1-H-pyrrolo[2,3-C]pyridine compounds that act against cancer via menine agonism

Abstract

Equation (I): [Formula 1] Compounds having the structure of JPEG2026511536000421.jpg64128 and pharmaceutically acceptable salts thereof (wherein R 1 , R 2 , R 3 , R 4 Pharmaceutical compositions comprising such compounds and salts (and A as defined herein), the use of such compounds and salts for the treatment or prevention of menine-mediated conditions, kits comprising such compounds and salts, and methods for producing such compounds and salts.

Description

[Technical Field]

[0001] This disclosure relates, in general, to 1-H-pyrrolo[2,3-c]pyridine and pharmaceutically acceptable salts thereof. Furthermore, this specification relates to pharmaceutical compositions comprising such compounds and salts, the use of such compounds and salts for the treatment or prevention of menine-mediated conditions, kits comprising such compounds and salts, and methods for producing such compounds and salts. [Background technology]

[0002] MLL1 is a histone methyltransferase encoded by the mixed-lineage leukemia 1 (MLL1) gene (also known as the KMT2A gene) on chromosome 11q23. MLL1 is a transcriptional coactivator that plays a crucial role in regulating gene expression during early development and hematopoiesis. Multiple chromosomal translocations involving the MLL1 gene are responsible for certain acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). These translocations have downstream effects that upregulate the expression of HOXA9 and MEIS1 genes, which are important for leukemia induction. HOXA9 and MEIS1 then contribute to enhanced proliferation and blockade of hematopoietic differentiation, ultimately leading to acute leukemia. MLL1-rearranged (MLL1-r) leukemia is associated with resistance to standard therapy and a higher relapse rate. Patients with MLL1-r leukemia generally have a less favorable prognosis and respond less favorably to available treatments compared to patients with non-MLL1-r leukemia.

[0003] MLL1 typically associates with a highly conserved cohort of cofactors to form macromolecular complexes. One of these cofactors is menin, a product of the MEN1 tumor suppressor gene. Menin is an essential cofactor required for the MLL1 complex to bind to the promoter of its target gene. The menin-binding site on MLL1 is located at the N-terminus and is conserved throughout the entire MLL1 fusion protein resulting from chromosomal rearrangements.

[0004] Current treatments for MLL1-r leukemia involve conventional chemotherapeutic agents that non-selectively kill all rapidly proliferating cells, including normal stem cells / progenitor cells, in the bone marrow and other organs, including the intestines. Such treatments can cause serious toxicity, side effects, and even secondary cancers. Targeted pharmacological inhibition of menin-MLL1 binding is a currently undeveloped therapeutic approach for treating leukemia and other diseases associated with menin activity. No approved pharmacological agents that inhibit menin activity in general or specifically inhibit menin activity are currently available. Therefore, there is a need for menin inhibitors, particularly those with pharmacologically appropriate properties, including selectivity and bioavailability, and suitable for administration to subjects requiring such treatment. This disclosure addresses this great unmet need by providing such compounds along with corresponding pharmaceutical compositions and methods for the treatment or prevention of cancer, particularly MLL1-r leukemia, and other menin-mediated conditions. [Overview of the Initiative]

[0005] In one aspect, this disclosure is expressed by formula (I):

[0006] [ka] The present invention provides a compound having the structure and a pharmaceutically acceptable salt thereof, wherein, R 1 However, selected from the group consisting of hydrogen and methyl, R 2 However, it is hydrogen or fluoro, R 3 However, it is hydrogen or fluoro, R 4 is (a) -C(O)NR 5 R 6 , (b) phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, cyano, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -cycloalkyl, and halo-C 3~4 -cycloalkyl, and (c) a 5- or 6-membered heteroaryl having 1, 2, or 3 ring atoms independently selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon, optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, cyano, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -cycloalkyl, and halo-C 3~4 -cycloalkyl, selected from the group consisting of 5- or 6-membered heteroaryl, R 5 and R 6 are selected independently from C 1~4 -alkyl and halo-C 1~4 -alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclyl, where the heterocyclyl is (i) a saturated monocyclic ring, (ii) has 1 or 2 ring atoms independently selected from nitrogen and oxygen, with the remaining ring atoms being carbon, and (iii) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1~4 -alkyl and halo-C 1~4 -alkyl, X is -C(R 9 )- or -N-, R 9 is selected from the group consisting of hydrogen, fluorine, and methyl, A is selected from the group consisting of the following, [[ID=5�]]

[0007] [ka] Each R A The substituents are fluoro and C 1~4 - Selected arbitrarily and independently from the group consisting of alkyl groups, r is 0, 1, or 2, s is 0, 1, 2, or 3, t is 0, 1, 2, 3, or 4, u is 0, 1, 2, 3, 4, or 5, R 10 However, C 1~10 -alkyl, -CH2R 11 , or -C(O)R 12 Selected from the group consisting of C 1~10 -alkyl, one or more -NR 13 R 14 It has been replaced with, R 11 However, C 1~4 -alkyl, -NR 15 R 16 , and -N(R 17 )S(O)2R 18 A cyclohexyl molecule that is optionally substituted with one or more substituents independently selected from the group consisting of the following: R 12 However, it is a 5-10 membered heterocyclyl, and the heterocyclyl is (i) a saturated or partially saturated monocyclic, bicyclic, or spirocyclic ring system, (ii) has one or two nitrogen ring atoms and the remaining ring atoms are carbon, and (iii) fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of the following: R 13 and R 14 However, C 1~6 -Alkyl and C 1~6- Alkoxy-C 1~6Independently selected from the group consisting of -alkyl, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , and R 23 However, hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0008] In another aspect, the present disclosure provides compounds of formula (I) having a structure selected from formulas (I-1) to (I-69) as further defined herein, and pharmaceutically acceptable salts thereof.

[0009] In another embodiment, the disclosure provides a pharmaceutical composition comprising a compound having the structure of formula (I) in a therapeutically effective amount or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] In another embodiment, the disclosure provides a pharmaceutical composition comprising a compound having the structure of formula (I) in a therapeutically effective amount or a pharmaceutically acceptable salt thereof, a second pharmacological agent, and a pharmaceutically acceptable carrier.

[0011] In another embodiment, the disclosure provides a method for treating or preventing a menin-mediated condition by administering a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof. In a further embodiment, the menin-mediated condition is a cancer. In a further embodiment, the menin-mediated condition is a hematological malignancy. In a further embodiment, the menin-mediated condition is a solid tumor cancer.

[0012] In another aspect, the disclosure provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmacopoeia for the treatment or prevention of menine-mediated conditions.

[0013] In another aspect, the disclosure provides the use of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of a menine-mediated condition.

[0014] In another embodiment, the present disclosure provides a kit comprising a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, the present disclosure provides a method for preparing a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawing]

[0016] [Figure 1] This study demonstrates the effect of treatment with a menin inhibitor (compound from Example 56-2) on tumor volume in the MLLr AML xenograft model MV-4-11. [Figure 2A] This study demonstrates the effect of treatment with a menin inhibitor (compound from Example 56-2) on tumor volume in the MLLr AML xenograft model MOLM-13. [Figure 2B] This study demonstrates the effect of treatment with a menin inhibitor (compound from Example 56-2) on tumor volume in the MLLr AML xenograft model MOLM-13. [Figure 3-A] This shows the effect of treatment with a menin inhibitor (compound from Example 56-2) on survival in the disseminated xenograft mouse model CBAM-68552 (Figure 3-A) derived from an MLLr AML patient. [Figure 3-B] This shows the effect of treatment with a menin inhibitor (compound from Example 56-2) on survival in the disseminated xenograft mouse model CBAM-44728 (Figure 3-B) derived from an MLLr AML patient. [Figure 3-C] This shows the effect of treatment with a menin inhibitor (compound from Example 56-2) on survival in the disseminated xenograft mouse model DFAL-49600 (Figure 3-C) derived from MLLr AML patients. [Figure 4]This study demonstrates the effect of treatment with a menin inhibitor (compound from Example 56-2) on survival in DFAM-16835, a disseminated xenotransplant model derived from an NPM1-mutated AML patient. [Figure 5] The combined signal heatmaps (percentage of growth signal inhibition) of MOLM-13 cells after treatment with a menin inhibitor (compound from Example 56-2), a BCL-2 inhibitor (venetoclax), or a combination of a menin inhibitor (compound from Example 56-2) and a BCL-2 inhibitor (venetoclax) are shown. [Figure 6] This study demonstrates the effects of a combination of a menin inhibitor (compound from Example 56-2), a BCL-2 inhibitor (venetoclax), and 5-azacitadine on human CD45 levels in DFAM-16835, a disseminated xenograft model derived from an NPM1-mutated AML patient. [Figure 7-A] The effect of treating menin protein levels with a menin inhibitor (compound from Example 56-2) in the MV-4-11 cell line is shown. Figure 7-A shows the treatment with DMSO control. [Figure 7-B] The effect of treatment with a menin inhibitor (compound from Example 56-2) on menin protein levels in the MV-4-11 cell line is shown. Figure 7-B shows treatment with a menin inhibitor (compound from Example 56-2). [Figure 7-C] The effect of treatment with a menin inhibitor (compound from Example 56-2) on menin protein levels in the MV-4-11 cell line is shown. Figure 7-C shows the total menin protein ("heavy" and "light") signals normalized to DMSO. [Modes for carrying out the invention]

[0017] Many embodiments are described in detail throughout this specification and will be apparent to those skilled in the art. This specification should not be construed as being limited to any particular embodiment described herein.

[0018] I. Definition With respect to the embodiments disclosed herein, the following terms have the meanings set forth below.

[0019] References to "a" or "an" indicate "one or more." Throughout, plural and singular forms should be treated as interchangeable, except when indicating quantity.

[0020] Unless the context requires a different interpretation, the words “comprise,” “comprises,” or “comprising” should be interpreted comprehensively, not exclusively, and the applicant uses each of these words with a clear understanding that they are intended to be interpreted in this way when interpreting the present patent, including the following claims.

[0021] The term "halogen" (either alone or in combination with another term) refers to a fluorine radical (which may be denoted as -F), a chlorine radical (which may be denoted as -Cl), a bromine radical (which may be denoted as -Br), or an iodine radical (which may be denoted as -I).

[0022] The term "cyano" (either alone or in combination with another term) means -CN.

[0023] The term "alkyl" (alone or in combination with another term) refers to a linear- or branched-chain saturated hydrocarbyl substituent (i.e., a substituent containing only carbon and hydrogen). Alkyl substituents typically contain 1 to about 20 carbon atoms, more typically 1 to about 12 carbon atoms, even more typically 1 to about 8 carbon atoms, and even more typically 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including n-pentyl, isoamyl, and 2,2-dimethylpropyl), and hexyl.

[0024] The term "alkenyl" (alone or in combination with other terms) refers to a linear or branched saturated hydrocarbyl substituent (i.e., a substituent containing only carbon and hydrogen) that contains one or more double bonds in an alkyl chain. Alkenyls typically contain 2 to about 20 carbon atoms, more typically 2 to about 12 carbon atoms, even more typically 2 to about 8 carbon atoms, and even more typically 2 to about 6 carbon atoms. Examples of such substituents include ethyleneyl, propyrenyl (including n-propyrenyl and isopropyrenyl), butyrenyl (including n-butyrenyl, isobutyrenyl, sec-butyrenyl, and tert-butyrenyl), pentyrenyl (including n-pentyrenyl), and hexylenyl.

[0025] The term "cycloalkyl" refers to a saturated carbocyclyl substituent containing 3 to approximately 14 carbocyclic atoms, more typically 3 to approximately 12 carbocyclic atoms, and even more typically 3 to approximately 8 carbocyclic atoms (either alone or in combination with other terms). Cycloalkyls typically contain a single carbocyclic ring containing 3 to 6 carbocyclic atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0026] The term "alkoxy" (alone or in combination with another term) refers to an alkyl ether substituent, i.e., alkyl-O-. Examples of alkoxys include methoxy(CH3-O-), ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. Therefore, for example, the term "alkoxyalkyl" (alone or in combination with another term) refers to an alkyl group substituted with an alkoxy, such as "methoxymethyl," which is...

[0027] [ka] It can be shown as follows.

[0028] The term "heterocyclyl" (alone or in combination with other terms) refers to a saturated, partially saturated, or completely unsaturated (i.e., "heteroaryl") ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur in stable combinations known to those skilled in the art.

[0029] In some examples, the number of carbon atoms in a substituent (e.g., alkyl, cycloalkyl, etc.) is determined by the prefix "C x~y This is shown by "-", where x is the minimum number of carbon atoms in the substituent and y is the maximum number. Therefore, for example, "C 1~6 "-alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. To explain further, C 3~6 -Cycloalkyl refers to a cycloalkyl substituent containing 3 to 6 carbon ring atoms.

[0030] The prefix "halo" indicates that the substituent to which it is prefixed is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced by a halogen radical. If there are two or more hydrogens replaced by halogens, the halogens may be the same or different. Examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, difluoropropyl, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyl, difluorochloromethyl, dichlorofluoromethyl, and dichloropropyl.

[0031] The term "atropisomer" refers to a stereoisomer arising from a bound rotation around one or more single bonds, where the energy barrier to the rotation is high enough to allow for the isolation of conformational isomers. In the chemical structures of this disclosure, atropisomers are indicated by wedge-shaped bonds (solid or dashed (hash)) in the aromatic ring, where the wedge-shaped bonds are connected to sigma bonds around which axial rotation is prevented.

[0032] A substituent is "substitutable" if it contains at least one carbon or nitrogen atom bonded to one or more hydrogen atoms. Therefore, for example, hydrogen, halogens, and cyanos are not included in this definition.

[0033] When a substituent is described as "substituted," a non-hydrogen radical is present instead of a hydrogen radical on the carbon or nitrogen of the substituent. Therefore, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is present instead of a hydrogen radical on the alkyl substituent. For example, a monofluoroalkyl is an alkyl substituted with a fluoro radical, and a difluoroalkyl is an alkyl substituted with two fluoro radicals. When there are two or more substitutions on a substituent, it should be recognized that (unless otherwise specified) each non-hydrogen radical may be the same or different.

[0034] If a substituent is described as "optionally substituted," it may be either (1) unsubstituted or (2) substituted. If a substituent's carbon is described as being optionally substituted with one or more substituents from the list, one or more hydrogens on the carbon (where available) may be replaced separately and / or together with independently selected optional substituents. If a substituent's nitrogen is described as being optionally substituted with one or more substituents from the list, one or more hydrogens on the nitrogen (where available) may each be replaced with independently selected optional substituents.

[0035] When a substituent is described as being "independently selected" from a group, each substituent is selected independently of the others. Therefore, each substituent may be identical or different from the others.

[0036] The term “pharmaceutically acceptable” is used adjectivally herein to mean that the modified noun is suitable for use as a drug or as part of a drug. For example, “pharmaceutically acceptable salt” is a salt suitable for use in mammals, particularly humans, and includes salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids suitable for use in mammals, particularly humans.

[0037] The "therapeutic dose" of a pharmacological agent is the amount sufficient to produce a beneficial or desired outcome, including clinical results, and therefore depends on the circumstances in which it is administered. For example, when a pharmacological agent is administered to treat cancer, the therapeutic dose of the agent is the amount sufficient to provide an anti-cancer effect in the subject, either alone or in combination with additional therapies, compared to the response obtained without the administration of the agent.

[0038] The term “prevent” is intended to be readily understood by a practicing physician and to have its usual meaning in relation to the treatment of a particular condition, and may include primary prevention, which is to prevent the onset of the condition, and secondary prevention, which is to protect the patient temporarily or permanently from exacerbation or worsening of the disease or the onset of new symptoms associated with the condition, once the condition has already developed.

[0039] The term “to treat” is readily understood by a normal, experienced physician and, in relation to the treatment of a particular condition, may include (1) reducing the degree or cause of the condition being treated, and / or (2) alleviating or improving one or more symptoms associated with that condition. Treatment of cancer may include, for example, stabilizing (i.e., preventing worsening), delaying, or slowing the spread or progression of cancer, extending survival compared to the survival expected if no treatment is provided, and / or otherwise improving or mitigating cancer or the severity of cancer, in whole or in part.

[0040] II. Compounds A. Compounds of formula (I) In one embodiment, the present disclosure is given by formula (I):

[0041] [ka] The present invention provides a compound having the structure and a pharmaceutically acceptable salt thereof, wherein, R 1 However, selected from the group consisting of hydrogen and methyl, R 2 However, it is hydrogen or fluoro, R 3 However, it is hydrogen or fluoro, R 4 but, (a)-C(O)NR 5 R 6 , (b) Fluoro, cyano, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -Cycloalkyl and halo-C 3~4 - Phenyls that are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyls, and (c) A 5 or 6-membered ring heteroaryl having 1, 2, or 3 ring atoms independently selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon, wherein the fluoro, cyano, C 1~4 -alkyl, halo-C 1~4-Alkyl, C 3~4 -Cycloalkyl, and halo-C 3~4 -Cycloalkyl, and is optionally substituted with 1 to 3 substituents independently selected from the group consisting of, and is selected from the group consisting of 5- or 6-membered heteroaryl, R 5 and R 6 are, C 1~4 -Alkyl and halo-C 1~4 -Alkyl, and are independently selected, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclyl, and the heterocyclyl is (i) a saturated monocyclic ring, (ii) has 1 or 2 ring atoms independently selected from nitrogen and oxygen, and the remaining ring atoms are carbon, (iii) C 1~4 -Alkyl and halo-C 1~4 -Alkyl, and is optionally substituted with 1 to 3 substituents independently selected from the group consisting of, X is, -C(R 9 )- or -N-, R 9 is selected from the group consisting of hydrogen, fluorine, and methyl, A is selected from the group consisting of,

[0042]

Chemical formula

[0043] In some embodiments, the present disclosure provides compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds are atrop isomers.

[0044] In some embodiments, this disclosure relates to formula (IA):

[0045] [ka] We provide a compound of formula (I) having the structure and a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 A and X are as defined in the various embodiments described herein.

[0046] In some embodiments, the present disclosure relates to formula (IB):

[0047] [ka] We provide a compound of formula (I) having the structure and a pharmaceutically acceptable salt thereof, wherein R 4 And A are as defined in the various embodiments described herein.

[0048] In some embodiments, the present disclosure relates to formula (IC):

[0049] [ka] We provide a compound of formula (I) having the structure and a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , and A are as defined in the various embodiments described herein.

[0050] In some embodiments, this disclosure relates to formula (ID):

[0051] [ka] We provide a compound of formula (I) having the structure and a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4A and X are as defined in the various embodiments described herein.

[0052] In some embodiments, the present disclosure relates to formula (IE):

[0053] [ka] We provide a compound of formula (I) having the structure and a pharmaceutically acceptable salt thereof, wherein R 4 And A are as defined in the various embodiments described herein.

[0054] In some embodiments, this disclosure relates to the formula (IF):

[0055] [ka] We provide a compound of formula (I) having the structure and a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , and A are as defined in the various embodiments described herein.

[0056] X and R 9 substituent In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), or formula (ID), and pharmaceutically acceptable salts thereof, wherein X is -C(R 9 )-. In one embodiment, R 9 is hydrogen. In another embodiment, R 9 is fluoro. In another embodiment, R 9 It is methyl.

[0057] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), or formula (ID), and pharmaceutically acceptable salts thereof, where X is -N-.

[0058] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), or formula (ID), and pharmaceutically acceptable salts thereof, wherein X is -C(R 9 )- or -N-, R 9 It is hydrogen or fluorocarbon.

[0059] R 1 substituent In some embodiments, the present disclosure provides compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof, R 1 It is hydrogen.

[0060] In some embodiments, the present disclosure provides compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof, R 1 It is methyl.

[0061] R 2 substituent In one embodiment, the present disclosure provides compounds having the structure of formula (I), formula (IA), or formula (ID), and pharmaceutically acceptable salts thereof, wherein R 2 It is hydrogen.

[0062] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), or formula (ID), and pharmaceutically acceptable salts thereof, where R 2 It is fluoro.

[0063] R 3 substituent In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), or formula (ID), and pharmaceutically acceptable salts thereof, where R 3 It is hydrogen.

[0064] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), or formula (ID), and pharmaceutically acceptable salts thereof, where R 3 It is fluoro.

[0065] R 4 =-C(O)NR 5 R 6 In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 4 is -C(O)NR 5 R 6 That is the case.

[0066] R 4 =-C(O)NR 5 R 6 And R 5 / R 6 =C 1~4 -alkyl or halo-C 1~4 -It is alkyl In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 4 is -C(O)NR 5 R 6 And R 5 and R 6 C 1~4 -alkyl and halo-C 1~4 - Selected independently of alkyl groups.

[0067] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 4 is -C(O)NR 5 R 6 And R 5 and R 6 C 1~4 - Selected independently of alkyl. In one embodiment, R 5 and R 6 C 1~4 - Selected independently of alkyl. In another embodiment, R 5 and R6 At least one of them is methyl. In another embodiment, R 5 and R 6 At least one of them is ethyl. In another embodiment, R 5 and R 6 At least one of them is isopropyl. In another embodiment, R 5 and R 6 Each of these is ethyl. In another embodiment, R 5 and R 6 One of them is methyl and the other is isopropyl. In another embodiment, R 5 and R 6 One of them is ethyl and the other is isopropyl. In another embodiment, R 5 and R 6 Each of these is isopropyl. In another embodiment, R 5 and R 6 It is independently selected from ethyl and isopropyl.

[0068] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 4 is -C(O)NR 5 R 6 And R 5 and R 6 One of them is C 1~4 - Alkyl, and the other is halo-C 1~4 -It is alkyl. In one embodiment, R 5 and R 6 One of them is methyl. In another embodiment, R 5 and R 6 One of them is ethyl. In another embodiment, R 5 and R 6 One of them is isopropyl. In another embodiment, R 5 and R 6 One of them is trifluoroethyl. In another embodiment, R 5 and R 6 One of them is trifluoroisopropyl. In another embodiment, R5 and R 6 One of them is ethyl, and the other is trifluoroethyl. In another embodiment, R 5 and R 6 One of them is ethyl, and the other is trifluoroisopropyl. In another embodiment, R 5 and R 6 One of them is isopropyl and the other is trifluoroethyl. In another embodiment, R 5 and R 6 One of them is isopropyl and the other is trifluoroisopropyl. In another embodiment, R 5 R is selected from ethyl and isopropyl, 6 R is selected from trifluoroethyl and trifluoroisopropyl. In another embodiment, R 5 and R 6 Hello-C 1~4 - Selected independently of alkyl. In another embodiment, R 5 and R 6 is trifluoro-C 1~4 -It is alkyl. In another embodiment, R 5 and R 6 This is independently selected from the group consisting of ethyl, isopropyl, trifluoroethyl, and trifluoroisopropyl.

[0069] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 4 is -C(O)NR 5 R 6 And R 5 and R 6 C 1~4 -alkyl and halo-C 1~4 - Selected independently of alkyl, C 1~4 -Alkyl and / or Halo-C 1~4 -One or more hydrogen atoms of the alkyl substituent are deuterium. In one embodiment, C 1~4 -One or more hydrogen atoms of the alkyl substituent are deuterium. In another embodiment, halo-C 1~4-One or more hydrogen atoms of the alkyl substituent are deuterium. In another embodiment, R 5 and R 6 Each is isopropyl, and one or more hydrogen atoms of one or both isopropyls are deuterium. In another embodiment, R 5 and R 6 Each of these is isopropyl, and all hydrogen atoms in one or both of the isopropyls are deuterium.

[0070] R 4 =-C(O)NR 5 R 6 And R 5 / R 6 They come together to form a ring. In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 5 and R 6 These, together with the nitrogen atom to which they are bonded, form a 5-7 membered heterocycline, and the heterocycline is (i) a saturated monocyclic ring, (ii) has one or two ring atoms independently selected from nitrogen and oxygen, the remaining ring atom is carbon, and (iii) C 1~4 -alkyl and halo-C 1~4 - They are optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups. In one embodiment, the 5- to 7-membered ring heterocyclyl is selected from the group consisting of optionally substituted pyrrolidinyl, piperidinyl, and morpholinyl. In another embodiment, the 5- to 7-membered ring heterocyclyl is substituted with 1 or 2 C 1~4 -Optionally substituted with alkyl groups. In another embodiment, the 5- to 7-membered heterocyclyl ring is optionally substituted with one or two methyl groups. In another embodiment, the 5- to 7-membered heterocyclyl ring is optionally substituted with one or two halo-C groups. 1~4 -Optionally substituted with alkyl groups. In another embodiment, a 5- to 7-membered ring heterocyclyl is optionally substituted with one or two trifluoromethyl groups.

[0071] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 5 and R 6 These, together with the nitrogen atom to which they are bonded, form optionally substituted pyrrolidinyl molecules. In one embodiment, the pyrrolidinyl molecules are substituted with one or two methyl groups.

[0072] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 5 and R 6 These, together with the nitrogen atom to which they are bonded, form optionally substituted piperidinyl molecules. In one embodiment, the piperidinyl molecules are substituted with one or two methyl groups.

[0073] In some embodiments, the present disclosure provides compounds having structural formulas (I), (IA), (IB), (IC), (ID), (IE), or (IF), and pharmaceutically acceptable salts thereof, where R 5 and R 6 These, together with the nitrogen atom to which they are bonded, form optionally substituted morpholinyl. In one embodiment, the morpholinyl is substituted with one or two methyl groups.

[0074] R 4 =phenyl In some embodiments, the Disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (ID), or formula (IE), and pharmaceutically acceptable salts thereof, where R 4 Fluoro, cyano, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -Cycloalkyl and halo-C 3~4- A phenyl compound optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups. In one embodiment, R 4 Fluoro, cyano, C 1~4 -alkyl, and halo-C 1~4 - A phenyl compound optionally substituted with 1 to 3 substituents independently selected from the alkyl group. In another embodiment, R 4 R is a phenyl compound optionally substituted with 1 to 3 fluorocarbons. In another embodiment, R 4 R is a phenyl compound optionally substituted with 1 to 3 cyano compounds. In another embodiment, R 4 This is 1 to 3 C 1~4 - A phenyl optionally substituted with an alkyl group. In another embodiment, R 4 This is 1 to 3 Halo-C 1~4 - A phenyl optionally substituted with an alkyl group. In another embodiment, R 4 This is 1 to 3 C 3~4 - A phenyl optionally substituted with a cycloalkyl group. In another embodiment, R 4 This is 1 to 3 Halo-C 3~4 - A phenyl molecule optionally substituted with a cycloalkyl group.

[0075] R 4 =heteroaryl In some embodiments, the Disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (ID), or formula (IE), and pharmaceutically acceptable salts thereof, where R 4 It is a 5 or 6-membered ring heteroaryl having 1, 2, or 3 ring atoms independently selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon, and the heteroaryl is fluoro, cyano, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -Cycloalkyl and halo-C 3~4 - It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl molecules.

[0076] In some embodiments, the Disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (ID), or formula (IE), and pharmaceutically acceptable salts thereof, where R 4 It is a five-membered ring heteroaryl having one or two ring atoms independently selected from nitrogen, oxygen, and sulfur, with the remaining ring atom being carbon, and the heteroaryl is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -Cycloalkyl and halo-C 3~4 - It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl molecules.

[0077] In some embodiments, the Disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (ID), or formula (IE), and pharmaceutically acceptable salts thereof, where R 4 It is a six-membered ring heteroaryl having one or two ring atoms independently selected from nitrogen, oxygen, and sulfur, with the remaining ring atom being carbon, and the heteroaryl is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -Cycloalkyl and halo-C 3~4 - It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl molecules.

[0078] In some embodiments, the Disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (ID), or formula (IE), and pharmaceutically acceptable salts thereof, where R 4This is a 5 or 6-membered ring heteroaryl selected from the group consisting of optionally substituted pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridadinyl. In one embodiment, the heteroaryl is selected from the group consisting of optionally substituted pyrazolyl, thiazolyl, pyridinyl, and pyrimidinyl. In another embodiment, the heteroaryl is optionally substituted pyrazolyl. In another embodiment, the heteroaryl is optionally substituted thiazolyl. In another embodiment, the heteroaryl is optionally substituted pyridinyl. In another embodiment, the heteroaryl is optionally substituted pyrimidinyl.

[0079] In some embodiments, the Disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (ID), or formula (IE), and pharmaceutically acceptable salts thereof, R 4 The heteroaryl is C 1~4 -alkyl, halo-C 1~4 -alkyl and C 3~4 - It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups. In one embodiment, R 4 The heteroaryl is C 1~4 -alkyl and halo-C 1~4 - It is optionally substituted with one or two substituents independently selected from the group consisting of alkyl groups. In another embodiment, R 4 The heteroaryl is substituted with one or two fluoropolymers. In another embodiment, R 4 The heteroaryl is substituted with one or two cyano compounds. In another embodiment, R 4 The heteroaryl is one or two C 1~4 - is substituted with alkyl. In another embodiment, R 4 The heteroaryl is one or two C 1~3 - is substituted with alkyl. In another embodiment, R 4 The heteroaryl group is substituted with methyl and isopropyl. In another embodiment, R 4The heteroaryl is one or two halo-C 1~4 - is substituted with alkyl. In another embodiment, R 4 The heteroaryl is substituted with one or two fluoropropyl groups. In another embodiment, R 4 The heteroaryl is one or two C 3~4 - It is substituted with a cycloalkyl compound. In another embodiment, R 4 The heteroaryl is substituted with one or two cyclopropyl groups. In another embodiment, R 4 The heteroaryl is one or two halo-C 3~4 - Substituted with a cycloalkyl group. In another embodiment, R selected from the group consisting of optionally substituted pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. 4 A heteroaryl.

[0080] R 4 substituent In further embodiments, the disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (ID), or formula (IE), and pharmaceutically acceptable salts thereof, R 4 teeth, (a)-C(O)NR 5 R 6 ,and (b) A 5 or 6-membered ring heteroaryl having 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atom being carbon, and being fluoro, cyano, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -Cycloalkyl and halo-C 3~4 - Selected from the group consisting of 5 or 6-membered ring heteroaryls, which are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyls, R 5 and R 6 C 1~4 -alkyl and halo-C 1~4 - Selected independently of alkyl, or R 5 and R6 These, together with the nitrogen atom to which they are bonded, form a 5-7 membered heterocycline, and the heterocycline is (i) a saturated monocyclic ring, (ii) has one or two ring atoms independently selected from nitrogen and oxygen, the remaining ring atom is carbon, and (iii) C 1~4 -alkyl and halo-C 1~4 - It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups.

[0081] In further embodiments, the disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (ID), or formula (IE), and pharmaceutically acceptable salts thereof, R 4 teeth, (a)-C(O)NR 5 R 6 ,and (b) A five-membered ring heteroaryl having one or two ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atom being carbon, wherein the ring atoms are fluoro, cyano, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -Cycloalkyl and halo-C 3~4 - Selected from the group consisting of 5-membered ring heteroaryls, which are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyls, R 5 and R 6 C 1~4 -alkyl and halo-C 1~4 - Selected independently of alkyl, or R 5 and R 6 These, together with the nitrogen atom to which they are bonded, form a 5 or 6-membered heterocycline, the heterocycline being (i) a saturated monocyclic ring, (ii) having one or two ring atoms independently selected from nitrogen and oxygen, the remaining ring atom being carbon, and (iii) C 1~4 -alkyl and halo-C 1~4 - It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups.

[0082] In further embodiments, the disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (ID), or formula (IE), and pharmaceutically acceptable salts thereof, R 4 teeth, (a)-C(O)NR 5 R 6 ,and (b) A six-membered ring heteroaryl having one or two ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atom being carbon, wherein the ring atoms are fluoro, cyano, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -Cycloalkyl and halo-C 3~4 - Selected from the group consisting of 6-membered ring heteroaryls, which are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyls, R 5 and R 6 C 1~4 -alkyl and halo-C 1~4 - Selected independently of alkyl, or R 5 and R 6 These, together with the nitrogen atom to which they are bonded, form a 5 or 6-membered heterocycline, the heterocycline being (i) a saturated monocyclic ring, (ii) having one or two ring atoms independently selected from nitrogen and oxygen, the remaining ring atom being carbon, and (iii) C 1~4 -alkyl and halo-C 1~4 - It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups.

[0083] R A substituent In some embodiments, the Disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where r, s, t, and u are independently 0 or 1. In one embodiment, r, s, t, and u are 1. In another embodiment, r, s, t, and u are 0.

[0084] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R A It is fluoro.

[0085] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R A C 1~4 -It is alkyl. In one embodiment, R A is methyl. In another embodiment, r, s, t, and u are 1, and R A It is methyl.

[0086] A ring In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, wherein A is

[0087] [ka] It is selected from the group consisting of. In one embodiment, A is

[0088] [ka] It is selected from the group consisting of. In another embodiment, A is

[0089] [ka] It is selected from the group consisting of the following.

[0090] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where A is

[0091] [ka] That is the case.

[0092] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where A is

[0093] [ka] That is the case.

[0094] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where A is

[0095] [ka] That is the case.

[0096] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where A is

[0097] [ka] That is the case.

[0098] R 10 =C 1~10 -Alkyl In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is one or more -NR 13 R 14 C replaced by 1~10 -It is alkyl, R 13 and R 14 C 1~6 -Alkyl and C 1~6 -alkoxy-C 1~6 - Independently selected from the group consisting of alkyl groups. In one embodiment, R 10 -NR 13 R 14 C replaced by 1~10 -It is alkyl, R 13 and R 14 C 1~6 -Alkyl and C 1~6 -alkoxy-C 1~6 - Independently selected from the group consisting of alkyl groups. In another embodiment, R 10 -NR 13 R 14 C replaced by 1~10 -It is alkyl. 13 is C 1~3 -It is alkyl, R 14 is C 1~3 -alkoxy-C 1~3 -It is alkyl. In another embodiment, R 10 -NR 13 R 14 C replaced by 1~10 -It is alkyl. 13 is methyl, and R 14 It is methoxyethyl.

[0099] R 10 =-CH2R 11 In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R10 is, -CH 2 R 11 And R 11 C 1~4 -alkyl, -NR 15 R 16 , and -N(R 17 )S(O)2R 18 A cyclohexyl molecule that is optionally substituted with one or more substituents independently selected from the group consisting of R 15 , R 16 , R 17 , and R 18 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups. In one embodiment, R 11 is one or more C 1~4 -A cyclohexyl optionally substituted with an alkyl group. In another embodiment, R 11 is a cyclohexyl molecule optionally substituted with one or more methyl groups. In another embodiment, R 11 is one or more -NR 15 R 16 It is a cyclohexyl that is optionally substituted with R 15 and R 16 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups. In another embodiment, R 11 is one or more -NR 15 R 16 It is a cyclohexyl that is optionally substituted with R 15 and R 16 R is independently selected from the group consisting of hydrogen and methyl. In another embodiment, R 11 is one or more -N(R 17 )S(O)2R 18 It is a cyclohexyl that is optionally substituted with R 17 and R 18 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups. In another embodiment, R 11 is one or more -N(R 17 )S(O)2R 18 It is a cyclohexyl that is optionally substituted with R 17 is hydrogen, R 18 is C1~4 -It is alkyl. In another embodiment, R 11 is one or more -N(R 17 )S(O)2R 18 It is a cyclohexyl that is optionally substituted with R 17 is hydrogen, R 18 is methyl. In another embodiment, R 11 The cyclohexyl molecule is substituted at the para position.

[0100] R 10 =-C(O)R 12 In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 and R 12 A heterocyclyl is a 5-10 membered ring heterocyclyl, where (i) it is a saturated or partially saturated monocyclic, bicyclic, or spirocyclic ring system, (ii) it has one or two nitrogen ring atoms, the remaining ring atoms are carbon, and (iii) it is fluorocarbon. 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of the following: R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0101] In one embodiment, R 12 The heterocycline is R 10 The substituent includes a nitrogen ring atom adjacent to the carbon ring atom bonded to the carbonyl group.

[0102] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is a saturated or partially saturated monocyclic ring that is optionally substituted. In one embodiment, R 12 The heterocyclyl is a saturated monocyclic ring that is optionally substituted. In another embodiment, R 12 The heterocyclyl is a partially saturated monocyclic ring that has been selectively substituted.

[0103] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is a saturated or partially saturated bicyclic ring that is optionally substituted. In one embodiment, R 12 The heterocyclyl is a saturated bicyclic ring that is optionally substituted. In another embodiment, R 12 The heterocyclyl is a saturated bicyclic ring that has been optionally substituted. In another embodiment, the bicyclic ring is a fused bicyclic ring. In yet another embodiment, the bicyclic ring is a bridged bicyclic ring.

[0104] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is a saturated or partially saturated spirocyclic ring system that is optionally substituted. In one embodiment, R 12 The heterocyclyl is a saturated spirocyclic ring system that is optionally substituted. In another embodiment, R12 The heterocyclyl is a partially saturated spirocyclic ring system that is optionally substituted.

[0105] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 It is a five-membered ring heterocycline that has been selectively substituted.

[0106] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 It is a six-membered ring heterocycline that has been selectively substituted.

[0107] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 It is a 7-membered ring heterocycline that has been selectively substituted.

[0108] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 It is an 8-membered ring heterocycline that has been selectively substituted.

[0109] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 It is a 9-membered ring heterocycline that has been selectively substituted.

[0110] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 It is a 10-membered ring heterocycline that has been selectively substituted.

[0111] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0112] [ka] Selected from the group consisting of, R 12 The heterocyclyl is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22, and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0113] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0114] [ka] Selected from the group consisting of, R 12 The heterocyclyl is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0115] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0116] [ka] Selected from the group consisting of, R 12 Heterocyclines are fluorocyclines, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0117] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R is optionally substituted. 12 The heterocyclyl is a monocyclic ring.

[0118] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R is optionally substituted. 12 The heterocyclyl is a fused bicyclic ring.

[0119] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12And R is optionally substituted. 12 The heterocyclyl is a bicyclic ring with bridges.

[0120] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R is optionally substituted. 12 The heterocyclyl is a spirocyclic ring system.

[0121] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0122] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0123] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0124] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0125] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0126] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0127] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0128] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0129] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12The heterocyclyl is,

[0130] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0131] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0132] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C1~4 - Independently selected from the group consisting of alkyl groups.

[0133] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0134] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0135] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0136] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0137] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0138] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0139] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0140] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0141] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0142] [ka] It is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenil, -OR 19 , -NR 20 R 21 , and -N(R22 )S(O)2R 23 It is optionally substituted with one or more substituents independently selected from the group consisting of R 19 , R 20 , R 21 , R 22 , and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups.

[0143] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is unsubstituted.

[0144] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -Alkenyl and -OR 19 It is optionally substituted with one or more substituents independently selected from the group consisting of . In one embodiment, R 12 The heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, halomethyl, methyleneyl, and methoxy. In another embodiment, R 12 The heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, trifluoromethyl, methyleneyl, and methoxy. In another embodiment, R 12The heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, methyl, and methyleneyl. In another embodiment, R 12 The heterocyclyl is optionally substituted with one or more fluoropolymers. In another embodiment, R 12 A heterocyclyl is one or more C 1~4 -Optionally substituted with alkyl. In another embodiment, R 12 The heterocyclyl is optionally substituted with one or more methyl groups. In another embodiment, R 12 The heterocyclyl has one or more halo-C 1~4 -Optionally substituted with alkyl. In another embodiment, R 12 The heterocyclyl is optionally substituted with one or more halomethyl groups. In another embodiment, R 12 The heterocyclyl is optionally substituted with one or more trifluoromethyl groups. In another embodiment, R 12 A heterocyclyl is one or more C 1~4 -It is optionally substituted with an alkenil. In another embodiment, R 12 The heterocyclyl is optionally substituted with one or more methenyl groups. In another embodiment, R 12 The heterocycline is one or more -OR 19 It is optionally substituted with, in the formula, R 19 C 1~4 -It is alkyl. In another embodiment, R 12 The heterocyclyl is optionally substituted with one or more methoxy groups. In another embodiment, R 12 The heterocycline has one or more -NR 20 R 21 It is optionally substituted with, in the formula, R 20 and R 21 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups. In another embodiment, R 12 The heterocycline has one or more -NR 20 R 21 It is optionally substituted with, in the formula, R 20 and R 21R is independently selected from the group consisting of hydrogen and methyl. In another embodiment, R 12 The heterocyclyl has one or more -N(R 22 )S(O)2R 23 It is optionally substituted with, in the formula, R 22 and R 23 is hydrogen and C 1~4 - Independently selected from the group consisting of alkyl groups. In another embodiment, R 12 The heterocyclyl has one or more -N(R 22 )S(O)2R 23 It is optionally substituted with, in the formula, R 22 and R 23 is independently selected from the group consisting of hydrogen and methyl. In another embodiment,

[0145] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 Heterocyclines are,

[0146] [ka] It is selected from the group consisting of the following.

[0147] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0148] [ka] It is selected from the group consisting of the following.

[0149] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0150] [ka] That is the case.

[0151] In some embodiments, the present disclosure provides compounds having the structure of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), or formula (IF), and pharmaceutically acceptable salts thereof, where R 10 is -C(O)R 12 And R 12 The heterocyclyl is,

[0152] [ka] That is the case.

[0153] The above R 10 In a further embodiment of the embodiment, A is

[0154] [ka] In one aspect, u is 0. In another aspect, u is 1, and R A is selected from the group consisting of fluoro and methyl. In another embodiment, u is 1, and R A is fluoro. In another embodiment, u is 1 and R A It is methyl.

[0155] The above R 10 In a further embodiment of the embodiment, A is

[0156] [ka] In one aspect, t is 0. In another aspect, t is 1, and R A is selected from the group consisting of fluoro and methyl. In another embodiment, t is 1, and R A is fluoro. In another embodiment, t is 1 and R A It is methyl.

[0157] The above R 10 In a further embodiment of the embodiment, A is

[0158] [ka] In one embodiment, s is 0. In another embodiment, s is 1, and R A is selected from the group consisting of fluoro and methyl. In another embodiment, s is 1, and R A is fluoro. In another embodiment, s is 1 and R A It is methyl.

[0159] The above R 10 In a further embodiment of the embodiment, A is

[0160] [ka] In one embodiment, r is 0. In another embodiment, r is 1, and R A is selected from the group consisting of fluoro and methyl. In another embodiment, r is 1, and R A is fluoro. In another embodiment, r is 1 and R A It is methyl.

[0161] B. Additional Embodiments In some embodiments, the present disclosure provides compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds of formula (I) are as follows: Formulas I-1 to I-69:

[0162] [Table 1-1]

[0163] [Table 1-2]

[0164] [Table 1-3]

[0165] [Table 1-4]

[0166] [Table 1-5]

[0167] [Table 1-6] It has a structure selected from the group consisting of, and in the formula, where applicable, R 1 , R 4 , R 5 , R 6 , R 10 , R 11 , R 12 X, A, R A ,r,s, andt are as previously defined herein, R present in the structure of equations I-54 to I-57 4 The phenyl in C is fluoro, cyano, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -Cycloalkyl and halo-C 3~4 -Optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl groups, R present in the structure of formulas I-58 to I-69 4 Pyrazolyl, pyridinyl, and pyrimidinyl are fluoro, cyano, and C.1~4 -alkyl, halo-C 1~4 -alkyl, C 3~4 -cycloalkyl, and halo-C 3~4 is optionally substituted with one or more substituents independently selected from the group consisting of R present in the structure of Formula I-53 11 The cyclohexyl of 1~4 -alkyl, -NR 15 R 16 , and -N(R 17 )S(O)2R 18 is optionally substituted with one or more substituents independently selected from the group consisting of R present in the structures of Formulas I-43 to I-52 12 The heterocyclyl of 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -alkenyl, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 is optionally substituted with one or more substituents independently selected from the group consisting of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , and R 23 are independently selected from the group consisting of hydrogen and C 1~4 -alkyl.

[0168] In one aspect, where applicable, R 1 , R 4 , R 5 , R 6 , R 10 , R 11 , R 12 , and A are as previously defined herein, and the phenyl of R present in the structures of Formulas I-54 to I-57 4 is fluoro, cyano, C 1~4-Alkyl, halo-C 1~4 -Alkyl, C 3~4- Cycloalkyl, and halo-C 3~4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of -cycloalkyl, and the R present in the structures of Formulas I-58 to I-69 4 The pyrazolyl, pyridinyl, and pyrimidinyl of are fluoro, cyano, C 1~4 -Alkyl, halo-C 1~4 -Alkyl, C 3~4 -Cycloalkyl, and halo-C 3~4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of -cycloalkyl, and X is -C(R 9 )-, R 9 is hydrogen, R A is methyl, r, s, and t are independently 0 or 1, and the cyclohexyl of R present in the structure of Formula I-53 11 is optionally substituted with one or more substituents independently selected from the group consisting of C 1~4 -Alkyl-NR 15 R 16 , and -N(R 17 )S(O)2R 18 The heterocyclyl of R present in the structures of Formulas I-43 to I-52 is fluoro, C 12 -Alkyl, halo-C 1~4 -Alkyl, C 1~4 -Alkenyl, -OR 1~4 , -NR 19 R 20 , and -N(R 21 )S(O)2R 22 is optionally substituted with one or more substituents independently selected from the group consisting of C 23 ​​​​​​​​​​​​​​​​​​​​​1 is methyl, r, s, and t are each 0, the structure is selected from Formula I-43 to Formula I-52, and the heterocyclyl of R present in the structure 12 is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -alkenyl, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 and R 19 , R 20 , R 21 , R 22 , and R 23 are independently selected from the group consisting of hydrogen and C 1~4 -alkyl. In another embodiment, R 1 is methyl, r, s, and t are each 0, the structure is selected from Formula I-43 to Formula I-52, and the heterocyclyl of R present in the structure 12 is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, and C 1~4 -alkenyl. In another embodiment, R 1 is hydrogen, r, s, and t are each 0, the structure is selected from Formula I-43 to Formula I-52, and the heterocyclyl of R present in the structure 12 is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl, C 1~4 -alkenyl, -OR 19 , -NR 20 R 21 , and -N(R 22 )S(O)2R 23 and; R 19 , R 20 , R 21 , R 22 , and R 23 are independently selected from the group consisting of hydrogen and C 1~4- Independently selected from the group consisting of alkyl groups. In another embodiment, R 1 is hydrogen, and r, s, and t are each 0, and the structure is selected from formulas I-43 to I-52, with R present in the structure 12 The heterocyclyl is fluoro, C 1~4 -alkyl, halo-C 1~4 -alkyl and C 1~4 - The compound is optionally substituted with one or more substituents independently selected from the group consisting of alkenyls. In another embodiment, the compound is an atropisomer.

[0169] In some embodiments, the present disclosure provides compounds having the structure of formula (I-5) and pharmaceutically acceptable salts thereof, wherein the compounds are of formula IB:

[0170] [ka] It has a structure, R 4 and R A This is as previously defined herein.

[0171] In some embodiments, the present disclosure provides compounds having the structure of formula (I-33) and pharmaceutically acceptable salts thereof, wherein the compounds are of formula I-33A:

[0172] [ka] It has a structure, R 4 , R 12 , R A , and t are as previously defined herein. In one embodiment, t is 0. In another embodiment, t is 1.

[0173] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, the compounds are 5-Fluoro-N,N-diisopropyl-2-(3-((S)-1-(((1r,4S)-4-(methylsulfonamide)-cyclohexyl)-methyl)pyrrolidine-3-carbonyl)-1H-pyrrolol[2,3-c]pyridine-1-yl)benzamide [Example 1], 2-(3-((S)-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 2], 2-(3-((R)-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 3], 5-Fluoro-N,N-diisopropyl-2-(3-((R)-1-(((1r,4R)-4-(methylsulfonamide)cyclohexyl)-methyl)pyrrolidine-3-carbonyl)-1H-pyrrolol[2,3-c]pyridine-1-yl)benzamide [Example 4], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 5], (S)-2-(3-(1-(2azabicyclo[2.2.2]octan-3-carbonyl)azetidine-3-carbonyl)-1H-pyrrolo-[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 6] 5-Fluoro-2-(3-(1-((1S,3S,4S,5S)-5-Fluoro-2-azabicyclo[2.2.1]heptan-3-carbonyl)-azetidine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N,N-diisopropylbenzamide [Example 7], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 8], (S)-2-(3-(1-(2-azabicyclo[2.2.2]octane-3-carbonyl)azetidine-3-carbonyl)-1H-pyrrolo-[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 9], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-yl)(1-(4-fluoro-2-(2-isopropylpyridine-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 10], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-yl)(1-(4-fluoro-2-(3-isopropylpyridine-4-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone 1·formic acid [Example 11] (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-yl)(1-(4-fluoro-2-(4-isopropylthiazole-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone 1·formic acid [Example 12] (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-yl)(1-(4-fluoro-2-(2-(2-fluoropropan-2-yl)pyridine-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 13], 2-(5-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-carbonyl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-5-fluoro-N,N-diisopropylbenzamide 1·formic acid [Example 14], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-carbonyl)-7-fluoro-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 15], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 16], 5-Fluoro-N,N-diisopropyl-2-(3-(1-(((1r,4r)-4-(methylsulfonamide)cyclohexyl)methyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 17], 5-Fluoro-N,N-diisopropyl-2-(3-(1-((1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 18], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 19], (S)-2-(3-(1-(2-azabicyclo[2.2.2]octane-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 20] 5-Fluoro-N,N-diisopropyl-2-(3-(1-((1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carbonyl)piperidine-4-carbonyl)-1H-pyrrole[2,3-c]pyridine-1-yl)benzamide [Example 21], 5-Fluoro-2-(3-(1-((1S,3S,4S,5S)-5-Fluoro-2-azabicyclo[2.2.1]heptan-3-carbonyl)-piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N,N-diisopropylbenzamide [Example 22], rac-(R)-5-fluoro-N,N-diisopropyl-2-(3-(1-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexane-3-yl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 23], (S)-2-(3-(1-(4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 24] rel-2-(3-(1-((1R,2R,5S)-3-azabicyclo[3.2.0]heptan-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 25], (S)-2-(3-(1-(5-azaspiro[2,4]heptan-6-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 26] (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 27] 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 28], (S)-2-(3-(1-(2-azabicyclo[2.2.2]octane-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 29] N-ethyl-5-fluoro-2-(3-(1-((1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-isopropylbenzamide [Example 30], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 31], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-((2R,5S)-2,5-dimethylpyrrolidine-1-carbonyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 32], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-((2R,6S)-2,6-dimethylpiperidine-1-carbonyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 33], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 34], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-((3R,5S)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 35], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(1-isopropyl-1H-pyrazole-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 36], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(4-isopropylpyrimidine-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 37], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(2-isopropylpyridine-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 38], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 39], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-(4-cyclopropylpyrimidine-5-yl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 40], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(4-isopropylpyridine-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 41], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(4-isopropylthiazole-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone 1·formic acid [Example 42] (1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(1-isopropyl-1H-pyrazole-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone 1·formic acid [Example 43] 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-4-fluoro-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide 1·formic acid [Example 44], 2-(3-((R * )-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azepan-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide 1·formic acid [Example 45]; 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 46], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 47], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 48-2], (S)-2-(3-(1-(4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 49-2], (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolol[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 50-2], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N-isopropyl-N-(2,2,2-trifluoroethyl)benzamide [Example 51-2], N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R * ,4S * )-2-methyl-1-((S)-4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide [Example 52-1], N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R * ,4S * )-2-methyl-1-((S)-4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide [Example 52-2], 2-(3-((2R * ,4S *)-1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)-2-methyl-piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N-isopropyl-N-(2,2,2-trifluoroethyl)benzamide [Example 53-3], 2-(3-((2R * ,4S * )-1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)-2-methyl-piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N-isopropyl-N-(2,2,2-trifluoroethyl)benzamide [Example 53-4], (1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(4-isopropylpyridine-3-yl)phenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 54], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 55-2], (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolol[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 56-2], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N-isopropyl-N-((R)-1,1,1-trifluoropropan-2-yl)benzamide [Example 57-1], (1-((S)-4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-yl)(1-(2-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 58-2], (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolol[2,3-c]pyridine-1-yl)-5-fluoro-N,N-bis(propan-2-yl-d7)benzamide [Example 59] 5-Fluoro-N,N-diisopropyl-2-(2-methyl-3-(1-((2S,5S)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolol[2,3-c]pyridine-1-yl)benzamide [Example 60], 5-Fluoro-N,N-diisopropyl-2-(2-methyl-3-(1-((2S,5R)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 61], 5-Fluoro-N,N-diisopropyl-2-(2-methyl-3-((2S,4RS)-2-methyl-1-((2S,5S)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 62], N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2S,4RS)-2-methyl-1-((2S,5S)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 63], 5-Fluoro-N,N-diisopropyl-2-(2-methyl-3-((2S,4RS)-2-methyl-1-((2S,5R)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolol[2,3-c]pyridine-1-yl)benzamide [Example 64], and Selected from the group consisting of N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2S,4RS)-2-methyl-1-((2S,5R)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 65].

[0174] C. Combination of Embodiments Any embodiment of the compounds described herein can be combined with any other preferred embodiment described herein to provide additional embodiments. For example, one embodiment may be combined individually or collectively with R 1 , R 2 , R 3 , and / or R 4 If a possible group for A is described in a separate embodiment, and a separate embodiment describes a possible group for A, then these embodiments are R 1 , R 2 , R 3 , and / or R 4 It is understood that possible groups described for A may be combined to provide further embodiments that describe together with possible groups described for A. In other words, in any embodiment of the compound described herein, the substituents of A may be as defined in any embodiment of A described herein.

[0175] D. Further Embodiments In some embodiments, the compounds of this disclosure exhibit an IC50 of less than approximately 200 nM for menin binding when measured by the fluorescence polarization assay described in Example 66 below. 50 It has a value. In one embodiment, IC 50 The value is less than approximately 100 nM. In another embodiment, IC 50 The value is less than approximately 50 nM. In another embodiment, IC 50 The value is less than approximately 25 nM.

[0176] In some embodiments, the compounds of this disclosure inhibit MOLM-13 cell proliferation when measured in the cell proliferation assay described in Example 67 below. In one embodiment, the compounds inhibit IC50 to less than approximately 300 nM in the assay. 50 It has a value. In another embodiment, IC 50 The value is less than approximately 150 nM. In another embodiment, IC 50 The value is less than approximately 75 nM.

[0177] In some embodiments, the compounds of this disclosure inhibit MV4-11 cell proliferation when measured in the cell proliferation assay described in Example 67 below. In one embodiment, the compounds inhibit IC50 to less than about 200 nM in the assay. 50 It has a value. In another embodiment, IC 50 The value is less than approximately 100 nM. In another embodiment, IC 50 The value is less than approximately 50 nM.

[0178] In some embodiments, the compounds of this disclosure inhibit OCI-AML3 cell proliferation when measured in the cell proliferation assay described in Example 67 below. In one embodiment, the compounds inhibit IC500 nM or less in the assay. 50 It has a value. In another embodiment, IC 50 The value is less than approximately 300 nM. In another embodiment, IC 50 The value is less than approximately 150 nM. In another embodiment, IC 50 The value is less than approximately 75 nM.

[0179] In some embodiments, the compounds of this disclosure do not significantly inhibit HEL cell proliferation when measured in the cell proliferation assay described in Example 67 below. In one embodiment, the compounds showed an IC50 greater than approximately 5 μM in the assay. 50 It has a value. In another embodiment, IC 50 The value is approximately 7 μM or greater. In another embodiment, IC 50 The value is approximately over 10 μM.

[0180] In some embodiments, the compounds of this disclosure, when measured by the hERG assay 1 (standard) described in Example 68 below, show an IC50 greater than approximately 5 μM for hERG inhibition. 50 It has a value. In one embodiment, IC 50 The value is approximately 10 μM or greater. In another embodiment, IC 50 The value is approximately 25 μM or greater. In another embodiment, IC 50 The value is approximately over 40 μM.

[0181] In some embodiments, the compounds of this disclosure are selective for menin compared to the muscarinic M2 receptor. In one embodiment, the compound, when measured by the muscarinic M2 receptor binding assay (Assay 1) described in Example 69 below, has an IC50 greater than approximately 0.1 μM. 50 It has a value. In another embodiment, IC 50 The value is approximately greater than 0.5 μM. In another embodiment, IC 50 The value is approximately 2.5 μM or greater. In another embodiment, IC 50 The value is approximately over 10 μM.

[0182] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable metabolic stability, as measured as described in the human hepatocyte (HH) assay reported in Example 70 below. In one embodiment, the compound is absorbed at HH CL less than approximately 10 μL / min / 1E6 int It has a value. In another embodiment, HH CL int The value is less than approximately 5 μL / min / 1E6. In another embodiment, HH CL int The value is less than approximately 1 μL / min / 1E6.

[0183] In some embodiments, the compounds of the present disclosure have a pharmaceutically acceptable Caco-2 AB intrinsic transmittance, as measured by the Caco-2 AB intrinsic transmittance assay described in Example 71 below. In one embodiment, the compound has at least about 0.2 × 10⁻⁶ 6 The compound has a Caco-2 intrinsic apparent transmittance of cm / s. In another embodiment, the compound has at least about 0.5 × 10⁻⁶ 6It has a Caco-2 intrinsic apparent transmittance of cm / s. In another embodiment, the compound has at least about 1 × 10⁻⁶ 6 It has a Caco-2 intrinsic apparent transmittance of cm / s. In another embodiment, the compound has at least about 3 × 10⁻⁶ 6 It has a Caco-2 intrinsic apparent transmittance of cm / s.

[0184] E. Salt The compounds of this disclosure may exist in salt form or unsalted form (i.e., as a free base), and this disclosure encompasses both salt and unsalted forms. The compounds may form acid addition salts or base addition salts. Generally, acid addition salts can be prepared using a variety of inorganic or organic acids. Such salts can typically be formed by mixing the compound with an acid (e.g., a stoichiometric amount of acid) using, for example, a variety of methods known in the art. This mixing may be carried out in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, methanol, isopropanol, or acetonitrile), or an aqueous / organic mixture. In another embodiment, acid addition salts are, for example, trifluoroacetate, formate, acetate, or hydrochloride salts. Generally, base addition salts can be prepared using salts with a variety of inorganic or organic bases, for example, alkali metal salts or alkaline earth metal salts, e.g., sodium, calcium, or magnesium salts, or other metal salts, e.g., potassium or zinc, or ammonium salts, or organic bases, e.g., methylamine, dimethylamine, trimethylamine, piperidine, or morpholine. Those skilled in the art will recognize the general principles and techniques for preparing medicinal salts, such as those described in J.Pharm.Sci.1977 66,1. Examples of pharmaceutically acceptable salts are also described in Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0185] F. Isomers The compounds and salts of this disclosure may exist in one or more geometric, optical, enantiomer, and diastereomer forms, including, but not limited to, cis- and trans- forms, E- and Z- forms, and R-, S- and meso- forms. Unless otherwise specified, references to a particular compound encompass all such isomeric forms, including racemates and other mixtures. If necessary, such isomers may be separated from their mixtures by the application or adaptation of known methods (e.g., chromatographic and recrystallization techniques). If necessary, such isomers may be prepared by the application or adaptation of known methods. In some embodiments, a single stereoisomer is obtained, for example, by isolation from a mixture of isomers (e.g., a racemate) using chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained, for example, by direct synthesis from chiral starting materials.

[0186] Certain enantiomers of the compounds described herein may be more active than other enantiomers of the same compound. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is a single enantiomer with an enantiomer excess (%ee) of ≥90, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%. In one embodiment, the single enantiomer exists with an enantiomer excess (%ee) of ≥99%.

[0187] In another embodiment, the disclosure relates to a pharmaceutical composition comprising a compound that is a single enantiomer having an enantiomer excess (%ee) of ≥90, ≥95%, ≥96%, ≥97, ≥98%, or ≥99%, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients. In one embodiment, the single enantiomer is present with an enantiomer excess (%ee) of ≥99%.

[0188] G. Further Forms The compounds and salts of this disclosure may exist in various tautomers, and this specification encompasses all such tautomers. A "tautomer" is a structural isomer that exists in equilibrium resulting from the movement of hydrogen atoms.

[0189] The compounds of this disclosure and their pharmaceutically acceptable salts may exist as solvates (such as hydrates) and non-solvated forms, and this specification encompasses all such solvates.

[0190] The compounds of this disclosure and their pharmaceutically acceptable salts may exist in crystalline or amorphous forms, and this specification encompasses all such forms.

[0191] The compounds and salts of this disclosure may be isotope-labeled (or "radioactively labeled"). In this case, one or more atoms are replaced by atoms having atomic masses or mass numbers different from those typically found in nature. This specification encompasses isotope-labeled forms of the compounds disclosed herein. Examples of isotopes that may be incorporated include: 2 H (deuterium is also written as "D") 3 H (tritium is also written as "T") 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, and 36 Cl is one example. The isotope used depends on the specific application of its radiolabeled derivative. For example, in in vitro receptor labeling and competitive assays, 3 H or 14 C is often useful. For radioactive imaging applications, 11 C is often useful. In some embodiments, the radionuclide is 3 It is H. In some embodiments, the radionuclide is 14 It is C. In some embodiments, the radionuclide is 11 It is C.

[0192] H. Intermediate In some embodiments, the Disclosure provides additional compounds and pharmaceutically acceptable salts thereof that are useful as intermediates for preparing the compounds of the Disclosure.

[0193] III.How to use The compounds disclosed herein and their pharmaceutically acceptable salts are inhibitors of menin activity.

[0194] Accordingly, in some embodiments, the present disclosure provides a method for treating or preventing a menin-mediated condition in a subject requiring such treatment or prevention by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to the subject.

[0195] In some embodiments, the present disclosure provides a method for treating or preventing a condition characterized by menine overexpression in subjects requiring such treatment or prevention by administering a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable salt thereof to the subject.

[0196] In some embodiments, the Disclosure provides a method for treating or preventing cancer in subjects requiring treatment or prevention by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to the subject. In one embodiment, the cancer is a hematological malignancy. In another embodiment, the cancer is a solid tumor carcinoma.

[0197] In some embodiments, the Disclosure provides a method for treating or prophylactic a hematological malignancy in a subject requiring treatment or prophylaxis by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to the subject, the hematological malignancy being selected from the group consisting of leukemia, myeloma, non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), myeloproliferative neoplasm (MPN), and myelodysplastic syndrome (MDS). In one embodiment, the hematological malignancy is leukemia. In another embodiment, the hematological malignancy is mixed-lineage leukemia (MLL) rearranged leukemia. In another embodiment, the hematological malignancy is multiple myeloma. In another embodiment, the hematological malignancy is non-Hodgkin lymphoma. In another embodiment, a hematological malignancy is diffuse large B-cell lymphoma (DLBCL). In another embodiment, a hematological malignancy is myeloproliferative neoplasm. In another embodiment, a hematological malignancy is myelodysplastic syndrome (MDS).

[0198] In some embodiments, the Disclosure provides a method for treating or preventing leukemia in subjects requiring treatment or prevention of leukemia by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to the subject, including acute leukemia, chronic leukemia, myeloid leukemia, myelogeneous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myelogeneous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), macrogranular lymphocytic leukemia, and hairy cell leukemia. The group is selected from cell leukemia (HCL), mixed lineage leukemia (MLL) rearrangement leukemia, mixed lineage leukemia-partial tandem duplication (MLL-PTD) leukemia, MLL amplification leukemia, MLL-positive leukemia, NPM1 mutation acute myeloid leukemia (AML), NUP98 rearrangement acute myeloid leukemia (AML), SETD2 / RUNX1 mutation leukemia, and leukemia exhibiting a HOX / MEIS1 gene expression signature. In one embodiment, the leukemia is acute myeloid leukemia (AML). In another embodiment, the leukemia is NPM1 mutation acute myeloid leukemia (AML). In another embodiment, the leukemia is NUP98 rearrangement acute myeloid leukemia (AML). In another embodiment, the leukemia is acute lymphoblastic leukemia (ALL).

[0199] In some embodiments, the Disclosure provides a method for treating or preventing solid tumor cancer in subjects requiring treatment or prevention by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to the subject, wherein the solid tumor cancer is selected from the group consisting of ovarian cancer, head and neck cancer, prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, liver cancer, melanoma, glioblastoma, and sarcoma cancer. In one embodiment, the solid tumor cancer is ovarian cancer. In another embodiment, the solid tumor cancer is head and neck cancer. In another embodiment, the solid tumor cancer is prostate cancer. In another embodiment, the solid tumor cancer is lung cancer. In another embodiment, the solid tumor cancer is breast cancer. In another embodiment, the solid tumor cancer is pancreatic cancer. In another embodiment, the solid tumor cancer is colorectal cancer. In another embodiment, the solid tumor cancer is liver cancer. In another embodiment, the solid tumor cancer is melanoma. In another embodiment, the solid tumor cancer is glioblastoma. In another context, solid tumor cancer is sarcoma cancer.

[0200] In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof are administered as first-line therapy.

[0201] In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof are administered as a second-line (or subsequent) therapy.

[0202] In some embodiments, subjects administered a therapeutically effective dose of the compound of this disclosure or a pharmaceutically acceptable salt thereof exhibit a partial response (PR) in response to such treatment.

[0203] In some embodiments, subjects administered a therapeutically effective dose of the compound of this disclosure or a pharmaceutically acceptable salt thereof exhibit a complete response (CR) in response to such treatment.

[0204] In some embodiments, subjects administered a therapeutically effective dose of the compound of this disclosure or a pharmaceutically acceptable salt thereof exhibit improved progression-free survival (PFS) in response to such treatment.

[0205] In some embodiments, subjects administered a therapeutically effective dose of the compound of this disclosure or a pharmaceutically acceptable salt thereof exhibit improved overall survival (OR) in response to such treatment.

[0206] The subjects of treatment are usually humans or non-human mammals, especially humans. Suitable subjects may also include domestic animals or wild animals; companion animals (including dogs, cats, etc.); livestock (including horses, cattle, and other ruminants, pigs, poultry, rabbits, etc.); primates (including monkeys, e.g., rhesus macaques, crab-eating macaques (also known as cercognates or long-tailed macaques), marmosets, tamarins, chimpanzees, macaques, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

[0207] In some embodiments, the present disclosure provides compounds of formula I and pharmaceutically acceptable salts thereof for use as pharmaceuticals.

[0208] In some embodiments, the present disclosure provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for treating or prophylactic the menin-mediated conditions discussed above.

[0209] In some embodiments, the disclosure provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing the menin-mediated conditions discussed above.

[0210] IV. Combination therapy and fixed dose combinations Compounds of formula I or pharmaceutically acceptable salts thereof may be used in the methods described above, either as a single pharmacological agent or in combination with other pharmacological agents or techniques. Such combination therapies may be achieved by administering the individual components of the treatment simultaneously, sequentially, or individually. These combination therapies (and corresponding combination products) utilize the compounds of the disclosure within the dosage range described herein, and other pharmacological agents, typically within their approved dosage ranges.

[0211] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and chemotherapy. In one embodiment, the chemotherapy is induction chemotherapy. In another embodiment, the chemotherapy is consolidation chemotherapy. In another embodiment, the chemotherapy comprises the administration of cytarabine. In another embodiment, the chemotherapy comprises the administration of cytarabine and anthracycline. In another embodiment, the chemotherapy comprises the administration of cytarabine and anthracycline selected from daunorubicin and idarubicin. In another embodiment, the chemotherapy comprises the administration of azacitidine. In another embodiment, the chemotherapy comprises the administration of all-trans-retinoic acid (ATRA) and arsenic trioxide or anthracycline. In another embodiment, the chemotherapy comprises the administration of all-trans-retinoic acid (ATRA) and arsenic trioxide, or anthracycline selected from daunorubicin and idarubicin. In another embodiment, chemotherapy includes the administration of two or more drugs selected from the group consisting of vincristine, cyclophosphamide, cytarabine, daunorubicin, etoposide, thioguanine, and mercaptopurine. In yet another embodiment, chemotherapy further includes the administration of methotrexate and / or a steroid selected from the group consisting of prednisolone, dexamethasone, and hydrocortisone.

[0212] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising compounds of formula I or pharmaceutically acceptable salts thereof, and radiotherapy.

[0213] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and allogeneic stem cell transplantation.

[0214] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising compounds of formula I or pharmaceutically acceptable salts thereof, and CAR-T therapy.

[0215] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and an epigenetic modulator. In one embodiment, the epigenetic modulator is selected from the group consisting of ivosidenib and enasidenib.

[0216] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a tyrosine kinase inhibitor. In one embodiment, the tyrosine kinase inhibitor is selected from the group consisting of adavocertib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, and sunitinib.

[0217] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a Bruton's kinase inhibitor. In one embodiment, the tyrosine kinase inhibitor is selected from the group consisting of acalabrutinib, ibrutinib, nemtabrutinib, olerabrutinib, piltobrutinib, remibrutinib, trebrutinib, and zambrutinib.

[0218] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax.

[0219] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those previously discussed, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 kinase inhibitor. In one embodiment, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, rerocilib (G1T38), trilaciclib (G1T28), darpiciclib (SHR-6390), and BPI-16350. In another embodiment, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, and darpiciclib.

[0220] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those previously discussed, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and an isocitrate dehydrogenase-1 (IDH1) inhibitor. In one embodiment, the IDH1 inhibitor is ortasidenib (Rezlidhia®).

[0221] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of a condition selected from the conditions discussed previously, the combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a bispecific T cell activator. In one embodiment, the bispecific T cell activator is blinatumomab.

[0222] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and an FLT3 inhibitor. In one embodiment, the FLT3 inhibitor is gilteritinib.

[0223] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and an XPO inhibitor.

[0224] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a chromatin modifier.

[0225] In some embodiments, the present disclosure provides combinations suitable for use in the treatment of conditions selected from those discussed previously, the combinations comprising compounds of formula I or pharmaceutically acceptable salts thereof, and immunomodulators from the class IMid.

[0226] V. Pharmaceutical Compositions Compounds of formula I and pharmaceutically acceptable salts thereof may be administered as pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients. Accordingly, in some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0227] The excipients selected for inclusion in a particular composition depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmacochemically acceptable excipients can function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, colorants, fillers, binders, disintegrants, lubricants, flow enhancers, thickeners, and coating agents. As those skilled in the art will understand, a particular pharmaceutically acceptable excipient may perform two or more functions, depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

[0228] The composition may be in a form suitable for oral use (e.g., as tablets, licks, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), a form suitable for topical use (e.g., as creams, ointments, gels, aqueous or oily solutions, or suspensions), a form suitable for administration by inhalation (e.g., as finely ground powders or liquid aerosols), a form suitable for administration by air (e.g., as finely ground powders), a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration), or a form suitable for suppositories for rectal administration. Compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0229] The total daily dose will inevitably vary depending on the subject being treated, the route of administration, any co-administered therapies, and the severity of the disease being treated, and may include single or multiple doses. Specific dosages may be adjusted, for example, depending on the condition being treated; the subject's age, weight, overall health, sex, and diet; the route of administration; the interval between doses; the rate of excretion; and other drugs administered concurrently to the subject. The compound of formula I or its pharmaceutically acceptable salts is typically administered at a dose of 2.5–5000 mg / m³ of an animal. 2 It is administered to warm-blooded animals in units of body area or within a range of approximately 0.05 to 100 mg / kg, which usually provides a therapeutically effective dose.

[0230] In some embodiments, the disclosure provides pharmaceutical compositions for therapeutic use comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0231] In some embodiments, the disclosure provides pharmaceutical compositions for use in the treatment of menin-mediated conditions, comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one embodiment, the menin-mediated condition is a hematological malignancy. In another embodiment, the menin-mediated condition is a solid tumor cancer.

[0232] VI. Kit The disclosure further provides a kit comprising a unit dosage form containing a compound of formula I or a pharmaceutically acceptable salt thereof contained within a packaging material, and a label or accompanying document indicating that the unit dosage form may be used to treat one or more of the conditions described above.

[0233] In some embodiments, the kit includes a unit dosage form containing a compound of formula I or a pharmaceutically acceptable salt thereof contained within packaging material, and a label or accompanying document indicating that the pharmaceutical composition may be used to treat a menin-mediated condition. In one embodiment, the menin-mediated condition is a hematological malignancy. In another embodiment, the menin-mediated condition is a solid tumor cancer.

[0234] In some embodiments, the kit includes (a) a first unit dosage form comprising a compound of formula I or a pharmaceutically acceptable salt thereof; (b) a second unit dosage form comprising a pharmacological agent selected from the group consisting of chemotherapeutic agents, epigenetic modulators, tyrosine kinases, Bruton kinase inhibitors, BCL2 inhibitors, CDK4 / 6 kinase inhibitors, isocitrate dehydrogenase-1 (IDH1) inhibitors, FLT3 inhibitors, XPO inhibitors, chromatin modifiers, and EGFR inhibitors; (c) a container means for containing the first and second dosage forms; and (d) a label or accompanying information indicating that the first and second unit dosage forms may be used to treat FAP-mediated conditions.

[0235] VII. Preparation method This disclosure further provides processes for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof.

[0236] The following schemes 1 to 14 show the synthetic routes to the compound of formula (I), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 10 , R 11 , R 12 , R 13 , R 14 , R A , and X are defined in equation (I), and X 2 R is a leaving group (e.g., I, Br, Cl, or OTf), and n and m determine the ring size of group A as defined by formula (I) (n = 1 or 2-CH2- and m = 1, 2, or 3-CH2-). Those skilled in the art will understand that these methods are representative and do not include all possible methods for preparing the compounds of this disclosure. R in each scheme XThe substituents are as defined for the compounds of this disclosure unless otherwise specified. It is understood that the preparation processes described in Schemes 1 to 14 can be carried out starting from any enantiomer or racemic mixture of compounds of formula (1), (2), (4), (6), (7), (8), (9), (10), (12), (14), (15), (18), (20), (21), (22), (23), (25), (34), (35), (41), (43), or (44) to obtain a compound of formula (I) or any stereoisomer of formula (I). All starting materials are readily available or are described in the "Intermediate Compounds" section.

[0237] Scheme 1

[0238] [ka]

[0239] Scheme 1 shows a synthesis route to a specific compound of formula (3). The compound of formula (3) is the compound of formula (1) and compound TsO-R 11 (2) can be formed from, where R 11 The reaction is as defined by formula (I). The reaction can be carried out at a temperature of 80°C in an organic solvent (e.g., MeCN) in the presence of a base (e.g., K2CO3).

[0240] Scheme 2

[0241] [ka]

[0242] Scheme 2 shows a synthesis route to a specific compound of formula (5). The compound of formula (1) is converted to carboxylic acid R 12 By reacting with -COOH(4), the compound of formula (5) can be obtained, where R 12The reaction is as defined by formula (I). The reaction can be carried out using a suitable coupling reagent (e.g., HATU, HOBt / EDC, T3P, etc.) in the presence of a base (typically an organic base such as DIPEA) and a solvent (such as DCM, DMF, SiO, or a mixture thereof) at a temperature typically in the range of 0°C to room temperature.

[0243] The compound of formula (5) may contain a Boc-protecting amine, which can be removed either directly or in a solvent such as DCM with a suitable acid such as TFA or FA. Alternatively, the reaction can be carried out in a solvent (such as MeCN, 1,4-dioxane, IPA, or a mixture thereof) at a temperature typically in the range of 0°C to 60°C using an acid such as HCl, MsOH, or TsOH.

[0244] Scheme 3

[0245] [ka]

[0246] Scheme 3 shows a synthesis route to a specific compound of formula (5). The compound of formula (5) is synthesized by converting the compound of formula (6) to formula BR 4 (7) can be formed by reacting with the compound of (7), where B is a boronic acid or boronic acid ester, and R 4 The reaction is selected from the group consisting of (b) and (c) as defined by formula (I). The reaction can be catalyzed with a suitable Pd reagent (e.g., Pd(dppf)Cl2) in the presence of a base (e.g., K2CO3), in a suitable solvent (e.g., 1,4-dioxane), optionally in the presence of water, at a temperature in the range of 60°C to 110°C.

[0247] The compound of formula (5) may contain a Boc-protecting amine, which can be removed using a suitable acid such as TFA or FA, either directly or in a solvent such as DCM. Alternatively, the reaction can be carried out in a solvent (such as MeCN, 1,4-dioxane, or a mixture thereof) at a temperature typically in the range of 0°C to room temperature, using an acid such as HCl.

[0248] Scheme 4

[0249] [ka]

[0250] Scheme 4 shows a further synthetic route to a specific compound of formula (5). The compound of formula (5) is the compound of formula (8) and the amine H-NR 5 R 6 (9) can be formed from, where R 5 and R 6 The reaction is as defined by formula (I). The reaction can be carried out using a suitable coupling reagent (e.g., HATU) in a solvent (e.g., DCM, DMF, or a mixture thereof) in the presence of a base (typically an organic base such as DIPEA) at a temperature typically in the range of 0°C to room temperature.

[0251] The compound of formula (5) may contain a Boc-protecting amine, which can be removed using a suitable acid such as TFA either directly or in a solvent such as DCM.

[0252] Scheme 5

[0253] [ka]

[0254] Scheme 5 shows a synthetic route to a specific compound of formula (13). By reacting the compound of formula (1) with the compound of formula (10), the compound of formula (11) can be obtained, and its structure is C 1~10 R consisting of -alkyl10 Represents C 1~10 -alkyl is one or more -NR as defined by formula (I). 13 R 14 It is substituted with. The reaction can be carried out at room temperature using a solvent (e.g., DMF) in the presence of Ti(OiPr)4 and a suitable reducing agent (e.g., STAB).

[0255] The compound of formula (11) may contain a Boc-protected amine, which can be removed at room temperature in a solvent (e.g., 1,4-dioxane) using a suitable acid (e.g., HCl). The free amine can be reacted with the compound of formula (12) to obtain the compound of formula (13), where X 2 R is a leaving group (e.g., I, Br, Cl, or OTf), and 14 The reaction is as defined by formula (I). The reaction can be carried out in the presence of a base (e.g., K2CO3, NaI, etc.) and a solvent (e.g., DMF, etc.) at temperatures ranging from room temperature to 50°C.

[0256] Scheme 6

[0257] [ka]

[0258] Scheme 6 shows a synthesis route to a specific compound of formula (1). The compound of formula (16) can be formed by reacting the compound of formula (14) with the compound of formula (15). The reaction can be catalyzed with a suitable Cu reagent (e.g., Cu, CuI, etc.) in the presence of a base (e.g., K2CO3, Cs2CO3, etc.) in a suitable solvent (e.g., DMF, etc.) at a temperature in the range of 80°C to 130°C.

[0259] The compound of formula (16) can be reacted with the compound of formula (9) to obtain the compound of formula (17), where R 5 and R 6The reaction is as defined by formula (I). The reaction can be carried out at room temperature using a solvent (such as DCM, DMF, or a mixture thereof) in the absence or presence of a base (typically an organic base such as DIPEA) and a suitable coupling reagent (e.g., HATU).

[0260] The compound of formula (19) can be formed by treating the compound of formula (17) with a strong base (e.g., n-BuLi), and then reacting it with the compound of formula (18) in a solvent (e.g., THF) at a temperature typically in the range of -78°C to room temperature, where the ring size (m, n) and R are defined in the formula. A This is defined by equation (I).

[0261] The compound of formula (19) can be converted to the compound of formula (1) at room temperature using a suitable acid such as TFA either directly or in a solvent such as DCM.

[0262] Scheme 7

[0263] [ka]

[0264] Scheme 7 shows a synthesis route to a specific compound of formula (1). The compound of formula (22) can be formed by reacting the compound of formula (20) with an aldehyde (21) and a base (e.g., KOH, KOt-Bu, etc.) in a suitable solvent (e.g., MeOH, EtOH, 1,4-dioxane, water, or a mixture thereof) at a temperature typically in the range of 0°C to 40°C, where R A n and m are defined by equation (I).

[0265] The compound of formula (23) can be formed by reacting the compound of formula (22) with a suitable oxidizing agent (e.g., MnO2, TEMPO / PIDA, etc.) in a suitable solvent (e.g., 1,4-dioxane, DCM, etc.) at a temperature typically in the range of room temperature to 100°C.

[0266] The compound of formula (24) can be formed by reacting the compound of formula (23) with the compound of formula (15). The reaction can be catalyzed with a suitable Cu reagent (e.g., Cu, CuI, etc.) in the presence of a base (e.g., K2CO3, Cs2CO3, etc.) in a suitable solvent (e.g., DMF, etc.) at a temperature in the range of 60°C to 100°C.

[0267] The compound of formula (24) can be reacted with the compound of formula (9) to obtain the compound of formula (19), where R 5 and R 6 The reaction is as defined by formula (I). The reaction can be carried out in the absence or presence of a base (e.g., DIPEA, DMAP, etc.) using a solvent (e.g., DCM, DMF, or a mixture thereof) and at a temperature typically in the range of room temperature to 40°C, using a suitable coupling reagent (e.g., HATU, T3P, etc.).

[0268] The compound of formula (19) can be converted to the compound of formula (1) using a suitable acid such as TFA or FA, either directly or in a solvent such as DCM. Alternatively, the reaction can be carried out at room temperature in a solvent such as 1,4-dioxane using a suitable acid (e.g., HCl).

[0269] Scheme 8

[0270] [ka]

[0271] Scheme 8 shows a synthetic route to a specific compound of formula (30). The compound of formula (25) can be reacted with MeI to obtain the compound of formula (26). The reaction can be carried out at room temperature using a solvent (e.g., DMF) in the presence of a base (e.g., K2CO3).

[0272] The compound of formula (27) can be formed by reacting the compound of formula (26) with a suitable oxidizing agent (e.g., m-CPBA) at room temperature using a solvent (e.g., DCM).

[0273] The compound of formula (28) can be formed by reacting the compound of formula (27) with a base (e.g., LiOH) at room temperature in an organic solvent (e.g., THF) in the optional presence of water.

[0274] The compound of formula (28) can be reacted with the compound of formula (9) to obtain the compound of formula (29), where R 5 and R 6 The reaction is as defined by formula (I). The reaction can be carried out in the absence or presence of a base (e.g., DIPEA) using a solvent (e.g., DCM, DMF, or a mixture thereof) and a suitable coupling reagent (e.g., T3P) at a temperature typically in the range of 0°C to room temperature.

[0275] The compound of formula (30) can be formed by reacting the compound of formula (29) with a suitable reducing agent (e.g., iron and NH4Cl, etc.) at a temperature of 80°C using a solvent (e.g., EtOH, water, or a mixture thereof).

[0276] Scheme 9

[0277] [ka]

[0278] Scheme 9 shows a synthesis route to a specific compound of formula (24). The compound of formula (22) can be reacted with the compound of formula (15) to obtain the compound of formula (31). The reaction can be catalyzed at 80°C in a suitable solvent (e.g., DMF) in the presence of a base (e.g., K2CO3) and with a suitable Cu reagent (e.g., Cu).

[0279] The compound of formula (24) can be formed by reacting the compound of formula (31) with a suitable oxidizing agent (e.g., Dess-Martin periodinane) in a suitable solvent (e.g., DCM) at room temperature.

[0280] Scheme 10

[0281] [ka]

[0282] Scheme 10 shows a synthetic route to a specific compound of formula (8). The compound of formula (23) can be converted to the compound of formula (32) at room temperature in a solvent (e.g., 1,4-dioxane, MeCN, or a mixture thereof) using a suitable acid (e.g., HCl).

[0283] The compound of formula (32) is a carboxylic acid R 12 By reacting with -COOH(4), a compound of formula (33) can be obtained, where R 12 The reaction is as defined by formula (I). The reaction can be carried out at room temperature using a suitable coupling reagent (e.g., HOBt / EDC) in the presence of a base (typically an organic base such as DIPEA) and a solvent (e.g., DCM, DMF, or a mixture thereof).

[0284] The compound of formula (33) can be reacted with the compound of formula (15) to obtain the compound of formula (8). The reaction can be catalyzed at 80°C in a suitable solvent (e.g., DMF) in the presence of a base (e.g., K2CO3) and a suitable Cu reagent (e.g., Cu).

[0285] Scheme 11

[0286] [ka]

[0287] Scheme 11 shows a synthetic route to a specific compound of formula (23). The compound of formula (32) can be formed by reacting the compound of formula (34) with a suitable agent (e.g., SOCl2) to form an acyl chloride, and then reacting the compound of formula (20) with the acyl chloride in a suitable solvent (e.g., DCM) in the presence of a Lewis acid (e.g., AlCl3) at a temperature typically in the range of 0°C to room temperature.

[0288] The compound of formula (23) can be formed by reacting the compound of formula (32) with Boc2O in the presence of a base (e.g., TEA / DMAP) in a suitable solvent (e.g., DCM) at room temperature, and then treating the resulting isolated product with a base such as NaOH in a suitable solvent (e.g., MeOH) at room temperature.

[0289] Scheme 12

[0290] [ka]

[0291] Scheme 12 shows a synthetic route to a specific compound of formula (6). The compound of formula (36) can be formed by reacting the compound of formula (23) with the compound of formula (35). The reaction can be carried out at 80°C using a solvent (e.g., DMF) in the presence of a base (e.g., K2CO3).

[0292] The compound of formula (36) can be converted to the compound of formula (37) by reduction in a solvent (e.g., EtOH, SiO, water, or a mixture thereof) at 80°C using a suitable reagent (e.g., iron / NH4Cl).

[0293] The compound of formula (37) can be converted to the compound of formula (38) by forming a bromide at room temperature in a solvent (e.g., MeCN) using a suitable reagent (e.g., t-BuONO / CuBr2).

[0294] The compound of formula (39) can be formed by reacting the compound of formula (38) with a suitable acid (e.g., HCl) in a solvent (e.g., 1,4-dioxane, MeCN, or a mixture thereof) at room temperature.

[0295] The compound of formula (39) is carboxylic acid R 12 By reacting with -COOH(4), the compound of formula (6) can be obtained, where R 12 The reaction is as defined by formula (I). The reaction can be carried out using a suitable coupling reagent (e.g., T3P) in a solvent (e.g., DCM, ethyl acetate, or a mixture thereof) in the presence of a base (typically an organic base such as DIPEA) at a temperature typically in the range of 0°C to room temperature.

[0296] Scheme 13

[0297] [ka]

[0298] Scheme 13 shows a synthesis route to a specific compound of formula (1). The compound of formula (40) is the compound of formula (15) and amine H-NR 5 R 6 (9) can be formed from, where R 5 and R 6 The reaction is as defined by formula (I). The reaction can be carried out using a suitable coupling reagent (e.g., T3P) in a solvent (e.g., DCM) in the presence or absence of a base (typically an organic base such as DIPEA) and at a temperature typically in the range of 0°C to room temperature, with or without a base. Alternatively, the reaction can be carried out by reacting the compound of formula (15) with a suitable agent (e.g., SOCl2) to form an acyl chloride, and then reacting the compound of formula (9) with the acyl chloride in a suitable solvent (e.g., toluene) at a temperature typically in the range of 0°C to 80°C.

[0299] The compound of formula (42) can be formed by reacting the compound of formula (40) with the compound of formula (41). The reaction can be catalyzed at 80°C in a suitable solvent (e.g., 1,4-dioxane, 2Me-THF, etc.) in the presence of a base (e.g., NaOtBu, Cs2CO3, etc.) and a suitable phosphine ligand (e.g., XantPhos, etc.) with a suitable Pd reagent (e.g., Pd2dba3, etc.).

[0300] The compound of formula (19) can be formed by reacting the compound of formula (42) with the compound of formula (43). The reaction can typically be catalyzed at a temperature in the range of 100°C to 110°C in a suitable solvent (e.g., DMSO) in the presence of a base (e.g., Cs2CO3) and a suitable Cu reagent (e.g., CuO).

[0301] The compound of formula (19) can be converted to the compound of formula (1) at room temperature in a solvent (e.g., DCM) using a suitable acid (e.g., TFA).

[0302] Scheme 14

[0303] [ka]

[0304] Scheme 14 shows a synthesis route to a specific compound of formula (1). The compound of formula (45) can be formed by reacting the compound of formula (44) with the compound of formula (41). The reaction can be catalyzed at 60°C in a suitable solvent (e.g., toluene) in the presence of a base (e.g., NaOtBu) and a suitable phosphine ligand (e.g., XantPhos) with a suitable Pd reagent (e.g., Pd2dba3).

[0305] The compound of formula (38) can be formed by reacting the compound of formula (45) with the compound of formula (43). The reaction can be catalyzed at 80°C in a suitable solvent (e.g., DMSO) in the presence of a base (e.g., Cs2CO3) and a suitable Cu reagent (e.g., CuO).

[0306] The compound of formula (19) is the compound of formula (38) BR 4 (7) can be formed by reacting with the compound of (7), where B is a boronic acid or boronic acid ester, and R 4 The reaction is selected from the group consisting of (b) and (c) as defined by formula (I). The reaction can be catalyzed at 100°C in the presence of a base (e.g., K2CO3), a suitable solvent (e.g., 1,4-dioxane), and optionally water, with a suitable Pd reagent (e.g., Pd(dppf)Cl2).

[0307] The compound of formula (19) can be converted to the compound of formula (1) in a solvent such as DCM using a suitable acid such as TFA. Alternatively, the reaction can be carried out at room temperature in a solvent such as 1,4-dioxane, MeCN, or a mixture thereof, using an acid such as HCl.

[0308] It should be understood that (i) the organic reactions described herein are carried out in accordance with laboratory practices known to those skilled in the art; (ii) some of the reactions described herein may optionally be carried out in a different order than those described herein; (iii) chiral isomers of the compounds of this disclosure may be divided at any stage of the synthetic process using chiral resolving agents described in the literature and known to those skilled in the art, or using chiral chromatography methods described in the literature and known to those skilled in the art, or as further described in the Examples; (iv) additional and / or other protecting groups may optionally be required in some of the steps described herein; therefore, (v) the deprotection step may optionally be carried out using methods described in the literature and known to those skilled in the art. Protection and deprotection of functional groups are described in "Protective Groups in Organic Synthesis" 3rd Ed, TW Greene and PGMWutz, Wiley-Interscience (1999), which is incorporated herein by reference. VIII. Examples

[0309] The following descriptions of experiments, procedures, examples, and intermediates are intended to illustrate embodiments of the present disclosure and are not intended to limit them in any way. Other compounds of the present disclosure may be prepared using the methods shown in these examples either alone or in combination with techniques generally known in the art.

[0310] A. General conditions Unless otherwise specified, (i) Unless otherwise specified, the operations were carried out at room temperature (rt), i.e., in the range of 17–25°C, under an atmosphere of an inert gas such as N2. (ii) Typically, the course of the reaction is tracked by thin-layer chromatography (TLC) and / or analytical (ultra) high-performance liquid chromatography (HPLC or UPLC) (usually coupled to a mass spectrometer (LCMS)). (iii) If necessary, the organic solution was dried with anhydrous Na2SO4 or MgSO4, or dried using a Kinesis TELOS® or Whatman® phase separator, and post-treatment procedures were performed using conventional phase separation techniques. (iv) Evaporation was carried out by rotational evaporation in a vacuum or in a Genevac HT-4 / EZ-2 or Biotage V10. (v) Unless otherwise specified, flash column chromatography is performed manually with normal-phase silica using either Acros silica gel (35-70 μm silica, item no. 240360010) or Orienda silica gel (38-60 μm silica, item no. F01-BK-1000), or pre-filled cartridges from Buchi (FlashPure, 35-45 μm silica, 4-330 g) or Orienda (FlashPure, 38-60 μm silica, 4-330 g), or with reverse-phase silica using either pre-filled cartridges from Agela (Claricep Spherical C18 20-35 μm, 100 Å, 120 g / branch, item no. SO230120-0) or (Claricep Spherical C18 20-35 μm, 100 Å, 330 g / branch, item no. SO230330-0), or with Buchi Automated using Pure, Biotage Isolera Four, or Agela Cheetah II flash systems. (vi) Unless otherwise specified, preparative TLC was performed on silica using Xin Nuo Kun Yu Mountain preparative TLC GF254 (item number XN1997-2-3). (vii)(a) Chiral preparative HPLC and (a) Chiral preparative SFC were performed using standard HPLC and SFC instruments equipped with either an MS and / or a UV-triggered fraction acquisition instrument, respectively, using either a fixed composition or gradient of the mobile phase as described in the Experimental Section, and one of the following methods as described below: HPLC separation methods: Separation method A: The compound was purified by preparative HPLC on a Luna® C18(2) column (5 μm, 150 × 21.2 mm ID) using a gradient of MeCN in H2O containing 0.1% TFA as the mobile phase. Separation method B: The compound was purified by preparative chiral HPLC on a Lux 5 μm cellulose-4 column (5 μm, 25 × 2.12 mm ID) using EtOH in hexane containing 0.5% 2 M NH3 in MeOH as the mobile phase. Separation method C: The compound was purified by preparative HPLC on an Xselect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O containing 0.1% FA. Separation method D: The compound was purified by preparative HPLC on an Atlantis Prep T3 OBD column (10 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O containing 0.1% FA. The compound E was purified by preparative HPLC using a gradient of MeCN in H2O containing 0.1% FA on an XSelect CHS Prep C18 OBD column (5 μm, 250 × 19 mm ID). The compound F was purified by preparative HPLC using a gradient of MeCN in H2O containing 0.1% FA on an Xbridge Shield RP18 OBD column (5 μm, 150 × 30 mm ID). The compound G was purified by preparative HPLC using a gradient of MeCN in H2O containing 0.1% FA on a Sunfire prep C18 column (5 μm, 150 × 30 mm ID). The compound H was purified by preparative HPLC using a gradient of EtOH in MTBE containing 0.5% 2M NH3 in MeOH on a Chiralpak ID column (5 μm, 250 × 20 mm ID). Preparative method I: The compound was purified by preparative HPLC using a MeCN gradient in H2O containing 0.3% NH4OH on a Waters CSH C18 OBD column (5 μm, 100 × 30 mm ID). Preparative method J: The compound was purified by preparative HPLC using a MeCN gradient in H2O containing 0.3% NH4OH on a Waters CSH C18 OBD column (5 μm, 100 × 30 mm ID).Preparative method K: The compound was purified by preparative HPLC using a gradient of MeCN in H2O containing H2O on a YMC-Actus Triart C18 ExRS column (5 μm, 150 × 30 mm ID). The compound was then purified by preparative HPLC using a gradient of MeCN in H2O containing 0.1% FA on a Phenomenex Luna C18 column (5 μm, 150 × 21.2 mm ID). SFC Separation Methods: Separation Method SFC-A: The compound was purified by preparative SFC on a Chiralpak IG-3 column (3 μm, 50 × 4.6 mm ID) using MeOH containing 0.1% DEA in CO2 as the mobile phase. Separation Method SFC-B: The compound was purified by preparative SFC on an Enanticel C9-3 column (5 μm, 150 × 30 mm ID) using IPA containing 0.1% DEA in CO2 as the mobile phase. Separation Method SFC-C: The compound was purified by preparative SFC on a Chiralpak IG column (5 μm, 250 × 20 mm ID) using MeOH containing 0.1% NH3 in CO2 as the mobile phase. Separation Method SFC-D: The compound was purified by preparative SFC on a YMC SZ column (5 μm, 250 × 20 mm ID) using MeOH containing 0.1% NH3 in CO2 as the mobile phase. The compound SFC-E, purified by preparative SFC at ID), was purified by preparative SFC on a Regis(R,R)-Whelk-O column (5 μm, 250 × 20 mm ID) using MeOH containing 0.1% NH3 in CO2 as the mobile phase, and the compound SFC-F, purified by preparative SFC on an IK column (5 μm, 250 × 20 mm ID) using MeOH containing 0.1% NH3 in CO2 as the mobile phase, and the compound SFC-G, purified by preparative SFC on a YMC SB column (5 μm, 250 × 20 mm ID) using MeOH containing 0.1% NH3 in CO2 as the mobile phase. The relevant fractions were collected, combined, and freeze-dried to obtain the purified compound, or the relevant fractions were collected, combined, concentrated under reduced pressure, extracted with DCM or siRNA in a basic post-treatment using saturated NaHCO3 aqueous solution, the organic phase was dried with Na2SO4 or MgSO4, and then concentrated under reduced pressure to obtain the purified compound. (viii) The yield, if any, is not necessarily the maximum achievable value, and if a larger amount of reaction product is needed, the reaction may be repeated as needed. (ix) If a particular compound is obtained as a salt, e.g., monohydrochloride or dihydrochloride, the stoichiometry of the salt is based on the number and nature of basic groups in the compound, or the stoichiometry is labeled as x. The exact stoichiometry of salts was not generally determined by elemental analysis data of hydrochloride and trifluoroacetate salts, for example. The stoichiometry of formate salts was determined by 1H-NMR and rounded to the nearest integer. (x) Generally, the structure of the final product of formula (I) was confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques. Proton NMR chemical shift values ​​were measured on a delta scale using a Bruker Avance III 400, 500 spectrometer operating at 1H frequencies of 300, 400, and 500 MHz. Experiments were typically recorded at 25°C. Chemical shifts are expressed in ppm using the solvent as an internal standard. Protons on heteroatoms such as NH and OH are reported only if detected in NMR and therefore may be missing. In certain cases, protons may be masked by solvent peaks and therefore either missing and not reported, or reported as multiples overlapping with the solvent. The following abbreviations (and their derivatives, e.g., dd, doublet doublet) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p: pentet. In some cases, the structure of the final product of formula (I) may appear as rotational isomers in the NMR spectrum, in which case only the peaks of the major rotational isomer are reported. Electrospray mass spectrum data are obtained using either an Agilent 1260 HPLC or Agilent 1290 UPLC coupled to an Agilent single quadrupole mass spectrometer, or a Shimadzu LC20XR HPLC or Shimadzu LC40XR HPLC coupled to a Shimadzu single quadrupole mass spectrometer, or a similar instrument, to obtain cation data, and generally only ions related to the parent structure are reported. (xi) Although intermediates were not always completely purified, their structure and purity were evaluated by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry. Generally, the purity of the intermediate is reported when it is found to be ≤85% by LC-UV (260±80 nm). Theoretical molars (th.) are reported for crude and impure starting materials. (xii) Specific optical rotation measurements were performed in a 2dm polarimeter tube using a Bellingham and Stanley ADP400+ Polarimeter. (xiii) Unless otherwise specified, compounds containing an asymmetric carbon and / or sulfur atom were not divided. (xiv) Examples and intermediate compounds are generally named using PerkinElmer's ChemDraw Professional version 21.0.0. ChemDraw Professional version 21.0.0 generates names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and adheres as strictly as possible to IUPAC rules when generating chemical names. Stereoisomers are distinguished from each other by stereodescriptors cited in the names and assigned according to the CIP rules.

[0311] ChemDraw optionally uses stereocenter labels such as "&" and "or" to indicate the stereochemical configurations of stereocenters present in a structure. Generally, the chemical structure of an example or intermediate containing the label "&" at a stereocenter means that the configuration of such example or intermediate at that stereocenter is a mixture of both (R) and (S), while the label "or" means that the configuration of such example or intermediate at that stereocenter is either (R) or (S). All unspecified absolute stereocenters "&" and "or" can exist within a single structure.

[0312] In general, for embodiments and intermediate structures where all stereocenters are specified as "&", the structure is named using the prefix "rac-". For embodiments and intermediate structures where all stereocenters are specified as "or", the structure is named using the prefix "rel-".

[0313] Generally, examples and intermediate compounds are named using descriptors (RS) and (SR) to indicate the general "&" center of a chemical structure having multiple chiral centers, some of which are designated as "&".* ) and (S * ) is used to indicate the general "or" center of a chemical structure that has multiple chiral centers, some of which are indicated as "or".

[0314] R 1 The compounds of the following examples (and their corresponding intermediate compounds) having a methyl substituent may exist as a mixture of atropisomers or as isolated atropisomers. The bond around which axial rotation is inhibited is a C-Nσ bond. Isolated atropisomers are indicated in the examples by wedge-shaped bonds (solid or dashed lines (hash)) in the phenyl ring connected to the C-Nσ bond around which axial rotation is inhibited. Mixtures of atropisomers are indicated in the examples by non-wedge-shaped bonds in the phenyl ring connected to the C-Nσ bond around which axial rotation is inhibited. (xv) If the reaction is degassed or purged, this can be done, for example, by purging the reaction solvent with a constant flow rate of nitrogen for a suitable time (e.g., 5-10 minutes). (xvi) In addition to the above, the following abbreviations are used: AlCl3 = aluminum chloride, aq. = water-based, ATP = adenosine triphosphate, BAST = Bis(2-methoxyethyl)aminosulfur trifluoride, BH3.THF = Boranetetrahydrofuran, Boc=t-butyloxycarbonyl, Boc2O = di-tert-butyl dicarbonate, C = Celsius, CDCl3 = Deuterated chloroform, CDI = 1,1'-carbonyldiimidazole, CHO = Chinese hamster ovary, CO2 = Carbon dioxide, Cs2CO3 = Cesium carbonate, CuBr2=copper(II) bromide, CuI = copper(I) iodide CuO = copper(II) oxide, DAST = Diethylamino sulfur rifluoride, DCM = Dichloromethane, DEA = Diethylamine, Des-Martinperiodinane = 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one, DIPEA = N,N-diisopropylethylamine, dm=diameter, DMAP = 2,6-dimethylaminopyridine, DME = 1,2-dimethoxyethane, DMF = N,N-dimethylformamide, DMSO = Dimethyl sulfoxide, DMSO-d6 = Deuterated Dimethyl Sulfoxide EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide EDTA = Ethylenediaminetetraacetic acid, ee = enantiomer excess, EGTA = Ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid eq=equivalent, ES = Electrospray, Et3N = triethylamine, Et2O = diethyl ether, HCl = ethyl acetate, EtOH = ethanol, FA = Formic acid, g = grams, GMF = Glass Microfiber, h=time, HATU = (dimethylamino)-N,N-dimethyl(3-oxide-1H-[1,2,3]triazolo[4,5-b]pyridinyl)-methaneaminonium hexafluorophosphate HCl = hydrochloric acid, HBSS=Hepes buffered saline solution, HEPES = (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid), hERG = Human delayed-rectifying potassium ion channel gene. HOBt = 1-hydroxybenzotriazole, H2O = water, HPLC = High-Performance Liquid Chromatography IBMX = 3-isobutyl-1-methylxanthine, I C 50 = Half-maximal inhibitory concentration, ID = inner diameter, IPA = Isopropanol, K2CO3 = potassium carbonate, KCl = potassium chloride, KF = potassium fluoride KOH = potassium hydroxide, KOtBu = potassium tert-butoxide, LCMS = Liquid Chromatography-Mass Spectrometry LiOH = Lithium hydroxide, M = moles, m-CPBA = meta-chloroperoxybenzoic acid, MeCN = Acetonitrile, MeI = methyl iodide, MeMgBr = Methylmagnesium bromide MeOD = Deuterated methanol, MeOH = methanol, 2Me-THF = 2-methyltetrahydrofuran Mg = magnesium, mg = milligram MgSO4 = Magnesium sulfate, MHz = megahertz, min = minutes, mL = milliliter, mm = millimeters, mmol = millimoles, MnO2 = manganese dioxide, MS=mass spectrometry, MsOH = methanesulfonic acid, MTBE = tert-butylmethyl ether, m / z = mass spectrometry peak, NaBH4 = Sodium borohydride Na2CO3 = sodium carbonate, NaCl = sodium chloride, NaOH = sodium hydroxide, n-BuLi=n-butyllithium, NaH = sodium hydride, NaHCO3 = sodium bicarbonate, NaOtBu = sodium tert-butoxide, Na2SO4 = sodium sulfate, Na2S2O3 = sodium thiosulfate, NH3 = ammonia, NH4Cl = Ammonium chloride NH4HCO3 = Ammonium bicarbonate, NMDG = N-methyl-d-glucamine NMR=nuclear magnetic resonance, OTf = Trifluoromethanesulfonate, Pd / C = Palladium-carbon Pd(dppf)Cl2=1,1'-bis(di-tert-butylphosphin)ferrocenepalladium dichloride, Pd2dba3 = Tris(dibenzylideneacetone)dipalladium(0), Pd2dba3.CHCl3 = Tris(dibenzylideneacetone)dipalladium-chloroform adduct, PIDA = (diacetoxyiodo)benzene, ppm = 1 part per million, prep=preparative, p-TsOH.H2O=p-toluenesulfonic acid monohydrate PVDF = Polyvinylidene difluoride quant.=quantitative, rt=room temperature, sat=saturated, SCX = Strong cation exchange, SFC = Supercritical Fluid Chromatography SOCl2 = thionyl chloride, STAB = Sodium triacetoxyborohydride, tBu = tert-butyl, t-BuONO = tert-butyl nitrite, TEA = triethylamine, TEMPO = (2,2,6,6-tetramethylpiperidine-1-yl)oxyl, TFA = Trifluoroacetic acid, th.=theory, THF = tetrahydrofuran, Ti(OiPr)4 = Titanium(IV) Isopropoxide, TLC = Thin-Layer Chromatography T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosfinan 2,4,6-trioxide Ts = tosile, TsCl = p-toluenesulfonyl chloride, TsOH = para-toluenesulfonic acid, μL = microliter, μm = micrometer, UPLC = Ultra-high-performance liquid chromatography UV = ultraviolet light, and Xantphos = (9,9-dimethyl-9H-xanthene-4,5-diyl)-bis(diphenylphosphan).

[0315] B. Intermediate compounds Intermediate 1: tert-butyl(S)-3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

[0316] [ka]

[0317] CDI (1.66 g, 10.2 mmol) was added at 0°C to a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.00 g, 9.29 mmol) in DCM (60 mL) and THF (20 mL). The mixture was stirred at room temperature for 1 hour, after which N,O-dimethylhydroxylamine hydrochloride (1.00 g, 10.2 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (40 mL) and extracted with DCM (3 × 40 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% ethyl acetate in heptane) to obtain the title compound (2.01 g, 84%) as a colorless oil; MS m / z(ES+)[M+H-tBu] + = 203.1.

[0318] Intermediate 2: 2-(3-bromo-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluorobenzoic acid

[0319] [ka]

[0320] Copper powder (387 mg, 6.09 mmol) was added to a deoxygenated solution of 5-fluoro-2-iodobenzoic acid (8.10 g, 30.5 mmol), 3-bromo-1H-pyrrolo[2,3-c]pyridine (6.00 g, 30.5 mmol), and K2CO3 (12.6 g, 91.4 mmol) in DMF (60 mL). The reaction mixture was purged with N2 for 5 minutes. The reaction mixture was stirred overnight at 130 °C. The reaction mixture was allowed to reach room temperature and acidified to pH 1 with aqueous HCl (6 M). The precipitate was collected by filtration, washed with water, and dried under vacuum to obtain the title compound (6.73 g, 66%) as a beige solid; MS m / z(ES+)[M+H] + = 335.0 / 337.0.

[0321] Intermediate 3: 2-(3-bromo-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropyl-benzamide

[0322] [ka]

[0323] Diisopropylamine (6.39 mL, 45.6 mmol) was added to a suspension of intermediate 2 (5.09 g, 15.2 mmol) and HATU (6.35 g, 16.7 mmol) in DMF (20 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with HCl (40 mL) and washed with aqueous HCl (1 M, 40 mL) and saturated aqueous NaHCO3 (40 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-100% HCl in heptane) to obtain the title compound (5.57 g, 88%) as a beige solid; MS m / z(ES+)[M+H] + = 418.1 / 420.1.

[0324] Intermediate 4: tert-butyl(S)-3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)pyrrolidine-1-carboxylate

[0325] [ka]

[0326] n-BuLi (1.64 mL, 2.63 mmol, 1.6 M in hexane) was added dropwise to a suspension of intermediate 3 (550 mg, 1.31 mmol) in THF (10 mL) under N2 at -78°C. The mixture was stirred at -78°C for 5-10 minutes, and then intermediate 1 (577 mg, 2.24 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -78°C for 1 hour. The reaction product was quenched with cold saturated NH4Cl aqueous solution and returned to room temperature, and extracted with SiO2 (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-5% MeOH in DCM), followed by HPLC and preparative method A (gradient: 20-75%). Appropriate fractions were pooled, diluted with saturated NaHCO3 aqueous solution, and extracted with siRNA (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (223 mg, 32%) as an orange, gum-like substance; MS m / z(ES+)[M+H] + = 537.3.

[0327] Intermediate 5a: (S)-5-fluoro-N,N-diisopropyl-2-(3-(pyrroridine-3-carbonyl)-1H-pyrrorol[2,3-c]pyridine-1-yl)benzamide 2,2,2-trifluoroacetic acid

[0328] [ka]

[0329] TFA (1 mL) was added to a solution of intermediate 4 (223 mg, 0.36 mmol th.) in DCM (5 mL). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to obtain the crude title compound as an orange solid in a quantitative yield (454 mg); MS m / z(ES+)[M+H] + = 437.4.

[0330] Intermediate 5b: (S)-5-fluoro-N,N-diisopropyl-2-(3-(pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0331] [ka]

[0332] TFA (1 mL) was added to a solution of intermediate 4 (45.1 mg, 0.08 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and washed with saturated NaHCO3 aqueous solution (10 mL) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (35.6 mg, 97%) as a brown gum-like substance; MS m / z(ES+)[M+H] + = 437.3.

[0333] Intermediate 6: tert-butyl(R)-3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

[0334] [ka]

[0335] CDI (1.66 g, 10.2 mmol) was added at 0°C to a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.00 g, 9.29 mmol) in DCM (60 mL) and THF (20 mL). The resulting mixture was stirred at room temperature for 1 hour, after which N,O-dimethylhydroxylamine hydrochloride (1.00 g, 10.2 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (40 mL) and extracted with DCM (3 × 40 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% ethyl acetate in heptane) to obtain the title compound (2.00 g, 83%) as a colorless liquid; MS m / z(ES+)[M+H-tBu] + = 203.2.

[0336] Intermediate 7: tert-butyl(R)-3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)pyrrolidine-1-carboxylate

[0337] [ka]

[0338] n-BuLi (1.64 mL, 2.63 mmol, 1.6 M in hexane) was added dropwise to a suspension of intermediate 3 (550 mg, 1.31 mmol) in THF (10 mL) under N2 at -78°C. The mixture was stirred at -78°C for 5-10 minutes, and then intermediate 6 (577 mg, 2.24 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -78°C for 1 hour. The reaction product was quenched with cold saturated NH4Cl aqueous solution and returned to room temperature, and extracted with SiO2 (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% SiO2 in heptane). The residue was purified by preparative HPLC, preparative method A (gradient: 0-75%). Appropriate fractions were pooled, diluted with 2M NaOH aqueous solution, and extracted with SiO2 (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (227 mg, 32%) as an orange, gum-like substance; MS m / z(ES+)[M+H] + =537.3; 1 H NMR(400MHz,CDCl3)δ0.12-0.20(3H,m),0.98-1.02(3H,m),1.05-1.13(3H,m),1.4 5-1.50(12H,m),2.13-2.22(1H,m),2.21-2.35(1H,m),3.21(1H,dt),3.39-3.49(2H ,m),3.53-3.71(3H,m),3.71-3.80(1H,m),7.16-7.20(1H,m),7.27-7.36(1H,m),7 .59(1H,dd),8.22-8.31(1H,m),8.30-8.37(1H,m),8.51(1H,d),8.64-8.72(1H,m).

[0339] Intermediate 8a: (R)-5-fluoro-N,N-diisopropyl-2-(3-(pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide hydrochloride

[0340] [ka]

[0341] 4M HCl was added to intermediate 7 (73.9 mg, 0.12 mmol th.) in 1,4-dioxane (2 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to obtain the crude title compound as an orange solid in a quantitative yield (73.0 mg); MS m / z(ES+)[M+H] + = 437.4.

[0342] Intermediate 8b: (R)-5-fluoro-N,N-diisopropyl-2-(3-(pyrroridine-3-carbonyl)-1H-pyrrorol[2,3-c]pyridine-1-yl)benzamide 2,2,2-trifluoroacetic acid

[0343] [ka]

[0344] TFA (1 mL) was added to a solution of intermediate 7 (105.6 mg, 0.18 mmol th.) in DCM (5 mL). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to obtain the crude title compound as an orange solid in a quantitative yield (152 mg); MS m / z(ES+)[M+H] + = 437.4.

[0345] Intermediate 9: tert-butyl 3-(hydroxy(1H-pyrrolo[2,3-c]pyridine-3-yl)methyl)azetidine-1-carboxylate

[0346] [ka]

[0347] KOtBu (21.0 g, 187 mmol) was added all at once at 0°C to a solution of 1H-pyrrolo[2,3-c]pyridine (11.1 g, 93.7 mmol) in EtOH (100 mL). The reaction mixture was stirred at room temperature for 20 minutes, and then tert-butyl 3-formylazetidine-1-carboxylate (17.4 g, 93.7 mmol) was added dropwise over 2 minutes. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with aqueous citric acid (340 mL, 1 M) and extracted with MTBE (340 mL). The pH was adjusted to pH 8 with solid NaOH, and ELISA (400 mL) was added. The formed precipitate was collected by filtration and dried to obtain the title compound (17.7 g, 62%) as a white solid. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ELISA (400 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-25% MeOH in DCM) to obtain the title compound (3.66 g, 13%) as a pale yellow foam; MS m / z(ES+)[M+H] + =304.2; 1 H NMR(400MHz,DMSO-d6,22℃C)δ1.35(9H,s),2.89-3.03(1H,m),3.47-3.67(1H,m),3.64-3.96(3H,m ),4.91(1H,dd),5.35(1H,d),7.47(1H,s),7.62(1H,dd),8.06(1H,d),8.69(1H,d),11.42(1H,s).

[0348] Intermediate 10: tert-butyl 3-(1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azetidine-1-carboxylate

[0349] [ka]

[0350] A mixture of intermediate 9 (17.7 g, 58.3 mmol) and MnO2 (25.3 g, 291 mmol) in 1,4-dioxane (150 mL) was heated at 100 °C for 48 hours. The reaction mixture was allowed to reach room temperature, and stirring was stopped for 30 minutes. The solvent was then carefully filtered through a Whatman 0.45 μm PVDF GMF filter. The remaining solid was diluted with MeOH (100 mL), filtered through filter paper, and then filtered again through a Whatman 0.45 μm PVDF GMF filter. The filtrate was filtered through a Celite® pathway, and the filtrate was concentrated under reduced pressure to obtain the title compound (14.3 g, 81%) as a brown solid; MS m / z(ES+)[M+H] + =302.1; 1 H NMR (400MHz, DMSO-d6, 22℃) δ1.31-1.43 (9H, m), 4.05 (4H, d), 4.25 (1H, tt), 8.06 (1H, dd), 8.28 (1H, d), 8.42 (1H, s), 8.83 (1H, s).

[0351] Intermediate 11: 2-(3-(1-(tert-butoxycarbonyl)azetidine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluorobenzoic acid

[0352] [ka]

[0353] Copper powder (107 mg, 1.69 mmol) was added to a deoxygenated solution of 5-fluoro-2-iodobenzoic acid (2.25 g, 8.44 mmol), intermediate 10 (2.54 g, 8.44 mmol), and K2CO3 (3.50 g, 25.3 mmol) in DMF (15 mL). The resulting mixture was purged with N2, the vial was sealed, and heated overnight at 100°C. The reaction mixture was diluted with water (20 mL) and acidified to pH 2 with aqueous HCl (1 M). The precipitate was collected by filtration and dried under vacuum to obtain the crude title compound (2.98 g) as a yellow solid; MS m / z(ES+)[M+H] + = 440.1.

[0354] Intermediate 12: tert-butyl 3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azetidine-1-carboxylate

[0355] [ka]

[0356] Diisopropylamine (3.01 mL, 21.8 mmol) was added to a mixture of intermediate 11 (1.91 g, 4.35 mmol th.), HATU (2.48 g, 6.53 mmol), and DIPEA (1.14 mL, 6.53 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (100 mL) and washed with saturated NaHCO3 aqueous solution (60 mL). The organic layer was washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-100% ethyl acetate in heptane) to obtain the title compound (1.40 g, 62%) as a brown solid; MS m / z(ES+)[M+H] + =523.2; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.28(3H,br s),0.72(3H,br s),0.99(3H,d),1.28-1.35(3H,m),1.36-1.45(9H,m),3.17-3.28(1H,m),3.43-3.55(1H,m),3.91-4.16(4H, m),4.14-4.25(1H,m),7.50-7.60(2H,m),7.84(1H,dd),8.14(1H,dd),8.40(1H,d),8.45(1H,s),8.64(1H,s).

[0357] Intermediate 13: 2-(3-(azetidine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide

[0358] [ka]

[0359] TFA (3 mL) was added to a solution of intermediate 12 (1.40 g, 2.69 mmol) in DCM (15 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (40 mL) and washed with saturated NaHCO3 aqueous solution (40 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (1.12 g, 99%) as a brown foam; MS m / z(ES+)[M+H] + =423.2; 1 H NMR(400MHz,DMSO-d6,27℃)δ0.26(3H,br s),0.72(3H,br s),0.90-1.04(3H,m),1.20-1.41(3H,m),3.17-3.30(2H,m),3.39-3.55(2H,m),3.84-4.13(3H,m),4. 26-4.40(1H,m),7.47-7.63(2H,m),7.82(1H,dd),8.11-8.21(1H,m),8.34-8.53(2H,m),8.65(1H,s).

[0360] Intermediate 14: tert-butyl 3-(1-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azetidine-1-carboxylate

[0361] [ka]

[0362] N-ethylpropan-2-amine (1.35 mL, 11.2 mmol) was added to a mixture of intermediate 11 (2.46 g, 5.59 mmol, th.) and HATU (3.19 g, 8.38 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with SiO2 (80 mL) and washed with saturated aqueous NaHCO3 (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-100% SiO2 in heptane) to obtain the title compound as a yellow gum-like substance in a quantitative yield (3.20 g), which was used directly in the next step; MS m / z(ES+)[M+H] + =509.2; 1 H NMR(400MHz,DMSO-d6,27℃)δ0.41(3H,d),0.92(3H,dd),1.18(3H,t),1.39(9H,s),2.75-2.85(1H,m),3.18-3.30(1H,m),3.54(1H,p),3.89-4.0 1(2H,m),4.06-4.16(2H,m),4.16-4.25(1H,m),7.53-7.64(2H,m),7.79 -7.89(1H,m),8.14(1H,d),8.40(1H,d),8.48(1H,s),8.55-8.67(1H,m).

[0363] Intermediate 15: 2-(3-(azetidine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0364] [ka]

[0365] TFA (6 mL) was added to a solution of intermediate 14 (2.84 g, 5.58 mmol, th.) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (2 × 30 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (1.43 g, 63%) as an orange gum; MS m / z(ES+)[M+H] + =409.1; 1 H NMR(400MHz,DMSO-d6,27℃)δ0.11-0.68(6H,m),0.84-1.03(4H,m),2.75-2.85(1H,m),3.17-3.29(1H,m),3.46-3.62(1H,m),4.10 -4.30(3H,m),4.32-4.45(1H,m),7.50-7.66(2H,m),7.78-7.88(1H,m),8.11-8.19(1H,m),8.36-8.46(1H,m),8.50-8.68(2H,m).

[0366] Intermediate 16: tert-butyl3-(1-(4-fluoro-2-nitrophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azetidine-1-carboxylate

[0367] [ka]

[0368] K2CO3 (23.4 g, 169 mmol) was added to a mixture of intermediate 10 (17.0 g, 56.4 mmol) and 1,4-difluoro-2-nitrobenzene (9.87 g, 62.1 mmol) in DMF (170 mL). The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with water (300 mL) and extracted with SiO2 (2 × 125 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% SiO2 in petroleum ether) to obtain the title compound (10.0 g, 40%) as a yellow solid; MS m / z(ES+)[M+H]+ =441.1; 1 H NMR(400MHz,DMSO-d6,22℃)δ1.39(9H,s),4.04(2H,br s),4.12(2H,br s),4.16-4.25(1H,m),7.95-8.01(1H,m),8.06-8.11(1H,m),8.17-8.21(1H,m),8.40(1H,dd),8.45(1H,d),8.58(1H,s),8.71(1H,s).

[0369] Intermediate 17: tert-butyl3-(1-(2-amino-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azetidine-1-carboxylate

[0370] [ka]

[0371] Iron powder (5.07 g, 90.8 mmol) was added to intermediate 16 (10.0 g, 22.7 mmol) in EtOH (80 mL), followed by the addition of NH4Cl (4.86 g, 90.8 mmol) in water (20 mL). The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered through Celite®. The filtrate was quenched with water (100 mL) and extracted with SiO2 (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound (9.30 g, 100%) as a pale yellow solid; MS m / z(ES+)[M+H] + =411.2; 1 H NMR(400MHz,DMSO-d6,22℃)δ1.40(9H,s),4.06(2H,br s),4.12(2H,br s),4.17-4.34(1H,m),5.53(2H,br s),6.51(1H,td),6.70(1H,dd),7.27(1H,dd),8.20(1H,d),8.39-8.43(2H,m),8.54(1H,s).

[0372] Intermediate 18: tert-butyl3-(1-(2-bromo-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azetidine-1-carboxylate

[0373] [ka]

[0374] t-BuONO (4.00 mL, 33.6 mmol) was added to intermediate 17 (9.20 g, 22.4 mmol) in MeCN (100 mL). The mixture was stirred at room temperature for 30 minutes, after which CuBr2 (5.01 g, 22.4 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with siRNA (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% siRNA in petroleum ether) to obtain the title compound (10.0 g, 94%) as a pale yellow solid; MS m / z(ES+)[M+H] + = 474.2 / 476.2.

[0375] Intermediate 19: Azethidine-3-yl (1-(2-bromo-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone hydrochloride

[0376] [ka]

[0377] 4M HCl in 1,4-dioxane (20 mL) was added to a mixture of intermediate 18 (8.00 g, 16.9 mmol) in 1,4-dioxane (60 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with Et2O (100 mL) and filtered through Celite®. The filtrate was concentrated under reduced pressure to obtain the crude title compound as a pale yellow solid in quantitative yield, which was used directly in the next step (7.20 g); MS m / z(ES+)[M+H] + =374.0 / 376.0; 1 H NMR(300MHz,DMSO-d6)δ4.13-4.32(4H,m),4.43-4.66(1H,m),7.52-7.72(1H,m),7.8 3-7.98(1H,m),8.07(1H,d),8.20-8.46(1H,m),8.97-9.21(1H,m),9.36-9.72(2H,m).

[0378] Intermediate 20: tert-butyl(1R,3S,4S)-3-(3-(1-(2-bromo-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azetidine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0379] [ka]

[0380] T3P (36.7 g, 57.7 mmol, 50% in ethyl acetate) was added to a mixture of intermediate 19 (7.20 g, 16.9 mmol th.), (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (4.64 g, 19.2 mmol), and DIPEA (13.4 mL, 77.0 mmol) in DCM (70 mL) at 0°C under N2. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography in silica (gradient: petroleum ether: 0-100% SiO) to obtain the title compound (4.60 g, 46%) as a pale yellow solid; MS m / z(ES+)[M+H] + = 597.2 / 599.2.

[0381] Intermediate 21: tert-butyl 3-(hydroxy(7H-pyrrolo[2,3-c]pyridazin-5-yl)methyl)azetidine-1-carboxylate

[0382] [ka]

[0383] A mixture of KOH (4.14 g, 73.9 mmol) in MeOH (150 mL) was stirred at room temperature for 30 minutes, after which 7H-pyrrolo[2,3-c]pyridazine (4.40 g, 36.9 mmol) and tert-butyl3-formylazetidine-1-carboxylate (13.7 g, 73.9 mmol) were added. The resulting mixture was stirred under N2 at room temperature for 4 days. The reaction mixture was diluted with water. The solvent was removed under reduced pressure and extracted with SiO2 (4 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (11.0 g, 98%) as a pale yellow solid; MS m / z(ES+)[M+H] +=305.2; 1 H NMR(300MHz,DMSO-d6)δ1.35(9H,s),2.95-3.06(1H,m),3.57-3.63(1H,m),3.73-3 .79(1H,m),3.80-3.90(2H,m),4.93(1H,d),7.76(1H,s),7.92(1H,d),8.83(1H,d).

[0384] Intermediate 22: tert-butyl3-(7H-pyrrolo[2,3-c]pyridazine-5-carbonyl)azetidine-1-carboxylate

[0385] [ka]

[0386] Dess-Martin periodinane (8.36 g, 19.7 mmol) was added in one step to a mixture of intermediate 21 (3.00 g, 9.86 mmol) in DCM (45 mL) cooled to 0°C under N2. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (150 mL) and Na2S2O3, and extracted with DCM (3 × 125 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (1.00 g, 34%) as a yellow solid; MS m / z(ES+)[M+H] + =303.2; 1 H NMR (300MHz, CDCl3) δ1.48(9H,s),4.01-4.17(1H,m),4.20-4.37(4H,m),8.38(1H,s),8.55(1H,d),9.18(1H,d).

[0387] Intermediate 23: 2-(5-(1-(tert-butoxycarbonyl)azetidine-3-carbonyl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-5-fluorobenzoic acid

[0388] [ka]

[0389] Copper powder (28.6 mg, 0.45 mmol) was added to a mixture of intermediate 22 (680 mg, 2.25 mmol), 5-fluoro-2-iodobenzoic acid (598 mg, 2.25 mmol), and Cs2CO3 (2.20 g, 6.75 mmol) in DMF (8 mL) under N2. The resulting mixture was stirred at 80°C for 18 hours. The reaction mixture was purified by reverse-phase flash chromatography on a C18 column (gradient: 20-40% MeCN in water containing 0.1% NH4HCO3). Appropriate fractions were pooled, concentrated to a small volume, and adjusted to pH 5 with aqueous HCl. The resulting precipitate was filtered and dried under vacuum to obtain the title compound (420 mg, 42%) as a yellow solid; MS m / z(ES+)[M+H] + =441.2; 1 H NMR(300MHz,DMSO-d6,26℃)δ1.40(9H,s),4.00-4.08(2H,m),4.09-4.20(2H,m),4.21-4.36(1H ,m),7.76-7.82(1H,m),7.83-7.94(2H,m),8.36(1H,d),9.02(1H,s),9.15(1H,d),13.32(1H,br s).

[0390] Intermediate 24: tert-butyl3-(7-(4-fluoro-2-(methoxycarbonyl)phenyl)-7H-pyrrolo[2,3-c]-pyridazine-5-carbonyl)azetidine-1-carboxylate

[0391] [ka]

[0392] MeI (267 mg, 1.88 mmol) was added to a mixture of intermediate 23 (830 mg, 1.88 mmol) and K2CO3 (781 mg, 5.65 mmol) in DMF (15 mL) under N2. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with SiO2 (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 60-100% SiO2 in petroleum ether) to obtain the title compound (580 mg, 68%) as a white solid; MS m / z(ES+)[M+H] + =455.2; 1 H NMR(300MHz,DMSO-d6,26℃)δ1.40(9H,s),3.46(3H,s),4.02-4.12(2H,m),4.12-4.19(2H,m),4 .20-4.37(1H,m),7.76-7.88(1H,m),7.89-7.99(2H,m),8.38(1H,d),9.03(1H,s),9.16(1H,d).

[0393] Intermediate 25: 5-(1-(tert-butoxycarbonyl)azetidine-3-carbonyl)-7-(4-fluoro-2-(methoxycarbonyl)phenyl)-7H-pyrrolo[2,3-c]pyridazine 1-oxide

[0394] [ka]

[0395] m-CPBA (740 mg, 4.29 mmol) was added to a mixture of intermediate 24 (650 mg, 1.43 mmol) in DCM (7 mL) under N2. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated Na2S2O3 aqueous solution (25 mL) and extracted with siRNA (3 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-100% siRNA in petroleum ether) to obtain the title compound (660 mg, 98%) as a white solid; MS m / z(ES+)[M+H] + =471.2; 1 H NMR(300MHz,DMSO-d6,24℃)δ1.39(9H,s),3.59(3H,s),4.00-4.07(2H,m),4.09-4.16(2H,m),4 .16-4.28(1H,m),7.78-7.90(2H,m),7.91-7.96(1H,m),8.31(1H,d),8.44(1H,d),8.80(1H,s).

[0396] Intermediate 26: 5-(1-(tert-butoxycarbonyl)azetidine-3-carbonyl)-7-(2-carboxy-4-fluorophenyl)-7H-pyrrolo[2,3-c]pyridazine 1-oxide

[0397] [ka]

[0398] LiOH (163 mg, 6.80 mmol) in water (3 mL) was added to a mixture of intermediate 25 (640 mg, 1.36 mmol) in THF (6 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was acidified with aqueous HCl (2 M). The resulting suspension was filtered and dried under vacuum to obtain the title compound (500 mg, 81%) as a white solid; MS m / z(ES+)[M+H] + =457.2; 1H NMR(300MHz,DMSO-d6,24℃)δ1.39(9H,s),3.93-4.06(2H,m),4.06-4.16(2H,m),4.17- 4.28(1H,m),7.62-7.79(2H,m),7.84(1H,dd),8.29(1H,d),8.42(1H,d),8.77(1H,s).

[0399] Intermediate 27: 5-(1-(tert-butoxycarbonyl)azetidine-3-carbonyl)-7-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-7H-pyrrolo[2,3-c]pyridazine 1-oxide

[0400] [ka]

[0401] T3P (1.88 g, 2.96 mmol, 50% in ethylethanol) was added dropwise to a mixture of intermediate 26 (450 mg, 0.99 mmol), DIPEA (861 μL, 4.93 mmol), and diisopropylamine (798 mg, 7.89 mmol) in DCM (8 mL) cooled to 0°C under N2. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (3 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC with silica (DCM:MeOH, 10:1) to obtain the title compound (440 mg, 83%) as a white solid; MS m / z(ES+)[M+Na] + =562.3; 1 H NMR(300MHz,DMSO-d6,26℃)δ0.52(3H,d),0.87(3H,d),1.07(3H,d),1.34(3H,d),1.39(9H,s),3.27-3.37(1H,m) ,3.45-3.64(1H,m),3.92-4.24(5H,m),7.50-7.59(2H,m),7.82(1H,dd),8.32(1H,d),8.44(1H,d),8.55(1H,s).

[0402] Intermediate 28: tert-butyl 3-(7-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-7H-pyrrolo[2,3-c]pyridazine-5-carbonyl)azetidine-1-carboxylate

[0403] [ka]

[0404] Iron powder (174 mg, 3.11 mmol) was added to a mixture of intermediate 27 (420 mg, 0.78 mmol) and NH4Cl (167 mg, 3.11 mmol) in EtOH (8 mL) and water (2 mL) under N2 conditions. The resulting mixture was stirred at 80°C for 5 hours. The reaction mixture was prepared using Celite®. The mixture was filtered through [a specific filter]. The filtrate was diluted with water (50 mL) and extracted with ₹ (3 × 25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to dryness to obtain the title compound (360 mg, 88%) as a yellow solid; MS m / z(ES+)[M+H] + =524.3; 1 H NMR(300MHz,DMSO-d6,26℃)δ0.52(3H,d),0.87(3H,d),1.07(3H,d),1.34(3H,d),1.39(9H,s),3.27-3.37(1H,m) ,3.45-3.64(1H,m),3.92-4.24(5H,m),7.50-7.59(2H,m),7.82(1H,dd),8.32(1H,d),8.44(1H,d),8.55(1H,s).

[0405] Intermediate 29: 2-(5-(azetidine-3-carbonyl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-5-fluoro-N,N-diisopropylbenzamide

[0406] [ka]

[0407] FA (5 mL) was added to intermediate 28 (200 mg, 0.38 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was suspended in saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (3 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound as a yellow solid in quantitative yield, which was used directly in the next step of Example 14a (220 mg); MS m / z (ES+)[M+H] + =424.2; 1 H NMR(300MHz,CDCl3,23℃)δ0.20(3H,d),0.95-1.04(6H,m),1.45(3H,d),3.16-3.26(1H,m),3.59-3.71(1H,m),3.86-3.94(2H,m ),4.07-4.16(2H,m),4.23-4.35(1H,m),7.15(1H,dd),7.28-7.37(1H,m),7.73(1H,dd),8.34(1H,s),8.48(1H,d),9.20(1H,d).

[0408] Intermediate 30: tert-butyl 3-((7-fluoro-1H-pyrrolo[2,3-c]pyridine-3-yl)(hydroxy)methyl)azetidine-1-carboxylate

[0409] [ka]

[0410] KOH (824 mg, 14.7 mmol) was added to a solution of 7-fluoro-1H-pyrrolo[2,3-c]pyridine (1.00 g, 7.35 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (1.36 g, 7.35 mmol) in MeOH (15 mL). The reaction mixture was stirred at room temperature for 18 hours. Another aliquot of tert-butyl 3-formylazetidine-1-carboxylate (408 mg, 2.20 mmol) was added, and the mixture was then stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL) and extracted with ELISA (2 × 100 mL). The combined organic layers were washed with brine (50 mL), passed through a phase separator, and concentrated under reduced pressure. The crude product was purified by normal-phase flash chromatography in silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (1.83 g, 78%) as a yellow foamy substance; MS m / z(ES+)[M+H] + =322.0; 1 H NMR (400MHz, CDCl3, 22℃) δ1.44(9H,s),2.12(1H,d),3.00-3.14(1H,m),3.60-3.69(1H,m),3.89(1H, t),3.99(1H,dd),4.08(1H,t),5.12(1H,dd),7.32(1H,d),7.52(1H,dd),7.79(1H,dd),8.98(1H,s).

[0411] Intermediate 31: 2-(3-((1-(tert-butoxycarbonyl)azetidine-3-yl)(hydroxy)methyl)-7-fluoro-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluorobenzoic acid

[0412] [ka]

[0413] Copper powder (106 mg, 1.66 mmol) was added to a deoxygenated solution of 5-fluoro-2-iodobenzoic acid (1.77 g, 6.65 mmol), intermediate 30 (1.78 g, 5.54 mmol), and K2CO3 (4.59 g, 33.2 mmol) in DMF (20 mL). The resulting mixture was purged with N2 and stirred and heated at 80°C for 4 hours. The reaction mixture was diluted with water and acidified to pH 2 with aqueous HCl (1 M). The formed precipitate was collected by filtration, washed with water, and freeze-dried from MeCN / H2O to obtain the crude title compound (2.51 g) as a light brown solid, which was used directly in the next step: MS m / z(ES+)[M+H] + =460.5; 1 H NMR(400MHz,DMSO-d6,22℃)δ1.20-1.45(9H,m),2.93-3.07(1H,m),3.55-3.67(1H,m),3.67-3.99(3H,m),4.85-5.04 (1H,m),5.34-5.77(1H,m),7.10-7.54(1H,m),7.57-7.66(2H,m),7.64-7.74(2H,m),7.72-7.86(1H,m),13.30(1H,br s).

[0414] Intermediate 32: 2-(3-(1-(tert-butoxycarbonyl)azetidine-3-carbonyl)-7-fluoro-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluorobenzoic acid

[0415] [ka]

[0416] Dess-Martin periodinane (609 mg, 1.44 mmol) was added to a solution of intermediate 31 (600 mg, 0.94 mmol th.) in DCM (12 mL). The resulting mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with SiO2 (40 mL) and washed with saturated Na2S2O3 aqueous solution (10 mL), saturated Na2CO3 aqueous solution (10 mL), and brine (10 mL). The organic layer was passed through a phase separator and concentrated under reduced pressure to obtain the crude title compound (670 mg) as a brown solid, which was used directly in the next step; MS m / z(ES+)[M+H] + = 458.1.

[0417] Intermediate 33: tert-butyl 3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-7-fluoro-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azetidine-1-carboxylate

[0418] [ka]

[0419] T3P (1.81 mL, 2.84 mmol, 50% in DCM) was added to a solution of intermediate 32 (650 mg, 0.99 mmol th.), diisopropylamine (1.20 mL, 8.53 mmol), and DMAP (87.0 mg, 0.71 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with  (50 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was passed through a phase separator and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-65%  in heptane) to obtain the title compound (114 mg, 21%) as a white solid; MS m / z(ES+)[M+H] + =541.2; 1H NMR (400MHz, CDCl3, 22℃) δ0.35(3H,d),0.95-1.12(6H,m),1.52(3H,s),1.55(9H,s),3.13-3.27(1H,m),3.52-3.64(1H,m),3.95-4.0 1(1H,m),4.11-4.31(4H,m),7.04-7.14(1H,m),7.42-7.51(1H,m),7.54-7.61(1H,m),8.01(1H,dd),8.05(1H,s),8.21-8.28(1H,m).

[0420] Intermediate 34: 2-(3-(azetidine-3-carbonyl)-7-fluoro-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide

[0421] [ka]

[0422] TFA (238 μL) was added to a solution of intermediate 33 (105 mg, 0.19 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (2 × 30 mL). The combined organic layers were passed through a phase separator and concentrated under reduced pressure to obtain the crude title compound (89.0 mg) as a yellow foam, which was used directly in the next step (Example 15a); MS m / z(ES+)[M+H] + =441.1; 1 H NMR(400MHz,CDCl3,22℃)δ0.31-0.47(3H,m),1.00(3H,d),1.04(3H,d),1.44(3H,d),3.13-3.28(1H,m),3.50-3.64(1H,m),3.79-3.94(2H,m), 4.00-4.15(2H,m),4.17-4.31(1H,m),7.09(1H,dd),7.21-7.25(1H,m), 7.42-7.51(1H,m),7.99(1H,dd),8.00-8.08(1H,m),8.18-8.35(1H,m).

[0423] Intermediate 35: tert-butyl 4-(hydroxy(1H-pyrrolo[2,3-c]pyridine-3-yl)methyl)piperidine-1-carboxylate

[0424] [ka]

[0425] KOH (17.5 g, 312 mmol) was added to a solution of 1H-pyrrolo[2,3-c]pyridine (18.5 g, 156 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (33.3 g, 156 mmol) in MeOH (300 mL). The reaction mixture was stirred at room temperature for 24 hours. Additional tert-butyl 4-formylpiperidine-1-carboxylate (13.3 g, 62.4 mmol) was added, and stirring was continued overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ELISA (600 mL) and diluted with water (400 mL). The precipitate formed during extraction was collected by filtration, washed with siRNA (50 mL), and dried under vacuum to obtain the title compound (22.0 g, 42%) as a white solid. The organic layer of the filtrate was separated, and the aqueous layer was extracted with siRNA (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-25% MeOH in DCM). A suitable fraction was concentrated under reduced pressure to obtain the title compound (17.6 g, 34%) as a yellow foam; MS m / z(ES+)[M+H] + = 332.2.

[0426] Intermediate 36: tert-butyl 4-(1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0427] [ka]

[0428] MnO2 (23.1 g, 265 mmol) was added to a solution of intermediate 35 (17.6 g, 53.1 mmol) in 1,4-dioxane (150 mL), and the mixture was stirred and heated at 100°C for 48 hours. The reaction mixture was allowed to reach room temperature, stirring was stopped, and the precipitate was allowed to settle to the bottom overnight. The supernatant was carefully filtered through a Whatman 0.45 μm PVDF GMF filter. The filtrate was concentrated under reduced pressure to obtain the crude title compound (16.4 g) as a brown foamy substance; MS m / z(ES+)[M+H] + =330.1; 1 H NMR(400MHz,DMSO-d6,22℃)δ1.41(9H,s),1.46-1.55(2H,m),1.76(2H,d),2.89(2H,br s),3.38-3.46(1H,m),4.01(2H,d),8.05(1H,dd),8.28(1H,d),8.63(1H,s),8.83(1H,d),12.46(1H,br s).

[0429] Intermediate 37: 2-(3-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid

[0430] [ka]

[0431] Copper powder (270 mg, 4.25 mmol) was added to a deoxygenated solution of 5-fluoro-2-iodobenzoic acid (5.65 g, 21.3 mmol), intermediate 36 (7.00 g, 16.8 mmol th.), and K2CO3 (8.81 g, 63.8 mmol) in DMF (60 mL). The resulting mixture was purged with N2 and stirred and heated at 80°C overnight. The reaction mixture was diluted with water (100 mL) and acidified to pH 2 with aqueous HCl (1 M). The formed precipitate was collected by filtration and dried under vacuum to obtain the crude title compound (9.80 g) as a yellow solid, which was used directly in the next step; MS m / z(ES+)[M+H] + = 468.1.

[0432] Intermediate 38: tert-butyl 4-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0433] [ka]

[0434] Diisopropylamine (14.7 mL, 105 mmol) was added to a mixture of intermediate 37 (9.80 g, 16.8 mmol th.) and HATU (12.0 g, 31.4 mmol) in DMF (60 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with SiO4 (400 mL) and washed with aqueous HCl (200 mL, 1 M) and saturated aqueous NaHCO3 (200 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-100% SiO4 in heptane) to obtain the title compound (7.23 g, 78%) as an orange foam; MS m / z(ES+)[M+H] + =551.3; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.09-0.87(6H,m),1.04(3H,d),1.31(3H,d),1.41(9H,s),1.46-1.57(2H,m),1.75-1.88(2H,m),2.87(2H,br s),3.20-3.32(1H,m),3.40-3.52(1H,m),3.54-3.61(1H,m),3.97-4.05(2H ,m),7.56-7.69(2H,m),7.95(1H,dd),8.53-8.65(2H,m),8.95-9.53(2H,m).

[0435] Intermediate 39: 5-Fluoro-N,N-diisopropyl-2-(3-(piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0436] [ka]

[0437] TFA (10 mL) was added to a solution of intermediate 38 (9.12 g, 16.6 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (7.27 g, 98%) as a yellow solid; MS m / z(ES+)[M+H] + =451.2; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.27(3H,br s),0.73(3H,br s),0.99(3H,d),1.33(3H,d),1.64-1.94(4H,m),2.79-2.98(2H,m),3.09-3.28(3H,m),3.37-3. 56(3H,m),7.45-7.66(2H,m),7.85(1H,dd),8.01-8.20(1H,m),8.32-8.48(1H,m),8.64(2H,s).

[0438] Intermediate 40: tert-butyl 4-(1-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0439] [ka]

[0440] N-ethylpropan-2-amine (1.52 mL, 12.5 mmol) was added to a mixture of intermediate 37 (1.75 g, 2.51 mmol th.) and HATU (1.43 g, 3.76 mmol) in DMF (15 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with HCl (100 mL) and washed sequentially with aqueous HCl (50 mL, 1 M), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-100% HCl in heptane) to obtain the title compound (1.12 g, 83%) as a yellow gum; MS m / z(ES+)[M+H] + =537.2; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.23-0.57(6H,m),0.98(3H,d),1.41(9H,s),1.45 -1.55(2H,m),1.72-1.83(2H,m),2.75-2.82(2H,m),3.23-3.30(1H,m),3.38-3 .43(1H,m),3.50-3.58(1H,m),3.94-4.07(2H,m),7.55-7.63(2H,m),7.80-7.9 0(1H,m),7.95(1H,s),8.10-8.14(1H,m),8.33-8.40(1H,m),8.54-8.72(2H,m).

[0441] Intermediate 41: N-ethyl-5-fluoro-N-isopropyl-2-(3-(piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0442] [ka]

[0443] TFA (2 mL) was added to a solution of intermediate 40 (1.12 g, 2.09 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in HCl (50 mL) and washed with saturated NaHCO3 aqueous solution (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (574 mg, 63%) as a yellow gum; MS m / z(ES+)[M+H] + = 437.2.

[0444] Intermediate 42: Piperidine-4-yl (1H-pyrrolo[2,3-c]pyridine-3-yl)methanone hydrochloride

[0445] [ka]

[0446] 4M HCl in 1,4-dioxane (35 mL) was added to a solution of intermediate 10 (4.00 g, 12.1 mmol) in MeCN (5 mL). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound (3.23 g) as a beige solid; MS m / z(ES+)[M+H] + = 230.5.

[0447] Intermediate 43: tert-butyl(1R,3S,4S)-3-(4-(1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0448] [ka]

[0449] Intermediate 42 (3.23 g, 12.1 mmol, th.) was added to a stirred solution of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (3.22 g, 13.4 mmol), EDC (2.79 g, 14.6 mmol), HOBt (2.23 g, 14.6 mmol), and DIPEA (4.24 mL, 24.3 mmol) in a mixture of DCM (25 mL) and DMF (25 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (3.04 g, 55%) as an orange, gum-like substance.

[0450] Intermediate 44: 2-(3-(1-((1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid

[0451] [ka]

[0452] Copper powder (85.0 mg, 1.34 mmol) was added to a deoxygenated solution of 5-fluoro-2-iodobenzoic acid (1.79 g, 6.71 mmol), intermediate 43 (3.04 g, 6.71 mmol), and K2CO3 (2.78 g, 20.1 mmol) in DMF (20 mL). The resulting mixture was purged with N2, the vial was sealed, and stirred overnight at 80°C. The reaction mixture was diluted with water (40 mL) and acidified to pH 2 with aqueous HCl (1 M). The formed precipitate was collected by filtration and dried under vacuum. Solid NaCl was added, and the aqueous layer was extracted with SiO2 (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, combined with the precipitate, and concentrated under reduced pressure to obtain the title compound (3.27 g, 82%) as an orange foam; MS m / z(ES+)[M+H] + = 591.2.

[0453] Intermediate 45: tert-butyl 4-(1-(4-fluoro-2-nitrophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0454] [ka]

[0455] K2CO3 (2.60 g, 18.8 mmol) was added to a mixture of intermediate 36 (3.10 g, 9.41 mmol) and 1,4-difluoro-2-nitrobenzene (1.80 g, 11.3 mmol) in DMF (40 mL). The resulting mixture was stirred at 80°C for 1 hour. The reaction mixture was diluted with HCl (50 mL) and sequentially washed with saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% HCl in heptane) to obtain the title compound (1.91 g, 43%) as an orange solid; MS m / z(ES+)[M+H] + =469.1; 1H NMR(400MHz,CDCl3,22℃)δ1.48(9H,s),1.79-1.94(4H,m),2.75-2.96(2H,m),3.10-3.20(1H,m),4.21(2H,br s),7.57-7.65(1H,m),7.69(1H,dd),7.93(1H,s),7.98(1H,dd),8.28(1H,d),8.48(1H,s),8.52(1H,d).

[0456] Intermediate 46: tert-butyl 4-(1-(2-amino-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0457] [ka]

[0458] Iron powder (387 mg, 6.94 mmol) and NH4Cl (371 mg, 6.94 mmol) were added to intermediate 45 (325 mg, 0.69 mmol) in a mixture of EtOH (16 mL), SiO (6 mL), and water (6 mL). The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered through Celite®, and Celite was rinsed with SiO. The filtrate was sequentially washed with aqueous NaHCO3 (5%) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% SiO in heptane) to obtain the title compound (196 mg, 64%) as a pale yellow solid; MS m / z(ES+)[M+H] + =439.6; 1 H NMR(400MHz, CDCl3, 22℃) δ1.48(9H,s),1.76-1.95(4H,m),2.76-2.96(2H,m),3.10-3.23(1H,m),3.80(2H,s),4.21(2H,br s),6.55-6.69(2H,m),7.19(1H,dd),7.95(1H,s),8.27(1H,dd),8.49(1H,d),8.54(1H,d).

[0459] Intermediate 47: tert-butyl 4-(1-(2-bromo-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0460] [ka]

[0461] t-BuONO (203 mL, 1.71 mmol) was added to a mixture of intermediate 46 (500 mg, 1.14 mmol) in MeCN (5 mL) under N2. The mixture was stirred at room temperature for 20 minutes, and then CuBr2 (280 mg, 1.25 mmol) in MeCN (1 mL) was added dropwise. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with RINKAN (50 mL) and washed with saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% RINKAN in heptane) to obtain the title compound (413 mg, 72%) as a white solid; MS m / z(ES+)[M+H] + =502.0 / 504.0; 1 H NMR(400MHz,CDCl3,22℃)δ1.48(9H,s),1.76-1.98(4H,m),2.72-2.97(2H,m),3.12-3.25(1H,m),4.21(2H,br s),7.27-7.33(1H,m),7.52(1H,dd),7.60(1H,dd),7.95(1H,s),8.29(1H,d),8.47-8.57(2H,m).

[0462] Intermediate 48: (1-(2-bromo-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)(piperidine-4-yl)methanone dihydrochloride

[0463] [ka]

[0464] 4M HCl in 1,4-dioxane (2 mL) was added to a solution of intermediate 47 (410 mg, 0.82 mmol) in MeCN (4 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound (409 mg) as a white solid; MS m / z(ES+)[M+H] + = 402.0 / 404.0.

[0465] Intermediate 49: tert-butyl(1R,3S,4S)-3-(4-(1-(2-bromo-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0466] [ka]

[0467] T3P (1.54 mL, 2.58 mmol, 50% in ethyl) was added dropwise to a solution of intermediate 48 (409 mg, 0.82 mmol, th.) in a mixture of ethyl (5 mL) and DCM (1 mL), (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (498 mg, 2.06 mmol), and DIPEA (1.50 mL, 8.60 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl (25 mL) and saturated aqueous NaHCO3 (25 mL) and stirred vigorously for 10 minutes. The organic layer was separated, washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography in silica (gradient: 0-100% toluene in heptane) to obtain the title compound (438 mg, 86%) as a white solid; MS m / z(ES+)[M+H] + =625.1 / 627.1; 1H NMR (400MHz, CDCl3, 22℃) δ1.19-1.31(1H,m),1.33-1.55(10H,m),1.64-1.68(1H,m),1.71-1. 83(2H,m),1.88-2.17(4H,m),2.43-2.61(1H,m),2.73-3.02(1H,m),3.12-3.39(2H,m),3.49( 1H,d),3.91-4.16(2H,m),4.26-4.44(1H,m),4.53-4.76(1H,m),7.27-7.35(1H,m),7.48-7.5 7(1H,m),7.57-7.65(1H,m),7.91-7.99(1H,m),8.24-8.32(1H,m),8.49(1H,d),8.52(1H,d).

[0468] Intermediate 50: tert-butyl(1S,2S,5R)-2-(4-(1-(2-bromo-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0469] [ka]

[0470] T3P (1.90 g, 2.98 mmol, 50% in ethyl acetate) was added to a solution of intermediate 48 (400 mg, 0.99 mmol), (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (226 mg, 0.99 mmol), and DIPEA (868 μL, 4.97 mmol) in DCM (5 mL) under N2 conditions. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography in silica (gradient: 0-100% siRNA in petroleum ether) to obtain the title compound (520 mg, 86%) as a pale yellow solid; MS m / z(ES+)[M+H] +=611.1 / 613.1; 1 H NMR(300MHz,DMSO-d6,24℃)δ0.18-0.39(1H,m),0.67-0.78(1H,m),0.81-0.90(1H,m),1.2 9-1.41(9H,m),1.48-1.65(3H,m),1.66-1.78(1H,m),1.92(2H,d),2.64-2.93(1H,m),3.21 -3.31(1H,m),3.40-3.68(2H,m),4.07-4.22(1H,m),4.37-4.70(2H,m),7.60(1H,td),7.9 2(1H,dd),8.01(1H,dd),8.13-8.22(1H,m),8.41(1H,dd),8.47(1H,s),8.91-8.98(1H,m).

[0471] Intermediate 51: tert-butyl 4-((4-fluoro-1H-pyrrolo[2,3-c]pyridine-3-yl)(hydroxy)methyl)-piperidine-1-carboxylate

[0472] [ka]

[0473] KOH (437 mg, 7.79 mmol) was added to a mixture of tert-butyl 4-formylpiperidine-1-carboxylate (1.66 g, 7.79 mmol) and 4-fluoro-1H-pyrrolo[2,3-c]pyridine (530 mg, 3.89 mmol) in EtOH (20 mL) under N2. The reaction mixture was stirred at 40°C for 2 hours. The reaction mixture was diluted with ELISA (150 mL) and washed with saturated NH4Cl aqueous solution (2 × 75 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-5% MeOH in DCM) to obtain the title compound as a white solid in quantitative yield (2.35 g); MS m / z(ES+)[M+H] + =350.1; 1H NMR(300MHz,DMSO-d6,23℃)δ1.02-1.17(2H,m),1.26-1.34(1H,m),1.37(9H,s),1.76-1.87(2H,m),2.61(2H,br s),3.85-4.00(2H,m),4.65-4.73(1H,m),5.11(1H,d),7.52(1H,d),7.99(1H,d),8.59(1H,d),11.80(1H,s).

[0474] Intermediate 52: tert-butyl 4-(4-fluoro-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0475] [ka]

[0476] MnO2 (1.62 g, 18.6 mmol) was added to a mixture of intermediate 51 (1.30 g, 3.72 mmol, th.) in 1,4-dioxane (25 mL) under N2. The reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The residue was diluted with SiO2 (100 mL) and washed with water (3 × 25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-60% SiO2 in petroleum ether) to obtain the title compound (1.02 g, 79%) as a white solid; MS m / z(ES+)[M+Na] + =370.1; 1 H NMR(300MHz,DMSO-d6,22℃)δ1.42(9H,s),1.44-1.56(2H,m),1.69-1.86(2H,m),2.76-3.00(2H, m),3.41-3.58(1H,m),3.90-4.13(2H,m),8.19(1H,d),8.67(1H,s),8.69(1H,d),12.77(1H,s).

[0477] Intermediate 53: 2-(3-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-4-fluoro-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluorobenzoic acid

[0478] [ka]

[0479] CuI (107 mg, 0.56 mmol) was added to a mixture of 5-fluoro-2-iodobenzoic acid (750 mg, 2.82 mmol), intermediate 52 (980 mg, 2.82 mmol), and Cs2CO3 (2.76 g, 8.46 mmol) in DMF (15 mL). The resulting mixture was stirred at 60°C for 8 hours. The reaction mixture was purified by reverse-phase flash chromatography on a C18 column (gradient: 0-40% MeOH in water containing 5% NH4HCO3) to obtain the title compound (1.00 g, 73%) as a white solid; MS m / z(ES+)[M+H] + = 486.2.

[0480] Intermediate 54: tert-butyl 4-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-4-fluoro-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0481] [ka]

[0482] T3P (3.93 g, 6.18 mmol, 50% in ethyl ether) was added to a mixture of intermediate 53 (500 mg, 1.03 mmol), DIPEA (1.80 mL, 10.3 mmol), and diisopropylamine (1.45 mL, 10.3 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into saturated NH4Cl aqueous solution (75 mL) and extracted with ethyl ether (3 × 25 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-70% ethyl ether in petroleum ether) to obtain the title compound (463 mg, 79%) as a white solid; MS m / z(ES+)[M+H] + =569.2; 1 H NMR(300MHz,DMSO-d6,24℃)δ0.36(3H,br s),0.75(3H,br s),1.02(3H,d),1.33(3H,d),1.42(9H,s),1.46-1.54(2H,m),1.70-1.86(2H,m),2.86(2H,br s),3.21-3.31(1H,m),3.36-3.51(1H,m),3.51-3.58(1H,m),3.94-4.06(2H,m) ,7.52-7.61(2H,m),7.82-7.93(1H,m),8.31(1H,d),8.48(1H,s),8.69(1H,s).

[0483] Intermediate 55: 5-Fluoro-2-(4-Fluoro-3-(piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N,N-diisopropylbenzamide dihydrochloride

[0484] [ka]

[0485] 4M HCl in 1,4-dioxane (4 mL) was added to a solution of intermediate 54 (420 mg, 0.74 mmol) in 1,4-dioxane (4 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with Et2O. The formed precipitate was collected by filtration, washed with Et2O (150 mL), and dried under vacuum to obtain the title compound (300 mg, 75%) as a white solid; MS m / z(ES+)[M+H] + =469.2; 1 H NMR(300MHz,DMSO-d6,24℃)δ0.03-0.98(6H,m),1.03(3H,d),1.32(3H,d),1.80-2.02(4H,m),2.92-3.06(2H,m),3.22-3.36 (3H,m),3.57(3H,s),7.54-7.64(2H,m),7.78-7.98(1H,m),8.50(1H,d),8.71(1H,s),8.82-9.06(2H,m),9.12-9.33(1H,m).

[0486] Intermediate 56: tert-butyl 4-(hydroxy(1H-pyrrolo[2,3-c]pyridine-3-yl)methyl)azepan-1-carboxylate

[0487] [ka]

[0488] KOH (475 mg, 8.46 mmol) was added to a solution of 1H-pyrrolo[2,3-c]pyridine (500 mg, 4.23 mmol) and tert-butyl 4-formylazepane-1-carboxylate (1.44 g, 6.35 mmol) in EtOH (25 mL) under N2. The reaction mixture was stirred at 60°C for 8 hours. The reaction mixture was diluted with DCM (100 mL) and sequentially washed with saturated NH4Cl aqueous solution (50 mL) and water (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (1.35 g, 92%) as a white solid; MS m / z(ES+)[M+H] +=346.2; 1 H NMR(300MHz,DMSO-d6,26℃)δ1.00-1.16(1H,m),1.23-1.43(11H,m),1.69-1.88(2H,m),3.08-3.22(3H,m),3.31-3.44( 3H,m),4.57-4.77(1H,m),4.96-5.13(1H,m),7.41-7.44(1H,m),7.57(1H,d),8.03(1H,d),8.69(1H,s),11.41(1H,s).

[0489] Intermediate 57: tert-butyl 4-(1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azepan-1-carboxylate

[0490] [ka]

[0491] MnO2 (1.01 g, 11.6 mmol) was added to a solution of intermediate 56 (800 mg, 2.32 mmol) in 1,4-dioxane (25 mL) under N2 conditions. The resulting mixture was stirred and heated at 100°C for 8 hours. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (770 mg, 97%) as a white solid; MS m / z(ES+)[M+H] + =344.2; 1 H NMR(300MHz,DMSO-d6)δ1.43(9H,s),1.47-1.53(1H,m),1.61-1.80(2H,m),1.83-1.97(3H,m),3.19-3.31(2H,m) ,3.37-3.45(2H,m),3.49-3.73(1H,m),8.00-8.11(1H,m),8.28(1H,d),8.52(1H,d),8.84(1H,s),12.42(1H,s).

[0492] Intermediate 58: 2-(3-(1-(tert-butoxycarbonyl)azepan-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluorobenzoic acid

[0493] [ka]

[0494] CuI (84.0 mg, 0.44 mmol) was added to a deoxygenated solution of 5-fluoro-2-iodobenzoic acid (589 mg, 2.21 mmol), intermediate 57 (760 mg, 2.21 mmol), and Cs2CO3 (2.16 g, 6.64 mmol) in DMF (25 mL). The resulting mixture was stirred and heated at 60°C for 8 hours. The crude product was purified by reverse-phase flash chromatography on a C18 column (gradient: 0-50% MeOH in water) to obtain the title compound (980 mg, 92%) as a yellow solid; MS m / z(ES+)[M+H] + =482.2; 1 H NMR(300MHz,DMSO-d6)δ1.40-1.44(9H,m),1.45-1.56(1H,m),1.63-1.80(2H,m),1.81-1.99(3H,m),3.14- 3.26(1H,m),3.30-3.43(3H,m),3.56-3.71(2H,m),7.45-7.58(1H,m),7.62-7.75(2H,m),8.07-8.22(2H,br s),8.42(1H,m),8.68(1H,s).

[0495] Intermediate 59: tert-butyl 4-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)azepan-1-carboxylate

[0496] [ka]

[0497] HATU (2.25 g, 5.92 mmol) was added to a mixture of intermediate 58 (950 mg, 1.97 mmol), diisopropylamine (1.94 mL, 13.8 mmol), and DIPEA (2.41 mL, 13.8 mmol) in DCM (25 mL), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (100 mL) and washed with saturated NH4Cl aqueous solution (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-5% MeOH in DCM) to obtain the title compound (472 mg, 42%) as a yellow solid; MS m / z(ES+)[M+H] + =565.5; 1 H NMR(300MHz,DMSO-d6,23℃)δ0.28(2H,br s),0.79(3H,br s),0.99(3H,d),1.26(4H,m),1.34(3H,d),1.38-1.47(9H,m),1.60-1.69(1H,m),1.84-1.94(2H,m),3.16-3.29(3H,m),3 .38-3.67(4H,m),7.49-7.59(2H,m),7.74-7.92(1H,m),8.11-8.19(1H,m),8.38(1H,d),8.47-8.60(1H,m),8.65(1H,s).

[0498] Intermediate 60: 2-(3-(azepan-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide hydrochloride

[0499] [ka]

[0500] 4M HCl in 3mL of 1,4-dioxane was added to a solution of intermediate 59 (440 mg, 0.78 mmol) in 9mL of 1,4-dioxane. The resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, washed with Et2O, and filtered to obtain the title compound (294 mg, 74%) as a white solid; MS m / z(ES+)[M+H]+ =465.5; 1 H NMR(300MHz,DMSO-d6,27℃)δ0.64(3H,br s),0.97-1.12(3H,m),1.27-1.34(6H,m),1.64-2.20(6H,m),3.06-3.37(5H,m),3.59-3 .79(2H,m),7.56-7.74(2H,m),7.91-8.02(1H,m),8.52-8.73(2H,m),9.08-9.53(3H,m).

[0501] Intermediate 61: 2-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridine

[0502] [ka]

[0503] NaH (11.2 g, 279 mmol, 60% dispersion in mineral oil) was gradually added at 0°C to a stirred solution of 6-azaindole (30.0 g, 254 mmol) in dry THF (1.5 L). After 10 minutes, the ice bath was removed, and the resulting suspension was stirred at room temperature for 1 hour, after which 4-methylbenzenesulfonyl chloride (53.3 g, 279 mmol) was added all at once. The reaction mixture was stirred at room temperature for 1 hour. The mixture was cooled to -78°C, and n-BuLi (238 mL, 381 mmol, 6 M in hexane) was added all at once. The mixture was stirred at -78°C for 1 hour. MeI (23.7 mL, 381 mmol) was added, and the stirred mixture was allowed to reach room temperature over 1 hour. The reaction mixture was quenched with water (500 mL), and the organic solvent was concentrated to dryness. The aqueous layer was extracted with ELISA (4 × 300 mL). The combined organic layers were washed with brine (2 × 250 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude title compound (80.0 g) as a brown solid, which was used directly in the next step; MS m / z(ES+)[M+H] + =287.0; 1H NMR (400MHz, MeOD, 22℃) δ2.37(3H,s),2.64(3H,d),6.52-6.57(1H,m),7.36(2H,d),7.50(1H,dd),7.71-7.80(2H,m),8.26(1H,d),9.28(1H,s).

[0504] Intermediate 62: 2-methyl-1H-pyrrolo[2,3-c]pyridine

[0505] [ka]

[0506] KOH (92.0 g, 1.40 mol) was added to a suspension of intermediate 61 (80.0 g, 254 mmol, th.) in MeOH (1 L), and the mixture was stirred overnight at 40°C. The reaction mixture was diluted with water (500 mL), and the organic solvent was concentrated under reduced pressure. The aqueous layer was extracted with SiO2 (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (36.8 g) as an orange solid; MS m / z(ES+)[M+H] + =133.1; 1 H NMR (400MHz, MeOD, 22℃) δ2.48 (3H, d), 6.22-6.27 (1H, m), 7.43 (1H, dd), 7.97 (1H, d), 8.51 (1H, s).

[0507] Intermediate 63: tert-butyl 4-(hydroxy(2-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl)methyl)-piperidine-1-carboxylate

[0508] [ka]

[0509] 39.7 mL, 205 mmol of tert-butyl 4-formylpiperidine-1-carboxylate was added to intermediate 62 (26.0 g, 157 mmol th.) in a mixture of 1,4-dioxane (500 mL) and water (100 mL), followed by the addition of KOH (20.8 g, 315 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (250 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (36.8 g, 68%) as a beige solid; MS m / z(ES+)[M+H] + =346.6; 1 H NMR(400MHz,MeOD,22℃)δ1.03(1H,qd),1.18-1.29(2H,m),1.42(9H,s),2.04-2.21(2H,m),2.46(3H,s),2.62(1H,br s),2.76(1H,br s),3.93-4.02(1H,m),4.10-4.20(1H,m),4.62(1H,d),7.63-7.69(1H,m),7.98(1H,d),8.50(1H,s).

[0510] Intermediate 64: tert-butyl 4-(2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0511] [ka]

[0512] TEMPO (5.15 g, 32.9 mmol) and water (3.6 mL, 198 mmol) were added to a mixture of intermediate 63 (22.8 g, 65.9 mmol) and PIDA (42.4 g, 132 mmol) in DCM (340 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with saturated NaHCO3 aqueous solution (50 mL) and stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (150 mL). The combined organic layers were concentrated under reduced pressure. The residue was filtered through silica and rinsed sequentially with heptane (2 × 100 mL), heptane / DCM (7:3), DCM / MeOH (75:25), and MeOH (500 mL). The filtrate was concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM), and after co-evaporation with toluene (3 × 50 mL), the title compound (18.7 g, 83%) was obtained as a beige solid; MS m / z(ES+)[M+H] + =344.6; 1 H NMR(400MHz,MeOD,22℃)δ1.50(9H,s),1.67(2H,m),1.89-1.98(2H,m),2.81(3H,s),3.07(2H,br s),3.47(1H,tt),4.13-4.22(2H,m),7.91-7.98(1H,m),8.27(1H,d),8.69(1H,s).

[0513] Intermediate 65: 2-(3-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid

[0514] [ka]

[0515] Copper powder (339 mg, 5.33 mmol) was added to a deoxygenated solution of 5-fluoro-2-iodobenzoic acid (9.45 g, 35.5 mmol), intermediate 64 (6.10 g, 17.8 mmol), and K2CO3 (8.59 g, 62.2 mmol) in DMF (72 mL). The resulting mixture was purged with N2 and stirred and heated overnight at 100°C. The reaction mixture was diluted with water (100 mL) and ethyl acetate (200 mL), filtered, and the filtrate was acidified to pH 2 with aqueous HCl (6 M). The filtrate was saturated with solid NaCl and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-100% siRNA in heptane, followed by 0-10% MeOH in DCM) to obtain the title compound (7.91 g, 92%) as a brown solid; MS m / z(ES+)[M+H] + = 482.1.

[0516] Intermediate 66 (mixture of atropisomers): tert-butyl 4-(1-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0517] [ka]

[0518] DIPEA (1.45 mL, 8.31 mmol) and N-ethylpropan-2-amine (2.51 mL, 20.8 mmol) were added to a mixture of intermediate 65 (2.00 g, 4.15 mmol), HATU (1.74 g, 4.57 mmol), and DMAP (101 mg, 0.83 mmol) in DMF (6 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (100 mL) and extracted with SiO2 (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-100% SiO2 in heptane) to obtain the title compound (2.13 g, 93%) as a brown gum-like substance, which was used directly in the next step; MS m / z(ES+)[M+H] + =551.3; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.12-0.46(5H,m),0.57-0.79(2H,m),0.95-1.08(3H,m),1.37-1.56(10H,m),1.81(2H,d),2.73(3H,s),3.01(2H,br s),3.12-3.25(1H,m),3.38-3.52(2H,m),3.62-3.74(1H,m),4.00(2H,br s),7.55-7.63(2H,m),7.71-7.80(1H,m),7.84-7.94(1H,m),8.25-8.42(2H,m).

[0519] Intermediate 67 (mixture of atropisomers): N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-(piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0520] [ka]

[0521] TFA (4 mL) was added to a solution of intermediate 66 (2.13 g, 3.44 mmol th.) in DCM (20 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (1.04 g, LC-UV purity 87%) as a brown gum-like substance; MS m / z(ES+)[M+H] + =451.2; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.15-0.47(4H,m),0.54-0.80(2H,m),0.92-1. 11(3H,m),1.07-1.37(2H,m),1.64-1.85(2H,m),1.94(2H,d),2.51(3H,s),2 .69-2.80(2H,m),3.05-3.23(3H,m),3.49-3.57(1H,m),3.65-3.75(1H,m), 7.55-7.65(2H,m),7.70-7.81(1H,m),7.88-7.98(1H,m),8.26-8.40(2H,m).

[0522] Intermediate 68 (mixture of atropisomers): tert-butyl 4-(1-(4-fluoro-2-(isopropyl(2,2,2-trifluoroethyl)carbamoyl)phenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0523] [ka]

[0524] T3P (3.71 mL, 6.23 mmol, 50% in ethyl) was added to a mixture of intermediate 65 (1.00 g, 2.08 mmol) in ethyl (8 mL), N-(2,2,2-trifluoroethyl)propan-2-amine HCl (738 mg, 4.15 mmol), and DIPEA (2.13 mL, 12.5 mmol). The mixture was stirred at 40°C for 4 days. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (40 mL) and extracted sequentially with ethyl (2 × 50 mL) and DCM (2 × 20 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, combined, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (581 mg, 46%) as an orange foamy substance; MS m / z(ES+)[M+H] + =605.3; 1 H NMR(400MHz,DMSO-d6,23℃)δ0.37(2H,br s),0.76-1.12(4H,m),1.41(9H,s),1.44-1.59(2H,m),1.81(2H,d),2.45(3H,s),3.03(2H,br s),3.36-3.48(1H,m),3.70-3.86(2H,m),3.89-4.11(3H,m),7.58-7.69(2H,m),7.72-7.82(1H,m),7.90(1H,br s),8.34(2H,br s).

[0525] Intermediate 69 (mixture of atrop isomers): 5-fluoro-N-isopropyl-2-(2-methyl-3-(piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0526] [ka]

[0527] TFA (2 mL) was added to a solution of intermediate 68 (581 mg, 0.96 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (419 mg, 86%) as a brown foam; MS m / z(ES+)[M+H] + =505.2; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.35(2H,br s),0.71-1.09(4H,m),1.35-1.96(5H,m),2.46(3H,s),2.65-3.19(4H,m),3.70-4.11 (3H,m),7.60-7.69(2H,m),7.71-7.80(1H,m),7.81-7.89(1H,m),8.23-8.46(2H,m).

[0528] Intermediate 70: rel-(2-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl)((2R,4R)-2-methylpiperidine-4-yl)methanone

[0529] [ka]

[0530] rel-(2R,4R)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid (10.0 g, 41.1 mmol) was added to SOCl2 (50 mL) under N2 at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in DCM (200 mL) and added dropwise to a mixture of intermediate 62 (5.43 g, 41.1 mmol) and anhydrous AlCl3 (38.4 g, 288 mmol) in DCM (200 mL) under N2. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into MeOH (100 mL) and the solvent was removed under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-10% 0.7M NH3 in MeOH in DCM) to obtain the title compound as a yellow solid in quantitative yield (11.0 g); MS m / z(ES+)[M+H] + = 258.3.

[0531] Intermediate 71:rel-tert-butyl3-((2R,4R)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

[0532] [ka]

[0533] A solution of Boc2O (29.8 mL, 128 mmol) in DCM (50 mL) was slowly added under N2 to a stirred mixture of Et3N (29.8 mL, 214 mmol), DMAP (1.04 g, 8.55 mmol), and intermediate 70 (11.0 g, 41.1 mmol, th.) in DCM (100 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated NaHCO3 aqueous solution (150 mL) and extracted with DCM (2 × 100 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-50% SiO in petroleum ether) to obtain the title compound (7.00 g, 37%); MS m / z ES+[M+H]+ =458.4; 1 H NMR(300MHz,DMSO-d6,25℃)δ0.94(1H,d),1.19(2H,d),1.39-1.41(9H,m),1.68(9H,s),2.79-2.84(3H,m),2.93-3.20(2H,m),3.42-3.62 (2H,m),3.65-3.75(1H,m),3.84-3.96(1H,m),3.96-4.06(1H,m),4.19-4.52(1H,m),7.75-7.90(1H,m),8.33-8.51(1H,m),9.27(1H,s).

[0534] Intermediate 72: rel-tert-butyl(2R,4S)-2-methyl-4-(2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0535] [ka]

[0536] NaOH (1.22 g, 30.6 mmol) was added to a solution of intermediate 71 (7.00 g, 15.3 mmol) in MeOH (60 mL) under N2. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated NaHCO3 aqueous solution (150 mL) and extracted with ELISA (3 × 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative SFC, preparative method SFC-A, to obtain the title compound (2.50 g, 46%) as a white solid; MS m / z ES+[M+H] + =358.1; 1 H NMR(300MHz,DMSO-d6,25℃)δ1.26(3H,d),1.41(9H,s),1.45-1.66(2H,m),1.67-1.84 (2H,m),2.73(3H,s),2.92-3.18(1H,m),3.38-3.58(1H,m),3.92(1H,d),4.39(1H,br s),7.81-7.86(1H,m),8.26(1H,d),8.73(1H,s),12.43(1H,br s).

[0537] Intermediate 73:rel-2-(3-((2R,4S)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluorobenzoic acid

[0538] [ka]

[0539] Copper powder (711 mg, 11.2 mmol) was added to a deoxygenated solution of 5-fluoro-2-iodobenzoic acid (2.23 g, 8.39 mmol), intermediate 72 (2.00 g, 5.60 mmol), and K2CO3 (2.71 g, 19.6 mmol) in DMF (30 mL). The resulting mixture was purged with N2 and stirred at 100°C for 2 hours. The reaction mixture was purified by reverse-phase flash chromatography on a C18 column (gradient: 0-80% MeOH in water containing 0.5% NH4HCO3) to obtain the title compound (1.80 g, 65%) as a yellow solid; MS m / z(ES+)[M+H] + = 496.4.

[0540] Intermediates 74-1, 74-2, 74-3, and 74-4 (separated atropisomers, monoisomers): rel-tert-butyl(2R,4S)-4-(1-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-2-methylpiperidine-1-carboxylate

[0541] [ka]

[0542] HATU (2.84 g, 7.47 mmol) was added to a mixture of intermediate 73 (1.85 g, 3.73 mmol), N-ethylpropan-2-amine (651 mg, 7.47 mmol), and DIPEA (1.96 mL, 11.2 mmol) in DCM (20 mL) under N2 conditions. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (3 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, combined, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-70% SiO2 in petroleum ether). The residue was purified by preparative HPLC and preparative method B (uniform concentration: 15%) to obtain intermediate 74-1 (250 mg, 12%) of the title compound as a white solid as the first elution product; MS m / z(ES+)[M+H] + =565.4; 1 H NMR(400MHz,DMSO-d6,21℃)δ0.11-0.30(1H,m),0.38-0.44(3H,m),0.59(1H,br s),0.66-0.79(1H,m),0.98-1.10(3H,m),1.27(3H,d),1.42(9H,s),1.45-1.53(1H,m ),1.55-1.67(1H,m),1.68-1.77(1H,m),1.81(1H,d),2.63-2.84(1H,m),3.08(1H,br s), 3.13-3.27 (1H,m), 3.50-3.62 (1H,m), 3.64-3.76 (1H,m), 3.92 (1H,d), 4.40 (1H,br s), 7.55-7.63 (2H,m), 7.71-7.83 (1H,m), 7.84-7.92 (1H,m), 8.31-8.36 (2H,m); Intermediate 74-2 (200 mg, 9%) was obtained as a white solid as the second elution product; MS m / z (ES+)[M+H] + =565.3; 1H NMR(400MHz,DMSO-d6,20℃)δ0.12-0.26(1H,m),0.39-0.45(3H,m),0.62(1H,br s),0.68-0.76(1H,m),0.99-1.11(3H,m),1.25(3H,d),1.41(9H,s),1.44-1 .63(2H,m),1.67-1.75(1H,m),1.81(1H,d),2.69-2.78(1H,m),3.07(1H,br s), 3.14-3.25 (1H,m), 3.52-3.62 (1H,m), 3.67-3.75 (1H,m), 3.93 (1H,d), 4.32-4.42 (1H,m), 7.56-7.62 (2H,m), 7.73-7.79 (1H,m), 7.88-7.92 (1H,m), 8.31-8.35 (2H,m); intermediate 74-3 (200 mg, 9%) was obtained as a white solid as the third elution product; MS m / z (ES+)[M+H] + =565.4; 1 H NMR(400MHz,DMSO-d6,23℃)δ0.14-0.30(1H,m),0.38-0.45(3H,m),0.60(1H,br s),0.67-0.78(1H,m),0.96-1.10(3H,m),1.22-1.35(3H,m),1.42(9H,s),1.43-1.51(1 H,m),1.55-1.67(1H,m),1.68-1.77(1H,m),1.81(1H,d),2.64-2.80(1H,m),3.08(1H,br s), 3.13-3.27 (1H,m), 3.50-3.61 (1H,m), 3.64-3.76 (1H,m), 3.92 (1H,d), 4.40 (1H,br s), 7.55-7.62 (2H,m), 7.70-7.82 (1H,m), 7.86-7.93 (1H,m), 8.31-8.37 (2H,m); intermediate 74-4 (200 mg, 9%) was obtained as a white solid as the fourth elution product; MS m / z (ES+)[M+H] + =565.4; 1H NMR(400MHz,DMSO-d6,23℃)δ0.10-0.29(1H,m),0.39-0.47(3H,m),0.61(1H,br s),0.67-0.79(1H,m),0.93-1.11(3H,m),1.25(3H,d),1.42(9H,s),1.44-1 .62(2H,m),1.66-1.76(1H,m),1.81(1H,d),2.72-2.81(1H,m),3.07(1H,br s),3.13-3.25(1H,m),3.48-3.63(1H,m),3.67-3.76(1H,m),3.93(1H,d),4.37(1H,br s),7.56-7.62(2H,m),7.73-7.80(1H,m),7.84-7.93(1H,m),8.31-8.36(2H,m).

[0543] Intermediate 75 (single atropisomer, single isomer): rel-N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R,4S)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0544] [ka]

[0545] FA (5 mL) was added to intermediate 74-1 (250 mg, 0.44 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (4 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (187 mg, 91%) as a pale yellow solid; MS m / z(ES+)[M+H] + =465.2; 1H NMR(300MHz,DMSO-d6,21℃)δ0.08-0.21(1H,m),0.34-0.42(3H,m),0.60-0.86 (2H,m),0.97-1.08(6H,m),1.09-1.31(1H,m),1.33-1.52(1H,m),1.75(2H,br s),1.82-2.00(1H,m),2.65-2.81(2H,m),2.86-3.00(1H,m),3.20-3.41(1H,m),3.52-3 .63(1H,m),3.63-3.75(1H,m),7.54-7.62(2H,m),7.71-7.84(2H,m),8.25-8.37(2H,m).

[0546] Intermediate 76 (single atropisomer, single isomer):rel-N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R,4S)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0547] [ka]

[0548] FA (5 mL) was added to intermediate 74-2 (190 mg, 0.34 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (4 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (180 mg) as a pale yellow solid; MS m / z(ES+)[M+H] + =465.2; 1H NMR(300MHz,DMSO-d6,21℃)δ0.10-0.18(1H,m),0.36-0.44(3H,m),0.60-0.74(1H,m), 0.82-0.91(1H,m),0.93-1.09(6H,m),1.20-1.30(1H,m),1.40-1.58(1H,m),1.75(1H,m ),1.78-1.95(2H,m),2.66-2.74(1H,m),2.76-2.88(2H,m),3.19-3.34(1H,m),3.53-3. 63(1H,m),3.64-3.74(1H,m),7.53-7.63(2H,m),7.70-7.85(2H,m),8.24-8.37(2H,m).

[0549] Intermediate 77 (single atropisomer, single isomer):rel-N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R,4S)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0550] [ka]

[0551] FA (5 mL) was added to intermediate 74-3 (200 mg, 0.35 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (4 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (180 mg) as a yellow solid; MS m / z(ES+)[M+H] + =465.3; 1H NMR(300MHz,DMSO-d6,21℃)δ0.10-0.19(1H,m),0.35-0.44(3H,m),0.58-0.77(1H,m),0 .78-0.90(1H,m),0.95-1.08(6H,m),1.18-1.30(1H,m),1.32-1.50(1H,m),1.76(2H,br s),1.85-1.95(1H,m),2.65-2.78(2H,m),2.86-2.99(1H,m),3.14-3.32(1H,m),3.54-3 .62(1H,m),3.63-3.74(1H,m),7.54-7.64(2H,m),7.70-7.89(2H,m),8.25-8.36(2H,m).

[0552] Intermediate 78 (single atropisomer, single isomer):rel-N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R,4S)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0553] [ka]

[0554] FA (5 mL) was added to intermediate 74-4 (210 mg, 0.37 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (4 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (180 mg) as a yellow solid; MS m / z(ES+)[M+H] + =465.4; 1H NMR(300MHz,DMSO-d6,21℃)δ0.09-0.18(1H,m),0.35-0.44(3H,m),0.68-0.75(1H,m ),0.83-0.92(1H,m),0.94-1.08(6H,m),1.20-1.26(1H,m),1.40-1.56(1H,m),1.63 -1.77(1H,m),1.78-1.95(2H,m),2.72-2.87(3H,m),3.15-3.30(1H,m),3.53-3.64( 1H,m),3.64-3.73(1H,m),7.54-7.63(2H,m),7.71-7.84(2H,m),8.25-8.37(2H,m).

[0555] Intermediates 79-1, 79-2, 79-3, and 79-4 (separated atropisomers, monoisomers): rel-tert-butyl(2R,4S)-4-(1-(4-fluoro-2-(isopropyl(2,2,2-trifluoroethyl)carbamoyl)phenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-2-methylpiperidine-1-carboxylate

[0556] [ka]

[0557] T3P (8.59 g, 13.5 mmol, 50% in ethyl acetate) was added to a mixture of intermediate 73 (2.23 g, 4.50 mmol), N-(2,2,2-trifluoroethyl)propan-2-amine (3.18 g, 22.5 mmol), and DIPEA (4.72 mL, 27.0 mmol) in DCM (20 mL) under N2 conditions. The mixture was stirred at room temperature for 45 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (300 mL) and washed with water (3 × 100 mL). The organic layers were dried over Na2SO4, filtered, combined, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography (gradient: 0-100% butyl in petroleum ether), followed by preparative SFC, and then by preparative SFC-B (uniform concentration: 15%) to obtain the title compound intermediate 79-1 (35.0 mg, 1%) as the first elution product as a white solid; MS m / z(ES+)[M+H] + =619.3; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.35-0.43(2H,m),0.80-0.88(1H,m),1.03-1.11(3H,m),1.25(3H,d),1.42(9H,s),1.47-1.64(2H,m),1.67-1.75(1 H,m),1.76-1.85(1H,m),2.41-2.48(3H,m),3.01-3.29(1H,m),3.50-3.6 2(1H,m),3.67-3.87(2H,m),3.93(1H,d),3.98-4.13(1H,m),4.37(1H,br s), 7.59-7.69 (2H,m), 7.73-7.81 (1H,m), 7.89 (1H,d), 8.29-8.35 (1H,m), 8.39 (1H,s); intermediate 79-2 (80.0 mg, 3%) was obtained as a second elution product as a white solid; MS m / z (ES+)[M+H] + =619.3; 1H NMR(400MHz,DMSO-d6,22℃)δ0.34-0.40(2H,m),0.84-0.92(1H,m),1.01-1.11(3H,m),1.24-1.27(3H,m),1.42 (9H,s),1.44-1.52(1H,m),1.57-1.67(1H,m),1.67-1.75(1H,m),1.76-1.88(1H,m),2.47(3H,s),3.07(1H,br s),3.48-3.61(1H,m),3.69-3.85(2H,m),3.91(1H,d),3.99-4.17(1H,m),4.39(1H,br s), 7.61-7.69 (2H,m), 7.74-7.82 (1H,m), 7.90 (1H,d), 8.33 (1H,d), 8.39 (1H,s); intermediate 79-3 (80.0 mg, 3%) was obtained as a third elution product as a white solid; MS m / z (ES+)[M+H] + =619.3; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.32-0.42(2H,m),0.83-0.91(1H,m),1.02-1. 08(3H,m),1.26(3H,d),1.42(9H,s),1.46-1.52(1H,m),1.61-1.67(1H,m),1 .69-1.77(1H,m),1.78-1.86(1H,m),2.47(3H,s),3.00-3.15(1H,m),3.49- 3.61(1H,m),3.71-3.87(2H,m),3.92(1H,d),3.99-4.13(1H,m),4.41(1H,br s), 7.62-7.69 (2H,m), 7.73-7.81 (1H,m), 7.90 (1H,d), 8.34 (1H,d), 8.39 (1H,s); intermediate 79-4 (80.0 mg, 3%) was obtained as a fourth elution product as a white solid; MS m / z (ES+)[M+H] + =619.3; 1H NMR(400MHz,DMSO-d6,22℃)δ0.37-0.45(2H,m),0.79-0.91(1H,m),1.01-1.14(3H,m),1.25(3H,d),1 .42(9H,s),1.47-1.60(2H,m),1.69-1.75(1H,m),1.77-1.90(1H,m),2.42-2.48(3H,m),3.10(1H,br s),3.51-3.65(1H,m),3.71-3.88(2H,m),3.89-3.98(1H,m),4.01-4.12(1H,m),4.40(1H,br s),7.61-7.68(2H,m),7.74-7.82(1H,m),7.86-7.94(1H,m),8.29-8.43(2H,m).

[0558] Intermediate 80 (single atropisomer, single isomer):rel-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R,4S)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0559] [ka]

[0560] FA (2 mL) was added to a solution of intermediate 79-1 (35.0 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (36.6 mg) as an off-white solid, which was used directly in the next step (Example 53-1a); MS m / z(ES+)[M+H] + = 519.2.

[0561] Intermediate 81 (single atropisomer, single isomer):rel-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R,4S)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0562] [ka]

[0563] FA (2 mL) was added to a solution of intermediate 79-2 (80.0 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (76.6 mg) as an off-white solid, which was used directly in the next step (Example 53-2a); MS m / z(ES+)[M+H] + = 519.2.

[0564] Intermediate 82 (single atropisomer, single isomer):rel-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R,4S)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0565] [ka]

[0566] FA (2 mL) was added to a solution of intermediate 79-3 (75.0 mg, 0.12 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (75.0 mg) as an off-white gum-like substance, which was used directly in the next step (Example 53-3a); MS m / z(ES+)[M+H] + = 519.2.

[0567] Intermediate 83 (single atropisomer, single isomer):rel-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R,4S)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-(2,2,2-trifluoroethyl)benzamide

[0568] [ka]

[0569] FA (2 mL) was added to a solution of intermediate 79-4 (80.0 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (76.3 mg) as an off-white solid, which was used directly in the next step (Example 53-4a); MS m / z(ES+)[M+H] + = 519.2.

[0570] Intermediate 84: tert-butyl 4-(3-oxobutanoyl)piperidine-1-carboxylate

[0571] [ka]

[0572] NaH (3.52 g, 88.0 mmol, 60% dispersion in mineral oil) was added to a cooled solution of tert-butyl 4-acetylpiperidine-1-carboxylate (9.50 mL, 44.0 mmol) in THF (100 mL) at 0°C under N2. The reaction mixture was allowed to reach room temperature and stirred for 1 hour, after which toluene (8.59 mL, 88.0 mmol) was added. The resulting mixture was stirred at 40°C for 3 hours. The reaction mixture was poured into water (150 mL) and saturated NH4Cl aqueous solution (200 mL) and extracted with toluene (3 × 200 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-40% toluene in heptane) to obtain the title compound (8.50 g, 72%) as a beige solid; MS m / z(ES+)[M+H-tBu] + =213.9; 1 H NMR (400MHz, CDCl3, 22℃) δ1.45-1.47(9H,m),1.57(2H,m),1.81(2H,d),2.07(3H, s),2.33(1H,tt),2.69-2.82(2H,m),4.05-4.23(2H,m),5.53(1H,s),15.54(1H,br s).

[0573] Intermediate 85: 4-bromo-N-(2-bromo-4-fluorophenyl)pyridine-3-amine

[0574] [ka]

[0575] Pd2dba3·CHCl3 (3.44 g, 3.32 mmol) was added to a deoxygenated mixture of 2-bromo-4-fluoro-1-iodobenzene (10.0 g, 33.2 mmol), 4-bromopyridine-3-amine (5.75 g, 33.2 mmol), XantPhos (3.85 g, 6.65 mmol), and NaOtBu (6.39 g, 66.5 mmol) in toluene (150 mL). The mixture was purged with N2 for 10 minutes and stirred under N2 at 60°C for 4 hours. The reaction mixture was diluted with RINKAN and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 10-20% SiO in heptane) to obtain the title compound (8.04 g, 70%) as a white solid; MS m / z(ES+)[M+H] + =344.9 / 346.9; 1 H NMR (400MHz, DMSO-d6, 22℃) δ7.08-7.19(1H,m),7.19-7.30(1H,m),7.50(1H,s),7.61-7.72(2H,m),7.89(1H,s),7.96(1H,d).

[0576] Intermediate 86: tert-butyl 4-(1-(2-bromo-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0577] [ka]

[0578] CuO (144 mg, 1.81 mmol) was added to a deoxygenated mixture of intermediate 84 (1.95 g, 7.23 mmol), intermediate 85 (1.25 g, 3.61 mmol), and Cs2CO3 (589 mg, 1.81 mmol) in DMSO (20 mL). The resulting mixture was purged with N2 for a further 10 minutes and stirred at 80°C for 48 hours. The mixture was diluted with SiO2 and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (514 mg, 28%) as a brown solid; MS m / z(ES+)[M+H] + =516.0 / 518.0; 1 H NMR(400MHz,DMSO-d6,22℃)δ1.35-1.47(9H,m),1.47-1.62(2H,m),1.87(2H,d),2.47(3H,s),3.03(2H,br s),3.42-3.54(1H,m),4.00(2H,d),7.54-7.66(1H,m),7.83(1H,dd),7.95(1H,d),8.02(1H,dd),8.20(1H,s),8.38(1H,d).

[0579] Intermediate 87 (mixture of atropisomers): tert-butyl 4-(1-(4-fluoro-2-(4-isopropylpyridine-3-yl)phenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0580] [ka]

[0581] Pd(dppf)Cl2 (31.9 mg, 0.04 mmol) was added under N2 to intermediate 86 (225 mg, 0.44 mmol), intermediate 121 (108 mg, 0.44 mmol, th.), and a deoxygenated solution of 1,4-dioxane (2.3 mL) and K2CO3 aqueous solution (440 μL, 0.88 mmol, 2 M). The resulting mixture was stirred at 100°C for 1.5 hours. The reaction mixture was concentrated in the presence of silica and purified by normal-phase flash chromatography with silica (gradient: 0-100% phenylethylamine in heptane) to obtain the title compound (70.0 mg, 29%) as a yellow oil; MS m / z(ES+)[M+H] + = 557.2.

[0582] Intermediate 88 (mixture of atropisomers): (1-(4-fluoro-2-(4-isopropylpyridine-3-yl)phenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl)(piperidine-4-yl)methanone

[0583] [ka]

[0584] TFA (414 μL) was added to a solution of intermediate 87 (70.0 mg, 0.13 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with RINKAN (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (50.6 mg, 88%) as an off-white solid; MS m / z(ES+)[M+H] + = 457.2.

[0585] Intermediate 89: 5-Fluoro-2-iodo-N,N-diisopropylbenzamide

[0586] [ka]

[0587] T3P (198 mL, 338 mmol, 50% in DCM) was added to a stirred solution of 5-fluoro-2-iodobenzoic acid (75.0 g, 282 mmol) and diisopropylamine (199 mL, 1.41 mol) in DCM (450 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was sequentially washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, filtered through a silica short plug, and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude title compound (40.0 g) as a beige solid. The silica plug was rinsed with DCM:MeOH (3:1), and the filtrate was concentrated under reduced pressure to obtain the crude title compound (63.0 g) as a brown solid; MS m / z(ES+)[M+H] + =350.0; 1 H NMR (400MHz, DMSO-d6, 22℃) δ1.06(3H,d),1.21(3H,d),1.46(6H,t),3.41(1H,p),3.57(1H,p),7.03(1H,td),7.20(1H,dd),7.87(1H,dd).

[0588] Intermediate 90: 2-((4-bromopyridine-3-yl)amino)-5-fluoro-N,N-diisopropylbenzamide

[0589] [ka]

[0590] Pd2dba3·CHCl3 (5.34 g, 10.3 mmol) was added to a deoxygenated mixture of intermediate 89 (36.0 g, 103 mmol, th.), 4-bromopyridine-3-amine (21.4 g, 124 mmol), XantPhos (5.97 g, 10.3 mmol), and Cs2CO3 (101 g, 309 mmol) in 2-MeTHF (360 mL). The mixture was purged with N2 for a further 5 minutes and stirred overnight at 80°C. The reaction mixture was filtered with Celite® and the Celite was rinsed with ELISA. The filtrate was concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% ELISA in heptane). Appropriate fractions were combined and concentrated under reduced pressure. The residue was dissolved in DCM and sequentially washed with aqueous N-acetyl-cysteine ​​(2%) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (23.6 g, 58%) as a yellow solid; MS m / z(ES+)[M+H] + =394.0 / 396.0; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.80-1.50(12H,m),3.67(2H,s),7.00(1H,s),7.1 9(1H,dd),7.26(1H,td),7.35(1H,dd),7.62(1H,d),7.88(1H,d),8.06(1H,s).

[0591] Intermediate 91 (mixture of atropisomers): tert-butyl 4-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0592] [ka]

[0593] CuO (171 mg, 2.16 mmol) was added to a deoxygenated mixture of intermediate 84 (1.37 g, 5.07 mmol), intermediate 90 (1.00 g, 2.54 mmol), and Cs2CO3 (1.16 g, 3.55 mmol) in DMSO (18 mL). The resulting mixture was purged with N2 for a further 10 minutes and stirred at 110°C for 6 hours. The above procedure was repeated 16 times. The reaction mixtures were combined, diluted with SiO2 (500 mL) and water (500 mL), and filtered. The organic layer of the filtrate was separated and washed with water (300 mL) and brine (500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 20-100% SiO in heptane) to obtain the title compound (17.9 g, 78%) as a brown foamy substance; MS m / z(ES+)[M+H] + =565.3; 1 H NMR(400MHz,DMSO-d6,27℃)δ0.41(3H,br s),0.53-0.77(3H,m),0.98-1.13(3H,m),1.26(3H,d),1.41(11H,s),1.73-1.89(2H,m),3.02(2H,br s),3.13-3.27(1H,m),3.38-3.54(1H,m),3.68(1H,br s),3.87-4.01(2H,m),7.16-9.27(6H,m).

[0594] Intermediate 92 (mixture of atrop isomers): 5-fluoro-N,N-diisopropyl-2-(2-methyl-3-(piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0595] [ka]

[0596] TFA (25 mL) was added to a solution of intermediate 91 (17.0 g, 30.2 mmol) in DCM (95 mL). The resulting mixture was stirred at room temperature for 4 hours. The mixture was diluted with DCM (400 mL) and quenched with saturated NaHCO3 aqueous solution (200 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound as a beige foam in a quantitative yield (14.9 g); MS m / z(ES+)[M+H] + =465.3; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.41(3H,d),0.50-0.75(3H,m),0.95-1.17(3H,m),1.26(3H,d),1.57-1.83(2H,m),1.90(2H,br s),2.94-3.11(2H,m),3.12-3.26(3H,m),3.43-3.58(2H,m),3.61-3.78(1H ,m),7.46-7.63(2H,m),7.65-7.79(1H,m),7.83-8.00(1H,m),8.32(2H,s).

[0597] Intermediate 93: (R)-1,1,1-trifluoro-N-isopropylpropane-2-amine hydrochloride

[0598] [ka]

[0599] A mixture of (R)-1,1,1-trifluoropropan-2-amine (5.00 g, 44.2 mmol) and dry acetone (6.55 mL, 88.4 mmol) in a mixture of dry DCM (30 mL) and acetic acid (2 mL) was stirred at room temperature for 2 hours in the presence of a molecular sieve (3 Å). NaBH4 (3.35 g, 88.4 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was filtered through Celite® and 4 M HCl in 1,4-dioxane (15 mL) was added to the filtrate. The solvent was concentrated to dryness and the residue was partitioned between Et2O (150 mL) and aqueous NaOH (150 mL, 1 M). The organic layer was washed with brine, dried over Na2SO4, filtered, treated with 4 M HCl in 1,4-dioxane (15 mL), and concentrated under reduced pressure. The product was freeze-dried from 1,4-dioxane / H2O to obtain the title compound (6.15 g, 73%) as a white solid; MS m / z(ES+)[M+H] + =156.1; 1 H NMR (400MHz, MeOD, 22°C) δ1.38(3H,d), 1.43(3H,d), 1.55(3H,d), 3.64(1H, hept), 4.37(1H, hept).

[0600] Intermediate 94: (R)-5-fluoro-2-iodo-N-isopropyl-N-(1,1,1-trifluoropropan-2-yl)benzamide

[0601] [ka]

[0602] SOCl2 (3.93 mL, 54.1 mmol) was added to 5-fluoro-2-iodobenzoic acid (600 mg, 2.26 mmol) in a sealed microwave tube. The resulting mixture was stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain acyl chloride. A solution of intermediate 93 (1.08 g, 5.64 mmol) in toluene (15 mL) was washed with aqueous NaOH solution (4 mL, 2 M). The organic layer was dried over Na2SO4, filtered, and added to a cooled solution of acyl chloride at 0°C. After the addition was complete, the mixture was stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and saturated aqueous NaHCO3 solution (15 mL). The aqueous layer was extracted with DCM (3 × 10 m). The combined organic layers were passed through a phase separator and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-20% ethyl acetate in heptane) to obtain the title compound (468 mg, 52%) as a yellow solid; MS m / z(ES+)[M+H] + =404.0; 1 H NMR (400MHz, CDCl3, 22℃) δ1.05-1.85(9H,m),3.61-3.78(1H,m),3.81-4.04(1H,m),6.77-7.02(2H,m),7.69-7.88(1H,m).

[0603] Intermediate 95: (R)-2-((4-bromopyridine-3-yl)amino)-5-fluoro-N-isopropyl-N-(1,1,1-trifluoropropan-2-yl)benzamide

[0604] [ka]

[0605] Pd2dba3·CHCl3 (120 mg, 0.12 mmol) was added to a deoxygenated mixture of intermediate 94 (468 mg, 1.16 mmol), 4-bromopyridine-3-amine (603 mg, 3.48 mmol), XantPhos (134 mg, 0.23 mmol), and NaOtBu (335 mg, 3.48 mmol) in dried 1,4-dioxane (7 mL). The mixture was purged with N2 and stirred at 80°C for 6 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% ethyl acetate in heptane) to obtain the title compound (320 mg, 62%) as a light brown oily substance; MS m / z(ES+)[M+H] + =448.0 / 450.0; 1 H NMR (400MHz, CDCl3, 22℃) δ1.01-1.31(3H,m),1.34-1.59(6H,m),3.50-4.49(2H,m),6.1 5-7.05(2H,m),7.10(1H,td),7.34-7.42(1H,m),7.46(1H,d),7.94(1H,d),8.33(1H,br s).

[0606] Intermediate 96 (mixture of atropisomers): tert-butyl(R)-4-(1-(4-fluoro-2-(isopropyl(1,1,1-trifluoropropan-2-yl)carbamoyl)phenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-piperidine-1-carboxylate

[0607] [ka]

[0608] CuO (46.8 mg, 0.59 mmol) was added to a deoxygenated mixture of intermediates 84 (559 mg, 2.07 mmol), 95 (310 mg, 0.69 mmol), and Cs2CO3 (315 mg, 0.97 mmol) in DMSO (5 mL). The resulting mixture was purged with N2 and stirred at 110°C for 18 hours. The mixture was diluted with toluene (50 mL) and washed with water (25 mL). The organic layer was passed through a phase separator and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% toluene in heptane) to obtain the title compound (280 mg, 65%) as a yellow oil; MS m / z(ES+)[M+H] + =619.6; 1 H NMR (400MHz, CDCl3, 22℃) δ0.39-0.49(1H,m),0.59(1H,d),0.72(1H,d),0.83-1. 19(3H,m),1.33-1.54(11H,m),1.65-2.01(4H,m),2.57-2.66(2H,m),2.88-3.11 (2H,m),3.16-3.52(3H,m),3.70-3.99(2H,m),4.12-4.30(2H,m),7.06-7.23(1H ,m),7.27-7.50(2H,m),7.73-7.91(1H,m),8.11-8.35(1H,m),8.35-8.56(1H,m).

[0609] Intermediate 97 (mixture of atrop isomers): (R)-5-fluoro-N-isopropyl-2-(2-methyl-3-(piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-(1,1,1-trifluoropropan-2-yl)-benzamide hydrochloride

[0610] [ka]

[0611] 4M HCl in 1 mL of 1,4-dioxane was added to a solution of intermediate 96 (266 mg, 0.43 mmol) in 5 mL of MeCN. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound (239 mg); MS m / z(ES+)[M+H] + = 519.2.

[0612] Intermediate 98: ((3R,5R)-3,5-dimethylmorpholino)(5-fluoro-2-iodophenyl)methanone

[0613] [ka]

[0614] T3P (91.0 mL, 152 mmol, 50% in DCM) was added at 0°C to a stirred solution of 5-fluoro-2-iodobenzoic acid (27.0 g, 102 mmol), (3R,5R)-3,5-dimethylmorpholine hydrochloride (18.5 g, 122 mmol), and DIPEA (70.7 mL, 122 mmol) in DCM (360 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was washed with 50% saturated NaHCO3 aqueous solution (2 × 360 mL) and brine (180 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM, filtered through silica, and the silica was washed with heptane:siRNA (1:1, 2 × 1 L). The filtrate was concentrated under reduced pressure. The residue was dissolved in ₹ (150 mL) and sequentially washed with saturated NaHCO3 aqueous solution (2 × 150 mL) and brine (100 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (27.7 g, 75%); MS m / z(ES+)[M+H] + =364.0; 1 H NMR(400MHz,CDCl3,22℃)δ1.06-1.38(3H,m),1.57-1.63(3H,m),3.45(1H,br s),3.60(2H,d),3.76-4.39(3H,m),6.85(1H,td),6.93-7.12(1H,m),7.62-7.85(1H,m).

[0615] Intermediate 99: (2-((4-bromopyridine-3-yl)amino)-5-fluorophenyl)((3R,5R)-3,5-dimethyl-morpholino)methanone

[0616] [ka]

[0617] Pd2dba3·CHCl3 (2.00 g, 1.93 mmol) was added to a deoxygenated mixture of intermediate 98 (14.0 g, 38.6 mmol), 4-bromopyridine-3-amine (8.00 g, 46.3 mmol), XantPhos (2.23 g, 3.85 mmol), and Cs2CO3 (37.7 g, 116 mmol) in 2-MeTHF (128 mL). The mixture was purged with N2 for a further 5 minutes and stirred overnight at 80°C. The reaction mixture was diluted with SiO2, filtered through Celite®, and the Celite was rinsed with SiO2. The filtrate was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 5-50% ethyl acetate in heptane) to obtain the title compound (10.1 g, 64%) as a yellow gum-like substance; MS m / z(ES+)[M+H] + =408.0 / 410.0; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.96(6H,d),3.22-3.33(2H,m),3.61-3.74(2H,m),3. 79(2H,dd),7.20-7.40(3H,m),7.53(1H,s),7.62(1H,d),7.89(1H,d),7.99(1H,s).

[0618] Intermediate 100 (mixture of atropisomers): tert-butyl 4-(1-(2-((3R,5R)-3,5-dimethyl-morpholine-4-carbonyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-piperidine-1-carboxylate

[0619] [ka]

[0620] CuO (103 mg, 1.29 mmol) was added to a deoxygenated mixture of intermediates 84 (818 mg, 3.04 mmol), 99 (620 mg, 1.52 mmol), and Cs2CO3 (692 mg, 2.13 mmol) in DMSO (19 mL). The resulting mixture was purged with N2 for 5 minutes and stirred overnight at 90°C. This procedure was repeated five times. The reaction mixtures were combined, diluted with SiO2, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% SiO2 in heptane) to obtain the title compound (2.10 g, 48%) as a brown solid; MS m / z(ES+)[M+H] + =579.3; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.57(2H,br s),0.87-1.2(3H,m),1.20-1.29(1H,m),1.42(9H,s),1.45-1.65(2H,m) ,1.75-1.93(2H,m),2.05-2.35(1H,m),2.41(2H,s),2.56(1H,s),2.80-3 .23(4H,m),3.35-3.73(4H,m),3.82-4.07(2H,m),7.58-7.68(1H,m),7.6 9-7.74(1H,m),7.75-7.84(1H,m),7.88-8.07(1H,m),8.08-8.85(2H,m).

[0621] Intermediate 101 (mixture of atrop isomers): (1-(2-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl)(piperidine-4-yl)methanone hydrochloride

[0622] [ka]

[0623] 4M HCl in 1,4-dioxane (8.15 mL) was added to a solution of intermediate 100 (1.89 g, 3.26 mmol) in MeCN (40 mL). The resulting mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to obtain the crude title compound (1.68 g) as a brown solid; MS m / z(ES+)[M+H] + =479.2; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.32-0.79(2H,m),0.80-1.37(3H,m),1.59-2.21(5H,m),2.54(2H,s),2.64-2.96(2H,m),3.10-3.39(5H,m),3.41-3 .49(1H,m),3.61-3.92(4H,m),7.63-7.76(1H,m),7.76-7.83(1H,m),7.8 3-7.93(1H,m),8.26-8.94(2H,m),8.95-9.17(1H,m),9.25-9.48(1H,m).

[0624] Intermediate 102: Methyl(1r,4r)-4-(methylsulfonamide)cyclohexane-1-carboxylate

[0625] [ka]

[0626] Methanesulfonic anhydride (36.6 g, 210 mmol) was added to methyl (1r,4r)-4-aminocyclohexane-1-carboxylate (22.0 g, 140 mmol) and Et3N (39.0 mL, 280 mmol) in DCM (300 mL) cooled to 0°C under N2. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated NH4Cl aqueous solution (300 mL) and extracted with DCM (3 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-40% siRNA in DCM) to obtain the title compound (30.0 g, 91%) as a white solid. 1H NMR (300MHz, CDCl3, 24℃) δ1.22-1.37(2H,m),1.46-1.61(2H,m),2.00-2.30(5H,m),2.98(3H,s),3.20-3.33(1H,m),3.67(3H,s),4.67(1H,d).

[0627] Intermediate 103: N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)methanesulfonamide

[0628] [ka]

[0629] BH3·THF (127 mL, 128 mmol, 1 M) was added to intermediate 102 (15.0 g, 63.8 mmol) in THF (150 mL) cooled to 0°C under N2. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was slowly added to saturated NaHCO3 aqueous solution (200 mL) and extracted with DCM (5 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound (11.0 g, 83%) as a white solid. 1 H NMR(300MHz, CDCl3, 25℃) δ0.97-1.15(2H,m),1.18-1.35(2H,m),1.37-1.54(1H,m),1.81-1.90(2H, m),1.93(1H,s),2.02-2.20(2H,m),2.98(3H,s),3.15-3.32(1H,m),3.38-3.53(2H,m),4.73(1H,d).

[0630] Intermediate 104: ((1r,4r)-4-(methylsulfonamide)cyclohexyl)methyl 4-methylbenzenesulfonate

[0631] [ka]

[0632] DMAP (660 mg, 5.40 mmol) was added to a cooled mixture of intermediate 103 (11.2 g, 54.0 mmol), TsCl (15.5 g, 81.1 mmol), and Et3N (22.6 mL, 162 mmol) in DCM (200 mL) at 0°C under N2. The resulting mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-60% SiO in petroleum ether) to obtain the title compound (19.0 g, 97%) as a white solid; MS m / z(ES+)[M+Na] + =384.2; 1 H NMR (300MHz, CDCl3, 25℃) δ0.98-1.31(4H,m),1.57-1.71(1H,m),1.76-1.85(2H,m),2.04-2.12(2H,m),2.4 7(3H,s),2.97(3H,s),3.15-3.29(1H,m),3.83(2H,d),4.35(1H,d),7.34-7.40(2H,m),7.75-7.83(2H,m).

[0633] Intermediate 105: 2-(tert-butyl)3-ethyl(1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

[0634] [ka]

[0635] DAST (56.5 mg, 0.35 mmol) was added at 0°C to a mixture of 2-(tert-butyl)3-ethyl(1S,3S,4S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate and 2-(tert-butyl)3-ethyl(1S3S,4R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate [synthesis described in U.S. Patent Application Publication No. 2020 / 0157114(A1)] (100 mg, 0.35 mmol) in DCM (1 mL). The mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with ELISA (3 × 50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-50% ethyl acetate in heptane), and the title compound (60.0 mg, 60%) was obtained as the first elution product as a yellow oily substance; MS m / z(ES+)[M+H-tBu] + =232.1; 1 ¹H NMR (400MHz, DMSO-d6, 22℃) δ 1.16-1.23 (3H,m), 1.27-1.43 (9H,m), 1.46-1.55 (1H,m), 1.56-1.73 (1H,m), 1.73-1.86 (1H,m), 1.88-2.17 (1H,m), 2.64-2.79 (1H,m), 3.61 (1H,d), 4.03-4.27 (3H,m), 4.55-4.84 (1H,m); an undesirable fluorinated isomer was obtained as a second elution product (33.0 mg, 33%).

[0636] Intermediate 106: (1S,3S,4S,5S)-2-(tert-butoxycarbonyl)-5-fluoro-2-azabicyclo[2.2.1]heptane-3-carboxylic acid

[0637] [ka]

[0638] A solution of NaOH (940 μL, 0.94 mmol, 1 M) was added to a solution of intermediate 105 (60.0 mg, 0.21 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with HCl aqueous solution (1 M, 10 mL) and extracted with SiO2 (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (41.0 mg, 76%) as a colorless gum; MS m / z(ES+)[M+H-tBu] + =204.0.

[0639] Intermediate 107: 2-(propa-1-en-2-yl)pyridine-3-amine

[0640] [ka]

[0641] Pd(dppf)Cl2 (2.85 g, 3.89 mmol) was added to a mixture of 1,4-dioxane (240 mL) and water (60 mL) containing 2-chloropyridine-3-amine (10.0 g, 77.8 mmol), isopropenylboronic acid pinacol ester (14.4 g, 85.6 mmol), and K2CO3 (32.3 g, 233 mmol) under N2. The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into water (200 mL) and extracted with siRNA (2 × 125 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-30% siRNA in petroleum ether) to obtain the title compound (10.0 g, 96%) as a yellow oil; MS m / z(ES+)[M+H] + =135.2; 1 H NMR (300MHz, DMSO-d6) δ2.07(3H,s),5.03(2H,s),5.25-5.31(1H,m),5.35-5.45(1H,m),6.91-6.99(1H,m),7.05(1H,dd),7.79(1H,dd).

[0642] Intermediate 108: 2-Isopropylpyridine-3-amine

[0643] [ka]

[0644] Pd / C (10.2 g, 9.61 mmol, 10%) was added to a mixture of intermediate 107 (12.9 g, 96.1 mmol) in MeOH (500 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to obtain the title compound (12.0 g, 92%) as an orange liquid; MS m / z(ES+)[M+H] + =137.3; 1 H NMR (300MHz, DMSO-d6, 24℃) δ1.15 (6H, d), 3.06-3.20 (1H, m), 5.02 (2H, s), 6.83-6.93 (2H, m), 7.74 (1H, dd).

[0645] Intermediate 109: 3-bromo-2-isopropylpyridine

[0646] [ka]

[0647] t-BuONO (3.49 mL, 29.4 mmol) was added to intermediate 108 (2.00 g, 14.7 mmol) in MeOH (70 mL) under N2. The mixture was stirred at room temperature for 30 minutes, after which CuBr2 (3.28 g, 14.7 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (100 mL) and extracted with SiO2 (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-4% SiO2 in petroleum ether) to obtain the title compound (1.29 g, 44%) as a yellow liquid; MS m / z(ES+)[M+H] + =200.0 / 202.0;1 H NMR (300MHz, CDCl3, 23℃) δ1.30 (6H, d), 3.58 (1H, hept), 7.00 (1H, dd), 7.82 (1H, dd), 8.52 (1H, dd).

[0648] Intermediate 110: 2-Isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0649] [ka]

[0650] n-BuLi (3.21 mL, 8.04 mmol, 2.5 M in hexane) was added dropwise to a mixture of intermediate 109 (1.34 g, 6.70 mmol) and pinacol isopropylboronic acid (1.64 mL, 8.04 mmol) in THF (23 mL) cooled to -78°C over 5 minutes under N2. The resulting mixture was stirred at -78°C for 1 hour, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into brine (50 mL) and extracted with SiO2 (4 × 75 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-40% SiO2 in petroleum ether) to obtain the title compound (1.20 g, 73%) as a yellow oil; MS m / z(ES+)[M+H] + = 248.1.

[0651] Intermediate 111: Methyl 3-(propa-1-en-2-yl)pyridine-4-amine

[0652] [ka]

[0653] Pd(dppf)Cl2 (4.23 g, 5.78 mmol) was added to a mixture of 1,4-dioxane (200 mL) and water (50 mL) containing 3-bromopyridine-4-amine (10.0 g, 57.8 mmol), isopropenylboronic acid pinacol ester (9.71 g, 57.8 mmol), and K2CO3 (24.0 g, 173 mmol) under N2 conditions. The resulting mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with HCl (1 L) and washed with water (2 × 500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography in silica (gradient: 0-50% toluene in DCM) to obtain the title compound (5.00 g, 65%) as a black oily substance; MS m / z(ES+)[M+H] + =135.2; 1 H NMR (300MHz, CDCl3, 24℃) δ2.01 (3H, s), 4.90-5.08 (1H, m), 5.19-5.38 (1H, m), 5.72 (2H, s), 6.61 (1H, s), 8.01 (2H, br s).

[0654] Intermediate 112: 3-Isopropylpyridine-4-amine

[0655] [ka]

[0656] Pd / C (3.97 g, 3.73 mmol, 10%) was added to a mixture of intermediate 111 (5.00 g, 37.3 mmol) in MeOH (100 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure to obtain the title compound (5.00 g, 99%) as a gray oily substance; MS m / z(ES+)[M+H] + =137.1; 1 H NMR (300MHz, CDCl3, 24℃) δ1.30 (6H, d), 2.84 (1H, hept), 4.30 (2H, s), 6.50 (1H, d), 8.08 (1H, d), 8.19 (1H, s).

[0657] Intermediate 113: 4-bromo-3-isopropylpyridine

[0658] [ka]

[0659] t-BuONO (5.40 mL, 45.0 mmol) was added to intermediate 112 (4.09 g, 30.0 mmol) in MeOH (100 mL) under N2. The mixture was stirred at room temperature for 10 minutes, after which CuBr2 (7.37 g, 33.0 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated NaHCO3 aqueous solution (200 mL) and extracted with SiO2 (3 × 150 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-20% SiO2 in petroleum ether) to obtain the title compound (1.00 g, 17%) as a pale yellow liquid; MS m / z(ES+)[M+H] + =199.9 / 201.9; 1 H NMR (400MHz, CDCl3, 0℃) δ1.34 (6H, d), 3.37 (1H, hept), 7.53 (1H, s), 7.88-8.97 (2H, m).

[0660] Intermediate 114: 3-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0661] [ka]

[0662] n-BuLi (3.54 mL, 8.84 mmol, 2.5 M in hexane) was added dropwise at -78°C to a mixture of intermediate 113 (1.36 g, 6.80 mmol) and pinacol isopropylboronic acid (1.80 mL, 8.84 mmol) in THF (25 mL) under N2. The resulting mixture was stirred at -78°C for 1 hour, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into brine (50 mL) and extracted with RINKAN (4 × 75 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-40% RINKAN in petroleum ether) to obtain the title compound (500 mg, 30%) as a white solid; MS m / z(ES+)[M+H] + =248.1; 1 H NMR (400MHz, CDCl3, 0℃) δ1.31 (6H, d), 1.38 (12H, s), 3.58 (1H, hept), 7.56 (1H, d), 8.45 (1H, d), 8.61 (1H, s).

[0663] Intermediate 115: Methyl 4-((tert-butoxycarbonyl)(methyl)amino)butanoate

[0664] [ka]

[0665] Boc2O (27.5 g, 126 mmol) was added to a mixture of methyl 4-(methylamino)butanoate (15.0 g, 114 mmol) and DMAP (4.19 g, 34.3 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (50 mL) and washed with brine (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to obtain the title compound (20.6 g, 78%) as a yellow oil; MS m / z(ES+)[M+H] + = 232.1.

[0666] Intermediate 116: tert-butylmethyl(5-methyl-4-oxohexyl)carbamate

[0667] [ka]

[0668] Isopropyl magnesium chloride (130 mL, 259 mmol, 2 M in THF) was added dropwise to intermediate 115 (20.0 g, 86.5 mmol) in THF (80 mL) under N2 at -78°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-20% siRNA in petroleum ether) to obtain the title compound (5.00 g, 24%) as a yellow oil; MS m / z(ES+)[M+H] + =244.1; 1 H NMR (300MHz, DMSO-d6, 22℃) δ1.00(6H,d),1.39(9H,s),1.57-1.70(2H,m),2.44(2H,t),2.53-2.67(1H,m),2.74(3H,s),3.12(2H,t).

[0669] Intermediate 117: rel-(1R,2R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.0]heptane-2-carboxylic acid

[0670] [ka]

[0671] Boc2O (170 mg, 0.78 mmol) was added to a mixture of rel-(1S,2S,5R)-3-azabicyclo[3.2.0]heptane-2-carboxylic acid (100 mg, 0.71 mmol) and saturated NaHCO3 aqueous solution (2 mL) in 1,4-dioxane (2 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was acidified with HCl aqueous solution (1 M, 20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (171 mg, 100%) as a colorless gum; MS m / z ES+[M+H-tBu] + 186.1; 1 H NMR(400MHz,DMSO-d6,22℃)δ1.36-1.47(9H,m),1.60-1.84(2H,m),2.09-2. 31(2H,m),2.83-3.00(2H,m),3.35-3.45(2H,m),4.09(1H,d),12.61(1H,br s).

[0672] Intermediate 118: 4-(propa-1-en-2-yl)pyridine-3-amine

[0673] [ka]

[0674] Pd(dppf)Cl2 (4.27 g, 5.83 mmol) was added under N2 to a mixture of 1,4-dioxane (200 mL), 4-chloropyridine-3-amine (15.0 g, 117 mmol), isopropenylboronic acid pinacol ester (21.6 g, 128 mmol), and K2CO3 (48.4 g, 350 mmol) in water (50 mL). The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (2 × 125 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 50-100% ethyl acetate in petroleum ether) to obtain the title compound (12.9 g, 82%) as a yellow oil; MS m / z(ES+)[M+H] + = 135.3.

[0675] Intermediate 119: 4-Isopropylpyridine-3-amine

[0676] [ka]

[0677] Pd / C (8.72 g, 8.20 mmol, 10%) was added to intermediate 118 (11.0 g, 82.0 mmol) in MeOH (150 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (7.00 g) as a yellow oil; MS m / z(ES+)[M+H] + =137.1; 1 H NMR (300MHz, CDCl3, 25℃) δ1.28 (6H, d), 2.90 (1H, hept), 3.64 (2H, s), 7.05 (1H, d), 8.03 (1H, d), 8.06 (1H, s).

[0678] Intermediate 120: 3-bromo-4-isopropylpyridine

[0679] [ka]

[0680] t-BuONO (6.60 mL, 55.1 mmol) was added dropwise at 0°C to a mixture of intermediate 119 (5.00 g, 36.7 mmol, th.) and CuBr2 (7.90 g, 55.1 mmol) in MeCN (300 mL) under N2. The resulting mixture was stirred at 60°C for 16 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: petroleum ether: 0-30% ethyl acetate) to obtain the title compound (1.50 g, 20%) as a yellow oil; MS m / z(ES+)[M+H] + = 200.0 / 202.0.

[0681] Intermediate 121: 4-Isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0682] [ka]

[0683] n-BuLi (3.12 mL, 7.80 mmol, 2.5 M in hexane) was added dropwise at -78°C to a mixture of intermediate 120 (1.30 g, 6.50 mmol) and pinacol isopropylboronic acid (1.59 mL, 7.80 mmol) in THF (20 mL) under N2. The resulting mixture was stirred at -78°C for 1 hour, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into brine (25 mL) and extracted with RINKAN (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness to obtain the crude title compound (1.60 g) as an orange oil; MS m / z(ES+)[M+H] + = 248.1.

[0684] Intermediate 122: 4-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole

[0685] [ka]

[0686] n-BuLi (2.60 mL, 6.50 mmol, 2.5 M in hexane) was added dropwise at -78°C to a mixture of 5-bromo-4-isopropylthiazole (1.03 g, 5.00 mmol) and isopropylboronic acid pinacol (1.43 mL, 7.00 mmol) in THF (20 mL) under N2 conditions. The resulting mixture was stirred at -78°C for 1 hour, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into brine (25 mL) and extracted with ₹ (200 mL). The organic layer was dried over MgSO4, filtered, and concentrated to dryness to obtain the title compound (1.03 g, 81%) as a pale yellow oil, which was used directly in the next step; MS m / z(ES+)[M+H] + =254.1; 1 H NMR (400MHz, CDCl3) δ1.32(6H,d),1.35(12H,s),3.63-3.79(1H,m),8.90(1H,s).

[0687] Intermediate 123: 2-(3-bromopyridine-2-yl)propan-2-ol

[0688] [ka]

[0689] MeMgBr (4.63 mL, 13.9 mmol, 3 M in THF) was added to methyl 3-bromopicolinate (1.00 g, 4.63 mmol) in THF (25 mL) under N2 conditions at -78°C. The resulting mixture was stirred at -78°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (200 mL) and washed with saturated NH4Cl (3 × 75 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-3% RINKAN in petroleum ether) to obtain the title compound (830 mg, 83%) as a yellow solid; MS m / z(ES+)[M+H]+ = 216.2 / 218.2.

[0690] Intermediate 124: 3-bromo-2-(2-fluoropropan-2-yl)pyridine

[0691] [ka]

[0692] BAST (2.13 mL, 11.5 mmol) was added to intermediate 123 (830 mg, 3.84 mmol) in DCM (25 mL) under N2. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (200 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography with silica (gradient: 0-3% ethylethanol in petroleum ether) to obtain the title compound (560 mg, 67%) as a yellow solid; MS m / z(ES+)[M+H] + =217.9; 1 H NMR (300MHz, DMSO-d6, 26℃) δ1.73 (3H, s), 1.80 (3H, s), 7.32 (1H, dd), 8.12 (1H, dd), 8.53 (1H, d).

[0693] Intermediate 125: 2-(2-fluoropropan-2-yl)-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-pyridine

[0694] [ka]

[0695] n-BuLi (1.23 mL, 3.08 mmol, 2.5 M in hexane) was added dropwise at -78°C to a mixture of intermediate 124 (560 mg, 2.57 mmol) and pinacol isopropylboronic acid (629 μL, 3.08 mmol) in THF (10 mL) under N2. The resulting mixture was stirred at -78°C for 1 hour, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into brine (25 mL) and extracted with ₹ (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness to obtain the title compound (500 mg, 73%) as a yellow oil; MS m / z(ES+)[M+H] + =266.2; 1 H NMR (400MHz, DMSO-d6, 25℃) δ1.28 (12H, s), 1.65 (6H, d), 7.27 (1H, dd), 7.74 (1H, dd), 8.47-8.59 (1H, m).

[0696] Intermediate 126: 5-Fluoro-2-iodo-N,N-bis(propan-2-yl-d7)benzamide

[0697] [ka]

[0698] T3P (3.87 mL, 6.51 mmol, 50% in DCM) was added at 0°C to a stirred solution of 5-fluoro-2-iodobenzoic acid (1.15 g, 4.34 mmol), bis(propan-2-yl-d7)amine (697 μL, 4.34 mol), and DIPEA (3.02 mL, 17.4 mmol) in toluene (5 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (75 mL) and stirred for 30 minutes. The organic solvent was removed under reduced pressure. The formed precipitate was filtered, washed with water, and dried under reduced pressure to obtain the title compound (100 mg, 6%) as a white solid; MS m / z(ES+)[M+H] + =364.0; 1 H NMR (400MHz, DMSO-d6, 22℃) δ7.03 (1H, td), 7.20 (1H, dd), 7.87 (1H, dd).

[0699] Intermediate 127: 2-((4-bromopyridine-3-yl)amino)-5-fluoro-N,N-bis(propan-2-yl-d7)benzamide

[0700] [ka]

[0701] Intermediate 126 (100 mg, 0.28 mmol) was added to a mixture of 4-bromopyridine-3-amine (57.2 mg, 0.33 mmol), XantPhos (15.9 mg, 0.03 mmol), and Cs2CO3 (269 mg, 0.83 mmol) in 2-MeTHF (1 mL). The resulting suspension was purged with N2 for 5 minutes, and then Pd2dba3·CHCl3 (14.3 mg, 0.01 mmol) was added. The mixture was further purged with N2 for 5 minutes and stirred overnight at 80°C. The reaction mixture was diluted with ₹ (25 mL) and sequentially washed with 2% N-acetylcysteine ​​aqueous solution (2 × 25 mL) and saturated NaHCO3 aqueous solution (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-100% toluene in heptane) to obtain the title compound (65.0 mg, 58%) as a colorless oil; MS m / z(ES+)[M+H] + =408.0 / 409.9; 1 H NMR (400MHz, DMSO-d6, 22℃) δ6.95(1H,s),7.19(1H,dd),7.25(1H,td),7.35(1H,dd),7.59(1H,d),7.87(1H,d),8.08(1H,s).

[0702] Intermediate 128 (mixture of atropisomers): tert-butyl 4-(1-(2-(bis(propan-2-yl-d7)carbamoyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-1-carboxylate

[0703] [ka]

[0704] CuO (10.8 mg, 0.14 mmol) was added to a deoxygenated mixture of intermediates 84 (129 mg, 0.48 mmol), 127 (65.0 mg, 0.16 mmol), and Cs2CO3 (72.6 mg, 0.22 mmol) in DMSO (1 mL). The resulting mixture was purged with N2 for a further 3 minutes and stirred overnight at 100°C. The reaction mixture was diluted with SiO2 (5 mL) and washed with water (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% SiO2 in heptane) to obtain the title compound (80.0 mg, 87%) as a brown dry film; MS m / z(ES+)[M+H] + =579.4; 1 H NMR(400MHz,DMSO-d6,22℃)δ1.21-1.31(1H,m),1.36-1.52(10H,m),1.81(2H,br s),3.02(2H,br s),3.37-3.53(1H,m),3.80-4.10(2H,m),7.41-7.63(2H,m),7.64-7.79(1H,m),7.93(1H,br s),8.37(2H,br s).

[0705] Intermediate 129 (mixture of atropisomers): 5-fluoro-2-(2-methyl-3-(piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N,N-bis(propan-2-yl-d7)benzamide

[0706] [ka]

[0707] TFA (1 mL) was added to a solution of intermediate 128 (80.0 mg, 0.14 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (5 mL) and quenched with saturated NaHCO3 aqueous solution (5 mL). The organic layer was separated by passing it through a phase separator and concentrated under reduced pressure to obtain the crude product, and the aqueous layer was extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound, which was used directly in the next step (Example 59a).

[0708] Intermediate 130: tert-butyl(2S,4RS)-4-cyano-2-methylpiperidine-1-carboxylate

[0709] [ka]

[0710] KOtBu (10.4 g, 92.2 mmol) was added at -10°C to a solution of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (9.83 g, 46.1 mmol) and tert-butyl(S)-2-methyl-4-oxopiperidine-1-carboxylate (6.00 g, 30.7 mmol) in DME (184 mL) and EtOH (3.6 mL). The resulting mixture was stirred at -10°C for 2 hours, then at room temperature overnight. The reaction mixture was diluted with ELISA (30 mL) and sequentially washed with water (30 mL) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-60% ELISA in heptane) to obtain the title compound (1.15 g, 17%) as a yellow oil; MS m / z(ES+)[M-Boc] + =125.2; 1H NMR(400MHz,DMSO-d6,22℃)δ1.06(3H,d),1.39(9H,d),1.44-1.52(1H,m),1.72(1H,td),1.85 (1H, ddt), 1.90-1.98 (1H, m), 2.81 (1H, td), 3.08 (1H, tt), 3.81 (1H, ddd), 4.25-4.35 (1H, m).

[0711] Intermediate 131: tert-butyl(2S,4RS)-4-acetyl-2-methylpiperidine-1-carboxylate

[0712] [ka]

[0713] MeMgBr (6.74 mL, 20.2 mmol, 3 M in Et2O) was added dropwise to intermediate 130 (2.27 g, 10.1 mmol) in DME (30 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with aqueous HCl (1 M, 10 mL), diluted with saturated NH4Cl (100 mL), and extracted with SiO2 (2 × 100 mL). The combined organic matter was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by normal-phase flash chromatography in silica (gradient: 0-75% SiO2 in heptane) to obtain the title compound (1.62 g, 66%) as a pale yellow oil; MS m / z(ES+)[M-tBu] + =186.1; 1 H NMR(400MHz,DMSO-d6,22℃)δ1.08(3H,dd),1.13-1.26(1H,m),1.39(9H,s),1.41-1.53(1H,m),1.63-1.74(1H,m ),1.74-1.89(1H,m),2.11(3H,s),2.65-2.76(1H,m),2.76-2.92(1H,m),3.78-3.91(1H,m),4.25-4.45(1H,m).

[0714] Intermediate 132: tert-butyl(2S,4RS)-2-methyl-4-(3-oxobutanoyl)piperidine-1-carboxylate

[0715] [ka]

[0716] NaH (635 mg, 15.9 mmol, 60% dispersion in mineral oil) was added to intermediate 131 (1.92 g, 7.94 mmol) in THF (25 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour, and then toluene (1.55 mL, 15.9 mmol) was added. The resulting mixture was stirred at 55°C for 3 hours. The reaction mixture was quenched with water (150 mL) and extracted with toluene (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by normal-phase flash chromatography in silica (gradient: 0-40% toluene in heptane) to obtain the title compound (1.68 g, 75%) as a yellow gum; MS m / z(ES+)[M-tBu] + =228.1; 1 H NMR(400MHz,DMSO-d6,22℃)δ1.02-1.14(3H,m),1.15-1.35(1H,m),1.39(9H,d),1.42-1.59(1H,m),1.61-1.98(2H,m),2.05(2H ,s),2.13(1H,s),2.56-2.68(1H,m),2.73-2.95(1H,m),3.73-3.79(1H,m),3.80-3.91(1H,m),4.24-4.44(1H,m),5.76(1H,s).

[0717] Intermediate 133 (mixture of atropisomers): tertN-butyl(2S,4RS)-4-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-2-methylpiperidine-1-carboxylate

[0718] [ka]

[0719] CuCl (67.8 mg, 0.69 mmol) was added to a deoxygenated mixture of intermediate 132 (1.29 g, 4.57 mmol), intermediate 90 (900 mg, 2.28 mmol), and Cs2CO3 (1.12 g, 3.42 mmol) in DMF (26 mL). The resulting mixture was purged with N2 for 1 minute and stirred overnight at 100°C. The reaction mixture was filtered and washed with SiO (100 mL). The filtrate was sequentially washed with a mixture of water and brine (100 mL, 1:1) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 20-100% SiO in heptane) to obtain the title compound (1.00 g, 76%) as a brown dry film; MS m / z(ES+)[M+H] + = 579.4.

[0720] Intermediate 134 (mixture of atrop isomers): 5-fluoro-N,N-diisopropyl-2-(2-methyl-3-((2S,4RS)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0721] [ka]

[0722] FA (10 mL) was added to intermediate 133 (1.00 g, 1.46 mmol, th.). The resulting mixture was stirred at room temperature for 3 hours. The mixture was poured into saturated NaHCO3 aqueous solution (100 mL), and solid NaHCO3 was added until the pH > 8. The aqueous layer was diluted with saturated NaOH (50 mL, 2 M), saturated with solid NaCl, and then extracted with DCM (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-25% 0.7 M NH3 in MeOH in DCM) to obtain the title compound (561 mg, 80%) as a pale yellow dry film; MS m / z(ES+)[M+H] + =479.3; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.34-0.45(3H,m),0.49-0.74(3H,m),1.00-1.1 0(3H,m),1.13-1.29(6H,m),1.69-1.87(1H,m),1.87-2.10(3H,m),2.53(3H,s ),2.75-3.12(3H,m),3.18-3.26(1H,m),3.28-3.58(1H,m),3.61-3.81(2H,m) ,7.43-7.63(2H,m),7.65-7.78(1H,m),7.78-7.96(1H,m),8.23-8.40(2H,m).

[0723] Intermediate 135: N-ethyl-5-fluoro-2-iodo-N-isopropylbenzamide

[0724] [ka]

[0725] T3P (28.7 mL, 45.1 mmol, 50% in DCM) was added to a stirred solution of 5-fluoro-2-iodobenzoic acid (10.0 g, 37.6 mmol) and N-ethylpropan-2-amine (22.8 mL, 188 mol) in DCM (104 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 aqueous solution. The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-100% ethylbenzoate in cyclohexane) to obtain the title compound (6.54 g, 52%) as a white solid; MS m / z(ES+)[M+H] + =336.0; 1 H NMR(400MHz, CDCl3, 22℃) δ1.02-1.12(3H,m),1.27-1.37(6H,m),2.95-3.22(1H,m ), 3.29 (1H, dq), 3.59 (1H, ddt), 6.77-6.85 (1H, m), 6.94 (1H, ddd), 7.75 (1H, ddd).

[0726] Intermediate 136: 2-((4-bromopyridine-3-yl)amino)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0727] [ka]

[0728] Pd2dba3·CHCl3 (154 mg, 0.15 mmol) was added to a deoxygenated mixture of intermediate 135 (1.00 g, 2.98 mmol), 4-bromopyridine-3-amine (619 mg, 3.58 mmol), XantPhos (173 mg, 0.30 mmol), and Cs2CO3 (2.92 g, 8.95 mmol) in 2-MeTHF (11 mL). The mixture was purged with N2 and stirred overnight at 80°C. The reaction mixture was filtered and diluted with ₹ (100 mL). The organic layer was sequentially washed with 2% (w / w%) aqueous solution of N-acetylcysteine ​​(100 mL), saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography in silica (gradient: 0-100% ethyl acetate in heptane). Appropriate fractions were combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and sequentially washed with 2% aqueous solution of N-acetylcysteine ​​(50 mL), saturated aqueous solution of NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (599 mg, 53%) as a beige solid; MS m / z(ES+)[M+H] + =380.1 / 382.1; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.93(3H,t),0.97-1.13(6H,m),3.08-3.31(2H,m) ,3.66-3.84(1H,m),7.05-7.33(4H,m),7.59(1H,d),7.88(1H,d),8.07(1H,s).

[0729] Intermediate 137 (mixture of atrop isomers): tert-butyl(2S,4RS)-4-(1-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-2-methylpiperidine-1-carboxylate

[0730] [ka]

[0731] CuCl (46.7 mg, 0.47 mmol) was added to a deoxygenated mixture of intermediate 132 (891 mg, 3.15 mmol), intermediate 136 (598 mg, 1.57 mmol), and Cs2CO3 (769 mg, 2.36 mmol) in DMF (18 mL). The resulting mixture was purged with N2 for a further 1 minute and stirred overnight at 100°C. The reaction mixture was filtered and washed with SiO2 (100 mL). The filtrate was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 20-100% SiO2 in heptane) to obtain the title compound (499 mg, 56%) as a brown dry film; MS m / z(ES+)[M+H] + = 565.3.

[0732] Intermediate 138 (mixture of atrop isomers): N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2S,4RS)-2-methylpiperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0733] [ka]

[0734] FA (5 mL) was added to intermediate 137 (499 mg, 0.74 mmol, th.). The resulting mixture was stirred at room temperature for 3 hours. The mixture was poured into saturated NaHCO3 aqueous solution (100 mL), and solid NaHCO3 was added until the pH was >8. The aqueous layer was diluted with saturated NaOH (50 mL, 2 M), saturated with solid NaCl, and then extracted with DCM (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-25% 0.7 M NH3 in MeOH in DCM) to obtain the title compound (321 mg, 93%) as a pale yellow dry film; MS m / z(ES+)[M+H] + =465.3;1 H NMR(400MHz,DMSO-d6,22℃)δ0.09-0.23(1H,m),0.28-0.47(4H,m),0.51-0.79(2H,m ),0.93-1.15(6H,m),1.47-1.70(1H,m),1.72-2.02(3H,m),2.41-2.48(1H,m),2.51 -2.57(2H,m),2.66-3.03(3H,m),3.05-3.15(1H,m),3.18-3.30(1H,m),3.41-3.74( 2H,m),7.51-7.65(2H,m),7.70-7.80(1H,m),7.80-7.90(1H,m),8.25-8.38(2H,m).

[0735] C. Final compound Example 1: 5-Fluoro-N,N-diisopropyl-2-(3-((S)-1-(((1r,4S)-4-(methylsulfonamide)-cyclohexyl)methyl)pyrrolidin-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide

[0736] [ka]

[0737] Intermediate 104 (33.6 mg, 0.09 mmol) was added to a suspension of intermediate 5a (99.3 mg, 0.10 mmol th.) and K2CO3 (64.3 mg, 0.47 mmol) in MeCN (1 mL). The resulting mixture was stirred overnight at 80°C. The reaction mixture was diluted with water (10 mL) and extracted with siRNA (3 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM). Appropriate fractions were pooled and concentrated under reduced pressure. The product was lyophilized from MeCN / H2O to obtain the title compound (26.7 mg, 44%) as an orange solid; MS m / z(ES+)[M+H] + = 626.3. 1H NMR(400MHz,DMSO-d6,22℃)δ0.28(3H,br s),0.75(3H,br s),0.83-0.95(2H,m),0.99(3H,d),1.10-1.25(2H,m),1.33(3H,t),1.72-1.92(4H,m),1.93-2.13(2H,m),2.18(2H,br s),2.30-2.46(2H,m),2.55-2.69(1H,m),2.88(3H,br s),2.94-3.08(2H,m),3.18-3.27(1H,m),3.31(1H,br s),3.44-3.56(1H,m),3.80(1H,br s),6.94-7.03(1H,m),7.48-7.58(2H,m),7.78-7.88(1H,m),8.14(1H,d),8.37(1H,d),8.56(1H,s),8.63(1H,s).

[0738] Example 2: 2-(3-((S)-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide

[0739] [ka]

[0740] Step a) tert-butyl(1R,3S,4S)-3-((S)-3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)pyrroridine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0741] [ka]

[0742] Intermediate 5b (35.6 mg, 0.08 mmol) was added to a solution of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (21.7 mg, 0.09 mmol), EDC (18.8 mg, 0.10 mmol), HOBt (15.0 mg, 0.10 mmol), and DIPEA (28.5 μl, 0.16 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (43.3 mg, 80%) as an orange gum; MS m / z(ES+)[M+H] + = 660.4.

[0743] Step b) 2-(3-((S)-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide (Example 2) TFA (1 mL) was added to a solution of tert-butyl(1R,3S,4S)-3-((S)-3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyrrolidine-3-carbonyl)pyrrolidine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (43.3 mg, 0.07 mmol) from step a) in DCM (5 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC, preparative method A (gradient: 0-50%). Appropriate fractions were pooled, diluted with aqueous NaOH (2 M), and extracted with ELISA (2 × 20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The product was freeze-dried from MeCN / H2O to obtain the title compound (27.8 mg, 76%) as a white solid; MS m / z(ES+)[M+H]+ =560.3; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.27(3H,br s),0.74(3H,br s),0.95-1.02(3H,m),1.15-1.19(1H,m),1.22-1.3(2H,m),1.33(3H,d),1.36-1.42 (1H,m),1.45-1.53(2H,m),2.04-2.31(2H,m),2.55(1H,s),3.19-3.31(2H,m),3.41 -3.58(4H,m),3.60-3.69(1H,m),3.71-3.79(1H,m),3.85-4.11(2H,m),7.52-7.59( 2H,m),7.83-7.89(1H,m),8.11-8.16(1H,m),8.37-8.41(1H,m),8.63-8.73(2H,m).

[0744] Example 3: 2-(3-((R)-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide

[0745] [ka]

[0746] Step a) tert-butyl(1R,3S,4S)-3-((R)-3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)pyrrolidine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0747] [ka]

[0748] Intermediate 8a (73.0 mg, 0.11 mmol th.) was added to a solution of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (30.3 mg, 0.13 mmol), EDC (26.3 mg, 0.14 mmol), HOBt (21.0 mg, 0.14 mmol), and DIPEA (40.0 μl, 0.23 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography with silica (gradient: 0-10% MeOH in DCM) to obtain the title compound (67.4 mg, 89%) as an orange, gum-like substance; MS m / z(ES+)[M+H] + = 660.4.

[0749] Step b) 2-(3-((R)-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide (Example 3) TFA (1 mL) was added to a solution of tert-butyl(1R,3S,4S)-3-((R)-3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyrrolidine-3-carbonyl)pyrrolidine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (67.4 mg, 0.10 mmol) from step a) in DCM (5 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC, preparative method A (gradient: 0-75%). Appropriate fractions were pooled, diluted with saturated NaHCO3 aqueous solution (20 mL), and extracted with ELISA (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was freeze-dried from MeCN / H2O to obtain the title compound (30.4 mg, 53%) as an off-white solid; MS m / z(ES+)[M+H] + =560.3; 1 H NMR(400MHz,DMSO-d6,22℃)δ0.27(3H,br s),0.75(3H,br s),0.99(3H,dd),1.16-1.25(2H,m),1.28-1.36(4H,m),1.36-1.45(2H,m) ,1.46-1.55(2H,m),2.01-2.34(3H,m),3.20-3.26(1H,m),3.40-3.58(4H,m ),3.62-3.70(1H,m),3.72-3.80(1H,m),3.87-4.11(2H,m),7.51-7.59(2H ,m),7.82-7.89(1H,m),8.14(1H,d),8.37-8.41(1H,m),8.63-8.72(2H,m).

[0750] Example 4: 5-Fluoro-N,N-diisopropyl-2-(3-((R)-1-(((1r,4R)-4-(methylsulfonamide)-cyclohexyl)methyl)pyrrolidine-3-carbonyl)-1H-pyrrol[2,3-c]pyridine-1-yl)benzamide

[0751] [ka]

[0752] A suspension of intermediate 8b (152 mg, 0.18 mmol th.) and K2CO3 (122 mg, 0.88 mmol) in MeCN (1 mL) was stirred at room temperature for 30 minutes, after which intermediate 104 (63.9 mg, 0.18 mmol) was added. The resulting mixture was stirred overnight at 80°C. The reaction mixture was diluted with water (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC, preparative method A (gradient: 0-50%). Appropriate fractions were pooled, diluted with saturated NaHCO3 aqueous solution, and extracted with siRNA (2 × 20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was freeze-dried from MeCN / H2O to obtain the title compound (35.9 mg, 33%) as an off-white solid; MS m / z(ES+)[M+H] + =...

Claims

1. Equation (I): 【Chemistry 1】 A compound having the structure of or a pharmaceutically acceptable salt thereof, wherein the formula is R １ However, selected from the group consisting of hydrogen and methyl, R ２ However, it is hydrogen or fluoro, R ３ However, it is hydrogen or fluoro, R ４ but, (a)-C(O)NR ５ R ６ 、 (b) Phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, cyano, C １～４ -alkyl, halo-C １～４ -alkyl, C ３～４ -cycloalkyl, and halo-C ３～４ -cycloalkyl, and (c) A 5 or 6-membered ring heteroaryl having 1, 2, or 3 ring atoms independently selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon, wherein the fluoro, cyano, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C ３～４ -Cycloalkyl and halo-C ３～４ - Selected from the group consisting of 5- or 6-membered ring heteroaryls, which are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyls, R ５ and R ６ However, C １～４ -Alkyl and halo-C １～４ - Selected independently of alkyl, or R ５ and R ６ However, together with the nitrogen atom to which they are bonded, they form a 5-7 membered heterocycline, wherein the heterocycline is (i) a saturated monocyclic ring, (ii) has one or two ring atoms independently selected from nitrogen and oxygen, and the remaining ring atom is carbon, and (iii) C １～４ -Alkyl and halo-C １～４ - It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups. X is -C(R ９ ) - or -N-, R ９ However, it is selected from the group consisting of hydrogen, fluorine, and methyl, A is selected from the following group: 【Chemistry 2】 Each R Ａ The substituents are fluoro and C １～４ - Selected arbitrarily and independently from the group consisting of alkyl groups, r is 0, 1, or 2, s is 0, 1, 2, or 3, t is 0, 1, 2, 3, or 4, u is 0, 1, 2, 3, 4, or 5, R １０ However, C １～１０ -alkyl, -CH ２ R １１ , or -C(O)R １２ Selected from the group consisting of the above C １～１０ - Alkyl group contains one or more -NR １３ R １４ It has been replaced with, R １１ However, C １～４ -alkyl, -NR １５ R １６ , and -N(R １７ ) S(O) ２ R １８ A cyclohexyl molecule that is optionally substituted with one or more substituents independently selected from the group consisting of the following: R １２ However, the heterocyclyl is a 5-10 membered ring heterocyclyl, wherein the heterocyclyl is (i) a saturated or partially saturated monocyclic, bicyclic, or spirocyclic ring system, (ii) has one or two nitrogen ring atoms and the remaining ring atoms are carbon, and (iii) fluoro, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C １～４ -Alkenil, -OR １９ , -NR ２０ R ２１ , and -N(R ２２ ) S(O) ２ R ２３ It is optionally substituted with one or more substituents independently selected from the group consisting of the following: R １３ and R １４ However, C １～６ - Alkyl and C １～６－ Alkoxy-C １～６ - Independently selected from the group consisting of alkyls, R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , and R ２３ However, hydrogen and C １～４ - A compound or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of alkyl groups.

2. The aforementioned compound is of formula (I-A): 【Transformation 3】 It has a structure, In the formula, R ２ , R ３ , R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is as defined in claim 1.

3. R ３ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is fluoro.

4. X is -C(R ９ ) - The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. R ９ The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

6. R ２ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.

8. R ４ However, -C(O)NR ５ R ６ The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. R ５ and R ６ However, C １～４ -Alkyl and halo-C １～４ - A compound according to claim 8, or a pharmaceutically acceptable salt thereof, independently selected from alkyl groups.

10. R ５ and R ６ However, together with the nitrogen atom to which they are bonded, they form a 5-7 membered heterocycline, wherein the heterocycline is (i) a saturated monocyclic ring, (ii) has one or two ring atoms independently selected from nitrogen and oxygen, and the remaining ring atom is carbon, and (iii) C １～４ -Alkyl and halo-C １～４ - The compound according to claim 8 or a pharmaceutically acceptable salt thereof, which is optionally substituted with one to three substituents independently selected from the group consisting of alkyl groups.

11. R ４ However, it is a 5 or 6-membered ring heteroaryl having 1, 2, or 3 ring atoms independently selected from nitrogen, oxygen, and sulfur, with the remaining ring atom being carbon, and the heteroaryl is fluoro, cyano, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C ３～４ -Cycloalkyl and halo-C ３～４ - The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which is optionally substituted with one to three substituents independently selected from the group consisting of cycloalkyl groups.

12. R ４ is (a)-C(O)NR ５ R ６ ,and (b) A 5 or 6-membered ring heteroaryl having 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atom being carbon, and being fluoro, cyano, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C ３～４ -Cycloalkyl and halo-C ３～４ - Selected from the group consisting of 5- or 6-membered ring heteroaryls, which are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyls, R ５ and R ６ are each independently selected from C １～４ -alkyl and halo-C １～４ -alkyl, or R ５ and R ６ together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclyl, said heterocyclyl being (i) a saturated monocyclic ring, (ii) having one or two ring atoms independently selected from nitrogen and oxygen, the remaining ring atoms being carbon, and (iii) optionally substituted with 1 to 3 substituents independently selected from the group consisting of C １～４ -alkyl and halo-C １～４ -alkyl, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein r, s, t, and u are 0.

14. A, 【Chemistry 4】 The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. R １０ However, one or more -NR １３ R １４ C is replaced by １～１０ -It is alkyl, R １３ and R １４ However, C １～６ - Alkyl and C １～６－ Alkoxy-C １～６ - A compound according to any one of claims 1 to 14, independently selected from the group consisting of alkyl groups, or a pharmaceutically acceptable salt thereof.

16. R １０ However, -C(O)R １２ And, R １２ However, the heterocyclyl is a 5-10 membered ring heterocyclyl, wherein the heterocyclyl is (i) a saturated or partially saturated monocyclic, bicyclic, or spirocyclic ring system, (ii) has one or two nitrogen ring atoms and the remaining ring atoms are carbon, and (iii) fluoro, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C １～４ -Alkenil, -OR １９ , -NR ２０ R ２１ , and -N(R ２２ ) S(O) ２ R ２３ It is optionally substituted with one or more substituents independently selected from the group consisting of the following: R １９ , R ２０ , R ２１ , R ２２ , and R ２３ However, hydrogen and C １～４ - A compound according to any one of claims 1 to 14, independently selected from the group consisting of alkyl groups, or a pharmaceutically acceptable salt thereof.

17. The aforementioned R １２ The heterocycline, 【Transformation 5】 Selected from the group consisting of, The aforementioned R １２ The heterocyclyl is fluoro, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C １～４ -Alkenil, -OR １９ , -NR ２０ R ２１ , and -N(R ２２ ) S(O) ２ R ２３ It is optionally substituted with one or more substituents independently selected from the group consisting of R １９ , R ２０ , R ２１ , R ２２ , and R ２３ However, hydrogen and C １～４ - A compound according to claim 16, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of alkyl groups.

18. The aforementioned R １２ The heterocycline, 【Transformation 6】 It is fluoro, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C １～４ -Alkenil, -OR １９ , -NR ２０ R ２１ , and -N(R ２２ ) S(O) ２ R ２３ It is optionally substituted with one or more substituents independently selected from the group consisting of R １９ , R ２０ , R ２１ , R ２２ , and R ２３ However, hydrogen and C １～４ - A compound according to claim 16, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of alkyl groups.

19. The aforementioned R １２ One or more heterocyclines １～４ - A compound according to any one of claims 16 to 18, or a pharmaceutically acceptable salt thereof, which is optionally substituted with an alkyl group.

20. The aforementioned R １２ The compound according to any one of claims 16 to 18 or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is optionally substituted with one or more methyl groups.

21. The aforementioned R １２ The heterocycline, 【Transformation 7】 A compound according to claim 16 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

22. The aforementioned compound, Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Having a structure selected from the group consisting of, In the formula, where applicable, R １ , R ４ , R ５ , R ６ , R １０ , R １１ , R １２ X, A, R Ａ ,r,s, andt are as defined in claim 1, R present in the structure of formulas I-54 to I-57 ４ The phenyl is fluoro, cyano, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C ３～４ -Cycloalkyl and halo-C ３～４ - It is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl groups. R present in the structure of formulas I-58 to I-69 ４ Pyrazolyl, pyridinyl, and pyrimidinyl are fluoro, cyano, and C １～４ -Alkyl, Halo-C １～４ - Alkyl, C ３～４ -Cycloalkyl and halo-C ３～４ - It is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl groups. R present in the structure of formula I-53 １１ The cyclohexyl in C １～４ -alkyl, -NR １５ R １６ , and -N(R １７ ) S(O) ２ R １８ It is optionally substituted with one or more substituents independently selected from the group consisting of the following: R present in the structure of formulas I-43 to I-52 １２ The heterocyclyl is fluoro, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C １～４ -Alkenil, -OR １９ , -NR ２０ R ２１ , and -N(R ２２ ) S(O) ２ R ２３ It is optionally substituted with one or more substituents independently selected from the group consisting of the following: R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , and R ２３ However, hydrogen and C １～４ - A compound according to claim 1, independently selected from the group consisting of alkyls, or a pharmaceutically acceptable salt thereof.

23. R １ However, it is methyl, r, s, and t are all 0. The aforementioned structure is selected from formulas I-43 to I-52. R present in the above structure １２ The heterocyclyl is fluoro, C １～４ -Alkyl, Halo-C １～４ - Alkyl, C １～４ -Alkenil, -OR １９ , -NR ２０ R ２１ , and -N(R ２２ ) S(O) ２ R ２３ It is optionally substituted with one or more substituents independently selected from the group consisting of the following: R １９ , R ２０ , R ２１ , R ２２ , and R ２３ However, hydrogen and C １～４ - A compound according to claim 22, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of alkyl groups.

24. R １ However, it is methyl, r, s, and t are all 0. The aforementioned structure is selected from formulas I-43 to I-52. R present in the above structure １２ The heterocyclyl is fluoro, C １～４ -Alkyl, Halo-C １～４ - Alkyl and C １～４ - The compound according to claim 22 or a pharmaceutically acceptable salt thereof, which is optionally substituted with one or more substituents independently selected from the group consisting of alkenyls.

25. The compound has the structure of formula I-5A, 【Transformation 8】 R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is as defined in claim 1.

26. The compound has the structure of formula I-33A, 【Chemistry 9】 R ４ , R １２ , R Ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein and t are as defined in claim 1.

27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein t is 0.

28. 5-Fluoro-N,N-diisopropyl-2-(3-((S)-1-(((1r,4S)-4-(methylsulfonamide)-cyclohexyl)-methyl)pyrrolin-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 1], 2-(3-((S)-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 2], 2-(3-((R)-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 3], 5-Fluoro-N,N-diisopropyl-2-(3-((R)-1-(((1r,4R)-4-(methylsulfonamide)cyclohexyl)-methyl)pyrroridine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 4], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 5], (S)-2-(3-(1-(2-azabicyclo[2.2.2]octane-3-carbonyl)azetidine-3-carbonyl)-1H-pyrrolo-[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 6], 5-Fluoro-2-(3-(1-((1S,3S,4S,5S)-5-Fluoro-2-azabicyclo[2.2.1]heptan-3-carbonyl)-azetidine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N,N-diisopropylbenzamide [Example 7], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 8], (S)-2-(3-(1-(2-azabicyclo[2.2.2]octane-3-carbonyl)azetidine-3-carbonyl)-1H-pyrrolo-[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 9], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-yl)(1-(4-fluoro-2-(2-isopropylpyridine-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 10], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-yl)(1-(4-fluoro-2-(3-isopropylpyridine-4-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone 1 / formic acid [Example 11], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-yl)(1-(4-fluoro-2-(4-isopropylthiazole-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone 1 / formic acid [Example 12], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-yl)(1-(4-fluoro-2-(2-(2-fluoropropan-2-yl)pyridine-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 13]; 2-(5-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-carbonyl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)-5-fluoro-N,N-diisopropylbenzamide 1 / formic acid [Example 14], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azetidine-3-carbonyl)-7-fluoro-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 15], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 16], 5-Fluoro-N,N-diisopropyl-2-(3-(1-(((1r,4r)-4-(methylsulfonamide)cyclohexyl)methyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 17], 5-Fluoro-N,N-diisopropyl-2-(3-(1-((1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 18], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 19], (S)-2-(3-(1-(2-azabicyclo[2.2.2]octane-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 20], 5-Fluoro-N,N-diisopropyl-2-(3-(1-((1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carbonyl)piperidine-4-carbonyl)-1H-pyrrole[2,3-c]pyridine-1-yl)benzamide [Example 21], 5-Fluoro-2-(3-(1-((1S,3S,4S,5S)-5-Fluoro-2-azabicyclo[2.2.1]heptan-3-carbonyl)-piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N,N-diisopropylbenzamide [Example 22], rac-(R)-5-fluoro-N,N-diisopropyl-2-(3-(1-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexane-3-yl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 23]; (S)-2-(3-(1-(4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 24], rel-2-(3-(1-((1R,2R,5S)-3-azabicyclo[3.2.0]heptan-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 25], (S)-2-(3-(1-(5-azaspiro[2,4]heptan-6-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 26], (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 27], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 28], (S)-2-(3-(1-(2-azabicyclo[2.2.2]octane-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 29], N-ethyl-5-fluoro-2-(3-(1-((1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-isopropylbenzamide [Example 30], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 31], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-((2R,5S)-2,5-dimethylpyrrolidine-1-carbonyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 32], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-((2R,6S)-2,6-dimethylpiperidine-1-carbonyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 33], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 34], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-((3R,5S)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 35], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(1-isopropyl-1H-pyrazole-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 36], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(4-isopropylpyrimidine-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 37], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(2-isopropylpyridine-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 38], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 39], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(2-(4-cyclopropylpyrimidine-5-yl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 40], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(4-isopropylpyridine-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 41], (1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(4-isopropylthiazole-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone 1 / formic acid [Example 42], (1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(1-isopropyl-1H-pyrazole-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone 1 / formic acid [Example 43], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-4-fluoro-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide 1 / formic acid [Example 44], 2-(3-((R ＊ )-1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)azepan-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide 1 / formic acid [Example 45], 2-(3-(1-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 46], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 47], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 48-2], (S)-2-(3-(1-(4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 49-2], (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrollo[2,3-c]pyridine-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide [Example 50-2], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N-isopropyl-N-(2,2,2-trifluoroethyl)benzamide [Example 51-2], N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R ＊ , 4S ＊ )-2-methyl-1-((S)-4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 52-1], N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2R ＊ , 4S ＊ )-2-methyl-1-((S)-4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridine-1-yl)benzamide [Example 52-2], 2-(3-((2R ＊ , 4S ＊ )-1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)-2-methyl-piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N-isopropyl-N-(2,2,2-trifluoroethyl)benzamide [Example 53-3], 2-(3-((2R ＊ , 4S ＊ )-1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)-2-methyl-piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N-isopropyl-N-(2,2,2-trifluoroethyl)benzamide [Example 53-4], (1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-yl)(1-(4-fluoro-2-(4-isopropylpyridine-3-yl)phenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 54], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 55-2], (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N,N-diisopropylbenzamide [Example 56-2], 2-(3-(1-((1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-1-yl)-5-fluoro-N-isopropyl-N-((R)-1,1,1-trifluoropropan-2-yl)benzamide [Example 57-1], (1-((S)-4-azaspiro[2,4]heptan-5-carbonyl)piperidine-4-yl)(1-(2-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl)methanone [Example 58-2], (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolol[2,3-c]pyridine-1-yl)-5-fluoro-N,N-bis(propan-2-yl-d7)benzamide [Example 59], 5-Fluoro-N,N-diisopropyl-2-(2-methyl-3-(1-((2S,5S)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolol[2,3-c]pyridine-1-yl)benzamide [Example 60], 5-Fluoro-N,N-diisopropyl-2-(2-methyl-3-(1-((2S,5R)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolol[2,3-c]pyridine-1-yl)benzamide [Example 61], 5-Fluoro-N,N-diisopropyl-2-(2-methyl-3-((2S,4RS)-2-methyl-1-((2S,5S)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolol[2,3-c]pyridine-1-yl)benzamide [Example 62], N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2S,4RS)-2-methyl-1-((2S,5S)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrollo[2,3-c]pyridine-1-yl)benzamide [Example 63], 5-Fluoro-N,N-diisopropyl-2-(2-methyl-3-((2S,4RS)-2-methyl-1-((2S,5R)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolol[2,3-c]pyridine-1-yl)benzamide [Example 64], and N-ethyl-5-fluoro-N-isopropyl-2-(2-methyl-3-((2S,4RS)-2-methyl-1-((2S,5R)-5-methylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-1H-pyrrolol[2,3-c]pyridine-1-yl)benzamide [Example 65], and A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of those pharmaceutically acceptable salts.

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

30. A method for treating or preventing a menin-mediated condition in a subject who is suffering from or susceptible to a menin-mediated condition, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 28.

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