1.6-naphthyridine compounds as SMARCA2 inhibitors useful for treatment of SMARCA4 deletion cancers

Abstract

The present invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, methods for preparing said compounds and uses of said compounds as SMARCA2 protein inhibitors and their use in the treatment of SMARCA4 deletion cancers, such as SMARCA4 deletion non-small cell lung cancer (NSCLC). (I)

Description

Technical Field

[0001] This invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, methods for preparing said compounds, the use of said compounds as SMARCA2 protein inhibitors, and their use in the treatment of SMARCA4-deficient cancers such as SMARCA4-deficient non-small cell lung cancer (NSCLC). Background Technology

[0002] The switch / sucrose non-fermentation (SWI / SNF) (also known as BAF) complex is a multi-subunit complex that regulates chromatin structure through the activity of two mutually exclusive helicase / ATPase catalytic subunits: SWI / SNF-associated matrix-associated actin-dependent chromatin regulator subfamily A member 2 (SMARCA2, BRAHMA, or BRM) and SWI / SNF-associated matrix-associated actin-dependent chromatin regulator subfamily A member 4 (SMARCA4 or BRG1). The core and regulatory subunits combine ATP hydrolysis with perturbations of histone-DNA contacts, thereby providing entry points for transcription factors and homologous DNA elements, thus promoting gene activation and repression.

[0003] Mutations in genes encoding twenty typical SWI / SNF subunits have been observed in nearly 20% of all cancers, with the highest frequency observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal cancer, and clear cell renal cell carcinoma. Although SMARCA2 and SMARCA4 are highly homologous and their functions are presumed to overlap, they have been reported to play distinct roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is uncommon in tumor development. In fact, many types of cancer have been shown to be SMARCA4-related (e.g., cancers with SMARCA4 mutations or SMARCA4 deletions, such as a lack of expression), including, for example, lung cancers (such as non-small cell lung cancer or NSCLC).

[0004] SMARCA2 has been shown to be one of the head essential genes in SMARCA4-related or mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells rely solely on SMARCA2 activity—that is, SMARCA2 is incorporated more into the complex to compensate for SMARCA4 deficiency. Therefore, SMARCA2 can be targeted in SMARCA4-related / deficient cancers. The co-occurrence of the loss of expression of two (or more) genes that lead to cell death is called synthetic lethality. Therefore, synthetic lethality can be used to treat certain SMARCA2 / SMARCA4-related cancers.

[0005] There remains a persistent need for effective treatments for diseases that can be treated by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, nonspecificity and the inability to selectively target and modulate SMARCA2 remain obstacles to the development of effective treatments. Therefore, small molecule therapeutics targeting SMARCA2 would be extremely valuable.

[0006] One object of the present invention is to provide compounds that are more selective for SMARCA2 than for SMARCA4.

[0007] One object of the present invention is to provide an effective SMARCA2 inhibitor for the treatment of SMARCA4-deficient cancers.

[0008] One object of the present invention is to provide a compound SMARCA2 inhibitor for the effective treatment of SMARCA4-deficient NSCLC. Summary of the Invention

[0009] Embodiments of the present invention relate to certain uses and methods of use of 1,6-naphthidine and isoquinoline chemical entities having SMARCA2 regulatory properties as claimed in the claims, and pharmaceutical compositions comprising these chemical entities, the use of said chemical entities as SMARCA2 protein inhibitors, and methods of treating SMARCA4-deficient cancers or their use in treating SMARCA4-deficient cancers.

[0010] Additional embodiments, features, and advantages of the present invention will become apparent from the following detailed description and by practicing the invention.

[0011] Embodiments of the present invention are uses and treatments utilizing compounds of formula (I). (I) in R 1 Choose from the following groups: (i) , , , or ; R a yes , , , , , , , , , , , , , , , , or ; R b yes or ; R c It is a halogenated group, C 1-4 Alkyl or OC 1-4 alkyl; R d yes , , or ; R e yes , R f It is a halogenated group, C 1-4 Alkyl or OC 1-4 alkyl; R g yes ; R h It is C 1-4 alkyl; (ii) by R j , , or Replacement C 2-3 alkyl; R j It is SO2-C 1-4 Halogenated alkyl groups, NH-SO2-C 1-4 Halogenated alkyl groups, N(CH3)-SO2-C 1-4 Halogenated alkyl groups or SO2-N(CH3)2, (iii) Selected from the following 5- or 6-membered heteroaryl groups: , , , or ; R n It is SO2CH3, CH2C(OH)(CH3)2, CH2CH2SO2CH3; R p It is SO2CH3 or CH2CH2CN; or R q It is H or CH3; (iv)C 3-6 cycloalkyl or bridged -C5-7 cycloalkyl groups, each of which is separated by SO2C 1-4 Alkyl, SO2-C 3-6 cycloalkyl, CO2CH3 or NH-SO2C 1-4 Halogenated alkyl substitution; or, (v) Carbon-linked pyrrolidine, piperidine, or aziridine heptane, each independently substituted by one or two substituents selected from the following: halogenated, C-linked, ... 1-4 Alkyl, C 1-4 Halogenated alkyl, CH2OH, OH, OC 1-4 Alkyl, SO2C 1-4 Alkyl, SO2C 1-4 Haloalkyl, SO2CH2CH2OH and C(=O)C 1-4 Halogenated alkyl groups; or each independently of SO2C 1-4 Halogenated alkyl-substituted 5-azaspiro[2.5]octane, 6-azaspiro[3.5]nonane, 2-azabicyclo[2.1.1]hexane and 3-azabicyclo[3.1.0]hexane; (vi) R 5 yes And X is CH or N; and its pharmaceutically acceptable salts and stereoisomers.

[0012] Incorporated by reference All publications, patents, patent applications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, patent application, or published nucleotide and amino acid sequence is specifically and individually indicated to be incorporated herein by reference. Detailed Implementation

[0013] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood in relation to the subject matter to which protection is sought. In the reference to URLs or other such identifiers or addresses, it should be understood that such identifiers can change, and specific information on the Internet can change over time, but equivalent information can be found by searching the Internet. The reference to such references demonstrates the availability and public dissemination of such information.

[0014] It should be understood that the foregoing general description and the following detailed description are merely exemplary and illustrative, and do not constitute a limitation on any subject matter claimed.

[0015] In this application, unless otherwise specified, the use of the singular includes the plural. It must be noted that, unless the context clearly indicates otherwise, as used in this specification and the appended claims, the singular forms “a,” “an,” “the,” and “described” include the plural referents. In this application, unless otherwise specified, the use of “or” means “and / or.”

[0016] When the word "about" is used to represent a value as an approximation, it should be understood that the specific value constitutes another implementation. As used herein, "about X" (where X is a numerical value) preferably refers to the referenced value ±10%, inclusive. For example, the phrase "about 8" refers to a value of 7.2 to 8.8, inclusive; similarly, the phrase "about 8%" refers to a value of 7.2% to 8.8%, inclusive. Where applicable, all ranges are inclusive and composable. For example, when a range of "1 to 5" is referenced, the referenced range should be understood to include ranges such as "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. Furthermore, when a list of alternatives is provided affirmatively, such a list may also include implementations that may exclude any of the alternatives. For example, when describing a range of “1 to 5”, such a description may cover cases in which any of 1, 2, 3, 4 or 5 is excluded; therefore, a reference to “1 to 5” may cover “1 and 3 to 5, but not 2”, or simply “not including 2”.

[0017] Some of the quantitative expressions given in this article are not modified by the term “approximately”. It should be understood that, whether or not the term “approximately” is explicitly used, each quantity given in this article is intended to refer to an actual given value, and also to an approximation of such given values ​​that can be reasonably inferred by one of ordinary skill in the art, including approximations of such given values ​​caused by experimental and / or measurement conditions and acceptable error tolerances.

[0018] As used in this article, the expression “one or more” means at least one, such as one, two, three, four, five or more, as long as possible and depending on the context.

[0019] Furthermore, the use of the term "including" and other forms such as "including," "containing," and "comprising" is not restrictive.

[0020] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0021] Definitions of standard chemical terms can be found in the references, including but not limited to Carey and Sundberg, "Advanced Organic Chemistry 4". thEd. A (2000) and B (2001), Plenum Press, New York.

[0022] Unless specifically defined, the nomenclature, laboratory procedures, and techniques used in analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are those generally accepted in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid transfection). Reaction and purification techniques can be performed, for example, using kits provided with the manufacturer's instructions or as commonly performed in the art or as described herein. The foregoing techniques and procedures can generally be performed according to conventional methods and are described in the various general and more specific references cited and discussed throughout this specification.

[0023] It should be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs, and reagents described herein, and therefore can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0024] In the preceding and following text, the term "compound having formula (I)" means including its addition salts as well as stereoisomers.

[0025] As used in this article, "C" x-y "(where x and y are integers) refers to the number of carbon atoms constituting the specified part (excluding optional substituents). Therefore, C 1-6 Alkyl groups contain 1 to 6 carbon atoms, C 3-6 Cycloalkyl groups contain 3 to 6 carbon atoms, etc.

[0026] The term “halogenated group” or alternatively “halogen” refers to fluorine, chlorine, bromine and iodine.

[0027] An alkyl group can have 1 to 6 carbon atoms (when used herein, numerical ranges such as "1 to 6" refer to each integer within a given range; for example, "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., and may contain up to 6 carbon atoms, but the definition of this invention also covers the term "alkyl" when no numerical range is specified). The alkyl group of the compounds described herein can be specified as "C". 1-6 Alkyl or similar names.

[0028] By way of example, as used herein, the term "C" as a group or part of a group 1-4 Alkyl or C 1-6"Alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1 to 4 or 1 to 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, etc.

[0029] The term "haloalkyl" refers to an alkyl group as defined herein, in which one or more hydrogen atoms are replaced by one or more halogens. The term "haloalkyl" includes "halogenated C..." 1-4 Alkyl group, halogenated C 1-6 Alkyl group, monohalogenated C 1-4 Alkyl, monohalogenated C 1-6 Alkyl, polyhalogenated C 1-4 Alkyl and polyhalogenated C 1-6 Alkyl groups. They can contain one, two, three, or more hydrogen atoms replaced by halogens, thus halogenated C... 1-4 Alkyl or halogenated C 1-6 Alkyl groups may have one, two, three or more halogens. Examples of “haloalkyl” groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that, in accordance with those skilled in the art and the teachings provided herein, would be considered equivalent to any of the foregoing examples.

[0030] As used in this article, the term "cyanoC" 1-4 Alkyl or cyano C 1-6 "Alkyl" refers to a C14 group substituted with one or two cyano groups, particularly one cyano group, as defined herein. 1-4 Alkyl or C 1-6 Alkyl groups.

[0031] "Amino" refers to the -NH2 group.

[0032] The term "carboxy" refers to -CO2H. In some embodiments, the carboxyl moiety may be replaced by a "carboxylic acid bioisostere," which is a functional group or moiety exhibiting similar physical and / or chemical properties to the carboxylic acid moiety. Carboxylic acid bioisosteres have biological properties similar to those of the carboxylic acid group. Compounds having a carboxylic acid moiety may have a carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to carboxylic acid-containing compounds. For example, in one embodiment, the carboxylic acid bioisostere will ionize at physiological pH to approximately the same extent as the carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to: , , , , , , , wait.

[0033] The term "aromatic" refers to a planar ring having a delocalized π-electron system comprising 4n+2 π electrons, where n is an integer. Aromatic rings can be formed of five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term "aromatic" includes aryl groups (e.g., phenyl, naphthyl) and heteroaryl groups (e.g., pyridyl, quinolinyl).

[0034] Unless the context otherwise indicates, the term "non-aromatic group" includes unsaturated ring systems without aromatic characteristics, partially saturated and fully saturated heterocyclic ring systems.

[0035] The terms "unsaturated" and "partially saturated" refer to rings in which the ring structure contains atoms sharing more than one valence bond, that is, the ring contains at least one multiple bond, such as C=C, CC, or N=C bond.

[0036] The term "fully saturated" refers to a ring in which there are no multiple bonds between the ring atoms. Saturated heterocyclic groups include piperidine, morpholine, thiomorpholine, and piperazine. Partially saturated heterocyclic groups include pyrazolines, such as 2-pyrazoline and 3-pyrazoline.

[0037] The term "aryl" refers to a monocyclic aromatic carbon ring (a ring structure in which all ring atoms are carbon) with 6 atoms per ring (the carbon atoms in the aryl group are sp2 hybridized).

[0038] The term "phenyl" refers to the following part: .

[0039] The term "cycloalkyl" refers to a monocyclic or polycyclic (bridged or fused) non-aromatic group in which each of the cyclic atoms (i.e., the skeleton atoms) is a carbon atom. Cycloalkyl groups can be saturated or partially unsaturated. An example of "cycloalkyl" is "C 3-6 "Cycloalkyl". Cycloalkyl groups can be fused with aromatic rings (in which case, the cycloalkyl group is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Exemplary examples of cycloalkyl groups include, but are not limited to, the following: The terms “heterocyclic” or “heterocyclic alkyl” as defined herein contain at least one heteroatom typically selected from nitrogen, oxygen, or sulfur, and particularly contain up to five, four, three, two, or a single heteroatom. In the context of reference to heterocyclic or heterocyclic cyclic systems, unless the context otherwise indicates, the heterocyclic or heterocyclic ring may optionally be substituted (i.e., unsubstituted or substituted) with one or more substituents as described herein. The group may be fused with an aryl or heteroaryl group. It should be understood that a heterocyclic or heterocyclic alkyl group may be bonded by a heteroatom in the ring (where chemically possible) or by one carbon atom comprising the heterocyclic alkyl ring. Illustrative examples of heterocyclic alkyl groups (also known as non-aromatic heterocycles) include: Heterocyclic ring systems or heterocyclic alkyl ring systems can be heteroaryl ring systems having 5 to 12 ring members, more typically 5 to 10 ring members.

[0040] The term "heteroaryl" is used herein to refer to a heterocyclic ring system having aromatic properties. The term "heteroaryl" includes polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system can be attached to the remainder of the compound via an aromatic ring or via a non-aromatic ring.

[0041] Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. A heteroaryl group can be, for example, a five- or six-membered monocyclic ring or a bicyclic structure formed by fused five- and six-membered rings, or two fused six-membered rings, or two fused five-membered rings. A heteroaryl ring system can contain up to about five heteroatoms, typically selected from nitrogen, oxygen, and sulfur. Typically, a heteroaryl ring will contain up to four heteroatoms, more typically up to three heteroatoms, and more typically up to two, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. It should be understood that a heteroaryl group can be bonded by a heteroatom in the ring (where chemically possible) or by one carbon atom comprising the carbon of the heteroaryl ring. Generally, the number of basic nitrogen atoms (including any amino substituents in the ring) present in a heteroaryl group will be less than five. An illustrative, non-limiting example of a heteroaryl group is: A nitrogen-containing heteroaryl ring must contain at least one cyclic nitrogen atom. In addition, each ring may contain up to about four other heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, such as one, two, or three, and more usually up to two nitrogen atoms, such as a single nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents in the ring) will be less than five.

[0042] Examples of non-aromatic heterocyclic groups are groups having 3 to 12 ring members, more typically 5 to 10 ring members. For example, such groups can be monocyclic or bicyclic and typically have 1 to 5 heteroatom ring members (more typically 1, 2, 3, or 4 heteroatom ring members) usually selected from nitrogen, oxygen, and sulfur. Heterocyclic groups can contain, for example, cyclic ether moieties (e.g., as in tetrahydrofuran and dioxane), cyclic sulfide moieties (e.g., as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g., as in pyrrolidine), and combinations thereof (e.g., thiomorpholine).

[0043] Heterocyclic and cycloalkyl rings also include bridging ring systems, such as bridging cycloalkanes, such as norbornane (1,4-methylene-cyclohexane), adamantane, and oxadamantane; bridging morpholine rings, such as 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, and 3-oxa-8-azabicyclo[3.2.1]octane; bridging piperazine rings, such as 3,6-diazabicyclo[3.1.1]heptane; and bridging piperidine rings, such as 1,4-ethylidene piperidine. For an explanation of the distinction between fused and bridging ring systems, see Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, pp. 131-133, 1992.

[0044] The lines drawn in the ring system indicate which ring atom the bond can attach to, and whichever ring atom is suitable and available. The term "variable attachment point" means that the group is allowed to attach at more than one alternative location in the structure. The attachment always replaces a hydrogen atom on one of the ring atoms. In other words, all permutations of the bonds are represented by a single schematic diagram, as illustrated in the following example.

[0045] Those skilled in the art will recognize that if a given ring contains more than one such substituent, the bonding of each substituent is independent of all other substituents. The groups listed or illustrated above are not exhaustive.

[0046] The terms “optional” or “optionally” mean that the event described below may or may not occur. This term includes situations in which the event may or may not occur.

[0047] In the compounds disclosed herein, the carbon atom represented by "*" in the drawn formula is a chiral center. When a carbon atom is represented by "(*R)", it indicates that it is a pure enantiomer, but it is unknown whether it is an R enantiomer or an S enantiomer. Similarly, when a carbon atom is represented by "(*S)", it indicates that it is a pure enantiomer, but it is unknown whether it is an R enantiomer or an S enantiomer.

[0048] The term “bond” or “single bond” refers to a chemical bond between two atoms, or a chemical bond between two parts when the atoms bonded by the bond are considered part of a larger substructure.

[0049] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally considered to be a chemical entity that is embedded in or attached to a molecule.

[0050] As used herein, the term “therapeutic effective amount” refers to the amount of an active compound or agent that, when administered to a mammal in need, effectively at least partially improves or at least partially prevents the disease, condition, or symptom described herein.

[0051] As used herein, the term "composition" is intended to cover a product containing a specified amount of a specified ingredient, and any product obtained directly or indirectly by combining a specified amount of the specified ingredient.

[0052] As used in this article, the term “expression” includes the process of transcribing polynucleotides into mRNA and translating them into peptides, polypeptides, or proteins.

[0053] As used herein, the term "antagonist" refers to a small molecule agent that binds to the receptor and subsequently reduces agonist-induced receptor transcriptional activity.

[0054] As used in this article, the term "agonist" refers to a small molecule agent that binds to a receptor in the absence of a known agonist and subsequently increases the receptor's transcriptional activity.

[0055] As used in this article, the term "reverse agonist" refers to a small molecule agent that binds to the receptor and subsequently reduces the baseline level of receptor transcriptional activity in the absence of a known agonist.

[0056] As used herein, the term “modulation” refers to interacting directly or indirectly with a target to alter the target’s activity, including (by way of example only) enhancing, inhibiting, limiting, or extending the target’s activity.

[0057] The terms "subject" or "patient" include mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs. In one respect, the mammal is human. Those skilled in the art recognize that a therapy that reduces the severity of a symptom in one mammal can predict the effect of that therapy on another mammal.

[0058] As used herein, the term "treat / treating / treatment" includes relieving, reducing or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, relieving a disease or condition, causing the remission of a disease or condition, relieving the condition caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0059] "Proliferative disorders" are diseases caused by abnormal growth or expansion of cells due to proliferation. Proliferative disorders may be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant growths"), benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0060] The terms “vesicle” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue that grows beyond and is not in harmony with the growth of normal tissue. A vegetation or tumor may be “benign” or “malignant” depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. A “benign vegetation” is typically well-differentiated, grows more slowly than a malignant vegetation, and remains confined to its primary site. Furthermore, a benign vegetation does not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign vegetations include, but are not limited to, lipomas, chondromas, adenomas, acral hemangiomas, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasia. In some cases, certain “benign” tumors may subsequently develop into malignant vegetations, possibly due to additional genetic changes in a subset of the tumor’s vesicular cells, and these tumors are referred to as “premalignant vegetations.” An exemplary premalignant vegetation is a teratoma. In contrast, "malignant growths" are typically poorly differentiated (underdeveloped) and are characterized by rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant growths often have the ability to metastasize to distant sites.

[0061] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in a subject's healthy body to heal wounds and restore blood flow to tissues after injury. The healthy body controls angiogenesis in several ways, such as through growth factors that stimulate angiogenesis and angiogenesis inhibitors. Many disease states, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal angiogenesis refers to angiogenesis that is larger than normal in the body, particularly in adults unrelated to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels to nourish diseased tissues and / or destroy normal tissues, and in the case of cancer, new blood vessels can allow tumor cells to escape into the circulation and remain in other organs (tumor metastasis).

[0062] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies of tissues); cell samples (e.g., cell smears (such as Pap smears or blood smears) or cell samples obtained through microdissection); samples of intact organisms (such as samples of yeast or bacteria); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspiration, breast milk, vaginal fluid, saliva, swabs (such as oral swabs), or any material containing biomolecules derived from the first biological sample. Biological samples also include those that are genetically modified, such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0063] Isomers, salts, N-oxides, isotope-labeled derivatives In the foregoing and hereinafter, the terms “compound of formula (I),” “compound of this disclosure or invention,” “compound provided herein,” or similar terms are intended to include its addition salts and stereoisomers.

[0064] In some embodiments, the compounds provided herein have one or more stereocenters, each center existing independently in either an R or S configuration. The compounds provided herein include all diastereomers, enantiomers, transisomers, and epimeric forms, and suitable mixtures thereof. Stereoisomers are obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography. In some embodiments, the compounds of this disclosure are used as single enantiomers. In some embodiments, the compounds of this disclosure are used as racemic mixtures. In some embodiments, the compounds of this disclosure have hindered rotation around a single bond, producing transisomers.

[0065] In some cases, compounds can exist as tautomers. All tautomers are included within the scope of the compounds provided herein.

[0066] To avoid ambiguity, when a compound can exist in one of several geometric isomers or tautomers and only one is specifically described or shown, all other forms are still included. Examples of tautomer forms include, for example, ketone forms, enol forms, and enolized forms, such as in the following tautomer pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / enediamine, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0067] Such forms, provided they can exist, are intended to be included within the scope of the compounds presented herein. Thus, a single compound can exist as both stereoisomers and tautomers.

[0068] Where a compound described herein contains one or more chiral centers and may exist in two or more optical isomers, unless the context otherwise requires, reference to a compound herein includes all its optical isomers (e.g., enantiomers, epimers, and diastereomers), as individual optical isomers, or mixtures of two or more optical isomers (e.g., racemic mixtures). When a compound has more than one chiral center and one chiral center is represented as having an absolute stereoconfiguration, unless the context otherwise requires, the other chiral centers include all their optical isomers, as individual optical isomers, or mixtures of two or more optical isomers (e.g., racemic mixtures). Optical isomers can be characterized and identified by their optical activity (i.e., as + and - isomers, depending on the direction of their rotational plane-polarized light, or d and l isomers), or they can be characterized by their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold, and Prelog, see Jerry March, Advanced Organic Chemistry, 4th ed., John Wiley & Sons, New York, 1992, pp. 109–114, and also see Cahn, Ingold & Prelog (1966), Angew. Chem. Int. Ed. Engl., 5, 385–415. For example, a split enantiomer with an unknown absolute configuration can be specified by (+) or (–) according to the direction of its rotational plane-polarized light.

[0069] Optical isomers can be separated by a variety of techniques, including chiral chromatography (chromatography on a chiral support), and these techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereomeric salts with chiral acids (such as (+)-tartaric acid, (–)-pyroglutamic acid, (–)-di-toluyl-L-tartaric acid, (+)-mandelic acid, (–)-malic acid, and (–)-camphorsulfonic acid), separating these diastereomeric isomers by preferential crystallization, and then dissociating these salts to obtain the individual enantiomers of the free base.

[0070] When a compound exists in two or more isomers, one isomer (e.g., one enantiomer of a pair of enantiomers) may exhibit superiority over another isomer (e.g., over another enantiomer), for example, in terms of biological activity. Therefore, in some cases, it may be necessary to use only one enantiomer of a pair, or only one diastereomer of a plurality of diastereomers, as a therapeutic agent.

[0071] When identifying a specific stereoisomer, this means that the stereoisomer is substantially free of other stereoisomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1%. Therefore, when a compound described herein is designated, for example, as (S), it means that the compound is substantially free of the (R) isomer; when a compound described herein is designated, for example, as E, it means that the compound is substantially free of the Z isomer; and when a compound described herein is designated, for example, as cis, it means that the compound is substantially free of the trans isomer.

[0072] As used herein, any chemical formula having bonds shown only as solid lines and not as solid wedges or scattered wedges, or otherwise not specified as having a particular configuration (e.g., R, S) around one or more atoms, envisions every possible stereoisomer, or a mixture of two or more stereoisomers.

[0073] The terms “stereoisomer,” “stereoisomeric form,” or “stereochemical isomeric form” are used interchangeably in the preceding or following text.

[0074] Enantiomers are stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture or a mixture of racemic components.

[0075] Diastereomers (or diastereomers) are stereoisomers that are not enantiomers, i.e., they are not mirror images. If the compound contains a double bond, the substituent can be E or Z configuration. Substituents on a divalent cyclic (partially) saturated group can have cis or trans configurations; for example, if the compound contains a disubstituted cycloalkyl group, the substituent can be cis or trans configuration. Therefore, this disclosure includes enantiomers, trans-blocked isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0076] Disubstituted cycloalkyl and heterocycloalkyl stereoisomers can be designated by nomenclature prefixes such as cis and trans. Cis and trans isomers are also called “geometric isomers.” When a compound described herein is designated as “cis,” it means that the two groups point in the same direction relative to the ring plane. In the “trans” isomer, they point in opposite directions. The following examples are “cis” and “trans” isomers of 2,6-dimethylmorpholine. Based on the relative positions of the two substituents and whether they are on the same side or opposite faces of the ring structure, there are two possible relative configurations.

[0077] For example, In this invention, the trisubstituted piperidine moiety having a stereocenter is defined as (3a, 4a, 5a) or (3a, 4b, 5a). For example: The meanings of all those terms, namely enantiomer, de-rotated isomer, diastereomer, racemic, E isomer, Z isomer, cis isomer, trans isomer, and mixtures thereof, are known to those skilled in the art.

[0078] The methods and formulations described herein include N-oxides (if appropriate) of compounds having the structure shown herein and having the same type of activity, pharmaceutically acceptable salts, and combinations thereof.

[0079] The salt forms of the compounds presented herein are generally pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977), “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1–19. However, non-pharmaceutically acceptable salts may also be prepared as intermediate forms, which can then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which can be used, for example, to purify or isolate the compounds of the present invention, also constitute part of this invention.

[0080] Pharmaceutically acceptable salts include pharmaceutically acceptable acid and base addition salts, and are intended to include non-toxic acid and base addition salt forms in which the compounds described herein can form therapeutically active salts.

[0081] The salts disclosed herein can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods, such as those described in "Pharmaceutical Salts: Properties, Selection, and Use," edited by P. Heinrich Stahl and Camille G. Wermuth, ISBN: 3-90639-026-8, hardcover, page 388, August 2002. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a suitable base or acid in water, in an organic solvent, or in a mixture of both; generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The compounds of the present invention can exist as monosalts or disalts, depending on the pKa of the acid forming the salt.

[0082] Pharmaceutically acceptable acid addition salts can be readily obtained by treating the base form with a suitable inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) in anionic form or an organic acid (such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.).

[0083] Suitable anions include, for example, acetates, 2,2-dichloroacetate, adipic acid salts, alginates, ascorbic acid salts (e.g., L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4-acetaminophen, butyrate, bicarbonate, tartrate, bromide, (+) camphorate, camphor sulfonate, (+)-(1S)-camphor-10-sulfonate, calcium edetate, camphor sulfonate, decanoate, hexanoate, octanoate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecyl sulfate, edetate, estolatate. e), ethanesulfonate, ethane-1,2-disulfonate, ethanesulfonate, formate, fumarate, galacturonate, gentianate, gluconate, gluconate, gluconate, D-gluconate, gluuronate (e.g., D-gluuronate), glutamate (e.g., L-glutamate), α-oxoglutarate, glycolate, glycolyllarsanilate, hexylresorcinol, hippurate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, hydroxynaphthylcarboxylate, iodide, hydroxyethylsulfonate ( isethionate, lactates (e.g., (+)-L-lactate, (±)-DL-lactate), lacturonate, malate, (-)-L-malate, maleate, malonate, mandelate, (±)-DL mandelate, mesylate, methansulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalene sulfonate (e.g., naphthalene-2-sulfonate), naphthalene-1,5-disulfonate, 1-hydroxy-2-naphthylcarboxylate, naphthalene sulfonate, nicotinate, nitrate, oleate, orotate Oxalate, palmitate, embonate, pantothenate, phosphate / bisphosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylic acid, sebate, stearate, basic acetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, theochloroate, thiocyanate, toluenesulphonate (e.g., p-toluenesulphonate), tosylate, triethyliodide, undecenoate, valeric acid, and acylated amino acids and cation exchange resins. Conversely, the salt forms can be converted to free base forms by treatment with a suitable alkali.

[0084] Compounds containing acidic protons can also be converted to their non-toxic metal or amine addition salt forms by treatment with suitable cationic organic and inorganic bases. Suitable basic salts include those that form with organic cations such as arginine, benzylamine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, diprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, tromethamine, etc.; and those that form with ammonium ions (i.e., NH4+). + ), Quaternary ammonium ion N(CH3)4 + and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + These salts can be formed with amine functional groups, and with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc. When the compounds described herein contain amine functional groups, these can form quaternary ammonium salts, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds presented herein.

[0085] Conversely, the salt form can be converted into a free form by treatment with a suitable acid.

[0086] In some embodiments, the sites on the compounds disclosed herein are susceptible to various metabolic reactions. Therefore, incorporating suitable substituents at metabolic reaction sites will reduce, minimize, or eliminate metabolic pathways. In specific embodiments, suitable substituents that reduce or eliminate the sensitivity of aromatic rings to metabolic reactions are (by way of example only) halogen, deuterium, or alkyl groups.

[0087] The compounds disclosed herein include isotopically labeled compounds (i.e., compounds having one or more isotopic substitutions). These compounds are identical to those listed in the various chemical formulas and structures presented herein, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. References to a particular element include, within their scope, all isotopes of that element, whether naturally occurring or synthetically produced, whether in natural abundance or in isotopically enriched forms. For example, references to hydrogen include, within their scope, all isotopes of that element. 1 H, 2 H(D) and 3 H(T). Similarly, references to carbon and oxygen within their scope include, respectively, 12 C 13 C and 14 C and 16 O and 18O. The isotope may be radioactive or non-radioactive. In one embodiment of the invention, the compound does not contain a radioactive isotope. In another embodiment, the compound may contain one or more radioactive isotopes. Compounds containing such radioactive isotopes can also be used for environmental diagnostics. The radiolabeled compounds described herein may include radioactive isotopes selected from the group consisting of: 2 H, 3 H, 11 C 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br、 76 Br、 77 Br and 82 Br. Preferably, the radioactive isotope is selected from... 2 H, 3 H, 11 C and 18 Group F. More preferably, the radioactive isotope is... 2 H. Specifically, deuterated compounds are intended to be included within the scope of this invention. In some embodiments, the metabolic sites on the compounds described herein are deuterated.

[0088] Throughout the specification, their groups and substituents can be selected to provide stable moieties and compounds.

[0089] The embodiments of the 1,6-naphthidine and isoquinoline compounds used as described herein are compounds of formula (I): (I) in R 1 Choose from the following groups: (i) , , , or ; R a yes , , , , , , , , , , , , , , , , or ; R b yes or ; R c It is a halogenated group, C 1-4 Alkyl or OC 1-4 alkyl; R d yes , , or ; R e yes , R f It is a halogenated group, C 1-4 Alkyl or OC 1-4 alkyl; R g yes ; R h It is C 1-4 alkyl; (ii) by R j , , or Replacement C 2-3 alkyl; R j It is SO2-C 1-4 Halogenated alkyl groups, NH-SO2-C 1-4 Halogenated alkyl groups, N(CH3)-SO2-C 1-4 Halogenated alkyl groups or SO2-N(CH3)2, (iii) Selected from the following 5- or 6-membered heteroaryl groups: , , , or ; R n It is SO2CH3, CH2C(OH)(CH3)2, CH2CH2SO2CH3; R p It is SO2CH3 or CH2CH2CN; or R q It is H or CH3; (iv)C 3-6 cycloalkyl or bridged -C 5-7 cycloalkyl groups, each of which is separated by SO2C1-4 Alkyl, SO2-C 3-6 cycloalkyl, CO2CH3 or NH-SO2C 1-4 Halogenated alkyl substitution; or, (v) Carbon-linked pyrrolidine, piperidine, or aziridine heptane, each independently substituted by one or two substituents selected from the following: halogenated, C-linked, ... 1-4 Alkyl, C 1-4 Halogenated alkyl, CH2OH, OH, OC 1-4 Alkyl, SO2C 1-4 Alkyl, SO2C 1-4 Haloalkyl, SO2CH2CH2OH and C(=O)C 1-4 Halogenated alkyl groups; or each independently of SO2C 1-4 Halogenated alkyl-substituted 5-azaspiro[2.5]octane, 6-azaspiro[3.5]nonane, 2-azabicyclo[2.1.1]hexane and 3-azabicyclo[3.1.0]hexane; (vi) R 5 It is a 6-membered ring selected from the following optional substitutions: And X is CH or N; and its pharmaceutically acceptable salts and stereoisomers.

[0090] In some implementations of formula (I), R 1 yes , , , , , , , , , or And R 5 yes .

[0091] In some embodiments of formula (I), X is CH. In some embodiments, X is N.

[0092] In some implementation schemes, R 1 yes In some implementation schemes, R 1 yes In some implementations, R 1 yes In some implementations, R 1yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 5 It is a 6-membered ring selected from the following optional substitutions: In some embodiments, the compounds of formula (I) are the compounds shown in Table 1 below.

[0093] And its pharmaceutically acceptable salts and stereoisomers.

[0094] In some embodiments, the 1,6-naphthidine or isoquinoline compound is selected from the group consisting of: N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)pyrrolid-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)pyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((R)-1-((difluoromethyl)sulfonyl)azacycloheptane-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((R)-1-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(3-((*S)-S-(difluoromethyl)sulfinimide)phenyl)-2-(6-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)isoquinoline-3-yl)acetamide; N-((3R,5R)-1-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-5-(difluoromethyl)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(2-((1,1-difluoro-N-methylmethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((cis)-3-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; and N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpyrrolidine-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; and its pharmaceutically acceptable salts and stereoisomers.

[0095] In some embodiments, the isoquinoline compound is a compound of formula (IA): in, R1 yes (i) (ii) (iii) (iv) R 5 yes , , , or Or its pharmaceutically acceptable salt or stereoisomer.

[0096] In some embodiments, the 1,6-naphthidine compound is a compound of formula (IB): in, R 1 Yes(i) R 1 Yes (ii) R 1 Yes (iii) R 1 Yes (iv) R 1 Yes (v) R 1 Yes (vi) R 5 yes , , , , , or Or its pharmaceutically acceptable salt or stereoisomer.

[0097] Another embodiment of the present invention is a method of treating a subject with cancer or non-small cell lung cancer (NSCLC), the method comprising administering an effective amount of a pharmaceutical composition, or the use of a pharmaceutical composition for treating cancer or non-small cell lung cancer (NSCLC), or a pharmaceutical composition for such use, the pharmaceutical composition comprising: at least one compound selected from compounds of formula (I); and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of compounds of formula (I); and (B) at least one pharmaceutically acceptable excipient.

[0098] In some embodiments, such pharmaceutical compositions comprise a therapeutically effective amount of at least one of the compounds in Table 1, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, or a pharmaceutically acceptable prodrug of at least one of the compounds in Table 1, or at least one pharmaceutically active metabolite of Table 1; and at least one pharmaceutically acceptable excipient.

[0099] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound of formula (IA), or a pharmaceutically acceptable salt, N-oxide or solvate, pharmaceutically acceptable prodrug or pharmaceutically active metabolite of a compound of formula (IA); and at least one pharmaceutically acceptable excipient.

[0100] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound of formula (IB), or a pharmaceutically acceptable salt, N-oxide or solvate, pharmaceutically acceptable prodrug or pharmaceutically active metabolite of a compound of formula (IB); and at least one pharmaceutically acceptable excipient.

[0101] Compound Synthesis In this section, as in all other sections of this application, unless the context otherwise indicates, the reference to formula (I) also includes all other subgroups and examples thereof as defined herein.

[0102] The compounds described herein were synthesized using methods described in the chemical literature, or by combination thereof. Furthermore, the solvents, temperatures, and other reaction conditions presented herein may be varied. The techniques and materials generally accepted in this field are described in, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991); Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989), March, Advanced Organic Chemistry, 4th Edition (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A and B (Plenum 2000, 2001); and Green and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (Wiley 1999) (all of which are incorporated herein by reference). General methods for preparing compounds as disclosed herein can be derived from reactions, and these reactions can be modified by using appropriate reagents and conditions to introduce the parts found in the formulas provided herein.

[0103] The starting materials and reagents used to synthesize the compounds described herein may be synthesized or available from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals) and AcrosOrganics.

[0104] In the reactions described herein, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl groups, which are required by the final product to prevent them from unnecessarily participating in the reaction. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in the chemical reaction until the protecting groups are removed. Preferably, each protecting group can be removed in a different manner. Protecting groups broken under completely different reaction conditions satisfy the requirement of differential removal.

[0105] Protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidizing conditions. Groups such as triphenylmethyl, dimethoxytriphenylmethyl, acetal, and tert-butyldimethylsilyl are acid-labile and can be used to protect the carboxyl and hydroxyl reactive moieties in the presence of an amino group protected with a Cbz group that can be removed by hydrogenolysis and a base-labile Fmoc group. The carboxylic acid and hydroxyl reactive moieties can be capped with base-labile unstable groups (such as, but not limited to, methyl, ethyl, and acetyl) in the presence of an amine capped with an acid-labile unstable group such as tert-butyl carbamate or with an amine capped with an acid- and base-stable but hydrolyzable carbamate.

[0106] The reactive moiety of the carboxylic acid and hydroxyl group can also be capped with a hydrolyzable protecting group such as a benzyl group, while the amino group capable of forming hydrogen bonds with acids can be capped with a base-labile group such as acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The reactive moiety of the carboxylic acid can be protected by conversion to simple ester compounds as illustrated herein, including conversion to alkyl esters, or they can be capped with an oxidically removable protecting group such as 2,4-dimethoxybenzyl, while the coexisting amino group can be capped with a fluorine-labile silyl carbamate.

[0107] Allyl-terminated groups are useful in the presence of both acid-protecting and base-protecting groups, as the former is stable and can subsequently be removed by metal or π-acid catalysts. For example, allyl-terminated carboxylic acids can be degraded using Pd in ​​the presence of acid-instable tert-butyl carbamate or base-instable amine acetate protecting groups. 0 Catalytic reactions can be protected. Another form of protecting group is a resin that can be attached to a compound or intermediate. Once the residue is attached to the resin, the functional group is capped and cannot react. Once released from the resin, the functional group can be used for the reaction.

[0108] Typically, the end-capping / protecting groups can be selected from: Other protecting groups, along with a detailed description of techniques applicable to the generation and removal of protecting groups, are described in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4th Edition, Wiley, Hoboken, New Jersey, 2007, the contents of which are incorporated herein by reference.

[0109] General synthetic route According to Scheme 1, a compound of formula (I) is prepared, wherein R 5It is aryl or heteroaryl, and all other substituents are as defined in the general scope.

[0110] Option 1 According to scheme 1, make the compound of formula (II) (where X is CH or N and R) 5 A compound of formula (I) is provided by reacting a suitable halide (such as a fluoride) with a commercially available or synthetically available nucleophilic heterocycle (such as cis-2,6-dimethylmorpholine) in the presence of a suitable base (such as DIPEA, etc.); in a suitable solvent (such as DMSO, etc.); and at a suitable temperature (such as 120 °C).

[0111] In an alternative approach, the compound of formula (II) (where X is CH or N and R) is used. 5 A compound of formula (I) is prepared by reacting a suitable halide (such as, for example, Cl, Br or I) with a suitable commercially available or synthetically available nucleophilic heterocycle (such as, for example, cis-2,6-dimethylmorpholine) under standard transition metal-catalyzed amination conditions.

[0112] Compounds of formula (III) (where X is CH or N) are combined with suitable commercially available or synthetically available compounds of formula R. 1 An amine of NH2 reacts with a suitable coupling agent (such as, for example, HATU, HBTU, or 1-propanephosphonic anhydride), a suitable base (such as, for example, DIPEA), a suitable solvent (such as, for example, DCM or DMF), and at a suitable temperature (such as, for example, room temperature) to provide a compound of formula (I). In an alternative method, the formation of the corresponding acyl halide of formula (III) is achieved using a suitable activator (such as, for example, thionyl chloride), followed by reacting the acyl halide intermediate with a suitable, commercially available or synthetically obtainable compound of formula R. 1 An amine of NH2, reacted in the presence of a suitable base (such as, for example, Et3N or DIPEA), in a suitable solvent (such as, for example, DCM), and at a suitable temperature (such as, for example, room temperature), provides a compound of formula (I).

[0113] According to Scheme 2, the intermediate of formula (II) is prepared, wherein R 5 It is a suitably substituted aryl or heteroaryl group, such as, for example, pyridyl; Hal is a suitable halide, such as, for example, a fluoride; and all other substituents are as defined in the general scope. The intermediate of formula (III) is prepared according to scheme 2, wherein R... 5 It is a suitably substituted aryl group or heteroaryl group, such as, for example, pyridyl, and all other substituents are as defined in the general scope.

[0114] Option 2 The compound of formula (VII) (where X is CH or N, such as, for example, 7-chloro-1,6-naphthidium-2(1H)-one (CAS [1345091-18-0])) is commercially available or synthesizable by a person skilled in the art according to the procedures described herein or in the literature. The compound of formula (VII) (where Hal is a suitable halide, such as, for example, a chloride) is reacted with a suitable 2-halogenated zinc acetate (such as, for example, 2-tert-butoxy-2-oxoethyl zinc bromide (CAS [51656-70-3])) in the presence of a suitable catalyst (such as, for example, X-Phos-Pd G2 (CAS [1310584-14-5])) in a suitable solvent (such as, for example, THF) at a suitable temperature (such as, for example, 60 °C) to provide the compound of formula (VI).

[0115] The compound of formula (V) is prepared in two steps by the following method: first, the intermediate of formula (VI) is reacted with a suitable activator such as, for example, PyBroP (CAS [132705-51-2]) in the presence of a suitable base (such as, for example, DBU) in a suitable solvent (such as, for example, 1,4-dioxane) at a suitable temperature (such as, for example, room temperature); and in the second step, the intermediate formed is reacted with a suitable aryl- or heteroaryl-boronic acid or boronic ester (such as, for example, 6-fluoropyridine-2-boronic acid pinacol ester) in the presence of a suitable base (such as, for example, Na2CO3) in the presence of a suitable catalyst (such as, for example, X-Phos-Pd G2 (CAS [1310584-14-5])) in a suitable solvent (such as, for example, 1,4-dioxane) at a suitable temperature (such as, for example, 100°C). Alternatively, the compound of formula (V) is prepared by treating the compound of formula (VI) with a suitable activator (such as, for example, phosphorus oxychloride), and then reacting it with a suitable aryl- or heteroaryl-boronic acid or borate ester (such as, for example, pinacol 6-fluoropyridine-2-boronic acid) in the presence of a suitable base (such as, for example, Na2CO3), in the presence of a suitable catalyst (such as, for example, X-Phos-Pd G2 (CAS [1310584-14-5])), in a suitable solvent (such as, for example, 1,4-dioxane), at a suitable temperature (such as, for example, 100 °C).

[0116] A compound of formula (V) (where Hal is a suitable halide, such as, for example, a chloride) is reacted with a suitable deprotecting agent (such as, for example, TFA when R is a tert-butyl group) in a suitable solvent (such as, for example, DCM) at a suitable temperature (such as, for example, room temperature) to provide a compound of formula (IV). A compound of formula (IV) is then reacted with a suitable commercially available or synthetically obtainable amine R. 1 NH2 reacts in the presence of a suitable coupling agent (such as, for example, HATU, HBTU or 1-propanephosphonic anhydride); in the presence of a suitable base (such as, for example, DIPEA); in a suitable solvent (such as, for example, DCM or DMF) at a suitable temperature (such as, for example, room temperature) to provide a compound of formula (II).

[0117] The compound of formula (VIII) is prepared in two steps; firstly, the compound of formula (VI) is reacted with a suitable activator (such as, for example, PyBroP (CAS [132705-51-2])) in the presence of a suitable base (such as, for example, DBU) in a suitable solvent (such as, for example, 1,4-dioxane) at a suitable temperature (such as, for example, room temperature). In the second step, the resulting intermediate is coupled with a suitably substituted aryl or heteroaryl boronic acid or boronic ester (such as, for example, [3-(pyridin-4-yl)phenyl]boronic acid (CAS [337536-25-1])) in the presence of a suitable base (such as, for example, Na2CO3) in the presence of a suitable catalyst (such as, for example, X-Phos-Pd G2 (CAS [1310584-14-5])) in a suitable solvent (such as, for example, 1,4-dioxane) at a suitable temperature (such as, for example, 100°C).

[0118] In an alternative approach, the compound of formula (VIII) (where R) 5 The substituted heteroaryl group (defined as a substituted aryl group) is prepared by reacting a compound of formula (V) (where Hal is a suitable halide, such as, for example, a fluoride) with a suitable nucleophile R. 5a H (such as, for example, amines R) 9a R 9b NH) reacts in the presence of a suitable base (such as, for example, DIPEA), in a suitable solvent (such as, for example, DMSO), and at a suitable temperature (such as, for example, 110°C).

[0119] In an alternative method, the compound of formula (VIII) is prepared by: making the compound of formula (V) (wherein R) 5 The reaction is carried out with a suitable halide (Hal, such as Cl, Br or I) and a suitable nucleophile (such as cis-2,6-dimethylmorpholine, for example) under standard transition metal-catalyzed amination conditions.

[0120] The compound of formula (III) is prepared by making the compound of formula (VIII) (where R is C) 1-4 Alkyl groups are reacted with a suitable hydrolytic agent (such as TFA) in a suitable solvent (such as, for example, DCM) at a suitable temperature (such as, for example, room temperature). In an alternative method, the saponification of the ester compound of formula (VIII) into the acid compound of formula (III) is achieved using conditions known to those skilled in the art (e.g., using a suitable base (such as NaOH, LiOH, etc.), in a suitable solvent (such as water / THF / MeOH), at a temperature of about 60°C, for a period of about 2 hours).

[0121] According to scheme 3, a compound of formula (I) is prepared, wherein R 5 It is defined as an optional 6-membered ring, and all other substituents are as defined in the general scope.

[0122] Option 3 According to scheme 3, the compound of formula (VI) (where R is C) is made into a compound of formula (VI) (where R is C) 1-4 An alkyl group is reacted with a suitable hydrolytic agent (such as TFA) in a suitable solvent (such as, for example, DCM) at a suitable temperature (such as, for example, room temperature) to provide a compound of formula (XV). In an alternative method, the saponification of an ester compound of formula (VI) to an acid compound of formula (XV) is achieved using conditions known to those skilled in the art (e.g., using a suitable base (such as NaOH, LiOH, etc.), in a suitable solvent (such as water / THF / MeOH), at a temperature of about 60°C, for a period of about 2 hours). The compound of formula (XV) is then reacted with a suitable commercially available or synthetically obtainable amine R. 1 NH2 (such as, for example, 3-methylsulfonyl-4-methylaniline) reacts in the presence of a suitable coupling agent (such as, for example, HATU), in the presence of a suitable base (such as, for example, DIPEA), in a suitable solvent (such as, for example, ACN), and at a suitable temperature (such as, for example, room temperature) to provide a compound of formula (XIV).

[0123] Compounds of formula (XIV) are reacted with suitable amines or formula R. 5 The heteroaryl group of H reacts in the presence of a suitable activator (such as, for example, BOP (CAS [56602-33-6])), in the presence of a suitable base (such as, for example, DBU), in a suitable solvent (such as, for example, ACN), and at a suitable temperature (such as, for example, 80°C).

[0124] Alternatively, compounds of formula (I) (where all substituents are as defined in the general context) may be prepared according to scheme 4.

[0125] Option 4 According to scheme 4, the compound of formula (XVI) is prepared by reacting the compound of formula (XIV) with a suitable chlorinating agent (such as, for example, phosphorus trichloride) at a suitable temperature (such as, for example, 80°C). The compound of formula (XVI) (where Hal is a suitable halide, such as, for example, a chloride) is reacted with a suitable borate ester or boric acid R. 5 B(OR)2 is reacted under standard transition metal-catalyzed coupling conditions known to those skilled in the art to provide a compound of formula (I).

[0126] Technicians will recognize that an alternative sequence of chemical reactions shown in the scheme can also produce the desired compound of formula (I).

[0127] Those skilled in the art will recognize that the intermediates and final compounds shown in the following scheme can be further functionalized using methods well known to those skilled in the art.

[0128] These compounds of formula (I) can also be transformed into each other via reactions or functional group transformations known in the art. For example, substituents such as C(=O)-OC 1-6 Alkyl or C 1-6 Alkyl-OC (=O)- can be converted into a carboxyl group in the presence of lithium hydroxide and a suitable solvent (such as, for example, tetrahydrofuran or an alcohol such as methanol).

[0129] Technicians will recognize that, in some cases, it may be desirable or necessary to conduct the reaction in an inert atmosphere (such as, for example, N2 atmosphere) in the reaction described in the protocol.

[0130] It is obvious to those skilled in the art that the reaction mixture may need to be cooled before post-reaction processing, which means a series of operations required to separate and purify the products of the chemical reaction, such as quenching, column chromatography, or extraction.

[0131] Technicians will recognize that heating the reaction mixture with stirring can enhance the reaction results. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[0132] The compounds of the invention prepared in the methods described herein can be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from each other according to resolution methods known in the art. Racemic compounds of formula (I) containing a basic nitrogen atom can be converted to their corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are released therefrom by a base. Alternative methods for separating the enantiomers of compounds of formula (I) and their pharmaceutically acceptable addition salts involve liquid chromatography using a chiral stationary phase, for example by supercritical fluid chromatography. The pure stereochemical isomers can also be derived from their corresponding pure stereochemical isomers from suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound is synthesized by a stereospecific preparation method. These methods will advantageously employ optically pure starting materials.

[0133] In all these preparations, the reaction products can be separated from the reaction medium and, if necessary, further purified according to methods commonly known in the art, such as extraction, crystallization, grinding, and chromatography. The purity of the reaction products can be determined according to methods commonly known in the art, such as LC-MS, TLC, and HPLC.

[0134] Treatment methods and medical uses, pharmaceutical compositions and combinations The present invention also provides methods for treating or preventing proliferative diseases (e.g., cancer, benign tumors, angiogenesis) in a subject. Such methods include the step of administering to a subject in need an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof.

[0135] The subjects being treated are mammals. Subjects can be humans. Subjects can be domesticated animals, such as dogs, cats, cattle, pigs, horses, sheep, or goats. Subjects can be companion animals, such as dogs or cats. Subjects can be livestock, such as cattle, pigs, horses, sheep, or goats. Subjects can be zoo animals. Subjects can be research animals, such as rodents, dogs, or non-human primates. Subjects can be non-human transgenic animals, such as transgenic mice or transgenic pigs.

[0136] The use of compounds of formula (I) to treat or prevent proliferative diseases is generally associated with aberrant activity of SMARCA2. Aberrant activity of SMARCA2 can be elevated and / or inappropriate (e.g., abnormal) SMARCA2 activity. In some embodiments, SMARCA2 is not expressed, and SMARCA2 activity is elevated and / or inappropriate. In some other embodiments, SMARCA2 is overexpressed, and SMARCA2 activity is elevated and / or inappropriate. The compounds disclosed herein, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, can inhibit SMARCA2 activity and can be used to treat and / or prevent proliferative diseases.

[0137] Proliferative diseases may also be associated with inhibition of apoptosis in biological samples or subjects. All types of biological samples described herein or known in the art are considered to be within the scope of this invention. Inhibition of SMARCA2 activity is expected to cause cytotoxicity via induction of apoptosis. The compounds disclosed herein, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, can induce apoptosis and are therefore useful for the treatment and / or prevention of proliferative diseases.

[0138] In some embodiments, the proliferative disease to be treated or prevented by using the compounds disclosed herein is cancer.

[0139] The cells described in this article may be abnormal cells. Cells may be in vitro or in vivo. Cells may be proliferating cells.

[0140] In another aspect, the present invention provides a method for downregulating SMARCA2 expression in biological samples or subjects.

[0141] In another aspect, the present invention provides the compounds disclosed herein, and their pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, for use in the treatment of proliferative disorders in subjects. The compounds described herein, and their pharmaceutically acceptable salts and compositions thereof, can be used to inhibit cell growth. The compounds described herein, and their pharmaceutically acceptable salts and compositions thereof, can be used to induce apoptosis. The compounds described herein, and their pharmaceutically acceptable salts and compositions thereof, can be used to inhibit transcription.

[0142] Those skilled in the art will recognize that the therapeutically effective amount of the compounds of the present invention is an amount sufficient to have therapeutic activity, and this amount varies particularly depending on the type of disease, the concentration of the compound in the therapeutic agent, and the patient's condition. Generally, the amount of the compounds of the present invention administered as a therapeutic agent for the treatment of the conditions referred to herein will be determined by the attending physician based on the specific circumstances.

[0143] Technicians treating such diseases can determine the effective daily therapeutic dose from the test results given below. An effective daily therapeutic dose can range from about 0.005 mg / kg body weight to 50 mg / kg body weight. The amount of the compound according to the invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect can vary depending on the specific circumstances, such as the specific compound, the route of administration, the recipient's age and symptoms, and the specific condition or disease being treated. Treatment methods may also include administration of the active ingredient in a regimen of one to four times daily. In these treatment methods, it is preferable to formulate the compound according to the invention prior to administration. As described below, suitable pharmaceutical formulations are prepared using well-known and readily available ingredients by known methods.

[0144] While the active ingredient can be administered alone, it is preferred to be present in the form of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of compatibility with the other components of the composition and harmless to its recipient.

[0145] The pharmaceutical compositions of the present invention can be prepared by any method well known in the pharmacy field, for example, using methods such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18th edition, Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A specific compound, in a therapeutically effective amount as the active ingredient, in the form of a base or addition salt, is combined with a pharmaceutically acceptable carrier in a close mixture, the carrier being available in various forms depending on the desired formulation for administration. These pharmaceutical compositions are advantageously preferably suitable for systemic administration, such as oral, transdermal, or parenteral administration; or for topical administration, such as via inhalation or nasal spray in unit dosage forms. For example, in preparing compositions for oral dosage forms, in the case of oral liquid formulations such as suspensions, syrups, elixirs, and solutions, any commonly used pharmaceutical medium, such as water, glycols, oils, alcohols, etc., can be used; or in the case of powders, pills, capsules, and tablets, solid carriers, such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc., can be used. Tablets and capsules represent the most advantageous oral unit dosage forms due to their ease of administration, in which case a solid pharmaceutical carrier is obviously employed. For parenteral compositions, the carrier will typically consist at least substantially of sterile water, but may also include other components, such as those that aid in dissolution. For example, injectable solutions can be prepared in which the carrier comprises an aqueous saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable suspensions can also be prepared, in which case a suitable liquid carrier, suspending agent, etc., can be used. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancer and / or a suitable wetting agent, optionally combined with a small proportion of a suitable additive of any nature that does not cause any significant adverse effects on the skin. The additive may facilitate application to the skin and / or may contribute to the preparation of the desired composition. These compositions can be administered in various ways, such as as transdermal patches, spot-on drops, or ointments.

[0146] Particularly advantageous is the formulation of the above-described pharmaceutical compositions into unit dosage forms that are easy to administer and provide uniform dosage. As used in this specification and the claims herein, a unit dosage form refers to a physically discrete unit suitable for a single dose, each unit containing a predetermined amount of the active ingredient, calculated to combine with a desired drug carrier to produce the desired therapeutic effect. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, dry films, injectable solutions or suspensions, teaspoon-sized amounts, tablespoon-sized amounts, and their separate multiple dosage forms.

[0147] As is well known to those skilled in the art, the exact dosage and frequency of administration depend on the specific compound used, the specific condition being treated, the severity of the condition being treated, the patient's age, weight, sex, severity of the condition, general health, and any other medications the individual may be taking. Furthermore, it is apparent that the effective daily dose may be reduced or increased based on the response of the treated subject and / or on the evaluation of the physician prescribing the compound of the present invention.

[0148] The method described herein may further include the additional step of administering one or more other agents in combination with the compounds of the present invention, pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof. Therefore, combinations of the compounds or compositions of the present invention with other agents can be used to treat proliferative diseases resistant to treatment with other agents that do not contain the compounds or compositions of the present invention.

[0149] Combination therapy includes administration of a single-dose formulation containing a compound according to the invention and one or more additional therapeutic agents, as well as administration of the compound according to the invention and each additional therapeutic agent in their respective separate drug dose formulations. For example, the compound and therapeutic agent according to the invention may be administered together to a patient in a single oral dose composition such as a tablet or capsule, or each agent may be administered in a separate oral dose formulation.

[0150] Therefore, one embodiment of the present invention relates to a product comprising a compound according to the invention as a first active ingredient and one or more anticancer agents as additional active ingredients, for use as a combination formulation in the treatment of patients with cancer, either simultaneously, alone or sequentially.

[0151] One or more other pharmaceutical agents and the compounds according to the invention may be administered simultaneously (e.g., in a single or individual composition) or sequentially. In the latter case, two or more compounds will be administered for a period of time sufficient to ensure a beneficial or synergistic effect and in an amount and manner sufficient to ensure a beneficial or synergistic effect. It should be understood that the preferred method and order of administration of each component of the combination, as well as the corresponding dosage and regimen, will depend on the specific other pharmaceutical agents and the compounds of the invention administered, their route of administration, the specific tumor treated, and the specific host treated. The optimal method and order of administration, as well as the dosage and regimen, can be readily determined by those skilled in the art using conventional methods and based on the information listed herein.

[0152] When administered in combination, the weight ratio of the compound according to the invention to one or more other anticancer agents can be determined by those skilled in the art. As is well known to those skilled in the art, the ratio, as well as the exact dosage and frequency of administration, depend on the specific compound according to the invention and the other anticancer agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, general condition, method of administration, and other medications the individual may be taking. Furthermore, it is apparent that the effective daily dose may be reduced or increased based on the response of the treated subject and / or based on the evaluation of the physician prescribing the compound of the invention. The specific weight ratio of the compound of formula (I) of the invention to another anticancer agent may range from 1 / 10 to 10 / 1, more particularly from 1 / 5 to 5 / 1, and even more particularly from 1 / 3 to 3 / 1.

[0153] Example The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. All references cited in these examples and throughout the specification are incorporated herein by reference for all legal purposes. Starting materials and reagents used to synthesize the compounds described herein may be synthesized or may be available from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0154] When the center of the solid is represented by "RS", it means that a racemic mixture has been obtained.

[0155] Example A: Preparation and characterization of intermediates and final compounds Several methods for preparing the compounds of the present invention are illustrated in the following examples. Unless otherwise stated, all starting materials are commercially available and can be used without further purification, or alternatively synthesized by a person skilled in the art using well-known methods.

[0156] Table 2: Abbreviations abbreviation meaning <![CDATA[ACN or CH3CN]]> Acetonitrile Boc tert-butoxycarbonyl Co compound Co. No. or Cmpd # Compound numbering Cbz benzyloxycarbonyl DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide eq. equivalent <![CDATA[Et3N]]> Triethylamine EtOAc Ethyl acetate EtOH ethanol h Hour HATU Azabenzotriazole tetramethylonium hexafluorophosphate HBTU Benzotriazole tetramethylureonium hexafluorophosphate HPLC High performance liquid chromatography <![CDATA[iPrNH2]]> Isopropylamine iPrOH Isopropanol Me methyl MeOH methanol <![CDATA[MgSO4]]> Magnesium sulfate MsCl Methanesulfonyl chloride <![CDATA[Na2CO3]]> Sodium carbonate <![CDATA[NH4OAc]]> ammonium acetate <![CDATA[NH4OH]]> ammonium hydroxide <![CDATA[NH4Cl]]> ammonium chloride <![CDATA[POCl3]]> Phosphorus oxychloride PyBroP Tripyrrolylphosphonium bromide hexafluorophosphate quant. Quantitative rac racemic RM reaction mixture r.t. room temperature <![CDATA[SOCl2]]> thionyl chloride TFA Trifluoroacetic acid THF Tetrahydrofuran XPhos Pd G2 Chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) As will be understood by those skilled in the art, compounds synthesized using the methods indicated may contain residual solvents or small amounts of impurities.

[0157] Technicians will recognize that, even if not explicitly mentioned in the following experimental protocol, the desired fraction is typically collected and the solvent evaporated after column chromatography purification.

[0158] In the absence of a specified stereochemistry, this means that it is a mixture of stereoisomers unless otherwise indicated or is clear from the context.

[0159] Preparation of intermediates : For intermediates used as crude products or as partially purified intermediates in the next reaction step, in some cases, the molar amount of such intermediates is not mentioned in the next reaction step, or alternatively, the estimated or theoretical molar amount of such intermediates in the next reaction step is indicated in the reaction scheme below.

[0160] Intermediate 1: 2-(2-oxo-1,2-dihydro-1,6-naphthid-7-yl)tert-butyl acetate .

[0161] XPhos Pd G2 (CAS [1310584-14-5], 787 mg, 1 mmol) was added to a suspension of 7-chloro-1,6-naphthid-2(1H)-one (CAS [1345091-18-0], 1792 mg, 9.92 mmol) in anhydrous THF (75 mL) at room temperature under a nitrogen atmosphere, followed by the addition of 2-tert-butoxy-2-oxoethyl zinc bromide (100 mL of 0.5 M THF solution, 50 mmol). The solution was heated to 60 °C and held for 2 hours, then cooled to room temperature. Water and a saturated aqueous solution of NH4Cl were added, and the aqueous layer was extracted with EtOAc / Et2O (1 / 1). The organic matter was combined, washed with brine, dried over MgSO4, and concentrated under vacuum. Purified by silica gel (80 g) column chromatography, eluted with 0 to 100% (10% MeOH / EtOAc) / heptane, providing intermediate 1 (2.85 g, yield: 90%) as a yellow solid.

[0162] Intermediate 2: 2-(2-(6-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)tert-butyl acetate .

[0163] PyBrop (CAS [132705-51-2], 1.24 g, 2.66 mmol) was added to a stirred solution of intermediate 1 (576 mg, 2.21 mmol) in 20 mL of 1,4-dioxane under a nitrogen atmosphere at room temperature, followed by the addition of DBU (0.66 mL, 4.43 mmol). After 30 minutes, pinacol 6-fluoropyridine-2-boronic acid (CAS [842136-58-7], 987 mg, 4.43 mmol), Catacxium Pd G4 (CAS [2230788-67-5], 164 mg, 0.22 mmol), and an aqueous solution of sodium carbonate (2N, 3.32 mL, 6.64 mmol) were added, and the solution was rapidly brought to 100 °C. After 16 hours at 100 °C, water was added, the aqueous layer was extracted with DCM, dried over MgSO4, and concentrated under vacuum. Purified by silica gel (40 g) column chromatography, eluted with 0 to 100% EtOAc / heptane, to provide intermediate 2 (452 ​​mg, yield: 60%).

[0164] Intermediate 3: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)ethyl tert-butyl ester .

[0165] To a solution of intermediate 2 (85 mg, 0.25 mmol) in DMSO (3.8 mL), cis-2,6-dimethylmorpholine (0.061 mL, 0.48 mmol) and DIPEA (0.16 mL, 0.95 mmol) were added. The solution was heated to 100 °C for 2 hours, then to 110 °C for 16 hours. Cis-2,6-dimethylmorpholine (0.031 mL, 0.24 mmol) and DIPEA (0.04 mL, 0.24 mmol) were added, and the mixture was heated at 110 °C for 24 hours. Water and brine were added, and the aqueous layer was extracted with EtOAc / Et2O (1 / 1), and the organic matter was washed with water and brine. The combined organic layers were dried over MgSO4 and concentrated under vacuum. Purification was performed by silica gel (12 g) column chromatography, eluting with 0 to 100% EtOAc / heptane, to provide intermediate 3 (104 mg, yield: 99%).

[0166] Intermediate 4: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)ethyl acid .

[0167] HCl (4M in 1,4-dioxane, 7.5 mL, 30 mmol) was added to a solution of intermediate 3 (1.27 g, 2.92 mmol) in DCM (15 mL). The solution was stirred overnight at room temperature, then diluted with Et2O (20 mL) and filtered to collect the solid. The filter cake was washed with Et2O and dried under suction to give intermediate 4 (1.21 g, yield: 99%) as a yellow solid.

[0168] Intermediate 5: 2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthid-7-yl)tert-butyl acetate .

[0169] PyBrop (CAS [132705-51-2], 159 mg, 0.34 mmol) was added to a solution of intermediate 1 (74 mg, 0.28 mmol) in 1,4-dioxane (3 mL) at room temperature under a nitrogen atmosphere, followed by the addition of DBU (0.084 mL, 0.57 mmol). After 30 minutes, β-[3-(4-pyridyl)phenyl]boronic acid (CAS [337536-25-1], 85 mg, 0.43 mmol), X-PhosPd G2 (CAS [1310584-14-5], 22 mg, 0.028 mmol), and an aqueous solution of sodium carbonate (2N, 0.43 mL, 0.85 mmol) were added, and the solution was rapidly brought to 100 °C. After 16 hours at 100 °C, the reaction was cooled to room temperature, water was added, and the aqueous layer was extracted with DCM. The organic layer was dried over MgSO4 and concentrated under vacuum. Purified by silica gel (24 g) column chromatography, eluted with 0 to 100% EtOAc / heptane, yielding the title compound (55 mg, yield: 49%).

[0170] Intermediate 6: 2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthidin-7-yl)acetic acid .

[0171] TFA (0.5 mL) was added to a solution of intermediate 5 (55 mg, 0.14 mmol) in DCM (2 mL). After 16 hours at room temperature, the solution was concentrated under vacuum. The title compound was ready for use without further purification.

[0172] Intermediate 7: (E)-5-bromo-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one .

[0173] Add 20 g of 5-bromo-2,3-dihydroindanone (94.8 mmol, 1.00 eq.), 200 mL of EtOH, and 16 mL of HCl to a 500 mL three-necked flask. Then add t-BuNO2 (10.5 g, 101.4 mmol, 1.07 eq.). Stir the resulting mixture at room temperature for 2 hours. Collect the precipitated solid by filtration and wash with Et2O (2 × 10 mL) to give intermediate 7 (20.4 g, yield: 90%) as a white solid.

[0174] Intermediate 8: 6-bromo-1,3-dichloroisoquinoline .

[0175] Intermediate 7 (20.4 g, 85.0 mmol, 1 eq.), POCl3 (200 mL), and PCl5 (22.4 g, 107.6 mmol, 1.3 eq.) were added to a 2000 mL four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. HCl (gas) was added to the mixture. The mixture was stirred at room temperature for 1 hour, and then at 60 °C for 6 hours. The resulting mixture was concentrated under vacuum. The reaction was then quenched by adding water / ice (200 mL). The resulting solution was extracted with EtOAc (3 × 500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was recrystallized from EtOAc / petroleum ether 1 / 10 to give intermediate 8 (20 g, yield: 85%) as a yellow solid.

[0176] Intermediate 9: 6-bromo-3-chloroisoquinoline .

[0177] To a 500-mL three-necked round-bottom flask, add intermediate 8 (20 g, 72.2 mmol, 1 eq.), AcOH (200 mL), P (5.6 g, 2.5 eq.), and HI (21 mL, 1.60 eq., 45% in water). Stir the resulting solution overnight at 120 °C. After cooling, concentrate the mixture under vacuum and dilute the resulting solution with H₂O (500 mL). Adjust the pH of the solution to 10 using a saturated sodium carbonate aqueous solution. Extract the resulting solution with EtOAc (3 × 200 mL). Wash the combined organic layers with brine (2 × 300 mL), dry over anhydrous sodium sulfate, and concentrate under vacuum. Purify the residue by silica gel column chromatography using EtOAc / petroleum ether (1 / 30) to give intermediate 9 (19.8 g, yield: 96%) as a yellow solid.

[0178] Intermediate 10: 3-chloro-6-(6-fluoropyridin-2-yl)isoquinoline .

[0179] Program A : Add 6-fluoropyridin-2-ylboronic acid (CAS [916176-61-9], 20.9 g, 148.0 mmol, 1.30 eq.), Pd(dppf)Cl2 (CAS [72287-26-4], 8.3 g, 11.4 mmol, 0.10 eq.), intermediate 9 (27.6 g, 113.8 mmol, 1.00 eq.), K2CO3 (47.2 g, 341.4 mmol, 3.00 eq.), 1,4-dioxane (828 mL), and H2O (276 mL) to a 2 L three-necked flask. Evacuate the system and refill with nitrogen three times. Heat the reaction mixture to 80 °C for 40 minutes. Cool the mixture to room temperature, dilute with EtOAc (1 L), and wash with brine (2 × 300 mL). Dry the organic layer with Na2SO4, filter, and concentrate. The coarse solid was ground with ACN (60 mL) and filtered to obtain intermediate 10 (23.6 g, yield: 80%), which was a dark gray solid.

[0180] Program B : Under a nitrogen atmosphere, 6-bromo-3-chloroisoquinoline (CAS [552331-06-3], 1.009 g, 4.161 mmol), pinacol 6-fluoropyridine-2-borate (CAS [842136-58-7], 1.329 g, 5.958 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (CAS [72287-26-4], 0.299 g, 0.409 mmol) were suspended in degassed 1,4-dioxane (29 mL) and degassed aqueous K₂CO₃ solution (11 mL, 22 mmol, 2 M). The reaction mixture was stirred at 80 °C for 40 min. After cooling, the mixture was diluted with EtOAc, washed with brine, dried (MgSO₄), filtered, and concentrated. The crude product was ultrasonically ground in ACN. The resulting solid was separated by filtration, washed with another ACN, and dried under high vacuum to obtain intermediate 15 (0.902 g, yield: 84%), which was a dark gray solid.

[0181] Intermediate 11: 2-(6-(6-fluoropyridin-2-yl)isoquinoline-3-yl)tert-butyl acetate .

[0182] Program A : Intermediate 10 (23.6 g, 91.2 mmol, 1.00 eq.), XPhos Pd G2 (CAS [1310584-14-5], 14.4 g, 18.2 mmol, 0.20 eq.), THF (944 mL), and 2-tert-butoxy-2-oxoethyl zinc bromide (CAS [51656-70-3], 118.8 g, 456.2 mmol, 5.00 eq.) were added to a 2 L 3-necked flask. The system was evacuated and refilled three times with nitrogen. The reaction mixture was heated to 70 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc (600 mL) and washed with saturated NH4Cl aqueous solution (3 × 300 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether 1:10) to give intermediate 11 (25 g, yield: 81%) as a yellow solid.

[0183] Program B : Under a nitrogen atmosphere, intermediate 10b (0.096 g, 0.371 mmol) and XPhos Pd G2 (CAS [1310584-14-5], 0.031 g, 0.0394 mmol) were suspended in degassed anhydrous THF (5 mL). 2-tert-butoxy-2-oxoethyl zinc bromide (CAS [51656-70-3], 4.0 mL, 2.0 mmol, 0.5 M in Et2O) was added, and the reaction mixture was stirred at 70 °C for 1 hour. After cooling, the reaction mixture was diluted with EtOAc, washed with brine, dried (MgSO4), filtered, and concentrated. The crude residue was purified by rapid column chromatography (12 g SiO2, 0 – 10% 2N NH3 / MeOH (in DCM)) to give intermediate 16 (0.12 g, yield: 91%, purity: 95%) as a yellow solid.

[0184] Intermediate 12: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetic acid tert-butyl ester .

[0185] Program A : Add intermediate 11 (25 g, 73.9 mmol, 1.00 eq.), DMSO (1250 mL), DIPEA (38.2 g, 295.5 mmol, 4.00 eq.), and (2R,6S)-2,6-dimethylmorpholine (CAS [6485-55-8], 17.0 g, 147.8 mmol, 2.00 eq.) to a 2 L, 3-necked flask. Stir the reaction mixture overnight at 110 °C. Then, add the remaining portion of DIPEA (9.1 g, 73.9 mmol, 1.00 eq.) and (2R,6S)-2,6-dimethylmorpholine (8.5 g, 73.9 mmol, 1.00 eq.). Stir the mixture overnight at 110 °C. Dilute the resulting mixture with EtOAc (2 L) and wash with brine (3 × 1 L). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc: petroleum ether 1:5) to give intermediate 12 (24.4 g, yield: 76%) as a yellow solid.

[0186] Program B : A solution of intermediate 11b (0.631 g, 1.865 mmol), cis-2,6-dimethylmorpholine (CAS [6485-55-8], 0.7 mL, 5.512 mmol), and DIPEA (1.5 mL, 8.704 mmol) in anhydrous DMSO (10 mL) was stirred at 110 °C for 16 h. After cooling, the reaction mixture was diluted with 5% Et2O / EtOAc, washed twice with water, and once with brine. The organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified by rapid column chromatography (40 g SiO2, EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 19 (0.741 g, yield: 82%, purity: 90%).

[0187] Intermediate 13: 2-(6-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetic acid dihydrochloride .

[0188] Intermediate 12 (24.4 g, 56.3 mmol, 1.00 eq.), DCM (244 mL), and HCl (140 mL, 4 M in 1,4-dioxane) were added to a 500 mL three-necked flask. The mixture was stirred overnight at room temperature. The mixture was diluted with Et2O (200 mL) and filtered to collect the solid. The yellow solid was washed with Et2O (2 × 30 mL) and dried under vacuum to give intermediate 13 (18.723 g, yield: 88%) as a yellow solid.

[0189] Intermediate 14: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)- N-((R)-piperidin-3-yl)acetamide.

[0190] Intermediate 4 (200 mg, 0.528 mmol), HATU (CAS [148893-10-1], 241 mg, 0.634 mmol), and Et3N (0.184 mL, 1.321 mmol) were added to a vial containing DCM (3 mL). The mixture was stirred at room temperature for 5 minutes. (R)-1-Boc-3-aminopiperidine (CAS [188111-79-7], 116 mg, 0.581 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Volatile substances were removed under vacuum. The residue was dissolved in 2 mL of DCM, filtered, and TFA (1 mL) was added. After 15 minutes, volatile substances were removed. The residue was dissolved in DCM and neutralized with a saturated aqueous solution of NaHCO3. The organic layer was extracted with HCl (1 M in water). The acidic aqueous layer was neutralized with a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic layer was washed with brine, dried with Na2SO4, and evaporated to give intermediate 14 (220 mg, yield: 90%), which was a yellow solid.

[0191] Intermediate 17: 2-(6-(6-fluoropyridin-2-yl)isoquinoline-3-yl)acetic acid .

[0192] A solution of intermediate 11 (0.12 g, 0.337 mmol, purity: 95%) in DCM (4 mL) was treated with HCl (3.0 mL, 12 mmol, 4 M in 1,4-dioxane) at room temperature under a nitrogen atmosphere. After 1 week, the reaction mixture was concentrated and dried under high vacuum to give intermediate 17 (0.115 g, yield: 96%, bisHCl salt) as a white solid.

[0193] Intermediate 18: 2-(6-(6-fluoropyridin-2-yl)isoquinoline-3-yl)-N-(4-methyl-3-(methylsulfonyl)benzene) Acetamide .

[0194] A suspension of intermediate 17 (0.115 g, 0.324 mmol, bisHCl salt), 3-methanesulfonyl-4-methylaniline (CAS [307989-41-9], 0.075 g, 0.405 mmol), and HATU (CAS [148893-10-1], 0.146 g, 0.384 mmol) in ACN (5 mL) was treated with DIPEA (0.3 mL, 1.741 mmol) and stirred at room temperature for 20 min. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (12 g SiO2, 0 – 10% 2N NH3 / MeOH (in DCM)) followed by another rapid column chromatography (12 g SiO2, EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 18 (0.143 g, yield: 73%, purity: 74%).

[0195] Intermediate 21: (4-methyl-3-(methylthio)phenyl)tert-butyl carbamate .

[0196] A suspension of (3-bromo-4-methylphenyl)carbamate tert-butyl ester (CAS [515813-02-2], 0.249 g, 0.87 mmol) and Xantphos Pd G4 (CAS [1621274-19-8], 0.076 g, 0.079 mmol) in anhydrous 1,4-dioxane (5 mL) was treated with sodium methanethiol (CAS [5188-07-8], 0.112 g, 1.518 mmol) and then with DIPEA (0.4 mL, 2.321 mmol) while stirring under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at 90 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified by rapid column chromatography (40 g SiO2, isocratic DCM) to obtain intermediate 21 (0.058 g, yield: 26%).

[0197] Intermediate 22: (4-methyl-3-(S-methylsulfinimino)phenyl) tert-butyl carbamate .

[0198] A solution of intermediate 21 (0.058 g, 0.229 mmol) in MeOH (3 mL) was treated with (diacetoxyiodine)benzene (CAS [3240-34-4], 0.188 g, 0.584 mmol), followed by treatment with ammonium carbamate (CAS [1111-78-0], 0.038 g, 0.487 mmol) while stirring at room temperature. After 30 minutes, the reaction mixture was concentrated and the residue was purified by rapid column chromatography (12 g SiO2, EtOAc / DCM, 0 / 100 to 100 / 0) to give intermediate 22 (0.041 g, yield: 63%).

[0199] Intermediate 23: (5-amino-2-methylphenyl)(imino)(methyl)-16-thione .

[0200] The solution of intermediate 22 (0.041 g, 0.144 mmol) in DCM (5 mL) was treated with HCl (0.25 mL, 1 mmol, 4 M in 1,4-dioxane) with stirring at room temperature. After 16 hours, additional HCl (0.5 mL, 2 mmol, 4 M in 1,4-dioxane) was added and the reaction mixture was stirred at 50 °C for 90 min. After cooling, the reaction mixture was concentrated and further dried under high vacuum to give intermediate 23 (0.054 g, quantified, purity: 78%) as a triHCl salt.

[0201] Intermediate 24: 2-(2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl) 2,5-Dioxopyrrolidine-1-ester of acetate .

[0202] (Civic) Intermediate 4 (110 mg, 0.194 mmol), N-hydroxysuccinimide (CAS [6066-82-6], 25 mg, 0.213 mmol), and DMAP (2 mg, 0.0136 mmol) were dissolved in DMF (1.3 mL) and cooled to 0 °C. EDCI (CAS [25952-53-8], 56 mg, 0.291 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C, and DIPEA (0.17 mL, 0.97 mmol), EDCI (74 mg, 0.388 mmol), and N-hydroxysuccinimide (0.045 g, 0.388 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (25 mL) and washed with a 1:1 saline / water solution (25 mL). The aqueous layer was further extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with water (4 × 50 mL), NaHCO3 (2 × 50 mL), and brine (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain intermediate 24, which was a brown oily substance and could be used without further purification.

[0203] Intermediate 25: 2-(2-(6-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)acetic acid .

[0204] HCl (4 M in 1,4-dioxane, 5 mL, 20 mmol) was added to a solution of intermediate 2 (150 mg, 0.442 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness. The residue was placed in a saturated aqueous solution of NaHCO3 (2 mL) and extracted with EtOAc (2 × 8 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give intermediate 25 (130 mg, quantified) as a yellow solid, which could be used without further purification.

[0205] Intermediate 26: 2-(2-(6-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-methyl-3-(methanesulfonyl)) (Phenylacetamide) .

[0206] T3P (CAS [68957-94-8], 50% in EtOAc, 0.51 mL, 0.857 mmol) was added to a solution of intermediate 25 (120 mg, 0.424 mmol) and 4-methyl-3-(methanesulfonyl)aniline (CAS [307989-41-9], 79 mg, 0.427 mmol) in DCM (5 mL), and DIPEA (0.38 mL, 2.182 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL). The organic layer was concentrated under vacuum, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether, 0 / 100 to 50 / 50) to give intermediate 26 (100 mg, yield: 52%) as a yellow solid.

[0207] Intermediate 27: 7-(6-(7-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-2-oxoethyl)-1, 6-Naphthid-2-yl)pyridin-2-yl)-4,7-diazaspiro[2,5]octane-4-carboxylic acid tert-butyl ester .

[0208] DIPEA (0.3 mL, 1.741 mmol) was added to a solution of intermediate 26 (90 mg, 0.2 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (CAS [674792-08-6], 148 mg, 0.7 mmol) in DMSO (4 mL). The reaction mixture was stirred at 145 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The organic layer was concentrated under vacuum, and the residue was purified by silica gel rapid column chromatography (petroleum ether / EtOAc 1 / 1) to give intermediate 27 (232 mg, quantified) as a brown oil.

[0209] Intermediate 28: (cis)-4-(6-bromo-4-nitropyridin-2-yl)-2,6-dimethylmorpholine .

[0210] (Civic) 2,6-Dibromo-4-nitropyridine (CAS [175422-04-5], 5 g, 17.737 mmol) and cis-2,6-dimethylmorpholine (CAS [6485-55-8], 2.42 mL, 19.511 mmol, 1.1 eq.) were dissolved in toluene (140 mL), and the solution was degassed by bubbling with nitrogen for 15 min. Then, Cs₂CO₃ (8.67 g, 26.606 mmol, 1.5 eq.), racemic-BINAP (CAS [98327-87-8], 1.10 g, 1.774 mmol, 0.1 eq.) and Pd(OAc)₂ (CAS [3375-31-3], 398 mg, 1.774 mmol, 0.1 eq.) were added, and the resulting mixture was refluxed and stirred under nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 × 250 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography (120 g column, EtOAc / heptane gradient, 0 / 100 to 40 / 60) to give intermediate 28 (3.2 g, yield: 56%) as an orange solid.

[0211] Intermediate 29: (cis)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine .

[0212] (Civic) Tetramethylammonium fluoride (CAS [373-68-2], 663 mg, 7.117 mmol, 1.5 eq.) was added to a solution of intermediate 28 (1500 mg, 4.745 mmol) in DMF (40 mL) in a sealed tube. The mixture was stirred at 65 °C for 3 h. The reaction was quenched by adding water, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (80 g column, EtOAc / heptane gradient, 0 / 100 to 30 / 70) to give intermediate 29 (1139 mg, yield: 81%) as an orange solid.

[0213] Intermediate 30: (cis)-4-(4-fluoro-6-(tributylmtinyl)pyridin-2-yl)-2,6-dimethylmorpholine (Civic) Pd2(dba)3 (CAS [51364-51-3], 100 mg, 0.109 mmol), tricyclohexylphosphine (CAS [2622-14-2], 60 mg, 0.214 mmol), and LiCl (132 mg, 3.114 mmol) were added to a solution of intermediate 29 (300 mg, 1.038 mmol) and 1,1,1,2,2,2-hexabutyldimethylstanane (CAS [813-19-4], 2.270 g, 3.913 mmol) in 1,4-dioxane (6 mL). The mixture was stirred at 105 °C under a nitrogen atmosphere for 12 hours. A saturated aqueous solution of KF (10 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 10 minutes and then filtered through a diatomaceous earth mat. The filtrate was extracted with EtOAc (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether, 0 / 100 to 10 / 90) to give intermediate 30 (600 mg, purity: 75%, yield: 86%), which was a yellow oil.

[0214] Intermediate 31: 2-(2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidine-7- tert-butyl acetate .

[0215] (Civic) PyBroP (CAS [132705-51-2], 324 mg, 0.695 mmol) and DBU (CAS [6674-22-2], 180 mg, 1.182 mmol) were added to a solution of intermediate 1 (150 mg, 0.576 mmol) in 1,4-dioxane (6 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Then, intermediate 30 (350 mg, 0.523 mmol), LiCl (78 mg, 1.840 mmol), Pd2(dba)3 (CAS [51364-51-3], 54 mg, 0.059 mmol) and tricyclohexylphosphine (CAS [2622-14-2], 30 mg, 0.107 mmol) were added to the mixture at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 105 °C for 12 hours. The mixture was filtered, concentrated under vacuum, and purified by silica gel column chromatography (EtOAc / petroleum ether, 0 / 100 to 60 / 40) to give intermediate 31 (150 mg, purity: 69%) as a yellow solid, which was used without further purification.

[0216] Intermediate 32: 2-(2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidine-7- acetic acid (Civic) Intermediate 32 is prepared using intermediate 31 instead of intermediate 5, following the same procedure as intermediate 6.

[0217] Intermediate 33: 3-(cyclopropylsulfonyl)bicyclo[1.1.1]pentane-1-amine .

[0218] Under a nitrogen atmosphere, a solution of dibutyl phosphate (CAS [107-66-4], 53 μL, 0.27 mmol) in DMA (0.8 mL) and ACN (0.8 mL) was added to 1,3-dihydro-1,3-dioxo-2H-isoindole-2-ester of 3-[[(1,1-dimethylethoxy)carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid 1,3-dihydro-1,3-dioxo-2H-isoindole-2-ester (CAS [2248340-09-0], 50 mg, 0.13 mmol), sodium cyclopropane sulfinate (CAS [910209-21-1], 35 mg, 0.28 mmol), 4CZIPN (CAS [1416881-52-1], 2 mg, 0.0003 mmol) and copper(II) trifluoromethanesulfonate (CAS [107-66-4], 53 μL, 0.27 mmol) in DMA (0.8 mL) and ACN (CAS [107-66-4], 53 μL, 0.27 mmol) in DMA (0.8 mL) and ACN (CAS [107-66-4], 53 μL, 0.27 mmol) in DMA (0.8 mL), 50 mg, 0.13 mmol), 50 mg, 0.13 mmol, ... A mixture of [34946-82-2] (10 mg, 0.027 mmol) was prepared. The mixture was irradiated in a Penn reactor (blue LED (100%), 6800 FAN) for 12 hours. The solvent was evaporated, and the residue was placed in water (1.5 mL) and DCM (1.5 mL). The mixture was stirred at room temperature for 10 minutes and then placed in an Isolute separator tube for elution with DCM. The filtrate was concentrated under vacuum. The residue was dissolved in DCM (0.5 mL) and then TFA (0.1 mL, 1.31 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated under vacuum. The residue was dissolved in MeOH and passed through an SCX-2 ion exchange tube, eluted with ammonia (7 N, in MeOH) to give intermediate 33 (25 mg, quantified), which was used without further purification.

[0219] Intermediate 34: 6-chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoquinoline .

[0220] 2-Bromo-4-chlorobenzaldehyde (CAS [84459-33-6], 4.4 g, 20.2 mmol), Et3N (5.6 mL, 40.5 mmol), and tert-butylamine (CAS [75-64-9], 6.4 mL, 61 mmol) were dissolved in ACN (60 mL) in a sealed tube at room temperature. Tetrahydro-2-(2-propynyloxy)-2H-pyran (CAS [6089-04-9], 4.3 mL, 31 mmol) was then added, and the reaction mixture was bubbled under nitrogen for 5 minutes. 1,2-bis(diphenylphosphino)ethane nickel(II) chloride (CAS [14647-23-5], 1.0 g, 2.0 mmol) was added, and the mixture was stirred at 80 °C for 16 hours. The mixture was diluted with water and extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (silica 12 g; AcOEt / heptane, 0 / 100 to 30 / 70) to give intermediate 34 (1 g, yield: 18%), which was an orange oil.

[0221] Intermediate 35: (6-chloroisoquinoline-3-yl)methanol .

[0222] p-Toluenesulfonic acid monohydrate (CAS [6192-52-5], 685 mg, 3.6 mmol) was added to a stirred solution of intermediate 34 (1 g, 3.6 mmol) in MeOH (30 mL). The reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with EtOAc and washed with water. The aqueous layer was neutralized with an aqueous solution of Na2CO3 (1 M) and extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (40 g silica; AcOEt / heptane, 0 / 100 to 80 / 20) to give intermediate 35 (462 mg, 66%) as a white solid.

[0223] Intermediate 36: 6-chloro-3-(chloromethyl)isoquinoline .

[0224] p-Toluenesulfonyl chloride (CAS [98-59-9], 589 mg, 3.1 mmol) was added to intermediate 35 (460 mg, 2.38 mmol), DIPEA (0.869 mL, 5.0 mmol), and DMAP (CAS [1122-58-3], 58 mg, 0.47 mmol) in a stirred solution of DCM (15 mL). The mixture was stirred at room temperature for 5 hours. The mixture was diluted with water, extracted with AcOEt, and the organic layer was washed with brine (×2). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (silica 12 g; AcOEt / heptane, 0 / 100 to 50 / 50) to give intermediate 36 (293 mg, yield: 58%) as a white solid.

[0225] Intermediate 37: 2-(6-chloroisoquinoline-3-yl)acetonitrile .

[0226] Sodium cyanide (118 mg, 2.40 mmol) was added to a stirred solution of intermediate 36 (285 mg, 1.34 mmol) in DMSO (3 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, extracted with AcOEt, and the organic layer was washed with brine (×2). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (12 g silica; AcOEt / heptane, 0 / 100 to 50 / 50) to give intermediate 37 (180 mg, yield: 65%) as a brown solid.

[0227] Compound 38: 2-(6-chloroisoquinoline-3-yl)acetic acid .

[0228] Intermediate 37 (175 mg, 0.86 mmol) was dissolved in NaOH (2.5 M in water, 20 mL). The mixture was stirred at 115 °C for 16 hours. The mixture was diluted with EtOAc and water, and the layers were separated. The aqueous layer was acidified to pH 1 with HCl (1 M in water) and then extracted with EtOAc (×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 38 (181 mg, yield: 95%) as a yellow solid.

[0229] Intermediate 39: 2-(6-chloroisoquinoline-3-yl)-N-(1-(methanesulfonyl)piperidin-3-yl)acetamide .

[0230] HATU (CAS [148893-10-1], 140 mg, 0.37 mmol) was added to intermediate 38 (180 mg, 0.81 mmol), 1-methanesulfonylpiperidin-3-ylamine (CAS [934107-80-9], 145 mg, 0.81 mmol), and DIPEA (0.567 mL, 3.2 mmol) in a stirred solution of DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, extracted with DCM, and the organic layer was washed with brine (×2). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (silica 12 g; EtOAc / heptane, 0 / 100 to 100 / 0) to give intermediate 39 (197 mg, yield: 63%) as a white solid.

[0231] Intermediate 40: Methyl 2-(6-chloroisoquinoline-3-yl)acetate .

[0232] Sulfuric acid (95%, 0.132 mL, 2.5 mmol) was added to a solution of intermediate 38 (55 mg, 0.25 mmol) in methanol (1 mL), and the mixture was stirred at 50 °C for 16 hours. The solvent was evaporated, and the residue was diluted with water and EtOAc and alkalized to pH 9–10 with a saturated aqueous Na₂CO₃ solution. The mixture was extracted with EtOAc, the organic layer was separated, dried over MgSO₄, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (12 g silica; AcOEt / heptane, 0 / 100 to 80 / 20) to give intermediate 40 (60 mg, yield: 98%) as a yellow oil.

[0233] Intermediate 41: 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)isoquinoline-3- Methyl acetate .

[0234] The mixture of intermediate 40 (60 mg, 0.24 mmol), bis(pinacol)diborane (CAS [73183-34-3], 123 mg, 0.48 mmol), and potassium acetate (74 mg, 0.751 mmol) in 1,4-dioxane (2 mL) was degassed by bubbling under nitrogen for 15 min. Then, Xphos Pd G3 (CAS [1445085-55-1], 21 mg, 0.024 mmol) and Xphos (CAS [564483-18-7], 23 mg, 0.05 mmol) were added, and the mixture was stirred at 70 °C for 16 h. After cooling, the mixture was filtered through a diatomaceous earth mat, and the solvent was evaporated under vacuum. The residue was purified by rapid column chromatography (80 g silica; EtOAc / heptane, 0 / 100 to 70 / 30) to give intermediate 41 (72 mg, yield: 86%) as a colorless oil.

[0235] Intermediate 42: 6-chloro-2-((cis)-2,6-dimethylmorpholino)-3-methylpyrimidin-4(3H)-one .

[0236] (Civic) Cis-2,6-dimethylmorpholine (CAS [6485-55-8], 0.45 mL, 3.6 mmol) was added to a stirred solution of 2,6-dichloro-3-methyl-4(3H)-pyrimidinone (812 mg, 4.5 mmol) and DIPEA (2.2 mL, 13.6 mmol) in DMSO (8 mL). The mixture was stirred at 130 °C for 16 hours. The mixture was diluted with water and extracted with EtOAc (×3). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (24 g silica; EtOAc / heptane, 0 / 100 to 70 / 30) to give intermediate 42 (870 mg, 74%) as a yellow solid.

[0237] Intermediate 43: 2-(6-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidine methyl 4-(isoquinoline-3-)acetate .

[0238] (Civic) In a sealed tube under a nitrogen atmosphere, PdCl2 (dppf) (CAS [95464-05-4], 8 mg, 0.01 mmol) was added to a stirred solution of intermediate 41 (68 mg, 0.21 mmol), intermediate 42 (53 mg, 0.21 mmol), and sodium bicarbonate (35 mg, 0.41 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL). The mixture was stirred at 90 °C for 16 hours. After cooling, the mixture was filtered through a diatomaceous earth pad, diluted with water, and extracted with AcOEt. The organic layer was washed with brine (×2). The organic layer was evaporated under vacuum. The crude product was purified by rapid column chromatography (silica 24 g; MeOH / DCM, 0 / 100 to 10 / 90) to give intermediate 43 (181 mg, yield: 63%) as a brown oil.

[0239] Intermediate 44: 2-(6-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidine (Pyridine-4-yl)isoquinoline-3-yl)acetic acid .

[0240] (Civic) Sodium hydroxide (2.5 M in water, 0.5 mL, 1.3 mmol) was added to a stirred solution of intermediate 43 (18.0 mg, 0.43 mmol) in MeOH (12 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH 5 with HCl (1 M in water) and then extracted with EtOAc (×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give intermediate 44 (144 mg, yield: 82%) as a beige solid.

[0241] Intermediate 45: Methyl 2-(6-phenylisoquinoline-3-yl)acetate .

[0242] In a sealed tube under a nitrogen atmosphere, PdCl2 (dppf) (CAS [95464-05-4], 103 mg, 0.13 mmol) was added to an intermediate 41 (827 mg, 2.5 mmol), bromobenzene (CAS [108-86-1], 266 mg, 2.5 mmol), and sodium bicarbonate (425 mg, 5.1 mmol) in a stirred solution of 1,4-dioxane (4 mL) and water (1 mL). The mixture was stirred at 90 °C for 16 hours. After cooling, the mixture was filtered through a diatomaceous earth mat, diluted with water, and extracted with AcOEt. The organic layer was washed with brine (×2) and evaporated under vacuum. The crude product was purified by rapid column chromatography (silica 24 g; MeOH / DCM, 0 / 100 to 10 / 90) to give intermediate 45 (864 mg, yield: 86%) as a brown solid.

[0243] Compound 46: 2-(6-phenylisoquinoline-3-yl)acetic acid .

[0244] Sodium hydroxide (1 M in water, 6.5 mL, 6.5 mmol) was added to a stirred solution of intermediate 45 (604 mg, 2.18 mmol) in methanol (3 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 4 with HCl (1 M in water) and then concentrated under vacuum. The residue was purified by rapid column chromatography (40 g silica; MeOH (containing acetic acid), in DCM, 0 / 100 to 10 / 90) to give intermediate 46 (307 mg, yield: 53%) as a yellow solid.

[0245] Intermediate 47: (3-aminophenyl)(difluoromethyl)(imino)-λ 6 -Thione; Intermediate 48: (*R)-(3-amino) phenyl)(difluoromethyl)(imino)-λ 6 -Thione and intermediate 49: (*S)-(3-aminophenyl)(difluoromethyl)(imine) (base)-λ 6 -Thione .

[0246] Iron powder (130 g, 2.33 mol, 5.0 eq.) was added in batches to (difluoromethyl)(imino)(3-nitrophenyl)-λ 6- A solution of thione (CAS [2361945-66-4], 110 g, 465 mmol) and NH4Cl (124 g, 2.33 mol, 5.0 eq.) in THF (500 mL), MeOH (500 mL), and water (500 mL). The reaction mixture was stirred at 60 °C for 6 hours. The reaction mixture was then filtered, and the filter cake was washed several times with EtOAc. The filtrate was evaporated. The residue was diluted with water (400 mL) and extracted with EtOAc (600 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography (330 g SepaFlash). ® Rapid silica column chromatography (25% to 28%, EtOAc, in petroleum ether) was used to purify intermediate 47 (70.0 g, yield: 71%), which was a yellow solid.

[0247] The batch of intermediate 47 was separated into its stereoisomers by SFC (Regis Reflect i-Cellulose-C 250mm×30mm 5um; 80% CO2 – 20% IPA + 0.1% DEA to 80% CO2 – 20% IPA + 0.1% DEA) to obtain intermediates 48 and 49.

[0248] Intermediate 50: 3-(cyclopropylsulfonyl)cyclobutane-1-amine .

[0249] Intermediate 50 was prepared using the same procedure as intermediate 33, but instead of intermediate 33, 3-[[(1,1-dimethylethoxy)carbonyl]amino]cyclobutanecarboxylic acid 1,3-dihydro-1,3-dioxo-2H-isoindole-2-ester (CAS [2248324-36-7]).

[0250] Intermediate 51: 3-(methylsulfonyl)cyclohexane-1-amine .

[0251] Following the same procedure as intermediate 33, intermediate 51 was prepared using (1R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexanecarboxylic acid relative-1,3-dihydro-1,3-dioxo-2H-isoindole-2-ester (CAS [2248335-83-1]) instead of 3-[[(1,1-dimethylethoxy)carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid 1,3-dihydro-1,3-dioxo-2H-isoindole-2-ester and sodium methanesulfinate (CAS [20277-69-4]) instead of sodium cyclopropanesulfinate.

[0252] Intermediate 52: 3-(cyclopropylsulfonyl)cyclohexane-1-amine .

[0253] Intermediate 52 was prepared using (1R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexanecarboxylic acid relative-1,3-dihydro-1,3-dioxo-2H-isoindole-2-ester (CAS [2248335-83-1]) instead of 3-[[(1,1-dimethylethoxy)carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid 1,3-dihydro-1,3-dioxo-2H-isoindole-2-ester, following the same procedure as intermediate 33.

[0254] Preparation of Examples Example 1: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N- (4-Methyl-3-(methylsulfonyl)phenyl)acetamide .

[0255] Step A: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetic acid. Add TFA (0.5 mL) to a solution of intermediate 3 (104 mg, 0.24 mmol) in DCM (2 mL). After 16 hours at room temperature, concentrate the solution under vacuum.

[0256] Step B: DMF (3 mL), DIPEA (0.24 mL, 1.41 mmol), HATU (134 mg, 0.35 mmol), and 3-methanesulfonyl-4-methylaniline (65 mg, 0.35 mmol) were added to 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthid-7-yl)acetic acid, and the mixture was stirred at room temperature for 2 hours. EtOAc and Et2O were added, the solution was washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. Purification was performed by HPLC (150 mm × 30 mm C18 column, eluted with 10% to 80% ACN / H2O + 0.1% TFA) to give the title compound (16 mg, yield: 12%).

[0257] The following compounds were prepared by substituting appropriate reagents in the appropriate steps according to the above procedure: Example 2: 2-(2-(6-((3) α ,4β,5 α )-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1, 6-Naphthid-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide .

[0258] The title compound and Example 9 were obtained by purification of Example 3 by RP HPLC (0.1% TFA in water and ACN, run for 16 min (s: 10% ACN slowly increased to 50% over 8 min, then rapidly increased to 100% to end), column: (OOD-4633-UO-AX Kinetex 5um EVO c18 100)).

[0259] Example 3: (racemic) 2-(2-(6-((3S,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridine-2- (4-methyl-3-(methylsulfonyl)phenyl)acetamide .

[0260] The title compound was prepared in a manner similar to intermediate 12, using racemic 3,5-dimethyl-4-piperidinol CAS RN 373603-93-1 instead of (2R,6S)-2,6-dimethylmorpholine and intermediate 26 instead of intermediate 11.

[0261] Example 4: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N- (1-(methylsulfonyl)indololin-6-yl)acetamide .

[0262] Step A: 2-(2-(6-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(methanesulfonyl)indoline-6-yl)acetamide. The title compound was prepared by using 1-(methanesulfonyl)indoline-6-amine instead of 3-methanesulfonyl-4-methylaniline, in a manner similar to intermediate 18.

[0263] Step B: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(1-(methanesulfonyl)indoline-6-yl)acetamide. The title compound is prepared by replacing intermediate 11 with 2-(2-(6-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(methanesulfonyl)indoline-6-yl)acetamide, similar to intermediate 12.

[0264] Example 5: N-(4-methyl-3-(methanesulfonyl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthalene (Pyridine-7-yl)acetamide .

[0265] Intermediate 6 (2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthid-7-yl)acetic acid) was dissolved in DMF (2 mL) and treated with DIPEA (0.095 mL, 0.55 mmol), HATU (79 mg, 0.21 mmol), and 3-methanesulfonyl-4-methylaniline (CAS [307989-41-9], 38 mg, 0.21 mmol), and the reaction mixture was stirred at room temperature for 2 hours. Water was added, the solution was extracted with DCM, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by HPLC (150 mm × 30 mm C18 column, eluted with 10% to 80% ACN / H2O + 0.1% TFA) to obtain the title compound as a solid (14 mg, yield: 21%).

[0266] Example 6: N-(3-(2-hydroxypropane-2-yl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthalene (Pyridine-7-yl)acetamide .

[0267] The title compound was prepared using intermediate 6 (2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthid-7-yl)acetic acid) and 2-(3-aminophenyl)propane-2-ol (CAS [23243-05-2]) in a manner similar to that of Example 5.

[0268] Example 7: N-(5-(methylsulfonyl)pyridin-3-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthalene (Pyridine-7-yl)acetamide The title compound was prepared using intermediate 6 (2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthid-7-yl)acetic acid) and 5-(methanesulfonyl)pyridine-3-amine (CAS [1067530-19-1]) in a manner similar to that of Example 5.

[0269] Example 8: N-(1-(methanesulfonyl)indoline-6-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthalene (Pyridine-7-yl)acetamide .

[0270] The title compound was prepared using intermediate 6 (2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthid-7-yl)acetic acid) and 2,3-dihydro-1-(methanesulfonyl)-1H-indole-6-amine (CAS [620985-93-5]) in a manner similar to that of Example 5.

[0271] Example 9: 2-(2-(6-((3) α ,4 α ,5 α )-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1, 6-Naphthid-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide .

[0272] (3α, 4α, 5α) Example 9 was separated from Example 3 by RP HPLC (using the same method as Example 2).

[0273] Example 10: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)- N-(3-((2-hydroxyethyl)sulfonyl)-4-methylphenyl)acetamide .

[0274] (Civic) Method E DIPEA (0.2 mL, 1.148 mmol) and T3P (CAS [68957-94-8], 50% in EtOAc, 0.3 mL, 0.504 mmol) were added to intermediate 4 (85 mg, 0.225 mmol) and a solution of 2-((5-amino-2-methylphenyl)sulfonyl)ethanol (CAS [41506-69-8], 48 mg, 0.225 mmol) in DCM (4 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL). The organic layer was concentrated under vacuum, and the residue was purified by preparative HPLC (Boston Green ODS 150 mm * 30 mm * 5 μm; water (FA) / ACN, 60 / 40 to 30 / 70) to give the title compound (25 mg, yield: 19%) as a yellow solid.

[0275] Prepare the compounds in Table 3 using the amines shown in Method E: Table 3 . Example 11: 2-(2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidine-7- 4-(4-methyl-3-(methylsulfonyl)phenyl)acetamide .

[0276] At 0 °C, TFA (3 mL) was added dropwise to a suspension of intermediate 27 (190 mg, 0.296 mmol) in DCM (10 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 2). The organic layer was concentrated under vacuum, and the residue was purified by silica gel column chromatography (DCM / MeOH 10 / 1) followed by preparative HPLC (Boston Green ODS 150 mm × 30 mm × 5 μm; water (FA) / ACN, 87 / 13 to 57 / 43) to give the title compound (36 mg, yield: 21%) as a yellow solid.

[0277] Example 23: 2-(2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidine-7- 4-(4-methyl-3-(methylsulfonyl)phenyl)acetamide .

[0278] (Civic) The title compound was prepared in a manner similar to Method E of Example 10, using intermediate 32 instead of intermediate 4 and 4-methyl-3-(methylsulfonyl)aniline (CAS [307989-41-9]) instead of 2-((5-amino-2-methylphenyl)sulfonyl)ethanol.

[0279] Example 26: 2-(6-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)isoquinoline-3-yl)- N-(4-Methyl-3-(methylsulfonyl)phenyl)acetamide .

[0280] A solution of intermediate 18 (0.07 g, 0.115 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (CAS [6747492-08-6], 0.064 g, 0.301 mmol), and DIPEA (0.1 mL, 0.58 mmol) in anhydrous DMSO (4 mL) was stirred at 130 °C for 48 h. After cooling, the reaction mixture was treated with TFA (0.1 mL, 1.307 mmol) and stirred at room temperature for 6 h, followed by heating at 100 °C for 16 h. After cooling, the reaction mixture was purified directly by reversed-phase HPLC (WatersXBridge BEH C18, 5µm, 19mm×150mm, 30%-65% ACN / H2O (containing 10mM NH4OH)), followed by purification by another reversed-phase HPLC (Waters XSelect CSH Fluoro Phenyl, 5µm, 19mm×150mm, 10%-40% ACN / H2O (containing 0.16% TFA)) to give the title compound (11mg, yield: 15%, TFA-salt) as a yellow solid.

[0281] Example 27: 2-(6-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)iso Quinoline-3-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide .

[0282] (3α,4β,5α) The title compound was prepared in a manner similar to that of Example 26, using (3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidine (CAS[374067-78-4]) ​​instead of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate, and omitting the TFA deprotection step.

[0283] Example 28: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N- (4-Methyl-3-(methylsulfonyl)phenyl)acetamide .

[0284] (Civic) Intermediate 13 (0.052 g, 0.115 mmol, bisHCl salt), 3-methanesulfonyl-4-methylaniline (CAS [307989-41-9], 0.027 g, 0.146 mmol), and HATU (CAS [148893-10-1], 0.047 g, 0.124 mmol) in a suspension in ACN (4 mL) were treated with DIPEA (0.1 mL, 0.58 mmol) with stirring at room temperature. After 10 minutes, the reaction mixture was filtered and directly purified by reversed-phase HPLC (Waters XBridge BEH C18, 5 μm, 19 mm × 150 mm, 40%–75% ACN / H2O (containing 10 mM NH4OH)) to give the title compound (29 mg, yield: 45%) as a brown solid.

[0285] Example 29: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N- (3-((2-hydroxyethyl)sulfonyl)-4-methylphenyl)acetamide .

[0286] (Civic) The title compound was prepared in a manner similar to that of Example 28, using 2-[(5-amino-2-methylphenyl)sulfonyl]ethanol (CAS[41506-69-8]) instead of 3-methanesulfonyl-4-methylaniline.

[0287] Example 30: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)- N-(5-(methylsulfonyl)pyridin-3-yl)acetamide .

[0288] (Civic) The title compound was prepared using intermediates 4 and 5-(methylsulfonyl)pyridine-3-amine (CAS [1067530-19-1]) following the same procedure as in Example 28.

[0289] Example 35: N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholine) (Pyridin-2-yl)-1,6-naphthid-7-yl)acetamide .

[0290] Method A An intermediate 4 (32 mg, 0.078 mmol) and a solution of DIPEA (0.07 mL, 0.39 mmol) in DMF (0.4 mL) were added to a vial containing 3-difluoromethanesulfonylaniline (CAS [24906-76-1], 20 mg, 0.065 mmol). A solution of HATU (CAS [148893-10-1], 58 mg, 0.15 mmol) in DMF (0.4 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The crude reaction mixture was purified by HPLC (19 mm × 100 mm C18 column, 35% to 75% ACN / H2O + 0.1% NH3) to give the title compound (8 mg, yield: 19%).

[0291] The compounds in Table 4 were prepared from intermediate 4 and the corresponding amine according to the procedure in Method A of Example 35.

[0292] Table 4. Example 53: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)- N-(1-(methylsulfonyl)piperidin-3-yl)acetamide .

[0293] (Civic) DIPEA (0.05 mL, 0.29 mmol) was added to a solution of intermediate 24 (46 mg, 0.097 mmol) in ACN (1 mL), followed by the addition of 1-methanesulfonylpiperidin-3-amine (CAS [934107-80-9], 34 mg, 0.193 mmol). The vial was sealed and the reaction mixture was stirred at 60 °C for 30 min. The reaction mixture was filtered, and the filtrate was purified directly by reversed-phase column chromatography (Waters XBridge BEH C18, 5 μm, 19 mm × 150 mm; water + pH 10 NH4OH / ACN + pH 10 NH4OH, 30% to 65% ACN) to give the title compound.

[0294] Example 56: N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6-dimethylmorpholine) (2-yl)pyridin-2-yl)isoquinoline-3-yl)acetamide .

[0295] Method B An intermediate 13 (50 mg, 0.132 mmol) and a solution of DIPEA (0.046 mL, 0.27 mmol) in DMF (0.5 mL) were added to a vial containing 3-difluoromethanesulfonylaniline (CAS [24906-76-1], 30 mg, 0.146 mmol). A solution of HATU (CAS [148893-10-1], 76 mg, 0.20 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred at room temperature for 5 hours. Purification by HPLC (19 mm × 100 mm C18 column, eluted with 10% to 90% ACN / H2O + 0.1% NH3) gave the title compound (36 mg, yield: 48%).

[0296] Examples 57 and 58: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthalene (Pyridine-7-yl)-N-((*R)-1-(methylsulfonyl)piperidin-3-yl)acetamide and 2-(2-(6-((cis)-2,6-dimethyl) (Pyridin-2-yl)-1,6-naphthid-7-yl)-N-((*S)-1-(methylsulfonyl)piperidin-3-yl)acetamide .

[0297] (*R), (cis) (*S), (cis) Chiral separation of the stereoisomers in Example 53 was performed using SFC (Waters 150AP (B41-1116); IB (30mm × 250mm ID, 5um); isocratic 20% MeOH w / 0.1% NH4OH-80% CO2) to obtain Examples 57 and 58.

[0298] Examples 59 and 60: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline- 3-yl)-N-((*R)-1-(methylsulfonyl)piperidin-3-yl)acetamide and 2-(6-(6-((cis)-2,6-dimethylmorpholine) (S)-1-(methylsulfonyl)piperidin-3-yl)acetamide .

[0299] (*R), (cis) (*S), (cis) DIPEA (0.11 mL, 0.636 mmol) and HATU (CAS [148893-10-1], 73 mg, 0.191 mmol) were added to a solution of intermediate 13 (60 mg, 0.159 mmol) and 1-methylsulfonylpiperidin-3-amine (CAS [934107-80-9], 31 mg, 0.175 mmol) in DMF. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and directly separated into stereoisomers by SFC chiral separation (Waters 150AP (B41-1116); IB (30 mm × 250 mm ID, 5 μm); 20% MeOH w / 0.1% NH4OH-80% CO2) to obtain Examples 59 and 60.

[0300] Example 61: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)- N-(4-methyl-3-(S-methylsulfinimide)phenyl)acetamide .

[0301] (Civic) The title compound was prepared in a manner similar to that of Example 28, using intermediate 4 instead of intermediate 13 and intermediate 23 instead of 3-methylsulfonyl-4-methylaniline.

[0302] Example 62: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N- ((3R,6R)-6-methyl-1-(methylsulfonyl)piperidin-3-yl)acetamide .

[0303] Cis Step A: (2R,5R)-5-(2-(6-(6-(((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamyl)-2-methylpiperidin-1-carboxylic acid tert-butyl ester. The title compound was prepared in a manner similar to Example 28, using (2R,5R)-5-amino-2-methylpiperidin-1-carboxylic acid tert-butyl ester (CAS [1807773-56-3]) instead of 3-methanesulfonyl-4-methylaniline. The title compound (244 mg, 98% yield) was purified by rapid column chromatography (2N NH3 / MeOH in DCM) to obtain a pale yellow solid.

[0304] Step B: 2-(6-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((3R,6R)-6-methylpiperidin-3-yl)acetamide. The title compound was prepared in a manner similar to intermediate 13 to obtain the title compound as an HCl salt (260 g, quantitative, 4*HCl salt).

[0305] Step C: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-((3R,6R)-6-methyl-1-(methanesulfonyl)piperidin-3-yl)acetamide. A homogeneous solution of 2-(6-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-((3R,6R)-6-methylpiperidin-3-yl)acetamide (260 mg, 0.42 mmol, 4*HCl salt) and DIPEA (0.4 mL, 2.321 mmol) in DCM (10 mL) was cooled to 0 °C under a nitrogen atmosphere. Methanesulfonyl chloride (CAS [124-63-0], 0.05 mL, 0.644 mmol) was slowly added while stirring. After 15 minutes, the reaction mixture was concentrated to dryness, and the residue was purified by rapid column chromatography (40 g SiO2, 0%-10% 2N NH3 / MeOH (in DCM)) to give the title compound (150 g, yield: 63%) as a grayish-white solid.

[0306] The compounds in Table 5 are prepared from intermediate 13 and the corresponding amine according to the procedure in method A or method B.

[0307] Table 5. Example number structure amine method 92 2-(Difluoromethylsulfonyl)ethylamine (CAS 1538958-14-3) B 93 N-(2-Aminoethyl)-1,1-difluoromethanesulfonamide (CAS 1038307-80-0) B 94 N-(3-aminopropyl)-1,1-difluoromethanesulfonamide (CAS 1038307-87-7) B 95 (RS)-S-(4-aminophenyl)-S-methylsulfonylimide (CAS 38764-51-1) B 96 3-(difluoromethylsulfonyl)propane-1-amine (CAS 1511228-11-7) B 97 S,S-Dimethyl-N-(3-aminophenyl)-sulfonamide (CAS 1610450-04-8) B 103 3-(fluoromethanesulfonyl)aniline (CAS 1780868-90-7) B 148 3-(1,1,2,2-Tetrafluoroethoxy)aniline (CAS 831-75-4) A 149 (4-Amino-phenyl)-difluoromethyl-sulfone (CAS 24906-77-2) A Examples 63 and 64: N-((*R)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-) ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide and N-((*S)-1-((difluoromethyl) (Sulfoyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyl-7- Acetamide .

[0308] (*R), (cis) (*S), (cis) Method C Step A: (1-((difluoromethyl)sulfonyl)piperidin-3-yl)tert-butyl carbamate. K₂CO₃ (2 eq.) was added to a solution of 3-Boc-aminopiperidine (CAS [172603-05-3], 200 mg, 0.97 mmol) in THF (5 mL). Difluoromethanesulfonyl chloride (CAS [1512-30-7], 0.09 mL, 1.02 mmol) was added dropwise to the stirred suspension. The mixture was stirred overnight at room temperature and then filtered. Volatiles were removed from the filtrate under vacuum to obtain the title compound, which was used in the next step without further purification.

[0309] Step B: 1-((difluoromethyl)sulfonyl)piperidin-3-amine. Dissolve tert-butyl (1-((difluoromethyl)sulfonyl)piperidin-3-yl)carbamate in DCM (2 mL) and add HCl (3 M in CPME, 10 eq.). Stir overnight, then remove volatiles under vacuum.

[0310] Step C: N-((*R)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide and N-((*S)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide. Add DMF (1 mL), DIPEA (3 eq.), and intermediate 4 (400 mg, 1 mmol) to 1-((difluoromethyl)sulfonyl)piperidin-3-amine. Add HATU (CAS [148893-10-1], 600 mg, 1.6 mmol) and stir the reaction mixture overnight at room temperature. The reaction mixture was purified directly by reversed-phase HPLC (19 mm × 100 mm C18 column, eluted with 10% to 90% ACN / H2O + 0.1% NH3), followed by SFC purification (OD 21 mm × 250 mm ID, 5 mm column, eluted with 13% MeOH - 87% CO2) to obtain Examples 63 and 64.

[0311] Examples 65 and 66: N-((*R)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolino-3-yl)acetamide and N-((*S)-1-((difluoromethyl) (sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetyl amine .

[0312] (*R), (cis) (*S), (cis) Examples 65 and 66 were prepared in a manner similar to Examples 63 and 64 by using intermediate 13 in step C. The enantiomers were separated by SFC (AD (21 mm × 250 mm ID, 5 μm) column; isocratic 30% IPA / ACN-70% CO2).

[0313] Examples 67 and 68: N-((*R)-1-((difluoromethyl)sulfonyl)pyrrolidine-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide and N-((*S)-1-((difluoromethyl)sulfonyl)pyrrolidine-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide.

[0314] (*R), (cis) (*S), (cis) Examples 67 and 68 were prepared in a manner similar to Examples 63 and 64, using 3-(tert-butoxycarbonylamino)pyrrolidine (CAS [99724-19-3]) instead of 3-Boc-aminopiperidine in step A. The enantiomers were separated by SFC (AD (21 mm × 250 mm ID, 5 μm) column; eluted with 35% EtOH-CO2).

[0315] Examples 69 and 70: N-((*R)-1-((difluoromethyl)sulfonyl)pyrrolidine-3-yl)-2-(6-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolino-3-yl)acetamide and N-((*S)-1-((difluoromethyl) (sulfonyl)pyrrolidine-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)ethyl amide .

[0316] (*R), (cis) (*S), (cis) The title compound was prepared in a manner similar to that of Examples 63 and 64, with 3-(tert-butoxycarbonylamino)pyrrolidine (CAS 99724-19-3) used instead of 3-Boc-aminopiperidine in step A; and with intermediate 13 used instead of intermediate 4 in step C. Enantiomers were separated by SFC (IG (21 mm × 250 mm ID, 5 μm) column; eluted with 35% IPA / ACN-CO2).

[0317] Examples 71, 72, 73 and 74: 2-(2-(6-(cis)-2,6-dimethylmorpholine) (1,3,3)-3-(methylsulfonyl)cyclohexyl)acetamide and 2-(2- (6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((1*S,3*R)-3-(methylsulfonyl) Acyl)cyclohexyl)acetamide and 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthyl-7- (N-((1*R,3*S)-3-(methylsulfonyl)cyclohexyl)acetamide and (2-(6-((cis)-2,6-dimethylmorpholino) Pyridin-2-yl)-1,6-naphthid-7-yl)-N-((1*S,3*S)-3-(methylsulfonyl)cyclohexyl)acetamide .

[0318] (*R), (*R), (cis) (*R), (*S), (cis) (*S), (*R), (cis) (*S), (*S), (cis) The title compound was isolated from the same reaction mixture and prepared in a manner similar to Example 28, using intermediate 4 instead of intermediate 13 and racemic 3-methanesulfonylcyclohexane-1-amine hydrochloride (CAS [1334147-71-5]) instead of 3-methanesulfonyl-4-methylaniline. It was purified by SFC (IH, 21 mm × 250 mm, 25% (1:1 ACN / iPrOH) / 75% CO2) to give Example 71 (19 mg, yield: 9%), Example 72 (23 mg, yield: 11%), Example 73 (22 mg, yield: 10%), and Example 74 (26 mg, yield: 12%).

[0319] Example 75: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N- ((3S,6R)-6-methyl-1-(methylsulfonyl)piperidin-3-yl)acetamide .

[0320] (Civic) The title compound was prepared in step A in a manner similar to that of Example 62, using (2R,5S)-5-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester (CAS [2306249-72-7]) instead of (2R,5R)-5-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester.

[0321] Example 76: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N- ((3S,6R)-6-methyl-1-(methylsulfonyl)piperidin-3-yl)acetamide .

[0322] (2S, 5R), (cis) The title compound was prepared in step A in a manner similar to that of Example 62, using (2S,5R)-5-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester (CAS [1450891-27-6]) instead of (2R,5R)-5-amino-2-methylpiperidine-1-carboxylic acid tert-butyl ester.

[0323] Examples 77, 78, 79 and 80: 2-(6-(6-(cis)-2,6-dimethylmorpholine) (1*R,3*R)-3-(methylsulfonyl)cyclohexyl)acetamide and 2-(6-(6-) ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolino-3-yl)-N-((1*S,3*R)-3-(methanesulfonyl)cyclo Hexyl)acetamide and 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-((1*R, 3*S)-3-(methylsulfonyl)cyclohexyl)acetamide and 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl) Isoquinoline-3-yl)-N-((1*S,3*S)-3-(methylsulfonyl)cyclohexyl)acetamide .

[0324] (*R), (*R), (cis) (*R), (*S), (cis) (*S), (*R), (cis) (*S), (*S), (cis) The title compound was isolated from the same reaction mixture and prepared in a manner similar to Example 28 using racemic 3-methanesulfonylcyclohexane-1-amine hydrochloride (CAS [1334147-71-5]) instead of 3-methanesulfonyl-4-methylaniline. It was purified by SFC (IG, 30 mm × 250 mm, 45% (MeOH w / 0.1% DEA) / 55% CO2) followed by further purification by SFC (IH, 21 mm × 250 mm, 20% MeOH / 80% CO2) to give Examples 77, 78, 79, and 80.

[0325] The compounds in Table 6 are prepared from intermediate 4 and the corresponding amine according to the procedure in Method C.

[0326] Table 6. The compounds in Table 7 were prepared from intermediate 4 and the corresponding amine using MsCl (CAS [124-63-0]) instead of difluoromethanesulfonyl chloride according to the procedure in Method C.

[0327] Table 7. Example 81: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)- N-((R)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)acetamide .

[0328] Method D The solution of intermediate 14 (28 mg, 0.058 mmol) and DIPEA (0.02 mL, 0.116 mmol) in DCM (0.5 mL) was cooled to 0 °C. Trifluoromethanesulfonic anhydride (CAS [358-23-6], 1 M in DCM, 60 µL, 0.060 mmol) was added dropwise. After stirring for 10 min, the volatiles were removed, and the residue was purified by HPLC (19 mm × 100 mm C18 column, eluted with 10% to 90% ACN / H2O + 0.1% NH3) to give the title compound (9 mg, yield: 26%) as a yellow solid.

[0329] Example 82: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)- N-((S)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)acetamide .

[0330] The title compound was synthesized following the same synthetic route as in Example 81, starting from intermediate 4 and using (3S)-3-amino-1-piperidinecarboxylate tert-butyl ester (CAS 216854-23-8) instead of (R)-1-Boc-3-aminopiperidine [CAS 188111-79-7].

[0331] Example 99: N-((R)-1-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethyl) (Pyridinyl)-2-yl)-1,6-naphthyl-7-yl)acetamide .

[0332] (R), (cis) Intermediate 14 (30 mg, 0.065 mmol), difluoroacetic acid (0.006 mL, 0.1 mmol), HATU (CAS [148893-10-1], 50 mg, 0.13 mmol), and DIPEA (0.034 mL, 0.2 mmol) were dissolved in DMF (0.5 mL). After stirring overnight, the mixture was purified directly by HPLC (19 mm × 100 mm C18 column, eluted with 10% to 90% ACN / H2O + 0.1% NH3) to give the title compound (10 mg, yield: 28%) as an orange solid.

[0333] Example 98: N-((S)-1-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethyl) (Pyridinyl)-2-yl)-1,6-naphthyl-7-yl)acetamide .

[0334] (S), (cis) Following a synthetic route similar to that of Example 99, the title compound was prepared starting from intermediate 4 and using (3S)-3-amino-1-piperidinecarboxylic acid tert-butyl ester (CAS [216854-23-8]) instead of (R)-1-Boc-3-aminopiperidine to prepare the compound.

[0335] Example 100: N-(1-(2,2-difluoroacetyl)pyrrolidine-3-yl)-2-(2-(6-(cis)-2,6-dimethyl) (Pyridinyl)-2-yl)-1,6-naphthyl-7-yl)acetamide .

[0336] (Civic) Step A: (1-(2,2-difluoroacetyl)pyrrolidine-3-yl)carbamate tert-butyl. DIPEA (0.278 mL, 1.611 mmol) was added to a solution of difluoroacetic acid ([CAS 381-73-7], 51 μL, 0.805 mmol) in DCM (1.5 mL). HATU (CAS [148893-10-1], 408 mg, 1.074 mmol) was added and the solution was stirred at room temperature for 5 minutes. DL-3-(Boc-amino)pyrrolidine (CAS [99724-19-3], 100 mg, 0.537 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through a silica stopper, and the solvent was evaporated; it was used for the next step without further purification.

[0337] Step B: 1-(3-aminopyrrolidone-1-yl)-2,2-difluoroethane-1-one. Add DCM (7 mL) to tert-butyl (1-(2,2-difluoroacetyl)pyrrolidone-3-yl)carbamate and add HCl (4 M in 1,4-dioxane, 0.8 mL, 3.2 mmol). Stir the solution at room temperature for 48 hours. Remove volatiles under vacuum and use it for the next step without further purification.

[0338] Step C: N-(1-(2,2-difluoroacetyl)pyrrolidine-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide. 1-(3-aminopyrrolidine-1-yl)-2,2-difluoroethane-1-one was dissolved in DMF (1.5 mL), and intermediate 4 (70 mg, 0.185 mmol) was added, followed by DIPEA (0.19 mL, 1.1 mmol) and HATU (141 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 30 min and then purified directly by HPLC (19 mm × 100 mm C18 column, eluted with 10% to 90% ACN / H2O + 0.1% NH3) to give the title compound (29 mg, yield: 24%) as an orange solid.

[0339] Example 113: N-((3S,5R)-1-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide .

[0340] Step A: (3S,5R)-3-(2-(2-(6-(((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamyl)-5-hydroxypiperidin-1-carboxylic acid tert-butyl ester. Intermediate 4 (60 mg, 0.159 mmol) and (3S,5R)-3-amino-5-hydroxy-piperidin-1-carboxylic acid tert-butyl ester (CAS [1312798-21-2], 34 mg, 0.159 mmol) were dissolved in ACN (1.3 mL). Et3N (132 μL, 0.951 mmol) was added, followed by T3P (CAS [68957-94-8], 50% in 2-methyltetrahydrofuran, 97 μL, 0.159 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the volatiles were removed under vacuum. The resulting title compound was used in the next step without further purification.

[0341] Step B: 2-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((3S,5R)-5-hydroxypiperidin-3-yl)acetamide. Dissolve (3S,5R)-3-(2-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamyl)-5-hydroxypiperidin-1-carboxylic acid tert-butyl ester in DCM (1 mL) and add HCl (4 M in 1,4-dioxane, 0.396 mL, 1.586 mmol). After 3 hours at room temperature, remove volatiles under vacuum and use for the next step without further purification.

[0342] Step C: N-((3S,5R)-1-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide. Dissolve 2-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((3S,5R)-5-hydroxypiperidin-3-yl)acetamide in THF (1 mL) and add K2CO3 (83 mg, 0.6 mmol). Add difluoromethanesulfonyl chloride (CAS [1512-30-7], 27 µL, 0.3 mmol) dropwise and stir the mixture overnight at room temperature. The reaction mixture was purified by HPLC (19 mm × 100 mm C18 column, eluted with 10% to 90% ACN / H2O + 0.1% NH3) to give the title compound (4 mg, yield: 5%) as a yellow solid.

[0343] Example 136: N-(1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide .

[0344] (Civic) HATU (CAS [94790-37-1], 105 mg, 0.28 mmol) was added to a stirred solution of 5-amino-1-(2,2-difluoroethyl)-3-fluoro-2(1H)-pyridone (CAS [2409117-63-9], 63 mg, 0.33 mmol), intermediate 4 (100 mg, 0.22 mmol), and DIPEA (0.15 mL, 0.87 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by rapid column chromatography (12 g silica, MeOH, in DCM, 0 / 100 to 20 / 80), followed by purification by reversed-phase column chromatography (Phenomenex Gemini C18 30 mm × 100 mm 5 µm; 59% [25 mM NH4HCO3]–41% [ACN:MeOH 1:1] to 17% [25 mM NH4HCO3]–83% [ACN:MeOH 1:1]) to give the title compound as a yellow solid (14 mg, yield: 11%).

[0345] Example 150: N-((R)-1-(difluoromethyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- Dimethylmorpholino)pyridin-2-yl)-1,6-naphthid-7-yl)acetamide .

[0346] (R), (cis) Similar to Example 113, the title compound was prepared using (5R)-5-amino-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (CAS1392473-32-3) instead of (3S,5R)-3-. The compounds in Table 8 were synthesized from intermediate 14 and the corresponding sulfonyl chloride according to the procedure of method D. Example 108 was synthesized starting from intermediate 4 and using (3S)-3-amino-1-piperidinecarboxylate tert-butyl ester (CAS 216854-23-8) instead of (R)-1-Boc-3-aminopiperidine [CAS 188111-79-7].

[0347] Table 8. Example number structure amine method 106 2-Hydroxyethane-1-sulfonyl chloride (CAS 78303-70-5) D 107 3,3-Difluoropropane-1-sulfonyl chloride (CAS 1314907-49-7) D 108 2-Hydroxyethane-1-sulfonyl chloride (CAS 78303-70-5) D Example 162: (*R)-N-(1-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinoline-3-yl)acetyl amine .

[0348] (*R) The title compound was isolated by purification in Example 156 using an SFC (Phenomenex amylose-1 250mm × 30mm 5µm; 35% CO2–65% (EtOH + 0.1% DEA) to 35% CO2–65% (EtOH + 0.1% DEA)). Both were white solids.

[0349] Example 167: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N- (1-(methylsulfonyl)piperidin-4-yl)acetamide .

[0350] (Civic) Method F K₂CO₃ (46.372 mg, 0.336 mmol) and methanesulfonyl chloride (0.026 mL, 0.335 mmol) were added to a solution of piperidine-4-ylcarbamate tert-butyl ester (CAS [73874-95-0], 35 mg, 0.168 mmol) in THF (1 mL). The reaction mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was treated with HCl (3 M in CPME, 0.5 mL, 1.5 mmol). The solution was stirred overnight, and then the volatiles were removed under vacuum. DIPEA (0.2 mL, 1.16 mmol), DMF (1 mL), intermediate 13 (32 mg, 0.084 mmol), and HATU (CAS [148893-10-1], 48 mg, 0.126 mmol) were added to the residue. The reaction mixture was stirred overnight at room temperature. The reaction mixture was purified directly by HPLC (19 mm × 100 mm C18 column, eluted with 10% to 90% ACN / H2O + 0.1% NH3) to give the title compound (6 mg, yield: 7%) as a pale yellow solid.

[0351] The compounds in Table 9 are prepared from intermediate 13 and the corresponding sulfonyl chloride according to the procedure in Method F.

[0352] Table 10. Example number structure sulfonyl chloride method 118 2,2-Difluoroethanesulfonyl chloride (CAS 1033906-60-3) F 168 Difluoromethanesulfonyl chloride (CAS 1512-30-7) F 169 2-Hydroxyethanesulfonyl chloride (CAS 78303-70-5) F Example 152: 3-(2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl) Methyl acetamyl)bicyclo[1.1.1]pentane-1-carboxylate .

[0353] (Civic) DIPEA (0.46 mL, 2.65 mmol) and methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (CAS [676371-65-6], 241 mg, 1.46 mmol) were added to intermediate 13 (500 mg, 1.32 mmol) and HATU (CAS [148893-10-1], 756 mg, 1.99 mmol) in a stirred solution of DMF (10 mL). The reaction mixture was stirred at room temperature for 16 hours. More methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (200 mg, 1.13 mmol), HATU (504 mg, 1.32 mmol), and DIPEA (0.46 mL, 2.65 mmol) were added, and the mixture was stirred at 40 °C for 5 hours. The solvent was evaporated under vacuum. Water (30 mL) and DCM (30 mL) were added. The mixture was stirred at room temperature for 10 minutes. The mixture was placed in an Isolute separator and eluted with DCM. The filtrate was concentrated and the residue was purified by rapid column chromatography (silica, EtOAc / DCM, 0 / 100 to 100 / 0) to give the title compound (381 mg, yield: 57%) as a light brown foam.

[0354] Example 153: (1s,3s)-3-(2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline Methyl 1-cyclobutane-1-carboxylate (3-yl)acetamyl)cyclobutane .

[0355] (Chorus), (Chorus) The title compound was prepared using cis-3-aminocyclobutanecarboxylate hydrochloride (CAS[1212304-86-3]) instead of 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride, following the same procedure as in Example 152.

[0356] Example 154: N-((3S,4S)-1-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidine-3-yl)-2-(6-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolino-3-yl)acetamide .

[0357] (3S, 4S), (cis) Step A: (3S,4S)-3-(2-(6-(6-(((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. (3S,4S)-N-Boc-3-amino-4-hydroxypyrrolidine (CAS [190792-74-6], 200 mg, 0.99 mmol), intermediate 13 (485 mg, 1.29 mmol), and HATU (CAS [148893-10-1], 564 mg, 1.48 mmol) were dissolved in DMF (5 mL). DIPEA (0.51 mL, 2.97 mmol) was added, and the reaction mixture was stirred overnight at room temperature. Add more (3S,4S)-N-Boc-3-amino-4-hydroxypyrrolidine (87 mg, 0.43 mmol), and stir the reaction mixture at room temperature for 4 hours. Dilute the reaction mixture with EtOAc and water. Separate the layers, and wash the organic layer with brine (3×) and saturated NaHCO3 aqueous solution. Extract the combined aqueous layer with EtOAc. Dry the combined organic layer with Na2SO4, filter, and concentrate. Purify the residue by reversed-phase column chromatography (30×100 C18 Gemini, 38%-58% ACN:H2O (10 mM NH4OH)).

[0358] Step B: 2-(6-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((3S,4S)-4-hydroxypyrrolidine-3-yl)acetamide. Dissolve (3S,4S)-3-(2-(6-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester in DCM (2.5 mL). Add TFA (0.19 mL, 2.53 mmol), and stir the reaction mixture overnight at room temperature. Remove volatiles under vacuum to obtain the title compound.

[0359] Step C: N-((3S,4S)-1-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidine-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolino-3-yl)acetamide. Dissolve 2-(6-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolino-3-yl)-N-((3S,4S)-4-hydroxypyrrolidine-3-yl)acetamide (233 mg, 0.51 mmol) and K₂CO₃ (349 mg, 2.53 mmol) in Me-THF (5 mL). Add difluoromethanesulfonyl chloride (CAS [1512-30-7], 0.13 mL, 1.52 mmol) dropwise at room temperature and stir the reaction mixture at room temperature for 3 days. The solvent was evaporated, and additional difluoromethanesulfonyl chloride (0.13 mL, 1.52 mmol) and K₂CO₃ (349 mg, 2.53 mmol) and Me-THF (5 mL) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over MgSO₄, filtered, and evaporated. The resulting residue was purified by preparative HPLC (30×100 C18 Gemini column, 34%–54% ACN:H₂O (10 mM NH₄OH)) to give the title compound.

[0360] Example 155: N-(3-(cyclopropylsulfonyl)bicyclo[1.1.1]pentan-1-yl)-2-(6-(6-((cis)-2, 6-Dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide .

[0361] (Civic) DIPEA (0.047 mL, 0.27 mmol) and intermediate 33 (25 mg, 0.13 mmol) were added to a stirred solution of intermediate 13 (26 mg, 0.068 mmol) and HATU (CAS [148893-10-1], 65 mg, 0.17 mmol) in DMF (0.5 mL). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum. Water (2 mL) and DCM (2 mL) were added. The mixture was stirred at room temperature for 10 minutes. The mixture was placed in an Isolute separator and eluted with DCM. The filtrate was concentrated under vacuum, and the residue was purified by reversed-phase HPLC (C18 XBridge 30 mm × 100 mm 10 µm; NH4HCO3 0.25% in water and ACN) to give the title compound (5 mg, yield: 14%).

[0362] Example 156: N-(1-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinoline-3-yl)acetamide .

[0363] Under a nitrogen atmosphere, in a sealed tube, PdCl2(dppf).CH2Cl2 (CAS [95464-05-4], 21 mg, 0.026 mmol) was added to a stirred solution of intermediate 39 (195 mg, 0.51 mmol), phenylboronic acid (CAS [98-80-6], 125 mg, 0.61 mmol), and sodium bicarbonate (86 mg, 1 mmol) in 1,4-dioxane (4 mL) and water (1 mL). The reaction mixture was stirred at 90 °C for 16 hours. After cooling, the mixture was diluted with water, extracted with EtOAc, and the organic layer was washed with brine (×2). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (12 g silica; EtOAc / heptane, 0 / 100 to 60 / 20) followed by reversed-phase column chromatography (Phenomenex Gemini C18 30 mm × 100 mm 5 µm; 81% [25 mM NH4HCO3]–19% ACN to 45% [25 mM NH4HCO3]–55% ACN) to give the title compound (22 mg, yield: 10%) and unreacted intermediate 39 (115 mg, yield: 58%), both as white solids.

[0364] Example 157: N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(2-((cis)-2,6-dimethylmorpholine) 1-Methyl-6-oxo-1,6-dihydropyrimidin-4-yl)isoquinoline-3-yl)acetamide .

[0365] (Civic) HATU (CAS [148893-10-1], 14 mg, 0.037 mmol) was added to a stirred solution of intermediate 44 (10 mg, 0.024 mmol), 3-[(difluoromethyl)sulfonyl]aniline (CAS [24906-76-1], 5 mg, 0.024 mmol), and DIPEA (0.013 mL, 0.07 mmol) in DCM (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (12 g silica; DCM:MeOH (9:1), in DCM, 0 / 100 to 4 / 96) to give the title compound (6 mg, yield: 40%) as a yellow solid.

[0366] Example 158: N-(3-(S-(difluoromethyl)sulfinimide)phenyl)-2-(6-phenylisoquinoline-3-yl) Acetamide .

[0367] Intermediate 47 (79 mg, 0.38 mmol) was added to a stirred solution of intermediate 46 (98 mg, 0.35 mmol), HATU (CAS [148893-10-1], 0.200 g; 0.52 mmol), and DIPEA (0.24 mL, 1.4 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with AcOEt. The organic layer was washed with brine (×2), filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (silica 24 g; MeOH / DCM, 0 / 100 to 10 / 90), followed by reversed-phase HPLC (Phenomenex Gemini C18 ID (mm) 100 × 21.2, 5 μm; 72% H2O (0.1% HCOOH) - 28% ACN:MeOH 1:1 to 36% H2O (0.1% HCOOH) - 64% ACN:MeOH 1:1) to give the title compound (2 1 mg, yield: 13%) as a white powder.

[0368] Example 159: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N- (3-(methylsulfonyl)cyclobutyl)acetamide .

[0369] (Civic) The title compound was prepared using the same procedure as in Example 155, with 3-(methylsulfonyl)cyclobutamine (CAS [1824081-10-8]) instead of intermediate 33.

[0370] Example 160: (R)-N-(1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-phenylisoquinoline-3-yl) Acetamide .

[0371] (R) The title compound was prepared using the same method as in Example 158, with (3R)-1-[(difluoromethyl)sulfonyl]-3-piperidinamine (CAS[1704939-33-2]) instead of intermediate 47.

[0372] Example 161: N-(3-(*S-(difluoromethyl)sulfinimide)phenyl)-2-(6-phenylisoquinoline-3-yl) Acetamide .

[0373] (*S) HATU (CAS [148893-10-1;], 122 mg; 0.32 mmol) was added to a stirred solution of intermediate 46 (60 mg, 0.214 mmol), intermediate 49 (49 mg, 0.24 mmol), and DIPEA (0.10 mL, 0.64 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (×2), dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by rapid column chromatography (24 g silica; MeOH / DCM, 0 / 100 to 10 / 90) to give the title compound (69 mg, yield: 70%) as a yellow solid.

[0374] Example 163: (*S)-N-(1-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinoline-3-yl)acetyl amine .

[0375] (*S) The title compound was purified and isolated as a white solid by SFC as described in Example 156: SFC (Phenomenexamylose-1 250mm × 30mm 5um; 35% CO2–65% (EtOH + 0.1% DEA) to 35% CO2–65% (EtOH + 0.1% DEA)).

[0376] Example 164: (*R)-N-(3-(S-(difluoromethyl)sulfinimide)phenyl)-2-(6-phenylisoquinoline- 3-yl)acetamide .

[0377] (*R) The title compound was prepared in a manner similar to that of Example 161, using intermediate 48 instead of intermediate 49.

[0378] Example 165: N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-phenylisoquinoline-3-yl)acetamide .

[0379] The title compound was prepared in a manner similar to that of Example 158, using N-(2-aminoethyl)-1,1-difluoromethanesulfonamide hydrochloride (CAS [2260936-13-6]) instead of intermediate 47.

[0380] Example 166: N-(3-(cyclopropylsulfonyl)cyclobutyl)-2-(6-(6-(cis)-2,6-dimethylmorpholine) (2-yl)pyridin-2-yl)isoquinoline-3-yl)acetamide .

[0381] (Civic) The title compound was prepared in a manner similar to that of Example 155, using intermediate 50 instead of intermediate 33.

[0382] Example 181: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N- (3-(methylsulfonyl)cyclohexyl)acetamide .

[0383] (Civic) The title compound was prepared using intermediate 51 instead of intermediate 33, following the same procedure as in Example 155.

[0384] Example 182: N-(3-(cyclopropylsulfonyl)cyclohexyl)-2-(6-(6-(cis)-2,6-dimethylmorpholine) (2-yl)pyridin-2-yl)isoquinoline-3-yl)acetamide .

[0385] (Civic) The title compound was prepared in a manner similar to that of Example 155, using intermediate 52 instead of intermediate 33.

[0386] Example 183: N-(3-((*R)-S-(difluoromethyl)sulfinimide)phenyl)-2-(6-(2-((cis)- 2,6-Dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)isoquinolin-3-yl)acetamide .

[0387] (*R), (cis) The title compound was prepared using the same procedure as in Example 161, with intermediate 48 used instead of intermediate 49 and intermediate 44 used instead of intermediate 46.

[0388] Example 184: N-(3-((*S)-S-(difluoromethyl)sulfinimide)phenyl)-2-(6-(2-((cis)- 2,6-Dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)isoquinolin-3-yl)acetamide .

[0389] (*S), (cis) The title compound was prepared in a manner similar to that of Example 161, using intermediate 44 instead of intermediate 46.

[0390] Example B: Analytical Characterization Methods for Intermediates and Compounds LC-MS method High-performance liquid chromatography (HPLC) measurements are performed using an LC pump, a diode array (DAD) or UV detector, and a column as specified in the respective method. Additional detectors may be included if necessary (see the methods in the table below).

[0391] The stream from the column is fed into a mass spectrometer (MS) equipped with an atmospheric pressure ion source. Adjustment parameters (e.g., scan range, residence time, etc.) are set to obtain ions with a nominal monoisotopic molecular weight (MW) that allows for the identification of compounds, within the knowledge of a technician. Data acquisition is performed using appropriate software.

[0392] Compounds are described by experimental retention time (Rt) and ion. Unless otherwise specified in the data sheet, the reported molecular ion corresponds to [M+H]. + (Protonated molecules) and / or [MH] - (Deprotonated molecules). In cases where the compound cannot be directly ionized, specify the type of adduct (i.e., [M+NH4)). + [M+HCOO] - (etc.). For molecules with multiple isotopic modes (Br, Cl), the reported values ​​are obtained for the lowest isotopic mass. All results were obtained with the experimental uncertainties typically associated with the methods used.

[0393] In the following text, “SQD” means single quadrupole detector, “MSD” means mass selective detector, “RT” means room temperature, “BEH” means bridged ethylsiloxane / silica hybrid, “DAD” means diode array detector, and “HSS” means high-strength silica.

[0394] LCMS method code (flow rate in mL / min; column temperature (T) in °C; run time) Table 11. LCMS Method Method code instrument column mobile phase gradient Flow rate (ml / min) ------- Column temperature (°C) Running time (min) 1 Agilent 1260 HPLC - G6130B MSD Agilent Infinity LabPoroshell 120 EC-C18 2.1mm × 50mm, 2.7 micrometers A: Water, containing 0.1% TFA; B: Acetonitrile, containing 0.1% TFA From 90% A to 2% A within 1.4 minutes, maintain for 0.4 minutes; from 0.1 minutes back to 90% A, maintain for up to 2 minutes. 1.2 ------- 55 2 2 Agilent 1260 HPLC - G6130B MSD Agilent Infinity LabPoroshell 120 EC-C18 2.1mm × 50mm, 2.7 micrometers A: Water, containing 0.1% TFA; B: Acetonitrile, containing 0.1% TFA From 90% A to 2% A within 4.5 minutes, maintain for 0.25 minutes; from 0.1 minutes back to 90% A, maintain for up to 6 minutes. 0.65 ------- 55 6 3 Agilent 1260 HPLC - G6130B MSD Agilent Infinity LabPoroshell 120 EC-C18 2.1mm × 50mm, 2.7 micrometers A: Water, containing 0.1% TFA; B: Acetonitrile, containing 0.1% TFA From 90% A to 2% A within 2.4 minutes, back to 90% A within 0.05 minutes, and maintain this level until 3 minutes. 1.2 ------- 55 3 4 Agilent 1260 HPLC - G6130B MSD Mac-Mod AVANTORACE 3, C18, 3.0mm×50mm A: Water, containing 0.1% TFA; B: Acetonitrile, containing 0.1% TFA From 95% A to 5% A within 1.6 minutes, maintain for 0.2 minutes; from 0.1 minutes back to 95% A, maintain for up to 2 minutes. 2.0 ------- 55 2 5 Agilent Prime-6125B Agilent Poroshell120 EC-C18 1.9um3.0mm*30mm A: TFA 0.025%, in water B: TFA 0.1% ACN From 95% A to 20% A within 1.2 minutes, to 95% B within 1.3 minutes, and to 5% A within 0.5 minutes. 1.5 ------- 50℃ 3.0 6 Agilent 1260 HPLC Agilent Infinity Poroshell 120 EC-C18 2.1mm × 50mm, 2.7 microns A: Water, containing 0.1% TFA B: ACN, containing 0.1% TFA From 90% A to 1% A within 1.4 minutes, back to 90% A within 0.4 minutes; maintain until 2 minutes. 1.2 55 2 7 Agilent 1260 HPLC Agilent Infinity LabPoroshell HPH-C18 2.1mm × 50mm, 2.7 micrometers A: Water B: ACN From 10% B to 100% B within 2 minutes 1.2 ------ 45 2.0 8 Agilent 1260 HPLC -G6120B MSD Agilent Infinity LabPoroshell 120 EC-C18 2.1mm × 50mm, 2.7 micrometers A: Water, containing 0.1% TFA; B: ACN, containing 0.1% TFA From 90% A to 2% A within 4.5 minutes, maintain for 0.25 minutes; from 0.1 minutes back to 90% A, maintain for up to 6 minutes. 0.65 ------ 55 6 9 Agilent: 1100-DAD and MSD YMC: Pack ODS-AQ (3µm, 4.6mm×50mm) <![CDATA[A: 0.1% HCOOH in water, B: CH3CN]]> It takes 4.8 minutes to go from 95% A to 5% A, maintain that level for 1 minute, and then recover to 95% A within 0.2 minutes. 2.6 ------- 35 6.0 10 Agilent 1260 HPLC -G6120 MSD Agilent Infinity LabPoroshell 120 EC-C18 2.1mm × 50mm, 2.7 micrometers; 699775-902(T) A: Water, containing 0.1% TFA; B: Acetonitrile, containing 0.1% TFA From 90% A to 2% A within 2.4 minutes, to 10% A within 0.05 minutes, and maintain this level until 3 minutes. 1.2 55 3.0 11 Waters Acquity Class I UPLC XBridge BEH C18 2.5μm, 2.1mm × 50mm column XP <![CDATA[A: Water, containing 0.1% NH3 (aqueous solution); B: ACN, containing 0.1% NH3 (aqueous solution)]]> From 95% A to 0% A within 1.4 minutes, maintain for 0.4 minutes; from 0.1 minutes to 95% A, maintain for up to 2 minutes. 1 ------- 50 2 12 Waters Acquity Class I UPLC XSelect CSH C18 2.5μm, 2.1mm × 50mm column XP A: Water, containing 0.1% TFA; B: ACN, containing 0.1% TFA From 95% A to 0% A within 1.4 minutes, maintain for 0.4 minutes; from 0.1 minutes to 95% A, maintain for up to 2 minutes. 1 ------- 50 2 14 Agilent 1260 HPLC -G6120 MSD Agilent Infinity LabPoroshell 120 EC-C18 2.1mm × 50mm, 2.7 micrometers A: Water, containing 0.1% TFA; B: Acetonitrile, containing 0.1% TFA From 90% A to 2% A within 1.3 minutes, to 10% A within 0.05 minutes, and maintain this level until 2 minutes. 1.2 ------- 55 2.0 15 <![CDATA[Waters:Acquity ® IClass UPLC ® -DAD and Xevo G2-S QTOF]]> Waters: BEH C18 (1.7µm, 2.1mm×50mm) <![CDATA[A:95% CH3COONH46.5mM+5% ACN,B:ACN]]> From 95% A to 5% A within 4.6 minutes, maintain for 0.4 minutes. 1 _____ 50 5 16 <![CDATA[Waters:Acquity ® UPLC ® -DAD and SQD]]> Waters: Xbridge BEHC18 (2.5µm, 2.1mm×50mm) <![CDATA[A:90% HCO3NH46.5mM,B:ACN]]> From 90% A to 0% A within 2.0 minutes, maintain for 0.5 minutes. 1 _____ 25 3 17 <![CDATA[Waters:Acquity ® UPLC ® H-Class -DAD and Qda (HCLASS-PMC)]]> Waters: Xbridge BEHC18 (2.1mm×50mm, 2.5µm) <![CDATA[A: H2O, containing HCO3NH4, 32 mM; B: ACN]]> From 90% A to 0% A within 2.0 minutes, maintain for 0.5 minutes (0.5 minutes of balancing step during pre-run). 1 _____ 25 2.5 18 Agilent 1260 HPLC - G6130B MSD Agilent Infinity LabPoroshell 120 EC-C18 2.1mm × 50mm, 2.7 micrometers A: Water, containing 0.1% TFA; B: ACN, containing 0.1% TFA From 99% A to 10% A within 1.4 minutes, maintain for 0.4 minutes; from 0.1 minutes back to 99% A, maintain for up to 2 minutes. 1.2 ------- 55 2 19 Agilent Prime-6125B Agilent Poroshell120 HPH-C18 1.9μm3.0*30mm <![CDATA[A: 0.05% NH4OH in water, B: CH3CN]]> From 95% A to 20% A within 1.2 minutes, to 95% B within 1.3 minutes, and to 5% A within 0.5 minutes. 1.5 mL / min ------- 30℃ 3.0 Table 12: LC-MS Results Example number MW LCMS results 1 545.7 <![CDATA[Confirm MW (RT: 1.36, [M+H] + 546.2 (LC-MS method 1)]]> 2 559.7 <![CDATA[Confirm MW (RT: 2.07, [M+H] + 560.3 (LC-MS method 2)]]> 3 559.7 <![CDATA[Confirmed MW (RT: 2.05, [[M+H] + 560.3 (LC-MS method 2)]]> 4 572.7 <![CDATA[Confirm MW (RT: 1.45, [M+H] + 573.2 (LC-MS method 3)]]> 5 508.6 <![CDATA[Confirm MW (RT: 0.83, [M+H] + 509.2 (LC-MS method 4)]]> 6 474.6 <![CDATA[Confirm MW (RT: 0.81, [M+H] + 475.2 (LC-MS method 4)]]> 7 495.6 <![CDATA[Confirm MW (RT: 0.72, [M+H] + 496.1 (LC-MS method 4)]]> 8 535.6 <![CDATA[Confirm MW (RT: 1.75, [M+H] + 536.2 (LC-MS method 2)]]> 9 559.7 <![CDATA[Confirm MW (RT: 2.07, [M+H] + 560.3, LCMS method: 8)]]> 10 575.7 <![CDATA[Confirm MW (RT: 1.48, [M+H] + 576.3, LCMS method: 5)]]> 11 564.5 <![CDATA[Confirm MW (RT: 1.59, [M+H] + 550.2, LCMS method: 5)]]> 12 565.1 <![CDATA[Confirm MW (RT: 1.59, [M+H] + 566.2, LCMS method: 5)]]> 13 542.7 <![CDATA[Confirm MW (RT: 1.23, [M+H] + 543.3, LCMS method: 5)]]> 14 521.6 <![CDATA[Confirm MW (RT: 1.64, [M+H] + 522.2, LCMS method: 5)]]> 15 531.6 <![CDATA[Confirm MW (RT: 1.66, [M+H] + 532.1, LCMS method: 5)]]> 16 543.7 <![CDATA[Confirm MW (RT: 1.504, [M+H] + 544.2, LCMS method: 5)]]> 17 545.7 <![CDATA[Confirm MW (RT: 1.713, [M+H] + 546.3, LCMS method: 5)]]> 18 549.6 <![CDATA[Confirm MW (RT: 1.541, [M+H] + 550.2, LCMS method: 5)]]> 19 512.6 <![CDATA[Confirm MW (RT: 1.571, [M+H] + 513.2, LCMS method: 5)]]> 20 487.6 <![CDATA[Confirm MW (RT: 1.477, [M+H] + 488.3, LCMS method: 5)]]> 21 510.6 <![CDATA[Confirm MW (RT: 1.469, [M+H] + 511.3, LCMS method: 5)]]> 22 549.7 <![CDATA[Confirm MW (RT: 1.504, [M+H] + 550.2, LCMS method: 5)]]> 23 563.7 <![CDATA[Confirm MW (RT: 1.78, [M+H] + 564.3, LCMS method: 19)]]> 24 521.6 <![CDATA[Confirm MW (RT: 1.506, [M+H] + 522.2, LCMS method: 5)]]> 25 499.6 <![CDATA[Confirm MW (RT: 1.440, [M+H] + 500.2, LCMS method: 5)]]> 26 655.7 <![CDATA[Confirm MW (RT: 0.801, [M+H] + 542.2, LCMS method: 14)]]> 27 672.7 <![CDATA[Confirm MW (RT: 0.976, [M+H] + 559.2, LCMS method: 1)]]> 28 544.7 <![CDATA[Confirm MW (RT: 1.081, [M+H] + 545.2, LCMS method: 1)]]> 29 574.7 <![CDATA[Confirm MW (RT: 1.026, [M+H] + 575.2, LCMS method: 1)]]> 30 532.6 <![CDATA[Confirm MW (RT: 1.20, [M+H] + 533.2, LCMS method: 10)]]> 31 508.6 <![CDATA[Confirm MW (RT: 1.061, [M+H] + 509.0, LCMS method: 11)]]> 32 545.7 <![CDATA[Confirm MW (RT: 0.782, [M+H] + 546.2, LCMS method: 12)]]> 33 561.7 <![CDATA[Confirm MW (RT: 0.969, [M+H] + 562.1, LCMS method: 11)]]> 34 543.7 <![CDATA[Confirmed MW (RT: 0.970, [M+H] + 544.2, LCMS method: 11)]]> 35 567.6 <![CDATA[Confirm MW (RT: 0.85, [M+H] + 567.9, LCMS method: 12)]]> 36 572.7 <![CDATA[Confirm MW (RT: 1.008, [M+H] + 573.2, LCMS method: 11)]]> 37 557.7 <![CDATA[Confirm MW (RT: 0.798, [M+H] + 558.2, LCMS method: 12)]]> 38 561.7 <![CDATA[Confirm MW (RT: 1.022, [M+H] + 562.0, LCMS method: 11) <!-- 108 -->]]> 39 520.6 <![CDATA[Confirm MW (RT: 0.988, [M+H] + 520.9, LCMS method: 11)]]> 40 585.6 <![CDATA[Confirm MW (RT: 0.954, [M+H] + 586.2, LCMS method: 12)]]> 41 545.7 <![CDATA[Confirm MW (RT: 1.026, [M+H] + 546.0, LCMS method: 11)]]> 42 560.7 Confirmed MW (RT: 0.817, [M+H]+ 561.1, LCMS method: 12) 43 561.7 Confirmed MW (RT: 0.692, [M+H]+ 562.4, LCMS method: 12) 44 520.6 Confirm MW (RT: 1.131, [M+H]+ 521.1, LCMS method: 11) 45 537.7 Confirm MW (RT: 1.203, [M+H]+ 538.2, LCMS method: 11) 46 523.6 Confirmed MW (RT: 1.059, [M+H]+ 524.3, LCMS method: 11) 47 536.6 Confirmed MW (RT: 0.897, [M+H]+ 537.3, LCMS method: 11) 48 515.6 Confirmed MW (RT: 0.868, [M+H]+ 516.3, LCMS method: 11) 49 523.6 Confirm MW (RT: 1.157, [M+H]+ 524.2, LCMS method: 11) 50 511.6 Confirm MW (RT: 1.022, [M+H]+ 512.1, LCMS method: 11) 51 542.7 Confirmed MW (RT: 0.870, [M+H]+ 543.2, LCMS method: 11) 52 682.6 Confirmed MW (RT: 0.955, [M+H]+ 569.0, LCMS method: 11) 53 538.7 Confirm MW (RT: 1.21, [M+H]+ 539.3, LCMS method: 10) 54 523.6 Confirmed MW (RT: 1.069, [M+H]+ 524.3, LCMS method: 11) 55 532.6 Confirm MW (RT: 1.05, [M+H]+ 533.2, LCMS method: 13) 56 566.6 Confirm MW (RT: 1.18, [M+H]+ 567.2, LCMS method: 13) 57 538.7 Confirm MW (RT: 1.24, [M+H]+ 539.3, LCMS method: 10) 58 538.7 Confirm MW (RT: 1.24, [M+H]+ 539.2, LCMS method: 10) 59 537.7 Confirm MW (RT: 1.31, [M+H]+ 538.2, LCMS method: 10) 60 537.7 Confirm MW (RT: 1.32, [M+H]+ 538.3, LCMS method: 10) 61 544.7 Confirmed MW (RT: 0.959, [M+H]+ 545.3, LCMS method: 14) 62 551.7 <![CDATA[Confirm MW (RT: 1.063, [M+H] + 552.3, LCMS method: 1)]]> 63 / 64 (racemic mixture) 574.7 <![CDATA[Confirm MW (RT: 1.10, [M+H] + 575.2, LCMS method: 13)]]> 65 / 66 (racemic mixture) 573.7 <![CDATA[Confirm MW (RT 1.13 minutes, [M+H] + 574.2 LCMS method: 13)]]> 67 / 68 (racemic mixture) 674.7 <![CDATA[Confirm MW (RT 1.07 minutes, [M+H] + 661.2 LCMS method: 13]]> 69 / 70 (racemic mixture) 559.6 Confirmed MW (RT 1.1 minutes, [M+H]+ 560.2, LCMS method: 13) 71 537.7 Confirmed MW (RT: 0.977, [M+H]+ 538.3, LCMS method: 1) 72 537.7 <![CDATA[Confirm MW (RT: 0.987, [M+H] + 538.3, LCMS method: 1)]]> 73 537.7 <![CDATA[Confirm MW (RT: 0.976, [M+H] + 538.3, LCMS method: 1)]]> 74 537.7 <![CDATA[Confirm MW (RT: 0.987, [M+H] + 538.3, LCMS method: 1)]]> 75 551.7 <![CDATA[Confirm MW (RT: 1.071, [M+H] + 552.2, LCMS method: 1)]]> 76 551.7 <![CDATA[Confirm MW (RT: 1.071, [M+H] + 552.2, LCMS method: 1)]]> 77 536.7 <![CDATA[Confirm MW (RT: 1.032, [M+H] + 537.2, LCMS method: 1)]]> 78 536.7 <![CDATA[Confirm MW (RT: 1.032, [M+H] + 537.2, LCMS method: 1)]]> 79 536.7 <![CDATA[Confirm MW (RT: 1.024, [M+H] + 537.2, LCMS method: 1)]]> 80 536.7 <![CDATA[Confirm MW (RT: 1.023, [M+H] + 537.2, LCMS method: 1)]]> 81 592.6 Confirm MW (RT: 1.10, [M+H]++592.9, LCMS method 11) 82 592.6 Confirm MW (RT: 1.19, [M+H]+593.2, LCMS method: 13) 83 524.6 <![CDATA[Confirm MW (RT: 1.395, [M+H] + 525.3, LCMS method: 5)]]> 84 524.6 <![CDATA[Confirm MW (RT: 1.379, [M+H] + 525.1, LCMS method: 5)]]> 85 524.6 <![CDATA[Confirm MW (RT: 1.378, [M+H] + 525.3, LCMS method: 5)]]> 86 509.6 <![CDATA[Confirm MW (RT: 1.343, [M+H] + 510.3, LCMS method: 5)]]> 87 519.6 <![CDATA[Confirm MW (RT: 0.917, [M+H] + 520.4, LCMS method: 1)]]> 88 534.6 <![CDATA[Confirm MW (RT: 0.905, [M+H] + 535.3, LCMS method: 1)]]> 89 548.6 <![CDATA[Confirm MW (RT: 0.924, [M+H] + 549.2, LCMS method: 1)]]> 90 533.6 <![CDATA[Confirm MW (RT: 0.919, [M+H] + 534.4, LCMS method: 1)]]> 91 544.7 <![CDATA[Confirm MW (RT: 0.884, [M+H] + 545.4, LCMS method: 1)]]> 92 518.6 <![CDATA[Confirm MW (RT: 0.852, [M+H] + 519.5, LCMS method: 1)]]> 93 533.6 <![CDATA[Confirm MW (RT: 0.837, [M+H] + 534.5, LCMS method: 1)]]> 94 547.6 <![CDATA[Confirm MW (RT: 0.855, [M+H] + 548.4, LCMS method: 1)]]> 95 529.7 <![CDATA[Confirm MW (RT: 0.759, [[M+H] + 530.3, LCMS method: 1)]]> 96 532.6 <![CDATA[Confirm MW (RT: 0.854, [M+H] + 533.4, LCMS method: 1)]]> 97 543.7 <![CDATA[Confirm MW (RT: 0.814, [M+H] + 544.3, LCMS method: 1)]]> 98 538.6 Confirm MW (RT: 1.01, [M+H]+ 539.3, LCMS method: 13) 99 538.6 Confirm MW (RT: 1.19, [M+H]+ 539.3, LCMS method: 13) 100 524.2 NT 101 530.7 <![CDATA[Confirm MW (RT: 0.850, [M+H] + 531.4, LCMS method: 1)]]> 102 549.6 <![CDATA[Confirm MW (RT: 0.865, [M+H] + 550.1, LCMS method: 1)]]> 103 548.6 <![CDATA[Confirm MW (RT: 1.13, [M+H] + 549.2, LCMS method: 1)]]> 104 552.7 <![CDATA[Confirm MW (RT: 1.553, [M+H] + 553.4, LCMS method: 5)]]> 105 590.7 <![CDATA[Confirm MW (RT: 1.14, [M+H] + 591.2, LCMS method: 1)]]> 106 568.7 <![CDATA[Confirm MW (RT: 0.671, [M+H] + 568.9, LCMS method: 1)]]> 107 602.7 <![CDATA[Confirm MW (RT: 0.808, [M+H] + 603.3, LCMS method: 1)]]> 108 568.7 <![CDATA[Confirm MW (RT: 0.830, [M+H] + 569.2, LCMS method: 1)]]> 109 576.6 <![CDATA[Confirm MW (RT: 0.975, [M+H] + 577.3, LCMS method: 1)]]> 110 576.6 <![CDATA[Confirm MW (RT: 0.969, [M+H] + 577.4, LCMS method: 1)]]> 111 588.7 <![CDATA[Confirm MW (RT: 0.832, [M+H] + 589.4, LCMS method: 1)]]> 112 588.7 <![CDATA[Confirm MW (RT: 0.832, [M+H] + 589.4, LCMS method: 1)]]> 113 590.2 NT 114 610.6 <![CDATA[Confirm MW (RT: 0.834, [M+H] + 611.0, LCMS method: 1)]]> 115 610.6 <![CDATA[Confirm MW (RT: 0.834, [M+H] + 611.0, LCMS method: 1)]]> 116 576.6 <![CDATA[Confirm MW (RT: 1.15, [M+H] + 577.2, LCMS method: 1)]]> 117 590.7 <![CDATA[Confirm MW (RT: 1.14, [M+H] + 591.2, LCMS method: 1)]]> 118 587.7 Confirm MW (RT: 0.771, [M+H]+ 588.5, LCMS method 1) 119 587.7 <![CDATA[Confirm MW (RT: 1.31, [M+H] + 588.6, LCMS method: 6)]]> 120 556.7 <![CDATA[Confirm MW (RT: 0.887, [M+H] + 557.6, LCMS method: 1)]]> 121 556.7 <![CDATA[Confirmation of MW (RT: 0.899, [M+H] + 557.2, LCMS method: 1)]]> 122 588.7 <![CDATA[Confirm MW (RT: 0.960, [M+H] + 589.4, LCMS method: 1) <!-- 110 -->]]> 123 600.7 <![CDATA[Confirm MW (RT: 1.106, [M+H] + 601.4, LCMS method: 1)]]> 124 614.7 <![CDATA[Confirmation of MW (RT: 1.144, [M+H] + 615.3, LCMS method: 1)]]> 125 592.6 <![CDATA[Confirm MW (RT: 1.002, [M+H] + 593.5, LCMS method: 1)]]> 126 592.6 <![CDATA[Confirm MW (RT: 1.022, [M+H] + 593.8, LCMS method: 1)]]> 127 592.6 <![CDATA[Confirm MW (RT: 1.021, [M+H] + 593.2, LCMS method: 1)]]> 128 592.6 <![CDATA[Confirm MW (RT: 1.007, [M+H] + 593.7, LCMS method: 1)]]> 129 602.7 <![CDATA[Confirm MW (RT: 1.111, [M+H] + 603.6, LCMS method: 1)]]> 130 624.7 <![CDATA[Confirm MW (RT: 1.066, [M+H] + 625.4, LCMS method: 1)]]> 131 624.6 <![CDATA[Confirm MW (RT: 1.072, [M+H] + 625.2, LCMS method: 1)]]> 132 642.7 <![CDATA[Confirm MW (RT: 1.119, [M+H] + 643.6, LCMS method: 1)]]> 133 642.7 <![CDATA[Confirm MW (RT: 1.114, [M+H] + 643.4, LCMS method: 1)]]> 134 642.7 <![CDATA[Confirm MW (RT: 1.117, [M+H] + 643.4, LCMS method: 1)]]> 135 588.7 <![CDATA[Confirm MW (RT: 0.838, [M+H] + 589.2, LCMS method: 1)]]> 136 552.6 <![CDATA[Confirm MW (RT: 3.23, [M+H] + 553.2, LCMS method: 5)]]> 137 548.6 <![CDATA[Confirm MW (RT: 0.956, [M+H] + 549.0, LCMS method: 1)]]> 138 560.6 <![CDATA[Confirm MW (RT: 0.690, [M+H] + 561.0, LCMS method: 1)]]> 139 574.7 <![CDATA[Confirm MW (RT: 0.834, [M+H] + 575.0, LCMS method: 1)]]> 140 600.7 <![CDATA[Confirm MW (RT: 0.852, [M+H] + 601.1, LCMS method: 1)]]> 141 560.6 <![CDATA[Confirm MW (RT: 0.742, [M+H] + 561.0, LCMS method: 1)]]> 142 574.7 <![CDATA[Confirm MW (RT: 0.978, [M+H] + 574.9, LCMS method: 1)]]> 143 572.6 <![CDATA[Confirm MW (RT: 1.001, [M+H] + 573.0, LCMS method: 1)]]> 144 546.6 <![CDATA[Confirm MW (RT: 0.586, [M+H] + 547.2, LCMS method: 1)]]> 145 588.7 <![CDATA[Confirm MW (RT: 0.840, [M+H] + 589.1, LCMS method: 1)]]> 146 574.7 <![CDATA[Confirm MW (RT: 0.825, [M+H] + 575.1, LCMS method: 1)]]> 147 574.7 <![CDATA[Confirm MW (RT: 0.804, [M+H] + 575.0, LCMS method: 1)]]> 148 569.6 <![CDATA[Confirm MW (RT: 0.962, [M+H] + 570.0, LCMS method: 1)]]> 149 567.6 <![CDATA[Confirm MW (RT: 0.882, [M+H] + 568.5, LCMS method: 1)]]> 150 546.6 NT 151 572.6 <![CDATA[Confirm MW (RT: 0.782, [M+H] + 573.0, LCMS method: 1)]]> 152 500.6 Confirm MW (RT: 2.41, [M+H]+ 501.2, LCMS method: 15) 153 488.6 Confirm MW (RT: 2.30, [M+H]+ 489.2, LCMS method: 15) 154 575.6 <![CDATA[Confirm MW (RT: 1.34, [M+H] + 576.2, LCMS method: 7)]]> 155 546.7 <![CDATA[Confirm MW (RT: 1.42, [M+H] + 424.2, LCMS method: 16)]]> 156 423.5 Confirm MW (RT: 1.42, [M+H]+ 424.2, LCMS method: 9) 157 597.6 Confirm MW (RT: 3.24, [M+H]+ 598.1, LCMS method: 9) 158 451.5 Confirmed MW (RT: 2.96, [M+H]+ 452.1, LCMS method: 9) 159 508.6 <![CDATA[Confirm MW (RT: 1.05, [M+H] + 509.4, LCMS method: 17)]]> 160 459.5 Confirmed MW (RT: 2.98, [M+H]+ 460.1, LCMS method: 9) 161 451.5 Confirmed MW (RT: 2.96, [M+H]+ 452.0, LCMS method: 9) 162 423.5 Confirmed MW (RT: 2.56, [M+H]+ 424.1, LCMS method: 9) 163 423.5 Confirm MW (RT: 2.55, [M+H]+ 424.1, LCMS method: 9) 164 451.5 Confirmed MW (RT: 2.96, [M+H]+ 452.1, LCMS method: 9) 165 419.5 Confirm MW (RT: 2.61, [M+H]+ 420.0, LCMS method: 9) 166 534.7 <![CDATA[Confirm MW (RT: 1.14, [M+H] + 535.4, LCMS method: 17)]]> 167 537.7 NT 168 573.7 NT 169 567.7 NT 170 573.7 <![CDATA[Confirm MW (RT: 1.060, [M+H] + 574.2, LCMS method: 1)]]> 171 573.7 <![CDATA[Confirm MW (RT: 1.072, [M+H] + 574.2, LCMS method: 1)]]> 172 573.7 <![CDATA[Confirm MW (RT: 0.810, [M+H] + 574.2, LCMS method: 1)]]> 173 589.7 <![CDATA[Confirm MW (RT: 0.729, [M+H] + 590.1, LCMS method: 1)]]> 174 589.7 <![CDATA[Confirm MW (RT: 0.730, [M+H] + 590.2, LCMS method: 1)]]> 175 573.7 <![CDATA[Confirm MW (RT: 0.814, [M+H] + 574.0, LCMS method: 1)]]> 176 573.7 <![CDATA[Confirm MW (RT: 0.815, [M+H] + 574.1, LCMS method: 1)]]> 177 573.7 <![CDATA[Confirm MW (RT: 0.807, [M+H] + 574.3, LCMS method: 1)]]> 178 573.7 <![CDATA[Confirm MW (RT: 0.814, [M+H] + 574.2, LCMS method: 1)]]> 179 589.7 <![CDATA[Confirm MW (RT: 0.800, [M+H] + 590.1, LCMS method: 1)]]> 180 589.7 <![CDATA[Confirm MW (RT: 0.743, [M+H] + 590.0, LCMS method: 1)]]> 181 536.7 <![CDATA[Confirm MW (RT: 1.12, [M+H] + 537.1, LCMS method: 16)]]> 182 562.7 <![CDATA[Confirm MW (RT: 1.20, [M+H] + 563.2, LCMS method: 16)]]> 183 596.7 Confirmed MW (RT: 2.81, [M+H]+ 597.0, LCMS method: 9) 184 596.7 Confirmed MW (RT: 2.81, [M+H]+ 597.0, LCMS method: 9) SFC method SFC measurements were performed using an analytical supercritical fluid chromatography (SFC) system, consisting of a binary pump for delivering carbon dioxide (CO2) and the modifier, an autosampler, a column oven, and a diode array detector equipped with a high-pressure flow cell capable of standing up to 400 bar. If a mass spectrometer (MS) was configured, the flow from the column was fed into the MS. Adjusted parameters (e.g., scan range, residence time, etc.) were set to obtain ions with nominal monoisotopic molecular weights (MW) that allowed the identification of compounds within the knowledge of a technician. Data acquisition was performed using appropriate software. The SFC-MS method was analyzed (flow rate in mL / min; column temperature (Col T) in °C; run time in minutes; back pressure (BPR) in bar). “iPrNH2” refers to isopropylamine, “iPrOH” to 2-propanol, “EtOH” to ethanol, “min” to minutes, and “DEA” to diethylamine.

[0395] Table 13. SFC Method Method code column mobile phase gradient Flow rate ---------- Column temperature Runtime --------- BPR 1 OD (2.1mm×100mm ID, 3um) <![CDATA[25% MeOH–75% CO2]]> isometry 2 ------- Unknown 7.5 ------- Unknown 2 AD (2.1mm×100mm ID, 3um) <![CDATA[30% ACN / IPA–70%CO2]]> isometry 2 ------- Unknown 15 ------- Unknown 3 AD (2.1mm×100mm ID, 3um) <![CDATA[30% EtOH–70% CO2]]> isometry 2 ------- Unknown 15 ------- Unknown 4 IG (2.1mm×100mm ID, 3um) <![CDATA[40% ACN / IPA–60%CO2]]> isometry 2 ------- Unknown 15 ------- Unknown 5 Phenomenex Lux Cellulose-1150mm×4.6mm, 5um <![CDATA[A: CO2 B: iPrOH + 0.1% diethylamine]]> From 5% B to 60% B within 10 minutes, maintain for 3 minutes. Return to 5% B within 1.9 minutes. 3 ------- 35 20 ------- 100 6 Phenomenex Lux Amylose-1 150mm×4.6mm, 5um <![CDATA[A: CO2B: EtOH + 0.1% diethylamine]]> From 5% B to 60% B within 10 minutes, maintain for 3 minutes. Return to 5% B within 1.9 minutes. 3 ------- 35 20 ------- 100 7 Phenomenex Lux Amylose-2 150mm×4.6mm, 5um <![CDATA[A: CO2 B: EtOH + 0.1% diethylamine]]> From 5% B to 60% B within 10 minutes, maintain for 3 minutes. Return to 5% B within 1.9 minutes. 3 ------- 35 20 ------- 100 SFC Results Table 14: Analytical SFC Data - R t This refers to the retention time (in minutes), [M+H] + This refers to the protons of a compound. Chemical quality, methods refer to the methods used for (SFC) MS analysis of optically pure compounds. . Example number SFC method code <![CDATA[R t ]]> purity <![CDATA[[M+H] + ]]> 109 1 3.71 100 575.0 110 1 4.16 98 575.1 111 2 4.66 100 574.0 112 2 7.72 100 574.1 113 3 4.50 100 561.0 114 3 7.70 100 561.1 115 4 4.01 100 560.1 116 4 6.14 99 560.1 256 5 4.39 99 460.1 258 6 10.61 99 424.1 259 6 12.11 99 424.1 260 5 7.70 98 452.1 279 7 10.60 99 597.0 280 7 10.41 99 597.0

[0396] NMR The following NMR experiments were performed: using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe with z-gradient, operated at 500 MHz for protons and 125 MHz for carbon. The following NMR experiments were performed using a Bruker Avance III 400 spectrometer with internal deuterium locking and equipped with a z-gradient reverse double resonance (BBFO). 1 H, 13 The C, SEI) probe was used, and operation was performed at 400 MHz for protons. Unless otherwise specified, experiments were conducted at ambient temperature (298.6 K). Chemical shifts (d) are reported in parts per million (ppm). J values ​​are expressed in Hz. Multiplicity is defined as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiply, br = broad peak, dd = doublet, dt = doubletuplet, td = triple doublet. It should be understood that for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used for NMR spectroscopy and the concentration of the compound in solution.

[0397] Table 15: 1 H NMR results Example number NMR peak list 1 <![CDATA[ 1 H NMR (CDCl3) δ (ppm): 10.06 (s, 1H), 9.33 (s, 1H), 8.68 (d, J = 8.3Hz, 1H), 8.40 (d, J = 8.8Hz, 1H),8.13 (dd, J = 8.3, 2.4Hz, 1H), 8.04 (d, J = 7.3Hz, 1H), 7.95 (s, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.72 (dd,J = 8.3, 7.3Hz, 1H), 7.30 (d, J = 8.3Hz, 1H), 6.79 (d, J = 8.3Hz, 1H), 4.22 (dd, J = 12.7, 2.0Hz, 2H),4.08 (s, 2H), 3.74-3.85 (m, 2H), 3.07 (s, 3H), 2.59-2.69 (m, 5H), 1.34 (d, J = 6.4Hz, 6H)]]> 2 <![CDATA 1 1H NMR (chloroform-d) δ (ppm): 10.08 (s, 1H), 9.33 (d, J = 0.7 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.40 (dd, J = 8.6, 0.7 Hz, 1H), 8.14 (dd, J = 8.3, 2.4 Hz, 1H), 7.99 (d, J = 7.1 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 8.4, 7.5 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 4.40 - 4.48 (m, 2H), 4.08 (s, 2H), 3.07 (s, 3H), 2.99 (td, J = 9.8, 5.7 Hz, 1H), 2.59 - 2.68 (m, 5H), 1.65 - 1.79 (m, 3H), 1.14 (d, J = 6.6 Hz, 6H) <!-- 113 -->]]> 3 <![CDATA[ 1 ¹H NMR (400MHz, chloroform-d): δ (ppm): 10.10, 9.33, 8.69, 8.40, 8.14, 7.98, 7.89, 7.68, 7.31, 6.84, 4.43, 4.13, 4.09, 3.74, 3.07, 2.95, 2.64, 1.91, 1.72, 1.12 (Diabetic isomer mixture, peak values ​​listed are for reference only). 4 <![CDATA 1 1H NMR (in chloroform-d) δ (ppm): 9.67 (s, 1H), 9.31 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H), 8.39 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.96 (s, 1H), 7.68 - 7.76 (m, 1H), 7.54 (dd, J = 8.3, 1.5 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.22 (dd, J = 12.7, 1.5 Hz, 2H), 4.07 (s, 2H), 3.98 (t, J = 8.6 Hz, 2H), 3.75 - 3.86 (m, 2H), 3.10 (t, J = 8.3 Hz, 2H), 2.88 (s, 3H), 2.64 (dd, J = 12.5, 10.5 Hz, 2H), 1.34 (d, J = 5.9 Hz, 6H)]]> 5 <![CDATA 1 1H NMR (chloroform-d) δ (ppm): 9.99 (s, 1H), 9.35 (s, 1H), 8.74 (br s, 2H), 8.51 (t, J = 1.7 Hz, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.21 - 8.27 (m, 1H), 8.15 (dd, J = 8.3, 2.4 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.00 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.78 - 7.84 (m, 1H), 7.66 - 7.73 (m, 1H), 7.64 (br d, J = 5.4 Hz, 2H), 7.31 (d, J = 8.8 Hz, 1H), 4.11 (s, 2H), 3.08 (s, 3H), 2.65 (s, 3H)]]> 6 <![CDATA 1 1H NMR (in chloroform-d) δ (ppm): 9.52 (s, 1H), 9.32 (s, 1H), 8.71 - 8.75 (m, 2H), 8.51 (t, J = 1.7 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.24 (dt, J = 7.8, 1.5 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 8.02 (s, 1H), 7.78 - 7.82 (m, 1H), 7.66 - 7.71 (m, 1H), 7.61 - 7.65 (m, 3H), 7.54 - 7.58 (m, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 4.09 (s, 2H), 1.83 (s, 1H), 1.58 (s, 6H)]]> 7 <![CDATA 1 1H NMR (chloroform-d) δ (ppm): 10.60 (s, 1H), 9.35 (s, 1H), 9.02 (d, J = 2.4Hz, 1H), 8.85 (d, J = 2.4Hz, 1H), 8.70 - 8.76 (m, 2H), 8.65 (t, J = 2.2Hz, 1H), 8.51 (t, J = 1.7Hz, 1H), 8.42 - 8.47 (m, 1H), 8.25 (dt, J = 7.8, 1.5Hz, 1H), 8.11 (d, J = 8.8Hz, 1H), 8.02 (s, 1H), 7.81 (ddd, J = 7.8, 2.0, 1.0Hz, 1H), 7.66 - 7.73 (m, 1H), 7.60 - 7.65 (m, 2H), 4.15 (s, 2H), 3.13 (s, 3H)]]> 8 <![CDATA 1 1H NMR (in chloroform-d) δ (ppm): 9.58 (s, 1H), 9.34 (s, 1H), 8.72 - 8.75 (m, 2H), 8.51 (t, J = 1.7 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.21 - 8.27 (m, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H), 7.78 - 7.83 (m, 1H), 7.66 - 7.72 (m, 1H), 7.62 - 7.66 (m, 2H), 7.56 (dd, J = 7.8, 2.0 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 4.08 (s, 2H), 3.98 (t, J = 8.6 Hz, 2H), 3.10 (t, J = 8.3 Hz, 2H), 2.89 (s, 3H)]]> 9 <![CDATA 1 1H NMR (400 MHz, chloroform-d, 25 °C): δ (ppm) = 10.09 (s, 1H), 9.33 (s, 1H), 8.70 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 8.3 Hz, 1H), 8.14 (dd, J = 8.3, 2.4 Hz, 1H), 7.93 - 7.98 (m, 2H), 7.89 (d, J = 2.0 Hz, 1H), 7.59 - 7.76 (m, 1H), 7.27 - 7.33 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.13 (dd, J = 13.0, 4.2 Hz, 2H), 4.08 (s, 2H), 3.70 - 3.78 (m, 1H), 3.07 (s, 3H), 2.93 (t, J = 12.2 Hz, 2H), 2.65 (s, 3H), 1.86 - 1.97 (m, 2H), 1.10 ppm (d, J = 6.8 Hz, 6H)]]> 26 <![CDATA 1 1H NMR (400 MHz, methanol-d4) δ 9.57 (s, 1H), 8.76 (s, 1H), 8.63 - 8.57 (m, 1H), 8.41 (d, J = 8.7 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.28 (s, 1H), 7.86 – 7.77 (m, 2H), 7.60 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.27 (s, 2H), 4.08 (t, J = 5.2 Hz, 2H), 3.90 (s, 2H), 3.51 (t, J = 5.2 Hz, 2H), 3.13 (s, 3H), 2.65 (s, 3H), 1.12 (s, 4H).]]> 27 <![CDATA 1 1H NMR (400 MHz, methanol-d4) δ 9.65 (s, 1H), 8.78 (s, 1H), 8.66 - 8.61 (m, 1H), 8.48 (d, J = 8.7 Hz, 1H), 8.37 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.47 - 7.38 (m, 2H), 6.99 (d, J = 8.6 Hz, 1H), 4.54 - 4.44 (m, 2H), 4.32 (s, 2H), 3.13 (s, 3H), 2.89 (t, J = 9.8 Hz, 1H), 2.73 - 2.59 (m, 5H), 1.68 – 1.55 (m, 2H), 1.11 (d, J = 6.5 Hz, 6H).]]> 28 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ 10.15 (s, 1H), 9.32 (s, 1H), 8.40 (s, 1H), 8.33 - 8.28 (m, 1H), 8.14 – 8.05 (m, 2H), 7.92 (d, J = 2.3 Hz, 1H), 7.74 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.32 - 7.26 (m, 2H), 6.68 (d, J = 8.5 Hz, 1H), 4.28 - 4.19 (m, 2H), 4.03 (s, 2H), 3.84 - 3.74 (m, 2H), 3.07 (s, 3H), 2.67 – 2.58 (m, 5H), 1.33 (d, J = 6.2 Hz, 6H).]]> 29 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ 10.17 (s, 1H), 9.31 (s, 1H), 8.40 (s, 1H), 8.33 - 8.27 (m, 1H), 8.11 - 8.02 (m, 2H), 7.96 (t, J = 1.9 Hz, 1H), 7.75 (s, 1H), 7.67 – 7.60 (m, 1H), 7.32 – 7.26 (m, 2H), 6.68 (d, J = 8.4 Hz, 1H), 4.28 - 4.19 (m, 2H), 4.07 - 3.99 (m, 4H), 3.83 – 3.75 (m, 2H), 3.40 – 3.34 (m, 2H), 2.67 - 2.57 (m, 5H), 1.36 - 1.29 (m, 6H).]]> 30 <![CDATA[ 1 H NMR (400MHz, CDCl3) δ (ppm) 10.67 (s, 1H), 9.33 (s, 1H), 9.02 (d, J = 2.4Hz, 1H), 8.86 (d, J = 2.1Hz,1H), 8.70 (d, J = 8.7Hz, 1H), 8.65 (t, J = 2.2Hz, 1H), 8.42 (d, J = 8.7Hz, 1H), 8.05 (d, J = 7.5Hz, 1H),7.97 (s, 1H), 7.76 – 7.68 (m, 1H), 6.80 (d, J = 8.5Hz, 1H), 4.22 (d, J = 12.4Hz, 2H), 4.13 (s, 2H), 3.12(s, 3H), 2.64 (dd, J = 12.6, 10.5Hz, 2H), 1.34 (d, J = 6.2Hz, 8H).]]> 35 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm): 10.93 (s, 1H), 9.57 (s, 1H), 8.75 (q, J = 8.7Hz, 2H), 8.44 (d, J =2.1Hz, 1H), 8.16 (s, 1H), 8.09 – 7.93 (m, 2H), 7.86 – 7.72 (m, 2H), 7.68 (d, J = 7.7Hz, 1H), 7.31 (t, J =52.0Hz, 1H), 7.08 (d, J = 8.5Hz, 1H), 4.34 (dd, J = 12.7, 2.4Hz, 2H), 4.24 (s, 2H), 3.77 – 3.60 (m, 2H),2.61 – 2.55 (m, 2H), 1.23 (d, J = 6.1Hz, 6H). <!-- 114 -->]]> 53 <![CDATA[ 1 H NMR (400MHz, CDCl3) δ (ppm) 9.27 (s, 1H), 8.37 (d, J = 8.6Hz, 1H), 8.10 (d, J = 7.9Hz, 1H), 8.03 (d, J= 7.4Hz, 1H), 7.88 (s, 1H), 7.71 (t, J = 7.9Hz, 1H), 6.78 (d, J = 8.4Hz, 1H), 4.31 – 4.11 (m, 3H), 3.94(s, 2H), 3.80 (ddd, J = 10.4, 6.2, 2.4Hz, 2H), 3.49 – 3.42 (m, 1H), 3.31 (dd, J = 11.8, 5.2Hz, 1H), 3.17(dd, J = 11.8, 3.0Hz, 1H), 3.04 – 2.91 (m, 1H), 2.77 (s, 3H), 2.63 (dd, J = 12.6, 10.6Hz, 2H), 1.89 –1.50 (m, 5H), 1.33 (d, J = 6.2Hz, 6H).]]> 56 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm): 10.49 (s, 1H), 9.33 (s, 1H), 8.40 (s, 1H), 8.31 (dd, J = 8.6, 1.7Hz,1H), 8.23 (ddd, J = 8.2, 2.2, 1.1Hz, 1H), 8.09 (d, J = 8.6Hz, 1H), 8.05 (t, J = 2.0Hz, 1H), 7.75 (s, 1H),7.71 – 7.55 (m, 3H), 7.28 (dd, J = 7.4, 0.5Hz, 1H), 6.69 (d, J = 8.4Hz, 1H), 6.18 (t, J = 53.4Hz, 1H),4.23 (dd, J = 12.9, 2.3Hz, 2H), 4.05 (s, 2H), 3.92 – 3.62 (m, 2H), 2.63 (dd, J = 12.7, 10.6Hz, 2H), 1.33(d, J = 6.3Hz, 6H)]]> 57 <![CDATA[ 1 H NMR (400MHz, CDCl3) δ (ppm) 9.27 (s, 1H), 8.63 (d, J = 8.6Hz, 1H), 8.35 (s, 1H), 8.10 (d, J = 7.9Hz,1H), 8.03 (d, J = 7.4Hz, 1H), 7.88 (s, 1H), 7.71 (t, J = 7.9Hz, 1H), 6.78 (d, J = 8.4Hz, 1H), 4.26 – 4.16(m, 3H), 3.94 (s, 2H), 3.80 (ddd, J = 9.5, 6.4, 2.3Hz, 2H), 3.45 (d, J = 11.9Hz, 1H), 3.31 (dd, J = 12.0,5.2Hz, 1H), 3.17 (dd, J = 11.8, 3.0Hz, 1H), 3.04 – 2.91 (m, 1H), 2.77 (s, 3H), 2.68 – 2.58 (m, 2H), 1.85– 1.73 (m, 2H), 1.68 (dd, J = 10.3, 4.4Hz, 2H), 1.33 (d, J = 6.2Hz, 6H)]]> 58 <![CDATA[ 1 H NMR (400MHz, CDCl3) δ (ppm) 9.27 (s, 1H), 8.63 (d, J = 8.6Hz, 1H), 8.37 (d, J = 8.7Hz, 1H), 8.10 (d, J= 7.8Hz, 1H), 8.03 (d, J = 7.5Hz, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 6.78 (d, J = 8.5Hz, 1H), 4.22 (d, J =12.9Hz, 3H), 3.94 (s, 2H), 3.80 (t, J = 8.6Hz, 2H), 3.45 (d, J = 11.6Hz, 1H), 3.30 (dd, J = 11.7, 5.2Hz,1H), 3.17 (d, J = 11.8Hz, 1H), 2.98 (t, J = 10.6Hz, 1H), 2.77 (s, 3H), 2.70 – 2.55 (m, 2H), 1.78 (d, J =6.7Hz, 2H), 1.67 (dt, J = 15.7, 8.1Hz, 2H), 1.33 (d, J = 6.2Hz, 6H)]]> 59 <![CDATA[ 1 H NMR (400MHz, CDCl3) δ (ppm) 9.24 (s, 1H), 8.37 (s, 1H), 8.26 (d, J = 8.6Hz, 1H), 8.02 (dd, J = 11.6,8.2Hz, 2H), 7.68 (s, 1H), 7.63 (t, J = 7.9Hz, 1H), 7.39 - 7.14 (m, 1H), 6.67 (d, J = 8.5Hz, 1H), 4.23 (d,J = 12.5Hz, 2H), 4.17 - 4.12 (m, 1H), 3.88 (s, 2H), 3.84 - 3.73 (m, 2H), 3.37 (dd, J = 11.3, 5.7Hz, 1H),3.23 (d, J = 4.3Hz, 2H), 3.04 (td, J = 10.1, 8.7, 3.2Hz, 1H), 2.76 (s, 3H), 2.62 (t, J = 11.6Hz, 2H),1.88 - 1.65 (m, 4H), 1.33 (d, J = 6.2Hz, 6H)]]> 60 <![CDATA[ 1 H NMR (400MHz, CDCl3) δ (ppm) 9.25 (s, 1H), 8.37 (s, 1H), 8.26 (dd, J = 8.6, 1.7Hz, 1H), 8.03 (dd, J =11.7, 8.2Hz, 2H), 7.68 (s, 1H), 7.63 (dd, J = 8.5, 7.4Hz, 1H), 7.28 - 7.24 (m, 1H), 6.67 (d, J = 8.5Hz,1H), 4.23 (dd, J = 13.0, 2.4Hz, 2H), 4.16 (p, J = 4.5Hz, 1H), 3.88 (s, 2H), 3.78 (dtd, J = 12.4, 6.2,2.4Hz, 2H), 3.37 (dd, J = 11.6, 5.6Hz, 1H), 3.27 - 3.17 (m, 2H), 3.04 (td, J = 9.7, 8.5, 3.1Hz, 1H), 2.76(s, 3H), 2.62 (dd, J = 12.8, 10.5Hz, 2H), 1.81 - 1.65 (m, 4H), 1.33 (d, J = 6.2Hz, 6H).]]> 61 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 10.00 (s, 1H), 9.32 (s, 1H), 8.67 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.12 - 8.07 (m, 1H), 8.04 (d, J = 7.4 Hz, 1H), 8.00 – 7.92 (m, 2H), 7.75 - 7.68 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.26 – 4.18 (m, 2H), 4.08 (s, 2H), 3.85 - 3.74 (m, 2H), 3.13 (s, 3H), 2.78 (s, 1H), 2.69 (s, 3H), 2.67 – 2.60 (m, 2H), 1.33 (d, J = 6.2 Hz, 6H).]]> 62 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.26 (s, 1H), 8.41 – 8.34 (m, 1H), 8.29 - 8.22 (m, 2H), 8.04 (d, J = 8.6 Hz, 1H), 7.71 – 7.59 (m, 2H), 7.26 - 7.24 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.31 – 4.20 (m, 3H), 4.18 - 4.12 (m, 1H), 3.93 - 3.84 (m, 2H), 3.83 - 3.74 (m, 2H), 3.61 - 3.54 (m, 1H), 3.23 - 3.17 (m, 1H), 2.76 (s, 3H), 2.66 - 2.57 (m, 2H), 1.95 – 1.83 (m, 1H), 1.80 – 1.76 (m, 2H), 1.42 – 1.37 (m, 1H), 1.33 (d, J = 6.2 Hz, 6H), 1.25 (d, J = 6.9 Hz, 3H).]]> 63 / 64 racemic mixture <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm): 9.34 (s, 1H), 8.70 – 8.57 (m, 2H), 8.27 (d, J = 7.1Hz, 1H), 7.94 (d, J= 7.4Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J = 8.5, 7.4Hz, 1H), 7.25 – 6.95 (m, 2H), 4.41 – 4.26 (m, 2H), 3.93(d, J = 5.7Hz, 2H), 3.86 (s, 2H), 3.71 (d, J = 10.8Hz, 4H), 3.55 (d, J = 13.0Hz, 1H), 3.14 (t, J =11.1Hz, 1H), 2.96 (dd, J = 20.3, 9.1Hz, 1H), 2.29 (d, J = 6.7Hz, 2H), 2.04 – 1.94 (m, 1H), 1.85 (t, J =13.5Hz, 1H), 0.87 – 0.84 (m, 6H).]]> 65 / 66 racemic mixture <![CDATA[(Racemate)]]> 1 1H NMR (401 MHz, DMSO-d6) δ (ppm): 9.25 (s, 1H), 8.56 (s, 1H), 8.32 (dd, J = 8.7, 1.7 Hz, 1H), 8.25 (d, J = 7.0 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.83 (s, 1H), 7.71 (dd, J = 8.5, 7.4 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 52.4 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.31 (d, J = 11.7 Hz, 2H), 3.78 (s, 2H), 3.76 – 3.60 (m, 4H), 3.61 – 3.46 (m, 1H), 3.15 (t, J = 10.8 Hz, 1H), 2.98 (dd, J = 12.1, 8.7 Hz, 1H), 1.91 – 1.79 (m, 2H), 1.51 (q, J = 10.0 Hz, 2H), 1.23 – 1.20 (m, 8H).]]> 67 / 68 racemic mixture <![CDATA[(Racemate) 1 1H NMR (401 MHz, DMSO-d6) δ (ppm): 9.39 (s, 1H), 8.71 – 8.61 (m, 2H), 8.57 (d, J = 6.4 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.79 (dd, J = 8.5, 7.4 Hz, 1H), 7.31 – 6.95 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.36 – 4.29 (m, 3H), 3.88 (s, 2H), 3.75 – 3.64 (m, 4H), 3.67 – 3.57 (m, 1H), 3.55 (dd, J = 14.4, 6.7 Hz, 1H), 3.29 (dd, J = 10.0, 4.7 Hz, 1H), 2.56 – 2.52 (m, 1H), 2.19 (dq, J = 13.7, 7.1 Hz, 1H), 2.00 – 1.87 (m, 1H), 1.22 (d, J = 6.2 Hz, 6H). <!-- 115 -->]]> 69 / 70 racemic mixture <![CDATA[(Racemate)]]> 1 H NMR (401 MHz, DMSO-d6) δ (ppm): 9.49 (s, 1H), 8.70 (s, 1H), 8.62 (d, J = 6.3 Hz, 1H), 8.46 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 8.7 Hz, 1H), 8.06 (s, 1H), 7.74 (dd, J = 8.5, 7.4 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.03 – 6.93 (m, 1H), 4.33 (d, J = 12.1 Hz, 3H), 3.90 (s, 2H), 3.72 – 3.49 (m, 8H), 3.31 (dd, J = 10.0, 4.4 Hz, 1H), 2.19 (dq, J = 13.7, 7.1 Hz, 1H), 2.01 – 1.89 (m, 1H), 1.22 (d, J = 6.2 Hz, 6H).]]> 71 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.22 (s, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.90 (s, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.28 - 4.16 (m, 2H), 3.97 – 3.74 (m, 5H), 3.03 - 2.92 (m, 1H), 2.83 (s, 3H), 2.68 - 2.58 (m, 2H), 2.41 (d, J = 12.4 Hz, 1H), 2.19 (d, J = 11.2 Hz, 1H), 2.06 – 1.95 (m, 2H), 1.57 – 1.55 - 1.15 (m, 10H).]]> 72 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.23 (s, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 8.7 Hz, 1H), 8.10 – 7.89 (m, 3H), 7.71 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 4.46 – 4.34 (m, 1H), 4.22 (d, J = 12.4 Hz, 2H), 3.93 (s, 2H), 3.86 – 3.72 (m, 2H), 2.98 (t, J = 11.9 Hz, 1H), 2.77 (s, 3H), 2.63 (t, J = 11.5 Hz, 2H), 2.42 - 2.19 (m, 2H), 1.95 – 1.72 (m, 3H), 1.64 – 1.50 (m, 3H), 1.33 (d, J = 6.2 Hz, 6H).]]> 73 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.22 (s, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.90 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.27 - 4.17 (m, 2H), 3.91 (s, 3H), 3.83 - 3.74 (m, 2H), 3.04 – 2.91 (m, 1H), 2.83 (s, 3H), 2.69 - 2.58 (m, 2H), 2.41 (d, J = 12.4 Hz, 1H), 2.19 (d, J = 11.2 Hz, 1H), 2.00 (d, J = 11.4 Hz, 2H), 1.54 – 1.28 (m, 10H).]]> 74 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.23 (s, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.98 - 7.90 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.43 - 4.35 (m, 1H), 4.27 - 4.17 (m, 2H), 3.93 (s, 2H), 3.85 – 3.74 (m, 2H), 3.05 - 2.94 (m, 1H), 2.77 (s, 3H), 2.68 - 2.58 (m, 2H), 2.42 – 2.31 (m, 1H), 2.28 - 2.20 (m, 1H), 1.93 - 1.85 (m, 1H), 1.81 - 1.72 (m, 2H), 1.62 – 1.52 (m, 3H), 1.33 (d, J = 6.2 Hz, 6H).]]> 75 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.21 (s, 1H), 8.38 (s, 1H), 8.30 - 8.25 (m, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.70 (s, 1H), 7.66 - 7.60 (m, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.25 (s, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.29 – 4.13 (m, 3H), 3.88 – 3.74 (m, 6H), 2.87 (s, 3H), 2.83 - 2.76 (m, 1H), 2.65 - 2.58 (m, 2H), 1.89 – 1.76 (m, 2H), 1.65 – 1.53 (m, 2H), 1.32 (d, J = 6.2 Hz, 6H), 1.26 (d, J = 6.8 Hz, 3H).]]> 76 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.21 (s, 1H), 8.38 (s, 1H), 8.31 - 8.25 (m, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.70 (s, 1H), 7.66 – 7.59 (m, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.25 (s, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.28 - 4.13 (m, 3H), 3.89 – 3.74 (m, 6H), 2.87 (s, 3H), 2.83 - 2.75 (m, 1H), 2.66 - 2.57 (m, 2H), 1.90 - 1.76 (m, 2H), 1.65 – 1.53 (m, 2H), 1.32 (d, J = 6.2 Hz, 6H), 1.26 (d, J = 6.8 Hz, 3H).]]> 77 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.22 (s, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.32 - 8.25 (m, 1H), 8.11 - 7.99 (m, 2H), 7.70 (s, 1H), 7.67 - 7.60 (m, 1H), 7.31 - 7.24 (m, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.29 – 4.17 (m, 2H), 3.87 (s, 2H), 3.83 - 3.74 (m, 2H), 3.02 - 2.90 (m, 1H), 2.73 (s, 3H), 2.67 - 2.58 (m, 2H), 2.40 – 2.31 (m, 1H), 2.28 - 2.19 (m, 1H), 1.93 – 1.85 (m, 1H), 1.81 - 1.71 (m, 2H), 1.63 – 1.49 (m, 3H), 1.33 (d, J = 6.2 Hz, 6H).]]> 78 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.22 (s, 1H), 8.38 (s, 1H), 8.33 – 8.25 (m, 1H), 8.10 - 7.99 (m, 2H), 7.71(s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.31 - 7.24 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.43 - 4.35 (m, 1H), 4.28 - 4.18 (m, 2H), 3.87 (s, 2H), 3.83 - 3.74 (m, 2H), 3.02 - 2.91 (m, 1H), 2.73 (s, 3H), 2.67 - 2.57 (m, 2H), 2.39 - 2.30 (m, 1H), 2.27 - 2.19 (m, 1H), 1.93 - 1.86 (m, 1H), 1.81 - 1.71 (m, 2H), 1.63 – 1.49 (m, 3H), 1.33 (d, J = 6.2 Hz, 6H).]]> 79 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.21 (s, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.31 - 8.24 (m, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.66 - 7.60 (m, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.30 - 7.24 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.30 – 4.18 (m, 2H), 3.94 – 3.73 (m, 5H), 3.02 - 2.91 (m, 1H), 2.82 (s, 3H), 2.67 - 2.57 (m, 2H), 2.45 – 2.37 (m, 1H), 2.22 - 2.14 (m, 1H), 2.03 – 1.94 (m, 2H), 1.50 – 1.20 (m, 10H).]]> 80 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.21 (s, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.31 - 8.25 (m, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.66 - 7.60 (m, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.30 - 7.24 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.29 – 4.18 (m, 2H), 3.93 – 3.75 (m, 5H), 3.01 - 2.91 (m, 1H), 2.82 (s, 3H), 2.67 - 2.57 (m, 2H), 2.45 – 2.36 (m, 1H), 2.22 - 2.15 (m, 1H), 2.04 – 1.94 (m, 2H), 1.48 – 1.25 (m, 10H).]]> 82 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.46 (d, J = 0.8Hz, 1H), 7.83 (d, J = 8.6Hz, 1H), 7.75 (dd, J = 8.6,0.9Hz, 1H), 7.19 – 7.12 (m, 2H), 6.95 (dd, J = 8.5, 7.4Hz, 1H), 6.19 – 6.12 (m, 1H), 4.08 – 4.04 (m, 6H),3.56 – 3.47 (m, 2H), 3.04 – 2.92 (m, 2H), 2.84 (s, 2H), 1.76 (dd, J = 12.8, 10.6Hz, 2H), 1.22 (s, 2H),0.87 (s, 2H), 0.50 (d, J = 6.3Hz, 6H) <!-- 116 -->]]> 98 <![CDATA[ 1 H NMR (400MHz, CDCl3) δ (ppm) 9.40 (d, J = 25.3Hz, 1H), 8.90 (dd, J = 8.8, 2.9Hz, 1H), 8.55 (dd, J =8.8, 5.8Hz, 1H), 8.45 (d, J = 8.9Hz, 1H), 8.35 (d, J = 7.9Hz, 1H), 8.16 – 8.07 (m, 2H), 7.76 (td, J =8.0, 7.4, 1.2Hz, 1H), 6.91 – 6.84 (m, 1H), 6.09 (dt, J = 62.6, 53.6Hz, 1H), 4.31 – 4.13 (m, 3H), 4.09 –4.05 (m, 1H), 3.98 (d, J = 13.2Hz, 1H), 3.86 – 3.68 (m, 4H), 3.65 – 3.57 (m, 1H), 3.45 – 3.38 (m, 1H),3.36 – 3.26 (m, 1H), 2.71 – 2.61 (m, 2H), 2.06 – 1.85 (m, 1H), 1.68 – 1.63 (m, 1H), 1.34 (d, J = 6.2Hz,6H) ; 19 F NMR (377MHz, CDCl3) δ (ppm) -75.66]]> 100 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.42 (d, J = 5.5Hz, 1H), 8.91 (d, J = 8.8Hz, 1H), 8.57 (d, J = 8.8Hz,1H), 8.48 (d, J = 4.5Hz, 1H), 8.12 (d, J = 7.4Hz, 1H), 7.81 – 7.73 (m, 1H), 6.90 (d, J = 8.5Hz, 1H), 6.00(td, J = 53.6, 27.5Hz, 1H), 4.42 (q, J = 5.9Hz, 1H), 4.24 – 4.08 (m, 4H), 3.92 – 3.75 (m, 1H), 3.80 (s,2H), 3.69 (td, J = 12.0, 5.3Hz, 1H), 3.61 – 3.48 (m, 1H), 2.73 – 2.62 (m, 2H), 1.99 (s, 4H), 1.34 (d, J =6.3Hz, 6H); 19F NMR (377MHz, CDCl3) δ (ppm) -75.68]]> 118 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.43 (s, 1H), 8.66 (s, 1H), 8.43 (d, J = 8.6Hz, 1H), 8.28 (dd, J = 8.1,4.9Hz, 2H), 8.00 (s, 1H), 7.78 – 7.69 (m, 1H), 7.50 (d, J = 7.4Hz, 1H), 6.95 (d, J = 8.5Hz, 1H), 6.37(tt, J = 54.7, 4.6Hz, 1H), 4.37 – 4.29 (m, 2H), 3.96 – 3.84 (m, 2H), 3.87 – 3.82 (m, 2H), 3.76 – 3.72 (m,1H), 3.72 – 3.63 (m, 2H), 3.62 – 3.54 (m, 2H), 3.03 – 2.92 (m, 2H), 2.56 – 2.53 (m, 1H), 1.90 – 1.82 (m,3H), 1.53 – 1.35 (m, 2H), 1.22 (d, J = 6.2Hz, 6H)]]> 119 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.25 (d, J = 1.0Hz, 1H), 8.57 (d, J = 1.4Hz, 1H), 8.33 (dd, J = 8.7,1.7Hz, 1H), 8.18 (dd, J = 16.0, 8.0Hz, 2H), 7.83 (s, 1H), 7.72 (dd, J = 8.5, 7.5Hz, 1H), 7.47 (d, J =7.4Hz, 1H), 7.11 (t, J = 52.5Hz, 1H), 6.92 (d, J = 8.5Hz, 1H), 4.32 (d, J = 11.8Hz, 2H), 3.85 (dd, J =12.1, 4.7Hz, 1H), 3.76 (s, 2H), 3.73 – 3.55 (m, 2H), 2.64 (dt, J = 17.6, 11.7Hz, 2H), 2.51 – 2.44 (m,4H), 1.91 (d, J = 12.9Hz, 1H), 1.69 (s, 1H), 1.22 (d, J = 6.2Hz, 6H), 1.16 – 1.04 (m, 1H), 0.90 (d, J =6.6Hz, 3H); 19F NMR (377MHz, DMSO-d6) δ (ppm) -123.13.]]> 136 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm)10.20 (br s, 1 H), 9.36 (s, 1 H), 8.59 - 8.69 (m, 2 H), 8.02 (s, 1 H),7.94 (d, J = 5.34Hz, 2 H), 7.79 (t, J = 7.92Hz, 1 H), 7.54 (dd, J = 11.30, 2.43Hz, 1 H), 7.05 (d, J =8.49Hz, 1 H), 6.15 - 6.48 (m, 1 H), 4.47 (td, J = 15.00, 3.48Hz, 2 H), 4.32 (br d, J = 11.44Hz, 2 H),4.03 (s, 2 H), 3.68 (ddd, J = 10.30, 6.29, 2.19Hz, 2 H), 2.54 (s, 2 H), 1.22 (d, J = 6.20Hz, 6 H)]]> 150 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm): 9.34 (d, J = 2.6Hz, 1H), 8.68 – 8.60 (m, 2H), 8.39 (t, J = 7.8Hz, 1H),8.15 – 8.03 (m, 1H), 7.94 (dd, J = 7.4, 2.0Hz, 1H), 7.91 – 7.85 (m, 1H), 7.79 (t, J = 7.9Hz, 1H), 7.05(d, J = 8.5Hz, 1H), 4.33 (d, J = 11.9Hz, 2H), 4.20 – 4.11 (m, 1H), 4.00 – 3.96 (m, 1H), 3.93 – 3.85 (m,2H), 3.85 – 3.76 (m, 1H), 3.72 – 3.65 (m, 2H), 3.59 (dd, J = 28.8, 13.7Hz, 1H), 3.11 (dd, J = 13.0,9.4Hz, 1H), 2.75 – 2.67 (m, 1H), 2.56 – 2.52 (m, 1H), 2.50 – 2.47 (m, 1H), 2.42 – 2.38 (m, 1H), 1.22 (d,J = 6.3Hz, 6H).]]> 152 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.23 (s, 1 H) 8.38 (s, 1 H) 8.27 (dd, J = 8.55, 1.62 Hz, 1 H) 8.04 (d, J = 8.55 Hz, 1 H) 7.74 (s, 1 H) 7.69 (s, 1 H) 7.63 (dd, J = 8.44, 7.51 Hz, 1 H) 7.26 (t, J = 3.70 Hz, 1 H) 6.68 (d, J = 8.55 Hz, 1 H) 4.23 (dd, J = 12.72, 1.85 Hz, 2 H) 3.74 - 3.82 (m, 2 H) 3.67 (s, 3 H) 3.04 (s, 2 H) 2.62 (dd, J = 12.72, 10.63 Hz, 2 H) 2.36 (s, 6 H) 1.33 (d, J = 6.24 Hz, 6 H).]]> 153 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.25 (s, 1 H) 8.38 (s, 1 H) 8.28 (dd, J = 8.55, 1.62 Hz, 1 H) 8.05 (d, J = 8.55 Hz, 1 H) 7.71 (s, 1 H) 7.64 (dd, J = 8.44, 7.51 Hz, 1 H) 7.51 (br d, J = 9.48 Hz, 1 H) 7.28 (s, 1 H) 6.68 (d, J = 8.55 Hz, 1 H) 4.35 - 4.51 (m, 1 H) 4.23 (dd, J = 12.83, 1.97 Hz, 2 H) 3.75 - 3.82 (m, 2 H) 3.67 (s, 3 H) 3.00 (br s, 2 H) 2.72 - 2.84 (m, 1 H) 2.53 - 2.68 (m, 4 H) 2.10 - 2.23 (m, 2 H) 1.33 (d, J = 6.24 Hz, 6 H).]]> 154 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.25 (s, 1H), 8.57 (s, 1H), 8.51 (d, J = 6.5Hz, 1H), 8.32 (dd, J = 8.7,1.7Hz, 1H), 8.16 (d, J = 8.6Hz, 1H), 7.82 (s, 1H), 7.71 (t, J = 7.9Hz, 1H), 7.46 (d, J = 7.5Hz, 1H), 7.10(t, J = 52.4Hz, 1H), 6.92 (d, J = 8.5Hz, 1H), 5.62 (d, J = 3.2Hz, 1H), 4.38 – 4.27 (m, 2H), 4.15 (s, 1H),4.09 (d, J = 6.5Hz, 1H), 3.78 (d, J = 15.4Hz, 3H), 3.68 (dd, J = 10.9, 4.7Hz, 4H), 3.36 (d, J = 10.6Hz,2H), 1.22 (d, J = 6.2Hz, 6H); 19F NMR (376MHz, DMSO-d6) δ (ppm) -122.42.]]> 155 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.23 (s, 1 H) 8.38 (s, 1 H) 8.29 (dd, J = 8.55, 1.62 Hz, 1 H) 8.03 - 8.09 (m, 2 H) 7.69 (s, 1 H) 7.64 (dd, J = 8.44, 7.51 Hz, 1 H) 7.23 - 7.30 (m, 1 H) 6.69 (d, J = 8.55 Hz, 1 H) 4.23 (dd, J = 12.72, 1.85 Hz, 2 H) 3.85 (s, 2 H) 3.72 - 3.82 (m, 2 H) 2.58 - 2.69 (m, 2 H) 2.55 (s, 6 H) 2.32 (tt, J = 7.98, 4.85 Hz, 1 H) 1.33 (d, J = 6.24 Hz, 6 H) 1.17 - 1.24 (m, 2 H) 0.96 - 1.08 (m, 2 H)]]> 156 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.27 (s, 1H), 8.31 – 8.11 (m, 3H), 7.98 (dd, J = 8.5, 1.6Hz, 1H), 7.86(d, J = 7.3Hz, 2H), 7.79 (s, 1H), 7.55 (t, J = 7.6Hz, 2H), 7.46 (t, J = 7.3Hz, 1H), 3.80 (s, 3H), 3.49(dd, J = 11.2, 3.7Hz, 1H), 2.91 – 2.78 (m, 4H), 2.64 (dd, J = 11.1, 8.9Hz, 1H), 1.81 (d, J = 6.8Hz, 2H),1.62 – 1.49 (m, 1H), 1.49 – 1.36 (m, 1H). <!-- 117 -->]]> 157 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.76 (s, 1H), 9.25 (s, 1H), 8.59 (s, 1H), 8.36 (d, J = 1.8Hz, 1H), 8.20(dd, J = 8.6, 1.5Hz, 1H), 8.12 (d, J = 8.7Hz, 1H), 8.05 – 7.91 (m, 1H), 7.87 (s, 1H), 7.67 (t, J = 8.0Hz,1H), 7.58 (d, J = 8.0Hz, 1H), 7.23 (t, J = 52.0Hz, 1H), 6.79 (s, 1H), 4.03 – 3.97 (m, 2H), 3.74 (dd, J =8.5, 6.4Hz, 2H), 3.57 (d, J = 12.5Hz, 2H), 3.37 (s, 3H), 2.61 (dd, J = 12.7, 10.7Hz, 2H), 1.10 (d, J =6.2Hz, 6H)]]> 158 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.67 (s, 1H), 9.23 (s, 1H), 8.30 (s, 1H), 8.20 - 8.11 (m, 2H), 7.98 -7.89 (m, 2H), 7.83 - 7.77 (m, 3H), 7.60 - 7.54 (m, 2H), 7.51 - 7.45 (m, 2H), 7.45 - 7.34 (m, 1H), 6.94 -6.61 (m, 1H), 5.52 (s, 1H), 3.98 (s, 2H)]]> 159 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.25 (d, J = 10.17 Hz, 1 H) 8.38 (d, J = 4.16 Hz, 1 H) 8.29 (ddd, J = 8.55, 3.93, 1.62 Hz, 1 H) 8.06 (dd, J = 8.55, 1.85 Hz, 1 H) 7.59 - 7.84 (m, 3 H) 7.25 - 7.31 (m, 1 H) 6.69 (dd, J = 8.44, 2.66 Hz, 1 H) 4.42 - 4.61 (m, 1 H) 4.24 (dd, J = 12.83, 1.50 Hz, 2 H) 3.68 - 3.94 (m, 4 H) 3.40 - 3.57 (m, 1 H) 2.85 - 2.95 (m, 1 H) 2.82 (d, J = 9.02 Hz, 3 H) 2.67 - 2.78 (m, 1 H) 2.52 - 2.67 (m, 3 H) 2.36 - 2.49 (m, 1 H) 1.34 (d, J = 6.24 Hz, 6 H)]]> 160 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.19 (s, 1H), 8.19 (br d, J = 7.1Hz, 1H), 8.16 - 8.09 (m, 2H), 7.90(dd, J = 1.7, 8.5Hz, 1H), 7.81 - 7.77 (m, 2H), 7.75 - 7.69 (m, 1H), 7.51 - 7.45 (m, 2H), 7.42 - 7.36 (m,1H), 7.19 - 6.87 (m, 1H), 3.72 (s, 2H), 3.68 - 3.59 (m, 2H), 3.55 - 3.40 (m, 1H), 3.10 (br d, J = 5.3Hz,1H), 2.96 - 2.87 (m, 1H), 1.84 - 1.72 (m, 2H), 1.45 (br d, J = 9.1Hz, 2H)]]> 161 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.74 (s, 1H), 9.29 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 8.20 (d, J =8.6Hz, 1H), 8.01 (ddd, J = 10.3, 7.2, 2.1Hz, 2H), 7.87 (s, 2H), 7.86 (s, 1H), 7.67 – 7.61 (m, 2H), 7.55(t, J = 7.5Hz, 2H), 7.46 (t, J = 7.3Hz, 1H), 6.86 (t, J = 53.5Hz, 1H), 5.59 (s, 1H), 4.03 (d, J = 9.4Hz,2H)]]> 162 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.18 (s, 1H), 8.26 – 8.03 (m, 3H), 7.88 (dd, J = 8.5, 1.2Hz, 1H), 7.77(d, J = 7.5Hz, 2H), 7.70 (s, 1H), 7.51 – 7.40 (m, 2H), 7.37 (t, J = 7.3Hz, 1H), 3.71 (s, 3H), 3.40 (dd, J= 11.2, 3.4Hz, 1H), 2.83 – 2.67 (m, 4H), 2.56 (dd, J = 10.8, 9.1Hz, 1H), 1.72 (d, J = 6.7Hz, 2H), 1.46(dt, J = 13.9, 7.1Hz, 1H), 1.40 – 1.27 (m, 1H)]]> 163 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.18 (s, 1H), 8.24 – 8.04 (m, 3H), 7.88 (d, J = 8.2Hz, 1H), 7.77 (d, J =7.5Hz, 2H), 7.70 (s, 1H), 7.45 (dd, J = 21.0, 13.6Hz, 2H), 7.37 (t, J = 7.1Hz, 1H), 3.71 (s, 3H), 3.40(d, J = 9.0Hz, 1H), 2.82 – 2.66 (m, 4H), 2.61 – 2.48 (m, 1H), 1.73 (s, 2H), 1.47 (d, J = 6.5Hz, 1H), 1.33(d, J = 9.8Hz, 1H)]]> 164 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 10.67 (s, 1H), 9.23 (s, 1H), 8.30 (s, 1H), 8.20 - 8.10 (m, 2H), 8.00 -7.87 (m, 2H), 7.83 - 7.77 (m, 3H), 7.59 - 7.54 (m, 2H), 7.51 - 7.45 (m, 2H), 7.45 - 7.34 (m, 1H), 6.97 -6.61 (m, 1H), 5.52 (s, 1H), 4.01 - 3.94 (m, 2H)]]> 165 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) = 9.18 (s, 1H), 8.50 - 8.38 (m, 1H), 8.16 - 8.06 (m, 3H), 7.89 (dd, J =1.6, 8.5Hz, 1H), 7.77 (d, J = 7.4Hz, 2H), 7.74 - 7.68 (m, 1H), 7.50 - 7.43 (m, 2H), 7.43 - 7.34 (m, 1H),7.04 - 6.68 (m, 1H), 3.69 (s, 2H), 3.12 (br t, J = 5.7Hz, 2H), 3.08 (br d, J = 5.7Hz, 2H)]]> 166 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.25 (d, J = 8.8 Hz, 1 H) 8.38 (d, J = 4.6 Hz, 1 H) 8.28 (ddd, J = 8.6, 4.2, 1.6 Hz, 1 H) 8.05 (d, J = 8.6 Hz, 1 H) 7.56 - 7.85 (m, 3 H) 7.27 (s, 1 H) 6.69 (dd, J = 8.4, 2.7 Hz, 1 H) 4.51 (dq, J = 16.8, 8.1 Hz, 1 H) 4.24 (dd, J = 12.8, 1.7 Hz, 2 H) 3.73 - 3.99 (m, 4 H) 3.40 - 3.65 (m, 1 H) 2.87 - 2.99 (m, 1 H) 2.68 - 2.81 (m, 1 H) 2.37 - 2.67 (m, 4 H) 2.21 - 2.36 (m, 1 H) 1.33 (d, J = 6.2 Hz, 6 H) 1.15 - 1.27 (m, 2 H) 0.94 - 1.06 (m, 2 H)]]> 167 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.64 (s, 1H), 8.78 (s, 1H), 8.55 (d, 1H, J = 8.8Hz), 8.3-8.5 (m, 2H),8.21 (s, 1H), 7.76 (t, 1H, J = 7.6Hz), 7.54 (d, 1H, J = 7.3Hz), 6.98 (d, 1H, J = 8.8Hz), 4.34 (br d, 2H,J = 11.2Hz), 3.95 (s, 1H), 3.6-3.7 (m, 3H), 3.51 (br d, 2H, J = 11.7Hz), 2.8-2.9 (m, 5H), 2.5-2.5 (m,1H), 1.89 (br d, 2H, J = 9.8Hz), 1.4-1.6 (m, 2H), 1.22 (d, 6H, J = 5.9Hz)]]> 168 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.59 (s, 1H), 8.74 (s, 1H), 8.51 (d, 1H, J = 8.8Hz), 8.3-8.4 (m, 2H),8.15 (s, 1H), 7.75 (t, 1H, J = 7.8Hz), 7.53 (d, 1H, J = 7.3Hz), 7.12 (s, 1H), 7.0 (m, 1H), 4.33 (br d,2H, J = 12.2Hz), 3.93 (s, 2H), 3.85 (br d, 1H, J = 7.3Hz), 3.7-3.8 (m, 4H), 3.24 (br t, 2H, J = 11.2Hz),2.5 (m, 1H), 1.89 (br d, 2H, J = 9.8Hz), 1.4-1.5 (m, 2H), 1.22 (d, 6H, J = 5.9Hz)]]> 169 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) d ppm 9.61 (s, 1H), 8.76 (s, 1H), 8.53 (d, 1H, J = 8.8Hz), 8.3-8.4 (m, 2H), 8.18(s, 1H), 7.75 (t, 1H, J = 7.7Hz), 7.54 (d, 1H, J = 7.3Hz), 6.98 (d, 1H, J = 8.3Hz), 4.34 (br d, 2H, J =11.7Hz), 3.94 (s, 2H), 3.7-3.8 (m, 5H), 3.54 (br d, 2H, J = 12.2Hz), 3.18 (t, 2H, J = 6.4Hz), 2.9-3.0 (m,2H), 2.5 (m, 1H), 1.87 (br d, 2H, J = 9.8Hz), 1.4-1.5 (m, 2H), 1.22 (d, 6H, J = 5.9Hz) <!-- 118 -->]]> 170 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.26 (s, 1H), 8.57 (s, 1H), 8.46 (d, J = 7.2Hz, 1H), 8.33 (dd, J = 8.7,1.7Hz, 1H), 8.16 (d, J = 8.6Hz, 1H), 7.83 (s, 1H), 7.71 (t, J = 7.9Hz, 1H), 7.46 (d, J = 7.4Hz, 1H), 7.16(t, J = 52.4Hz, 1H), 6.91 (d, J = 8.5Hz, 1H), 4.32 (d, J = 12.5Hz, 2H), 4.06 – 3.96 (m, 1H), 3.83 – 3.78(m, 2H), 3.80 – 3.71 (m, 1H), 3.75 – 3.63 (m, 1H), 3.70 – 3.65 (m, 2H), 3.26 – 3.17 (m, 1H), 3.13 (t, J =8.9Hz, 1H), 2.51 – 2.44 (m, 2H), 2.27 (p, J = 7.3Hz, 1H), 1.22 (d, J = 6.1Hz, 6H), 1.02 (d, J = 6.6Hz,3H)]]> 171 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.26 (s, 1H), 8.56 (s, 1H), 8.42 (d, J = 8.1Hz, 1H), 8.36 – 8.29 (m,1H), 8.16 (d, J = 8.6Hz, 1H), 7.84 (s, 1H), 7.71 (t, J = 7.9Hz, 1H), 7.46 (d, J = 7.5Hz, 1H), 7.13 (t, J= 52.4Hz, 1H), 6.91 (d, J = 8.5Hz, 1H), 4.42 (s, 1H), 4.32 (d, J = 12.6Hz, 2H), 3.85 (s, 2H), 3.75 – 3.59(m, 6H), 3.23 (t, J = 9.0Hz, 1H), 2.51 – 2.44 (m, 2H), 1.22 (d, J = 6.2Hz, 6H), 0.94 (d, J = 6.8Hz, 3H)]]> 172 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.26 (s, 1H), 8.56 (s, 1H), 8.42 (d, J = 8.1Hz, 1H), 8.32 (dd, J = 8.6,1.7Hz, 1H), 8.16 (d, J = 8.6Hz, 1H), 7.84 (s, 1H), 7.71 (t, J = 7.9Hz, 1H), 7.46 (d, J = 7.4Hz, 1H), 7.13(t, J = 52.4Hz, 1H), 6.91 (d, J = 8.5Hz, 1H), 4.46 – 4.40 (m, 1H), 4.32 (d, J = 12.5Hz, 2H), 3.91 – 3.79(m, 2H), 3.70 – 3.66 (m, 6H), 3.24 (t, J = 9.0Hz, 1H), 2.54 – 2.44 (m, 2H), 1.22 (d, J = 6.2Hz, 6H), 0.94(d, J = 6.9Hz, 3H)]]> 173 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.25 (s, 1H), 8.56 (s, 1H), 8.47 (d, J = 6.1Hz, 1H), 8.36 – 8.29 (m,1H), 8.16 (d, J = 8.6Hz, 1H), 7.83 (s, 1H), 7.71 (t, J = 8.0Hz, 1H), 7.46 (d, J = 7.4Hz, 1H), 7.08 (t, J= 52.6Hz, 1H), 6.91 (d, J = 8.5Hz, 1H), 5.08 (t, J = 5.4Hz, 1H), 4.42 – 4.28 (m, 3H), 4.08 (dd, J = 8.6,4.5Hz, 1H), 3.78 (s, 2H), 3.72 – 3.63 (m, 2H), 3.59 (dd, J = 10.1, 6.1Hz, 1H), 3.53 – 3.42 (m, 2H), 3.42– 3.31 (m, 1H), 2.54 – 2.44 (m, 2H), 2.19 (dt, J = 11.5, 5.4Hz, 1H), 2.04 (dt, J = 13.5, 7.2Hz, 1H), 1.22(d, J = 6.1Hz, 6H)]]> 174 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.25 (s, 1H), 8.56 (s, 1H), 8.47 (d, J = 6.1Hz, 1H), 8.32 (dd, J = 8.7,1.8Hz, 1H), 8.16 (d, J = 8.6Hz, 1H), 7.83 (s, 1H), 7.71 (t, J = 8.0Hz, 1H), 7.46 (d, J = 7.4Hz, 1H), 7.08(t, J = 52.5Hz, 1H), 6.91 (d, J = 8.6Hz, 1H), 5.08 (t, J = 5.4Hz, 1H), 4.35 (ddd, J = 21.6, 12.6, 4.2Hz,4H), 4.09 (dt, J = 8.7, 4.6Hz, 1H), 3.78 (s, 2H), 3.67 (ddt, J = 13.6, 7.3, 3.5Hz, 2H), 3.47 (td, J =5.2, 2.7Hz, 2H), 3.42 – 3.31 (m, 1H), 2.54 – 2.44 (m, 2H), 2.19 (ddd, J = 13.0, 6.7, 4.3Hz, 1H), 2.10 –1.98 (m, 1H), 1.21 (d, J = 6.2Hz, 6H)]]> 175 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.27 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 6.3Hz, 1H), 8.34 (d, J = 8.7Hz,1H), 8.18 (d, J = 8.7Hz, 1H), 7.84 (s, 1H), 7.73 (t, J = 8.0Hz, 1H), 7.48 (d, J = 7.6Hz, 1H), 7.07 (t, J= 52.3Hz, 1H), 6.93 (d, J = 8.6Hz, 1H), 4.33 (d, J = 12.6Hz, 2H), 4.24 (d, J = 7.7Hz, 1H), 4.06 (d, J =6.7Hz, 1H), 3.85 (d, J = 9.1Hz, 1H), 3.79 (s, 2H), 3.69 (s, 2H), 3.21 (t, J = 9.3Hz, 2H), 2.54 – 2.44 (m,2H), 1.70 – 1.54 (m, 1H), 1.32 (d, J = 6.3Hz, 3H), 1.23 (d, J = 6.2Hz, 6H)]]> 176 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.27 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 6.3Hz, 1H), 8.34 (d, J = 8.7Hz,1H), 8.18 (d, J = 8.7Hz, 1H), 7.84 (s, 1H), 7.73 (t, J = 8.0Hz, 1H), 7.48 (d, J = 7.6Hz, 1H), 7.07 (t, J= 52.3Hz, 1H), 6.93 (d, J = 8.6Hz, 1H), 4.33 (d, J = 12.6Hz, 2H), 4.24 (d, J = 7.7Hz, 1H), 4.06 (d, J =6.7Hz, 1H), 3.85 (d, J = 9.1Hz, 1H), 3.79 (s, 2H), 3.69 (s, 2H), 3.21 (t, J = 9.3Hz, 2H), 2.54 – 2.44 (m,2H), 1.70 – 1.54 (m, 1H), 1.32 (d, J = 6.3Hz, 3H), 1.23 (d, J = 6.2Hz, 6H)]]> 177 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.25 (s, 1H), 8.56 (s, 1H), 8.48 (d, J = 6.0Hz, 1H), 8.32 (d, J = 8.7Hz,1H), 8.16 (d, J = 8.8Hz, 1H), 7.83 (s, 1H), 7.70 (d, J = 8.1Hz, 1H), 7.46 (d, J = 7.2Hz, 1H), 7.14 (t, J= 52.2Hz, 1H), 6.97 – 6.88 (m, 1H), 4.32 (d, J = 12.3Hz, 3H), 4.25 – 4.13 (m, 1H), 3.78 (s, 2H), 3.68 –3.64 (m, 3H), 3.43 – 3.38 (m, 1H), 2.48 – 2.42 (m, 2H), 2.27 – 2.05 (m, 1H), 2.00 – 1.83 (m, 1H), 1.26(d, J = 6.3Hz, 3H), 1.22 (d, J = 6.2Hz, 6H)]]> 178 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.26 (s, 1H), 8.57 (s, 1H), 8.45 (d, J = 7.2Hz, 1H), 8.33 (d, J = 8.6Hz,1H), 8.16 (d, J = 8.6Hz, 1H), 7.83 (s, 1H), 7.71 (t, J = 8.0Hz, 1H), 7.46 (d, J = 7.5Hz, 1H), 7.15 (t, J= 52.4Hz, 1H), 6.91 (d, J = 8.5Hz, 1H), 4.36 – 4.28 (m, 2H), 3.99 (q, J = 7.4Hz, 1H), 3.86 – 3.63 (m,6H), 3.25 – 3.16 (m, 1H), 3.12 (t, J = 8.9Hz, 1H), 2.48 – 2.44 (m, 2H), 2.26 (p, J = 7.1Hz, 1H), 1.22 (d,J = 6.2Hz, 6H), 1.01 (d, J = 6.7Hz, 3H)]]> 179 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.26 (s, 1H), 8.65 – 8.55 (m, 2H), 8.33 (d, J = 8.6Hz, 1H), 8.17 (d, J =8.6Hz, 1H), 7.83 (s, 1H), 7.72 (t, J = 7.9Hz, 1H), 7.46 (d, J = 7.4Hz, 1H), 7.12 (t, J = 52.4Hz, 1H),6.91 (d, J = 8.5Hz, 1H), 4.36 – 4.28 (m, 3H), 3.89 – 3.85 (m, 1H), 3.81 (s, 2H), 3.77 – 3.63 (m, 6H),3.54 (d, J = 11.2Hz, 1H), 3.33 – 3.29 (m, 2H), 2.48 – 2.41 (m, 2H), 1.22 (d, J = 6.2Hz, 6H) <!-- 119 -->]]> 180 <![CDATA[ 1 H NMR (401MHz, DMSO-d6) δ (ppm) 9.25 (s, 1H), 8.57 (s, 1H), 8.48 (d, J = 6.6Hz, 1H), 8.33 (d, J = 8.7Hz,1H), 8.16 (d, J = 8.5Hz, 1H), 7.82 (s, 1H), 7.71 (t, J = 7.9Hz, 1H), 7.46 (d, J = 7.4Hz, 1H), 7.11 (t, J= 52.5Hz, 1H), 6.91 (d, J = 8.5Hz, 1H), 5.16 – 5.11 (m, 1H), 4.32 (d, J = 12.6Hz, 2H), 4.29 – 4.21 (m,1H), 4.01 – 3.96 (m, 1H), 3.89 – 3.80 (m, 1H), 3.77 (s, 2H), 3.70 – 3.65 (m, 3H), 3.57 – 3.51 (m, 2H),3.11 (t, J = 9.8Hz, 1H), 2.41 – 2.34 (m, 1H), 2.07 (s, 1H), 1.93 – 1.88 (m, 1H), 1.22 (d, J = 6.2Hz, 6H)]]> 181 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.17 - 9.31 (m, 1 H), 8.38 (s, 1 H), 8.25 - 8.33 (m, 1 H), 8.01 - 8.11 (m, 1 H), 7.68 - 7.74 (m, 1 H), 7.63 (dd, J = 8.3, 7.4 Hz, 1 H), 7.47 (br d, J = 7.9 Hz, 1 H), 7.27 (t, J = 3.7 Hz, 1 H), 6.68 (d, J = 8.3 Hz, 1 H), 4.23 (dd, J = 12.9, 1.8 Hz, 2 H), 3.73 - 3.97 (m, 5 H), 2.90 - 3.05 (m, 1 H), 2.82 (s, 3 H), 2.56 - 2.68 (m, 2 H), 2.33 - 2.47 (m, 1 H), 2.11 - 2.28 (m, 1 H), 1.92 - 2.06 (m, 2 H), 1.36 - 1.54 (m, 3 H), 1.33 (d, J = 6.2 Hz, 6 H), 1.07 - 1.25 (m, 1 H)]]> 182 <![CDATA 1 1H NMR (400 MHz, chloroform-d) δ (ppm) 9.22 (s, 1 H) 8.38 (s, 1 H) 8.22 - 8.34 (m, 1 H) 8.05 (d, J = 8.6 Hz, 1 H) 7.69 - 7.73 (m, 1 H) 7.60 - 7.68 (m, 1 H) 7.44 (br d, J = 8.1 Hz, 1 H) 7.25 - 7.30 (m, 1 H) 6.61 - 6.77 (m, 1 H) 4.24 (dd, J = 12.7, 1.8 Hz, 2 H) 3.71 - 4.02 (m, 5 H) 3.02 (tt, J = 12.3, 3.4 Hz, 1 H) 2.58 - 2.71 (m, 3 H) 2.43 - 2.53 (m, 1 H) 2.16 - 2.39 (m, 2 H) 1.88 - 2.05 (m, 2 H) 1.38 - 1.58 (m, 2 H) 1.34 (d, J = 6.2 Hz, 6 H) 1.11 - 1.28 (m, 3 H) 0.94 - 1.09 (m, 2 H)]]> 183 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.74 (s, 1H), 9.32 (s, 1H), 8.65 (d, J = 13.2Hz, 1H), 8.37 (s, 1H),8.27 (dd, J = 8.7, 1.5Hz, 1H), 8.19 (d, J = 8.7Hz, 1H), 8.08 – 7.97 (m, 1H), 7.93 (s, 1H), 7.65 (dd, J =7.9, 5.7Hz, 2H), 7.06 – 6.62 (m, 2H), 5.59 (s, 1H), 4.06 (s, 2H), 3.82 (dd, J = 8.6, 6.3Hz, 2H), 3.64 (d,J = 12.6Hz, 2H), 3.44 (s, 3H), 2.68 (dd, J = 12.6, 10.8Hz, 2H), 1.18 (d, J = 6.2Hz, 6H)]]> 184 <![CDATA[ 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.74 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 8.32 – 8.12 (m,2H), 8.04 – 7.98 (m, 1H), 7.93 (s, 1H), 7.68 – 7.57 (m, 2H), 7.06 – 6.65 (m, 2H), 5.59 (s, 1H), 4.09 –4.00 (m, 2H), 3.82 (dd, J = 8.4, 6.4Hz, 2H), 3.64 (d, J = 12.6Hz, 2H), 3.43 (d, J = 11.3Hz, 3H), 2.68(dd, J = 12.7, 10.7Hz, 2H), 1.18 (d, J = 6.2Hz, 6H)]]> Melting point For melting point, the values ​​are peak values, and the obtained values ​​have the experimental uncertainties typically associated with this analytical method. Melting point was determined using a Mettler-Toledo MP50 or FP62 apparatus. Melting point was measured with a temperature gradient of 10 °C / min. The highest temperature was 300 °C.

[0398] Table 16. Melting Point Example number Melting point 229 154.7℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 252 218.3℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 253 234.9℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 254 130.0℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 256 173.0℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 257 163.1℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 258 243.0℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 259 245.0℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 260 91.0℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 261 173.0℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 279 206.5℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected 280 191.8℃ (Mettler-Toledo MP50); 10℃ / min; uncorrected High-resolution mass spectrometry Agilent 1260 Infinity DAD TOF-LC / MS G6224A; Column: YMC-pack ODS-AQ C18 (50 mm × 4.6 mm, 3 μm); Mobile phase: A: 0.1% HCOOH in H2O, B: CH3CN; Gradient: from 95% A to 5% A in 4.8 min, hold for 1.0 min, then to 95% A in 0.2 min; Flow rate: 2.6 mL / min; Temperature: 35 °C; Run time: 6.8 min.

[0399] Table 17: HRMS Results : Example number Molecular formula Calculation quality <![CDATA[Measured mass ([M+H] + )]]> Method code 136 <![CDATA[C 28 H 27 F3N6O3]]> 552.2098 553.2013 1 Optical rotation Optical rotation was measured at 20°C or 23°C using a Perkin Elmer 341 digital polarimeter with a sodium lamp at λ = 589 nm (i.e., the sodium D line) using 0.2 mL of cells (l = 1 dm) and given as [α]D (concentration in g / 100 mL solvent). Rotation is reported in degrees.

[0400] Table 18: Optical Rotation Compound numbering <![CDATA[Specific rotation [α]D 20 :]]> 160 +15.0° (589nm, c 0.0667w / v, DMF, 23℃) 161 -0.0° (589nm, c 0.0733w / v, DMF, 23℃) 164 -13.4° (589nm, c 0.0800w / v, MeOH, 23℃) Example C: Pharmacological Determination The following enzyme assays were performed using ADP Glo ™ The kinase assay kit (Promega, V9101) monitors ADP production to measure the DNA or nucleosome-dependent ATPase activity of various SMARCA2 and SMARCA4 protein constructs. The assay is performed in two steps after the enzymatic reaction is complete. In the first step, the ATPase reaction is terminated and the remaining ATP is depleted. In the second step, ADP is converted to ATP, and the newly synthesized ATP is measured using a luciferase / luciferin reaction. The generated light is measured using an Envision luminescence reader.

[0401] ADP-Glo ​​assay for SMARCA2 or 4 / SMARCC1 / SMARCC2 / SMARCB1: Prepare the following assay buffers fresh and use them as indicated below: 20 mM Tris-HCl pH 7.5 in biological grade water (Invitrogen, catalog 15567-027), 20 mM NaCl (VWR, catalog E529), 0.25 mM MgCl2 (Sigma, catalog M1028), 1 mM DTT (Sigma, catalog 646563), 1 mM EGTA (Alfa Caesar, catalog J60767), 0.005% Pluronic F-127 (Sigma, catalog 540025), and 0.2 mg / mL BSA (Sigma, catalog B8667). The enzyme mixture and ATP / nucleosome mixture were prepared by diluting the corresponding stock solutions in the assay buffer to the concentrations shown below: (a) 0.664 nM for the SMARCA2 or SMARCA4 core complex, and (b) 250 μM ATP and 2.5 nM biotin-GatC2 nucleosome (Epicypher, catalog number 16-4112).

[0402] Dissolve the compound in DMSO or a medium control and 3 μL of assay buffer or enzyme mixture into each well of a white 384-well PerkinElmer Proxiplate (PerkinElmer, catalog number 6008289). Centrifuge the plate at 1000 rpm for 1 minute and incubate at room temperature for 30 minutes. Then, add 2 μL of ATP / nucleosome mixture, followed by centrifugation at 1000 rpm for 1 minute and incubation at room temperature for 180 minutes. Next, add 3 μL of ADP-Glo ​​supplemented with 14.5 mM MgCl2 and 0.1% CHAPS. ™ Reagent (G Biosciences, catalog number DG097). Then, centrifuge the plate at 1000 rpm for 1 minute and incubate at room temperature for 60 minutes. Finally, dispense 6 μL of kinase assay reagent supplemented with 0.1% CHAPS, centrifuge the plate at 1000 rpm for 1 minute, seal, and incubate at room temperature for at least 30 minutes.

[0403] The results obtained in this assay by testing the compounds of this disclosure (shown as IC50) 50 (in nM) is shown in Table 19 below.

[0404] Table 19: ADP-Glo ​​Measurement Results of SMARCA2 or 4 / SMARCC1 / SMARCC2 / SMARCB1 . Example number <![CDATA[SMARCA2 / SMARCC1 / SMARCC2 / SMARCB1 ADP-Glo assay IC 50 (nM)]]> <![CDATA[SMARCA4 / SMARCC1 / SMARCC2 / SMARCB1 ADP-Glo assay IC 50 (nM)]]> 1 1.79 73.81 2 2.25 50.58 3 1.64 70.18 4 10.92 >20000 5 33.88 441.16 6 2217.17 12488.20 7 368.72 10270.70 8 273.91 >20000 9 NT NT 10 2.10 102.99 11 85.39 7151.55 12 9.20 278.16 13 1.88 70.10 14 104.83 1859.94 15 361.83 >20000 16 103.92 5734.56 17 6.73 221.21 18 13.50 583.58 19 4688.13 >20000 20 5422.51 >20000 21 4434.04 >20000 22 10053.10 >20000 23 0.57 18.34 24 120.31 913.06 25 14477.70 >20000 26 0.53 12.74 27 0.59 7.93 28 0.48 6.70 29 0.58 14.07 30 46.86 1536.39 31 90.70 >20000 32 681.24 >20000 33 485.40 >20000 34 1109.43 >20000 35 0.45 9.46 36 219.13 >20000 37 236.16 >20000 38 2562.12 >20000 39 1.05 13.24 40 237.03 >20000 41 283.66 >20000 42 27.54 2089.78 43 2.75 124.31 44 58.87 15146.10 45 695.67 >10000 46 275.30 >20000 47 550.68 >20000 48 1135.80 5684.60 49 5.63 34.82 50 20.89 >20000 51 4911.34 >10000 52 18548.10 >20000 53 28.13 674.06 54 576.63 >20000 55 118.52 1874.99 56 16.00 2.50 57 12.57 262.79 58 566.76 7350.22 59 1.25 26.07 60 184.25 2407.13 61 122.04 4646.22 62 868.76 13455.50 63 1.26 3.72 64 38.08 156.57 65 0.86 1.14 66 173.70 228.35 67 4.16 21.15 68 456.88 >20000 69 0.53 4.74 70 298.20 1769.70 71 >20000 >20000 72 >20000 >20000 73 386.37 3448.26 74 11040.80 >20000 75 3604.96 >20000 76 1.60 21.47 77 5239.62 >20000 78 959.18 >4949.94 79 47.64 833.11 80 >4217.94 >20000 81 30.55 284.97 82 >3373.65 >20000 83 106.88 >1480.47 84 227.77 >2018.37 85 >20000 >20000 86 >20000 >20000 87 >20000 >20000 88 5.79 49.68 89 28.31 257.69 90 153.07 422.86 91 >9965.52 >20000 92 418.41 1711.59 93 1.47 8.23 94 ＜4.28252 63.94 95 >6972.68 >20000 96 10.18 30.07 97 1604.72 >10202.3 98 >20000 >20000 99 2446.25 >9069.85 100 >6967.87 >20000 101 NT NT 102 1.19 21.45 103 0.59 5.36 104 >645.952 >20000 105 25.00 >20000 106 2.14 36.41 107 >301.509 >20000 108 2128.63 >6987.15 109 >5704.27 >15995.6 110 704.53 >5085.1 111 1.08 16.39 112 303.81 >1591.48 113 >20000 >20000 114 0.43 4.11 115 0.90 7.79 116 276.25 >3836.19 117 ＜7.13181 141.03 118 1277.03 >5197.56 119 10.74 2.34 120 18.37 >573.06 121 135.05 >2643.02 122 >4898.92 >20000 123 12.25 >20000 124 585.73 >20000 125 0.50 1.81 126 0.80 25.07 127 3131.12 >6654.26 128 3338.10 >9896.92 129 >20000 >20000 130 1.72 >38.1768 131 158.82 3856.56 132 499.80 >20000 133 7.00 >20000 134 >3225.52 >20000 135 0.78 14.15 136 3763.57 >9642.73 137 4.88 21.11 138 >20000 >20000 139 170.02 1909.85 140 128.09 >1882.78 141 2243.37 >6234.47 142 852.71 >6269.03 143 74.23 592.65 144 1369.30 >3619.93 145 313.91 4708.69 146 1.81 41.11 147 3554.67 >14164.50 148 >303.67 >20000 149 383.62 >20000 150 >4658.01 >20000 151 128.94 984.24 152 563.51 >3373.65 153 320.26 >20000 154 54.85 >20000 155 5107.40 >9497.30 156 714.99 >2279.82 157 ＜6.92468 52.16 158 97.34 2118.36 159 >3039.48 >6191.56 160 1.61 23.87 161 68.93 3088.16 162 212.96 >2507.26 163 >5151.1 >20000 164 128.41 2401.04 165 65.42 218.68 166 >1130.58 >20000 167 >2383.96 >7917.72 168 >7431.9 >20000 169 975.66 >2059.68 170 498.54 >3333.50 171 >20000 >20000 172 25.80 >20000 173 25.92 907.82 174 238.67 >3980.15 175 275.49 >2479.71 176 0.33 1.34 177 ＜5.18 51.20 178 50.91 16.96 179 25.30 57.29 180 1333.52 >8306.16 181 96.56 2743.47 182 1265.32 >6302.31 183 64.45 700.97 184 35.29 802.05

[0405] Example D: Hypothetical Formulation As used throughout these embodiments, “active ingredient” (ai) refers to a compound having formula (I), including any tautomer or stereoisomer thereof, or a pharmaceutically acceptable addition salt thereof; particularly any of the exemplified compounds.

[0406] Typical examples of formulations used in the preparations of this invention are as follows: 1. Tablets 2. Suspension Prepare an aqueous suspension for oral administration, such that each milliliter contains 1 to 5 mg of the active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol, and water to a final volume of 1 ml.

[0407] 3. Injectable substances The parenteral composition was prepared by stirring 1.5% (by weight / volume) of the active ingredient in a 0.9% NaCl solution or in a 10% (by volume) aqueous propylene glycol solution.

[0408] 4. Ointment In this embodiment, the active ingredient can be replaced with the same amount of any compound according to the present invention, especially the same amount of any compound in the exemplary compounds.

Claims

1. A compound having the structure of formula (I): (I) Or its pharmaceutically acceptable salts or stereoisomers. in R 1 Choose from the following groups: (i) , , , or ; Where R a yes , , , , , , , , , , , , , , , , or ; R b yes or ; R c It is a halogenated group, C 1-4 Alkyl or OC 1-4 alkyl; R d yes , , or ; R e yes , R f It is a halogenated group, C 1-4 Alkyl or OC 1-4 alkyl; R g yes ; R h It is C 1-4 alkyl; (ii) by R j , , or Replacement C 2-3 alkyl; Where R j It is SO2-C 1-4 Halogenated alkyl groups, NH-SO2-C 1-4 Halogenated alkyl groups, N(CH3)-SO2-C 1-4 Halogenated alkyl groups or SO2-N(CH3)2, (iii) Selected from the following 5- or 6-membered heteroaryl groups: , , , or ; Where R n It is SO2CH3, CH2C(OH)(CH3)2, CH2CH2SO2CH3; R p It is SO2CH3 or CH2CH2CN; or R q It is H or CH3; (iv)C 3-6 cycloalkyl or bridged -C 5-7 cycloalkyl groups, each of which is separated by SO2C 1-4 Alkyl, SO2-C 3-6 cycloalkyl, CO2CH3 or NH-SO2C 1-4 Halogenated alkyl substitution; or, (v) Carbon-linked pyrrolidine, piperidine, or aziridine heptane, each independently substituted by one or two substituents selected from the following: halogenated, C-linked, ... 1-4 Alkyl, C 1-4 Halogenated alkyl, CH2OH, OH, OC 1-4 Alkyl, SO2C 1-4 Alkyl, SO2C 1-4 Haloalkyl, SO2CH2CH2OH and C(=O)C 1-4 Halogenated alkyl groups; or each independently of SO2C 1-4 Halogenated alkyl-substituted 5-azaspiro[2.5]octane, 6-azaspiro[3.5]nonane, 2-azabicyclo[2.1.1]hexane and 3-azabicyclo[3.1.0]hexane; (we) R 5 It is a 6-membered ring selected from the following optional substitutions: And X is CH or N.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: (i)R 1 yes: or, (ii)R 1 yes: or, (iii)R 1 yes: or, (iv)R 1 yes: or, (v)R 1 yes: or (vi)R 1 yes:

3. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound, or a pharmaceutically acceptable salt or stereoisomer thereof, has formula (IA). in, R 1 Yes(i) (ii) (iii) (iv) R 5 yes , , , or .

4. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound, or a pharmaceutically acceptable salt or stereoisomer thereof, has the formula (IB). in, R 1 Yes(i) R 1 Yes (ii) R 1 Yes (iii) R 1 Yes (iv) R 1 Yes (v) R 1 Yes (vi) R 5 yes , , , , , or .

5. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 yes , , , , , , , , , or ;and R 5 yes .

6. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X is N.

7. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X is CH.

8. The compound according to claim 1, wherein the compound is selected from the group consisting of: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((3S,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(1-(methanesulfonyl)indoline-6-yl)acetamide; N-(4-methyl-3-(methanesulfonyl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthid-7-yl)acetamide; N-(3-(2-hydroxypropan-2-yl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthidin-7-yl)acetamide; N-(5-(methylsulfonyl)pyridin-3-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthidin-7-yl)acetamide; N-(1-(methylsulfonyl)indoline-6-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((3α,4α,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-((2-hydroxyethyl)sulfonyl)-4-methylphenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-fluoro-5-(methylsulfonyl)phenyl)acetamide; N-(4-chloro-3-(methylsulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(1-(methanesulfonyl)-1H-pyrazol-4-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1,1-dioxy-2,3-dihydrobenzo[b]thiophene-6-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-(ethylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-fluoro-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(2-(N,N-dimethylaminosulfonyl)ethyl)acetamide; N-(2-(2-oxabicyclo[ 2.1.1] Hexane-1-yl)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(1-(2-cyanoethyl)-5-methyl-1H-pyrazol-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(2-(methanesulfonyl)ethyl)-1H-pyrazol-4-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(1-(methanesulfonyl)-1H-pyrazol-3-yl)acetamide; N-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(6-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridin-2-yl)isoquinoline-3-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(6-(6-((3α,4β,5α)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)isoquinoline-3-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-(3-((2-hydroxyethyl)sulfonyl)-4-methylphenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(5-(methylsulfonyl)pyridin-3-yl)acetamide; N-(3-(cyanomethoxy)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-methyl-5-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-methoxy-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(2,2-dioxy-1,3-dihydrobenzo[c]thiophene-5-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-(1,1-isothiazolidin-2-yl)phenyl)acetamide; N-(3-(cyclopropylsulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-methoxy-5-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(methanesulfonyl)-1H-pyrrolo-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(2-methyl-5-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-(N,N-dimethylaminosulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-((2-hydroxyethyl)sulfonyl)phenyl)acetamide; N-(3-(2-cyanopropan-2-yl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(2,2-Dimethylchromo-7-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-(tetrahydrofuran-3-yl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azacycloheptatrien-8-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)acetamide; N-(3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-methyl-1-oxo-3H-1l4-benzo[d]isothiazo-5-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-(2,5-dioxopyrrolidone-1-yl)-4-fluorophenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(methanesulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-(2-methyloxetane-2-yl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(6-(methanesulfonyl)pyridin-2-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((*R)-1-(methylsulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((*S)-1-(methanesulfonyl)piperidin-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-((*R)-1-(methanesulfonyl)piperidin-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-((*S)-1-(methanesulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-methyl-3-(S-methylsulfinimide)phenyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((3R,6R)-6-methyl-1-(methylsulfonyl)piperidin-3-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((*S)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((*S)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)pyrrolid-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((*S)-1-((difluoromethyl)sulfonyl)pyrrolid-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)pyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((*S)-1-((difluoromethyl)sulfonyl)pyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((1*R,3*R)-3-(methylsulfonyl)cyclohexyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((1*S,3*R)-3-(methylsulfonyl)cyclohexyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((1*R,3*S)-3-(methylsulfonyl)cyclohexyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((1*S,3*S)-3-(methylsulfonyl)cyclohexyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((3S,6R)-6-methyl-1-(methylsulfonyl)piperidin-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((3R,6S)-6-methyl-1-(methylsulfonyl)piperidin-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((1*R,3*R)-3-(methylsulfonyl)cyclohexyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((1*S,3*R)-3-(methylsulfonyl)cyclohexyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((1*R,3*S)-3-(methylsulfonyl)cyclohexyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((1*S,3*S)-3-(methylsulfonyl)cyclohexyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((*R)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((*S)-1-((trifluoromethyl)sulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(1-(1-(methanesulfonyl)pyrrolidine-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((R)-1-(methanesulfonyl)pyrrolidine-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((S)-1-(methanesulfonyl)pyrrolidine-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((1s,3s)-3-(methylsulfonyl)cyclobutyl)acetamide; N-(2-((difluoromethyl)sulfonyl)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(3-((difluoromethyl)sulfonamido)propyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)propyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(3-((dimethyl(oxo)-16-thionyl)amino)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(2-((difluoromethyl)sulfonyl)ethyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-(3-((difluoromethyl)sulfonamido)propyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-(4-(S-methylsulfinimide)phenyl)acetamide; N-(3-((difluoromethyl)sulfonyl)propyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-(3-((dimethyl(oxo)-16-thionyl)amino)phenyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolino-3-yl)acetamide; N-((S)-1-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((R)-1-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(1-(2,2-difluoroacetyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(4-(S-methylsulfinimide)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-((fluoromethyl)sulfonyl)phenyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-(3-((fluoromethyl)sulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)acetamide; N-((3R,5R)-1-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((R)-1-((2-hydroxyethyl)sulfonyl)piperidin-3-yl)acetamide; N-((R)-1-((3,3-difluoropropyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((S)-1-((2-hydroxyethyl)sulfonyl)piperidin-3-yl)acetamide; N-((3R,4S)-1-((difluoromethyl)sulfonyl)-4-hydroxypyrrolid-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,4R)-1-((difluoromethyl)sulfonyl)-4-hydroxypyrrolid-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((R)-1-((difluoromethyl)sulfonyl)azacycloheptane-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((S)-1-((difluoromethyl)sulfonyl)azacycloheptane-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3S,5R)-1-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((R)-1-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((S)-1-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3S,4S)-1-((difluoromethyl)sulfonyl)-4-hydroxypyrrolid-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(1-((2,2-difluoroethyl)sulfonyl)piperidin-4-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-(3-((*S)-S-(difluoromethyl)sulfinimide)phenyl)-2-(6-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)isoquinoline-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((3R,5R)-5-fluoro-1-(methanesulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-((3R,5S)-5-fluoro-1-(methanesulfonyl)piperidin-3-yl)acetamide; N-((3R,5R)-5-(difluoromethyl)-1-(methanesulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(5-((difluoromethyl)sulfonyl)-5-azaspiro[2.5]octane-7-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(6-((difluoromethyl)sulfonyl)-6-azaspiro[3.5]nonane-8-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5R)-1-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3S,5R)-1-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3S,5S)-1-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((S)-1-((difluoromethyl)sulfonyl)-5,5-dimethylpiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-5-(difluoromethyl)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5R)-5-(difluoromethyl)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5R)-1-((difluoromethyl)sulfonyl)-5-(trifluoromethyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-(trifluoromethyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3S,5R)-1-((difluoromethyl)sulfonyl)-5-(trifluoromethyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(1-(2,2-difluoroethyl)-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(2-((1,1-difluoro-N-methylmethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((1R,2S)-2-((difluoromethyl)sulfonamido)cyclobutyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((1R,2R)-2-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(5-((difluoromethyl)sulfonamido)bicyclo[3.1.1]heptane-1-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((1R,2R)-2-((difluoromethyl)sulfonamido)cyclobutyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(((S)-1-((difluoromethyl)sulfonyl)pyrrolid-3-yl)methyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(2-((difluoromethyl)sulfonyl)-2-azabicyclo[ 2.1.1] Hexane-4-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((1S,2S)-2-((difluoromethyl)sulfonamido)cyclopropyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((1-((difluoromethyl)sulfonyl)piperidin-3-yl)methyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((cis)-3-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((1R,2S)-2-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)-N-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)acetamide; N-(4-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((R)-1-(difluoromethyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((1R,5S)-3-((difluoromethyl)sulfonyl)-3-azabicyclo[3.1.0]hexane-1-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; 3-(2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamyl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester; (1s,3s)-3-(2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamyl)methyl cyclobutane-1-carboxylate; N-((3S,4S)-1-((difluoromethyl)sulfonyl)-4-hydroxypyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-(3-(cyclopropylsulfonyl)bicyclo[1.1.1]pentan-1-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-(1-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinoline-3-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)isoquinoline-3-yl)acetamide; N-(3-(S-(difluoromethyl)sulfinimide)phenyl)-2-(6-phenylisoquinoline-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-(3-(methylsulfonyl)cyclobutyl)acetamide; (R)-N-(1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-phenylisoquinoline-3-yl)acetamide; N-(3-(S-(difluoromethyl)sulfinimide)phenyl)-2-(6-phenylisoquinoline-3-yl)acetamide; (*R)-N-(1-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinoline-3-yl)acetamide; (*S)-N-(1-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinoline-3-yl)acetamide; (*R)-N-(3-(S-(difluoromethyl)sulfinimide)phenyl)-2-(6-phenylisoquinoline-3-yl)acetamide; N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-phenylisoquinoline-3-yl)acetamide; N-(3-(cyclopropylsulfonyl)cyclobutyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-(1-(1-(methanesulfonyl)piperidin-4-yl)acetamide; N-(1-((difluoromethyl)sulfonyl)piperidin-4-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)-N-(1-((2-hydroxyethyl)sulfonyl)piperidin-4-yl)acetamide; N-((3S,4R)-1-((difluoromethyl)sulfonyl)-4-methylpyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3S,4S)-1-((difluoromethyl)sulfonyl)-4-methylpyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((3R,4R)-1-((difluoromethyl)sulfonyl)-4-methylpyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-(hydroxymethyl)pyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((3S,5R)-1-((difluoromethyl)sulfonyl)-5-(hydroxymethyl)pyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((3S,5R)-1-((difluoromethyl)sulfonyl)-5-methylpyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((3R,5R)-1-((difluoromethyl)sulfonyl)-5-methylpyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((3R,4S)-1-((difluoromethyl)sulfonyl)-4-methylpyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3S,4S)-1-((difluoromethyl)sulfonyl)-4-methoxypyrrolidine-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3S,5S)-1-((difluoromethyl)sulfonyl)-5-(hydroxymethyl)pyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-(3-(methylsulfonyl)cyclohexyl)acetamide; N-(3-(cyclopropylsulfonyl)cyclohexyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-(3-((*R)-S-(difluoromethyl)sulfinimide)phenyl)-2-(6-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)isoquinoline-3-yl)acetamide; and N-(3-((*S)-S-(difluoromethyl)sulfinimide)phenyl)-2-(6-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)isoquinoline-3-yl)acetamide; and their pharmaceutically acceptable salts or stereoisomers.

9. The compound according to claim 1, wherein the compound is selected from the group consisting of: N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)pyrrolid-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((*R)-1-((difluoromethyl)sulfonyl)pyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; N-((R)-1-((difluoromethyl)sulfonyl)azacycloheptane-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((R)-1-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(3-((*S)-S-(difluoromethyl)sulfinimide)phenyl)-2-(6-(2-((cis)-2,6-dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)isoquinoline-3-yl)acetamide; N-((3R,5R)-1-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-5-(difluoromethyl)-1-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-(2-((1,1-difluoro-N-methylmethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; N-((cis)-3-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)acetamide; and N-((3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpyrrolid-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinoline-3-yl)acetamide; And its pharmaceutically acceptable salts and stereoisomers.

10. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of the preceding claims; and at least one pharmaceutically acceptable excipient.

11. The compound according to any one of claims 1 to 9, for use in a therapeutic manner.

12. The compound according to any one of claims 1 to 9, wherein the compound is used in the treatment of SMARCA4-deficient cancers.

13. The compound for use according to claim 12, wherein the SMARCA4-deficient cancer is SMARCA4-deficient non-small cell lung cancer (NSCLC).

14. The compound according to any one of claims 1 to 9, wherein the compound is used in the treatment of disease states or symptoms mediated by the SMARCA2 protein.

15. The compound for use according to claim 14, wherein the disease state or symptom mediated by the SMARCA2 protein is cancer or non-small cell lung cancer (NSCLC).

16. Use of the compound as defined in any one of claims 1 to 9 for the manufacture of a medicament for the treatment of cancer or NSCLC.

17. An in vitro method for modulating SMARCA2 activity, the method comprising contacting SMARCA2 protein or a portion thereof with a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9.

18. A method for treating SMARCA4-deficient cancer, the method comprising administering to a subject in need a compound as defined in any one of claims 1 to 9.

19. The method of claim 18, wherein the SMARCA4-deficient cancer is SMARCA4-deficient NSCLC.

20. A method for treating a disease state or symptom mediated by the SMARCA2 protein, the method comprising administering to a subject in need a compound as defined in any one of claims 1 to 9.

21. The method of claim 20, wherein the disease or symptom is selected from cancer or NSCLC.

22. The method according to any one of claims 18 to 21, wherein the subject is a mammal.

Images