TEA (15.32 mL, 110.21 mmol), and HATU (18.16 g, 47.76 mmol) in THF (50 mL) was stirred at 20 °C for 18 h. The mixture was diluted with HO and extracted with EtOAc. The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 125-2.

[0370] Step 2: To a solution of 1-bromo-3-iodobenzene (500 mg, 1.77 mmol) in THF (20 mL), isopropylmagnesium chloride (1.06 mL, 2.12 mmol) was added, and the reaction was stirred at −78° C. for 1 h. 125-2 (348.3 mg, 1.94 mmol) was added to the mixture. The mixture was stirred at −78° C. for 2 h. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 125-3.

[0371] Step 3: To a solution of 1-12 (180 mg, 0.56 mmol) in dioxane (5 mL), 125-3 (231.9 mg, 0.84 mmol), XantPhos Pd G (50.0 mg, 0.056 mmol), and CsCO (549.4 mg, 1.67 mmol) were added, and the mixture was stirred at 80 °C under N for 5 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 125-4.

[0372] Step 4: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 125-4: compound 125-5.

[0373] Step 5: To a solution of 125-5 (60 mg, 0.11 mmol) in THF (2 mL), NaBH4 (8.4 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 1 h. The crude material was purified by reverse-phase HPLC (HO / MeCN = 2 / 1) to give 125. LCMS (ESI, m / z): [M+H] + =545.1; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.22(s,1H),7.92(d,J=8.5Hz,1H),7.43-7.33(m,3H),7.20-7.30(m,3H),5.63(d,J=4.6Hz,1H),4.58(t,J=4.8Hz,1H),3.91(s,2H), 3.24-3.11(m,2H),2.68-2.53(m,2H),2.50-2.30(m,3H),1.90-1.70(m,6H),1.23(d,J=7.5Hz,3H),0.89(d,J=8.5Hz,2H),0.28(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-80.55 (1F), -94.39 (1F).

[0374] Example 47 Synthesis of Compound 126 [ka]

[0375] Step 1: At 0 °C, TBAF (57.3 mL, 57.37 mmol) was added to a solution of 41-3 (17 g, 52.15 mmol) and TMSCN (7.18 mL, 57.37 mmol) in THF (50 mL). The mixture was then stirred at 20 °C for 4.5 h. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was separated, washed with H2O, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 126-1.

[0376] Step 2: A solution of methyl 126-1 (5.52 g, 16.23 mmol), 67-6 (6.51 g, 17.04 mmol), and CsCO (18.5 g, 56.81 mmol) in CHCN (60 mL) was stirred at 85 °C for 1.5 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 126-2.

[0377] Step 3: 126-2 (2.78 g, 6.98 mmol), tert-butyl carbamate (2.45 g, 20.94 mmol), CsCO (5.7 g, 17.45 mmol), and XantPhos Pd G (0.6 g, 0.69 mmol) in dioxane (30 mL) were stirred at 90 °C for 6 h. The mixture was filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 126-3.

[0378] Step 4: To a solution of 126-3 (2.37 g, 5.46 mmol) and ammonium hydroxide (4.20 mL, 109.10 mmol) in MeOH (60 mL) was added Raney Ni (1.9 g, 32.73 mmol) at 20 °C. The mixture was stirred at 40 °C under a H balloon for 20 h. The mixture was filtered, and the filtrate was concentrated to give 126-4.

[0379] Step 5: At 20 °C, a solution of 126-4 (500 mg, 1.23 mmol) in THF (4 mL) and HO (4 mL) was added with TFA (4 mL, 52.24 mmol) and stirred at 20 °C for 2.5 h. The pH of the mixture was adjusted to 9 with NaCO solution, and the mixture was extracted with EtOAc. The combined organic phase was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 126-5.

[0380] Step 6: To a solution of 126-5 (454 mg, 1.13 mmol) in DCM (12 mL) at 0 °C, DAST (0.89 mL, 6.77 mmol) was added. The mixture was stirred at 0 °C for 3.5 h. The mixture was poured into H2O and extracted with DCM. The combined organic phase was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 126-6.

[0381] Step 7: A solution of 126-6 (160 mg, 0.25 mmol), 27-3 (70.79 mg, 0.28 mmol), Xantphos (14.5 mg, 0.025 mmol), CsCO (203.4 mg, 0.62 mmol), and Pd(dba) (22.9 mg, 0.025 mmol) in dioxane (6 mL) was stirred under N at 90 °C for 2 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to give 126-7.

[0382] Step 8: A solution of 126-7 (120 mg, 0.19 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (2 mL) was stirred at 100 °C in a microwave for 25 minutes. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 126-8.

[0383] Step 9: Following the procedure for synthesizing compound 6 in Example 4, the following was prepared from compound 126-8: compound 126. LCMS (ESI, m / z): [M+H] + =614.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.12(s,1H),8.17-8.09(m,1H),7.85-7.75(m,2H),7.61-7.55(m,1H),5.02(s,1H),4. 40(s,2H),3.83-3.75(m,6H),3.43-3.36(m,2H),2.19-2.04(m,8H),1.98-1.76(m,4H). 19F NMR (376MHz, DMSO-d6, ppm): δ -89.80 (1F), -94.97 (2F), -98.74 (1F), -125.87 (1F).

[0384] Example 48 Synthesis of Compound 127 [ka]

[0385] Step 1: A solution of 127-1 (1.0 g, 3.25 mmol) in THF (15 mL) was cooled to -5 °C, and then isopropyl magnesium chloride (1.95 mL, 3.90 mmol) was added to the solution. The mixture was stirred at 0 °C for 0.5 h, and then cyclopentanecarbaldehyde (0.42 mL, 3.90 mmol) was added. The mixture was then stirred at less than 10 °C for 2 h. Water was added to quench the reaction, and the mixture was extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 127-2.

[0386] Step 2: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 127-2: Compound 127. LCMS (ESI, m / z): [M+H] + =548.1; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.31(s,1H),8.22(d,J=8.4Hz,1H),7.95(d,J=8.5Hz,1H),7.77-7.67(m ,2H),7.41(d,J=1.8Hz,1H),7.26(d,J=8.5Hz,1H),5.90(d,J=5.6Hz,1H) ,4.03(s,2H),3.26-3.18(m,3H),2.49-2.41(m,1H),1.91-1.76(m,7H),1 .69-1.44(m,6H),1.21(t,J=7.3Hz,4H),0.96-0.77(m,2H),0.27(s,4H).

[0387] Example 49 Synthesis of Compound 132 [ka]

[0388] Step 1: To a solution of 27 (160 mg, 0.27 mmol) in DMF (3 mL), N-{[(2-methylpropan-2-yl)oxy]carbonyl}-L-valine (89.0 mg, 0.410 mmol), DIPEA (0.14 mL, 0.82 mmol), and HATU (155.8 mg, 0.41 mmol) were added, and the mixture was stirred at 25 °C for 20 h. Water was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) to give 132-1.

[0389] Step 2: To a solution of 132-1 (127 mg, 0.16 mmol) in DCM (0.5 mL) was added TFA (0.2 mL, 0.019 mmol), and the reaction was stirred at 25 °C for 1 hour. The reaction was concentrated in vacuo. The residue was diluted with EtOAc, and the pH was adjusted to 9 with NaHCO solution. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) and reverse-phase HPLC (MeCN / water: 5%-80%) to give 132. LCMS (ESI, m / z): [M+H] + =685.4; 1H NMR(400MHz,DMSO-d6,ppm):δ 8.08(d,J=8.6Hz,1H),7.98(d,J=8.6Hz,1H),7.85(d,J=8.6Hz,1H),7.29(s,1H),7.24 -7.19(m,1H),4.44-4.34(m,4H),3.87-3.80(m,4H),3.60-3.57(m,2H),3.05(d,J=5.2 Hz,1H),2.21-2.09(m,4H),1.98-1.88(m,2H),1.85-1.72(m,3H),1.69-1.62(m,2H),0 .86(d,J=13.5Hz,2H),0.80(d,J=6.8Hz,3H),0.75(d,J=6.8Hz,3H),0.35-0.23(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.68 (2F).

[0390] Example 50 Synthesis of Compound 133 [ka]

[0391] Step 1: To a solution of 133-1 (950 mg, 4.61 mmol) and 4,4-difluoropiperidine hydrochloride (799.4 mg, 5.07 mmol) in DMSO (10 mL) at room temperature, DIPEA (2.29 mL, 13.83 mmol) was added. The mixture was stirred at 100 °C for 1 hour. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 133-2.

[0392] Step 2: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 133-2: Compound 133. LCMS (ESI, m / z): [M+H] + =591.0; 1H NMR(400MHz,DMSO-d6,ppm):δ 10.22(s,1H),7.95(d,J=8.4Hz,1H),7.59(d,J=8.5Hz,1H),7.38(d,J=8. 6Hz,1H),7.33(s,1H),7.22(d,J=8.5Hz,1H),4.99(s,1H),4.24(s,2H),3. 84(s,3H),3.76(t,J=6.5Hz,2H),3.58-3.53(m,4H),3.33-3.31(m,2H),2 .10-1.96(m,6H),1.83-1.68(m,4H),0.86(d,J=13.3Hz,2H),0.29(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.51 (2F).

[0393] Example 51 Synthesis of Compound 136 [ka]

[0394] Step 1: At room temperature, DIPEA (43.04 mL, 260.43 mmol) was added to a solution of 136-1 (10 g, 52.09 mmol) and 4,4-difluoropiperidine hydrochloride (16.42 g, 104.17 mmol) in DMSO (100 mL). The mixture was stirred at 100 °C for 12 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 136-2.

[0395] Step 2: To a solution of 136-2 (3 g, 10.24 mmol) in THF (60 mL), 2-methoxyethan-1-ol (1.21 mL, 15.35 mmol) and PPh3 (5.4 g, 20.470 mmol) were added, and the mixture was stirred at 0 °C for 30 min. DIAD (4.1 g, 20.47 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 136-3.

[0396] Step 3: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 136-3: Compound 136. LCMS (ESI, m / z): [M+H] + =635.4; 1 H NMR (400 MHz, DMSO-d, ppm): δ 10.17(s,1H),7.96(d,J=8.5Hz,1H),7.56(d,J=8.5Hz,1H),7.42-7.32(m,2 H),7.23(d,J=8.6Hz,1H),4.98-4.95(m,1H),4.25(s,2H),4.18-4.13(m,2H) ),3.77(t,J=6.4Hz,2H),3.72-3.67(m,2H),3.59(s,4H),3.38-3.31(m,5H) ,2.14-1.94(m,6H),1.87-1.57(m,4H),0.86(d,J=13.0Hz,2H),0.30(s,4H).

[0397] Example 52 Synthesis of Compound 137 [ka]

[0398] Step 1: At 0 °C, 2-(trimethylsilyl)ethoxymethyl chloride (0.52 mL, 2.93 mmol) was added to a solution of 136-2 (430 mg, 1.47 mmol) and DIPEA (0.73 mL, 4.40 mmol) in DCM (6.0 mL), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with NH4Cl solution and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 137-1.

[0399] Step 2: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 137-1: compound 137-2.

[0400] Step 3: A solution of 137-2 (60 mg, 0.085 mmol) and TFA (1.0 mL, 13.06 mmol) in DCM (5 mL) was stirred at room temperature for 10 min. The mixture was adjusted to pH > 7 with NaHCO3 solution and extracted with DCM. The combined organic phases were dried and concentrated, and the residue was purified by reverse-phase HPLC (MeCN / H2O (5-95%)) to give 137. LCMS (ESI, m / z): [M+H] + =577.4; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.22(s,1H),9.80(s,1H),7.93(d,J=8.5Hz,1H),7.43(d,J=8.3Hz,1H),7.33(s,1H),7.23-7.20(m,1H),7.14(d,J=8.3Hz,1H),4.99(s,1H), 4.21(s,2H),3.77-3.74(m,2H),3.58-3.51(m,4H),3.35-3.31(m,2H), 2.10-1.97(m,6H),1.80-1.68(m,4H),0.87-0.84(m,2H),0.29(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.42 (2F).

[0401] Example 53 Synthesis of Compound 138 [ka]

[0402] Step 1: A mixture of 136-1 (1.0 g, 5.21 mmol), tert-butyl (2-hydroxyethyl)(methyl)carbamate (2.28 g, 13.02 mmol), and PPh3 (3.4 g, 13.02 mmol) in THF (15 mL) was stirred under N2 at room temperature for 5 minutes. Diethyl azodicarboxylate (2.05 mL, 13.02 mmol) was slowly added at 0 °C, and the mixture was then stirred at room temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 138-1.

[0403] Step 2: A solution of 138-1 (1.0 g, 2.86 mmol), 4,4-difluoropiperidine hydrochloride (676.9 mg, 4.30 mmol), and DIPEA (2.37 mL, 14.32 mmol) in DMSO (10 mL) was stirred at 100 °C for 12 h. Water was added to the mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 138-2.

[0404] Step 3: A solution of 138-2 (410 mg, 1.17 mmol) and TFA (3 mL, 0.22 mmol) in DCM (9 mL) was stirred at room temperature for 0.5 h. NaHCO solution was added to the mixture, and the pH was adjusted to >7, and the mixture was extracted with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated to give 138-3, which was used directly in the next step without further purification.

[0405] Step 4: To a mixture of 138-3 (310 mg, 0.885 mmol) and polyacetal (53.2 mg, 1.77 mmol) in DCM (6.0 mL), DIPEA (0.29 mL, 1.77 mmol) and AcOH (0.005 mL, 0.089 mmol) were added. After stirring at room temperature for 1 h, sodium triacetylborohydride (562.8 mg, 2.66 mmol) was added. The mixture was then stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and water. The mixture was extracted with DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 138-4.

[0406] Step 5: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 138-4: Compound 138. LCMS (ESI, m / z): [M+H] + =648.2; 1 H NMR (400 MHz, DMSO-d, ppm): δ 7.94(d,J=8.5Hz,1H),7.56(d,J=8.5Hz,1H),7.39(d,J=8.6Hz,1H),7.32(s, 1H),7.21(d,J=8.5Hz,1H),4.23(s,2H),4.10(t,J=5.6Hz,2H),3.76(t,J=6. 5Hz,2H),3.60-3.57(m,4H),3.31(s,2H),2.66(t,J=5.6Hz,2H),2.24(s,6H) ,2.10-1.96(m,6H),1.82-1.68(m,4H),0.86(d,J=13.4Hz,2H),0.29(s,4H).

[0407] Example 54 Synthesis of Compound 139 [ka]

[0408] Step 1: To a solution of 27 (120 mg, 0.21 mmol) in DMSO (6 mL) at 0 °C, add KCO 3( 141.7 mg, 1.03 mmol) and H2O2( To the mixture was added HCl (348.6 mg, 3.08 mmol). The mixture was then stirred at room temperature for 12 hours. To the mixture was added HO. The mixture was stirred at room temperature for 1 hour. The mixture was filtered and the solid was collected and dried to give 139. LCMS (ESI, m / z): [M+H] + =604.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 7.90-7.73(m,4H),7.49(s,1H),7.01(s,1H),6.93(d,J=8.6Hz,1H),4.35(s,2H),3.74-3.69(m,2H),3.47-3.41(m,4H),3.10-3. 03(m,2H),2.19-2.06(m,4H),2.02-1.91(m,2H),1.84-1.74(m,2H),1.63(d,J=12.8Hz,2H),0.83(d,J=13.4Hz,2H),0.28(s,4H).

[0409] Example 55 Synthesis of Compound 140 [ka]

[0410] Step 1: A mixture of 140-1 (500 mg, 2.38 mmol), 1-methyl-4-(tributyl-λ-stannane)imidazole (1.06 g, 2.85 mmol) and Pd(PPh3)4 (274.6 mg, 0.238 mmol) in DMF (10 mL) was added to 100 mL of 140-1. o The mixture was stirred at 100°C and N2 for 16 hours. The mixture was quenched with saturated KF solution and extracted with EtOAc. The organic layers were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 140-2.

[0411] Step 2: To a solution of 140-2 (150 mg, 0.709 mmol) and 4,4-difluoropiperidine hydrochloride (167.6 mg, 1.06 mmol) in DMSO (0.5 mL) at room temperature, DIPEA (458.1 mg, 3.54 mmol) was added. The mixture was stirred at 120 °C for 16 h. The mixture was diluted with EtOAc and washed with saturated NH Cl solution. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 140-3.

[0412] Step 3: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 140-3: compound 140. LCMS (ESI, m / z): [M+H] + =641.4; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.21(s,1H),8.24(d,J=8.5Hz,1H),8.00-7.91(m,2H),7.73-7.70(m,2H),7.35(s,1H),7.26-7.23(m,1H),4.98-4.95(m,1H),4.41(s,2 H),3.79-3.73(m,5H),3.37-3.25(m,6H),2.18-2.15(m,4H),2.07-2.00(m,2H),1.82-1.68(m,4H),0.86(d,J=13.4Hz,2H),0.29(s,4H).

[0413] Example 56 Synthesis of Compound 141 [ka]

[0414] Step 1: To a solution of 140-1 (3 g, 14.26 mmol) in DMSO (50 mL), 4,4-difluoropiperidine hydrochloride (3.37 g, 21.39 mmol) and DIPEA (9.46 mL, 57.03 mmol) were added, and the mixture was stirred at 120 °C for 3 h. The reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 141-1.

[0415] Step 2: A mixture of 141-1 (500 mg, 1.61 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (400.7 mg, 1.93 mmol), Pd(dppf)ClCHCl (117.4 mg, 0.14 mmol), and KCO (665.4 mg, 4.82 mmol) in dioxane (8 mL) and HO (0.8 mL) was heated at 90 °C for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give 141-2.

[0416] Step 3: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 141-2: Compound 141. LCMS (ESI, m / z): [M+H] + =641.5; 1 H NMR (400 MHz, DMSO-d, ppm): δ 8.20(s,1H),7.99-7.92(m,2H),7.88(d,J=8.3Hz,1H),7.82(d,J=8.3Hz,1 H),7.33-7.29(m,1H),7.24-7.19(m,1H),4.39(s,2H),3.90(s,3H),3.76(t ,J=6.5Hz,2H),3.33-3.30(m,2H),3.25-3.19(m,4H),2.19-1.97(m,6H),1 .85-1.74(m,2H),1.73-1.65(m,2H),0.91-0.82(m,2H),0.35-0.23(m,4H).

[0417] Example 57 Synthesis of Compound 143 [ka]

[0418] Step 1: To a solution of 143-1 (200 mg, 0.91 mmol) in DMF (1.5 mL), DIPEA (0.45 mL, 2.73 mmol), HATU (518.5 mg, 1.36 mmol), and methylamine hydrochloride (79.8 mg, 1.18 mmol) were added, and the mixture was stirred at 0 °C for 2 h. The reaction was diluted with EtOAc and water. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 143-2.

[0419] Step 2: Following the procedure for synthesizing compound 141-1 in Example 56, the following was prepared from compound 143-2: compound 143-3.

[0420] Step 3: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 143-3: Compound 143. LCMS (ESI, m / z): [M+H] + =618.4; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.23(s,1H),8.37-8.25(m,1H),7.99(d,J=8.5Hz,1H),7.84-7.75(m,2H),7.35(d ,J=1.7Hz,1H),7.27-7.20(m,1H),4.97(s,1H),4.40(s,2H),3.76(t,J=6.5Hz,2H), 3.47-3.40(m,4H),3.38-3.36(m,2H),2.83-2.76(m,3H),2.18-2.05(m,4H),2.03- 1.92(m,2H),1.83-1.77(m,2H),1.73-1.64(m,2H),0.93-0.80(m,2H),0.30(s,4H).

[0421] Example 58 Synthesis of Compound 147 [ka]

[0422] Step 1: At 0 °C, PPh3 (26.8 mg, 0.10 mmol) was added to a solution of 27 (30 mg, 0.051 mmol) and tetrabromomethane (33.8 mg, 0.10 mmol) in DCM (3 mL). The reaction mixture was stirred at 0 °C for 2 h. The mixture was quenched with water and extracted with DCM. The organic layers were combined, washed with brine, concentrated, and dried to give 147-1, which was used directly in the next step without further purification.

[0423] Step 2: To a solution of 147-1 (33.1 mg, crude) in MeCN (3 mL) was added dimethylamine (2 M in THF, 0.050 mL, 0.10 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated and purified by reverse-phase HPLC (0.05% FA in water / MeCN, 10%-50%) to give the 1.5% FA salt of 147. LCMS (ESI, m / z): [M+H] + =613.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.35(s,1.5 H),8.12-8.00(m,1H),7.96-7.89(m,1H),7.87-7.82(m,1H),7.28-7.1 8(m,1H),7.17-7.09(m,1H),4.39(s,2H),3.89-3.79(m,4H),3.26-3.20 (m,2H),2.66-2.60(m,2H),2.26-2.02(m,10H),1.99-1.87(m,2H),1.85 -1.74(m,2H),1.71-1.60(m,2H),0.93-0.79(m,2H),0.39-0.20(m,4H).

[0424] Example 59 Synthesis of Compound 149 [ka]

[0425] Step 1: To a solution of 149-1 (2 g, 11.36 mmol) in DCM (15 mL) was added DAST (5.5 g, 34.09 mmol), and the reaction was stirred at 0 °C for 1 h. The mixture was diluted with DCM and saturated NaHCO solution. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 149-2.

[0426] Step 2: To a solution of 114-8 (100 mg, 0.36 mmol) in dioxane (4 mL), 149-2 (71.8 mg, 0.36 mmol), XantPhos Pd G (32.2 mg, 0.036 mmol), and CsCO (354.4 mg, 1.09 mmol) were added, and the mixture was stirred at 90 °C for 1 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 149-3.

[0427] Step 3: To a solution of 149-3 (90 mg, 0.21 mmol) in DMA (2 mL), 4,4-difluoropiperidine hydrochloride (648.65 mg, 4.12 mmol) and DIPEA (1.02 mL, 6.17 mmol) were added, and the mixture was stirred at 130 °C for 6 h. The mixture was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 3) to give 149-4.

[0428] Step 4: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 149-4: Compound 149. LCMS (ESI, m / z): [M+H] + =611.2; 1H NMR(400MHz,DMSO-d6,ppm):δ 10.24(s,1H),8.09-7.94(m,3H),7.35(s,1H),7.32-7.22(m,1H),7.18-7.00(m,1H),4.97(s,1H),4.42(s,2H),3.77(t,J=6.4Hz,2H) ,3.45-3.33(m,6H),2.26-2.11(m,4H),2.10-1.90(m,2H),1.82-1.77(m,2H),1.70-1.67(m,2H),0.86(d,J=13.2Hz,2H),0.30(s,4H).

[0429] Example 60 Synthesis of Compound 150 [ka]

[0430] Step 1: To a solution of 141-1 (1.0 g, 3.21 mmol) in dioxane (10 mL) and HO (2 mL) was added potassium ethenyltrifluoroborate (20.1 mg, 0.18 mmol), pd(dppf)Cl.CHCl (262.1 mg, 0.32 mmol), and CsCO (2.09 g, 6.42 mmol). The mixture was stirred at 100 °C under N atmosphere for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 2) to give 150-1.

[0431] Step 2: A mixture of 150-1 (720 mg, 2.78 mmol) and Rh / C (636.5 mg) in MeOH (50 mL) was stirred at room temperature under a H atmosphere for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give 150-2, which was used directly in the next step without further purification.

[0432] Step 3: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 150-2: compound 150. LCMS (ESI, m / z): [M+H] + =589.4; 1H NMR(400MHz,DMSO-d6,ppm):δ 10.19(s,1H),7.97(d,J=8.5Hz,1H),7.83(d,J=8.2Hz,1H),7.67(d,J=8.3Hz,1H),7. 34(s,1H),7.27-7.19(m,1H),4.97(s,1H),4.35(s,2H),3.87-3.66(m,2H),3.33(s,2 H),3.28-3.19(m,4H),2.66-2.60(m,2H),2.21-2.08(m,4H),2.07-1.96(m,2H),1.85 -1.73(m,2H),1.73-1.63(m,2H),1.25-1.18(m,3H),0.92-0.75(m,2H),0.29(s,4H).

[0433] Example 61 Synthesis of Compound 152 [ka]

[0434] Step 1: To a solution of 141-1 (500 mg, 1.61 mmol) in dioxane (20 mL), tert-butyl carbamate (188.0 mg, 1.61 mmol), CsCO (1568.7 mg, 4.82 mmol), and XantPhos Pd G (142.6 mg, 0.16 mmol) were added, and the mixture was stirred at 80 °C under a N atmosphere for 12 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 152-1.

[0435] Step 2: A mixture of 152-1 (550 mg, 1.58 mmol) in HCl / dioxane (5 mL) / dioxane (15 mL) was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to give 152-2, which was used directly in the next step without further purification.

[0436] Step 3: To an ice-cold solution of 152-2 (400 mg, crude) in DMSO (10 mL) was added NaH (323.0 mg, 8.08 mmol). The mixture was stirred at room temperature for 1 h. Then, CHCl (0.50 mL, 8.08 mmol) was added to the mixture at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated NHCl solution and extracted with EtOAc. The organic layers were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 152-3.

[0437] Step 4: Following the procedure for synthesizing compound 114 in Example 43, the following was prepared from compound 152-3: Compound 152. LCMS (ESI, m / z): [M+H] + =604.4; 1 H NMR (400 MHz, DMSO-d, ppm): δ 9.78(s,1H),7.95(d,J=8.5Hz,1H),7.62(d,J=8.4Hz,1H),7.31(dd,J=7.6,5.3 Hz,2H),7.21(dd,J=8.5,1.9Hz,1H),4.28(s,2H),3.76(t,J=6.5Hz,2H),3.68-3 .51(m,4H),3.33-3.30(m,3H),2.73(s,6H),2.19-2.06(m,4H),2.06-1.93(m,2 H),1.84-1.73(m,2H),1.73-1.65(m,2H),0.93-0.77(m,2H),0.37-0.20(m,4H).

[0438] Example 62 Synthesis of Compound 157 [ka]

[0439] Step 1: A mixture of 157-1 (1.50 g, 7.81 mmol), 4,4-difluoropiperidine hydrochloride (1.29 g, 8.20 mmol), and DIPEA (3.87 mL, 23.44 mmol) in NMP (15 mL) was stirred at 90 °C for 2 h. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine. The organic layer was dried over Na SO , filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 157-2.

[0440] Step 2: To a solution of 157-2 (800 mg, 2.9 mmol) in DCM (10 mL) was added (methoxycarbonylsulfonyl)triethylammonium hydroxide inner salt (2.07 g, 8.68 mmol) (Burgess reagent), and the mixture was stirred at room temperature for 1 hour. H2O was added to the mixture, and the mixture was extracted with DCM. The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to give 157-3.

[0441] Step 3: To a solution of 114-8 (200 mg, 0.73 mmol) in dioxane (2.0 mL) at room temperature, 157-3 (197 mg, 0.76 mmol), Xantphos Pd G (64.5 mg, 0.073 mmol), and CsCO (708.9 mg, 2.18 mmol) were added, and the mixture was stirred at 100 °C for 3 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 157-4.

[0442] Step 4: To a solution of 157-4 (160 mg, 0.32 mmol) in dioxane (2.0 mL), tert-butyl carbamate (75.3 mg, 0.64 mmol), CsCO (261.7 mg, 0.80 mmol), and Xantphos Pd G (28.6 mg, 0.032 mmol) were added, and the mixture was stirred at 100 °C for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give 157-5.

[0443] Step 5: Following the procedure for synthesizing compound 59 in Example 29, the following was prepared from compound 157-5: Compound 157. LCMS (ESI, m / z): [M+H] + =587.4; 1 H NMR(400MHz,DMSO-d6,ppm):δ 9.04(s,1H),8.02(d,J=8.6Hz,1H),7.36(s,1H),7.26(d,J=8.5Hz,1H),4.36(s,2H),3.96-3.89(m,4H),3.76(t,J=6.3Hz,2H),3.39-3.3 1(m,2H),2.19-2.14(m,4H),1.92(t,J=12.0Hz,2H),1.80(t,J=11.8Hz,2H),1.69(d,J=12.2Hz,2H),0.87(d,J=13.2Hz,2H),0.30(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.67 (2F).

[0444] Example 63 Synthesis of Compound 158 [ka]

[0445] Step 1: Following the procedure for synthesizing compound 27-4 in Example 18, the following was prepared from compound 114-8: compound 158-1.

[0446] Step 2: Following the procedure for synthesizing compound 157-5 in Example 62, the following was prepared from compound 158-1: compound 158-2.

[0447] Step 3: Following the procedure for synthesizing compound 59-7 in Example 29, the following was prepared from compound 158-2: compound 158-3.

[0448] Step 4: Following the procedure for synthesizing compound 6-15 in Example 4, the following was prepared from compound 158-3: compound 158. LCMS (ESI, m / z): [M+H] + =624.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.08(d,J=8.3Hz,1H),7.99(d,J=8.2Hz,1H),7.85(d,J=8.4Hz,1H),7.30(s,1H),7.24(d,J=8.1Hz,1H),4.66-4.51(m,2H),4.41(s,2H) ),3.88-3.81(m,4H),2.21-2.08(m,4H),2.00-1.87(m,2H),1.86-1.74(m,2H),1.71-1.60(m,2H),0.86(d,J=11.7Hz,2H),0.29(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-60.89(3F),-94.69(2F).

[0449] Example 64 Synthesis of Compound 169 [ka]

[0450] Step 1: To a solution of 140-1 (3 g, 14.257 mmol) in DMSO (30 mL), 3,3-difluorocyclobutan-1-amine hydrochloride (3.07 g, 21.39 mmol) and DIPEA (9.46 mL, 57.03 mmol) were added, and the reaction was stirred at 120 °C for 3 h. The mixture was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 169-1.

[0451] Step 2: Following the procedure for synthesizing compound 140-2 in Example 55, the following was prepared from compound 169-1: compound 169-2.

[0452] Step 3: Following the procedure for synthesizing compound 140 in Example 55, the following was prepared from compound 169-2: Compound 169. LCMS (ESI, m / z): [M+H] + =627.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.19(s,1H),9.09(d,J=5.4Hz,1H),7.98(d,J=8.5Hz,1H),7.83-7.80(m,2H),7.67(s ,1H),7.51(d,J=8.2Hz,1H),7.35(d,J=1.8Hz,1H),7.22(m,1H),4.97(t,J=5.6Hz,1H), 4.39(s,3H),3.81-3.70(m,5H),3.39-3.32(m,2H),3.19-3.08(m,2H),2.69-2.55(m,2H ),2.09-2.01(m,2H),1.84-1.68(m,4H),0.88(d,J=13.5Hz,2H),0.31(d,J=4.6Hz,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-81.68(1F),-95.19(1F).

[0453] Example 65 Synthesis of Compound 171 [ka]

[0454] Step 1: A solution of 171-1 (358.0 mg, 2.04 mmol), 4-chloro-2-methylpyrimidine (250 mg, 1.95 mmol), K2CO3 (806.2 mg, 5.83 mmol), and Pd(dppf)Cl2.CHCl2 (158.8 mg, 0.19 mmol) in dioxane (8 mL) was stirred at 80 °C for 2 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 171-2.

[0455] Step 2: Following the procedure for synthesizing compound 140 in Example 55, the following was prepared from compound 171-2: Compound 171. LCMS (ESI, m / z): [M+H] + =653.2; 1 H NMR (400 MHz, DMSO-d, ppm): δ 10.24(s,1H),8.71(d,J=5.3Hz,1H),8.13(d,J=8.4Hz,1H),8.04-7.95(m, 2H),7.90(d,J=5.3Hz,1H),7.36(d,J=1.9Hz,1H),7.29-7.22(m,1H),4.97( s,1H),4.46(s,2H),3.77(t,J=6.4Hz,2H),3.36-3.25(m,6H),2.68(s,3H), 2.15-1.95(m,6H),1.87-1.66(m,4H),0.89(d,J=13.5Hz,2H),0.33(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-95.27 (2F).

[0456] Example 66 Synthesis of Compound 173 [ka]

[0457] Step 1: A solution of 141-1 (450 mg, 1.44 mmol), tetrahydropyrrol-2-one (200 mg, 2.35 mmol), CuI (275.1 mg, 1.44 mmol), KPO (919.8 mg, 4.33 mmol), and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (102.7 mg, 0.72 mmol) in DMF (mL) was heated at 90 °C for 6 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 173-1.

[0458] Step 2: Following the procedure for synthesizing compound 141 in Example 56, the following was prepared from compound 173-1: Compound 173. LCMS (ESI, m / z): [M+H] + =644.2; 1 H NMR (400 MHz, DMSO-d, ppm): δ 7.80(d,J=8.5Hz,1H),7.71(d,J=8.6Hz,1H),7.55(d,J=8.5Hz,1H),6.91(s,1H ),6.84(d,J=8.6Hz,1H),4.29(s,2H),3.73-3.65(m,4H),3.41-3.35(m,4H),2.9 8(t,J=6.6Hz,2H),2.43(t,J=7.9Hz,2H),2.16-2.04(m,6H),2.02-1.92(m,2H), 1.85-1.74(m,2H),1.63(d,J=12.8Hz,2H),0.82(d,J=13.3Hz,2H),0.28(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-95.04 (2F).

[0459] Example 67 Synthesis of Compound 177 [ka]

[0460] Step 1: Following the procedure for synthesizing compound 114-11 in Example 43, the following was prepared from compound 140-3: compound 177-1.

[0461] Step 2: Following the procedure for synthesizing compound 158-3 in Example 63, the following was prepared from compound 177-1: compound 177-2.

[0462] Step 3: To a solution of 177-2 (300 mg, 0.56 mmol) and tert-butyl nitrite (100 μL, 0.85 mmol) in MeCN (5 mmol) at room temperature, CuI (160.9 mg, 0.85 mmol) was added. The mixture was stirred at 80 °C for 1 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 20 / 1) to give 177-3.

[0463] Step 4: A solution of 177-3 (100 mg, 0.16 mmol), sodium methanesulfinate (31.7 mg, 0.31 mmol), CuI (29.6 mg, 0.16 mmol), KPO (99.0 mg, 0.47 mmol), and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (11.1 mg, 0.078 mmol) in DMF (2 mL) was stirred at 100° C. for 0.5 h. The mixture was filtered, and the filtrate was purified by reverse-phase HPLC (0-100% MeCN in water) to give 177. LCMS (ESI, m / z): [M+H] + =596.2; 1 H NMR(400MHz,DMSO-d6,ppm):δ 8.30-8.26(m,2H),8.06(s,1H),7.99(d,J=9.0Hz,1H),7.95(d,J=8.4Hz,1H),7.76(s,1H),7.69(s,1H),4.50(s,2H),3.74(s,3H),3.3 5-3.31(m,3H),3.28-3.22(m,4H),2.24-2.05(m,6H),2.00-1.95(m,2H),1.74(d,J=12.5Hz,2H),0.87(d,J=13.0Hz,2H),0.32(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-95.44 (2F).

[0464] Example 68 Synthesis of Compound 181 [ka]

[0465] Step 1: Following the procedure for synthesizing compound 177-1 in Example 67, the following was prepared from compound 133-2: compound 181-1.

[0466] Step 2: Following the procedure for synthesizing compound 177-2 in Example 67, the following was prepared from compound 181-1: compound 181-2.

[0467] Step 3: To a solution of 181-2 (100 mg, 0.21 mmol), TEA (0.06 mL, 0.41 mmol), and DMAP (12.7 mg, 0.10 mmol) in THF (5 mL) was added methylaminosulfonyl chloride (40.3 mg, 0.31 mmol), and the mixture was stirred at 40 °C for 2 h. The reaction was quenched with MeOH, and the mixture was concentrated in vacuo. The residue was purified by reverse-phase HPLC (0-68% MeCN in HO) to give 181. LCMS (ESI, m / z): [M+H] + =576.5; 1 H NMR(400MHz,DMSO-d6,ppm):δ 10.11(s,1H),7.91(d,J=8.5Hz,1H),7.62-7.55(m,2H),7.37(d,J=8.7H z,1H),7.26(d,J=1.6Hz,1H),7.18(d,J=8.5,1.8Hz,1H),4.23(s,2H),3 .83(s,3H),3.57-3.53(m,4H),2.49-2.45(m,3H),2.14-1.94(m,6H),1. 86-1.72(m,2H),1.73-1.59(m,2H),0.83(d,J=13.3Hz,2H),0.28(s,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.53 (2F).

[0468] Example 69 Synthesis of Compound 182 [ka]

[0469] Step 1: To a solution of (oxomethylene)azasulfonyl chloride (0.31 mL, 3.53 mmol) in DCM (10 mL) was added benzyl alcohol (0.39 mL, 3.75 mmol) at −10°C, and the mixture was stirred at −10°C for 30 min. Then, a solution of TEA (0.74 mL, 5.30 mmol) and 182-1 (335.7 mg, 4.59 mmol) in DMF (5 mL) was added, and the mixture was stirred at −10°C for 30 min. The mixture was stirred at 20°C for 16 h. The mixture was diluted with H2O and adjusted to pH 4 with HCl (1 M) and extracted with DCM. The combined organic phase was washed with H2O and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 20 / 1) to give 182-2.

[0470] Step 2: A solution of 182-2 (454 mg, 1.59 mmol) and Pd / C (10%, 100 mg) in propan-2-ol (12 mL) was stirred at 20 °C under a H balloon for 2.5 h. The mixture was filtered, and the filtrate was concentrated to give 182-3, which was used directly in the next step without further purification.

[0471] Step 3: A solution of 182-3 (242 mg, 0.95 mmol), TEA (0.20 mL, 1.43 mmol), DMAP (58.3 mg, 0.48 mmol), and tert-butyldimethylsilylchloro (215.7 mg, 1.43 mmol) in DMF (8 mL) was stirred at 20 °C for 2 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 0 / 1) to give 182-4.

[0472] Step 4: A solution of 181-1 (80 mg, 0.16 mmol), 182-4 (84.9 mg, 0.32 mmol), CuO (23.1 mg, 0.16 mmol), potassium 2-methylpropanoate (53.6 mg, 0.48 mmol), and 4-hydroxy-N-(2-methyl-1-naphthyl)pyridine-2-formamide (22.2 mg, 0.080 mmol) in DMSO (8 mL) was stirred at 130 °C for 16 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 10 / 1) and reverse-phase HPLC (MeCN / water: 5%-65%) to give 182. LCMS (ESI, m / z): [M+H] + =618.2; 1 H NMR (400 MHz, DMSO-d, ppm): δ 10.37(s,1H),7.93(d,J=8.5Hz,1H),7.59(d,J=8.5Hz,1H),7.38(d,J=8.6Hz, 1H),7.32(s,1H),7.25-7.19(m,1H),5.87-5.78(m,1H),4.40-4.31(m,1H),4.2 3(s,2H),3.94-3.87(m,2H),3.84(s,3H),3.69-3.62(m,2H),3.59-3.50(m,4H ),2.15-1.90(m,6H),1.83-1.64(m,4H),0.92-0.81(m,2H),0.35-0.23(m,4H). 19 F NMR (376MHz, DMSO-d6, ppm): δ-94.53 (2F).

[0473] Table 1 below provides the identities of some exemplary compounds of the present disclosure.

[0474] [Table 6] JPEG2025538601000137.jpg237159 JPEG2025538601000138.jpg222159 JPEG2025538601000139.jpg208159 JPEG2025538601000140.jpg213159 JPEG2025538601000141.jpg237159 JPEG2025538601000142.jpg213159 JPEG2025538601000143.jpg237159 JPEG2025538601000144.jpg217159 JPEG2025538601000145.jpg237159 JPEG2025538601000146.jpg237159 JPEG2025538601000147.jpg237159 JPEG2025538601000148.jpg237159 JPEG2025538601000149.jpg200159 JPEG2025538601000150.jpg237159 JPEG2025538601000151.jpg214159 JPEG2025538601000152.jpg203159 JPEG2025538601000153.jpg237149 JPEG2025538601000154.jpg218159 JPEG2025538601000155.jpg237159 JPEG2025538601000156.jpg223159 JPEG2025538601000157.jpg232159 JPEG2025538601000158.jpg209159 JPEG2025538601000159.jpg237159 JPEG2025538601000160.jpg237159 JPEG2025538601000161.jpg204159 JPEG2025538601000162.jpg195159 JPEG2025538601000163.jpg229159 JPEG2025538601000164.jpg218159 JPEG2025538601000165.jpg237159 JPEG2025538601000166.jpg237159 JPEG2025538601000167.jpg237159 JPEG2025538601000168.jpg127159

[0475] Biological Example A: OVCAR3 Cell Viability Assay OVCAR3 cells (ATCC, Cat# HTB-161) were seeded at a density of 2000 cells / well in 100 μL of complete medium (RPMI1640 + 20% FBS + 0.01 mg / mL human insulin) in a 96-well clear-bottom plate (Greiner, Cat# 655098). 100 μL of complete medium was added to the black well (column 1) and used as the low control. The cells were allowed to adhere to the plate overnight in an incubator at 37°C and 5% CO2. The next day, 0.5 μL of serially diluted compounds was added to the cells (columns 2-10) and incubated at 37°C and 5% CO2 (final DMSO concentration of 0.5%) for 6 days; 0.5 μL of DMSO solution was added to the well (column 11) and used as the high control. Cell viability was detected according to the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, Cat# G7573). Luminescence was recorded using a Tecan Spark plate reader. The inhibition rate (IR) of the test compound was determined by the following formula: IR (%) = (1 - (RLU) 化合物- RLU 低対照 ) / (RLU 高対照- RLU 低対照 )) × 100%. IC using a nonlinear regression equation 50 The value was calculated: Y = Min + (Max - Min) / (1 + 10^((LogIC 50- X) × HillSlope), where X is the logarithm of the compound concentration, Y is the percentage inhibition (IR(%)), and the highest and lowest values ​​are the plateau in the same units as Y.

[0476] Table 2 below lists the ICs measured and / or calculated for this biological example. 50 The values ​​are shown.

[0477] [Table 7] JPEG2025538601000170.jpg57149

[0478] Biological Example B: HCC1806 Cell Viability Assay HCC1806 cells (ATCC, Cat# CRL-2335) were seeded at a density of 500 cells / well in 100 μL of complete medium (RPMI1640 + 10% FBS) in a 96-well clear-bottom plate (Greiner, Cat# 655098). 100 μL of complete medium was added to the black well (column 1) and used as the low control. The cells were allowed to adhere to the plate overnight in a 37°C, 5% CO2 incubator. The next day, 0.5 μL of serially diluted compounds were added to the cells (columns 2-10) and incubated at 37°C, 5% CO2 (final DMSO concentration of 0.5%) for 6 days; 0.5 μL of DMSO solution was added to the well (column 11) and used as the high control. Cell viability was detected using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, Cat# G7573). Luminescence was recorded on a Tecan Spark plate reader. The inhibition rate (IR) of the measured compound was determined by the following formula: IR (%) = (1-(RLU) 化合物- RLU 低対照 ) / (RLU 高対照- RLU 低対照 )) × 100%. IC using a nonlinear regression equation 50 The value was calculated: Y = Min + (Max - Min) / (1 + 10^((LogIC 50- X) × HillSlope), where X is the logarithm of the compound concentration, Y is the percentage inhibition (IR(%)), and the highest and lowest values ​​are the plateau in the same units as Y.

[0479] Table 3 below lists the ICs measured and / or calculated for this biological example. 50 The values ​​are shown.

[0480] [Table 8]

[0481] Biological Example C: Human Microsomal Clearance Measurements This study aimed to assess the metabolic stability of compounds in human liver microsomes by microsomal clearance assay.

[0482] Mixtures containing 100 mM potassium phosphate, pH 7.4, 0.5 mg / mL liver microsomes, 2 mM NADPH, and 1 μM compound were prepared and placed in a 96-well plate. The plates were then incubated at 37°C for different times (0, 5, 15, 30, and 45 minutes), and the reaction was stopped with an acetonitrile solution containing an internal standard. The samples were then analyzed by LC / MS / MS to determine the amount of compound remaining at each time point. The elimination rate constant and half-life were calculated from the data as follows: elimination rate constant (k) = -slope; half-life (T) = 0.693 / k.

[0483] Extracorporeal intrinsic clearance Cl int is as follows: 1 / 2 Calculated from: Cl int =(0.693 / T 1 / 2 ) × (1 / (microsomal protein concentration (0.5 mg / mL))) × physiological scaling factor.

[0484] Table 4 below shows the in vitro intrinsic clearance values ​​of representative compounds.

[0485] [Table 9]

[0486] Biological Example D: Human Plasma Protein Binding Assays The plasma protein binding of the compound was measured in human plasma by dialysis. Dialysis membrane strips were prepared as follows: they were immersed in ultrapure water at room temperature for approximately 1 hour, then separated and immersed in ethanol:water (20:80 v:v) for approximately 20 minutes, and finally rinsed with ultrapure water. Before use, the membranes were rinsed and immersed in ultrapure water for another 20 minutes.

[0487] Blank plasma samples were thawed and centrifuged to determine their pH values. Only plasma samples with a pH between 7.0 and 8.0 were used in the experiments. The final concentration of compound in spiked plasma was 1 μM, and final DMSO was <= 1%. All samples were prepared in triplicate. A time zero (T0) sample was used to determine the recovery of the target compound after dialysis. It was prepared identically to the other dialyzed samples, except that it was stored at 2-8°C before LC-MS / MS analysis.

[0488] The other spiked plasma samples were loaded into the dialyzer and incubated for 6 hours at 37±1°C and 5% CO. After dialysis was completed, equal amounts of samples were taken from the plasma and buffer sides of the dialyzer and analyzed by LC-MS / MS.

[0489] The % unbound, % bound and % recovery of the compound were calculated from the peak area ratios of the analyte and internal standard in plasma and buffer samples as shown in the following formula: Unbonded rate %=100×F / T Combined rate %=100-Uncombined rate% Recovery rate %=100*(F+T) / T0 where [F] is the peak area ratio of analyte / internal standard on the buffer (receptor) side of the membrane; [T] is the peak area ratio of analyte / internal standard on the plasma (donor) side of the membrane; and [T0] is the peak area ratio of analyte / internal standard in the plasma sample at time zero.

[0490] Table 5 below shows human plasma protein binding values ​​for representative compounds.

[0491] [Table 10]

[0492] Biological Example E: Mouse PK Assays This study measured the pharmacokinetic profile of compounds after a single oral administration to male BALB / c mice. Each test compound was formulated into a clear solution at 0.1 mg / ml and administered at a dose of 5 mg / kg to three male mice weighing approximately 18 g (Vital River Laboratory Animal Technology Co., Ltd.). Blood samples (0.02 mL) were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, and 24 hours after administration.

[0493] The collected blood samples were centrifuged to prepare plasma samples, which were then cooled at -70°C until analysis. The plasma samples were mixed with an ACN solution containing the internal standard and vortexed for 5 minutes. The mixture was centrifuged at 14,000 rpm at 4°C for 10 minutes, and the resulting supernatant was injected into an LC-MS / MS system for plasma concentration measurement.

[0494] Pharmacokinetic parameters were calculated using standard non-compartmental methods in Phoenix WinNonLin Professional version 8.1. Calculated parameters included terminal half-life (T 1 / 2 ), area under the concentration-time curve (AUC), T max , C max and other parameters.

[0495] Table 6 below shows mouse PK data for representative compounds.

[0496] [Table 11]

[0497] Biological Example F: In Vitro Cytochrome P450 Inhibition Studies CYP inhibition was assessed by incubating known industry-accepted CYP450 substrates, assays, and microsomes (HLMs) followed by monitoring the reduction of the corresponding metabolites.

[0498] Eight reaction wells were prepared, each containing 30 μL of solution containing 100 mM potassium phosphate, pH 7.4, and a 1:3 serial dilution of the test compound. Eight wells were also prepared with a 1:3 serial dilution of sulfaphenazole (positive control inhibitor). After adding 15 μL of probe substrate to the appropriate wells, the assay plate was preheated. The reaction was then initiated by adding 15 μL of preheated 8 mM NADPH solution, resulting in a final NADPH concentration of 2 mM. The concentrations of the test compounds ranged from 0.137 μM to 10 μM. The enzyme was inactivated by adding 135 μL of acetonitrile (ACN) (containing 200 ng / mL tolbutamide as an internal standard (1S)) to the 30 μL reaction solution, followed by the addition of the probe substrate. A control reaction without inhibitor was also prepared. After appropriate incubation at 37°C for 10 minutes, the reaction was stopped by adding 135 μL of IS-containing ACN. The reactions were prepared and analyzed for metabolite forms of the probe substrate by LC-MS / MS.

[0499] Table 7 below shows P450 2C9 inhibition data for representative compounds.

[0500] [Table 12]

[0501] Biological Example G: In vitro PXR activation study DPX2 cell culture medium was prepared using DPX2 medium supplemented with 10% FBS. DPX2 cells were cultured in a T-75 flask in a cell incubator set at 37°C, 5% CO2, and 95% relative humidity. After the cells reached 80-90% confluence, they were detached and split. The T-75 flask was rinsed with 5 mL of PBS, aspirated, and 1.5 mL of trypsin was added. The cells were then incubated at 37°C for approximately 5 minutes or until the cells detached and floated. An excess of serum-containing medium was added to inactivate the trypsin. The cell suspension was transferred to an Erlenmeyer flask, and the cells were centrifuged at 150 × g for 5 minutes. 3.2 × 10 cells were added to the inoculation medium. 5 The cells were resuspended at a density of 1000 cells / mL. 25 μL was transferred to each well of a 384-well cell culture plate. The plate was placed in an incubator and incubated at 37°C for 24 hours.

[0502] Stock solutions of test compounds and inducers were prepared in DMSO. The final concentration of DMSO in the treatment groups was 0.1%. Plates were removed from the incubator and immediately added with 25 μL of negative control, inducer, or test compound solution. Plates were returned to the incubator for 48 hours. Before starting experiments using substrates, cell morphology and monolayer integrity were inspected to confirm that the monolayers were of acceptable research quality. After 48 hours of treatment, the cultures were prepared for quantitative measurement of PXR activation.

[0503] Fold activation mRNA levels were determined by the following formula:

number

[0504] Table 8 below shows the PXR data for representative compounds.

[0505] [Table 13]

[0506] Biological Example H: OVCAR3 Intravitreal Mouse Xenograft Model Study Human ovarian cancer cell line OVCAR3 (TP53 MUT , CCNE1 AMP In vivo efficacy studies were conducted to evaluate the antitumor activity of KIF18A inhibitors in a mouse xenograft model. Female BALB / c nude mice (6-8 weeks old) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. OVCAR3 cells in the exponential growth phase were harvested and used for tumor inoculation. OVCAR3 cells (1 × 10 7 The cells were subcutaneously implanted into the right flank of BALB / c nude mice. 3 After reaching a tumor size of 100 mg / kg, the mice were treated orally (PO, QD) with a KIF18A inhibitor or vehicle control once daily. The tumor volume and body weight of the mice were recorded twice weekly. Tumor size was measured in two directions with a vernier caliper and calculated in mm using the following formula: 3 Shown as: Volume = 0.5a x b 2 where a and b are the longest and shortest diameters of the tumor, respectively. The tumor growth inhibition rate (TGI) was calculated by the following formula: TGI (%) = (1 - (TV 治療 / Dn- TV 治療 / D0 ) / (TV 対照 / Dn- TV 対照 / D0 ) × 100%, where Dn is the final tumor volume and D0 is the starting tumor volume before treatment. The tumor regression rate was calculated using the following formula: regression rate (%) = -(TV 治療 / Dn -TV 治療 / D0 ) / TV 治療 / D0 ×100%.

[0507] Exemplary compounds were tested in this model and found to inhibit tumor growth (see Figures 1a and 1b).

[0508] The Summary and Abstract sections may describe one or more exemplary embodiments of the invention as conceived by the inventors and, therefore, are not intended to limit the scope of the invention and the appended claims in any way.

[0509] The present invention has been described above with the aid of functional components that describe the implementation of certain functions and their relationships. The boundaries of these functional components are arbitrarily defined in this disclosure for the convenience of the description. Other boundaries may be defined as long as the specified functions and their relationships can be appropriately performed.

[0510] For aspects of the invention described as genus, all individual species are considered individually as separate aspects of the invention. When an aspect of the invention is described as "comprising" a feature, the embodiment is also considered to "consist of" or "consist essentially of" the feature.

[0511] The foregoing description of specific embodiments fully reveals the general nature of the present invention, so that others can readily modify and / or adapt to various uses, such as specific embodiments for their respective applications, by applying knowledge within the skill of those skilled in the art, without undue experimentation and without departing from the general concept of the present invention. Accordingly, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented in this disclosure. It should be understood that the phrases or terms of this disclosure are for the purpose of description, not limitation, and that the phrases or terms of this disclosure will be interpreted by one of ordinary skill in the art in accordance with the teaching and guidance.

[0512] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

[0513] All of the various aspects, embodiments, and options described in this disclosure can be combined in any and all variations.

[0514] All publications, patents, and patent applications mentioned in this disclosure are incorporated by reference into this disclosure to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If a meaning or definition of a term in this document conflicts with a meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall control.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony: R １ may be substituted C ３－１０ carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; R ２ is hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C １－６ is a heteroalkyl or nitrogen protecting group; or R １ and R ２ are linked together with the C, C, C and N atoms therebetween to form an optionally substituted 5-14 membered heterocyclyl; R ３ But, R Ａ , OR Ａ , S.R. Ａ , S(O)R Ａ , S(O) ２ R Ａ , C.O.R. Ａ , COOR Ａ , C.N., N.H.R. Ａ , CONHR Ａ , S(O) ２ NHR Ａ , S(O)(NH)R Ａ , NHCOR Ａ , NHS(O) ２ R Ａ Or NO ２ where R Ａ are independently hydrogen, halogen, CN, OH, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C １－６ Haloalkyl, optionally substituted C ３－１０ carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; X １ But N or CR ４ where R ４ H, F, Cl, OH, NH ２ , C.N., C.D. ３ , C.F. ３ , optionally substituted C １－４ Alkyl, optionally substituted C １－４ Heteroalkyl or optionally substituted C ３－６ is cycloalkyl; X ２ But N or CR ５ where R ５ H, F, Cl, OH, NH ２ , C.N., C.D. ３ , C.F. ３ , optionally substituted C １－４ Alkyl, optionally substituted C １－４ Heteroalkyl or optionally substituted C ３－６ is cycloalkyl; X ３ But N or CR ６ where R ６ H, F, Cl, OH, NH ２ , C.N., C.D. ３ , C.F. ３ , optionally substituted C １－４ Alkyl, optionally substituted C １－４ Heteroalkyl or optionally substituted C ３－６ is cycloalkyl; or R ５ and R ６ are linked together with the C and C atoms therebetween to form an optionally substituted 5-8 membered heteroaryl; 【Chemistry 2】 may be substituted C ３－１０ a carbocycle, an optionally substituted 4-10 membered heterocycle, an optionally substituted aryl ring containing 0, 1, 2 or 3 heteroatoms independently selected from N, O and S; R Ｓ Each time, R Ｔ , OR Ｔ , S.R. Ｔ , N.H.R. Ｔ , C.O.R. Ｔ , COOR Ｔ , CONHR Ｔ , NHCOR Ｔ , CN or NO ２ where R Ｔ are independently hydrogen, halogen (e.g., F, Cl, or Br), CN, OH, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C １－６ Haloalkyl, optionally substituted C ３－１０ carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and n is 0, 1, 2 or 3; A compound or a pharmacologically acceptable salt thereof.

2. having formula I-1 or I-2, Table 1 R in Formula I-1 ７ａ and R ７ｂ are each independently hydrogen, halogen, CN, OH, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C １－６ Heteroalkyl or optionally substituted C １－６ haloalkyl; or R ７ａ and R ７ｂ are connected together with the C atom therebetween to form an optionally substituted C ３－１０ forming a carbocyclyl or an optionally substituted 4- to 10-membered heterocyclyl; R in Formula I-1 ８ａ and R ８ｂ are each independently H, F, Cl, CN, OH, C １－４ Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), C １－４ haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, etc.), C １－４ Alkoxy (e.g., methoxy, ethoxy, isopropyloxy, etc.) or C １－４ Haloalkoxy (e.g., CF ３ O-, CF ３ CH ２ O-, etc.); R in Formula I-2 １ and R ２ do not, when not linked, form an optionally substituted 5- to 14-membered heterocyclyl; 2. The compound according to claim 1 or a pharmacologically acceptable salt thereof.

3. having the formula I-1-A, 【Transformation 3】 In the formula, R ９ａ and R ９ｂ are each independently hydrogen, halogen, or optionally substituted C １－６ Alkyl or optionally substituted C １－６ is heteroalkyl; or R ９ａ and R ９ｂ are connected together with the C atom therebetween to form an optionally substituted C ３－６ forming a carbocyclyl or an optionally substituted 4- to 6-membered heterocyclyl; or R ９ａ and R ９ｂ But when connected, it becomes =CF ２ , = CCl ２ or =C(CH ３ ) ２ Forming 3. The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof.

4. having the formula I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, Table 2 During the ceremony: R Ｂ , R Ｅ and R Ｆ are each independently hydrogen, halogen, CN, OH, NH ２ , optionally substituted C １－６ Alkyl, optionally substituted C １－４ Heteroalkyl or optionally substituted C ３－６ is cycloalkyl; R Ｃ But, -L １ -L ２ where L １ is blank, -O-, -NH-, -N(C １－６ alkyl)-, -CH ２ -, -CH(C １－６ alkyl)-, -CH(OH)-, -C(O)-, -S-, -S(O) ２ - or -S(O) ２ NH— and L ２ may be substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl, optionally substituted C １－６ Haloalkyl, optionally substituted C ３－１０ carbocyclyl or optionally substituted 4- to 10-membered heterocyclyl, preferably L ２ is a monocyclic ring or contains spirocyclic, bridged and / or fused rings, unsubstituted or substituted with F, OH and C １－６ substituted with one or more groups independently selected from alkyl, C ４－８ carbocyclyl, or monocyclic or containing spirocyclic, bridged and / or fused rings, unsubstituted or substituted with F, OH and C １－６ C substituted with one or more groups independently selected from alkyl and containing one, two or three heteroatoms independently selected from N, O and S; ４－１０ is heterocyclyl; R Ｄ But hydrogen, halogens, CN, OH, NH ２ , C １－６ Alkyl, O(C １－６ alkyl), O(CH ２ ) １－３ O (C １－６ alkyl), O(CH ２ ) １－３ NH (C １－６ alkyl), O(CH ２ ) １－３ N (C １－６ alkyl) (C １－６ alkyl), NH(C １－６ alkyl), N(C １－６ alkyl) (C １－６ alkyl), C(O)NH ２ , C(O)NH(C １－６ alkyl), C(O)N(C １－６ alkyl) (C １－６ alkyl), optionally substituted C ３－６ cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl, wherein C １－６ The alkyl may be substituted; or R Ｄ is C(O)-(5-6 membered heterocyclyl), wherein said heterocyclyl is optionally substituted; 4. The compound according to claim 1, or a pharmacologically acceptable salt thereof.

5. In formula I, I-1, I-2, I-1-A, I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R ３ But, -CONHR Ａ , -S(O) ２ NHR Ａ , -NHCOR Ａ , or -NHS(O) ２ R Ａ where R Ａ is F, OH or NH ２ C which may be substituted with ２－４ alkyl; preferably, R ３ but, 【Chemistry 4】 or R ３ But -NHS(O) ２ R Ａ where R Ａ But -CH ２ CH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ N (CH ３ ) ２ or CH ２ CH ２ OC(O)CH(NH ２ ) CH(CH ３ ) ２ or R ３ But -NHS(O) ２ R Ａ where R Ａ C, which may be substituted with F １－４ alkyl, for example, CF ３ or CH ２ CF ３ and preferably, R ３ but, 【Transformation 5】 or 【Transformation 6】 or R ３ But -NHS(O) ２ R Ａ where R Ａ may be substituted with F and / or OH, NH—C １－４ alkyl or 4-membered heterocyclyl, for example, NH—CH ３ or 【Transformation 7】 and preferably, R ３ but, 【Transformation 8】 or 【Chemistry 9】 or R ３ But S(O) ２ R Ａ where R Ａ C, which may be substituted with F and / or OH １－４ alkyl, for example, CH ３ and preferably, R ３ but, 【Chemistry 10】 or R ３ However, NHR Ａ where R Ａ C, which may be substituted with F and / or OH １－６ alkyl, for example, C(CH ３ ) ２ CH ２ OH; preferably, R ３ but, 【Chemistry 11】 That is, 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. In formula I, I-1, I-2, I-1-A, I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R ３ But -NHS(O) ２ R Ａ where R Ａ But -CH ２ CH ２ OH, -CH ２ CH ３ or -CH ２ CH ２ N (CH ３ ) ２ That is, 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

7. In formula I, I-1, I-2, I-1-A, I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R ３ But -NHS(O) ２ R Ａ where R Ａ But -CH ２ CH ２ OC(O)R″, where R″ is optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C １－６ Heteroalkyl or optionally substituted C ３－６ cycloalkyl, for example, R Ａ But -CH ２ CH ２ OC(O)CH(NH ２ ) CH(CH ３ ) ２ That is, 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

8. In formula I-1-A, I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R ９ａ and R ９ｂ are both F or methyl; or R ９ａ is F and R ９ｂ is methyl; or R ９ａ and R ９ｂ are linked together with the C atom therebetween to form an optionally substituted cyclopropyl or cyclobutyl; or R ９ａ and R ９ｂ But when connected, it becomes =CF ２ Forming 8. The compound according to any one of claims 3 to 7, or a pharmaceutically acceptable salt thereof.

9. In formula I-1-A-a, I-1-A-c, I-1-A-f or I-1-A-g, R Ｂ H, halogen, CN, C １－３ Alkyl or C １－３ alkoxy; preferably H, F, Cl, CN, CH ３ or OCH ３ That is, 9. The compound according to any one of claims 4 to 8, or a pharmaceutically acceptable salt thereof.

10. In formula I-1-A-a, I-1-A-c, I-1-A-f or I-1-A-g, R Ｂ is H, or R Ｂ But F, 9. The compound according to any one of claims 4 to 8, or a pharmaceutically acceptable salt thereof.

11. In the formula I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f or I-1-A-g, R Ｅ is H, 11. The compound according to any one of claims 4 to 10, or a pharmaceutically acceptable salt thereof.

12. In the formula I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-f, I-1-A-g or I-1-A-h, R Ｆ is H, 12. The compound according to any one of claims 4 to 11, or a pharmaceutically acceptable salt thereof.

13. In the formula I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R Ｃ may be substituted C １－６ Alkyl, optionally substituted C １－６ Heteroalkyl or optionally substituted C １－６ haloalkyl; or R Ｃ is selected from the following groups, which may be further substituted: 【Chemistry 12】 13. The compound according to any one of claims 4 to 12, or a pharmaceutically acceptable salt thereof.

14. In the formula I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R Ｃ is selected from the following groups, which may be further substituted: 【Chemistry 13】 13. The compound according to any one of claims 4 to 12, or a pharmaceutically acceptable salt thereof.

15. In the formula I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R Ｃ is selected from the following groups, which may be further substituted: 【Chemistry 14】 13. The compound according to any one of claims 4 to 12, or a pharmaceutically acceptable salt thereof.

16. In the formula I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R Ｃ But CH ３ , C.H. ２ CF ３ , C.H. ２ CH ２ CF ３ , OCF ３ , OCH ２ CF ３ , OCH ２ CH ２ CF ３ or CF ３ or R Ｃ But NHCH ２ CH ２ CF ３ That is, 13. The compound according to any one of claims 4 to 12, or a pharmacologically acceptable salt thereof.

17. In the formula I-1-A-a, I-1-A-b, I-1-A-c, I-1-A-d, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R Ｃ is selected from the following groups, which may be further substituted: 【Chemistry 15】 ； or 【Chemistry 16】 ； or 【Chemistry 17】 ； or [Chemistry 18] ； or 【Chemistry 19】 ； or 【Chemistry 20】 13. The compound according to any one of claims 4 to 12, or a pharmaceutically acceptable salt thereof.

18. In formula I-1-A-a, I-1-A-b, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R Ｄ is hydrogen, F, Cl, CN, OH, NH ２ , C １－６ Alkyl, O(C １－６ alkyl), O(CH ２ ) １－３ O (C １－６ alkyl), O(CH ２ ) １－３ NH (C １－６ alkyl), O(CH ２ ) １－３ N (C １－６ alkyl) (C １－６ alkyl), NH(C １－６ alkyl), N(C １－６ alkyl) (C １－６ alkyl), C(O)NH ２ , C(O)NH(C １－６ alkyl), C(O)N(C １－６ alkyl) (C １－６ alkyl), C ３－５ cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl or heteroaryl is unsubstituted or substituted with halogen (e.g., F or Cl) and C １－６ substituted with one or more groups independently selected from the group consisting of alkyl, and C １－６ alkyl is unsubstituted or substituted with F; 18. The compound according to any one of claims 4 to 17, or a pharmaceutically acceptable salt thereof.

19. In formula I-1-A-a, I-1-A-b, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R Ｄ is hydrogen, F, Cl, CN, OH, NH ２ , C １－６ Alkyl, O(C １－６ alkyl), O(CH ２ ) １－３ O (C １－６ alkyl), O(CH ２ ) １－３ NH (C １－６ alkyl), O(CH ２ ) １－３ N (C １－６ alkyl) (C １－６ alkyl), NH(C １－６ alkyl), N(C １－６ alkyl) (C １－６ alkyl), C(O)NH ２ , C(O)NH(C １－６ alkyl), C(O)N(C １－６ alkyl) (C １－６ alkyl), C ３－５ cycloalkyl or 5-6 membered heteroaryl containing 1, 2 or 3 ring-forming nitrogen atoms, where the cycloalkyl or heteroaryl is unsubstituted or substituted with halogen (e.g., F or Cl) and C １－６ substituted with one or more groups independently selected from the group consisting of alkyl, C １－６ alkyl is unsubstituted or substituted with F; 18. The compound according to any one of claims 4 to 17, or a pharmaceutically acceptable salt thereof.

20. In formula I-1-A-a, I-1-A-b, I-1-A-e, I-1-A-f, I-1-A-g or I-1-A-h, R Ｄ H, halogen, CN, C １－３ Alkyl or C １－３ alkoxy; preferably H, F, Cl, CN, CH ３ or OCH ３ or R Ｄ H, F, Cl, OH, CN, CH ３ , OCH ３ , CHF ２ , C.F. ３ , OCHF ２ , C.H. ２ CH ３ , N(CH ３ ) ２ , C(O)NH ２ , C(O)NHCH ３ , C(O)NHCH ２ CH ３ , OCH ２ CH ２ OCH ３ , OCH ２ CH ２ N (CH ３ ) ２ or cyclopropyl; or R Ｄ contains 1, 2 or 3 ring-forming nitrogen atoms, C １－２ is a 5-membered heteroaryl optionally substituted with alkyl, such as pyrazolyl optionally substituted with methyl, imidazolyl optionally substituted with methyl, or triazolyl optionally substituted with methyl; preferably, R Ｄ but, 【Chemistry 21】 or selected from the group consisting of R Ｄ contains one or two ring-forming nitrogen atoms, C １－２ 6-membered heteroaryl optionally substituted with alkyl, for example, pyridyl optionally substituted with methyl or pyrimidyl optionally substituted with methyl; preferably, R Ｄ but, 【Chemistry 22】 or selected from the group consisting of R Ｄ contains one or two ring-forming nitrogen atoms and is oxo and / or C １－２ is a 5- or 6-membered heterocyclyl optionally substituted by alkyl, such as pyrrolidinyl optionally substituted by oxo, piperidinyl optionally substituted by methyl, piperazinyl optionally substituted by oxo and methyl, or tetrahydropyridyl optionally substituted by methyl; preferably, R Ｄ but, 【Chemistry 23】 or selected from the group consisting of R Ｄ is C(O)-(5-6 membered heterocyclyl), wherein said heterocyclyl contains 1 or 2 ring-forming nitrogen atoms, and C １－２ C(O)-piperazinyl, which may be substituted with alkyl, for example, methyl; preferably, R Ｄ but, 【Chemistry 24】 That is, 18. The compound according to any one of claims 4 to 17, or a pharmaceutically acceptable salt thereof.

21. A compound selected from the group consisting of the compounds shown in Table A, or a pharmaceutically acceptable salt thereof.

22. 22. A prodrug (e.g., an ester prodrug or aminoester prodrug) of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

23. 23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, or a prodrug according to claim 22, and a pharmaceutically acceptable excipient.

24. 1. A method for inhibiting KIF18A protein in a cell, comprising:

22. A method comprising contacting a cell with a compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

25. 1. A method of treating cancer in a test subject, comprising:

24. A method comprising administering to the test taker a therapeutically effective amount of a compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 23.

26. The cancer is selected from the group consisting of breast cancer, bladder cancer, colon cancer, cervical cancer, lung cancer, pancreatic cancer, prostate cancer and / or ovarian cancer; 26. The method of claim 25.

27. further comprising treating the subject with another therapy, wherein the other therapy is, for example, a chemotherapeutic agent, a therapeutic antibody, radiation therapy, cell therapy, or immunotherapy.

27. The method of claim 25 or 26.

28. the test taker has a cancer associated with the KIF18A protein; 28. The method of any one of claims 25 to 27.

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