Smarca2 inhibitors useful for the treatment of smarca4 deficient cancers

Abstract

The invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds as inhibitors of the SMARCA2 protein and to its use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC).

Description

SMARCA2 INHIBITORS USEFUL FOR THE TREATMENTOF SMARCA4 DEFICIENT CANCERSFIELD OF THE INVENTION

[0001] The invention relates to a pharmaceutical compound and pharmaceutical compositions comprising said compound, to processes for the preparation of said compound and to the use of said compound as inhibitor of the SMARCA2 protein and to its use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC).BACKGROUND OF THE INVENTION

[0002] The Switch / SucroseNon-Fermentable (SWI / SNF), also known as BAF complex, is a multi-subunit complex that modulates chromatic structure through the activity of two mutually exclusive helicase / ATPase catalytic subunits: SWI / SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2, BRAHMA or BRM) and SWI / SNF-Related, Matrix- Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 (SMARCA4 or BRG1). The core and the regulatory subunits couple ATP hydrolysis to the perturbation of histone-DNA contacts, thereby providing access points to transcription factors and cognate DNA elements that facilitate gene activation and repression.

[0003] Mutations in the genes encoding the twenty canonical SWI / SNF subunits are observed in nearly 20% of all cancers with the highest frequency of mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical and endometrial), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma. Despite having a high degree of homology, and their presumed overlapping functions, SMARCA2 and SMARCA4 have been reported as having different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is infrequent in tumor development. In fact, numerous types of cancer have been shown to be SMARCA4-related (e.g., cancers having a SMARCA4-mutation or a SMARCA4-deficiency, such as lack of expression), including, e.g., lung cancer (such as non-small cell lung cancer or NSCLC).

[0004] SMARCA2 has been demonstrated as one of the top essential genes in SMARCA4-related or -mutant cancer cell lines. This is because SMARCA4 -deficient patient populations or cells depend exclusively on SMARCA2 activity - i.e., there is a greater incorporation of SMARCA2 into the complex to compensate for the SMARCA4 deficiency.Thus, SMARCA2 may be targeted in SMARCA4-related / deficient cancers. The cooccurrence of the deficiency of the expression of two (or more) genes that leads to cell death is known as synthetic lethality. Accordingly, synthetic lethality can be leveraged in the treatment of certain SMARCA2 / SMARCA4-related cancers.

[0005] There is an ongoing need for effective treatment for diseases that are treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, non-specific effects, and the inability to selectively target and modulate SMARCA2 remains an obstacle to the development of effective treatments. As such, small-molecule therapeutic agents that target SMARCA2 would be very useful.

[0006] An objective of the present invention is to provide compounds that are selective on SMARCA2 over SMARCA 4.

[0007] An objective of the present invention is to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient cancers.

[0008] An objective of the present invention is to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient NSCLC.SUMMARY OF THE INVENTION

[0009] The present invention relates to a compound having the structure of Formula (I):O R2

[0010] wherein R1, R2, and R3are defined in the claims.

[0011] The present invention further relates to the compounds disclosed in the claims.

[0012] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention; and at least one pharmaceutically acceptable excipient.

[0013] The present invention further relates to the compounds presented herein for use in therapy, in particular for use in the treatment of a SMARCA4 deficient cancer.

[0014] The SMARCA4 deficient cancer may be a SMARCA4 deficient non-small cell lung cancer (NSCLC).

[0015] The present invention further relates to the compounds presented herein for use in the treatment of a disease state or condition mediated by the SMARCA2 protein.

[0016] In one embodiment, the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC).

[0017] The present invention further relates to the use of a compound as defined herein for the manufacture of a medicament for the treatment of cancer or NSCLC.

[0018] The present invention further relates to an in vitro method of modulating SMARCA2 activity comprising contacting the SMARCA2 protein, or portion thereof, with a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0019] The present invention further relates to a method for the treatment of a SMARCA4 deficient cancer, which method comprises administering to a subject in need thereof, a compound as defined herein.

[0020] In one embodiment, the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.

[0021] The present invention further relates to a method for the treatment of a disease state or condition mediated by the SMARCA2 protein, which method comprises administering to a subject in need thereof, a compound as defined herein.

[0022] In one embodiment, the disease or condition is selected from a cancer or NSCLC.

[0023] In one embodiment, the subject is a mammal.INCORPORATION BY REFERENCE

[0024] 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 herein incorporated by reference to the same extent as if each individual publication, patent, patent application, or published nucleotide and amino acid sequence, was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0025] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs.Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0026] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0027] In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise.

[0028] When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. As used herein, “about X” (where X is a numerical value) preferably refers to ±10% of the recited value, inclusive. For example, the phrase “about 8” refers to a value of 7.2 to 8.8, inclusive; as another example, the phrase “about 8%” refers to a value of 7.2% to 8.8%, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of “1 to 5” is recited, the recited range should be construed as including ranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, and the like. In addition, when a list of alternatives is positively provided, such a listing can also include embodiments where any of the alternatives may be excluded. For example, when a range of “1 to 5” is described, such a description can support situations whereby any of 1, 2, 3, 4, or 5 are excluded; thus, a recitation of “1 to 5” may support “1 and 3-5, but not 2”, or simply “wherein 2 is not included.”

[0029] Some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions and acceptable error margins, for such given value.

[0030] As used herein, the expression “one or more” refers to at least one, for example one, two, three, four, five or more, whenever possible and depending on the context.

[0031] Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0032] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0033] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4thEd.” Vols. A (2000) and B (2001), Plenum Press, New York.

[0034] As used herein, “Cx-y” (where x and y are integers) refers to the number of carbon atoms that make up the moiety to which it designates (excluding optionalsubstituents). Thus, a C1-6alkyl group contains from 1 to 6 carbon atoms, a C3-6cycloalkyl group contains from 3 to 6 carbon atoms, a C1-4alkoxy group contains from 1 to 4 carbon atoms, and so on.

[0035] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.

[0036] The “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “Ci-ealkyl” or similar designations. By way of example, the term “Ci-4alkyl”, or “Ci-ealkyl” as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 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, and the like.

[0037] The term “alkenyl” refers to a type of alkyl group in which at least two atoms of the alkyl group form a double bond that is not part of an aromatic group. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2 and -C(CH3)=CHCH3. The alkenyl moiety may be branched or a straight chain. Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group). Examples of “alkenyl” include also “C2-4alkenyl” or “C2-ealkenyl”.

[0038] The term “alkynyl” refers to a type of alkyl group in which at least two atoms of the alkyl group form a triple bond. Non-limiting examples of an alkynyl group include –C≡CH, –C≡CCH₃, –C≡CCH₂CH₃ and –C≡CCH₂CH₂CH₃. The alkynyl moiety may be branched or a straight chain. An alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group). Examples of “alkynyl” include also “C2-4alkynyl” or “C2-6alkynyl”.

[0039] An “alkoxy” refers to a “-O-alkyl” group, where alkyl is as defined herein. The term “Ci-4alkoxy” or “Ci-ealkoxy” as used herein as a group or part of a group refers to an -O-C1-4alkyl group or an –O-C1-6alkyl group wherein C1-4alkyl and C1-6alkyl are as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.

[0040] The term “hydroxyCi-4alkyl” or “hydroxyCi-ealkyl” as used herein as a group or part of a group refers to a Ci-4alkyl or Ci-ealkyl group as defined herein wherein one or more than one hydrogen atoms are replaced with a hydroxyl group. The terms “hydroxyCi-4alkyl” or “hydroxyCi-ealkyl” therefore include monohydroxyCi-4alkyl, monohydroxyCi-ealkyl and also polyhydroxyCi-4alkyl and polyhydroxyCi-ealkyl. There may be one, two, three or more hydrogen atoms replaced with a hydroxyl group, so the hydroxyCi-4alkyl or hydroxyCi-ealkyl may have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.

[0041] The term “haloalkyl” refers to an alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with one or more halogens. The term “haloalkyl” includes “haloCi-4alkyl”, “haloCi-ealkyl”, monohaloCi-4alkyl, monohaloCi-ealkyl, polyhaloCi-4alkyl, and polyhaloCi-ealkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi-4alkyl or haloCi-ealkyl may have one, two, three or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, fluoroethyl, fluoromethyl, trifluoroethyl, and the like.

[0042] The term “heteroalkyl” refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms.

[0043] The term “haloCi-4alkoxy” or “haloCi-ealkoxy” as used herein as a group or part of a group refers to a -O-Ci-4alkyl group or a -O-C1-6 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen. The terms “haloCi-4alkoxy” or “haloCi-ealkoxy” therefore include monohaloCi-4alkoxy, monohaloCi-ealkoxy and also polyhaloCi-4alkoxy and polyhaloCi-ealkoxy. There may be one, two, three or more hydrogenatoms replaced with a halogen, so the haloC1-4alkoxy or haloC1-6alkoxy may have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy, or trifluoromethoxy and the like.

[0044] The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, and the like. Non-limiting examples of fluoroalkoxy groups, include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, and the like.

[0045] The term “cyanoCi-4alkyl” or “cyanoCi-ealkyl” as used herein refers to a Ci-4alkyl or Ci-ealkyl group as defined herein which is substituted with one or two cyano groups, in particular with one cyano group.

[0046] “Amino” refers to a -NH2group.

[0047] The term “alkylamine” or “alkylamino” refers to the -N(alkyl)xHygroup, where alkyl is as defined herein and x and y are selected from the group x=l, y=l and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. “Dialkylamino” refers to a -N(alkyl)2group, where alkyl is as defined herein.

[0048] The terms “carboxy” or “carboxyl” refer to -CO2H. In some embodiments, carboxy moi eties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples oflike.

[0049] The term “carbocyclyl” as used herein, unless the context indicates otherwise, includes aromatic, non-aromatic, unsaturated, partially saturated, and fully saturated carbon ring systems. In general, unless the context indicates otherwise, such ring systems may be monocyclic or bicyclic or bridged and may contain, for example, 3 to 12 ring members, or 4 to 10 ring members, or more usually 5 to 10 ring members. Reference to 3 to 6 ring members include 3,4, 5, or 6 atoms in the ring, reference to 4 to 7 ring members include 4, 5, 6 or 7 atoms in the ring, and reference to 4 to 6 ring members include 4, 5, or 6 atoms in the ring. Examples of monocyclic carbocyclyl ring systems are ring systems containing 3, 4, 5, 6, 7 and 8 ring members, more usually 3 to 7, and preferably 4, 5, 6 or 7 ring members, more preferably 5 or 6 ring members. Examples of bicyclic carbocyclyl ring systems are those containing 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10 ring members. Where reference is made herein to a carbocyclyl ring system, the carbocyclyl ring can, unless the context indicates otherwise, be optionally substituted (i.e. unsubstituted or substituted) by one or more substituents as discussed herein. Particular examples of 3 to 12 membered carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclyhexyl, cycloheptyl, cyclooctyl, phenyl naphthyl, indenyl, tetrahydronaphthyl, azulenyl, norbornane (1,4-endo-methylene-cyclohexane), adamantane ring systems.

[0050] The term “aromatic” refers to a planar ring having a delocalized 7t-electron system containing 4n+2 TI electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0051] The term “non-aromatic group” embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and fully saturated heterocyclyl ring systems.

[0052] The terms “unsaturated” and “partially saturated” refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond i.e. the ring contains at least one multiple bond e.g. a C=C, C=C or N=C bond.

[0053] The term “fully saturated” refers to rings where there are no multiple bonds between ring atoms. Saturated heterocyclyl groups include piperidine, morpholine, thiomorpholine, piperazine. Partially saturated heterocyclyl groups include pyrazolines, for example 2-pyrazoline and 3-pyrazoline.

[0054] The carbocyclyl ring systems can be aryl ring systems.

[0055] The term “aryl” as used herein refers to carbocyclyl aromatic groups and embraces polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system may be attached to the remainder of the compound by an aromatic ring or by a non-aromatic ring. The term “aryl” includes phenyl, naphthyl or naphthalenyl, indenyl, and tetrahydronaphthyl groups. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0056] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. An example of a “cycloalkyl” is “Cs-ecycloalkyl”. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to,

[0057] The term “heterocycle”, “heterocyclyl”, “heterocycloalkyl”, or “heteroalicyclic” group refers to a carbocyclyl, as defined herein, containing at least one heteroatom typically selected from nitrogen, oxygen or sulphur, in particular containing up to 5, up to 4, up to 3, up to 2, or a single heteroatom. Where reference is made herein to a heterocyclyl ring system, the heterocyclyl ring can, unless the context indicates otherwise, be optionally substituted (i.e. unsubstituted or substituted) by one or more substituents as discussed herein. The radicals may be fused with an aryl or heteroaryl. Illustrative examples of heterocycloalkyl groups,O / O fl u s' ualso referred to as non-aromatic heterocycles, include:,, and the like.

[0058] The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).

[0059] The heterocyclyl ring systems can be heteroaryl ring systems having from 5 to 12 ring members, more usually from 5 to 10 ring members.

[0060] The term “heteroaryl” is used herein to denote a heterocyclyl ring system having aromatic character. The term “heteroaryl” embraces polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system may be attached to the remainder of the compound by an aromatic ring or by a non-aromatic ring. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings, or two fused five membered rings. The heteroaryl ring system may contain up to about five heteroatoms typically selected from nitrogen, oxygen and sulphur. Typically, the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, oxatriazole, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups. In particular, examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl and triazolyl groups. Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0061] A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered aromatic ring containing 1, 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered aromatic ring containing 1, 2 or 3 ring heteroatoms. Particular examples of bicyclic heteroaryl groups containing a fivemembered ring fused to another five membered ring include but are not limited to imidazothiazolyl (e.g. imidazo[2,l-b]thiazole) and imidazoimidazolyl (e.g. imidazo[l,2-a]imidazole). Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl, indazolyl, pyrazolopyrimidinyl (e.g. pyrazolo[l,5-a]pyrimidine), triazolopyrimidinyl (e.g. [l,2,4]triazolo[l,5-a]pyrimidine), benzodioxolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl and pyrazolopyridinyl (e.g. pyrazolo[l,5-a]pyridine) groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, chromanyl, isochromanyl, thiochromanyl, benzopyranyl, benzodi oxanyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolizinyl, quinolinyl, isoquinolinyl, benzopyranyl, benzodioxanyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0062] Examples of polycyclic heteroaryl groups containing an aromatic ring and a nonaromatic ring include, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[l,4]dioxinyl, benzo[l,3]dioxolyl, 4,5,6,7-tetrahydro-benzofuranyl, tetrahydrotriazolopyrazinyl (e.g. 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]-pyrazinyl), and indolinyl.

[0063] A nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. Each ring may, in addition, contain up to about four other heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, for example 1, 2 or 3, more usually up to 2 nitrogens, for example a single nitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0064] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g.,1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizinyl, isoindolinyl, purinyl, indazolyl, quinolizinyl, benzoxazinyl, pyrido-pyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0065] Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

[0066] Examples of non-aromatic heterocyclyl groups are groups having from 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, and typically have from 1 to 5 heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ring members), usually selected from nitrogen, oxygen and sulphur. The heterocyclyl groups can contain, for example, cyclic ether moieties (e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine), and combinations thereof (e.g. thiomorpholine).

[0067] Particular examples include morpholinyl, thiomorpholinyl, piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3 -pyrrolidinyl), azetidinyl, pyranyl (2H-pyranyl or 4H-pyranyl), dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, dioxolanyl, tetrahydropyranyl, imidazolinyl, oxazolinyl, oxazolidinyl, oxetanyl, thiazolinyl, 2-pyrazolinyl, pyrazolidinyl and piperazinyl. In general, preferred non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl and piperazinyl. In general, preferred non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl and piperazinyl.

[0068] In a nitrogen-containing non-aromatic heterocyclyl ring the ring must contain at least one ring nitrogen atom.

[0069] Particular examples of nitrogen-containing non-aromatic heterocyclyl groups include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3 -pyrrolidinyl), dihydrothiazolyl, imidazolinyl, oxazolinyl, thiazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl and piperazinyl.

[0070] Particular examples of 3 to 6 membered monocyclic saturated heterocyclyls include morpholinyl, thiomorpholinyl, dioxanyl, piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), piperazinyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3 -pyrrolidinyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl (e.g. 4-tetrahydro pyranyl), dithianyl, trioxanyl, trithianyl, aziridinyl, oxiranyl, thiiranyl, diaziridinyl, dioxarinyl, oxetanyl, azetidinyl, thietanyl, dioxetanyl ring systems.

[0071] Particular examples of 3 to 6 membered monocyclic heterocyclyls include morpholinyl, thiomorpholinyl, piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3 -pyrrolidinyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, tetrahydropyranyl (e.g. 4-tetrahydro pyranyl), dithianyl, trioxanyl, trithianyl, aziridinyl, oxiranyl, thiiranyl, diaziridinyl, dioxarinyl, oxetanyl, azetidinyl, thietanyl, dioxetanyl, azirinyl, azetyl, 1,2-dithietyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dithiazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, thiazinyl, oxazinyl, triazinyl ring systems.

[0072] Particular examples of 3 to 12 membered heterocycles include morpholinyl, thiomorpholinyl, piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and4-piperidinyl), pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3 -pyrrolidinyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxanyl, tetrahydropyranyl (e.g. 4-tetrahydropyranyl), dithianyl, trioxanyl, trithianyl, aziridinyl, oxiranyl, thiiranyl, diaziridinyl, dioxarinyl, oxetanyl, azetidinyl, thietanyl, dioxetanyl, azirinyl, azetyl, 1,2-dithietyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dithiazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, thiazinyl, oxazinyl, triazinyl, azepanyl, oxepanyl, thiepanyl, 1,2-diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, azocanyl, azocinyl, imidazothiazolyl (e.g. imidazo[2,l-b]thiazolyl), imidazo-imidazolyl (e.g. imidazo[l,2-a]imidazolyl), benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl, indazolyl, pyrazolopyrimidinyl (e.g. pyrazolo[l,5-a]pyrimidinyl), triazolopyrimidinyl (e.g. [l,2,4]triazolo[l,5-a]pyrimidinyl), benzodioxolyl, imidazopyridinyland pyrazolopyridinyl (e.g. pyrazolo[l,5-a]pyridinyl), quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, isochromanyl, benzodi oxanyl, quinolizinyl, benzoxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, tetrahydro-isoquinolinyl, tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydrobenzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrotriazolo-pyrazinyl (e.g. 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl), 8-oxa-3-azabicyclo-[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3.6-diazabicyclo[3.1.1]heptanyl ring systems.

[0073] Particular examples of 5 to 6 membered aromatic heterocycles include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl ring systems.

[0074] The heterocyclyl and carbocyclyl rings also include bridged ring systems such as for example bridged cycloalkanes, such as for example norbornane (1,4-endo-methylenecyclohexane), adamantane, oxa-adamantane; bridged morpholine rings such as for example 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane; bridged piperazine rings such as for example3.6-diazabicyclo[3.1.1]heptane; bridged piperidine rings such as for example 1,4-ethylenepiperidine. For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992.

[0075] Lines drawn into ring systems indicate that the bond may be attached to any of the suitable and available ring atoms.

[0076] The term “optional” or “optionally” means the event described subsequent thereto may or may not happen. This term encompasses the cases that the event may or may not happen.

[0077] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions andpurification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0078] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to 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, compositions described herein.

[0079] The term “optional” or “optionally” means the event described subsequent thereto may or may not happen. This term encompasses the cases that the event may or may not happen.

[0080] The term “optionally substituted” or “substituted”, if not explicitly defined, means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkynyl, C1-6alkylalkynyl, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di -substituted amino groups (e.g. -NH2, -NHR, -N(R)2), and the protected derivatives thereof. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atoms, excluding aromatic carbon atoms) includes oxo (=0).

[0081] In the compounds of the present disclosure when the carbon atom is indicated with “(R*)”, it means that it is a pure enantiomer but that it is unknown whether is it an R or S enantiomer. Similarly, when the carbon atom is indicated with “(S*)”, it means that it is apure enantiomer but that it is unknown whether is it an R or S enantiomer. When each of two or more carbon atoms are indicated each with RS, it denotes that the compound is a mixture of stereoisomers; in some cases it is a racemate mixture of an established cis or trans configuration at the two indicated chiral centers, unless otherwise indicated. In intermediates / compounds wherein bonds are indicated either with a bold wedged bond or a dashed wedged bond while the stereocenters are designated (RS), the representation indicates that the sample is a mixture of stereoisomers, one stereoisomer having the indicated substituents or groups projected above or below the plane of the drawing as represented, one stereoisomer having the substituents or groups in the opposite projection below or above the plane of the drawing, e.g.

[0082] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moi eties when the atoms joined by the bond are considered to be part of larger substructure.

[0083] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0084] As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0085] The term a “therapeutically effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that, when administered to a mammal in need, is effective to treat diseases, disorders or conditions described herein.

[0086] As used herein, the term “composition” is intended to encompass a product comprising specified ingredients in specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0087] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0088] The term “antagonist” as used herein, refers to a small-molecule agent that binds to a receptor and subsequently decreases the agonist induced transcriptional activity of the receptor.

[0089] The term “agonist” as used herein, refers to a small-molecule agent that binds to a receptor and subsequently increases receptor transcriptional activity in the absence of a known agonist.

[0090] The term “inverse agonist” as used herein, refers to a small-molecule agent that binds to a receptor and subsequently decreases the basal level of receptor transcriptional activity that is present in the absence of a known agonist.

[0091] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0092] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non -human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0093] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0094] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells. A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0095] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.

[0096] As used herein, the term “cancer” refers to a malignant neoplasm.

[0097] The term “angiogenesis” refers to the formation and the growth of new blood vessels. Normal angiogenesis occurs in the healthy body of a subject for healing wounds and for restoring blood flow to tissues after injury. The healthy body controls angiogenesis through a number of means, e.g., angiogenesis-stimulating growth factors 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 greater than that in a normal body, especially angiogenesis in an adult not related to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels that feed diseased tissues and / or destroy normal tissues, and in the case of cancer, the new vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).

[0098] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of wholeorganisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. Biological samples also include those biological samples that are transgenic, such as transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus.Isomers, salts, N-oxides, isotopically labeled derivatives

[0099] Hereinbefore and hereinafter, the terms compounds, compound of formula (I), compound of the present disclosure or invention, compound presented herein, or similar terms or expressions, is meant to include the addition salts, and the stereoisomers thereof.

[0100] In certain embodiments, the compound presented herein possesses one or more stereocenters and each center independently exists in either the R or S configuration. The compound presented herein includes all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns. In some embodiments, a compound of the present disclosure is used as a single enantiomer. In some embodiments, a compound of the present disclosure is used as a racemic mixture. In some embodiments, a compound of the present disclosure possesses hindered rotation about a single bond resulting in atropisomers.

[0101] In some situations, the compound may exist as tautomers. All tautomers are included within the scope of the compound presented herein.

[0102] For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced. Examples of tautomeric forms include, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / enediamines, nitroso / oxime, thioketone / enethiol, and nitro / aci -nitro.II1 / O \ OH H+xO’-c-c' === c—c' === c=czI \ \ H+ / \keto enol enolate

[0103] Such forms in so far as they may exist, are intended to be included within the scope of the compound presented herein. It follows that a single compound may exist in both stereoisomeric and tautomeric form.

[0104] Disubstituted cycloalkyl and heterocycloalkyl stereoisomers may 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 for instance specified as “cis”, this means that the two groups point in the same direction relative to the plane of the ring. In the “trans” isomer, they point in the opposite direction. Exemplified below are “cis” isomers of 2,6-dimethyl-morpholine. There is one possible relative configuration based on the relative positions of the two substituents, whether they are on the same side or opposite faces of the cyclic structure.Relative Configuration(2R.6S) (2S.6R)(cis)-2,6-dimethyl-morpholino

[0105] The present disclosure includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

[0106] The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

[0107] The methods and formulations described herein include the use of N-oxides (if appropriate), pharmaceutically acceptable salts, and combinations thereof, of the compound having the structure presented herein and having the same type of activity.

[0108] The salt forms of the compound presented herein are typically 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, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compound of the invention, also form part of the invention.

[0109] The pharmaceutically acceptable salts include pharmaceutically acceptable acid and base addition salts and are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compound described herein are able to form.

[0110] The salts of the present disclosure can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in “Pharmaceutical Salts: Properties, Selection, and Use”, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of the compound with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The compound of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.

[0111] The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like) or organic acids (such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid and the like) in an anion form.

[0112] Appropriate anions comprise, for example, acetate, 2,2-dichloroacetate, adipate, alginate, ascorbate (e.g. L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4-acetamidobenzoate, butanoate, bicarbonate, bitartrate, bromide, (+) camphorate, camphorsulphonate, (+)-(15)-camphor-10-sulphonate, calcium edetate, camsylate, caprate, caproate, caprylate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecylsulphate, edetate, estolate, esylate, ethane- 1,2-di sulphonate, ethanesulphonate, formate, fumarate, galactarate, gentisate, glucoheptonate, gluceptate, gluconate, D-gluconate, glucuronate (e.g. D-glucuronate), glutamate (e.g. L-glutamate), a-oxoglutarate, glycolate, glycollylarsanilate, hexylresorcinate, hippurate, hydrabamine, hydrobromide, hydrochloride, hydriodate, 2-hydroxyethane-sulphonate, hydroxynaphthoate, iodide, isethionate, lactate (e.g. (+)-L-lactate, (±)-DL-lactate), lactobionate, malate, (-)-L-malate, maleate, malonate, mandelate, (±)-DL-mandelate, mesylate, methansulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthalene-sulphonate (e.g.naphthalene-2-sulphonate), naphthalene-1,5 -di sulphonate, 1 -hydroxy -2-naphthoate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate (embonate), pantothenate, phosphate / diphosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacate,stearate, subacetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, teoclate, thiocyanate, toluenesulphonate (e.g. -toluenesulphonate), tosylate, triethiodide, undecylenate, valeric acids, as well as acylated amino acids and cation exchange resins. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

[0113] The compound of the present disclosure containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases in a cation form. Appropriate basic salts comprise those formed with organic cations such as arginine, benzathine, benzylamine, butylamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, diethanolamine, diethylamine, ethanolamine, ethylamine, ethylenediamine, lysine, meglumine, phenylbenzylamine, piperazine, procaine, triethylamine, tromethamine, and the like; those formed with ammonium ion (i.e., NH4+), quaternary ammonium ion N(CH3)4+, and substituted ammonium ions (e.g., NH3R, NH2R2+, NHR3+, NR4+); and those formed with metallic cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. Where the compound described herein contain an amine function, this may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compound is within the scope of the compound presented herein.

[0114] Conversely said salt forms can be converted by treatment with an appropriate acid into the free form.

[0115] In some embodiments, sites on the compound disclosed herein are susceptible to various metabolic reactions. Therefore, incorporation of appropriate substituents at the places of metabolic reactions will reduce, minimize or eliminate the metabolic pathways. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium or an alkyl group.

[0116] The compound of the present disclosure includes compounds that are isotopically labeled, i.e., with one or more isotopic substitutions. These compounds are identical to those recited in the formula and structure presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. A reference to a particular element includes within its scope all isotopes of the element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, referencesto carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. In another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may also be useful in a diagnostic context. Radiolabeled compounds described herein may comprise a radioactive isotope selected from the group of3H,11C,18F,122I,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,11C and18F. Deuterated compounds with2H (D) are intended to be included within the scope of the present invention. In some embodiments, metabolic sites on the compounds described herein are deuterated.

[0117] Also encompassed within the invention are modifications of the compounds of the formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof using PROTAC technology (Schapira M. et al, Nat. Rev. Drug Discov. 2019, 18(12), 949-963). Specifically, the PROTAC technology designs a bifunctional small molecule, one end of which is a compound of the general formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof, and the other end of which is connected with a ligand of E3 ubiquitin ligase through a connecting chain, to form a target-induced protein degradation complex. Because this degradation has a catalytic effect, a lower dosage can achieve efficient degradation. The compound of the general formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof can be connected via a linker arm (e.g. long-chain ethylene glycol with the length of 2-10, long-chain propylene glycol with the length of 2-10 and long-chain fatty alkane with the length of 2-10) to a ligand of E3 ubiquitin ligase such as e.g. thalidomide analogs.

[0118] Also encompassed within the invention are protected compounds, which may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo.Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products afterdeprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.Synthesis of Compounds

[0119] The synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions presented herein may vary. Techniques and materials recognized in the field are described, for example, in 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 Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of the compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein.

[0120] The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

[0121] In the reactions described herein, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0122] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyl dimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbzgroups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[0123] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and9-fluorenylmethyleneoxycarbonyl (Fmoc). Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.

[0124] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.

[0125] Typically blocking / protecting groups may be selected from:Fmoc

[0126] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosure.

[0127] General synthetic pathways

[0128] Compounds of Formula (I), wherein R1, R2, and R3are defined as in the general scope can be prepared according to Scheme 1,Scheme 1

[0129] By reacting an intermediate of Formula (II) with a suitable carboxylic acid R1CO2H, 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, EtsN, in a suitable solvent such as, for example, DCM or DMF, at a suitable temperature such as, for example, room temperature.

[0130] Alternatively, compounds of Formula (I) can be prepared by reacting an intermediate of Formula (II) with a suitable activated form of a carboxylic acid, such as, for example, an acyl chloride or its corresponding anhydride, in the presence of a suitable base such as, for example, DIPEA or EtsN, in a suitable solvent such as, for example, DCM or DMF, at a suitable temperature such as, for example, 0 °C or room temperature.

[0131] Intermediates of Formula (II) can be prepared by reacting an intermediate of Formula (III), wherein P is a suitable protecting group such as, for example, Boc, with a suitable deprotecting agent such as, for example, TFA, MSA, or HC1, in a suitable solvent such as, for example, DCM or 1,4-di oxane, at a suitable at a suitable temperature such as, for example, room temperature.I I J

[0132] Intermediates of Formula (III), wherein R is defined as, can be prepared according to Scheme 2,R2N(IV) (III)Scheme 2

[0133] By reacting an intermediate of Formula (IV), wherein P is a suitable protecting group such as, for example, Boc, and X is a suitable leaving group such as, for example, fluoride, with a suitable amine such as, for example, cis-2,6-dimethylmorpholine, in a suitable solvent such as, for example, DMSO, at a suitable temperature such as, for example, 130 °C.

[0134] Intermediates of Formula (IV) can be prepared by reacting an intermediate of Formula (V), wherein Y is a suitable leaving group such as, for example, chloride, with a suitable heteroaryl-boronate or -boronic acid such as, for example, 6-fluoropyridine-2-boronic acid, in the presence of a suitable base such as, for example, potassium phosphate, in the presence of a suitable catalyst such as, for example, XantPhos Pd G4 (CAS [1621274-19-8]) or Pd(dppf)Cl2.DCM (CAS [95464-05-4]), in a suitable solvent such as, for example, 1,4-di oxane, at a suitable temperature such as, for example, 80-100 °C.

[0135] Alternatively, Intermediates of Formula (III), wherein P is a suitable protecting group such as, for example, Boc, and R3is defined as C-linked heteroaryl, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, or pyrazolyl, can be prepared according to Scheme 3:(VI) (in)Scheme 3

[0136] By reacting an intermediate of Formula (VI), wherein Z is a suitable boron derivative such as, for example, 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl, with a suitable heteroaryl -halide such as, for example, 2,4-dichloropyrimidine, in the presence of a suitable base such as, for example, Na2CO3, in the presence of a suitable catalyst such as, for example, [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (CAS [95464-05-4]), in a suitable solvent such as, for example, 1,4-di oxane or a mixture of 1,4-dioxane and water, at a suitable temperature such as, for example, 80 °C.

[0137] Alternatively, intermediates of Formula (III), wherein P is a suitable protecting group such as, for example, Boc, and R3is defined as an aryl group, such as, for example, phenyl, can be prepared by reacting an intermediate of Formula (V), wherein Y is a suitable leaving group such as, for example, chloride, with a suitable arylboronate ester or boronic acid such as, for example, phenylboronic acid (CAS [98-80-6]), in the presence of a suitable base such as, for example, sodium carbonate, in the presence of a suitable catalyst such as, for example, Pd(ddpf)C12. DCM (CAS [95464-05-4]), in a suitable solvent such as, for example, 1,4-di oxane or a mixture of 1,4-di oxane and water, at a suitable temperature such as, for example, 85 °C.

[0138] Alternatively, intermediates of Formula (III), wherein P is a suitable protecting group such as, for example, Boc, and R3is defined as aN-linked heteroaryl, such as, for example, pyrazolyl, can be prepared according to Scheme 3, by reacting an intermediate of Formula (VI), wherein Z is a suitable boron derivative such as, for example, a boronic acid, with a suitable heteroaryl such as, for example, 4-fluoro-1H-pyrazole (CAS [35277-02-2]), in the presence of a suitable base such as, for example, pyridine, in the presence of a suitable catalyst such as, for example, copper(II) acetate (CAS [142-71-2]), in a suitable solvent such as, for example, dimethoxyethane, at a suitable temperature such as, for example, 65 °C.

[0139] Alternatively, intermediates of Formula (III), wherein P is a suitable protecting group such as, for example, Boc, and R3is defined as aN-linked heteroalkyl, such as, for example, 3-(dimethylphosphinyl)piperidin-l-yl, can be prepared according to Scheme 3, by reacting an intermediate of Formula (V), wherein Y is a suitable leaving group such as, for example, chloride, with 3-(dimethylphosphinyl)piperidine (CAS [2287312-67-6]), in the presence of a suitable base such as, for example, cesium carbonate, in the presence of a suitable catalyst such as, for example, tris(dibenzylideneacetone)dipalladium (CAS [51364-51-3], in a suitable solvent such as, for example, 1,4-dioxane, at a suitable temperature such as, for example, 90 °C.

[0140] Intermediates of Formula (VI) can be prepared according to Scheme 3, by reacting an intermediate of Formula (V), wherein Y is a suitable leaving group such as, for example, chloride, with a suitable reagent such as, for example, bis(pinacolato)diboron (CAS [73183-34-3]), in the presence of a suitable base such as, for example, potassium acetate, in the presence of a suitable catalyst such as, for example, (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1, 1 '-biphenyl)[2-(2'-amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3, CAS [1445085-55-1]), in a suitable solvent such as, for example, 1,4-dioxane, at a suitable temperature such as, for example, 80-90 °C.

[0141] Intermediates of Formula (V) wherein Y is a suitable leaving group such as, for example, chloride, can be prepared according to Scheme 4,(VII) (V)Scheme 4

[0142] By reacting a suitable substituted 2-bromobenzaldehyde such as, for example, 2-bromo-4-chlorobenzaldehyde (CAS [84459-33-6]) with a suitably protected aminomethylalkyne such as, for example, tert-butyl N-(prop-2-yn-l-yl)carbamate (CAS [92136-39-5]), in the presence of a suitable source of nitrogen such as, for example, tertbutylamine, in the presence of a suitable base such as, for example, EtsN, in the presence of a suitable catalyst such as, for example, l,2-bis(diphenylphosphino)ethane nickel(II) chloride (CAS [14647-23-5], in a suitable solvent such as, for example, CH3CN, at a suitable temperature such as, for example, 80 °C.

[0143] Wherein a compound of Formula (I) has a protecting group such as, for example, Boc or THP, the protecting group can be removed employing conditions known to one skilled in the art. For example, reaction with a reagent such as, for example, pTsOH (p-toluenesulfonic acid), MSA, TFA, or HC1, in a suitable solvent such as, for example, DCM, or 1,4-di oxane, at a suitable temperature such as, for example, room temperature or 40 °C.

[0144] Compounds of Formula (I) bearing a halogen such as, for example, Br, Cl, or I on R1or R3can be further functionalized using methods known in the art, such as, for example, Suzuki, Negishi, or Buchwald couplings, or other similar procedures.

[0145] In some cases, compounds of Formula (I) bearing a fluorine on the R1group can be further functionalized by nucleophilic aromatic substitution, for example by reaction withan alcohol in the presence of a suitable base, such as, for example, NaH, at a suitable temperature such as, for example, 85 °C, in a suitable solvent such as, for example, DMF.

[0146] Compounds of Formula (I) bearing a ketone group can also be further functionalized, for example by reductive amination, reduction, or addition of a Grignard reagent.

[0147] The skilled person will realize that in the reactions described in the Schemes, in certain cases it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N2-gas atmosphere.

[0148] It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before reaction work-up, meaning those series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, or extraction.

[0149] The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.

[0150] The compounds of the invention as prepared in the processes described herein may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. Racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I), and the pharmaceutically acceptable addition salts thereof, involves liquid chromatography using a chiral stationary phase e.g., by supercritical fluid chromatography. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereo specifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0151] In all these preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration, and chromatography. Thepurity of the reaction products may be determined according to methodologies generally known in the art such as for example LC-MS, TLC, HPLC.Methods of Treatment and Medical Uses, Pharmaceutical compositions, and combinations

[0152] The present invention also provides methods for the treatment or prevention of a proliferative disease (e.g., cancer, benign neoplasm, angiogenesis) in a subject. Such methods comprise the step of administering to the subject in need thereof 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.

[0153] The subject being treated is a mammal. The subject may be a human. The subject may be a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. The subject may be a companion animal such as a dog or cat. The subject may be a livestock animal such as a cow, pig, horse, sheep, or goat. The subject may be a zoo animal. The subject may be a research animal such as a rodent, dog, or non-human primate. The subject may be a non-human transgenic animal such as a transgenic mouse or transgenic pig.

[0154] The proliferative disease to be treated or prevented using the compounds described herein will typically be associated with aberrant activity of SMARCA2. Aberrant activity of SMARCA2 may be an elevated and / or an inappropriate (e.g., abnormal) activity of SMARCA2. In certain embodiments, SMARCA2 is not overexpressed, and the activity of SMARCA2 is elevated and / or inappropriate. In certain other embodiments, SMARCA2 is overexpressed, and the activity of SMARCA2 is elevated and / or inappropriate. The compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, inhibits the activity of SMARCA2 and may be useful in treating and / or preventing proliferative diseases.

[0155] A proliferative disease may also be associated with inhibition of apoptosis of a cell in a biological sample or subject. All types of biological samples described herein or known in the art are contemplated as being within the scope of the invention. Inhibition of the activity of SMARCA2 is expected to cause cytotoxicity via induction of apoptosis. The compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, may induce apoptosis, and therefore, be useful in treating and / or preventing proliferative diseases.

[0156] In certain embodiments, the proliferative disease to be treated or prevented using the compounds of the present disclosure is cancer.

[0157] The cell described herein may be an abnormal cell. The cell may be in vitro or in vivo. The cell may be a proliferative cell.

[0158] In another aspect, the present invention provides methods of downregulating the expression of SMARCA2 in a biological sample or subject.

[0159] In yet another aspect, the present invention provides the compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, for use in the treatment of a proliferative disease in a subject. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting cell growth. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inducing apoptosis in a cell. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting transcription.

[0160] One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compounds in the therapeutic formulation, and the condition of the patient. Generally, the amount of the compounds of the present invention to be administered as a therapeutic agent for treating the disorders referred to herein will be determined on a case by case by an attending physician.

[0161] Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount may be from about 0.005 mg / kg to 50 mg / kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect may vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment, the compound according to the invention is preferably formulated prior to administration. As described herein below, suitablepharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

[0162] While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

[0163] The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington’s Pharmaceutical Sciences (18thed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, or a nose spray. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives may facilitate the administration to the skin and / or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.

[0164] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions, or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

[0165] The exact dosage and frequency of administration depends on the particular compound used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the instant invention.

[0166] The methods described herein may also comprise the additional step of administering one or more additional pharmaceutical agents in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof. Thus, the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating proliferative diseases resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions.

[0167] Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound according to the present invention and one or more additional therapeutic agents, as well as administration of the compounds according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound according to the present invention and a therapeutic agent may be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

[0168] Therefore, an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more anticancer agent, as a combined preparation for simultaneous, separate, or sequential use in the treatment of patients suffering from cancer.

[0169] The one or more other medicinal agents and a compound according to the present invention may be administered simultaneously (e.g., in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated, and the particular host being treated. The optimum method and order of administration and the dosage amounts, and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

[0170] The weight ratio of a compound according to the present invention and the one or more other anti cancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of Formula (I) and another anti cancer agent may range from 1 / 10 to 10 / 1, more in particular from 1 / 5 to 5 / 1, even more in particular from 1 / 3 to 3 / 1.EXAMPLES

[0171] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout this specification are incorporated herein by references for all legal purposes to be served thereby. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich of Merck; Acros Organics, Fluka, and Fischer Scientific, part of Thermo Fischer Scientific.

[0172] When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained.

[0173] For intermediates that may be used in a next reaction step as a crude or as a partially purified intermediate, theoretical mol amounts may be indicated in the reaction protocols described below.

[0174] Hereinafter, DCM and CH2Cl2means dichloromethane; r.t. means room temperature; Boc means tert-butoxycarbonyl; CH3CN and ACN means acetonitrile; MeOH means methanol; EtOH means ethanol; iPrOH means isopropanol; DMF means dimethylformamide; iPrNH2 means isopropylamine; SOCI2 means thionyl chloride; Et3N means triethylamine; NH4OAc means ammonium acetate; NH4OH means ammonium hydroxide; NH4Cl means ammonium chloride; Na2CO3means sodium carbonate; KHSO4 means potassium hydrogenosulfate, HBTU means 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; NH4HCO3means ammonium bicarbonate; TFA means trifluoroacetic acid; THF means tetrahydrofuran; h means hours; SFC means Supercritical fluid chromatography; EtOAc means ethyl acetate; K2CO3means potassium carbonate; MgSO4means magnesium sulfate; BOC2O means di-tert-butyl decarbonate.Example 1: Preparation of the Intermediates and the final Compounds, and characterization thereof

[0175] Several methods for preparing the Compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods.Table 1: Abbreviations.Abbreviation MeaningACN acetonitrileAbbreviation MeaningCelite® diatomaceous earthCo CompoundCo. No. Compound NumberDCM dichloromethaneDEA diethylamineDIPEA N,N-diisopropylethylamineDMF N, N-di methyl form am ideeq- equivalent(s)Et3N or TEA triethylamineEtOAc ethyl acetateEtOH ethanolHATU hexafluorophosphate azabenzotriazole tetramethyl uronium HPLC high performance liquid chromatography iPrNH2isopropylamineiPrOH isopropanolMe methylMeOH methanolMW Molecular WeightNMP N -Methyl -2-py rroli doneNT not testedPIDA phenyliodine(III) diacetatePPh3triphenylphosphinequant. quantitativerac racemicRP reversed phaseSelectfluor l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)SFC supercritical fluid chromatographyTFA trifluoroacetic acidTHF tetrahydrofuran

[0176] As understood by a person skilled in the art, Compounds synthesized using the protocols as indicated may contain residual solvent or minor impurities.

[0177] A skilled person will realize that, even where not mentioned explicitly in the experimental protocols below, typically after a column chromatography purification, the desired fractions were collected and the solvent was evaporated.

[0178] In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context.

[0179] In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0180] Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were dried, they were generally dried over a drying agent such as Na2SO4or MgSO4Where mixtures, solutions, and extracts were concentrated, they were typically concentrated on a rotary evaporator under reduced pressure.

[0181] The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+(protonated molecule) and / or [M-H]’ (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]', etc). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

[0182] Some NMR experiments were carried out using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe head with z gradients and operating at 500 MHz for the proton and 125 MHz for carbon. Some NMR experiments were carriedout using a Bruker Avance III 400 spectrometer, using internal deuterium lock and equipped with reverse double-resonance (1H,13C, SEI) probe head with z gradients and operating at 400 MHz for the proton. Experiments were performed at ambient temperature (298.6 K), unless otherwise mentioned. Chemical shifts (5) are reported in parts per million (ppm). J values are expressed in Hz. Definitions for multiplicity are as follows: s = singlet, d = doublet, t= triplet, q = quartet, p = pentet, hept = heptet, dd = doublet of doublets, dt = doublet of triplets, dq = double of quartets, dp = doublet of pentets, td = triplet of doublets, tt = triplet of triplets, ddd = doublet of doublet of doublets, m = multiplet, br = broad. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.Preparation of intermediates

[0183] For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below.

[0184] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0185] Compounds designated as *R or *S are enantiopure compounds where the absolute configuration was not determined.IntermediatesIntermediate 1O(R)

[0186] A 20 mL reactor was charged with 2-bromo-4-chlorobenzaldehyde (CAS [84459-33-6], 1 g, 4.557 mmol), (R)-tert-butyl but-3-yn-2-ylcarbamate (CAS [118080-82-3], 1.157 g, 6.835 mmol, 1.5 eq.), ACN (10 mL), EtsN (1.27 mL, 9.113 mmol, 2 eq.), and tertbutylamine (1.44 mL, 13.67 mmol, 3 eq.). The mixture was purged with nitrogen and the reactor was closed with a septum, and degassed with nitrogen for 20 min. To this was addedl,2-bis(diphenylphosphino)ethane nickel(II) chloride (CAS [14647-23-5], 241 mg, 0.456 mmol, 0.1 eq.) and the mixture was heated overnight to 80 °C. After cooling, the reaction mixture was diluted with EtOAc (60 mL) and washed with water, then brine. The organic layer was concentrated and the residue was purified by silica gel chromatography (EtOAc / heptane) to give Intermediate 1 (370 mg, yield 26 %) as light brown solid.Intermediate 2O N O N H IIN

[0187] A suspension of Intermediate 1 (370 mg, 1.206 mmol), 6-fluoropyridine-2-boronic acid (CAS [916176-61-9], 204 mg, 1.447 mmol, 1.2 eq.), and sodium carbonate (383 mg, 3.618 mmol, 3 eq.), in 1,4-dioxane (3 mL) and water (1 mL) was degassed by bubbling nitrogen through for 5 min. Bis(triphenylphosphine)palladium(II)chloride (CAS [13965-03-2], 42 mg, 0.060 mmol, 0.05 eq.) was added and the mixture was further degassed with nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 90 °C for 1 h in a microwave oven. More 6-fluoropyridine-2-boronic acid (CAS [916176-61-9], 204 mg, 1.447 mmol, 1.2 eq.) and bis(triphenylphosphine)palladium(II)chloride (CAS [13965-03-2], 42 mg, 0.060 mmol, 0.05 eq.) were added to the reaction mixture and it was degassed by bubbling nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 90 °C for 1 h in a microwave oven. Again, more 6-fluoropyridine-2-boronic acid (CAS [916176-61-9], 204 mg, 1.447 mmol, 1.2 eq.) and bis(triphenylphosphine)palladium(II)chloride (CAS [13965-03-2], 42 mg, 0.060 mmol, 0.05 eq.) were added to the reaction mixture and it was degassed by bubbling nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 100 °C for 2 h in a microwave oven. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3, and the solvent was evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane: EtOH / EtOAc 1 / 3 from 100:0 to 20:80) to give Intermediate 2 (255 mg, 46 % pure, yield: 44 %) as a brown solid, dried under vacuum at 50 °C and used without further purification.Intermediate 3(R), (CIS)

[0188] A solution of Intermediate 2 (255 mg, 76 % pure, 0.527 mmol), cis-2,6-dimethylmorpholine (260 pL, 2.11 mmol, 4 eq.), and DIPEA (273 pL, 1.582 mmol, 3 eq.) in dry DMSO (4 mL) was introduced into a thick-wall pressure vial. The vial was closed and the reaction mixture was stirred at 130 °C overnight. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO₄, filtered, and the solvent was evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent:heptane: EtOH / EtOAc 1 / 3 from 100:0 to 50:50) to give Intermediate 3 (221 mg, 80 % pure, yield: 72 %) as a brown solid, dried under vacuum at 50 °C, and used without further purification.Intermediate 4(R), (CIS)

[0189] HC1 (4 M in 1,4-dioxane, 2.4 mL, 9.555 mmol, 25 eq.) was added to a solution of Intermediate 3 (221 mg, 80 % pure, 0.382 mmol) in dry 1,4-dioxane (4 mL). The reaction mixture was stirred at room temperature for 2 days. The solvent was evaporated to give Intermediate 4 (219 mg, 76 % pure, quantitative) as a yellow solid (HC1 salt), dried under vacuum at 50 °C, and used without further purification.Intermediate 5

[0190] 2-Bromo-4-chlorobenzaldehyde (CAS [84459-33-6], 5 g, 22.8 mmol), N-Boc-propargylamine (CAS [92136-39-5], 5.35 g, 34.5 mmol, 1.5 eq.), ACN (50 mL), triethylamine (6.4 mL, 45.7 mmol, 2 eq.) and tert-butylamine (7.2 mL, 68.52 mmol, 3 eq.) were combined in a sealed tube at room temperature. The reaction mixture was sparged with nitrogen for 20 min. To this solution was added l,2-bis(diphenylphosphino)ethane nickel (II) chloride (CAS [14647-23-5], 1.2 g, 2.3 mmol) and the mixture was stirred at 80 °C for 16 h. The mixture was diluted with EtOAc and filtered through a celite pad. The filtrate was washed with brine and concentrated to dryness. The residue was purified by flash column chromatography (120 g silica; EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 5 (2.5 g, yield: 30 %) as a brown solid.Intermediate 6

[0191] 6-Fluoropyridine-2-boronic acid (CAS [916176-61-9], 3.369 g, 23.91 mmol, 1.4 eq.), Intermediate 5 (5 g, 17.079 mmol, 1 eq.), and sodium carbonate (5.43 g, 51.236 mmol, 3 eq.) were suspended in 1,4-di oxane (45 mL) and water (15 mL) under nitrogen atmosphere, then bis(triphenylphosphine)palladium(II)chloride (CAS [13965-03-2], 600 mg, 0.855 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 85 °C overnight. The mixture was diluted with water and extracted 3x with DCM. The combined organic layer was washed with brine, then dried over MgSO4, filtered, and the solvent was evaporated. The residue was purified by silica flash chromatography (120 g, heptane / EtOAc 100 / 0 to 30 / 70) to afford Intermediate 6 (4112 mg, yield: 68 %) as a beige solid.Intermediate 7

[0192] 6-Bromo-3-isoquinolinemethanamine (CAS [1780722-74-8], 500 mg, 1.898 mmol, 1.2 eq.) was added to a stirred solution of 4-methyl-3-(methylsulfonyl)benzoic acid (CAS [51522-22-6], 342 mg, 1.582 mmol), HATU (CAS [148893-10-1], 902 mg, 2.372 mmol, 1.5 eq.), and DIPEA (828 pL, 4.745 mmol, 3 eq.) in DCM (10 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvent concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g, AcOEt / heptane from 0 / 100 to 3 / 97) to yield Intermediate 7 (657 mg, yield: 95 %) as a white solid.Intermediate 8

[0193] Pd(dppf)Cl2.DCM (CAS [95464-05-4], 123 mg, 0.150 mmol, 0.1 eq.) was added to a stirred solution of 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS [842136-58-7], 502 mg, 2.252 mmol, 1.5 eq.), Intermediate 7 (657 mg, 1.501 mmol), and NaHCO₃ (252 mg, 3.002 mmol, 2 eq.) in 1,4-di oxane (5 mL) and water (3 mL) under nitrogen atmosphere. The vial was sealed and the reaction mixture was stirred at 90 °C for 16 h. After cooling, the mixture was filtered through a pad of celite, diluted with H2O, and extracted with EtOAc. The organic layer was washed with brine (x 2), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g; MeOH:DCM 1:9 in DCM from 0 / 100 to 50 / 50) to yield Intermediate 8 (323 mg, yield: 47 %) as a brown solid.Intermediate 9

[0194] In a thick glass vial, potassium acetate (980 mg, 9.988 mmol, 6 eq.) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1, 1 '-biphenyl)[2-(2'-amino- 1,1'-biphenyl)]palladium(II) methanesulfonate (CAS [1445085-55-1], 70 mg, 0.0832 mmol, 0.05 eq.) were added to a solution of Intermediate 5 (513 mg, 1.665 mmol) andbis(pinacolato)diboron (CAS [73183-34-3], 845 mg, 3.329 mmol, 2 eq.) in dry 1,4-dioxane (5 mL) and the mixture was degassed with nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 90 °C for 5 h. After cooling, the solvent was evaporated and the residue was purified by column chromatography (Biotage Sfar 50 g; eluent:heptane: EtOH / EtOAc 1 / 3 100:0 to 50:50) to give Intermediate 9 (873 mg, quantitative) as a brown thick oil.Intermediate 10

[0195] A solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 10.04 g, 35.62 mmol), CIS-2, 6-dimethylmorpholine (CAS [6485-55-8], 4.83 mL, 39.182 mmol, 1.1 eq.), and Et₃N (14.85 mL, 106.86 mmol, 3 eq.) in dry toluene (50 mL) was stirred at reflux for 2 h. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluent: heptane: EtOH / EtO Ac 1 / 3 100:0 to 50:50) to give Intermediate 10 (10.18 g, yield: 90 %) as a bright orange solid.Intermediate 11(CIS)

[0196] Tetramethylammonium fluoride (CAS [373-68-2], 2210 mg, 23.722 mmol, 1.5 eq.) was added to a solution of Intermediate 10 (5 g, 15.815 mmol) in dry DMF (80 mL) in a thick-walled tube. The tube was sealed and the reaction mixture was stirred at 65 °C for 3.5 h. The reaction mixture was poured into brine and the mixture was extracted several times withEtOAc. The combined organic layer was dried on MgSO₄, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluent:heptane: EtOH / EtO Ac 1 / 3 from 100:0 to 100:0) to give Intermediate 11 (4.5 g, yield: 92 %) as a white solid.Intermediate 12(CIS)

[0197] [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (CAS [95464-05-4], 118 mg, 0.144 mmol, 0.1 eq.) was added to a suspension of Intermediate 9 (555 mg, 1.443 mmol) and Intermediate 11 (459 mg, 1.587 mmol, 1.1 eq.) in a mixture of sodium carbonate in water (2.89 mL, 1 M, 2.886 mmol, 2 eq.) and 1,4-di oxane (5 mL). The reaction mixture was degassed with nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 90 ° C overnight. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane: EtOH / EtOAc 1 / 3 from 100:0 to 80:20) to give Intermediate 12 (347 mg, yield: 52 %) as a brown solid.Intermediate 13(CIS)

[0198] HC1 (37 % in H2O, 621 pL, 7.437 mmol, 10 eq.) was added dropwise to a solution of Intermediate 12 (347 mg, 0.744 mmol) in 1,4-dioxane (5 mL) at roomtemperature. The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated and the residue was co-evaporated with toluene to give Intermediate 13 (330 mg, quantitative) as a brown solid, used without further purification.Intermediate 14

[0199] A mixture of Intermediate 9 (1.07 g, 2.784 mmol), 2,4-dichloropyrimidine (CAS [3934-20-1], 503 mg, 3.341 mmol, 1.2 eq.), l,l'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (CAS [95464-05-4], 114 mg, 0.139 mmol, 0.05 eq.), andNa2CO3 (885 mg, 8.353 mmol, 3 eq.) in 1,4-dioxane (13 mL) and water (3 mL) was degassed with nitrogen. The reaction mixture was stirred at 80 °C for 50 min. The reaction mixture was diluted with EtOAc and filtered through a celite pad. The filtrate was concentrated and the residue was purified by SiO₂ column chromatography (40 g, EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 14 (651 mg, yield: 63 %).Intermediate 15

[0200] HC1 (37 % in H2O, 13.72 mL, 164.33 mmol, 20 eq.) was added dropwise (1 drop / sec) to a solution of Intermediate 14 (3.047 g, 8.217 mmol) in 1,4-dioxane (50 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature overnight. The solid was filtered and washed with 1,4-dioxane to give Intermediate 15 (3530 mg, quantitative) as a grey solid, dried under vacuum at 45 °C, and used without further purification.Intermediate 16

[0201] A solution of 5-bromo-6-methyl-3-pyridinecarboxylic acid, methyl ester (CAS [1174028-22-8], 3.3 g, 14.344 mmol), sodium methanesulfmate (5.857 g, 57.377 mmol, 4 eq.), copper (I) iodide (2.732 g, 14.344 mmol, 1 eq.) in DMSO (50 mL) was stirred at 120 °C overnight. After cooling, the reaction mixture was poured into cold water. The solid was filtered and washed with cold water and a small quantity of EtOAc. The filtrate was extracted 3 times with EtOAc. The combined organic layer was dried over MgSO4, filtered, and the solvent was evaporated to give Intermediate 16 (2 g, yield: 61 %) as a yellow solid, used without further purification.Intermediate 17O

[0202] A solution of Intermediate 16 (2000 mg, 8.724 mmol) in sodium hydroxide (26.172 mL, 1 M in water, 26.172 mmol, 3 eq.) and MeOH (20 mL) was stirred at room temperature for 18 h. The mixture was acidified with aqueous HC1 (1 M) to pH=l and then extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 17 (1.2 g, yield: 64 %) as a light yellow solid, used without further purification.Intermediate 18

[0203] Intermediate 17 (72 mg, 0.33 mmol, 1.2 eq.) and Intermediate 15 (75 mg, 0.28 mmol) were suspended in DCM (2 mL) and 1-propanephosphonic anhydride (CAS [68957-94-8], 50 % solution in EtOAc, 0.3 mL, 0.5 mmol, 1.8 eq.) and tri ethylamine (0.27 mL, 1.94 mmol, 7 eq.) were added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, the residue was suspended in EtOH and water and filtered. The solid was washed with EtOH and ACN, then dried under vacuum to obtain Intermediate 18 (130 mg, quantitative), used without further purification.Intermediate 19(CIS)

[0204] A solution of Intermediate 14 (4017 mg, 10.832 mmol), CIS-2, 6-dimethylmorpholine (CAS [6485-55-8], 1.868 mL, 15.165 mmol, 1.4 eq.), and DIPEA (5.6 mL, 32.497 mmol, 3 eq.) in dry DMSO (30 mL) was introduced in two microwave vials. The vials were sealed and the reaction mixtures were stirred at 130 °C for 1 h in a microwave oven. Both vials were combined and the mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was washed with brine, dried on MgSO4, filtered, and the solvent was evaporated to give Intermediate 19 (5790 mg, quantitative) as a dark brown solid, used without further purification.Intermediate 20(CIS)

[0205] HC1 (37 % in water, 10.7 mL, 128.8 mmol, 10 eq.) was added dropwise to a solution of Intermediate 19 (5790 mg, 12.879 mmol) in 1,4-dioxane (100 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1,4-dioxane and the solid was filtered and washed with Et2O to give Intermediate 20 (5328 mg, quantitative) as a yellow solid, dried under vacuum at 45 °C and used without further purification.Intermediate 21

[0206] Intermediate 5 (4.98 g, 17.02 mmol) and Na2CO3 (7.22 g, 68.08 mmol, 4 eq.) were added to a stirred solution of phenyl boronic acid (CAS [98-80-6], 6.23 g, 51.06 mmol, 3 eq.) in 1,4-di oxane (240 mL) at room temperature under nitrogen atmosphere. Then Pd(dppf)Cl2.DCM (CAS [95464-05-4], 697 mg, 0.85 mmol, 0.05 eq.) was added and the mixture was stirred at 85 °C under nitrogen stream for 16 h. After cooling, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Biotage, 350 g, heptane / EtOAc from 100 / 0 to 0 / 100) to yield Intermediate 21 (5 g, yield: 77 %) as a sticky paste.Intermediate 22IIN

[0207] Intermediate 21 (5 g, 14.951 mmol) was dissolved in HC1 (6 M in iPrOH, 50 mL, 299 mmol, 20 eq.) and the resulting mixture was stirred at room temperature for 48 h. The solvent was evaporated under reduced pressure to give Intermediate 22 (4.456 g, quantitative) as a beige solid, used without further purification.Intermediate 23O N H IIN

[0208] Pd(dppf)Cl2.DCM (CAS [95464-05-4], 240 mg, 0.293 mmol, 0.15 eq.) was added to a stirred and nitrogen-degassed solution of Intermediate 9 (1.095 g, 1.995 mmol), 1-bromo-3 -chlorobenzene (CAS [108-37-2], 0.47 mL, 4.002 mmol, 2 eq.), and sodium bicarbonate (1 M in water, 4 mL, 4 mmol, 2 eq.) in 1,4-dioxane (10 mL) and water (4 mL) under nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 6 h. After cooling, the mixture was diluted with water, extracted with EtOAc (30 mL), washed with brine (20 mL x 2), and the solvent was evaporated in vacuo. The residue was purified by flash columnchromatography (12 g silica; EtOAc / heptane from 0 / 100 to 100 / 0) to yield Intermediate 23 (637 mg, yield: 84 % ) as a brown oil.Intermediate 24

[0209] Xphos Pd G3 (CAS [1445085-55-1], 172 mg, 0.203 mmol, 0.12 eq.) was added to a solution of Intermediate 23 (637 mg, 1.676 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 0.84 g, 3.308 mmol, 2 eq.), and potassium acetate (0.5 g, 5.095 mmol, 3 eq.) in 1,4-dioxane (25 mL) previously degassed by bubbling nitrogen for 15 min. The mixture was stirred at 90 °C for 16 h. After cooling, the mixture was filtered through a pad of celite and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (silica 25 g, EtOAc / heptane from 0 / 100 to 50 / 50) to afford Intermediate 24 (636 mg, yield: 74 %) as a yellow solid.Intermediate 25

[0210] Pd(dppf)Cl2.DCM (CAS [95464-05-4], 53 mg; 0.065 mmol, 0.16 eq.) was added to a stirred and nitrogen-degassed solution of Intermediate 24 (0.2 g; 0.391 mmol), 4-chloro-2 -methylpyrimidine (CAS [4994-86-9], 84 mg; 0.653 mmol, 1.7 eq.), and aqueous NaHCO3 (1 M, 1 mL; 1 mmol, 2.6 eq.) in 1,4-dioxane (4 mL) under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 16 h. After cooling, the mixture was diluted with water and extracted with EtOAc (15 mL). The organic layer was washed with brine (10 mL x 2) and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (12 g silica; EtOAc / heptane from 40 / 60 to 100 / 0) to yield Intermediate 25 (77 mg, yield: 46 %) as a pale brown oil.Intermediate 26H2N

[0211] TFA (0.54 mL 7.246 mmol, 40 eq.) was added to a solution of Intermediate 25 (77 mg, 0.181 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was treated with amberlyst A26, filtered, and concentrated in vacuo to yield Intermediate 26 (59 mg, quantitative) as a pale brown solid.Intermediate 27IIN

[0212] Intermediate 5 (555 mg, 1.9 mmol) was suspended in HC1 (4 M in 1,4-dioxane, 10 mL, 40 mmol, 21 eq.) and the mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue was co-evaporated twice with toluene, then with MeOH, and dried under vacuum at 45 °C to yield Intermediate 27 (570 mg, quantitative) as a brown solid, used without further purification.Intermediate 28N >HAo=s=o

[0213] 1-Propanephosphonic anhydride (CAS [68957-94-8], 50 % in EtOAc, 10.2 mL, 14.731 mmol, 0.75 eq.) was added dropwise to a solution of Intermediate 27 (4.5 g, 19.641 mmol), 3-[(2-hydroxyethyl)sulfonyl]-4-methylbenzoic acid (CAS [1094404-86-0], 4.5 g, 19.641 mmol), and EtsN (10.9 mL, 78.565 mmol, 4 eq.) in DCM (70 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NH4CI and brine, dried over MgSO4, filtered, and concentrated underreduced pressure. The residue was purified by flash column chromatography (DCM: MeOH from 100:0 to 90:10) to obtain Intermediate 28 (6.3 g, yield: 77 %).Intermediate 29

[0214] A mixture of Intermediate 28 (6.3 g, 15.039 mmol), XPhos Pd G4 (CAS [1599466-81-5], 259 mg, 0.301 mmol, 0.02 eq.), bis(pinacolato)diboron (CAS [73183-34-3], 4.965 g, 19.551 mmol, 1.3 eq.), KOAc (4.428 g, 45.118 mmol, 3 eq.) in 1,4-dioxane (90 mL) was charged to a flask, purged with nitrogen, and the flask was sealed. The reaction mixture was stirred at 80 °C for 16 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 90 / 10) to afford Intermediate 29 (7.3 g, yield: 95 %).Intermediate 30

[0215] Cs2CO3(1.5 g, 4.60 mmol, 3.5 eq.) and 1-(4-methylbenzenesulfonate) 3-fluoro-cyclobutanol (CAS [1427501-88-9], 409 mg, 1.67 mmol, 1.3 eq.) was added to a solution of 4-iodo-3-methoxy-1H-pyrazole (CAS [1350325-05-1], 289 mg, 1.29 mmol, 1 eq.) in anhydrous DMF (6 mL). The resulting mixture was stirred at 80 °C for 3 h. The mixture was then diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography (25 g, EtOAc / heptane from 0 / 100 to 15 / 85) to yield Intermediate 30 (247 mg, yield: 61 %) as a yellow oil.Intermediate 31

[0216] Pd(dppf)Cl2.DCM (CAS [95464-05-4], 68 mg, 0.08 mmol, 0.1 eq.) was added to a stirred solution of Intermediate 9 (321 mg, 0.84 mmol, 1 eq.), Intermediate 30 (247 mg, 0.83 mmol, 1 eq.) and sodium bicarbonate (140 mg, 1.67 mmol, 2 eq.) in 1,4-dioxane (10 mL) and water (2.5 mL) in a sealed tube under nitrogen atmosphere. The mixture was stirred at 70 °C for 16 h. After cooling, the mixture was diluted with water, extracted with EtOAc, washed with brine (x 2), and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (20 g, EtOAc / heptane from 0 / 100 to 55 / 45) to yield Intermediate 31 (125 mg, yield: 34 %) as a yellow solid.Intermediate 32'2N

[0217] TFA (0.5 mL, 6.40 mmol, 22 eq.) was added to a stirred solution of Intermediate 31 (125 mg, 0.29 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, and a saturated aqueous NaHCO3 was added until pH 8. DCM was added and the mixture was extracted with DCM (x 3). The combined organic layer was dried (MgSO4), filtered, and the solvent was evaporated in vacuo to yield Intermediate 32 (86 mg, yield: 81 %) as an orange oil.Intermediate 33, Intermediate 34 and Intermediate 35F F I NH I NHX y.Intermediate 33 (*R) Intermediate 34 (*S) Intermediate 35

[0218] Methyl 3-[(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoate (CAS [2361963-35-9], 714 mg, 2.865 mmol) was dissolved in a mixture of THF (2.5 mL), water (2.5 mL), and MeOH (2.5 mL) and then NaOH (229 mg, 5.729 mmol, 2 eq.) was added at room temperature. The reaction mixture was stirred at room temperature overnight. DCM (20 mL), and water (20 mL) were added to the mixture. The layers were separated and the aqueous layer was acidified with 2 M aqueous HC1 (to pH=2), then extracted with DCM (2 x 25 mL). The combined organic layer was evaporated to yield Intermediate 33 (360 mg, yield: 53 %). A sample of Intermediate 33 (1.5 g) was separated into its stereoisomers by semipreparative SFC (aLux Amylose-1 250 x 30 mm 5 pm; isocratic mode method: 20 % [EtOH + 0.1 % DEA] - 80 % [CO2]) to yield Intermediate 34 (670 mg, yield: 34 %) and Intermediate 35 (550 mg, yield: 28 %), both as a white solids.Intermediate 36

[0219] Ammonium acetate (336 mg, 4.357 mmol, 3 eq.) in water (5 mL) was added to a solution of Intermediate 9 (550 mg, 1.431 mmol) in THF (10 mL). Then, sodium periodate (CAS [7790-28-5], 925 mg, 4.324 mmol, 3 eq.) was added in one portion at room temperature. The resulting suspension was stirred at room temperature for 15 h. The reaction mixture was diluted with water and was extracted with EtOAc (x 3). The combined organic layer was dried over MgSO4, filtered, and the solvent was evaporated to yield Intermediate 36 (400 mg, yield: 92 %) as a white solid.Intermediate 37

[0220] Pyridine (145 pL, 1.798 mmol, 2.9 eq.) was added to a solution of Intermediate 36 (190 mg, 0.629 mmol), 4-fluoro-1H-pyrazole (CAS [35277-02-2], 84 mg, 0.976 mmol, 1.6 eq.) and copper (II) acetate (CAS [142-71-2], 172 mg, 0.947 mmol, 1.5 eq.) in dry DME (6 mL). The reaction mixture was stirred at 65 °C under oxygen atmosphere for 16 h. Themixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g; SiO2, EtOAc / heptane from 0 / 100 to 60 / 40) to afford Intermediate 37 (127 mg, yield: 58 %) as a white solid.Intermediate 38<2NN

[0221] TFA (0.75 mL; 9.801 mmol, 23 eq.) was added to a solution of Intermediate 37 (152 mg; 0.444 mmol) in DCM (2 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (x 3). The combined organic layer was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure to afford Intermediate 38 (93 mg, yield: 85 %) as a brown oil.Intermediate 39l\K Nk UN yHA

[0222] 1-Propanephosphonic anhydride solution (CAS [68957-94-8], 50 % solution in EtOAc, 9.173 mL, 15.408 mmol, 1.5 eq.) was added to a suspension of 3-difluoromethanesulfonylbenzoic acid (CAS [4837-21-2], 2.669 g, 11.3 mmol, 1.1 eq.) and Intermediate 15 (3.53 g, 10.272 mmol) in DCM (80 mL) at room temperature, under nitrogen atmosphere. EtsN (7.14 mL, 51.361 mmol, 5 eq.) was then added dropwise to the suspension. The reaction mixture was stirred at room temperature for 2 days. To push the reaction to completion, more 1-propanephosphonic anhydride solution (50 % solution in EtOAc, 1.835 mL, 3.082 mmol, 0.3 eq) was added and the reaction mixture was stirred further at room temperature for 5 h. EtsN (1.4 mL, 1.43 eq.) was added to the reaction mixture and it was stirred at room temperature overnight. The reaction mixture was diluted with DCM and was washed with water. The organic layer was dried on MgSO4, filtered, and evaporated. The residue was triturated in a small amount of DCM and EtOAc and the solid was filtered to give Intermediate 39 (1794 mg, yield: 33 %) as an off-white solid.Intermediate 40

[0223] In a sealed tube, 3-(dimethylphosphinyl)piperidine (CAS [2287312-67-6], 444 mg, 0.218 mmol, 1.5 eq.) and Cs2CO3(2393 mg, 7.346 mmol, 4 eq.) were added to a solution of Intermediate 5 (633 mg, 1.836 mmol) in 1,4-dioxane (15 mL) under nitrogen atmosphere. The mixture was bubbled with nitrogen for 10 min. Then, tris(dibenzylideneacetone)dipalladium (CAS [51364-51-3], 168 mg, 0.184 mmol, 0.1 eq.) and Xphos (CAS [564483-18-7] (175 mg, 0.367 mmol, 0.2 eq.) were added and the reaction mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. The mixture was filtered on celite and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (25 g silica; DCM: MeOH (9:1) in DCM from 0 / 100 to 100 / 0) to afford Intermediate 40 (285 mg, yield: 37 % ) as a pale brown solid.Intermediate 41(rac)

[0224] Intermediate 40 (379 mg, 0.908 mmol) was dissolved in a solution of HC1 in 1,4-dioxane (4 M, 4.54 mL, 18.156 mmol, 20 eq.) and 1,4-dioxane (14 mL) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuo and the residue was triturated in diethyl ether, and filtered, to yield Intermediate 41 (288 mg, yield: 99 %) as a pale solid, used without further purification.Intermediate 42

[0225] NaHMDS (CAS [1070-89-9], 1 M in THF, 4.8 mL; 4.8 mmol, 1.1 eq.) was added dropwise to a solution of 2-bromo-6-(1H-pyrazol-3-yl)pyridine (CAS [474707-68-1], 974 mg; 4.3 mmol) and 3-iodooxetane (CAS [26272-85-5], 0.7 mL; 7.8 mmol, 1.8 eq.) in DMF (15 mL) at 0 °C. The reaction mixture was stirred at 45 °C for 16 h. After cooling, the mixture was diluted with EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted again with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (80 g; EtOAc / heptane from 0 / 100 to 100 / 0) to yield Intermediate 42 (1 g, yield: 75 %) as a yellow solid.Intermediate 43

[0226] Intermediate 43 was prepared following the same procedure as Intermediate 12, using Intermediate 42 instead of Intermediate 11.Intermediate 44

[0227] Intermediate 44 was prepared following the same procedure as Intermediate 26, using Intermediate 43 instead of Intermediate 25.Intermediate 45

[0228] Pd(dppf)Cl2.CH2Cl2(CAS [95464-05-4], 66 mg, 0.08 mmol, 0.06 eq.) was added to a solution (sparged with nitrogen for 5 min) of 6-chloro-2',6'-dimethyl-2,4'-bipyridine (CAS [2282644-36-2], 306 mg, 1.40 mmol), Intermediate 9 (807 mg, 2.10 mmol, 1.5 eq.) and sodium bicarbonate (241 mg, 2.84 mmol, 2.0 eq.) in 1,4-dioxane (20 mL) and water (8 mL). The vial was sealed and the reaction mixture was stirred at 90 °C for 80 h. After cooling, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined extracts were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (25 g silica; EtOAc / heptane from 0 / 100 to 50 / 50) to yield Intermediate 45 (200 mg, yield: 30 %) as a yellow oil.Intermediate 46

[0229] HC1 (4 N in 1,4-dioxane, 1.7 mL, 6.81 mmol) was added to a solution of Intermediate 45 (200 mg, 0.45 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated to dryness to yield Intermediate 46 (196 mg, quantitative) as an oil.Intermediate 47(3-α, 4-β, 5-α)

[0230] (3a,40,5a)-3,5-Dimethyl-4-piperidinol (CAS [374067-78-4], 596 mg, 4.61 mmol, 1.1 eq.) was added to a mixture of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 1.13 g, 4 mmol) and triethylamine (10 mL, 7.95 mmol, 2 eq.) in toluene (14 mL) at room temperature. The reaction vial was sealed and the reaction mixture was stirred at 120 °C for 8 h. After cooling, the mixture was diluted with water (20 mL) and extracted with EtOAc (3x 10 mL). The combined organic layer was washed with brine (2 x lOmL), dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (40 g silica; EtOAc / heptane from 0 / 100 to 20 / 80) to yield Intermediate 47 (984 mg, yield: 74 %) as an orange solid.Intermediate 48(3-α, 4-β, 5-α)

[0231] Benzoyl chloride (CAS [98-88-4], 0.51 mL, 4.40 mmol, 1.5 eq.) was added to a solution of Intermediate 47 (0.995 g, 3 mmol), EtsN (2.1 mL, 15 mmol, 5 eq.), and DMAP (65 mg, 0.53 mmol, 0.2 eq.) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (12 g silica; EtOAc / heptane from 0 / 100 to 10 / 90) to afford Intermediate 48 (1.49 g, yield: 83 %) as an orange solid.Intermediate 49(3-α, 4-β, 5-α)

[0232] Tetramethylammonium fluoride (CAS [373-68-2], 0.24 g; 2.58 mmol, 1.2 eq.) was added to a solution of Intermediate 48 (0.95 g; 2.19 mmol) in dry DMF (10 mL). The vial was sealed and the reaction mixture was stirred at 65 °C for 3 h. After cooling, EtOAc (10 mL) and water (10 mL) were added. The organic layer was separated, washed once more with water (20 mL) and brine (15 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (25 g silica;EtOAc / heptane from 0 / 100 to 30 / 70) to afford Intermediate 49 (750 mg, yield: 83 %) as an orange solid.Intermediate 50N(3-α, 4-β, 5-α)

[0233] Intermediate 49 (750 mg, 1.84 mmol, 1.5 eq;) was added to a solution of Intermediate 9 (674 mg, 1.23 mmol) and sodium bicarbonate (206 mg, 2.45 mmol, 2 eq.) in 1,4-di oxane (20 mL) and water (5 mL). The mixture was sparged with nitrogen for 5 min before adding bis(diphenylphosphino)ferrocene]palladium(II), complex with dichloromethane(CAS [95464-05-4], 101 mg, 0.12 mmol, 0.1 eq.). The mixture was stirred at 85 °C for 6 h. The reaction mixture was diluted with brine and extracted three times with EtOAc. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (25 g; EtOAc / heptane from 0 / 100 to 40 / 60) to yield Intermediate 50 (600 mg, yield: 83 %) as a yellow solid.Intermediate 51(3-α, 4-β, 5-α)

[0234] Trifluoroacetic acid (1.55 mL, 20.32 mmol, 20 eq.) was added to a solution of Intermediate 50 (0.6 g, 1.026 mmol) in DCM (4 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, and saturated aqueous NaHCO₃ was added until pH 8. DCM was added and the layers were separated. The aqueous layer was extracted with DCM (x 5). The combined organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (12 g; MeOH / DCM from 0 / 100 to 3 / 97) to afford Intermediate 51( 390 mg, yield: 78 %) as a yellow solid.Intermediate 52(3-α, 4-β, 5-α)

[0235] NaOH (2.5 M in water, 3.22 mL, 8.05 mmol, 10 eq.) was added to a solution of Intermediate 51 (390 mg, 0.80 mmol) in 1,4-dioxane (9 mL). The vial was sealed and the reaction mixture was stirred at 75 °C for 72 h. After cooling, the mixture was diluted with EtOAc (10 mL) and water (10 mL). The organic layer was separated, washed once more with water (20 mL) and brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 52 (210 mg, yield: 68 %) as a pale yellow solid, used without further purification.Intermediate 53, Intermediate 54, and Intermediate 55Intermediate 53 (*R) Intermediate 54 (*S) Intermediate 55

[0236] Step A: methyl 3-chloro-5-((difluoromethyl)thio)benzoate. Sodium 2-chloro-2,2-difluoroacetate (CAS [1895-39-2], 129.6 g, 849.8 mmol, 1.5 eq.) was added to a solution of methyl 3-chloro-5-mercaptobenzoate (CAS [1566273-16-2], 115 g, 566.5 mmol), DMF (1150 mL), and K2CO3 (156 g, 1130.0 mmol, 2 eq.) at room temperature. The resulting mixture was stirred for 0.5 h at 90 °C. After cooling, the reaction mixture was diluted with water (3000 mL). The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layer was washed with water (3 x 1500 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc 2 / 3) to afford methyl 3-chloro-5-((difluoromethyl) thio)benzoate (80 g, yield: 56 %) as a white solid.

[0237] Step B: methyl 3-chloro-5-[(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoate. A mixture of methyl 3-chloro-5-[(difluoromethyl)sulfanyl]benzoate (80 g, 316.63 mmol), 2,2,2-trifluoroethanol (800 mL), PIDA (CAS [3240-34-4], 316.16 g, 981.55 mmol, 3.1 eq.), and ammonium carbamate (61.80 g, 791.57 mmol, 2.5 eq.) was stirred for 2 h at room temperature. The mixture was concentrated under vacuum. The residue was quenched by the addition of water (400 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layer was washed with brine (800 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (petroleum ether / THF 12 / 1) to afford methyl 3-chloro-5-[(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoate (61 g, yield: 66 %) as a yellow oil.

[0238] Step C: 3-chloro-5-[(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoic acid (Intermediate 53). A mixture of methyl 3-chloro-5-[(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoate (63 g, 222.089 mmol), THF (315 mL), water (157 mL), and LiOH·H₂O (18.64 g, 444.178 mmol, 2 eq.) was stirred for 1 h at 0 °C. The resulting mixture was concentrated under vacuum. The residue was acidified to pH 1 with 1 M aqueous HC1. The resulting mixture was extracted with EtOAc (3 x 630 mL). The combined organic layer was washed with brine (630 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford Intermediate 53 (3-chloro-5-[(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoic acid, 47 g, yield: 76 %) as an off-white solid. A sample of Intermediate 53 was purified by chiral SFC (Column: CHIRALPAK IG 5 * 30 cm, 10 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Gradient: isocratic 30 % B) to afford Intermediate 54 and Intermediate 55, both as light yellow solids.Intermediate 56I

[0239] To a mixture of methyl 3-(hydroxymethyl)-5-iodobenzoate (CAS [177734-81-5], 200 g, 685 mmol) in DCM (200 mL) and H2O (1 L) was added KHF2 (214 g, 2.74 mol, 4 eq.). Then, (bromodifluoromethyl)trimethylsilane (CAS [115262-01-6], 278 g, 1.37 mol, 2 eq.) was added at 25 °C. The reaction mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The mixture was poured into water (I L) and DCM (1 L). The organic layer was separated, the aqueous layer was extracted with DCM (1 L x 2), the combined organic layer was washed with brine (1 L), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gel chromatography (400 g SepaFlash®Silica, petroleum ether / EtOAc from 100 / 0 to 80 / 20) to give Intermediate 56 (176 g, yield: 71 %) as a white solid and starting material (39.0 g, yield: 18 %).Intermediate 57O F

[0240] To a solution of Intermediate 56 (176 g, 515 mmol) in toluene (1.26 L) and acetone (500 mL) was added potassium thioacetate (CAS [10387-40-3], 64.6 g, 566 mmol, 1.1 eq.) and Xantphos (CAS [161265-03-8], 35.7 g, 61.7 mmol, 0.12 eq.), Pd2(dba)s (CAS [51364-51-3], 28.3 g, 30.9 mmol, 0.06 eq.) at 25 °C. The mixture was stirred at 70 °C for 12 h. After cooling, the mixture was poured into water (1.5 L) and EtOAc (1.5 L). The layers were separated, and the aqueous layer was extracted with EtOAc (2 L x 2). The combined organic layer was washed with brine (2 L), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gel chromatography (400 g SepaFlash® Silica, petroleum ether / EtOAc from 100 / 0 to 70 / 30) to afford Intermediate 57 (115 g, yield: 69 %) as a yellow oil.Intermediate 58O FSH

[0241] To a solution of Intermediate 57 (110 g, 379 mmol) in MeOH (2.2 L) was added K2CO3 (105 g, 758 mmol, 2 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (1 L) and DCM (2 L), then KHSO4 (1 M in water) was added dropwise over 10 min with vigorous stirring until the pH reached the value of 2-3. The layers were separated, and the aqueous layer was extracted with DCM (2 x 2 L). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gel chromatography (330 g SepaFlash® Silica, petroleum ether / EtOAc from 100 / 0 to 80 / 20) to give Intermediate 58 (55.8 g, yield: 56 %) as a colourless oil.Intermediate 59S^FF

[0242] This reaction was carried out in 29 batches that were combined for the work-up and purification. To a solution of Intermediate 58 (2 g, 8.06 mmol) in DMF (20 mL) was added sodium 2-chloro-2,2-difluoro-acetate (CAS [1895-39-2], 2.46 g, 16.1 mmol, 2 eq.) at 25 °C, then the mixture was warmed to 95 °C, and K2CO3 (2.24 g, 16.2 mmol, 2.01 eq.) was added. The mixture was stirred at 95 °C for 30 min. The crude reaction mixture was combined with other batches for workup. After cooling, the mixture was poured into water (500 mL) and EtOAc (1 L), the organic layer was separated, the aqueous layer was extracted with EtOAc (500 mL x 2). The combined organic layer was washed with brine (1 L), dried over Na₂SO₄, filtered, and concentrated to dryness under reduce pressure. The residue was purified by flash silica gel chromatography (330 g SepaFlash®Silica, petroleum ether / EtOAc from 100 / 0 to 80 / 20) to afford Intermediate 59 (26.0 g, yield: 37 %) as a colourless oil.Intermediate 60 and Intermediate 61Intermediate 60 (*S)Intermediate 61 (*R)

[0243] To a solution of Intermediate 59 (26.0 g, 87.2 mmol) in MeOH (156 mL) was added ammonium carbamate (CAS [1111-78-0], 23.8 g, 305 mmol, 3.5 eq.) and(di acetoxy iodo)benzene (CAS [3240-34-4], 70.2 g, 218 mmol, 2.5 eq.) at 25 °C. The mixture was stirred at 40 °C for 2 h. After cooling, the mixture was poured into water (500 mL) and EtOAc (500 mL), the organic layer was separated, the aqueous layer was extracted with EtOAc (300 mL x 2), the combined organic layer was washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gelchromatography (120 g SepaFlash®Silica, petroleum ether / EtOAc from 100 / 0 to 70 / 30) followed by SFC (DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 urn), [CO2-EtOH (0.1 % NH₃H₂O)]) to afford Intermediate 60 (8.90 g, yield: 29 %) and Intermediate 61 (9.70 g, yield: 32 %), both as yellow oils.Intermediate 62°x, NH.. S' / (*S)

[0244] To a solution of Intermediate 60 (8.90 g, 27.0 mmol) in MeOH (50 mL), THF (50 mL), and H2O (50 mL) was added LiOH·H₂O (2.27 g, 54.1 mmol, 2 eq.) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and DCM (200 mL x 2). The aqueous phase was acidified with KHSO4 (1 N in water) to pH = 2. The aqueous layer was extracted with DCM (300 mL x 2), the combined organic layer was washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was triturated with petroleum ether (50 mL) at 25 °C for 1 h. The solid was filtered to give Intermediate 62 (7.70 g, yield: 89 %) as an off-white solid.Intermediate 63(*R)

[0245] Intermediate 63 was prepared following the same procedure as Intermediate 62, starting from Intermediate 61 instead of Intermediate 60.

[0246] The procedures for the synthesis of intermediates described below are representative examples of methods used for the preparation of Compounds that are not described in full details elsewhere in this document.Intermediate 64

[0247] [l,l'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (CAS [95464-05-4], 0.079 g, 0.097 mmol, 0.1 eq.) was added to a suspension of chloro-6-(2,6-dimethyl-4-pyridinyl)pyrazine (CAS [2283748-94-5], 213 mg, 0.97 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 0.295 g, 1.164 mmol, 1.2 eq.), and KOAc (0.285 g, 2.909 mmol, 3 eq.) in dry 1,4-dioxane (10 mL). The mixture was degassed with nitrogen for 5 min then the vial was sealed. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried on Na2SO4, filtered, and evaporated to give Intermediate 64 (433 mg, impure, assumed quantitative) as a black solid, used directly in the next step.Intermediate 65OH(CIS)

[0248] [l,r-Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (CAS [95464-05-4], 153 mg, 0.187 mmol, 0.1 eq.) was added to a suspension of rel-(2R,6S)-4-(6-bromo-2-pyrazinyl)-2,6-dimethylmorpholine (CAS [2850376-50-8], 598 mg, 1.868 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 569 mg, 2.241 mmol, 1.2 eq.), and KOAc (550 mg, 5.603 mmol, 3 eq.) in dry 1,4-dioxane (10 mL). The mixture was degassed with nitrogen for 5 min then the vial was sealed. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried on Na2SO4, filtered, and evaporated to give Intermediate 65 (1096 mg, 42 % pure, quantitative) as a black solid, used without further purification.Intermediate 66FF—

[0249] Difluoromethanesulfonyl chloride (CAS [1512-30-7], 225 pL, 2.41 mmol, 1.5 eq.) was added to a solution of ethyl lH-pyrrolo[3,2-b]pyridine-6-carboxylate (CAS [1261885-66-8], 300 mg, 1.58 mmol) and 1 -methylimidazole (CAS [616-47-7], 200 pL, 2.48 mmol, 1.6 eq.) in dry DCM (8 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous Na2CO3 (1 M, 1 mL) and extracted with DCM (3 x 15 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (12 g SiCh; EtOAc / heptane from 0 / 100 to 15 / 85) to yield Intermediate 66 (330 mg, yield: 67 %) as a white solid.Intermediate 67

[0250] Palladium hydroxide (400 mg, 0.57 mmol, 0.4 eq.) was added to solution of Intermediate 66 (430 mg, 1.41 mmol) in MeOH (14 mL) under nitrogen atmosphere at 0 °C. The reaction mixture was evacuated and placed under hydrogen atmosphere, then was stirred under hydrogen atmosphere (1 atm) for 18 h at room temperature. The mixture was filtered through a pad of celite that was further washed with MeOH (3 x 50 mL). The filtrate was evaporated to afford Intermediate 67 (155 mg, yield: 35 %) as a white solid.Intermediate 68

[0251] NaOH (1 M in water, 1 mL, 1 mmol, 2 eq.) was added to a solution of Intermediate 67 (150 mg, 0.49 mmol) in MeOH (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated, and the residue wasdissolved in water (10 mL). KHSO4 (1 M in water) was added until pH 3-4, and the mixture was extracted with DCM (10 mL x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated to give Intermediate 68 (80 mg, yield: 58 %) as a white solid.Intermediate 69Br

[0252] To a solution of methyl 3-bromo-5-(methylsulfonyl)benzoate (CAS [154117-77-8], 100 g, 340 mmol) and ethyl trifluoroacetate (242 g, 1.70 mol, 234 mL, 5 eq.) in THF (1 L) was added LiHMDS (1 M in THF, 511 mL, 1.5 eq.) at -65 °C. The mixture was stirred at -65 °C for 1 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO3 (500 mL) at 0-5 °C. The mixture was diluted with EtOAc (1 L). The layers were separated, and the aqueous layer was extracted again with EtOAc (600 mL x 3). The combined organic layer was washed with brine (400 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give Intermediate 69 (140 g, yield: 82 %), used without further purification.Intermediate 70Br

[0253] To a solution of Intermediate 69 (120 g, 240 mmol) in ACN (1200 mL) was added Selectfluor (CAS [140681-55-6], 340 g, 960 mmol, 4 eq.) at 0-5 °C. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (1000 mL), then the mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give Intermediate 70 (140 g, quantitative) as a yellow oil, used without further purification.Intermediate 71Br7p°"F^ '°F

[0254] To a solution of Intermediate 70 (130 g, 190 mmol, 1 eq.) in water (400 mL) and THF (800 mL) was added DIPEA (89.3 mL, 513 mmol, 2.7 eq.) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with EtOAc (1000 mL), washed with brine (300 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (330 g SepaFlash® Silica Flash Column; EtOAc / petroleum ether from 0 / 100 to 20 / 80). The combined desired fractions were evaporated and the residue was triturated with MBTE (200 mL) at 20 °C for 12 h. The solid was filtered and dried to give Intermediate 71 (47.0 g, yield: 35 %) as a white solid.Intermediate 72

[0255] A mixture of Intermediate 71 (494 mg, 1.494 mmol, 1.46 eq.), 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl 2-(difluoromethoxy)acetate (CAS [2248358-15-6], 278 mg, 1.025 mmol), Nickel(II) chloride hexahydrate (CAS [7791-20-0], 49 mg, 0.205 mmol, 0.2 eq.), and 2,2'-bipyridine (CAS [366-18-7], 32 mg, 0.205 mmol, 0.2 eq.) in dry NMP (8 mL) was stirred until full dissolution. Then, silver nitrate (CAS [7761-88-8], 87 mg, 0.513 mmol, 0.5 eq.) was added. The vial was closed with an ElectraSyn 2.0 vial cap with a magnesium sacrificial anode and a 100 ppi RVC (carbon) cathode (3 mm x 7 mm x 51 mm). The vial was then placed on an IKA ElectraSyn 2.0 stirring plate and electrolysis was performed (12 mA, 1 mmol, 3 F / mol), in the presence of air for 6.5 h. The reaction mixture was poured into water (50 mL) and EtOAc was added. The emulsion was filtered on a pad of dicalite and the layers of the filtrate were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and evaporated.The residue was purified by silica gel chromatography (heptane / EtOAc 100 / 0 to 60 / 40) followed by preparative HPLC (RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm; 0.25 % NH4HCO3solution in water, ACN) to yield Intermediate 72 (58 mg, yield: 17 %) as a white solid.Intermediate 73

[0256] LiOH (21 mg, 0.878 mmol, 5 eq.) was added to a solution of Intermediate 72 (58 mg, 0.176 mmol) in THF: MeOH: Water (1:1:1, 3 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and was acidified to pH=l with HC1 (1 M in water). The mixture was extracted 3 times with EtOAc. The combined organic layer was dried over MgSO4, filtered, and evaporated, yielding Intermediate 73 (52 mg, yield: 94 %) as a white solid, used without further purification.Intermediate 74N

[0257] N, N-Diisopropylethylamine (1922 pL, 11.035 mmol, 3 eq.) was added to a solution of 2-bromo-6-fluoropyrazine (CAS [1209458-12-7], 651 mg, 3.678 mmol) and 6-methyl-2-azaspiro[3.3]heptan-6-ol (CAS [1638920-25-8], methanesulfonate salt, 821 mg, 3.678 mmol, 1 eq.) in dry DMSO (10 mL) and the reaction mixture was stirred at 50 °C for 1.5 h. The reaction mixture was diluted with DCM / MeOH 9 / 1 and water. The layers were separated, and the aqueous layer was extracted again with DCM / MeOH 9 / 1. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: AcOEt / EtOH 3 / 1:heptane from 0:100 to 20:80) to give Intermediate 74 (487 mg, 68 % pure, yield: 32 %) as a yellow solid.Intermediate 75

[0258] A solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 10.04 g, 35.62 mmol), cis-2,6-dimethylmorpholine (CAS [6485-55-8], 4.83 mL, 39.182 mmol, 1.1 eq.), and Et₃N (14.85 mL, 106.86 mmol, 3 eq.) in dry toluene (50 mL) was stirred at reflux for 2 h. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluent: heptane: EtOH / EtO Ac 1 / 3 from 100:0 to 50:50) to give Intermediate 75 (10.18 g, yield: 90 %) as a bright orange solid.Intermediate 76(CIS)

[0259] Tetramethylammonium fluoride (CAS [373-68-2], 2210 mg, 23.722 mmol, 1.5 eq.) was added to a solution of Intermediate 75 (5 g, 15.815 mmol) in dry DMF (80 mL) in a thick-walled tube. The tube was sealed, and the reaction mixture was stirred at 65 ° C for 3.5 h. The reaction mixture was poured into brine and the mixture was extracted several times with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluent:heptane: EtOH / EtO Ac 1 / 3 from 100:0 to 100:0) to give Intermediate 76 (4.49 g, yield: 92 %) as a white solid.Intermediate 77

[0260] Methanesulfonyl chloride (2.1 mL, 27.281 mmol, 1.2 eq.) was added to a solution of methyl 3-(hydroxymethyl)-5-iodobenzoate (CAS [177734-81-5], 6.64 g, 22.734 mmol) and triethylamine (6.3 mL, 45.200 mmol, 2 eq.) in DCM (100 mL) at 0 °C. The solution was then stirred at room temperature for 3 h. The mixture was diluted with water (600 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layer was washed with brine (2 x 40 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (80 g SiCh; EtOAc / heptane from 0 / 100 to 30 / 70) to afford Intermediate 77 (4.98 g, yield: 59 %) as a colourless sticky solid.Intermediate 78

[0261] Cyclopropanol (1.04 mL, 16.128 mmol, 1.2 eq.) was added dropwise to a suspension of sodium hydride (60 % in mineral oil, 618 mg, 16.137 mmol, 1.2 eq.) in dry DMF (30 mL) at 0 °C. The resulting white suspension was stirred for 30 min at 0 °C. A solution of Intermediate 77 (4.98 g, 13.454 mmol) in DMF (50 mL) was added dropwise to the stirring suspension, giving a yellow homogeneous mixture which was stirred for 2 h at 60 °C. The mixture was diluted with saturated aqueous NaHCO₃ (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (40 g SiO₂; EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 78 (535 mg, yield: 12 %) as a colorless oil.Intermediate 79

[0262] A mixture of Intermediate 78 (1.4 g, 4.215 mmol), potassium thioacetate (0.530 g, 4.636 mmol, 1.1 eq.) in acetone (4 mL) and toluene (8 mL) was sparged with nitrogen for 5 min before adding Pd2dba3 (CAS [51364-51-3], 0.233 g, 0.254 mmol, 0.06 eq.) and Xantphos (CAS [161265-03-8], 0.297 g, 0.512 mmol, 0.1 eq.). The vial was sealed, and the reaction mixture was stirred at 70 °C for 16 h. After cooling, the mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layer was dried (MgSO₄), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (12 g silica; EtOAc / heptane from 0 / 100 to 20 / 80) to yield Intermediate 79 (786 mg, yield: 66 %) as an oil.Intermediate 80

[0263] Potassium carbonate (0.776 g, 5.611 mmol, 2 eq.) was added to a solution of Intermediate 79 (0.786 g, 1.34 mmol) in MeOH (10 mL) at room temperature. The solution was stirred at room temperature for 2h. The reaction mixture was diluted with water (15 mL) and DCM (10 mL), then KHSO4 (1 M in water) was added dropwise over 10 min with vigorous stirring until the pH reached the value of 2-3. The mixture was extracted with DCM (3 x 20 mL). The combined organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g SiCh; EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 80 (446 mg, yield: 66 %) as a colourless oil.Intermediate 81A

[0264] A solution of Intermediate 80 (0.446 g, 1.872 mmol) in anhydrous DMF (6 mL) was treated with potassium carbonate (0.516 g, 3.735 mmol, 2 eq.) and sodium 2-chloro-2,2-difluoroacetate (CAS [1895-39-2], 0.558 g, 3.657 mmol, 2 eq.). The reaction mixture was stirred at 95 °C for 50 min. After cooling, the mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography (12 g silica; EtOAc / heptane from 0 / 100 to 60 / 40) to yield Intermediate 81 (300 mg, yield: 55 %) as a colourless oil.Intermediate 82A

[0265] Ruthenium(III) chloride hydrate (4.24 mg, 0.016 mmol, 0.076 eq.) was added to a solution of Intermediate 81 (68 mg, 0.212 mmol) and sodium periodate (181 mg, 0.847 mmol, 4 eq.) in DCM (6 mL), ACN (6 mL), and water (12 mL). The mixture was stirred at room temperature for 1 h. The mixture was then diluted with water (20 mL) and extracted with EtOAc (3 x 20mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g SiO₂; EtOAc / heptane from 0 / 100 to 50 / 50) to afford Intermediate 82 (43 mg, yield: 63 %) as a yellow solid.Intermediate 83

[0266] A mixture of Intermediate 82 (125 mg, 0.35 mmol) and NaOH (2.5 M aqueous solution, 0.84 mL, 2.1 mmol, 6 eq.) in MeOH (3 mL) was stirred for 16 h at room temperature. The reaction mixture was diluted with EtOAc (20 mL) and water (10 mL) and the layers were separated. The aqueous layer was acidified to pH 4 using HC1 (1 M in water) and extracted with EtOAc (5 x 20 mL). The combined extract was dried over MgSO4, filtered, and concentrated in vacuo to give Intermediate 83 (118 mg, yield: 99 %) as a colourless oil.Intermediate 84OH OCl

[0267] Step A: methyl 3-chloro-5-(2-hydroxypropan-2-yl)benzoate. Under nitrogen atmosphere, 3-chloro-5-iodobenzoic acid methyl ester (CAS [289039-85-6], 500 mg, 1.686 mmol) was dissolved in dry THF (5 mL) and the reaction mixture was cooled to -50 °C and stirred for 10 min. i-PrMgCl (2 M in THF, 1.212 mL, 2.425 mmol, 1.44 eq.) was added dropwise and the reaction mixture was stirred at -50 °C for 2 h. After cooling to -78 °C, a solution of acetone (250 pL, 3.373 mmol, 2 eq.) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for 1 h. The solvent was removed under vacuum, DCM was added, and the reaction mixture was washed with saturated aqueous NaHCO3. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography (silica; EtOAc in heptane 0 / 100 to 30 / 70) to yield impure title compound (350 mg, 25 % pure, yield: 23 %) as a colorless oil, used without further purification.

[0268] Step B: 3-chloro-5-(2-hydroxypropan-2-yl)benzoic acid. NaOH (1 M in water, 765 pL, 0.765 mmol, 2 eq.) was added to solution of methyl 3-chloro-5-(2-hydroxypropan-2-yl)benzoate (25 % pure, 350 mg, 0.383 mmol) in MeOH (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was dilutedwith water and aqueous KHSO4 (1 M) was added dropwise over 10 min with vigorous stirring. The pH reached 2-3. EtOAc was added and the mixture was stirred for 2 min. The layers were separated and the organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g SiO2, DCM: Methanol (9:1) in DCM, 0 / 100 to 40 / 60) to yield Intermediate 84 (80 mg, yield: 96 %) as a white solid.Intermediate 85

[0269] tert-Butyl 3-[(5-bromo-2-pyridyl)oxy]azetidine-l-carboxylate (CAS [1335049-06-3], 821 mg, 2.494 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 915 mg, 3.605 mmol, 1.4 eq.), Pd(dppf)C12. CH2C12 (CAS [95464-05-4], 102 mg, 0.124 mmol, 0.05 eq.), and potassium acetate (763 mg, 7.773 mmol, 3 eq., previously dried at 100 °C) were added to 1,4-dioxane (15 mL) under nitrogen atmosphere. The vial was sealed, and the reaction mixture was stirred at 90 °C for 2.5 h. The mixture was diluted with Na2CO3 (1 M in water) and extracted twice with EtOAc. The combined organics layer was dried over MgSO4, filtered, and the solvents were evaporated under vacuo. The residue was purified by flash column chromatography ( silica gel 80 g; EtOAc / heptane from 0 / 100 to 50 / 50) to give Intermediate 85 (452 mg, yield: 47 %) as an orange solid.Intermediate 86F

[0270] Step A: methyl 3-fluoro-5-((3,3,3-trifluoro-2-oxopropyl)sulfonyl)benzoate. A solution of methyl 3-fluoro-5-(methylsulfonyl)benzoate (CAS [2113829-39-1], 791 mg, 3.406 mmol) and 2,2,2-trifluoroethyl trifluoroacetate (CAS [407-38-5], 0.988 mL, 7.375 mmol, 2.2 eq.) in dry THF (30 mL) was cooled to -78 °C under nitrogen atmosphere and treated dropwise with LiHMDS (CAS [4039-32-1], 1 M in THF, 5.1 mL, 5.079 mmol, 1.5 eq.). After 5 min, the reaction mixture was allowed to warm to room temperature and was stirred for 30 min. The reaction was quenched with saturated aqueous NaHCO3 and the mixture wasextracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to afford the title compound (1118 mg, quantitative), used without further purification.

[0271] Step B: methyl 3 -fluoro- 5 -((1, 1,3,3, 3-pentafluoro-2-oxopropyl)sulfonyl)benzoate. A solution of methyl 3-fluoro-5-((3,3,3-trifluoro-2-oxopropyl)sulfonyl)benzoate (1118 mg, 3.406 mmol) in dry ACN (21 mL) and cooled to 0 °C. Then, the mixture was treated with l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS [140681-55-6], 3.62 g, 10.219 mmol, 3 eq.) in 3 portions, over the course of 5 min. Upon complete addition, the reaction mixture was stirred at 60 °C for 30 min. The solvent was evaporated and the was suspended in EtOAc and sonicated to obtain a suspension. The solid was filtered and rinsed with EtOAc. The filtrate was concentrated and dried to yield the title compound (1240 mg, quantitative) used without further purification.

[0272] Step C: methyl 3-((difluoromethyl)sulfonyl)-5-fluorobenzoate. DIPEA (1.17 mL, 6.809 mmol, 2 eq.) was added to a solution of methyl 3-fluoro-5-((l, 1,3,3, 3-pentafluoro-2-oxopropyl)sulfonyl)benzoate (1240 mg, 3.405 mmol) in THF (21 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated. The crude product was purified via flash column chromatography (25 g SiO2, EtOAc / heptane 0 / 100 to 30 / 70) to afford the title compound (729 mg, yield: 80 %) as a white solid.

[0273] Step D: 3-((difluoromethyl)sulfonyl)-5-fluorobenzoic acid. LiOH (98 mg, 4.077 mmol, 1.5 eq.) was added to a solution of methyl 3-((difluoromethyl)sulfonyl)-5-fluorobenzoate (729 mg, 2.718 mmol) in THF (10 mL), MeOH (3 mL), and water (3 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated under reduced pressure. The residue was dissolved in water and this solution was acidified to pH=2-3 using HC1 (1 M in water). The formed precipitate was filtered and dried under vacuum to afford Intermediate 86 (558 mg, yield 81 %) as a white solid.Intermediate 87

[0274] To a solution of 4-methyl-3-(methylthio)benzoic acid (CAS 166811-59-2, 150 mg, 0.82 mmol) in MeOH / H₂O (8 mL / 4 mL) was added NaICk (177 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to room temperature, diluted with H₂O (10 mL), and extracted with EtOAc (10 mL x 2). The organic layer was dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to give Intermediate 87 (127 mg, yield: 71 %).Intermediate 88

[0275] DIPEA (2.08 mL, 12.05 mmol, 4 eq.) was added to a solution of 2,6-dichloro-3-fluoropyridine (CAS [52208-50-1], 500 mg, 3.012 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (CAS [674792-08-6], 671 mg, 3.163 mmol, 1.05 eq.) in DMSO (5 mL) at room temperature. The reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was poured into water. The mixture was extracted with EtOAc and the organic layer was washed with brine (3 x), dried (MgSO₄), filtered, and concentrated. The residue was purified by column chromatography (40g silica, EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 88 (830 mg, yield: 81 %) as an oil.Intermediate 89

[0276] Intermediate 88 (140 mg, 0.409 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 127 mg, 0.49 mmol, 1.2 eq.), potassium acetate (121 mg, 1.226 mmol, 3 eq.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS [72287-26-4], 30 mg, 0.041 mmol, 0.1 eq.) were placed in a vial and it was evacuated and backfilled with nitrogen (5 x). Anhydrous 1,4-dioxane (1.4 mL) was added, followed by 5 evacuation / refill cycles. The reaction mixture was stirred at 90 °C for 2 h. The mixture was diluted with anhydrous DMF (0.5 mL) to give Intermediate 89 as a dark brown solution, used directly without further purification.Intermediate 90

[0277] Cs2CO3(3.31 g, 10.157 mmol, 1.3 eq.) was added to a mixture of 5-bromo-3-fluoro-2-pyridinone (CAS [156772-63-3], 1.5 g, 7.813 mmol) and N-Boc-3 -iodoazetidine (CAS [254454-54-1], 1.9 mL, 10.157 mmol, 1.3 eq.) in DMF (25 mL). The mixture was stirred at 60 °C for 24 h. The mixture was then diluted with water and EtOAc and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated under vacuo. The residue was purified by flash column chromatography (40 g SiO2; EtOAc / heptane 0 / 100 to 100 / 0) to yield Intermediate 90 (2492 mg, yield: 82 % ) as a white solid.Intermediate 91

[0278] Intermediate 90 (2.492 g, 7.178 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 2.370 g, 9.331 mmol, 1.3 eq.), Pd(dppf)Cl2. CH2Cl2(CAS [95464-05-4], 292 mg, 0.358 mmol, 0.05 eq.), and potassium acetate (2.193 g, 22.340 mmol, 3.1 eq., previously dried at 100 °C) were dissolved in 1,4-dioxane (15 mL) under nitrogen atmosphere. The reaction vessel was closed tight (screw cap) and the reaction mixture was stirred at 90 °C for 3 h. The mixture was quenched with 1 M aqueous Na2CO3 and was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica gel 25 g; EtOAc / heptane from 0 / 100 to 50 / 50) to give Intermediate 91 as a white solid (624 mg, yield: 21 %).of final compoundsCompound 5Method A (includes the steps leading to Compound 5)(R), (CIS)

[0279] 1-Propanephosphonic anhydride (50 % in EtOAc, CAS [68957-94-8], 92 µL, 0.154 mmol, 1.3 eq.) was added to a suspension of Intermediate 4 (HC1 salt, 76 % pure, 68 mg, 0.119 mmol) and 2,3-dihydro-1-(methylsulfonyl)-1-indole-6-carboxylic acid (CAS [1566993-05-2], 32 mg, 0.131 mmol, 1.1 eq.) in dry DCM (3 mL) at room temperature. Et3N (83 µL, 0.593 mmol, 5 eq.) was then added dropwise to the orange suspension. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane:EtOH / EtOAc 1 / 3 from 100:0 to 0:100), followed by preparative HPLC (RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm, 0.25 % NH4HCO3solution in water, CH3CN) to give Compound 5 (22 mg, yield: 32 %) as a white solid, dried under vacuum at 50 °C.Compound 589Method B (includes the steps leading to Compound 589)(CIS)

[0280] Step 1: Cis-2,6-dimethylmorpholine (0.6 mmol, 100 µL) and DIPEA (138 µL, 0.8 mmol) were added to Intermediate 6 (800 pL of a 0.25 M stock solution in DMSO (0.2 mmol)). The reaction mixture was heated to 120 °C overnight. Upon cooling, the reaction mixture was diluted with 0.1 M aqueous citric acid and extracted with EtOAc. The organiclayer was concentrated to give tert-butyl ((6-(6-((CIS)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)methyl)carbamate.

[0281] Step 2: The product from step 1 was dissolved in DCM (1 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was re-dissolved in toluene (0.5 mL), and stirred for 10 min, followed by a second evaporation to give (6-(6-((CIS)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)methanamine (TFA salt).

[0282] Step 3: DIPEA (950 µL of a 0.8 M solution in DMF (0.76 mmol)) was added to the crude product from step 2 and the mixture was stirred for 10 min at room temperature, before addition of 3-chloro-5-[(difluoromethyl)sulfonyl]-benzoic acid (CAS [2592405-50-8], 950 µL of a 0.25 M solution in DMF). Finally, HATU (CAS [148893-10-1], 85 mg, 0.22 mmol) was added and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum and the residue was purified by preparative HPLC (RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm; 0.25 % NH4HCO3solution in water, ACN) to give Compound 589 (7 mg, yield: 5 %).Compound 1Method C (includes the steps leading to Compound 1)O NNHill(3-a, 4-P, 5-a)

[0283] (3a,4p,5a)-3,5-Dimethyl-4-piperidinol (CAS [374067-78-4], 75 mg, 0.454 mmol, 1.2 eq.) was added to a solution of Intermediate 8 (170 mg, 0.378 mmol) and DIPEA (187 µL, 1.135 mmol, 3 eq.) in dry DMSO (1.5 mL). The mixture was stirred at 130 °C for 16 h. More (3a,4p,5a)-3,5-dimethyl-4-piperidinol (19 mg, 0.113 mmol, 0.3 eq.) was added and the mixture was stirred at 130 °C for 16 h. Again, more (3a,4p,5a)-3,5-dimethyl-4-piperidinol (24 mg, 0.189 mmol, 0.5 eq.) was added and the mixture was stirred at 130 °C for 48 h. The mixture was diluted with EtOAc and water. The organic layer was separated, washed with brine (x 2), dried over MgSO4, filtered, and concentrated in vacuo. The residuewas purified by flash column chromatography (silica 25 g; MeOH / DCM from 0 / 100 to 2 / 98) to yield Compound 1 (104 mg, yield: 48 %) as a white solid.Compound 20Method D (includes the steps leading to Compound 20)o=s=o(CIS)

[0284] 4-Fluoro-3-(methylsulfonyl)benzoic acid ([CAS 158608-00-5], 109 mg; 0.5 mmol, 1.1 eq.) was added to a stirred solution of Intermediate 13 (200 mg; 0.45 mmol), HATU (CAS [148893-10-1], 260 mg; 0.68 mmol, 1.5 eq.), and DIPEA (0.64 mL, 3.6 mmol, 8 eq.) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water, extracted with EtOAc and washed with brine (x 2). The organic layer was dried on MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (silica 24 g; MeOH / DCM from 0 / 100 to 10 / 90), followed by preparative HPLC (Phenomenex Gemini; I. D. (mm) 100 x 21.2; from 59 % of H2O (25 mM NH4HCO3) - 41 % ACN: MeOH 1: 1 to 17 % of H2O (25 mM NH4HCO3) - 83 % ACN: MeOH 1: 1) to yield Compound 20 (75 mg, yield: 29 %) as a white solid.Compound 26Method E (includes the steps leading to Compound 26)(CIS)

[0285] Intermediate 18 (50 mg, 0.107 mmol) and CIS-2, 6-dimethylmorpholine (CAS [6485-55-8], 62 mg, 0.534 mmol, 5 eq.) were suspended in DMSO (0.5 mL) and DIPEA (92pL, 0.53 mmol, 5 eq.) was added. The reaction mixture was stirred at 120 °C overnight. The reaction mixture was directly purified by preparative HPLC (RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm; 0.25 % NH4HCO3solution in water, ACN) to yield Compound 26 (36 mg, yield: 61 %) as a beige solid.Compound 22Method F (includes the steps leading to Compound 22)(CIS)

[0286] 3-(Methylsulfonyl)benzoic acid (CAS [5345-27-7], 110 mg; 0.55 mmol, 1.1 eq.) was added to a stirred solution of Intermediate 20 (211 mg; 0.5 mmol), HATU (CAS [148893-10-1] (285 mg; 0.75 mmol, 1.5 eq.), and DIPEA (0.7 mL, 4 mmol, 8 eq.) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (x 2), filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (silica 24 g; MeOH / DCM from 0 / 100 to 10 / 90) to yield Compound 22 (149 mg, yield: 55 %) as a white solid.Compound 32Method G (includes the steps leading to Compound 32)o=s=o

[0287] HATU (CAS [148893-10-1], 3.7 g, 9.734 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 22 (2 g, 6.489 mmol), 4-methyl-3-(methylsulfonyl)benzoic acid (CAS [51522-22-6], 1529 mg, 7.138 mmol, 1.1 eq.) and DIPEA (5.6 mL, 32.445 mmol, 5 eq.) in DMF (100 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with aqueous Na2CO3(1 M), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC(RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm, 0.25 % NH4HCO3solution in water, ACN) to yield Compound 32 (1.211 g, yield: 43 %).Compound 771Method H (includes the steps leading to Compound 771)Cl

[0288] Propylphosphonic anhydride solution (CAS [68957-94-8], 50 % in EtOAc, 0.271 mL, 0.456 mmol, 2.5 eq.) was added to a mixture of Intermediate 26 (59 mg, 0.18 mmol), 3-chloro-5-[(difluoromethyl)sulfonyl]-benzoic acid (CAS [2592405-50-8], 73 mg, 0.27 mmol, 1.5 eq.), and DIPEA (209 µL, 1.265 mmol, 7 eq.) in DCM (3.4 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (2 x 25 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (12 g silica gel, DCM / MeOH (9 / 1 v:v) in DCM from 0 % to 100 %), followed by preparative reverse phase HPLC (59 % [0.1 % HCOOH] - 41 % [ACN: MeOH 1:1] to 17 % [0.1 % HCOOH] - 83 % [ACN: MeOH 1:1]) to yield Compound 771 (44 mg, yield: 42 %) as a white solid.Compound 72Method I (includes the steps leading to Compound 72)

[0289] A stock solution of Intermediate 29 (51 mg, 0.1 mmol), Et3N (42 µL, 0.3 mmol, 3 eq.) in 1,4-dioxane (330 pL) and water (330 pL) was added to 3-bromo-1-methyl-1-pyrazole (CAS [151049-87-5], 32 mg, 0.2 mmol, 2 eq.), followed by a stock solution of cataCXium Pd G4 (CAS [2230788-67-5], 7 mg, 0.01 mmol, 0.1 eq.) in 1,4-dioxane (330 pL) under nitrogen atmosphere. The reaction vessel was sealed and the mixture was stirred at 90 °C for 16 h. After cooling, the solvent was evaporated under reduced pressure and the residuewas purified by preparative HPLC (RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm; 0.25 % NH4HCO3solution in water, ACN) to give Compound 72 (12 mg, yield: 24 %).Compound 579Method J (includes the steps leading to Compound 579)(*S)

[0290] HATU (CAS [148893-10-1], 126 mg, 0.33 mmol, 1.3 eq.) was added in one portion to a solution of Intermediate 32 (86 mg, 0.26 mmol) and Intermediate 35 (81 mg, 0.26 mmol, 1 eq.) in DMF (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCO3and extracted with DCM (x 3). The combined organic layer was dried (MgSO₄), filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (20 g SiCh; DCM: MeOH (9: 1) in DCM from 0 % to 30 %) and the solid obtained was triturated with ACN (x 2), filtered, and washed with diethyl ether to yield Compound 579 (48 mg, yield: 33 %) as a white solid.Compound 673Method K (includes the steps leading to Compound 673)(*R)

[0291] HATU (CAS [148893-10-1], 84 mg, 0.221 mmol, 1.2 eq.) was added slowly to a solution of Intermediate 38 (45 mg, 0.184 mmol), Intermediate 34 (48 mg, 0.202 mmol, 1.1 eq.) and DIPEA (0.048 mL, 0.276 mmol, 1.5 eq.) in DMF (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (x 3). The combined organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by flashcolumn chromatography (silica 20 g; EtOAc / heptane from 0 / 100 to 60 / 40) to yield Compound 673 (34 mg, yield: 39 %) as a yellow solid.Compound 677Method L (includes the steps leading to Compound 677)

[0292] Compound 672 (310 mg, 0.48 mmol), 1,3-dihydro-1,3-dioxo-2-isoindol-2-yl tetrahydro-2-pyran-4-carboxylate (CAS [1872262-74-2], 159 mg, 0.576 mmol, 1.2 eq.), 2,2'-bipyridine (CAS [366-18-7], 15 mg, 0.096 mmol, 0.2 eq.), nickel(II) chloride hexahydrate (CAS [7791-20-0], 23 mg, 0.096 mmol, 0.2 eq.), andNMP (3 mL) were introduced in a 5 mL ElectraSyn vial to give a blue-green solution. Silver nitrate (CAS [7761-88-8], 41 mg, 0.24 mmol, 0.5 eq.) was added and the cap, equipped with Mg (+) and RVC (-) electrodes, was quickly put on. A constant current of 12 mA was passed through the solution until 4 F / mol had been delivered. The reaction mixture was filtered through a plug of celite and the residue was diluted with EtOAc and aqueous NaHCO₃. The layers were separated and the aqueous layer was extracted with EtOAc and DCM. The combined organic layer was washed with LiCl (10 % in water), then brine, dried over Na₂SO₄, and filtered through a pad of silica-based metal scavenger. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC (19 x 100 mm C18 column, eluting with 10 to 90 % ACN / H2O + 0.1 % NH3) to afford Compound 677 (175 mg, yield: 48 %).Compound 560Method M (includes the steps leading to Compound 560)(CIS)The following solutions were prepared and degassed for 15 min with nitrogen: Compound 418 (2.04 g) in 1,4-dioxane (14.4 mL) (Solution 1), RockPhos Pd G3 (CAS [2009020-38-4], 241 mg) in 1,4-dioxane (7.2 mL) (Solution 2), and potassium phosphate tribasic (2.44 g) in 1,4-dioxane (7.2 mL) (Solution 3). Solution 1 (0.5 mL, 0.1 mmol), Solution 2 (0.25 mL, 0.01 mmol) and Solution 3 (0.25 mL, 0.4 mmol) were introduced in a 1-dram vial containing 3-amino-2-methoxy-l -propanol (CAS [858834-75-0], 0.2 mmol). The reaction mixture was stirred at 85 °C for 16 h. Silicycle DMT-S (20 mg) was added to the reaction mixture and it was stirred for 2 h, filtered, and concentrated under vacuum. The residue was purified by reverse phase HPLC (RP XBridge Prep C18 OBD – 10 µm, 30 x 150 mm; 0.1 % NH4HCO3solution in water + 5 % CH3CN, CH3CN) followed by preparative SFC (Torus Diol 30 x 150 mm; CO2, MeOH + 20 mM NH4OH) to give Compound 560 (2 mg, yield: 3 %).Compound 562Method N (includes the steps leading to Compound 562)(rac), (CIS)

[0293] A solution of Compound 417 (1.72 g) in DMF (14.4 mL) was prepared and degassed for 15 min with nitrogen (solution 1). NaH (60 % dispersion in mineral oil, 0.22 mmol) was added to a solution 1-m ethoxy-3 -(methylamino)-2-propanol (CAS [60755-68-2], 0.2 mmol) in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 30 min. Solution 1 (0.5 mL, 0.1 mmol) was added and the reaction mixture was stirred at 85 °Cfor 16 h. The reaction was quenched with water (1 mL), filtered, and concentrated under vacuum. The residue was purified by reverse phase HPLC (RP XBridge Prep C18 OBD – 10 µm, 30 x 150 mm; 0.1 % NH4HCO3solution in water + 5 % CH3CN, CH3CN) to give Compound 562 (13 mg, yield: 20 %).Compound 338Method O (includes the steps leading to Compound 338)o os9Os zo O N5 Uh

[0294] This experiment was performed in flow. The alkyl zinc iodide in THF. LiCl was prepared as follows: An Omnifit column (1 cm x 15 cm) was stoppered with cotton wool and filled with granular zinc (10 g, 20-30 mesh). The zinc was activated by flowing a solution of TMSC1 (1 mL) and chlorobromoethane (0.75 mL) in THF (10 mL) at 0.5 mL / min. After activation, 4-iodotetrahydro-2-thiopyran 1,1-dioxide (CAS [858822-85-2], 1040 mg, 4 mmol) was dissolved in LiCl (0.5 M in THF, 8 mL) and flowed through the zinc column at 45 °C, flow rate 0.4 mL / min. The resulting solution was collected under nitrogen and titrated with iodine to reveal tetrahydro-2-thiopyran 1,1-dioxide zinc iodide (8 mL, 0.26 M). The alkyl zinc iodide (2 mL, 0.26 M) was mixed with a solution of Intermediate 39 (50 mg, 0.1 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS [72287-26-4], 7 mg, 0.01 mmol, 0.1 eq.) in DMF (1 mL) through a chip mixer, before entering a 10 mL coil at 100 °C for 20 min residence time. After cooling, the solvent was evaporated and the residue was taken up in DCM. A solution of 1 / 1 20 % aqueous NH4Cl / aqueous ammonia was added, and the organic layer was extracted through a hydrophobic frit. The solvent was evaporated under vacuum and the residue was purified by reverse phase HPLC (RP XBridge Prep C18 OBD - 10 pm, 30 x 150 mm; 0.1 % NH4HCO3 solution in water + 5 % CH3CN, CH3CN) to give Compound 338 (17 mg, yield: 28 %).Compound 374Method P (includes the steps leading to Compound 374)(*S)

[0295] HBTU (CAS [94790-37-1], 308 mg, 0.812 mmol, 1.1 eq.) was added to a stirred solution of Intermediate 41 (288 mg, 0.738 mmol), 3-[(difluoromethyl)sulfonyl]benzoic acid (CAS [4837-21-2], 192 mg, 0.812 mmol, 1.1 eq.), and DIPEA (0.514 mL, 2.952 mmol, 4 eq.) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with aqueous Na2CO3 (1 M). The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g silica, DCM: MeOH (9:1) in DCM from 0 / 100 to 100 / 0), followed by SFC purification (i-Cellulose-C 250 mm x 30 mm 5 pm; isocratic CO2(40 %) -MeOH (60 %) + 0.1% diethylamine) to give the inactive enantiomer of Compound 374 (58 mg, yield: 14 %) and Compound 374 itself (37 mg, yield: 9 %).Compound 727Method Q (includes the steps leading to Compound 727)

[0296] Compound 727 was prepared following the same procedure as Compound 5, using Intermediate 44 instead of Intermediate 4.Compound 783Method R (includes the steps leading to Compound 783)

[0297] 1-Propanephosphonic anhydride (CAS [68957-94-8], 50 % solution in EtOAc, 102 pL, 0.171 mmol, 1.5 eq.) was added to a solution of Intermediate 13 (50 mg, 0.114 mmol), Intermediate 62 (37 mg, 0.117 mmol, 1 eq.), and DIPEA (118 pL, 0.683 mmol, 6 eq.) in DCM (0.6 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and the solution was washed with saturated aqueous NaHCO3, and concentrated under vacuum. The residue was purified by silica gel flash chromatography (heptane / AcOEt: EtOH (3:1) from 100 / 0 to 20 / 80) followed by preparative HPLC (RP XBridge Prep C18 OBD - 10 pm, 30 x 150 mm; 0.25 % NH4HCO3solution in water, CH3CN) to yield Compound 783 (25 mg, yield: 32 %) as a yellow solid.Compound 784Method S (includes the steps leading to Compound 784)Fy

[0298] Propylphosphonic anhydride (CAS [68957-94-8], 50 % in EtOAc, 700 pL, 1.176 mmol, 2.5 eq.) was added to a solution of Intermediate 46 (196 mg, 0.465 mmol), 3-chloro-5-[(difluoromethyl)sulfonyl]-benzoic acid (CAS [2592405-50-8], 140 mg, 0.517 mmol, 1.1 eq.), and DIPEA (500 pL, 2.863 mmol, 6.2 eq.) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with aqueous saturated NaHCO3 and extracted with EtOAc (3 x 10 mL). The organic layer was dried on MgSO4, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica 12 g, EtOAc / heptane from 0 / 100 to 100 / 0) followed by reverse phae HPLC (Phenom enex Gemini C18 30 x 100 mm 5 pm; [25 mM NH4HCO3 / CH3CN from 70 / 30 to 27 / 73) to yield Compound 784 (70 mg, yield: 25 %) as a white solid.Compound 733Method T (includes the steps leading to Compound 733)OHQ 0ar<ZI( o=a:(*S), (3-α, 4-β, 5-α)

[0299] A mixture of Intermediate 52 (92 mg, 0.24 mmol), Intermediate 55 (75 mg, 0.28 mmol, 1.1 eq.), and DIPEA (0.16 mL, 0.94 mmol, 3.9 eq.) in DMF (3 mL) was stirred for 5 min at room temperature Propylphosphonic anhydride solution (CAS [68957-94-8], 50 % in EtOAc, 0.21 mL, 0.35 mmol, 1.5 eq.) was added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was dried on MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (12 g;MeOH / DCM from 0 / 100 to 3 / 97) to afford Compound 733 (32 mg, yield: 20 %) as a white solid.

[0300] The compounds in Table la were prepared following a synthetic pathway similar to the method listed in the table.Table la:OCo. Co.R1R3Method R1R3Method No. No.Cl4 C 2 C%% HO *H< N“t>(3-a, 4-f, 5-a) F.)=N8 D / — N3 C %% Q Cl09 B %■QO C Co.1 3Co. o' R R Method R1R3Method No. No.Q> QH10 ^N B 18 D <ZI Q^ 0=F^fVl a: O- )=N / NN^N11 D 19 D H<5 * 2= / o(3-α, 4-β, 5-α) / 'OHFHfV| F.)=N ’12 D )=N ‘21 / — N D I ) o %(C SF.T^ J ° (CIS)13 / =N ’^N D>— N% 25 D (rac)< (CIS)14 ^N D / — N^S'° 27 B °'s\Cl\ F(CIS)15 ^N D^S'°°'S\ ™-fr> 28 D / 'NHF. (*R)(CIS)16 ^N B%^NF, 29 D / NH(*S)17 / =N D (CIS)^N<yi / >>— N30 D(CIS)a: O C Co.1 3Co.R R Method R1R3Method No. No. / — N 220 0 II \ / =N I 31 D — S=NHOZ< 1zx(rac)(CIS) ^ 0=O'331 B F^F.034 D / VO / %0—6(rac) F.(CIS))=N<)=N^ 342 D y— N36 D F4S^" F HN—F-( "F ° \ (CIS) (rac) (CIS)00O'343 ^~N C 43 B F^ HN—F F A (CIS)<ZX< o= y— N 344 C 45 o' B F^F^ HQF F HO *(3-a, 4-P, 5-a)N 348 B 50 C F^ QFN-o"p\^ > (*R)o^•N52 B 349 B F^° F^ 0.F F oAH0Z(*S) QH / =Ni / — N64 NH D351 B F(*S)_ (CIS) _ °'S\ H<5 *(3-a, 4-P, 5-a)o'O C Co.1 3Co.R R Method R1R3Method No. No.F.)— F0 / — N356 B 417 B <zx% (CIS) ^ 0= (CIS)F. XX XJ? 'L a: t°y— F cn o o o L'0 / — N35 B 418 y^ 8NBx° \(F (CIS) CIS)OH N F. / ^N387 B )— F0 0— '419 B (CIS) 400 NHO'%395 E O\F4S^ (rac-TRANS)F / %< QHZX< o= ^=i?x C398 B 420 7=o B F^ — P=o HNF 1(rac) 0 / (rac) / — N406 BF 421 B (CIS)o —l(CIS)F.408 B / =N |%)=N * (CIS) 424 / ^ND -S^°°'S\X°— \HO> / — N416?ZB_ (CIS) _F— (F(rac)_ (CIS) _o'O C Co.1 3Co.R R Method R1R3Method No. No.\, FFA425 B 470 r'NC <zx F rjFF (CIS) j a: Cl. ooF'FOH F / Me / y— F d I\ Oz'zHO— <427 B 471 C % (CIS)(rac) OHFF" VAFP! / — NH°sy '428 B 473 B F— (F M M% (*R)(CIS) 00 (CIS)F. O')— F0 \ CM0— < / NNH / — N9 474H0 / ,Z '42 > Q B B 0 o— < F— (F M< (2-S),(6-R) (*S)% (CIS)ZXCl < o=\ 0^ CMx1p iNH / — N430 >rC Bo oj— 6 476 B % (2-S),(6-R) F^ 0.F O'"P\(rac)oQHMyj HO— (7— N462 B48 / ^ / _ J 'NH o —I 6NB HOZo —I(CIS) %(*R) (rac) (CIS) o A^A-J463 B 487 B NH M HC> (CIS) (CIS)(*S)x 0^ C )=MN ’NH / — N464 B 489 F. B> C?Z0 o— 6HO / °F M(rac) (2-S),(6-R)(CIS)O C Co.1 3Co. o' R R Method R1R3Method No. No.Q l^N490 B F.y— F <x° \ O zx(CIS) 503 6 o=a: "" d B NH%^N491 B oz\0—6 2-(*S),6-(*R)F (CIS)F.<)=r / >)— FO498 B 504 B Q. dF NHoA(*R) 00O'oz\2-(*R),6-(*S)499 o BF^ 0— <F F. ^N<ZX )— F(*S)<= O oAox 505 B NH500 C %F^ OF \OH 2-(*S),6-(*S)QHE / — N F.)— F )— F0 O502 506 B. d B HNNH% %0oz / \(*R)2-(*R),6-(*R)O C Co.1 3Co. o' R R Method R1R3Method No. No.^=N^F F.)— F )— F0 0 O <0\ zx o— / 507 7=° B 538 ^ 0= 7=° B HN a: HN% %0 / / (*S) 2-(S), 6-(S)^=N^^NCl Clo 0— (X° \508 B 539 7=° B Hl / ” HN% %0 / 00 / (*R) O' 2-(S), 6-(S)QHClCl / ^\N0<0\ o— 509 ZX 7=° B 540 B HN HN^< o=%z XX cnJ xX cP' % / CM / \ c / iOYz X o' O 0X / / (*S) 2-(R), 6-(R)QH>— N F.512 B )— FO. QHN^ 541 B (CIS) HNQH 0y^N / 517 B2-(R), 6-(R)(CIS) ^=N^^NO —Iy^N534 B 543 1 _ / NH 7=° BZHN HO° \(rac)(CIS) 0 / _ 2-(S), 6-(S) _IXZ?\O CCo.1Co. a:R R3Method R1R3Method No. No.HO_ O_J544 B 556 B <H2N o 0— ( zx 0 — ((CIS) \=^N 0= ’a: (CIS) O_J / — N545 ^4 B561HN / ^\O\NM H2N 0 — ((CIS) of(rac) (CIS) QH>— N546 BH2N HO > y^N ^=i?563 11 N (3-a, 4-P, 5-a) 6o ow \ °==00 \O xO' o '—(CIS)_ O_|?— NHN--.X$°547 / _ / NH BZHl / ” 564FHO / ^°NN <xjl 1 / (rac) ZXoxo=f0 — ( < (rac)x / (CIS)2-(R), 6-(R) 1HNJ^565 / ^NN 550 B o — (HO * (rac) (CIS)(3-a, 4-P, 5-a)^=1 / * _O_J 566 N 551 B ipY 0 — (H2N HO » (rac) (CIS)(3-a, 4-P, 5-a)y^NQH 567 N y^N554 dl BoA_ (Ol __ (Ol _' O '<n —, O C Co.1 3Co. Q:R R Method R1R3Method No. No.HF F\N—1 F0=<\ ^=N^ 0. ZX N ^N568 N 576 < B zx(rac) (CIS) F a: (CIS)u'" NH^=N^HCk / ^N^N569 N 578 B FF(rac)(rac) (CIS) (CIS)^=N^^N570 \ ) 0 N 581 B yv— o' \ 0—6 F^ — ^ P=0OF F(rac), (r 00 1ac) (CIS O)' (*S) \ / \HN—\z / — N571 N ^N590 B vN O — / (rac), (racX) <Z (CIS) (CIS)< o=x / , ow—CzZ= \ °^ o / — N572 N 591 B 0—6(CIS) (CIS)•fi, QH ^=N^ / — N,.p573xj jLfN ^No C 592F_c 'NH B F(rac) H(5 »(CIS) (*R) (3-a, 4-P, 5-a) ^=N^ QH ^N574 N593F_^ 'NH B F(CIS) HC) »(*S)(3-a, 4-P, 5-a)575 B\=N ’x° \(CIS)O C Co.1 3Co. o' R R Method R1R3Method No. No.y^NHOz— N 613 s?594 B B <FFZI 0— / He / * (*R^ 0=)(3-α, 4-β, 5-α) a: (CIS)CH HO,,?Zy^N595 B 614FB'>c 'A o— / (*S)(CIS) (CIS)Cl\<?=N^ 1 ^N599 B — 0-1 oHNH615 B F HN ~(*R) (CIS) HO(*R)Cl\ 0 / (*R)600 %; BNH F CC<(*S) (CIS) _ 0-1 II II 1 / 4 0 616 c 'NH ° ~ X B 0 ^ HO7HNX601 B (*S)F4S^ — P=OF / 1(*R) _ (*R) _ QH _ O-|C|617 B 603 B H0ZNH (*R)%\(rac),(rac)°\XzN-vO ^N607 BH(J »(3-α, 4-β, 5-α)Oo c Co.1 3Co. Q:R R Method R1R3Method No. No._^A_J ~X'" °'I iC|< c> Y zx618 e II II V ° \NH B HOz624°x a: B )=°(*S)% HNO / (R)^N619 B625 HN— ( B (CIS) / \(rac)(CIS) / — N620 B^N626 Fx? ' B (CIS)V *X° \(CIS)<621 ZX / ^NBHI4 < O u. < o=A v 1 A V w ° 627 B \ _ / \ / X O O \? o w (CIS)(CIS)o—?Q-i QH622 B F.)— F C?OF (CIS) 628 B (*R) / HN=o0\QH <b / 623 B(R)o —IF^F (CIS)(*S)O C Co.1 3Co. o' R R Method R1R3Method No. No.o / <y_ / >— 1 ^N634 'K^NZ0 B <X zx 0— / 629 B o' \y x zLf o=- F O xi ft A a:LL(CIS)J o(CIS) / — \,0635 < s( B \ — / 'oHO' (CIS)F. (R))— F c o—0 ^=i? ® 630 B6HO>? ' io 36 B HN F— (F% J^ O\ / z00 (xrac)O' OH0 / ° — \ 1(S)Br 641 o=s=o B 631 XT# * y— N< BZXo OH (CIS)—I-S'°< o=°'S\ x (CIS)<)=il642 BCl o 0— < (CIS)a632 Bio QH% HN 643 / ^NB F^X H(5 *0 F / (3-a, 4-P, 5-a)(S)^N644 B / — \,0633 \ s' B\ — ( 'o Hd’ *(3-a, 4-P, 5-a) / HO (CIS)(S)645 c NH X B F(*R) i(CIS)O C Co.1 3Co. o' R R Method R1R3Method No. No.p i-d HO,,. / 657 B 650 I F— ( <F ZI)— F (*S^ 0)=a: OHOH F Cl(CIS) / — NQH 658HOxZ ' BHO>2 F— ( O —ID F651 F— ( o —IF (rac) (CIS)(rac) (CIS) / — N659 B o —I^''OH(*R), (*S) (CIS)652 B / x° \HO 660 B (CIS)(*S), (*R) CT'" X)H< (*S), (*R) (CIS)653 / ^NB / — Nx° \ 661 B HOZ(CIS)(*R), (*S) ''OH HC) »(*R), (*R) (3-α, 4-β, 5-α) QH654 B No —I 663 % B ^>OH(*S), (*S) (CIS) ^*OH HC) *(*S), (*S) (3-α, 4-β, 5-α)655 B664H0V ' B ''OH F— ( o — / (*R), (*R) (CIS) F(*R) (CIS)656H0SC ' BF— (F 665 HO,,? ' / ^NB (*R) F— (OH Fx° \(*S) (CIS)o'O C Co.1 3Co.R R Method R1R3Method No. No.F.666 HO, / ' / — NB 674 < B F— ( zxF / ^ 0=(rac) (CIS) HO a: (CIS)(*S), (*R)F^ / — N667 BF OH 675 / ^NB (rac)(CIS)X° \HO (CIS)(*R), (*S)F\A— <=\668 F OHM. B(rac)(CIS) 678 B 00F r^s. O'f1H<5 *HON669FB (rac), (rac) (3-α, 4-β, 5-α)(rac)x° \ 01(CIS)<ZX 680HOS / ' D < o=F. \ x / ‘ QH F— (= F670 B (*R) (CIS)' NH / o —I Gl(rac) (CIS)681H0''Z ' / ^ND (X F— (FX° \ / — N F671 HO - ( B (*S) (CIS)F F.OH (CIS)(rac)Br 682HO*Z B F— ( / — N F672 B (*R) (CIS)F.F4 F^_ (CIS) _683HO / 'Z ' / ^ND F— ( o —IF(CIS)_ _Co. Co.R1R3Method R1R3Method No. No.QH 0X684 / ^NB691 < / ^NLZHd' *HO a:(*R), (*S) (3-α, 4-β, 5-α) (CIS)FQ3QH HNO=J=O685 B / ^NHtf > 692 L HO'X(3-α, 4-β, 5-α)(TRANS) (CIS)\O F687 / ^NB0 —I 693 L F (CIS)x° \F (CIS)o< / N\688 L<^=NZ>i L 1 p ° 7— NY / ^ni x c / u. 694 L o o fHs<°" (CIS) F4 FS^x° \F (CIS)(rac)° \689 / ^NL<^=NZ>o —I / — N695 L (CIS)F4S^ (CIS)F(rac) / 690 L CNF4S^ (CIS) 696 / ^NLFx° \(CIS)FCo. Co.R1R3Method R1R3Method No. No.QH?— N703 B 697 L <''OH(*R) a:, (*R) (CIS)(CIS) / 0 / — N704 B ^ ''OH0 (*R), (*S) (CIS) 698 L(CIS) / — N705 B F<tyx / HO *HO (3-α, 4-β, 5-α)(*S), (*R)699 / ^NLFXS^x° \ / — NF 706 IX B (CIS)(rac) < '" XJH Hd *(*S), (*R) (3-α, 4-β, 5-α)T ^ ca ru.< z^X~X~"0HNo700 / ^NL 707 Bx° \ / HO »(CIS) HO( (3-α, 4-β, 5-α) F^S"°" *S), (*R)F70701 B / — N708 B ^ X)H 0— 6(*S), (*R) (CIS) (CIS)F TH Cl702 X1B^ O—6 o' \— / 1 / — NXH 709 B (*S), (*S) 'K-S(CI II=OS) NH H<5’ *(rac)(3-α, 4-β, 5-α)Q: O C Co.1 3Co.R R Method R1R3Method No. No.Cl FQ i H0748 rNB760 <zx B F ^ 0=0 a:ClHs'°"F (TRANS) QH F750 r%<NB HF_c 'NH 0F(*R) 0 761 B ClQ is / OHH '°"F (CIS)753 rNB FF^NHF o^s-^ H0(*S) 0 00 QHO'766 B oFQ *° OH755 B F< FZX F.H< o= OH 0Hsx'°"F )=N *F 781 ^N D ofQrQ "°rNF (CIS)758 BF H F.Hs<" o 0°F)=N *782 R o^=N^F_ °"<si 'NH ^759 B F (CIS)(*R)Hs<°" OHFCo.R1R3Method No.F0796 L (CIS)F<

[0301] The compounds in Table lb were prepared following a synthetic pathway similar to the method listed.Table lb:Comp.R1R3MethodID / — N6 ryi A%(CIS)7 A%_ OO _an CO / g {I / II"ZI< o=a:

[0302] The compounds in Table 2 were prepared following a synthetic pathway similar to the method listed.Table 2: I? / 0R’JIN^YYR3Co. No. R1R3Method Co. No. R1R3Method N^VI >=N^^NN^VI>=N” 48 _ / NH F ^N HO23 E(rac) (CIS)(CIS)N^VI >=N^ N^VI 49 ^N F >=N^^N24 EO' N^VI (CIS)^N56N^VI F— (NHFNF>= ^^N41 F (rac) (CIS) / 'NH <zrX° \(r< oa=c) N^VI o' (CIS) >=N^^N59 _ / NH F N^VI>=N^ HOZ-Q^N44 F (*R) (CIS)X° \N^VI (CIS) >=N^ / — N60 c NH F N^VI>=N” HOZy^N46 F (*S) / 'NH (CIS)y(*R)(CIS) N^VI >=N^^N61F_c 'NHN^VI F >=N^ F^N47 F (*R)°C1(CIS) y(*S)(CIS)a: O CCo. No. R1R3Method Co. No. R1R3Method N^X-I N^V|)=N1 / — N62 NH F 70 < E F F^ zxF(*S) (CIS) O' HON^V| N^VI >=N^ >=N *63 F123 EF°< / O F^F HN 8^ / 1N^V| (rac)>=NZ*65 / — M F zy-l )=N5% ANXO127 E HN-Y00z Ov' i F O^N^°H>=N^66 l~- N FF > NX° zvi' H226 E <ZX zvi %< o= 4^> 67 o' oEF4 ^F HO' *(3-α, 4-β, 5-α) 228 F N^VI>=N^ HO68 EF4 ^F >=N^HOZ0H^y-|229 F >=N^ HOZ69 EF4 ^ zvi a2)=N ’F H N F(rac) 230 EF^ HN— (F(rac)O Co'Co. No. R1R3Method Co. No. R1R3Method F.N^VI zy-i >=N” >=N^231 XNNF%< 300 < E / NH O — ( ZIF^ 0=HN" W(*R) (CIS) a:(rac)F. N^VI zvi>=N^232 XNF / 'NH 0 — ( 301O $ E =S=NH(*S) (CIS) F(rac), (rac) N^VI>=Nri^N VI 233 E 302 E F^F jp F^F (rac)oN^V| <yi 303 ^ t E 295 F^0=\ > E< H — F (rac)N (F(S) " N-sO^304 E N^V|F (rac)^N296 E zvi HN— ( )=N!F(R) 305 p E HN. / F %N^VI(rac)298 E ZVI N=SP )=N1F O 306 E (rac) F^—spF S=N1N^VIN^V| >=N^299 EF^ 307 E 0F •6\s-o F 0 'HN(rac), (rac)o'O CCo. No. R1R3Method Co. No. R1R3Method N^VI N^V| ON * )=N1315 ^N E <308 E F zx HO—'O oF c?HN' 0 O' N^VI (rac) ^N318 E ovA HN—N r \ F(CIS)309 <N / — \ E5, noN^VIF 'NH F^ >=N^^^N(rac), (rac) 325 F Z"0=HOS— \ N^O> —Z310 00 EO'F^F >= 326N^EF4 ^ \ / ^NX )=o zvi FZHN^311 < N^V|ZX EFZ< o=°" ON^1F OH 327 E o'(rac)FN^VIN^VI >=N^312 E ^•N328F^OHF^ HOO F F F(rac) HO01N^VI N^VI >=" *313 E >=N^y^NF^ 336 F F — o / 'NHy(*S)N^VI (CIS)314 ECl\ N^F^ OV p N^1IF HO y^N337 F / 'NH y(*R) (CIS)o'O CCo. No. R1R3Method Co. No. R1R3Method N^VI zvi Y^ *340 E 4110"st "l / ^N<F zxo=H\N— ( ) E F ( 4 o= oOH a: ^> C / LCLL X -X A I w(rP'ac)\ _ / o Y d' (S)F. N^VI1zvi Y"345 F|_^NH ° 412o— / r-(NHE F HN— ((CIS) (rac) (R)0 / F N^VI iiHN-S— < y^N YN^353 j / - / ' 0 II V- F ^•NF 422 F 00O'(CIS) HOE F.)— F N^VI N^VI0 YN^1354 F 426 E <ZX o— / < o=% Fx (CIS) OHzy-i)=N1N^VI o / — NH YN^385 —3 II— / E 435 F F^ NHF -Q(rac)(CIS) N^VIY^ * N^Vl386 E )=N1r'NF^ 469 YNE F o—' F / FFj= OHHO \ / ^° N^VI>=N^ zviOHQ >=N^403 F 483 HNXL YNHE FY ^ 'o(rac) HOZF (*R), (rac), (rac)o'O CCo. No. R1R3Method Co. No. R1R3Method HO / — \N^VI484 HNXL >"'s;NHE'o 5490< — \ F F (*S), (rac), (rac) zxf o<=a: (*S) OHN^VIci^) — | OH / — N488 F N^VI rNCo oz559 F (CIS)OHo FN^VI496 F^ 'NH >=N * N^VIH I IF5 2 o o ^N 00 8 F (rac) O' O —I(CIS) 4*J (CIS)Clo N^VI<ZX N^VIF^ < o= 583 F 510 _ 'NH >=N * HxFF (CIS)(*R)(CIS) N^VI584 / ^NF oX° \N^VI511 NH >=N^ (CIS?— N H )FN^VI (*S)9>(CIS) 585 F V'b xHFHO—\z > (CIS)H \ — N \^N513N" ■*)v^ / E N^VIF^ >=N^ F(rac), (rac), (rac) 586 FH(5 *(3-α, 4-β, 5-α)O Co'Co. No. R1R3Method Co. No. R1R3Method N^VI N^VI >=N^y^N / ^587F_< 'NHNo F 639 A, < F ZI F HC)' » ^ 0= Hd' » (*R) a:(3-α, 4-β, 5-α) (3-α, 4-β, 5-α)zvi?— N588 NH F 640 F F Hd' » Hd' * (*S) (3-α, 4-β, 5-α) (3-α, 4-β, 5-α)N^VI598 Fo,"' Oz^ (CIS)O' v<602 EJkl1 O > FN^VI>=N^^N606 FrNCo(CIS)ClN^VI\ >=N”608 F% -Q(CIS)Cl\ N^VI^N638 FF^ Hd' »F(3-α, 4-β, 5-α)

[0303] I I I X The compounds in Table 3 were prepared following a synthetic pathway similar to the o o o omethod listed.Table 3:N WMMVM*Co. Co.R1R3Method R1R3Method No. No.33 — 1 G 90 X X< HM— I39 — 1 G 93 I %F. X X X X X Xo o O O O O40 — 1 G;o95 I % CO ^ IZa:42 — 10 SG O / ''NH105 Q I (rac) < 7)ZI H2H—^Fco( o=or57 — 1 G117 I F84 IQ H2N odS119 I O / N^\85 izI i° X — S-V \' O " \\ XL-Y / )NH2120 I (rac)89 I°CVx OH138 INH2X X X I X X X I Io o o o o o o o oCo. 44b**35 ' Co. COR1R3Method R1R3Method No. J AMuwM* No.143 I 176 I H2N '= / ' < cPZI< o=□c147 I X X177 I HO p°151 <0 I182 I X X X X X Xo O O O O O (S)153 IQ JP COor 183 / / • • I sn 5 Uo=o (R)b '154 IHN'^sk< 184 I ZI / 'O( o=o'0H157 IOH=N' P-V-X187 \ I H0Z159 INH190 I H2N(rac)163 IH2N^ 192 ^^^OH I172 H2^U=^ I OH193 I— NHI I I I I I I Io o o o o o o oCo. 4*i A3 Co.R1R3Method R1R3Method No. J MWwwUU* No.243 <^^5=0196 I < I ~ HbN— (2- S 4 ^ (rac)( ), 5-(R) T244 I 205 I0=\ / HN— ' (rac)207 I 245 I I I I I I I I Io o o o o o o O(rac)\COor(N^fyj 215 I 247 O7\= / ‘ I (R)OH218 < I 257 I ZI( o=o'H221 N-V \ I 263 H2N^^, I V / (S)n^Q-l O-y222 I 268 I HO7\= / ’O-y270 I 235 I H2N \= / ‘OH271 H2NAZ^ I(R)I I I I I I I Io o o o o o o oCo. Co.R1R3Method R1R3at Method No. V MMUVW No.ANzr^\ >277 I 292 -U II \ _y / i 1 I < 0x—f(rac) ZI< o=oi o c / ur XX' 1?FV^ IIAA-I 6'278 \ _ / |NH ' — ' I 341 1°C / 01G (rac)(rac)280.. P3I 357 — 1 G 4NHHI F0(rac) o O A / / (rac)c / \ -n ^CO281_ °" / st or'N ^ IH400 G (rac)286 <4 ZI °>c I^ — N O -i< o= °<O' (rac) 401 — 1 G T HF0(*S)287 o IO-y / 444 I (rac) F^ HO7\= / ‘F289 % / ; I'NH(rac) 453 1 I290 >'FIF)H2N O-^ / 459 _ / NH I HO7HO7\= / ’291 I (rac)Co. Co.R1R3Method R1R3Method No. No.461 t _ / NH 1 I 558F_c 'NH < G HOZF F^^ rNP1 \(rac) (*R) FC|4 cP 0^68 ^N G 772 H P~NF. L JjF FFVN FC|477F_c NH 773 H F ( ^VN GFp ^O Cor F(*R) FC|774 H 479 'NH cP N< ^N GF ZI FP '^( o= FFo' (*S) P^FC|776 H 519 xP GF'~- / <N FPS'^F 1 \ FFC|FR\ O II / >= / ’555 — 1 G 779 H ( FP '^ p( rac) F557F_^ 'NH rP GF F^X^N1 \(*S) F

[0304] The compounds in Table 4 were prepared following a synthetic pathway similar to the method listed.Table 4:OHN^UID R1R3Method ID R1R3Method 0— >. Cl\=N ’122 I739 if N Q HO NF^F F^F\=N * Cl131 I2=N740(rac) if N Q HnhNFF^F(*R)201 \=N CO ’ IHO^ a: Cl\=N ’747F_( 'NH if N Q 255 I NF< NH2F^FZI (*S)( o=or FX X X o\=N '460 / _ / NH IHOZNH2749 ^; N Q N(rac)Cl 4F\=N 'Cl728F_c NH n QN \=NF 751 N=< F Q 4s N^Z(*R) 4 F4S^ NFClCl\=N738 o Q \=N 'NH N 756F_< 'NH N=( F Q F Is, N^ZF N(*S) 4(*R)

[0305] The compounds in Table 5 were prepared following a synthetic pathway similar to the method listed.Table 5:O Y Y Y Y Y MWWWV R’JINH^YY NCUR3Co. No. R1R3Method Co. No. R1R3Method 2 N*\ i 71 I 92.. N^ / 1 I CCH "'0\v_73 oz)-Y J |> — / 0^\ / I 94 I \74 I 96 I I I I I I I I I Yc I o o o o o o o o oCO \anY Y Y Y Y75 YJH I 98HtjH I <ZI< o=1 a:76 I 100 I I I CH OY HOCH N«=\ |78 I 101 ANH I79 I 102 £ H I HOZF81 I 109N"NVJ>-NH I83 I 112 A l I N-^VI I I I I I Io o o o o o oo co'Co. No. R1R3Method Co. No. R1R3Method i AW MMWW AVWW r-N J HN^\ |113 I 149 I H \ / *N ’<zx 0 ^ 0=[CV-I O'115 >^V- ■> I 152 I IX IM - -. N*=\ | 118 " NsI 156 I 0^ (rac) rvi \ Q— / / N^1121 I 158 I I I I I I I I I I I o o o o o o o o o o00HOZO' (rac)4*3130 HNQH I 166 idd I < dZX< o=4 ^ o'132 / r^yN -l * I 169 I I 5 HOZ Hr-N S133 OH I 170 I \ o\134 HS^H °f 1I 171 PH I (rac)A142 X^N i I 173 'PH I hEsH HOZ144 I 174 SZ^H I \ZNHI I I I I I I Io o o o o o o oO Co'Co. No. R1R3Method Co. No. R1s R3Method A A A A A A N MMWW MWIWIZ* r"N1178 NJH I 203 I <zxA □a:180 NQH I 208 I \181 I209 I F(rac)1860 / N?I I I I I I I I I Io o o o o o o o o00 211 I HOZO'HN'NA A A A A A 191 vJ I HN^\ |213 I <ZX< o=n*\ i 0x1 HNM 1 z197 I214 I HOZAM198 r-N JAH I216 I A(rac)199 I219 I A200 CH IF AF223 I202 'OH II I I I I Io o o o o oCo. No. R1R3Method Co. No. R1R3Method i AMWWWVN<=\ |237 / O~ _ * I 254oO^N / I <a: N^\ 10 / N?-Jv238 I 256 I Her258 I 239 N-N IN^H0259 I I I I I I I I I I o o o o o o o o o w240 IHOZ6 F”3Z >^n260 00FV-u I 242 N-N I \< 0 OH261 I I N*\ |248 N0 i Irvi262 I 0F jfVI F250 Z-N ‘ IN~NHN*=\ | 264 I 252 I(rac) ( tl1- 265 <\N'NI 0 o~v253 1 I (rac)HOZI I I I I Io o o o o oO Co'Co. No. R1R3Method Co. No. R1R3Method A A A Ai AA 1 P MMWWN267 I392 < +zx P ^ 0=a: F \ N— I273 IA393 P 274 oJ I FM ^F rn—1FF" V1N |275 I‘ IF 001HOZO' 394 P A F276 M IMF AxF<ZX r°< o= r-Nx282 NLNH JIFvF404HOZF-(NHJ F0NA (ra28 1 c)5 I409 J F4 '^F o294 IFv \F410 J F^F 0JQ391 Cl PF^° 415 ' 'F^ °"st-XH ^ N^V / I 1 J F F OClO Co'Co. No. R1R3Method Co. No. R1R3Method ClAU N*\ |436N'N * I 447F 1 I F U <F % zxa: F. Xj,l t°U oo' )— F437 >^H I 0 Au448 I F F UF438 CH I F.U y— FF FF 0449 I NL39NH4 I %00F O' F.y— F0450 HN I 440 HQ I QHN HF %<ZXF.U o )— Fx441HNL^H I 0451HNL^H I FN*\ |442 IF N<=\ I452XN^ / 1 I443 \^H IFCl AU454 j _ / NHN'N^ * I 445 I HO F UF% (rac)Cl446HtjH I%o'O C Co. No. R1R3Method Co. No. R1R3Method455 / _ / NH I 482F_ °"^sN 'NH ^ p J < HHOZF zx pF-y< / * / ^ 0=o I(rac) a: (*S) FT456 / _ / NHN0 ^NH ’N'ZI HOZ^~-F 485 I F F^ NH(rac) FC>1457 / _ / NH HNQH IHOZ497F_^ 'NH( F pH J rac) 00O' / °(*S)458 S _ / NHHOZHpH IF'^-\516 \ N— 1 J (rac) < ^N ’ZX< o= 0^1xy465 pHo J548 I FF'Y F 'TF0^1472 pH J 552 Y'V-I J o N^ / 1F^S<°F 0°^\Fx _^475F_< 'NH pH JFNsC "’596 _<- 'NHF N ' ^ 0 <y -1 J i F(*R) 0(*R)°^\ F481F_^- 'NH N^ / 1 J 597 J F OF-y F^F 0(*R) FCo. No. R1R3Method F604F_< 'NH J F0zz zz zz--- (*R)F605 NH J F0(*S)637 J F^F00O'646F< 'NH J F(*R)<ZX< o=x647F_^ 'NH J F(*S)F'^-\662 \ N— i J F^FF'^-\679F_^ 'NH \ N— 1 J F ^N ‘(*S)686FJH J F GN^N

[0306] The compounds in Table 6 were prepared following a synthetic pathway similar to the method listed.Table 6:0Z.H-'Y N^YUY"’Co. Co.R1R3Method R1R3Method No. No.-d ryi F35 % H 54 E 4 %0(TRANS)(CIS)- 4 5 + Fry | 5 d E 37 % E%COa:(CI 4S)0-d — N^d — 1N ry-|58 >=N^ D 38 % < EZI %( o=.4 4or(CIS)0 77 N=Z ‘ I )— F— N ^d — 1 F>=N^ HO51 % HO^F80 I ^F y; 0H0a ) ( a )Z / (r c, r c0— N ^d — 1 82 QH I >=N^ 4c 05?— N H0Z / 3 % H(CIS) 86Z< Q-| I H0X Xe Ox.Co. Co. atR1R3Method R1R3Method No. cc No.0 10887 0 < I I c.FN^VI\=N ’110 < CH \" OH I 88 CC IHO (R)HO^91 CH I 111 N NH I\=N8(S)X X X X Xo o o o o97 CH COor I 114 CH \" OH I HN \ cc c c cJ MWvvVW* (R)N=Z '99 < )-OH IZI 116 NH \=NA I ( o= ’ ) C o' (R)X) OX X X X X X103 I HN V — 1ctyi ry_| >=N^124 ^N D % 0— / N^-|104 I (CIS)oHO— N ~”^ — 1 HOry_| >=N^106 I 125°. o D z%0■- VFF(*R), (*R) C107 H ICl OHX X XCX CXX (Co. Co. atR1R3Method R1R3Method No. No.0Q_|— N ”^ — 1ryi 141 I >=" * <0 / 126 D%0^FX145 I (*S), (*S)128 O INfy-I146 I o—'X X X X X X X XN / — o o o o o o o o129 I CH0 CO 148 I / or%% ■ ■ ^0JJ wizizww* wizizww*N=Z ‘135 I ^_-loz150 I <ZI( o=4 o ^' (Q_|136 X) IX X X X 0 / 155 i / VI5=N?I o—' / 137 D I r N=NZrl N^VI 160 ’ I \=N ’^0139 o / NI CH161 \" OH I 0HO (R) ry_| — O N— x.162 \ _ / / _ | I 140 I N=z ’VNH2X XO O..Co. Co. atR1R3Method R1R3Method No. No.164 z 5=vN i ’ I 194 zvio < ^=N1I —' / \0165NVN s\jp I 195 I r / Vl^>=N ' £y_|167 I)— F 204 I QH F X X X X X X X Xo o o o o o o o168 CO Ior 206N=p IFFN^VI175 \=N ’ I C rlF— (<ZI F 210 F / OHI ( o= FFo'(rac)X)179 X X X X X XK H I212 I HO7185 I— NH217 zvi I \=N7‘OH188 IJc11 '=N * £y_| HO7224 I 189 pH I HO7225 D N=NF^°1FCO Co. Co. atR1R3Method R1R3Method No. No.FV°SF269 < WVI I ZI F N= / N227 % H < o=□c.ft1X X272 H<^ <^=1^ I (*S), (*R)(S)ry-| FjpH234 % H279 I OH(*R), (*S) X X X X X (R)o o o o op CO236 or H I 283 ftn I O- ' — NH / H24 N1 I 284 IZI4 ^( o= OH^—o'X) X)X X X X X X CH246 I 288 I HN— Z 1N7O °\ / pH 293 I 249 I — NHOH(S) O— N7^ — 1 >=N^251 I297 ^N D HO N= / 8FP°F H<5~ *(3-α, 4-β, 5-α)266 \0^yj IN=N!Co. Co. atR1R3Method R1R3Method No. No.0316 D — N ~y~ i yyyj < >=N^FN= / « 329 F-(NHD Fy(rac)317 D (CIS),. dO Vo F oF— N ~^ — 1 N^X 1 >=N ^ 3 HO— — | 330 / ^ND 19 GF^F^ F 0— / FF0 (CIS)— N A — 1COor°"sC ^0 / — N \o-\32 F— (NHD 332 F-(NHD F F °— AA — 1N=N ’ HO *(rac) (rac)(3-α, 4-β, 5-α)<ZI 0( o=o' HN V — 333 0=(0C >=N^ F^ / — N F v / yt321 D N= / 1F y(CIS)334 F^ °"sC'NH ^ D F O Vo F o=( (rac)322N-> CF^F0\ / I yF335 E F4S^F323 D (PHO F N=N 'N^yq5=N ’339 0 N^yq324 z\ ANE F o—'F^ HN 5-0FCo. Co.R1R3Method R1R3Method No. No.zy-i N^V| 5=N1346 0 362 / >=N< 0 o~vF % F (rac) N^VI5=N * N^V| 347 0 363 5=N ’ 0 F4 ^ F^F HN— ' o—'F / _ N^ 5=VN I1350 E 364 0 F^ 'oF —0 F (rac) / 0 zvi\- CONs)=N ’ C or>=NH352 D 365 0 / — N O^NF4 ^ F^Z1FF(rac)(CIS)<ZI N^V|5=N *( o=o'355 D 366 0CK ^NTF^ \=NIF F 1(rac) N^V|5=N ’ N^V| 359 0 5=N ‘R / Z367 0\ / — / F FFF^ N— KF7Ozyj)=N1N^VI 360 \ \0II / / — ' 0 ^=N!F^ N-S^F ' 6 368 0O NH FN^V| (rac)361 / — \ )=N 0F^ O / —F zvi369 / — \ )HN ) —=N 10 F4^ / FCo. Co. atR1R3Method R1R3Method No. No.zyu370 i^\ ^=nHN^ 0 380 < C F^Q / F (rac) F \ — / o N^V|371. 5=N * 0 381 CHN\Z —F FN^VI\=N ‘372 0 382 C F^ F^F F HN^N^V|\= CO N1383 V Z T C 373 orF0FF^F HN384< yH°o=^SvC F^ZI F375 ( o= y,yyj CF^ o' N= / 5F(rac) 388 E F^F F376 DN^\ iF389 °"sC "l D F—NH / F377 (rac)F^ 's4T° CFF.y— F 390 E 378 C F^ QF FF (rac)379 ^4. CF^FCo. Co. atR1R3Method R1R3Method No. No. / O<396 ENC >=H413 F^ %F N'NH ^N D F F F(*R) (rac)(CIS)397 E -d ^NF 414 VNiF-(NHE F C 'H(*S)(rac)N^V| (CIS)\=N ’CO 0SN—399 orO^N 0423 P F HO^ F^ / F (rac)(rac)0<ZI HN ) -d ^N( o= ) —. LL )=N?402 o' 431F_< NH E T o' ^^N DF^ F C 'H F (*R)HO7(CIS)°"sC ^ -d ^N405 F— (NHE432 'NH E F0 F C 'H—(rac)(*S)(CIS) / 0407 °"sPF^NH^ EF -OF “"sF1>=NH433F_; S 'NH E (rac)(rac) Fo— / (*R)(CIS)Co. Co. CLR1R3Method R1R3Method No. No. / 0N iC >=N'H 494F_< 'NH < E 434 'NH N E FF F(*R)(*S)(CIS)495F_0"^sN 'NH ^ E 466 K F— N 0 F\ (*S)F0 zvi467 D > 'NC / =MN °"sC ^ ^N1> TN501 F^ 'NH D F F CO For(rac)(CIS) zvi478 F-(NHDF > TNF<(*S) ZI 514F_^ 'NH CP E ( o=o' FF Q N— | (*S)(*R)480 PF °" / p^(*S)515F_^ 'NH E F PpH F492 °"sC ^ (*S)F E (*S)—NHCpFF(*R)(*R)518F< 'NH D F ■A(*R)493F_< NH EF N^VIF )=N^-0(*R)(*S) 520 EHN O%(rac)Co. Co. atR1R3Method R1R3Method No. No.N^V| N^N O"\ )“N.0 < 1 >— o529 E 521 E% F% °^ lI _ NH (R), (R)(rac)N^VI N^N HN^ >=N530 E 522 E %^. N^ / %(rac)N^VI >=N^HN^\ )“N?-°523 E 531 E % %(r CO 1ac or)(S) zvi>=" *524 E% N=\ 532 E < z ZI V~ %( o=o' zviO" N )“525 1 )— 0NE N^VI HN^. )=N ’ % yF( Y- O533 E (rac) %(rac) zvi>526=NE o% 535 — P II— < N— 1 s P (rac) 1 ’FN^VI527 )=NO II / y-Q E N^V|% — P—' )=NA’1 536 NH D FN^ |<^FV>=N^ F (*R)(*S)528 E%\(rac)at z JCo. Co.R1R3Method R1R3Method No. No.N^VI°"sC ^ zvi 537 'NH D 611F_; S 'NH < D rF F > T FNF(*S) (*S) (*R)N^VI542 D612 D ■cF F^ FF(rac)553 NH DF■A 648F_< 'NH P (*S) FCOor (*R)N^V|)=N *577 °" csP 'NH^F F DF^ ^PF 649F_^ 'NH P (*R) < (*R) FZI( o= (*S)o' N^VI°"sC ^580F_c 'NHF £ D 676 P F F^ f: ^N(*R) F(*S)o' N— 1 N^VI^=N ‘ Q>. NO=6 722NX09 DFY% V? b P F4S^<P'FF FF(*R) OHN^VICl\610 D 723 FFb^ FF(*S) F(CIS)Co. Co. CLR1R3Method R1R3Method No. No.Cl ClC 2=MN ’ 726 F 764 < DF F OH FCl0b r*N745 b P 1V 767FY \ > P F^FrbQ FClKN— 1Cl\746 PF^ 0 COor 768FF_< NHF F bb P VCl (*R)Cl\752 rNOSN— I< FZI( o=o' Fuu 769 P 0 'NHF QCl ^F(*S) F\=N '754 O' HN 0 N-^F4S^F 4 M775 P ClQ N— I bHO FZ762FP_c 'NH FF 0o O N— |hF(*R) F777C b P l763 CH E OHFF4S^FCO Co. Co. atR1R3Method R1R3Method No. No.Cl N— x j0 o' N— |< $=> H794 ZI D N=\ F778 P < o=□c FNyOHFc0780 PF COorCl\=N ’789 C N;NDF <ZI( o=C a:l790 PNHF(*S)ClpH791 D<, NN F F^FClCH793 DN=\ FF FExample 2: Analytical characterization methods of Intermediates and Compound NMR

[0307] Some NMR experiments were carried out using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe head with z gradients and operating at 500 MHz for the proton and 125 MHz for carbon. Some NMR experiments were carried out using a Bruker Avance III 400 spectrometer, using internal deuterium lock and equipped with reverse double-resonance (1H, 13C, SEI) probe head with z gradients and operating at 400 MHz for the proton. Experiments were performed at ambient temperature (298.6 K), unless otherwise mentioned. Chemical shifts (δ) are reported in parts per million (ppm). J values are expressed in Hz.Table 7: ¹H NMR Results.Co. No. NMR peaks list1 ‘HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.28 (s, 1H), 9.04 (s, 1H), 8.49(s, 2H), 8.29 (dd, J = 8.6, 1.6 Hz, 1H), 8.15 (d, J = 8.2 Hz, 2H), 7.82 (s, 1H), 7.64 (dd, J = 8.4, 7.5 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 4.79 (d, J = 5.8 Hz, 2H), 4.39 (dd, J = 12.2, 3.5 Hz, 2H), 4.18 (d, J = 6.7 Hz, 1H), 3.22 (d, J = 2.5 Hz, 3H), 2.81 -2.74 (m, 1H), 2.73 (s, 3H), 2.57 (dd, J = 20.0, 7.1 Hz, 2H), 1.60 - 1.47 (m, 2H), 1.04 (d, J = 6.5 Hz, 6H).2 ‘HNMR (400 MHz, DMSO-d6) d 9.54 (t, J = 5.7 Hz, 1H), 9.24 (s, 1H),8.51 (s, 1H), 8.41 - 8.33 (m, 1H), 8.32 - 8.22 (m, 2H), 8.19 - 8.02 (m, 2H), 7.80 (s, 1H), 7.62 - 7.52 (m, 1H), 7.31 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 4.71 (d, J = 5.7 Hz, 2H), 4.49 (d, J = 7.0 Hz, 1H), 4.34 (dd, J = 12.6, 3.2 Hz, 2H), 3.27 (d, J = 4.5 Hz, 3H), 2.65 (dt, J = 18.8,9.3 Hz, 1H), 2.47 (t, J = 8.7 Hz, 2H), 1.46 - 1.31 (m, 2H), 0.92 (t, J =9.1 Hz, 6H).31H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.46 (br t, J = 5.8 Hz, 1H), 9.31(s, 1H), 8.59 (s, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.34 (dd, J = 1.3, 8.6 Hz, 1H), 8.26 - 8.12 (m, 2H), 7.84 (s, 1H), 7.75 - 7.56 (m, 2H), 7.46 (d, J =7.4 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 4.77 (br d, J = 5.7 Hz, 2H), 3.67(br s, 2H), 3.64 - 3.56 (m, 2H), 3.46 (s, 2H), 3.28 (s, 3H), 2.72 (s, 3H), 1.43 (s, 9H), 0.99 - 0.90 (m, 2H), 0.87 (br d, J = 4.7 Hz, 2H) 41H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.45 (br t, J = 6.0 Hz, 1H), 9.31(s, 1H), 8.57 (s, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.32 (dd, J = 1.3, 8.6 Hz, 1H), 8.24 - 8.13 (m, 2H), 7.83 (s, 1H), 7.70 - 7.57 (m, 2H), 7.41 (d, J =7.4 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 4.76 (br d, J = 5.7 Hz, 2H), 3.69 - 3.55 (m, 2H), 3.45 (s, 2H), 3.28 (s, 3H), 3.18 (d, J = 4.8 Hz, 1H), 2.98 - 2.83 (m, 2H), 2.72 (s, 3H), 0.59 - 0.47 (m, 4H)Co. No. NMR peaks list5 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.31 (s), 8.91 (d, J=7.8 Hz),8.58 (s), 8.34 (dd, J=8.6, 1.6 Hz), 8.17 (d, J=8.7 Hz), 7.88 (s), 7.76 (d, J=1.3 Hz), 7.70 (br dd, J=8.4, 7.6 Hz), 7.68 (brdd, J=7.8, 1.5 Hz), 7.46 (d, J=7.4 Hz), 7.37 (d, J=7.8 Hz), 6.90 (d, J=8.6 Hz), 5.37 (quin, J=7.1 Hz), 4.31 (br d, J=12.9 Hz), 3.98 (t, J=8.5 Hz), 3.62 - 3.71 (m), 3.14 - 3.21 (m), 3.03 (s), 2.44 - 2.49 (m), 1.62 (d, J=7.0 Hz), 1.21 (d, J=6.2 Hz) 6 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.48 (br d, J=7.6 Hz), 9.39 (d,J=2.1 Hz), 9.33 (s), 9.22 (d, J=2.2 Hz), 8.81 (t, J=2.1 Hz), 8.62 (s), 8.34 (dd, J=8.6, 1.6 Hz), 8.18 (d, J=8.7 Hz), 7.96 (s), 7.70 (dd, J=8.4, 7.5 Hz), 7.45 (d, J=7.4 Hz), 6.90 (d, J=8.6 Hz), 5.41 (quin, J=7.0 Hz), 4.31 (br d, J=13.1 Hz), 3.62 - 3.71 (m), 3.39 (s), 2.44 - 2.49 (m), 1.66 (d, J=7.0 Hz), 1.21 (d, J=6.2 Hz)7 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.32 (s), 9.20 (d, J=7.7 Hz),8.60 (s), 8.46 (d, J=1.9Hz), 8.34 (dd, J=8.6, 1.6 Hz), 8.15 - 8.22 (m), 7.90 (s), 7.70 (dd, J=8.4, 7.5 Hz), 7.59 (d, J=8.2 Hz), 7.46 (d, J=7.4 Hz), 6.90 (d, J=8.5 Hz), 5.35 - 5.44 (m), 4.31 (br d, J=12.8 Hz), 3.62 - 3.71 (m), 3.26 (s), 2.71 (s), 2.44 - 2.49 (m), 1.64 (d, J=7.1 Hz), 1.21 (d, J=6.3 Hz)819F NMR (376 MHz, DMSO-d6) 5 (ppm) -109.49, -129.54.8 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.59 (t, J = 5.9 Hz, 1H), 9.31 (s, 1H), 8.56 (s, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.30 (dd, J = 8.6, 1.6 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.15 - 8.10 (m, 1H), 8.05 - 7.97 (m, 1H), 7.85 (s, 1H), 7.65 - 7.56 (m, 2H), 4.77 (d, J = 5.7 Hz, 2H), 3.53 (s, 2H), 3.38 (s, 2H), 3.34 (s, 3H), 2.94 (s, 2H), 0.51 (d, J = 9.6 Hz, 4H).9 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 0.46 - 0.51 (m, 2 H) 0.51 - 0.57(m, 2 H) 2.85 - 2.92 (m, 2 H) 3.17 (d, J=4.8 Hz, 1 H) 3.33 - 3.37 (m, 3 H) 3.44 (s, 2 H) 3.60 (dd, J=5.9, 4.2 Hz, 2 H) 4.77 (d, J=5.7 Hz, 2 H) 6.82 (d, J=8.6 Hz, 1 H) 7.39 (d, J=7.5 Hz, 1 H) 7.64 (dd, J=8.6, 7.5 Hz, 1 H) 7.87 (s, 1 H) 8.15 - 8.20 (m, 2 H) 8.32 (dd, J=8.7, 1.7 Hz, 1 H) 8.36 (t, J=1.8 Hz, 1 H) 8.44 (t, J=1.5 Hz, 1 H) 8.57 (s, 1 H) 9.30 (s, 1 H) 9.59 (t, J=5.8 Hz, 1 H)10 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 0.48 (s, 2 H) 0.54 (s, 2 H) 2.84- 2.93 (m, 2 H) 3.06 (s, 3 H) 3.18 (t, J=8.4 Hz, 2 H) 3.44 (s, 2 H) 3.57 - 3.64 (m, 2 H) 3.99 (t, J=8.5 Hz, 2 H) 4.73 (d, J=5.9 Hz, 2 H) 6.81 (d, J=8.6 Hz, 1 H) 7.36 - 7.43 (m, 2 H) 7.51 - 7.69 (m, 3 H) 7.77 - 7.83 (m, 2 H) 8.16 (d, J=8.6 Hz, 1 H) 8.31 (dd, J=8.7, 1.7 Hz, 1 H) 8.55 (s, 1 H) 9.18 (t, J=5.8 Hz, 1 H) 9.29 (s, 1 H)Co. No. NMR peaks list1119F NMR (376 MHz, DMSO-d6) 5 (ppm) -129.01.11 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.45 (t, J = 5.8 Hz, 1H), 9.31(s, 1H), 8.57 - 8.53 (m, 1H), 8.46 (d, J = 1.9 Hz, 1H), 8.31 (dd, J = 8.6, 1.7 Hz, 1H), 8.23 - 8.15 (m, 2H), 7.79 (s, 1H), 7.67 - 7.54 (m, 3H), 4.84 (t, J = 5.4 Hz, 1H), 4.76 (d, J = 5.8 Hz, 2H), 4.59 (d, J = 7.0 Hz, 1H), 4.14 - 4.05 (m, 2H), 3.72 (q, J = 5.9 Hz, 2H), 3.51 (t, J = 6.1 Hz, 2H), 2.70 (s, 3H), 2.65 (t, J = 12.5 Hz, 2H), 1.66 - 1.54 (m, 1H), 0.99 (s, 3H), 0.98 (s, 3H).1219F NMR (376 MHz, CDC13) 5 (ppm) -129.53.12 'HNMR (400 MHz, CDC13) 5 (ppm) 9.18 (s, 1H), 8.51 (d, J = 2.0 Hz,1H), 8.29 (s, 1H), 8.18 (dd, J = 8.6, 1.6 Hz, 1H), 8.05 (dd, J = 7.9, 1.9 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.94 (t, J = 5.4 Hz, 1H), 7.77 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.37 - 7.29 (m, 2H), 4.87 (d, J = 5.3 Hz, 2H), 4.10 - 3.99 (m, 4H), 3.86 (dqd, J = 12.6, 6.2, 2.0 Hz, 2H), 3.60 (s, 1H), 3.40 (t, J = 5.3 Hz, 2H), 2.79 - 2.65 (m, 5H), 1.30 (s, 3H), 1.29 (s, 3H).13 'HNMR (400 MHz, CDC13) 5 (ppm) 9.17 (s, 1 H) 8.41 (d, J=1.7 Hz, 1H) 8.29 (s, 1 H) 8.11 (s, 1 H) 7.96 (d, J=8.6 Hz, 1 H) 7.72 (s, 1 H) 7.49 (br s, 1 H) 7.38 (d, J=7.9 Hz, 2 H) 6.90 (dd, J=9.4, 1.5 Hz, 1 H) 6.22 (dd, J=11.9, 1.4 Hz, 1 H) 4.85 (d, J=5.2 Hz, 2 H) 3.52 - 3.68 (m, 2 H) 3.38 - 3.46 (m, 3 H) 3.06 (br d, J=5.2 Hz, 2 H) 3.04 (s, 3 H) 2.70 (s, 3 H) 0.62 (br d, J=9.3 Hz, 4 H)14 'HNMR (400 MHz, CDCI3) 5 (ppm) 9.16 (s, 1 H) 8.33 (s, 1 H) 8.13 - 8.22 (m, 1 H) 7.95 (d, J=8.6 Hz, 1 H) 7.72 (s, 1 H) 7.50 - 7.62 (m, 2 H) 7.37 (s, 1 H) 7.32 (br s, 1 H) 7.15 - 7.18 (m, 1 H) 6.57 (d, J=8.5 Hz, 1 H) 4.82 (d, J=5.2 Hz, 2 H) 3.89 - 4.08 (m, 3 H) 3.51 - 3.65 (m, 2 H) 3.44 (s, 2 H) 2.97 - 3.13 (m, 4 H) 2.83 (s, 3 H) 2.22 (s, 3 H) 0.70 - 0.86 (m, 1 H) 0.59 - 0.67 (m, 3 H)15 'HNMR (400 MHz, CDCI3) 5 (ppm) 9.16 (s, 1 H) 8.33 (s, 1 H) 8.14 - 8.22 (m, 1 H) 7.95 (d, J=8.7 Hz, 1 H) 7.72 (s, 1 H) 7.64 (s, 1 H) 7.48 - 7.60 (m, 2 H) 7.41 (br s, 1 H) 7.17 - 7.18 (m, 1 H) 6.58 (d, J=8.5 Hz, 1 H) 4.81 (br d, J=5.1 Hz, 2 H) 3.95 - 4.10 (m, 3 H) 3.57 - 3.64 (m, 2 H) 3.44 (s, 2 H) 3.04 - 3.20 (m, 4 H) 2.87 (s, 3 H) 0.62 (br d, J=5.9 Hz, 4 H)Co. No. NMR peaks list16 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 0.44 - 0.51 (m, 2 H) 0.51 - 0.58(m, 2 H) 2.30 - 2.39 (m, 1 H) 2.88 (br s, 2 H) 3.33 (s, 3 H) 3.44 (s, 2 H) 3.60 (br dd, J=5.8, 4.1 Hz, 2 H) 4.78 (d, J=5.7 Hz, 2 H) 6.82 (d, J=8.6 Hz, 1 H) 7.39 (d, J=7.5 Hz, 1 H) 7.64 (dd, J=8.4, 7.5 Hz, 1 H) 7.87 (s, 1 H) 8.01 (dt, J=7.9, 1.9 Hz, 1 H) 8.10 - 8.20 (m, 2 H) 8.32 (dd, J=8.6, 1.5 Hz, 1 H) 8.36 (t, J=1.4 Hz, 1 H) 8.57 (s, 1 H) 9.30 (s, 1 H) 9.57 (t, J=5.8 Hz, 1 H)17 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.39 (t, J=5.9 Hz, 1 H) 9.25 (s,1 H) 8.54 (s, 1 H) 8.35 - 8.45 (m, 1 H) 8.18 - 8.31 (m, 1 H) 8.04 - 8.18 (m, 2 H) 7.75 (s, 1 H) 7.53 (d, J=8.0 Hz, 1 H) 7.24 (br d, J=9.8 Hz, 1 H) 6.49 - 6.71 (m, 1 H) 4.86 (br s, 1 H) 4.70 (br d, J=5.5 Hz, 2 H) 3.66 (br t, J=6.0 Hz, 2 H) 3.58 (br s, 2 H) 3.37 - 3.49 (m, 5 H) 2.74 - 2.87 (m, 2 H) 2.64 (s, 3 H) 0.48 (br s, 2 H) 0.42 (br s, 2 H)18 'HNMR (400 MHz, CDC13) 5 (ppm) 9.12 (s, 1 H) 8.30 (s, 1 H) 8.09 - 8.21 (m, 1 H) 7.87 - 8.01 (m, 2 H) 7.71 (s, 1 H) 7.46 - 7.60 (m, 2 H) 7.34 (br s, 1 H) 7.15 (t, J=8.0 Hz, 2 H) 6.56 (d, J=8.5 Hz, 1 H) 4.81 (d, J=5.3 Hz, 2 H) 3.53 - 3.67 (m, 2 H) 3.43 (s, 2 H) 3.00 - 3.13 (m, 2 H) 2.54 (s, 3 H) 1.77 (br s, 8 H) 0.62 (br d, J=13.1 Hz, 4 H)19 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.38 (s, 1 H) 9.19 (s, 1 H) 8.67(s, 1 H) 8.41 (dd, J=8.7, 1.3 Hz, 1 H) 8.17 - 8.32 (m, 1 H) 8.11 (d, J=1.5 Hz, 1 H) 7.86 (s, 1 H) 7.75 - 7.85 (m, 2 H) 7.62 - 7.72 (m, 1 H) 7.55 (d, J=7.5 Hz, 1 H) 7.32 (br s, 2 H) 7.27 (s, 1 H) 6.96 (d, J=8.6 Hz, 1 H) 5.09 (br d, J=9.6 Hz, 2 H) 4.81 (br d, J=5.7 Hz, 2 H) 3.78 - 3.92 (m, 4 H) 3.74 (br s, 6 H) 2.60 - 2.71 (m, 6 H) 1.61 (d, J=8.5 Hz, 12 H)20 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.58 (t, J = 5.7 Hz, 1H), 9.33 (s, 1H), 8.65 (s, 1H), 8.48 (dd, J = 2.3, 6.8 Hz, 1H), 8.40 (ddd, J = 2.3, 4.8, 8.6 Hz, 1H), 8.36 (dd, J= 1.5, 8.7 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.84 (s, 1H), 7.74 - 7.68 (m, 1H), 7.38 (dd, J = 1.3, 9.9 Hz, 1H), 6.78 (dd, J= 1.4, 12.5 Hz, 1H), 4.77 (d, J = 5.7 Hz, 2H), 4.33 (brd, J= 12.3 Hz, 2H), 3.65 (ddd, J = 2.4, 6.3, 10.4 Hz, 2H), 3.39 (s, 3H), 2.58 - 2.52 (m, 2H), 1.23 - 1.18 (m, 6H)21 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.54 (t, J = 5.8 Hz, 1H), 9.34 (s, 1H), 8.66 (s, 1H), 8.52 (s, 1H), 8.38 - 8.31 (m, 2H), 8.23 - 8.11 (m, 2H), 7.87 - 7.80 (m, 2H), 7.41 - 7.36 (m, 1H), 6.78 (d, J = 12.5 Hz, 1H), 4.85 - 4.74 (m, 2H), 4.33 (br d, J = 12.6 Hz, 2H), 3.69 - 3.60 (m, 2H), 3.29 (s, 3H), 2.57 - 2.52 (m, 2H), 1.20 (d, J = 6.2 Hz, 6H)Co. No. NMR peaks list22 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.55 (t, J = 5.9 Hz, 1H), 9.38 (s, 1H), 8.77 (s, 1H), 8.55 - 8.50 (m, 2H), 8.39 (dd, J = 1.4, 8.6 Hz, 1H), 8.34 - 8.29 (m, 1H), 8.29 - 8.21 (m, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.91 (s, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 5.1 Hz, 1H), 4.80 (d, J = 5.7 Hz, 2H), 4.75 - 4.61 (m, 2H), 3.66 - 3.57 (m, 2H), 3.29 (s, 3H), 2.60 (dd, J = 10.8, 13.0 Hz, 2H), 1.22 - 1.14 (m, 6H)23 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.59 (t, J = 5.7 Hz, 1H), 9.38 (s, 1H), 8.75 (s, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.48 (dd, J = 2.2, 6.7 Hz, 1H), 8.42 - 8.36 (m, 2H), 8.25 (d, J = 8.7 Hz, 1H), 7.90 (s, 1H), 7.71 (t, J = 9.3 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H), 4.78 (d, J = 5.7 Hz, 2H), 4.75 - 4.61 (m, 2H), 3.66 - 3.57 (m, 2H), 3.39 (s, 3H), 2.61 (dd, J = 10.8, 13.0 Hz, 2H), 1.20 (d, J = 6.2 Hz, 6H)24 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.55 (t, J = 5.8 Hz, 1H), 9.38 (s, 1H), 8.77 (s, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.48 (s, 1H), 8.42 - 8.36 (m, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.28 - 8.22 (m, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 5.1 Hz, 1H), 4.90 (t, J = 5.3 Hz, 1H), 4.80 (br d, J = 5.7 Hz, 2H), 4.74 - 4.62 (m, 2H), 3.72 (q, J = 6.0 Hz, 2H), 3.66 - 3.58 (m, 2H), 3.58 - 3.49 (m, 2H), 2.61 (dd, J= 10.9, 12.9 Hz, 2H), 1.22 - 1.18 (m, 6H)25 'HNMR (400 MHz, CDC13) 5 (ppm) 9.20 (s, 1H), 8.57 (s, 1H), 8.38 (s,1H), 8.25 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.78 (s, 1H), 7.71 (t, J = 5.5 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.29 - 7.23 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.91 (d, J = 5.2 Hz, 2H), 4.29 - 4.17 (m, 2H), 3.84 - 3.72 (m, 2H), 3.14 (s, 3H), 2.94 (s, 1H), 2.79 (s, 3H), 2.61 (t, J= 11.5 Hz, 2H), 1.33 (d, J = 6.2 Hz, 6H).26 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.20 (d, J=6.2 Hz, 6 H) 2.60 (dd, J=13.0, 10.8 Hz, 2 H) 2.91 (s, 3 H) 3.37 (s, 3 H) 3.56 - 3.66 (m, 2 H) 4.67 (br d, J=12.5 Hz, 2 H) 4.80 (br d, J=5.5 Hz, 2 H) 7.40 (d, J=5.3 Hz, 1 H) 7.93 (s, 1 H) 8.24 (d, J=8.6 Hz, 1 H) 8.38 (dd, J=8.6, 1.5 Hz, 1 H) 8.52 (d, J=5.3 Hz, 1 H) 8.71 - 8.77 (m, 2 H) 9.27 (d, J=2.0 Hz, 1 H) 9.38 (br s, 1 H) 9.66 (br t, J=5.4 Hz, 1 H)2719F NMR (376 MHz, CDC13) 5 (ppm) -121.17.Co. No. NMR peaks list27 'HNMR (400 MHz, CDC13) 5 (ppm) 9.24 (s, 1H), 8.43 (d, J = 17.4 Hz,2H), 8.30 (dd, J = 20.5, 8.2 Hz, 2H), 8.08 (dd, J = 31.1, 8.2 Hz, 2H), 7.77 (dd, J = 16.1, 8.3 Hz, 2H), 7.64 (q, J = 8.0, 7.0 Hz, 2H), 7.28 (s, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.23 (t, J = 53.3 Hz, 1H), 4.93 (d, J = 5.0 Hz, 2H), 4.24 (dd, J = 12.7, 2.3 Hz, 2H), 3.78 (ddt, J = 11.7, 7.8, 3.9 Hz, 2H), 2.62 (dd, J = 12.5, 10.6 Hz, 2H), 1.33 (d, J = 6.2 Hz, 6H).28 'HNMR (400 MHz, CDCI3) 5 (ppm) 9.24 (s, 1H), 8.56 (s, 1H), 8.40 (s,1H), 8.27 (d, J = 8.6 Hz, 1H), 8.05 (t, J = 7.4 Hz, 2H), 7.79 (s, 1H), 7.63 (t, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.28 (s, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.92 (d, J = 5.2 Hz, 2H), 4.24 (d, J = 12.5 Hz, 2H), 3.80 (d, J = 9.9 Hz, 2H), 3.16 (s, 3H), 2.82 (s, 3H), 2.62 (t, J = 11.5 Hz, 2H), 1.33 (d, J = 6.2 Hz, 6H).29 'HNMR (400 MHz, CDC13) 5 (ppm) 9.25 (s, 1H), 8.56 (s, 1H), 8.40 (s,1H), 8.27 (d, J = 8.7 Hz, 1H), 8.05 (t, J = 6.7 Hz, 2H), 7.80 (s, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.28 (s, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.92 (d, J = 5.1 Hz, 2H), 4.24 (d, J = 12.6 Hz, 2H), 3.79 (s, 2H), 3.16 (s, 3H), 2.82 (s, 3H), 2.62 (t, J = 11.6 Hz, 2H), 1.33 (d, J = 6.2 Hz, 6H).30 'HNMR (400 MHz, CDC13) 5 (ppm) 8.26 (d, J = 8.6 Hz, 1H), 8.04 (dd,J = 11.0, 8.5 Hz, 2H), 7.76 (s, 1H), 7.62 (s, 2H), 7.26 (d, J = 6.7 Hz, 2H), 6.67 (d, J = 8.4 Hz, 1H), 4.27 - 4.20 (m, 2H), 3.85 - 3.72 (m, 2H), 3.42 - 3.34 (m, 2H), 3.06 (t, J = 6.3 Hz, 2H), 2.62 (t, J = 11.6 Hz, 2H), 2.52 (p, J = 6.3 Hz, 2H), 1.33 (d, J = 6.2 Hz, 6H).31 'HNMR (400 MHz, CDC13) 5 (ppm) 9.23 (s, 1H), 8.38 (d, J = 1.9 Hz,2H), 8.26 (dd, J = 8.6, 1.7 Hz, 1H), 8.06 - 7.99 (m, 2H), 7.78 (s, 1H), 7.62 (dd, J = 8.4, 7.4 Hz, 2H), 7.31 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.93 (d, J = 5.3 Hz, 2H), 3.79 (dqd, J = 12.5, 6.2, 2.4 Hz, 2H), 2.70 (s, 3H), 2.67 - 2.56 (m, 2H), 2.40 (s, 3H), 1.33 (d, J = 6.2 Hz, 6H).32 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.46 (t, J=5.8 Hz, 1 H) 9.32 (s,1 H) 8.51 (d, J=1.8 Hz, 1 H) 8.26 (s, 1 H) 8.17 - 8.23 (m, 2 H) 7.98 (dd, J=8.5, 1.7 Hz, 1 H) 7.83 - 7.88 (m, 2 H) 7.78 - 7.82 (m, 1 H) 7.62 (d, J=8.1 Hz, 1 H) 7.49 - 7.56 (m, 2 H) 7.40 - 7.49 (m, 1 H) 4.78 (d, J=5.7 Hz, 2 H) 3.27 (s, 3 H) 2.72 (s, 3 H)33 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.47 (t, J=5.8 Hz, 1 H) 9.32 (s,1 H) 8.46 - 8.50 (m, 1 H) 8.24 - 8.28 (m, 1 H) 8.17 - 8.23 (m, 2 H) 7.94 - 8.00 (m, 1 H) 7.77 - 7.88 (m, 3 H) 7.58 - 7.62 (m, 1 H) 7.49 - 7.56 (m, 2 H) 7.41 - 7.47 (m, 1 H) 4.77 (d, J=5.7 Hz, 2 H) 3.72 - 3.78 (m, 2 H) 3.50 - 3.55 (m, 2 H) 2.71 (s, 3 H)Co. No. NMR peaks list34 'HNMR (400 MHz, CDC13) 5 (ppm) 9.22 (s, 1H), 8.39 (d, J = 1.6 Hz,1H), 8.26 (dd, J = 8.6, 1.6 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.70 (s, 1H), 7.63 (dd, J = 8.4, 7.5 Hz, 1H), 7.31 - 7.22 (m, 1H), 6.87 (d, J = 5.9 Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 4.78 - 4.62 (m, 2H), 4.31 -4.14 (m, 2H), 3.85 (dd, J = 12.0, 3.9 Hz, 1H), 3.78 (dtd, J = 12.4, 6.2, 2.4 Hz, 2H), 3.70 (d, J = 11.8 Hz, 1H), 2.97 (dd, J = 11.9, 10.1 Hz, 1H), 2.78 (s, 3H), 2.72 (dd, J = 11.3, 2.9 Hz, 1H), 2.67 - 2.51 (m, 3H), 2.06 - 1.96 (m, 1H), 1.86 (dq, J = 13.2, 3.6 Hz, 1H), 1.81 - 1.56 (m, 2H), 1.33 (d, J = 6.2 Hz, 6H).35 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.35 (s, 1H), 9.30 (s, 1H), 9.24(d, J = 2.1 Hz, 1H), 8.73 (d, J = 1.7 Hz, 2H), 8.38 - 8.33 (m, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 5.54 (s, 1H), 4.83 (d, J = 5.7 Hz, 2H), 4.24 (d, J = 11.7 Hz, 2H), 3.68 - 3.58 (m, 2H), 3.32 (s, 3H), 2.92 (s, 3H), 2.57 (dd, J = 12.9, 10.6 Hz, 2H), 1.20 (d, J = 6.2 Hz, 6H).3619F NMR (376 MHz, CDC13) 5 (ppm) -113.35 - -126.46 (m).36 'HNMR (400 MHz, CDC13) 5 (ppm) 9.23 (s, 1H), 8.54 (s, 1H), 8.41 (s,1H), 8.27 (dt, J = 5.7, 2.8 Hz, 2H), 8.20 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.81 (s, 1H), 7.78 - 7.69 (m, 2H), 7.63 (t, J = 7.9 Hz, 1H), 7.26 (d, J = 3.8 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.18 (t, J = 54.7 Hz, 1H), 4.93 (d, J = 5.1 Hz, 2H), 4.23 (dd, J = 12.8, 2.4 Hz, 2H), 3.78 (ddt, J = 11.4, 7.6, 3.8 Hz, 2H), 2.62 (dd, J = 12.6, 10.5 Hz, 2H), 1.33 (d, J = 6.2 Hz, 6H).37 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.68 (s, 1H), 9.40 (s, 1H), 9.25(s, 1H), 8.72 (s, 1H), 8.29 - 8.22 (m, 2H), 7.90 - 7.80 (m, 2H), 5.52 (s, 1H), 4.79 (s, 2H), 3.42 (s, 3H), 3.36 (s, 6H), 3.20 (s, 3H), 1.14 (s, 12H).38 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.68 (t, J = 5.8 Hz, 1H), 9.41(s, 1H), 9.27 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.86 - 7.82 (m, 1H), 5.53 (s, 1H), 4.80 (d, J = 5.7 Hz, 2H), 4.14 - 3.98 (m, 2H), 3.63 - 3.44 (m, 2H), 3.40 - 3.35 (m, 3H), 3.21 (s, 3H), 2.91 (s, 3H), 2.48 - 2.39 (m, 2H), 1.10 (d, J = 6.2 Hz, 6H)39 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.62 - 9.71 (m, 1 H) 9.32 (s, 1H) 9.27 (d, J=2.0 Hz, 1 H) 8.74 (d, J=2.0 Hz, 1 H) 8.19 - 8.28 (m, 2 H) 7.99 (dd, J=8.4, 1.8 Hz, 1 H) 7.81 - 7.88 (m, 3 H) 7.50 - 7.58 (m, 2 H) 7.42 - 7.49 (m, 1 H) 4.76 - 4.85 (m, 2 H) 3.36 (s, 3 H) 2.92 (s, 3 H)Co. No. NMR peaks list40 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.56 - 9.64 (m, 1 H) 9.30 - 9.34(m, 1 H) 8.33 - 8.38 (m, 1 H) 8.20 - 8.30 (m, 2 H) 8.11 (s, 1 H) 7.96 - 8.04 (m, 2 H) 7.83 - 7.88 (m, 3 H) 7.51 - 7.57 (m, 2 H) 7.42 - 7.49 (m, 1 H) 4.76 - 4.81 (m, 2 H) 3.32 (s, 3 H)41 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.37 (d, J = 6.8 Hz, 2H), 8.76 - 8.74 (m, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.38 (dd, J = 8.7, 1.7 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 7.9, 2.0 Hz, 1H), 7.87 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 4.77 (d, J = 5.8 Hz, 2H), 4.67 (d, J = 12.9 Hz, 2H), 4.37 (s, 1H), 3.66 - 3.55 (m, 2H), 3.12 (s, 3H), 2.75 (s, 3H), 2.60 (dd, J = 13.2, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).42 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.42 (br t, J=5.8 Hz, 1 H) 9.32(s, 1 H) 8.62 (d, J=1.8 Hz, 1 H) 8.24 (s, 1 H) 8.18 - 8.22 (m, 1 H) 8.12 - 8.18 (m, 1 H) 7.93 - 8.01 (m, 1 H) 7.77 - 7.89 (m, 3 H) 7.48 - 7.58 (m, 3 H) 7.41 - 7.48 (m, 1 H) 4.80 (br d, J=5.7 Hz, 2 H) 4.40 (s, 1 H) 3.15 (s, 3 H) 2.77 (s, 3 H)43 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.64 (t, J = 5.6 Hz, 1H), 9.31 (s, 1H), 8.54 (dd, J = 17.4, 9.6 Hz, 3H), 8.32 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H), 7.95 (t, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.53 - 7.23 (m, 2H), 6.82 (d, J = 8.5 Hz, 1H), 4.78 (d, J = 5.8 Hz, 2H), 3.60 (s, 2H), 3.44 (s, 2H), 2.88 (s, 2H), 0.53 (s, 2H), 0.48 (s, 2H).44 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.55 (t, J = 5.7 Hz, 1H), 9.37 (s, 1H), 8.75 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.44 (dd, J = 6.7, 2.1 Hz, 1H), 8.40 - 8.33 (m, 2H), 8.24 (d, J = 8.6 Hz, 1H), 7.90 (s, 1H), 7.69 - 7.62 (m, 1H), 7.42 (d, J = 5.1 Hz, 1H), 4.87 (t, J = 5.2 Hz, 1H), 4.77 (d, J = 5.7 Hz, 2H), 4.67 (d, J = 12.6 Hz, 2H), 3.76 (q, J = 5.5 Hz, 2H), 3.61 (dd, J= 11.1, 5.6 Hz, 4H), 2.60 (dd, J = 12.9, 10.8 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).45 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.65 (t, J = 5.7 Hz, 1H), 9.31 (s, 1H), 8.56 (d, J = 10.2 Hz, 2H), 8.52 (d, J = 7.9 Hz, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.18 (dd, J = 8.2, 4.1 Hz, 2H), 7.94 (t, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.53 - 7.22 (m, 2H), 6.92 (d, J = 8.5 Hz, 1H), 4.78 (d, J = 5.6 Hz, 2H), 4.55 (d, J = 7.0 Hz, 1H), 4.41 (d, J = 10.3 Hz, 2H), 2.72 (dd, J = 16.8, 9.5 Hz, 1H), 2.58 - 2.52 (m, 2H), 1.54 - 1.39 (m, 2H), 1.00 (d, J = 6.4 Hz, 6H).Co. No. NMR peaks list46 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.39 (d, J = 6.0 Hz, 1H), 9.37(s, 1H), 8.76 - 8.71 (m, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.38 (dd, J = 8.7, 1.7 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 7.9, 2.0 Hz, 1H), 7.87 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H), 4.77 (d, J = 5.9 Hz, 2H), 4.67 (d, J = 12.9 Hz, 2H), 4.37 (d, J = 1.5 Hz, 1H), 3.67 - 3.54 (m, 2H), 3.12 (s, 3H), 2.75 (s, 3H), 2.60 (dd, J= 13.2, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).47 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.39 (d, J = 6.0 Hz, 1H), 9.37(s, 1H), 8.74 (d, J = 1.5 Hz, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.38 (dd, J = 8.6, 1.7 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 7.9, 2.0 Hz, 1H), 7.87 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 4.77 (d, J = 5.8 Hz, 2H), 4.67 (d, J = 13.0 Hz, 2H), 4.37 (d, J = 1.5 Hz, 1H), 3.67 - 3.53 (m, 2H), 3.12 (d, J = 1.2 Hz, 3H), 2.75 (s, 3H), 2.60 (dd, J = 13.1, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).48 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.42 - 9.32 (m, 2H), 8.75 (s,1H), 8.54 - 8.46 (m, 2H), 8.38 (dd, J = 8.6, 1.7 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.11 (dd, J = 7.8, 2.0 Hz, 1H), 7.88 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H), 4.81 (t, J = 5.6 Hz, 1H), 4.77 (d, J = 5.8 Hz, 2H), 4.71 - 4.64 (m, 2H), 4.48 (s, 1H), 3.73 - 3.53 (m, 4H), 3.45 - 3.35 (m, 2H), 2.74 (s, 3H), 2.60 (dd, J = 13.1, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).49 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.90 (t, J = 5.8 Hz, 1H), 9.44 (s, 1H), 9.31 (s, 1H), 8.97 (s, 1H), 8.63 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.89 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 4.76 (d, J = 5.7 Hz, 2H), 3.78 (s, 2H), 3.64 (s, 2H), 3.39 (s, 3H), 2.81 - 2.73 (m, 2H), 1.16 (s, 1H), 0.46 (d, J = 6.3 Hz, 2H), 0.39 (t, J = 4.8 Hz, 2H).50 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.03 (br s, 2 H) 1.23 - 1.29 (m,2 H) 2.16 (s, 3 H) 2.91 (s, 3 H) 3.37 (s, 3 H) 3.54 (s, 2 H) 3.57 - 3.83 (m, 4 H) 4.78 (d, J=5.6 Hz, 2 H) 6.86 (d, J=8.6 Hz, 1 H) 7.44 (d, J=7.4 Hz, 1 H) 7.65 - 7.72 (m, 1 H) 7.88 (s, 1 H) 8.18 (d, J=8.7 Hz, 1 H) 8.33 (dd, J=8.6, 1.5 Hz, 1 H) 8.59 (s, 1 H) 8.74 (d, J=2.1 Hz, 1 H) 9.27 (d, J=2.1 Hz, 1 H) 9.31 (s, 1 H) 9.65 (t, J=5.9 Hz, 1 H)51 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.67 (t, J = 5.9 Hz, 1H), 9.35 (s, 1H), 9.26 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.64 (s, 1H), 8.24 (dt, J = 20.6, 5.0 Hz, 2H), 7.83 (s, 1H), 6.89 (s, 1H), 4.78 (d, J = 5.7 Hz, 2H), 4.69 - 4.50 (m, 1H), 3.94 (dd, J = 8.3, 6.3 Hz, 1H), 3.87 (d, J = 12.6 Hz, 1H), 3.66 (d, J = 13.2 Hz, 1H), 3.44 (s, 3H), 3.31 (s, 3H), 3.11 - 3.02 (m, 1H), 2.90 (s, 3H), 2.81 (dd, J= 13.2, 10.7 Hz, 1H), 1.20 (d, J = 6.2 Hz, 3H).Co. No. NMR peaks list5219F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.37 (s, 1 F) -124.23 (s, 1F)52 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.99 - 2.07 (m, 2 H) 2.44 - 2.48(m, 1 H) 3.96 (s, 2 H) 3.99 - 4.08 (m, 3 H) 4.79 (d, J=5.7 Hz, 2 H) 5.05 (d, J=6.2 Hz, 1 H) 6.39 (d, J=8.2 Hz, 1 H) 7.39 (t, J=52.0 Hz, 1 H) 7.40 (d, J=7.5 Hz, 1 H) 7.64 (t, J=7.8 Hz, 1 H) 7.84 (s, 1 H) 7.95 (t, J=7.8 Hz, 1 H) 8.15 - 8.21 (m, 2 H) 8.32 (dd, J=8.6, 1.6 Hz, 1 H) 8.52 (dd, J=7.9, 1.1 Hz, 1 H) 8.54 - 8.59 (m, 2 H) 9.31 (s, 1 H) 9.64 (t, J=5.9 Hz, 1 H) 53 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.66 (t, J = 5.8 Hz, 1H), 9.33 (d, J = 13.3 Hz, 1H), 9.26 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.65 (s, 1H), 8.26 (dd, J = 8.6, 1.4 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.88 (s, 1H), 6.83 (d, J = 7.5 Hz, 1H), 4.78 (d, J = 5.7 Hz, 2H), 3.79 (dd, J = 8.6, 6.4 Hz, 2H), 3.61 (d, J = 12.4 Hz, 2H), 3.42 (s, 3H), 3.36 (s, 3H), 2.91 (s, 3H), 2.65 (dd, J= 12.6, 10.7 Hz, 2H), 1.15 (d, J = 6.2 Hz, 6H).54 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.67 (t, J = 5.7 Hz, 1H), 9.41(s, 1H), 9.26 (d, J = 1.8 Hz, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.30 - 8.22 (m, 2H), 7.88 (s, 1H), 7.85 - 7.79 (m, 1H), 5.59 (s, 1H), 4.79 (d, J = 5.6 Hz, 2H), 4.48 (d, J = 7.3 Hz, 1H), 4.11 (s, 1H), 3.82 (ddd, J = 31.2, 20.6, 9.4 Hz, 3H), 3.36 (s, 3H), 3.23 (s, 3H), 3.16 (dd, J = 13.2, 7.9 Hz, 1H), 2.90 (s, 3H), 1.18 (dd, J = 6.5, 4.6 Hz, 3H).55 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.38 (s, 1H), 9.29 (t, J = 5.6 Hz, 1H), 9.23 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 5.59 (s, 1H), 4.82 (d, J = 5.8 Hz, 2H), 4.33 (d, J = 12.7 Hz, 1H), 4.29 - 4.18 (m, 1H), 4.07 (d, J = 12.4 Hz, 1H), 3.86 - 3.72 (m, 1H), 3.31 (s, 3H), 3.26 (s, 3H), 2.91 (s, 3H), 2.69 - 2.60 (m, 2H), 1.21 (d, J = 6.2 Hz, 3H).5619F NMR (376 MHz, DMSO-d6) 5 (ppm) -120.73 (d, J = 258.5 Hz), - 122.64 (d, J = 258.4 Hz).Co. No. NMR peaks list56 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.58 (t, J = 5.9 Hz, 1H), 9.37(s, 1H), 8.80 - 8.72 (m, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.40 (ddd, J = 10.4, 8.4, 1.5 Hz, 2H), 8.24 (d, J = 8.7 Hz, 1H), 8.15 (dt, J = 8.1, 1.3 Hz, 1H), 7.90 (s, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 6.95 (t, J = 53.5 Hz, 1H), 5.79 (d, J = 1.8 Hz, 1H), 4.79 (d, J = 5.8 Hz, 2H), 4.67 (d, J = 13.0 Hz, 2H), 3.61 (ddd, J = 10.5, 6.2, 2.6 Hz, 1H), 2.60 (dd, J= 13.2, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).57 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.66 (t, J=5.7 Hz, 1 H) 9.32 (s,1 H) 8.51 - 8.57 (m, 2 H) 8.27 (s, 1 H) 8.20 (t, J=8.9 Hz, 2 H) 7.92 - 8.03 (m, 2 H) 7.81 - 7.89 (m, 3 H) 7.49 - 7.56 (m, 2 H) 7.42 - 7.48 (m, 1 H) 7.22 - 7.57 (m, 1 H) 4.79 (d, J=5.7 Hz, 2 H)58 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.67 (t, J = 5.8 Hz, 1H), 9.35(s, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.67 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.89 (s, 1H), 6.88 (s, 1H), 4.78 (d, J = 5.7 Hz, 2H), 3.52 (s, 3H), 3.36 (s, 3H), 3.15 (s, 4H), 2.91 (s, 3H), 1.29 (s, 12H).59 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.37 (d, J = 4.2 Hz, 2H), 8.75(d, J = 1.4 Hz, 1H), 8.54 - 8.49 (m, 2H), 8.39 (dd, J = 8.6, 1.7 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.11 (dd, J = 7.8, 2.0 Hz, 1H), 7.88 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 5.1 Hz, 1H), 4.80 (t, J = 5.6 Hz, 1H), 4.77 (d, J = 5.8 Hz, 2H), 4.67 (d, J = 12.9 Hz, 2H), 4.48 (s, 1H), 3.71 - 3.54 (m, 4H), 3.38 (dd, J = 8.1, 5.0 Hz, 2H), 2.74 (s, 3H), 2.60 (dd, J= 13.1, 10.6 Hz, 2H), 1.20 (d, J = 6.2 Hz, 6H).60 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.37 (d, J = 4.2 Hz, 2H), 8.75(s, 1H), 8.52 (d, J = 5.2 Hz, 2H), 8.39 (dd, J = 8.6, 1.7 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 7.9, 2.0 Hz, 1H), 7.88 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 5.1 Hz, 1H), 4.81 (t, J = 5.6 Hz, 1H), 4.77 (d, J = 5.8 Hz, 2H), 4.68 (d, J = 12.9 Hz, 2H), 4.48 (s, 1H), 3.72 - 3.55 (m, 4H), 3.38 (td, J = 6.7, 6.2, 2.9 Hz, 2H), 2.74 (s, 3H), 2.60 (dd, J = 13.1, 10.6 Hz, 2H), 1.20 (d, J = 6.2 Hz, 6H).6119F NMR (376 MHz, DMSO-d6) 5 (ppm) -120.73 (d, J = 258.5 Hz), - 122.64 (d, J = 258.4 Hz).Co. No. NMR peaks list61 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.58 (t, J = 5.9 Hz, 1H), 9.37 (s, 1H), 8.76 (s, 1H), 8.54 (t, J = 1.8 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.40 (d, J= 10.3 Hz, 2H), 8.24 (d, J = 8.6 Hz, 1H), 8.17 - 8.11 (m, 1H), 7.90 (s, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 6.95 (t, J = 53.5 Hz, 1H), 5.79 (s, 1H), 4.79 (d, J = 5.8 Hz, 2H), 4.67 (d, J = 12.9 Hz, 2H), 3.67 - 3.54 (m, 2H), 2.60 (dd, J = 13.1, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).6219F NMR (376 MHz, DMSO-d6) 5 (ppm) -120.73 (d, J = 258.7 Hz), - 122.64 (d, J = 258.6 Hz).62 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.59 (t, J = 5.9 Hz, 1H), 9.37 (s, 1H), 8.76 (s, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.44 - 8.33 (m, 2H), 8.24 (d, J = 8.6 Hz, 1H), 8.21 - 8.09 (m, 1H), 7.90 (s, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H), 6.95 (t, J = 53.5 Hz, 1H), 5.79 (d, J = 1.7 Hz, 1H), 4.79 (d, J = 5.8 Hz, 2H), 4.67 (d, J = 12.9 Hz, 2H), 3.71 - 3.43 (m, 2H), 2.60 (dd, J = 13.1, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).63 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.77 (t, J = 5.8 Hz, 1H), 9.43 (d, J = 1.9 Hz, 1H), 9.31 (s, 1H), 8.82 (s, 1H), 8.64 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.30 - 8.25 (m, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.89 (s, 1H), 7.71 - 7.41 (m, 1H), 7.27 (d, J = 5.1 Hz, 1H), 4.76 (d, J = 5.7 Hz, 2H), 3.80 (s, 2H), 3.66 (s, 2H), 3.42 (s, 3H), 2.84 - 2.73 (m, 2H), 1.16 (s, 1H), 0.47 (t, J = 5.1 Hz, 2H), 0.42 (t, J = 5.0 Hz, 2H).64 'HNMR (400 MHz, CDC13) 5 (ppm) 9.24 (s, 1H), 8.53 (s, 1H), 8.41 (s,1H), 8.28 (dt, J = 8.7, 1.9 Hz, 2H), 8.20 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.81 (s, 1H), 7.76 - 7.67 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.17 (t, J = 54.7 Hz, 1H), 4.93 (d, J = 5.1 Hz, 2H), 4.24 (dd, J = 12.8, 2.4 Hz, 2H), 3.87 - 3.75 (m, 2H), 3.50 (s, 1H), 2.62 (dd, J = 12.7, 10.5 Hz, 2H), 1.33 (d, J = 6.2 Hz, 6H).65 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 9.68 (t, 1H, J=5.9 Hz), 9.40 (s,1H), 9.29 (d, 1H, J=2.2 Hz), 8.82 (s, 1H), 8.75 (d, 2H, J=3.3 Hz), 8.75 (s, 1H), 8.48 (dd, 1H, J=1.8, 8.6 Hz), 8.28 (d, 1H, J=8.6 Hz), 7.91 (s, 2H), 7.84 (d, 1H, J=5.3 Hz), 7.44 (s, 1H), 4.81 (d, 3H, J=5.7 Hz), 3.88 (s, 3H), 3.4-3.4 (m, 4H), 2.92 (s, 3H), 1.3-1.3 (m, 7H) 66 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 9.67 (t, 1H, J=5.9 Hz), 9.39 (s,1H), 8.82 (s, 1H), 8.74 (d, 1H, J=5.1 Hz), 8.55 (t, 1H, J=1.7 Hz), 8.52 (td, 1H, J=1.4, 7.8 Hz), 8.47 (dd, 1H, J=1.7, 8.7 Hz), 8.27 (d, 1H, J=8.8 Hz), 8.18 (d, 1H, J=8.4 Hz), 7.95 (t, 1H, J=7.7 Hz), 7.89 (s, 1H), 7.83 (d, 1H, J=5.3 Hz), 7.43 (s, 1H), 7.38 (t, 1H, J=52.0 Hz), 4.81 (d, 2H, J=5.7 Hz), 3.88 (s, 2H), 1.31 (s, 6H)Co. No. NMR peaks list6719F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.35 (s, 1 F) -124.21 (s, 1F)67 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.01 (d, J=6.5 Hz, 6 H) 1.34 - 1.50 (m, 2 H) 2.58 (t, J=12.5 Hz, 2 H) 2.70 - 2.81 (m, 1 H) 4.62 (br d, J=5.1 Hz, 1 H) 4.78 (br s, 1 H) 4.80 (br d, J=5.5 Hz, 3 H) 7.38 (t, J=52.0 Hz, 1 H) 7.34 (d, J=5.2 Hz, 1 H) 7.92 (s, 1 H) 7.95 (t, J=7.8 Hz, 1 H) 8.18 (d, J=7.8 Hz, 1 H) 8.25 (d, J=8.8 Hz, 1 H) 8.36 (dd, J=8.7, 1.5 Hz, 1 H) 8.49 (d, J=5.1 Hz, 1 H) 8.52 (d, J=7.9 Hz, 1 H) 8.55 (s, 1 H) 8.72 (s, 1 H) 9.37 (s, 1 H) 9.67 (t, J=5.8 Hz, 1 H)6819F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.35 (s, 1 F) -124.21 (s, 1F)681H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.00 - 2.08 (m, 2 H) 2.44 - 2.50(m, 2 H) 3.98 - 4.04 (m, 1 H) 4.09 (br d, J=21.5 Hz, 4 H) 4.80 (d, J=5.4 Hz, 2 H) 5.00 - 5.16 (m, 1 H) 7.24 - 7.54 (m, 1 H) 7.40 (d, J=5.3 Hz, 1 H) 7.88 (s, 1 H) 7.96 (t, J=7.8 Hz, 1 H) 8.19 (d, J=8.0 Hz, 1 H) 8.23 (d, J=8.7 Hz, 1 H) 8.34 (dd, J=8.6, 1.6 Hz, 1 H) 8.47 (d, J=5.1 Hz, 1 H) 8.50 - 8.54 (m, 1 H) 8.55 (d, J=1.6 Hz, 1 H) 8.70 (s, 1 H) 9.37 (s, 1 H) 9.67 (brt, J=5.6 Hz, 1 H)6919F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.35 (s, 1 F) -109.75 (s, 1F)691H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.48 - 1.62 (m, 1 H) 1.69 - 1.81(m, 2 H) 1.89 (dt, J=8.8, 4.3 Hz, 1 H) 3.12 - 3.24 (m, 2 H) 3.49 - 3.60 (m, 1 H) 3.77 (ddd, J=24.2, 13.9, 2.9 Hz, 1 H) 4.43 (br d, J=13.4 Hz, 1 H) 4.65 - 4.77 (m, 1 H) 4.80 (d, J=5.7 Hz, 2 H) 7.38 (t, J=52.0 Hz, 1 H) 7.45 (d, J=5.1 Hz, 1 H) 7.91 - 7.99 (m, 2 H) 8.18 (d, J=7.9 Hz, 1 H) 8.25 (d, J=8.7 Hz, 1 H) 8.38 (dd, J=8.6, 1.6 Hz, 1 H) 8.49 - 8.58 (m, 3 H) 8.76 (s, 1 H) 9.38 (s, 1 H) 9.67 (t, J=5.8 Hz, 1 H)7019F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.37 (s, 1 F) -124.23 (s, 1F)Co. No. NMR peaks list70 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.48 - 1.58 (m, 3 H) 1.63 (ddd,J=9.7, 7.2, 2.3 Hz, 2 H) 1.73 - 1.79 (m, 1 H) 2.20 (ddd, J=9.8, 7.4, 2.5 Hz, 2 H) 3.57 - 3.64 (m, 1 H) 3.80 (dt, J=18.1, 5.1 Hz, 3 H) 4.15 (dq, J=13.6, 6.8 Hz, 1 H) 4.80 (br d, J=5.6 Hz, 2 H) 4.93 (br d, J=6.1 Hz, 1 H) 7.39 (t, J=52.0 Hz, 1 H) 7.33 (d, J=5.1 Hz, 1 H) 7.86 - 8.01 (m, 2 H) 8.14 - 8.27 (m, 2 H) 8.35 (dd, J=8.6, 1.6 Hz, 1 H) 8.48 (d, J=5.1 Hz, 1 H) 8.50 - 8.59 (m, 2 H) 8.72 (s, 1 H) 9.36 (s, 1 H) 9.66 (br t, J=5.8 Hz, 1 H)123 'H NMR (DMSO-d6, 400 MHz) 5 (ppm) 9.38 (br t, 1H, J=5.7 Hz), 9.33(s, 1H), 8.66 (s, 1H), 8.52 (t, 1H, J=1.6 Hz), 8.4-8.5 (m, 2H), 8.35 (dd, 1H, J=1.7, 8.6 Hz), 8.21 (d, 1H, J=8.7 Hz), 8.14 (td, 1H, J=1.4, 7.9 Hz), 7.9-7.9 (m, 2H), 7.30 (d, 1H, J=5.2 Hz), 7.26 (t, 1H, J=52.2 Hz), 4.80 (d, 2H, J=5.7 Hz), 3.83 (d, 1H, J=12.1 Hz), 3.7-3.7 (m, 2H), 3.6-3.7 (m, 3H), 2.8-2.9 (m, 2H), 2.74 (t, 2H, J=4.8 Hz), 2.1-2.2 (m, 1H), 2.0-2.1 (m, 1H)12319F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.35 (s, 1 F) -124.21 (s, 1F)124 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 11.37 (br s, 1H), 9.67 (br t, J =5.6 Hz, 1H), 9.35 (s, 1H), 9.30 - 9.25 (m, 1H), 8.76 - 8.71 (m, 1H), 8.64 (s, 1H), 8.26 (br d, J = 8.9 Hz, 1H), 8.23 - 8.14 (m, 1H), 7.91 (s, 1H), 6.48 (br s, 1H), 4.79 (br d, J = 5.6 Hz, 2H), 4.50 (br d, J = 11.9 Hz, 2H), 3.67 - 3.54 (m, 2H), 3.37 (s, 3H), 2.91 (s, 3H), 2.60 (brt, J = 11.9 Hz, 2H), 1.17 (d, J = 6.1 Hz, 6H)125 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.69 (t, J = 5.8 Hz, 1H), 9.36 (s, 1H), 9.28 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.65 (s, 1H), 8.25 (dt, J = 20.6, 5.1 Hz, 2H), 7.82 (d, J = 14.7 Hz, 1H), 6.90 (s, 1H), 4.79 (d, J = 5.8 Hz, 2H), 4.71 - 4.53 (m, 1H), 4.00 - 3.91 (m, 1H), 3.92 - 3.84 (m, 1H), 3.66 (t, J = 13.4 Hz, 1H), 3.45 (s, 3H), 3.37 (s, 3H), 3.08 (dd, J= 12.5, 11.0 Hz, 1H), 2.92 (s, 3H), 2.82 (dd, J = 13.3, 10.7 Hz, 1H), 1.20 (t, J = 6.6 Hz, 3H).126 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.68 (t, J = 5.8 Hz, 1H), 9.36 (s, 1H), 9.28 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.65 (s, 1H), 8.25 (dt, J = 20.5, 5.1 Hz, 2H), 7.84 (s, 1H), 6.90 (s, 1H), 4.79 (d, J = 5.8 Hz, 2H), 4.70 - 4.53 (m, 1H), 3.94 (dd, J = 16.5, 10.3 Hz, 1H), 3.88 (d, J = 12.8 Hz, 1H), 3.67 (d, J = 13.1 Hz, 1H), 3.45 (s, 3H), 3.36 (d, J = 12.0 Hz, 3H), 3.15 - 3.00 (m, 1H), 2.92 (s, 3H), 2.81 (dt, J = 26.7, 13.4 Hz, 1H), 1.21 (d, J = 6.2 Hz, 3H).Co. No. NMR peaks list127 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 10.84 (s, 1H), 9.66 (s, 1H),9.37 (s, 1H), 8.74 (s, 1H), 8.60 (s, 1H), 8.5-8.6 (m, 2H), 8.52 (d, 1H, J=7.7 Hz), 8.34 (d, 1H, J=1.8 Hz), 8.25 (d, 1H, J=8.8 Hz), 8.17 (s, 1H), 7.9-8.0 (m, 1H), 7.89 (s, 1H), 7.52 (d, 1H, J=5.3 Hz), 7.38 (t, 1H, J=52.0 Hz), 4.80 (d, 2H, J=5.7 Hz), 4.41 (s, 2H), 4.22 (br d, 2H, J=9.5 Hz), 2.5- 2.6 (m, 12H)192 'HNMR (500 MHz, DMSO-d6) 5 (ppm) 9.41 (t, J = 5.9 Hz, 1H), 9.31(s, 1H), 8.43 (d, J = 1.9 Hz, 1H), 8.16 (dd, J = 7.9, 2.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.0, 1.4 Hz, 2H), 7.74 (s, 1H), 7.61 - 7.52 (m, 2H), 7.38 (td, J = 7.7, 1.5 Hz, 1H), 7.25 (td, J = 7.4, 1.4 Hz, 1H), 7.01 (dd, J = 7.5, 1.5 Hz, 1H), 4.83 (d, J = 8.5 Hz, 2H), 4.74 (d, J = 5.8 Hz, 2H), 3.71 (q, J = 5.7 Hz, 2H), 3.50 (t, J = 6.1 Hz, 2H), 2.69 (s, 3H), 1.25 (s, 6H).225 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.69 (s, 1H), 9.37 (s, 1H), 8.66(s, 1H), 8.55 (t, J = 1.5 Hz, 1H), 8.52 (dd, J = 7.9, 1.5 Hz, 1H), 8.42 (dd, J = 8.6, 1.7 Hz, 1H), 8.37 (d, J = 9.3 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.40 (d, J = 9.3 Hz, 1H), 7.39 (t, J = 50.8 Hz, 1H), 4.80 (s, 2H), 4.11 (s, 3H). 226 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 0.78 - 1.13 (m, 4 H) 2.06 (br d,J=7.7 Hz, 1 H) 2.08 - 2.25 (m, 3 H) 2.91 (s, 3 H) 3.37 (s, 3 H) 3.60 - 4.04 (m, 5 H) 4.80 (d, J=5.7 Hz, 2 H) 7.40 (d, J=5.1 Hz, 1 H) 7.91 (s, 1 H) 8.24 (d, J=8.8 Hz, 1 H) 8.37 (dd, J=8.6, 1.5 Hz, 1 H) 8.51 (d, J=5.1 Hz, 1 H) 8.74 (d, J=2.0 Hz, 2 H) 9.27 (d, J=2.2 Hz, 1 H) 9.37 (s, 1 H) 9.66 (brt, J=5.7 Hz, 1 H)227 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.67 (t, J = 5.6 Hz, 1H), 9.41(s, 1H), 9.26 (d, J = 1.7 Hz, 1H), 8.71 (d, J = 1.7 Hz, 1H), 8.26 (t, J = 6.3 Hz, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 5.59 (s, 1H), 4.79 (d, J = 5.6 Hz, 2H), 4.48 (d, J = 7.2 Hz, 1H), 4.11 (s, 1H), 3.89 - 3.70 (m, 3H), 3.36 (s, 3H), 3.23 (s, 3H), 3.16 (dd, J = 13.1, 7.9 Hz, 1H), 2.90 (d, J = 4.8 Hz, 3H), 1.17 (d, J = 6.2 Hz, 3H).228 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 9.3-9.4 (m, 2H), 8.70 (s, 1H),8.46 (d, 1H, J=5.3 Hz), 8.34 (dd, 1H, J=1.5, 8.6 Hz), 8.23 (d, 1H, J=8.6 Hz), 8.12 (t, 1H, J=1.7 Hz), 7.98 (td, 1H, J=1.3, 7.8 Hz), 7.84 (s, 1H), 7.7-7.8 (m, 1H), 7.5-7.6 (m, 1H), 7.40 (d, 1H, J=5.1 Hz), 5.05 (br d, 1H, J=5.5 Hz), 4.79 (d, 2H, J=5.7 Hz), 4.0-4.2 (m, 5H), 2.4-2.5 (m, 1H), 2.0- 2.1 (m, 2H), 1.75 (s, 6H)Co. No. NMR peaks list229 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 9.34 (s, 1H), 9.10 (t, 1H, J=5.8Hz), 8.69 (s, 1H), 8.46 (d, 1H, J=5.1 Hz), 8.33 (dd, 1H, J=1.5, 8.6 Hz), 8.22 (d, 1H, J=8.8 Hz), 7.79 (s, 1H), 7.62 (d, 1H, J=2.2 Hz), 7.6-7.6 (m, 1H), 7.41 (d, 1H, J=5.1 Hz), 7.06 (d, 1H, J=8.4 Hz), 5.05 (br d, 1H, J=6.2 Hz), 4.73 (d, 2H, J=5.9 Hz), 4.21 (td, 5H, J=5.6, 8.7 Hz), 4.0-4.1 (m, 6H), 2.5-2.5 (m, 2H), 2.16 (quin, 3H, J=5.6 Hz), 2.0-2.1 (m, 3H) 230 'HNMR (400 MHz, CDC13) 5 (ppm) 1.33 (d, J=6.48 Hz, 3 H) 3.41 (dd,J=13.33, 8.41 Hz, 1 H) 3.76 - 3.85 (m, 1 H) 4.28 (d, J=18.71 Hz, 1 H) 4.64 (dd, J=13.33, 3.61 Hz, 1 H) 4.88 (d, J=18.60 Hz, 1 H) 4.96 (d, J=5.23 Hz, 2 H) 6.25 (t, J=53.30 Hz, 1 H) 6.21 (br s, 1 H) 7.18 (d, J=5.12 Hz, 1 H) 7.77 (t, J=7.94 Hz, 1 H) 7.79 - 7.83 (m, 1 H) 7.85 (s, 1 H) 8.08 (d, J=8.57 Hz, 1 H) 8.13 (d, J=7.94 Hz, 1 H) 8.28 (dd, J=8.57, 1.46 Hz, 1 H) 8.36 (d, J=7.94 Hz, 1 H) 8.47 - 8.52 (m, 3 H) 9.29 (s, 1 H) 23119F NMR (376 MHz, DMSO-d6) 5 (ppm) -110.49.231 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.56 (t, J = 5.9 Hz, 1H), 9.37(s, 1H), 8.76 (s, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.42 - 8.35 (m, 2H), 8.24 (d, J = 8.6 Hz, 1H), 8.06 (dt, J = 9.4, 2.0 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 5.1 Hz, 1H), 4.79 (d, J = 5.8 Hz, 2H), 4.68 (d, J = 12.9 Hz, 2H), 4.50 (s, 1H), 3.61 (ddd, J = 9.1, 6.6, 2.5 Hz, 2H), 3.16 (s, 3H), 2.60 (dd, J= 13.1, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).232 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.56 (t, J = 5.9 Hz, 1H), 9.37(s, 1H), 8.76 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.41 - 8.35 (m, 2H), 8.24 (d, J = 8.6 Hz, 1H), 8.06 (dt, J = 9.3, 2.0 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 5.1 Hz, 1H), 4.79 (d, J = 5.8 Hz, 2H), 4.67 (d, J = 12.9 Hz, 2H), 4.50 (s, 1H), 3.67 - 3.52 (m, 2H), 3.16 (s, 3H), 2.64 - 2.57 (m, 2H), 1.19 (d, J = 6.1 Hz, 6H).23219F NMR (376 MHz, DMSO-d6) 5 (ppm) -110.49.233 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 0.78 - 1.14 (m, 4 H) 2.00 - 2.21(m, 3 H) 3.17 (d, J=5.0 Hz, 1 H) 3.55 - 4.12 (m, 6 H) 4.80 (d, J=5.6 Hz, 2 H) 7.39 (br t, J=52.0 Hz, 1 H) 7.41 (d, J=5.2 Hz, 1 H) 7.91 (s, 1 H) 7.95 (t, J=7.8 Hz, 1 H) 8.18 (d, J=8.0 Hz, 1 H) 8.24 (d, J=8.7 Hz, 1 H) 8.37 (dd, J=8.6, 1.3 Hz, 1 H) 8.48 - 8.54 (m, 2 H) 8.55 (d, J=1.6 Hz, 1 H) 8.75 (s, 1 H) 9.37 (s, 1 H) 9.67 (t, J=5.7 Hz, 1 H)Co. No. NMR peaks list234 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.67 (t, J = 5.8 Hz, 1H), 9.41(s, 1H), 9.26 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.83 (dd, J = 8.5, 1.5 Hz, 1H), 5.59 (s, 1H), 4.79 (d, J = 5.7 Hz, 2H), 4.48 (d, J = 7.6 Hz, 1H), 4.11 (s, 1H), 3.88 - 3.79 (m, 2H), 3.76 (d, J = 12.2 Hz, 1H), 3.36 (s, 3H), 3.23 (s, 3H), 3.16 (dd, J = 13.2, 7.9 Hz, 1H), 2.90 (s, 3H), 1.17 (d, J = 6.3 Hz, 3H).295 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.16 (d, J=6.38 Hz, 3 H) 3.46(dd, J=13.31, 7.81 Hz, l H) 3.62 (br s, 1 H) 4.13 (d, J=18.27 Hz, 1 H) 4.37 (br dd, J=13.09, 3.19 Hz, 1 H) 4.47 (br d, J=18.27 Hz, 1 H) 4.80 (d, J=5.72 Hz, 2 H) 7.38 (t, J=52.05 Hz, 1 H) 7.46 (d, J=5.06 Hz, 1 H) 7.92 - 7.97 (m, 2 H) 8.15 (s, 1 H) 8.18 (d, J=8.36 Hz, 1 H) 8.26 (d, J=8.80 Hz, 1 H) 8.40 (dd, J=8.69, 1.65 Hz, 1 H) 8.52 (dt, J=7.70, 1.32 Hz, 1 H) 8.54 - 8.58 (m, 2 H) 8.78 (s, 1 H) 9.38 (s, 1 H) 9.65 (t, J=5.83 Hz, 1 H) 296 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.17 (d, J=6.38 Hz, 3 H) 3.46(br dd, J=12.98, 7.92 Hz, 1 H) 3.57 - 3.67 (m, 1 H) 4.14 (d, J=18.27 Hz, 1 H) 4.37 (br dd, J=13.09, 2.97 Hz, 1 H) 4.47 (br d, J=18.27 Hz, 1 H) 4.81 (d, J=5.72 Hz, 2 H) 7.38 (t, J=52.05 Hz, 1 H) 7.46 (d, J=5.06 Hz, 1 H) 7.90 - 7.99 (m, 2 H) 8.15 (s, 1 H) 8.18 (br d, J=8.14 Hz, 1 H) 8.26 (d, J=8.58 Hz, 1 H) 8.40 (dd, J=8.58, 1.32 Hz, 1 H) 8.52 (d, J=7.92 Hz, 1 H) 8.54 - 8.59 (m, 2 H) 8.77 (s, 1 H) 9.38 (s, 1 H) 9.65 (t, J=5.72 Hz, 1 H) 297 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.32 (s, 1H), 9.26 (t, J = 5.4 Hz, 1H), 8.57 (s, 1H), 8.52 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 8.22 (dd, J = 8.6, 1.5 Hz, 1H), 8.18 (s, 1H), 8.17 - 8.11 (m, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.21 (t, J = 52.3 Hz, 1H), 6.71 (s, 1H), 4.82 (d, J = 5.8 Hz, 2H), 4.32 (d, J = 6.6 Hz, 1H), 3.64 (d, J = 15.2 Hz, 2H), 3.44 (s, 3H), 2.78 - 2.72 (m, 1H), 2.72 - 2.64 (m, 2H), 1.81 - 1.68 (m, 2H), 1.01 (d, J = 6.5 Hz, 6H).313 'HNMR (DMSO-d6, 600 MHz) 5 (ppm) 9.68 (br t, 1H, J=5.3 Hz), 9.37(s, 1H), 8.72 (s, 1H), 8.5-8.6 (m, 1H), 8.5-8.6 (m, 1H), 8.49 (d, 1H, J=5.1 Hz), 8.35 (br d, 1H, J=8.6 Hz), 8.25 (d, 1H, J=8.4 Hz), 8.19 (br d, 1H, J=7.9 Hz), 7.96 (t, 1H, J=7.9 Hz), 7.90 (s, 1H), 7.42 (d, 1H, J=5.1 Hz), 7.39 (br t, 1H, J=52.0 Hz), 5.75 (br s, 1H), 4.80 (br d, 1H, J=5.5 Hz), 4.61 (br s, 1H), 4.34 (br t, 1H, J=7.6 Hz), 3.9-3.9 (m, 1H)314 'HNMR (DMSO-d6, 600 MHz) 5 (ppm) 9.69 (br t, 1H, J=5.5 Hz), 9.37(s, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 8.53 (br d, 1H, J=8.1 Hz), 8.50 (d, 1H, J=5.1 Hz), 8.36 (br d, 1H, J=8.8 Hz), 8.25 (d, 1H, J=8.8 Hz), 8.19 (br d, 1H, J=7.7 Hz), 7.96 (t, 1H, J=7.9 Hz), 7.89 (s, 1H), 7.44 (d, 1H, J=5.1 Hz), 7.39 (br t, 1H, J=52.1 Hz), 4.80 (br d, 2H, J=5.5 Hz), 4.3-4.4 (m, 3H), 3.95 (br d, 2H, J=7.3 Hz), 3.28 (s, 1H)Co. No. NMR peaks list316 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.67 (t, J = 5.8 Hz, 1H), 9.32(s, 1H), 8.66 (d, J = 2.6 Hz, 1H), 8.57 - 8.50 (m, 2H), 8.27 (s, 1H), 8.20 (dd, J = 13.2, 4.6 Hz, 3H), 8.01 - 7.93 (m, 2H), 7.79 (s, 1H), 7.39 (t, J = 52.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 5.31 - 5.23 (m, 1H), 4.79 (d, J = 5.8 Hz, 2H), 3.89 (dt, J = 11.5, 4.2 Hz, 2H), 3.57 - 3.48 (m, 2H), 2.09 - 2.01 (m, 2H), 1.72 - 1.62 (m, 2H).317 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.69 (t, J = 5.7 Hz, 1H), 9.33(s, 1H), 8.53 (dd, J= 11.4, 4.4 Hz, 3H), 8.33 (s, 1H), 8.27 (dd, J= 11.8, 1.9 Hz, 1H), 8.21 (t, J = 9.2 Hz, 2H), 8.03 (dd, J = 8.6, 1.4 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.39 (t, J = 52.0 Hz, 1H), 5.39 - 5.30 (m, 1H), 4.79 (d, J = 5.7 Hz, 2H), 3.89 (dt, J = 11.2, 4.1 Hz, 2H), 3.58 - 3.50 (m, 2H), 2.07 (d, J = 9.4 Hz, 2H), 1.78 - 1.65 (m, 2H).318 'HNMR (400 MHz, CDC13) 5 (ppm) 1.20 (d, J=6.38 Hz, 6 H) 2.55 (dd,J=12.76, 10.78 Hz, 2 H) 2.91 - 2.99 (m, 2 H) 4.79 - 4.86 (m, 2 H) 4.95 (d, J=5.06 Hz, 2 H) 6.22 (t, J=53.37 Hz, 1 H) 7.06 (d, J=5.06 Hz, 1 H) 7.58 - 7.63 (m, 1 H) 7.77 (t, J=7.70 Hz, 1 H) 7.85 (s, 1 H) 8.08 (d, J=8.36 Hz, 1 H) 8.13 (br d, J=7.26 Hz, 1 H) 8.27 (dd, J=8.80, 1.32 Hz, 1 H) 8.34 (d, J=7.70 Hz, 1 H) 8.44 - 8.49 (m, 3 H) 9.29 (s, 1 H)319 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.61 (t, J = 5.9 Hz, 1H), 9.20(s, 1H), 8.48 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 11.8 Hz, 2H), 8.07 (d, J = 8.7 Hz, 1H), 8.01 (dd, J = 12.4, 2.0 Hz, 1H), 7.89 (t, J = 8.0 Hz, 2H), 7.80 (s, 1H), 7.63 (s, 1H), 7.32 (t, J = 52.0 Hz, 1H), 4.70 (d, J = 5.7 Hz, 2H).320 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.58 (t, J = 5.8 Hz, 1H), 9.35(s, 1H), 8.65 (s, 1H), 8.54 (s, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.32 - 8.17 (m, 2H), 8.15 (d, J = 7.9 Hz, 1H), 7.90 - 7.76 (m, 2H), 6.92 (dd, J = 83.5, 30.0 Hz, 2H), 4.79 (d, J = 5.6 Hz, 2H), 4.70 (d, J = 6.8 Hz, 1H), 3.62 (t, J = 13.9 Hz, 2H), 3.40 (d, J = 12.6 Hz, 3H), 2.77 - 2.57 (m, 3H), 1.76 - 1.60 (m, 2H), 0.98 (d, J = 6.5 Hz, 6H).321 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 11.37 (s, 1H), 9.65 (t, J = 5.7Hz, 1H), 9.34 (s, 1H), 8.64 (s, 1H), 8.55 - 8.48 (m, 2H), 8.25 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H), 7.94 (t, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.38 (t, J = 52.0 Hz, 1H), 6.47 (s, 1H), 4.78 (d, J = 5.6 Hz, 2H), 4.49 (d, J = 12.4 Hz, 2H), 3.65 - 3.56 (m, 2H), 2.63 - 2.55 (m, 2H), 1.16 (d, J = 6.1 Hz, 6H).322 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.69 (t, J = 5.8 Hz, 1H), 9.34(s, 1H), 8.53 (dd, J = 14.5, 4.4 Hz, 3H), 8.33 (d, J = 15.7 Hz, 2H), 8.21 (dd, J = 12.3, 8.4 Hz, 2H), 8.03 (d, J = 8.8 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.39 (t, J = 52.0 Hz, 1H), 5.44 (t, J = 7.3 Hz, 1H), 4.79 (d, J = 5.7 Hz, 2H), 4.31 (s, 2H), 3.93 (d, J = 7.7 Hz, 2H), 1.40 (s, 9H).Co. No. NMR peaks list323 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.62 (s, 1H), 9.28 (s, 1H), 8.47(t, J = 7.9 Hz, 3H), 8.20 - 8.14 (m, 3H), 8.12 (d, J = 8.0 Hz, 1H), 7.89 (t, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.32 (t, J = 52.0 Hz, 1H), 7.05 (d, J = 9.8 Hz, 1H), 5.05 (tt, J= 11.5, 4.0 Hz, 1H), 4.73 (s, 2H), 3.95 (dd, J = 11.1, 4.0 Hz, 2H), 3.46 (t, J = 11.3 Hz, 2H), 2.08 - 1.96 (m, 2H), 1.74 (dd, J = 12.3, 2.2 Hz, 2H).325 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 9.3-9.4 (m, 1H), 9.3-9.4 (m,2H), 8.70 (s, 1H), 8.47 (d, 1H, J=5.1 Hz), 8.34 (dd, 1H, J=1.3, 8.6 Hz), 8.22 (d, 1H, J=8.6 Hz), 8.0-8.1 (m, 2H), 7.85 (s, 1H), 7.47 (dd, 1H, J=9.0, 11.2 Hz), 7.40 (d, 1H, J=5.3 Hz), 5.06 (d, 1H, J=5.9 Hz), 4.78 (d, 2H, J=5.7 Hz), 4.11 (s, 2H), 4.06 (s, 2H), 4.0-4.1 (m, 2H), 2.5-2.5 (m, 1H), 2.0-2.1 (m, 2H), 1.80 (s, 6H)326 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 9.68 (t, 1H, J=5.9 Hz), 9.40 (s,1H), 8.93 (d, 1H, J=5.3 Hz), 8.82 (s, 1H), 8.5-8.6 (m, 1H), 8.52 (td, 1H, J=1.4, 7.8 Hz), 8.41 (dd, 1H, J=1.7, 8.6 Hz), 8.30 (d, 1H, J=8.8 Hz), 8.18 (td, 1H, J=1.2, 8.0 Hz), 8.11 (d, 1H, J=5.3 Hz), 7.96 (t, 1H, J=7.8 Hz), 7.92 (s, 1H), 7.39 (t, 1H, J=52.0 Hz), 4.81 (d, 2H, J=5.7 Hz), 3.77 (s, 2H), 3.45 (br s, 2H), 2.6-2.7 (m, 1H), 1.20 (s, 6H) 327 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.72 - 1.94 (m, 6 H) 2.67 - 2.79(m, 2 H) 3.79 (br s, 4 H) 4.80 (d, J=5.72 Hz, 2 H) 7.38 (t, J=52.05 Hz, 1 H) 7.34 (d, J=5.06 Hz, 1 H) 7.91 (s, 1 H) 7.95 (t, J=7.92 Hz, 1 H) 8.18 (d, J=8.14 Hz, 1 H) 8.25 (d, J=8.58 Hz, 1 H) 8.37 (dd, J=8.58, 1.54 Hz, 1 H) 8.49 (d, J=5.06 Hz, 1 H) 8.52 (dt, J=7.81, 1.16 Hz, 1 H) 8.55 (d, J=1.76 Hz, 1 H) 8.73 (s, 1 H) 9.37 (s, 1 H) 9.66 (t, J=5.83 Hz, 1 H) 328 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 9.35 (s, 1H), 9.22 (t, 1H, J=5.9Hz), 8.69 (s, 1H), 8.46 (d, 1H, J=5.3 Hz), 8.34 (dd, 1H, J=1.7, 8.7 Hz), 8.29 (dd, 1H, J=2.4, 8.1 Hz), 8.22 (d, 1H, J=8.6 Hz), 7.92 (ddd, 1H, J=2.4, 4.6, 8.4 Hz), 7.81 (s, 1H), 7.41 (d, 1H, J=5.1 Hz), 7.25 (dd, 1H, J=8.5, 11.6 Hz), 5.39 (s, 1H), 5.04 (d, 1H, J=6.2 Hz), 4.75 (d, 2H, J=5.7 Hz), 4.11 (s, 2H), 4.06 (s, 3H), 4.0-4.0 (m, 2H), 2.4-2.5 (m, 1H), 2.0-2.1 (m, 2H), 1.52 (s, 6H)329 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.58 (t, J = 5.7 Hz, 1H), 9.35 (s, 1H), 8.62 (d, J = 29.8 Hz, 1H), 8.54 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.94 - 7.80 (m, 2H), 7.14 - 6.75 (m, 2H), 4.79 (d, J = 5.6 Hz, 2H), 3.88 - 3.75 (m, 2H), 3.62 (d, J = 12.6 Hz, 2H), 3.43 (s, 3H), 2.70 - 2.61 (m, 2H), 1.15 (d, J = 6.2 Hz, 6H).Co. No. NMR peaks list330 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.66 (t, J = 5.7 Hz, 1H), 9.34 (s, 1H), 8.65 (s, 1H), 8.55 - 8.47 (m, 2H), 8.26 (d, J = 8.7 Hz, 1H), 8.22 - 8.15 (m, 2H), 7.94 (t, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.38 (t, J = 52.0 Hz, 1H), 6.83 (s, 1H), 4.79 (d, J = 5.6 Hz, 2H), 3.79 (dd, J = 8.6, 6.5 Hz, 2H), 3.61 (d, J= 12.5 Hz, 2H), 3.42 (s, 3H), 2.69 -2.60 (m, 2H), 1.15 (d, J = 6.2 Hz, 6H).331 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.30 - 1.39 (m, 6 H) 1.41 - 1.58(m, 2 H) 1.80 - 1.95 (m, 3 H) 2.84 - 2.93 (m, 2 H) 4.60 (br d, J=12.21 Hz, 2 H) 4.79 (d, J=5.72 Hz, 2 H) 6.91 (d, J=8.49 Hz, 1 H) 7.24 - 7.55 (m, 2 H) 7.67 (t, J=7.96 Hz, 1 H) 7.86 (s, 1 H) 7.95 (t, J=7.87 Hz, 1 H) 8.14 - 8.23 (m, 2 H) 8.34 (dd, J=8.63, 1.29 Hz, 1 H) 8.50 - 8.56 (m, 2 H) 8.59 (s, 1 H) 9.31 (s, 1 H) 9.65 (t, J=5.82 Hz, 1 H)332 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.61 (t, J = 5.9 Hz, 1H), 9.37 (s, 1H), 8.68 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.45 - 8.41 (m, 2H), 8.39 (d, J = 9.3 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 10.4, 5.0 Hz, 2H), 7.35 (d, J = 9.3 Hz, 1H), 6.96 (t, J = 53.5 Hz, 1H), 5.83 - 5.75 (m, 2H), 4.80 (d, J = 5.7 Hz, 2H), 2.22 (dd, J = 12.3, 4.2 Hz, 2H), 1.46 (t, J= 11.6 Hz, 2H), 1.35 (s, 6H), 1.22 (s, 6H).333 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.69 (t, J = 5.9 Hz, 1H), 9.32 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.56 - 8.51 (m, 2H), 8.29 (s, 1H), 8.26 (dd, J = 8.7, 2.6 Hz, 1H), 8.20 (t, J = 8.9 Hz, 2H), 8.00 (dd, J = 8.6, 1.7 Hz, 1H), 7.96 (t, J = 7.9 Hz, 1H), 7.79 (s, 1H), 7.40 (t, J = 52.0 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 5.41 - 5.34 (m, 1H), 4.79 (d, J = 5.7 Hz, 2H), 4.33 - 4.24 (m, 2H), 3.86 (d, J = 6.0 Hz, 2H), 1.40 (s, 9H).334 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.53 (s, 1H), 9.26 (s, 1H), 8.52- 8.40 (m, 2H), 8.34 (d, J = 7.9 Hz, 1H), 8.26 (s, 1H), 8.20 (dd, J = 11.9, 2.1 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.95 (dd, J = 8.6, 1.7 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.69 (s, 1H), 6.89 (t, J = 53.5 Hz, 1H), 5.74 (s, 1H), 5.31 - 5.23 (m, 1H), 4.71 (d, J = 4.8 Hz, 2H), 3.82 (dt, J= 11.5, 4.2 Hz, 2H), 3.50 - 3.42 (m, 2H), 2.03 - 1.95 (m, 2H), 1.69 - 1.58 (m, 2H).335 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.54 - 1.69 (m, 6 H) 2.21 (ddd,J=9.7, 7.4, 2.5 Hz, 2 H) 3.64 (dt, J=17.7, 5.5 Hz, 4 H) 4.10 - 4.22 (m, 1 H) 4.80 (d, J=5.7 Hz, 2 H) 4.93 (d, J=6.2 Hz, 1 H) 7.39 (t, J=52.0 Hz, 1 H) 7.88 (s, 1 H) 7.96 (t, J=7.8 Hz, 1 H) 8.19 (d, J=8.1 Hz, 1 H) 8.23 (d, J=8.6 Hz, 1 H) 8.33 (dd, J=8.7, 1.7 Hz, 1 H) 8.36 (s, 1 H) 8.53 (dt, J=7.7, 1.3 Hz, 1 H) 8.54 - 8.57 (m, 1 H) 8.58 (s, 1 H) 8.66 (s, 1 H) 9.35 (s, 1 H) 9.65 (t, J=5.7 Hz, 1 H)Co. No. NMR peaks list336 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.59 (t, J = 5.8 Hz, 1H), 9.37 (s, 1H), 8.76 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.45 (s, 1H), 8.42 - 8.36 (m, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.92 (s, 1H), 7.41 (d, J = 5.2 Hz, 1H), 4.78 (d, J = 5.7 Hz, 2H), 4.67 (d, J = 13.0 Hz, 2H), 4.52 (s, 1H), 3.68 - 3.56 (m, 2H), 3.17 (s, 3H), 2.60 (dd, J = 13.1, 10.6 Hz, 2H), 1.19 (d, J = 6.1 Hz, 6H).337 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.60 (t, J = 5.9 Hz, 1H), 9.37 (s, 1H), 8.76 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.45 (s, 1H), 8.42 - 8.37 (m, 1H), 8.28 (t, J = 1.7 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.92 (s, 1H), 7.42 (d, J = 5.1 Hz, 1H), 4.78 (d, J = 5.7 Hz, 2H), 4.68 (d, J = 13.0 Hz, 2H), 4.52 (s, 1H), 3.68 - 3.53 (m, 2H), 3.17 (s, 3H), 2.60 (dd, J = 13.1, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).338 'HNMR (500 MHz, DMSO-d6) 5 (ppm) 2.32 - 2.48 (m, 5 H) 2.51 - 2.52(m, 2 H) 2.54 (s, 4 H) 2.63 (dt, J=3.69, 1.78 Hz, 1 H) 3.16 (br dd, J=15.32, 2.69 Hz, 2 H) 3.29 - 3.30 (m, 1 H) 3.33 - 3.42 (m, 3 H) 4.81 (d, J=5.75 Hz, 2 H) 7.39 (t, J=52.03 Hz, 1 H) 7.92 (s, 1 H) 7.96 (t, J=7.88 Hz, 1 H) 8.14 (d, J=5.25 Hz, 1 H) 8.18 (d, J=7.86 Hz, 1 H) 8.30 (d, J=8.75 Hz, 1 H) 8.45 (dd, J=8.57, 1.69 Hz, 1 H) 8.53 (dt, J=7.82, 1.34 Hz, 1 H) 8.55 (t, J=1.63 Hz, 1 H) 8.84 (s, 1 H) 8.92 (d, J=5.25 Hz, 1 H) 9.40 (s, 1 H) 9.68 (t, J=5.82 Hz, 1 H)339 'HNMR (500 MHz, DMSO-d6) 5 (ppm) 1.87 - 2.05 (m, 4 H) 2.52 - 2.55(m, 6 H) 3.15 - 3.29 (m, 1 H) 3.29 - 3.30 (m, 2 H) 3.51 (td, J=11.54, 2.56 Hz, 2 H) 3.89 - 4.05 (m, 2 H) 4.81 (d, J=5.75 Hz, 2 H) 7.39 (t, J=52.03 Hz, 1 H) 7.89 - 8.01 (m, 2 H) 8.10 (d, J=5.25 Hz, 1 H) 8.18 (d, J=8.25 Hz, 1 H) 8.29 (d, J=8.63 Hz, 1 H) 8.46 (dd, J=8.63, 1.63 Hz, 1 H) 8.53 (dt, J=7.82, 1.34 Hz, 1 H) 8.55 (s, 1 H) 8.85 (s, 1 H) 8.90 (d, J=5.25 Hz, 1 H) 9.39 (s, 1 H) 9.68 (t, J=5.98 Hz, 1 H)34019F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.35 (s, 1 F) -124.21 (s, 1F)340 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.22 (s, 3 H) 2.19 - 2.30 (m, 4H) 4.08 (s, 2 H) 4.15 (s, 2 H) 4.80 (d, J=5.3 Hz, 2 H) 4.92 (s, 1 H) 7.39 (t, J=52.0 Hz, 1 H) 7.40 (d, J=5.2 Hz, 1 H) 7.89 (s, 1 H) 7.95 (t, J=7.8 Hz, 1 H) 8.18 (d, J=7.9 Hz, 1 H) 8.23 (d, J=8.7 Hz, 1 H) 8.35 (dd, J=8.6, 1.6 Hz, 1 H) 8.47 (d, J=5.1 Hz, 1 H) 8.52 (dd, J=7.8, 1.1 Hz, 1 H) 8.55 (d, J=1.6 Hz, 1 H) 8.70 (s, 1 H) 9.37 (s, 1 H) 9.66 (br t, J=5.6 Hz, 1 H)Co. No. NMR peaks list341 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.27 (s, 1H), 8.28 (s, 1H), 8.20- 8.13 (m, 2H), 7.94 (dd, J = 8.6, 1.5 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.73 (s, 1H), 7.54 (t, J = 7.7 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 4.56 (d, J = 5.8 Hz, 2H), 3.71 (dd, J= 12.2, 3.8 Hz, 1H), 3.55 (d, J = 11.9 Hz, 1H), 2.91 (m, 1H), 2.86 (s, 3H), 2.78 (dd, J = 15.8, 7.2 Hz, 1H), 2.64 - 2.54 (m, 1H), 1.97 (d, J = 9.9 Hz, 1H), 1.87 - 1.79 (m, 1H), 1.68 - 1.49 (m, 2H).342 'HNMR (400 MHz, CDC13) 5 (ppm) 1.21 (d, J=6.16 Hz, 6 H) 2.53 (dd,J=12.32, 10.78 Hz, 2 H) 2.93 - 3.07 (m, 2 H) 4.28 (dd, J=12.43, 2.31 Hz, 2 H) 4.93 (d, J=5.06 Hz, 2 H) 6.24 (br t, J=53.37 Hz, 1 H) 6.34 (br dd, J=11.88, 1.54 Hz, 1 H) 6.95 (dd, J=9.35, 1.65 Hz, 1 H) 7.75 (t, J=7.81 Hz, 1 H) 7.81 (s, 1 H) 7.86 (br t, J=4.73 Hz, 1 H) 8.04 (d, J=8.80 Hz, 1 H) 8.11 (d, J=7.92 Hz, 1 H) 8.22 (dd, J=8.58, 1.54 Hz, 1 H) 8.32 - 8.37 (m, 1 H) 8.38 (s, 1 H) 8.48 (s, 1 H) 9.24 (s, 1 H)343 'HNMR (400 MHz, CDCI3) 5 (ppm) 1.24 (d, J=6.38 Hz, 6 H) 2.54 (br t,J=11.55 Hz, 2 H) 2.99 - 3.10 (m, 2 H) 4.34 (dd, J=12.54, 2.20 Hz, 2 H) 4.93 (d, J=4.84 Hz, 2 H) 6.23 (t, J=53.37 Hz, 1 H) 6.69 (d, J=8.36 Hz, 1 H) 7.24 (d, J=7.48 Hz, 1 H) 7.61 (t, J=7.84 Hz, 1 H) 7.71 - 7.79 (m, 2 H) 7.80 (s, 1 H) 8.03 (d, J=8.80 Hz, 1 H) 8.12 (d, J=7.92 Hz, 1 H) 8.28 (dd, J=8.58, 1.54 Hz, 1 H) 8.33 (d, J=7.70 Hz, 1 H) 8.41 (s, 1 H) 8.47 (s, 1 H) 9.23 (s, 1 H)344 'HNMR (400 MHz, CDCI3) 8 ppm 1.82 - 1.95 (m, 4 H) 2.08 - 2.20 (m,2 H) 2.92 - 3.05 (m, 2 H) 3.62 (s, 2 H) 3.64 - 3.70 (m, 2 H) 4.93 (d, J=5.06 Hz, 2 H) 6.23 (t, J=53.26 Hz, 1 H) 6.71 (d, J=8.58 Hz, 1 H) 7.23 (d, J=7.39 Hz, 1 H) 7.61 (dd, J=8.25, 7.59 Hz, 1 H) 7.70 - 7.78 (m, 2 H) 7.80 (s, 1 H) 8.03 (d, J=8.58 Hz, 1 H) 8.11 (d, J=7.92 Hz, 1 H) 8.29 (dd, J=8.58, 1.54 Hz, 1 H) 8.33 (d, J=7.92 Hz, 1 H) 8.43 (s, 1 H) 8.47 (s, 1 H) 9.23 (s, 1 H)345 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 9.34 (s, 1H), 8.72 (s, 1H), 8.67(brt, 1H, J=5.7 Hz), 8.54 (br d, 2H, J=5.1 Hz), 8.36 (dd, 1H, J=l.1, 8.6 Hz), 8.23 (d, 1H, J=8.6 Hz), 7.83 (s, 1H), 7.40 (d, 1H, J=5.1 Hz), 6.94 (t, 1H, J=52.9 Hz), 4.69 (br d, 2H, J=12.8 Hz), 4.56 (br d, 2H, J=5.7 Hz), 3.62 (dt, 2H, J=3.2, 6.7 Hz), 3.3-3.4 (m, 2H), 2.61 (br dd, 2H, J=10.9, 12.9 Hz), 2.5-2.6 (m, 2H), 1.2-1.3 (m, 7H)346 'HNMR (400 MHz, CDCI3) 5 (ppm) 0.07 (s, 1 H) 1.21 - 1.33 (m, 1 H)1.98 - 2.18 (m, 4 H) 2.62 (s, 1 H) 2.89 - 2.96 (m, 3 H) 3.02 - 3.23 (m, 4 H) 4.96 (d, J=5.09 Hz, 2 H) 6.24 (t, J=53.29 Hz, 1 H) 7.62 (br t, J=4.85 Hz, 1 H) 7.70 (d, J=5.09 Hz, 1 H) 7.78 (t, J=7.86 Hz, 1 H) 7.87 (s, 1 H) 8.13 (d, J=7.91 Hz, 2 H) 8.29 - 8.36 (m, 2 H) 8.44 - 8.48 (m, 1 H) 8.59 (s, 1 H) 8.80 (d, J=5.32 Hz, 1 H) 9.31 (s, 1 H)Co. No. NMR peaks list347 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.91 - 2.03 (m, 2 H) 2.17 (br d,J=11.56 Hz, 2 H) 2.44 - 2.47 (m, 3 H) 2.90 - 3.08 (m, 3 H) 3.13 - 3.26 (m, 1 H) 3.33 - 3.35 (m, 1 H) 4.74 (d, J=5.55 Hz, 2 H) 7.31 (t, J=52.02 Hz, 1 H) 7.84 - 7.90 (m, 2 H) 8.07 (d, J=5.32 Hz, 1 H) 8.11 (d, J=8.09 Hz, 1 H) 8.20 - 8.30 (m, 2 H) 8.37 - 8.49 (m, 3 H) 8.57 (br d, J=8.79 Hz, 1 H) 8.78 (s, 1 H) 8.86 (d, J=5.32 Hz, 1 H) 9.36 (s, 1 H) 9.63 (t, J=5.90 Hz, 1 H)348 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.40 (dd, J=17.69, 12.64 Hz, 6H) 1.45 - 1.53 (m, 1 H) 1.55 - 1.68 (m, 1 H) 1.72 - 1.83 (m, 1 H) 1.83 - 2.03 (m, 2 H) 2.86 - 3.04 (m, 2 H) 4.38 (br d, J=13.26 Hz, 1 H) 4.71 - 4.85 (m, 3 H) 6.92 (d, J=8.49 Hz, 1 H) 7.39 (br t, J=52.02 Hz, 1 H) 7.42 (br d, J=7.44 Hz, 1 H) 7.68 (t, J=7.96 Hz, 1 H) 7.81 (s, 1 H) 7.96 (t, J=7.82 Hz, 1 H) 8.13 - 8.22 (m, 2 H) 8.34 (dd, J=8.58, 1.43 Hz, 1 H) 8.49 - 8.59 (m, 2 H) 8.62 (s, 1 H) 9.31 (s, 1 H) 9.67 (t, J=5.77 Hz, 1 H) 349 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.40 (dd, J=17.64, 12.68 Hz, 6H) 1.48 (dt, J=12.71, 3.71 Hz, 1 H) 1.55 - 1.67 (m, 1 H) 1.77 (br dd, J=12.49, 2.48 Hz, 1 H) 1.84 - 2.01 (m, 2 H) 2.86 - 3.03 (m, 2 H) 4.38 (br d, J=12.97 Hz, 1 H) 4.73 - 4.83 (m, 3 H) 6.92 (d, J=8.58 Hz, 1 H) 7.39 (t, J=52.02 Hz, 1 H) 7.42 (d, J=7.34 Hz, 1 H) 7.68 (dd, J=8.34, 7.58 Hz, 1 H) 7.81 (s, 1 H) 7.96 (t, J=7.82 Hz, 1 H) 8.18 (d, J=7.77 Hz, 2 H) 8.34 (dd, J=8.63, 1.57 Hz, 1 H) 8.53 (dd, J=7.87, 1.10 Hz, 1 H) 8.55 (d, J=1.53 Hz, 1 H) 8.62 (s, 1 H) 9.31 (s, 1 H) 9.66 (t, J=5.82 Hz, 1 H) 350 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 3.28 (s, 3 H) 3.97 (dd, J=9.58,3.48 Hz, 2 H) 4.32 - 4.42 (m, 3 H) 4.79 (d, J=5.72 Hz, 2 H) 7.39 (t, J=52.02 Hz, 1 H) 7.86 (s, 1 H) 7.91 - 7.98 (m, 2 H) 8.18 (d, J=7.92 Hz, 1 H) 8.20 - 8.25 (m, 1 H) 8.32 (dd, J=8.63, 1.48 Hz, 1 H) 8.49 - 8.57 (m, 2 H) 8.62 - 8.66 (m, 2 H) 9.34 (s, 1 H) 9.62 - 9.69 (m, 1 H)351 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.00 (d, J=6.5 Hz, 6 H) 1.39 - 1.53 (m, 2 H) 2.52 - 2.58 (m, 2 H) 2.68 - 2.77 (m, 1 H) 3.17 (s, 3 H) 3.27 (s, 2 H) 4.10 (t, J=8.7 Hz, 2 H) 4.40 (br dd, J=12.9, 3.0 Hz, 2 H) 4.54 (d, J=7.0 Hz, 1 H) 4.77 (d, J=6.0 Hz, 2 H) 6.91 (d, J=8.6 Hz, 1 H) 7.38 (d, J=7.4 Hz, 1 H) 7.64 (t, J=7.9 Hz, 1 H) 7.77 (s, 1 H) 7.91 (s, 1 H) 8.18 (d, J=8.7 Hz, 1 H) 8.32 (dd, J=8.6, 1.4 Hz, 1 H) 8.48 (s, 1 H) 8.53 (s, 1 H) 9.30 (s, 1 H) 9.37 (t, J=6.0 Hz, 1 H)352 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.20 (br dd, J=13.54, 6.10 Hz,6 H) 2.62 - 2.76 (m, 2 H) 3.54 - 3.68 (m, 2 H) 3.99 (s, 3 H) 4.56 (br d, J=12.78 Hz, 1 H) 4.80 (d, J=5.63 Hz, 2 H) 4.87 (br d, J=12.68 Hz, 1 H) 7.38 (t, J=52.02 Hz, 1 H) 7.94 (t, J=7.87 Hz, 1 H) 8.00 (s, 1 H) 8.17 (d, J=8.01 Hz, 1 H) 8.24 (d, J=8.68 Hz, 1 H) 8.50 - 8.57 (m, 3 H) 8.99 (s, 1 H) 9.40 (s, 1 H) 9.64 (t, J=5.82 Hz, 1 H)Co. No. NMR peaks list353 'HNMR (DMSO-d6, 400 MHz) 5 (ppm) 9.34 (s, 1H), 8.71 (s, 1H), 8.5- 8.6 (m, 2H), 8.4-8.5 (m, 1H), 8.37 (dd, 1H, J=1.5, 8.6 Hz), 8.23 (d, 1H, J=8.8 Hz), 7.80 (s, 1H), 7.41 (d, 1H, J=5.3 Hz), 6.94 (t, 1H, J=52.8 Hz), 4.68 (br d, 2H, J=12.8 Hz), 4.54 (d, 2H, J=5.9 Hz), 3.6-3.7 (m, 2H), 3.14 (t, 2H, J=7.2 Hz), 2.61 (dd, 2H, J=10.7, 13.1 Hz), 2.31 (t, 2H, J=7.4 Hz), 1.78 (quin, 2H, J=7.3 Hz), 1.21 (d, 6H, J=6.2 Hz)354 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.20 (d, J=6.17 Hz, 6 H) 2.54 - 2.67 (m, 2 H) 3.34 (s, 3 H) 3.53 - 3.66 (m, 2 H) 4.68 (br d, J=12.65 Hz, 2 H) 4.80 (br d, J=5.54 Hz, 2 H) 7.47 (t, J=73.05 Hz, 1 H) 7.42 (d, J=5.12 Hz, 1 H) 7.91 (s, 1 H) 7.93 (s, 1 H) 8.09 (s, 1 H) 8.25 (d, J=8.67 Hz, 1 H) 8.35 - 8.43 (m, 2 H) 8.53 (d, J=5.12 Hz, 1 H) 8.76 (s, 1 H) 9.38 (s, 1 H) 9.63 (t, J=5.80 Hz, 1 H)355 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.69 (t, J = 5.7 Hz, 1H), 9.37 (s, 1H), 8.91 (t, J = 4.1 Hz, 1H), 8.77 (s, 1H), 8.54 (d, J = 12.2 Hz, 2H), 8.48 - 8.43 (m, 2H), 8.27 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.79 (dd, J = 10.8, 4.6 Hz, 1H), 7.39 (t, J = 52.0 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 1.81 (s, 3H), 1.77 (s, 3H).356 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.20 (d, J=6.16 Hz, 6 H) 2.48(dd, J=12.54, 10.78 Hz, 2 H) 3.33 (s, 3 H) 3.62 - 3.71 (m, 2 H) 4.31 (br d, J=11.22 Hz, 2 H) 4.78 (br d, J=5.28 Hz, 2 H) 6.90 (d, J=8.36 Hz, 1 H) 7.46 (t, J=73.50 Hz, 1 H) 7.45 (d, J=7.70 Hz, 1 H) 7.70 (t, J=7.92 Hz, 1 H) 7.88 (s, 1 H) 7.90 (t, J=1.54 Hz, 1 H) 8.08 (br s, 1 H) 8.19 (d, J=8.80 Hz, 1 H) 8.34 (dd, J=8.58, 1.54 Hz, 1 H) 8.39 (t, J=1.21 Hz, 1 H) 8.60 (s, 1 H) 9.31 (s, 1 H) 9.60 (t, J=5.91 Hz, 1 H)357 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.30 (s, 1H), 8.70 (t, J = 5.8 Hz, 1H), 8.24 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.98 (dd, J = 8.6, 1.7 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.71 (s, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 52.5 Hz, 1H), 4.62 - 4.37 (m, 2H), 3.81 (dd, J = 12.9, 3.8 Hz, 1H), 3.69 (d, J = 12.9 Hz, 1H), 3.25 - 3.14 (m, 1H), 3.07 (t, J= 11.3 Hz, 1H), 2.60 - 2.53 (m, 1H), 2.03 (d, J= 13.3 Hz, 1H), 1.81 (dd, J = 10.1, 3.2 Hz, 1H), 1.64 (ddd, J = 15.1, 12.6, 3.4 Hz, 1H), 1.49 (dt, J = 25.1, 8.2 Hz, 1H).358 'HNMR (400 MHz, CDC13) 5 (ppm) 1.32 (d, J=6.27 Hz, 6 H) 2.61 (dd,J=12.59, 10.71 Hz, 2 H) 3.78 (ddd, J=10.48, 6.30, 2.46 Hz, 2 H) 4.23 (dd, J=12.70, 1.72 Hz, 2 H) 4.87 (d, J=5.23 Hz, 2 H) 6.55 (t, J=72.84 Hz, 2 H) 6.67 (d, J=8.47 Hz, 1 H) 7.03 (t, J=2.04 Hz, 1 H) 7.23 - 7.27 (m, 1 H) 7.48 (d, J=2.19 Hz, 2 H) 7.62 (dd, J=8.36, 7.63 Hz, 1 H) 7.75 (br s, 1 H) 7.77 (s, 1 H) 8.01 (d, J=8.57 Hz, 1 H) 8.26 (dd, J=8.57, 1.57 Hz, 1 H) 8.38 (s, 1 H) 9.20 (s, 1 H)Co. No. NMR peaks list369 'H NMR (500 MHz, CDC13) 5 (ppm) 1.96 - 2.11 (m, 3 H) 2.14 - 2.22 (m, 2 H) 2.62 (s, 2 H) 2.99 - 3.10 (m, 1 H) 3.15 - 3.24 (m, 3 H) 3.43 - 3.58 (m, 1 H) 3.73 (brt, J=10.44 Hz, 1 H) 3.87 (dt, J=11.98, 2.70 Hz, 1 H) 3.96 (dd, J=11.88, 3.13 Hz, 1 H) 4.95 (d, J=5.25 Hz, 2 H) 6.25 (t, J=53.28 Hz, 1 H) 7.66 - 7.69 (m, 1 H) 7.69 - 7.74 (m, 1 H) 7.75 - 7.80 (m, 1 H) 7.84 (s, 1 H) 8.07 - 8.11 (m, 1 H) 8.11 - 8.15 (m, 1 H) 8.24 (dd, J=8.50, 1.63 Hz, 1 H) 8.36 (dt, J=7.85, 1.39 Hz, 1 H) 8.48 (t, J=1.56 Hz, 1 H) 8.51 (s, 1 H) 8.77 (d, J=5.38 Hz, 1 H) 9.27 (s, 1 H)370 'HNMR (500 MHz, DMSO-d6) 5 (ppm) 1.41 - 1.54 (m, 1 H) 1.81 - 1.92(m, 1 H) 2.52 - 2.55 (m, 8 H) 2.64 - 2.83 (m, 2 H) 2.86 - 2.96 (m, 1 H) 2.98 - 3.11 (m, 3 H) 4.81 (d, J=5.75 Hz, 2 H) 7.39 (t, J=51.97 Hz, 1 H) 7.92 (s, 1 H) 7.96 (t, J=7.82 Hz, 1 H) 8.05 - 8.14 (m, 1 H) 8.18 (d, J=7.88 Hz, 1 H) 8.29 (d, J=8.63 Hz, 1 H) 8.43 (d, J=8.51 Hz, 1 H) 8.53 (dt, J=7.85, 1.33 Hz, 1 H) 8.55 (d, J=1.63 Hz, 1 H) 8.83 (d, J=5.33 Hz, 1 H) 8.86 - 8.89 (m, 1 H) 9.39 (s, 1 H) 9.66 - 9.71 (m, 1 H)371 'HNMR (500 MHz, DMSO-d6) 5 (ppm) 2.51 - 2.53 (m, 4 H) 3.42 - 3.52(m, 2 H) 3.68 (br t, J=7.44 Hz, 1 H) 4.80 (d, J=5.75 Hz, 2 H) 7.39 (t, J=52.03 Hz, 1 H) 7.91 - 7.98 (m, 2 H) 8.01 - 8.11 (m, 1 H) 8.18 (br d, J=8.00 Hz, 1 H) 8.29 (d, J=8.51 Hz, 1 H) 8.35 (br s, 0 H) 8.42 (br d, J=7.88 Hz, 1 H) 8.51 - 8.56 (m, 2 H) 8.79 - 8.89 (m, 2 H) 9.32 - 9.41 (m, 1 H) 9.68 (br t, J=5.75 Hz, 1 H)372 'HNMR (500 MHz, DMSO-d6) 5 (ppm) 2.46 (dt, J=3.63, 1.81 Hz, 1 H)2.53 - 2.62 (m, 7 H) 3.54 (s, 1 H) 3.61 - 3.74 (m, 2 H) 4.80 (d, J=5.63 Hz, 2 H) 7.23 - 7.56 (m, 1 H) 7.92 (s, 1 H) 7.95 (t, J=7.82 Hz, 1 H) 8.06 (d, J=5.38 Hz, 1 H) 8.16 - 8.20 (m, 1 H) 8.26 - 8.31 (m, 1 H) 8.42 - 8.46 (m, 1 H) 8.52 (dt, J=7.82, 1.28 Hz, 1 H) 8.54 - 8.56 (m, 1 H) 8.82 (s, 1 H) 8.88 (d, J=5.25 Hz, 1 H) 9.35 - 9.42 (m, 1 H) 9.68 (t, J=5.82 Hz, 1 H) 373 'HNMR (500 MHz, DMSO-d6) 5 (ppm) 1.09 - 1.15 (m, 1 H) 2.98 - 3.10(m, 2 H) 3.22 - 3.31 (m, 3 H) 4.81 (d, J=5.75 Hz, 2 H) 7.25 - 7.60 (m, 3 H) 7.91 - 7.98 (m, 2 H) 8.09 (d, J=5.25 Hz, 1 H) 8.18 (dt, J=8.13, 1.25 Hz, 1 H) 8.29 (d, J=8.63 Hz, 1 H) 8.44 (dd, J=8.63, 1.75 Hz, 1 H) 8.53 (dt, J=7.82, 1.34 Hz, 1 H) 8.55 (s, 1 H) 8.84 (s, 1 H) 8.88 (d, J=5.25 Hz, 1 H) 9.39 (s, 1 H) 9.68 (t, J=5.88 Hz, 1 H)374 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.59 (t, J = 5.8 Hz, 1H), 8.98 (s, 1H), 8.54 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.94 (dd, J= 13.4, 5.6 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.49 (s, 1H), 7.45 (dd, J = 9.2, 2.2 Hz, 1H), 7.32 (t, J = 52.0 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 4.68 (d, J = 5.7 Hz, 2H), 4.04 (dd, J = 34.0, 13.1 Hz, 2H), 2.88 (ddd, J = 24.4, 12.7, 3.0 Hz, 2H), 1.93 (dd, J = 12.6, 9.5 Hz, 2H), 1.79 (d, J = 9.5 Hz, 1H), 1.69 - 1.49 (m, 2H), 1.45 (d, J = 12.7 Hz, 3H), 1.41 (d, J = 12.7 Hz, 3H).Co. No. NMR peaks list375 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.69 (s, 1H), 9.29 (s, 1H), 8.56(s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.23 - 8.14 (m, 3H), 8.07 (dd, J = 9.6, 2.6 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.90 (dd, J = 8.6, 1.6 Hz, 1H), 7.72 (s, 1H), 7.40 (t, J = 52.0 Hz, 1H), 6.59 (d, J = 9.5 Hz, 1H), 4.95 (d, J = 4.0 Hz, 1H), 4.78 (s, 2H), 4.28 (ddd, J = 21.6, 13.8, 5.9 Hz, 2H), 3.63 (t, J = 8.9 Hz, 1H), 3.30 - 3.16 (m, 2H). 376 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 2.16 (t, J=19.31 Hz, 3 H) 4.81(d, J=5.72 Hz, 2 H) 7.39 (t, J=52.02 Hz, 1 H) 7.92 (s, 1 H) 7.96 (t, J=7.82 Hz, 1 H) 8.19 (d, J=8.11 Hz, 1 H) 8.32 (d, J=8.68 Hz, 1 H) 8.44 (dd, J=8.58, 1.53 Hz, 1 H) 8.53 (d, J=7.92 Hz, 1 H) 8.55 (s, 1 H) 8.86 (s, 1 H) 9.02 (s, 1 H) 9.40 (s, 1 H) 9.63 (s, 1 H) 9.69 (t, J=5.82 Hz, 1 H) 385 'HNMR (400 MHz, CDC13) 5 (ppm) 3.08 (s, 3 H) 3.48 - 3.55 (m, 3 H)4.11 (q, J=6.0 Hz, 2 H) 4.95 (d, J=5.3 Hz, 2 H) 6.03 (br t, J=6.1 Hz, 1 H) 6.24 (t, J=53.3 Hz, 1 H) 7.19 (d, J=5.3 Hz, 1 H) 7.71 - 7.86 (m, 3 H) 8.05 - 8.14 (m, 2 H) 8.24 (dd, J=8.6, 1.5 Hz, 1 H) 8.34 (dt, J=7.9, 1.4 Hz, 1 H) 8.43 - 8.50 (m, 3 H) 9.29 (s, 1 H)386 'HNMR (400 MHz, CDCI3) 5 (ppm) 2.96 - 3.06 (m, 1 H) 3.42 (s, 3 H)3.65 (d, J=6.6 Hz, 2 H) 4.01 (dd, J=8.8, 5.3 Hz, 2 H) 4.33 (t, J=8.6 Hz, 2 H) 4.94 (d, J=5.1 Hz, 2 H) 6.24 (t, J=53.3 Hz, 1 H) 7.09 (d, J=5.3 Hz, 1 H) 7.68 - 7.86 (m, 3 H) 8.06 (d, J=8.6 Hz, 1 H) 8.12 (d, J=7.9 Hz, 1 H) 8.26 (dd, J=8.6, 1.5 Hz, 1 H) 8.32 - 8.52 (m, 4 H) 9.27 (s, 1 H)387 'HNMR (400 MHz, CDCI3) 5 (ppm) 1.33 (d, J=6.17 Hz, 6 H) 2.62 (dd,J=12.59, 10.71 Hz, 2 H) 3.04 (s, 3 H) 3.78 (ddd, J=10.42, 6.35, 2.46 Hz, 2 H) 4.23 (dd, J=12.75, 1.67 Hz, 2 H) 4.77 (s, 2 H) 4.90 (d, J=5.33 Hz, 2 H) 6.67 (d, J=8.47 Hz, 1 H) 7.25 (d, J=7.52 Hz, 1 H) 7.62 (dd, J=8.26, 7.63 Hz, 1 H) 7.81 (s, 1 H) 8.01 (d, J=7.97 Hz, 1 H) 8.00 (s, 1 H) 8.11 (s, 1 H) 8.20 (t, J=5.65 Hz, 1 H) 8.23 - 8.30 (m, 2 H) 8.38 (s, 1 H) 9.20 (s, 1 H)388 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 4.17 - 4.29 (m, 2 H) 4.44 - 4.56(m, 2 H) 4.80 (d, J=5.72 Hz, 2 H) 5.45 - 5.69 (m, 1 H) 7.24 - 7.54 (m, 1 H) 7.87 (s, 1 H) 7.96 (t, J=7.82 Hz, 1 H) 8.00 (s, 1 H) 8.19 (br d, J=7.82 Hz, 1 H) 8.24 (d, J=8.68 Hz, 1 H) 8.33 (dd, J=8.58, 1.43 Hz, 1 H) 8.53 (br d, J=7.92 Hz, 1 H) 8.55 (s, 1 H) 8.66 - 8.71 (m, 2 H) 9.35 (s, 1 H) 9.67 (brt, J=5.77 Hz, 1 H)389 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 2.16 (t, J=19.31 Hz, 3 H) 4.81(d, J=5.63 Hz, 2 H) 5.78 (s, 1 H) 6.95 (t, J=53.50 Hz, 1 H) 7.87 (t, J=7.82 Hz, 1 H) 7.90 (s, 1 H) 8.15 (d, J=7.92 Hz, 1 H) 8.31 (d, J=8.68 Hz, 1 H) 8.39 - 8.47 (m, 2 H) 8.55 (s, 1 H) 8.86 (s, 1 H) 9.01 (s, 1 H) 9.40 (s, 1 H) 9.59 (brt, J=5.77 Hz, 1 H) 9.63 (s, 1 H)Co. No. NMR peaks list390 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 2.17 - 2.39 (m, 2 H) 3.52 - 4.06(m, 4 H) 4.80 (d, J=5.72 Hz, 2 H) 5.40 - 5.64 (m, 1 H) 7.25 - 7.54 (m, 1 H) 7.88 (s, 1 H) 7.96 (t, J=7.82 Hz, 1 H) 8.07 (s, 1 H) 8.16 - 8.21 (m, 1 H) 8.21 - 8.26 (m, 1 H) 8.37 (dd, J=8.58, 1.62 Hz, 1 H) 8.50 - 8.58 (m, 2 H) 8.62 (s, 1 H) 8.70 (s, 1 H) 9.35 (s, 1 H) 9.67 (t, J=5.82 Hz, 1 H) 395 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.43 (d, J=12.87 Hz, 6 H) 3.05- 3.16 (m, 1 H) 4.10 - 4.28 (m, 4 H) 4.79 (br d, J=5.63 Hz, 2 H) 6.48 (d, J=8.20 Hz, 1 H) 7.25 - 7.56 (m, 2 H) 7.70 (t, J=7.87 Hz, 1 H) 7.85 (s, 1 H) 7.95 (t, J=7.82 Hz, 1 H) 8.19 (br d, J=8.68 Hz, 2 H) 8.35 (d, J=8.68 Hz, 1 H) 8.49 - 8.58 (m, 2 H) 8.60 (s, 1 H) 9.32 (s, 1 H) 9.66 (br t, J=5.67 Hz, 1 H)396 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 2.16 - 2.40 (m, 2 H) 3.55 - 4.03(m, 4 H) 4.80 (d, J=5.72 Hz, 2 H) 5.42 - 5.64 (m, 1 H) 8.19 (d, J=8.11 Hz, 1 H) 8.23 (d, J=8.68 Hz, 1 H) 8.37 (dd, J=8.63, 1.57 Hz, 1 H) 8.53 (dd, J=7.87, 1.10 Hz, 1 H) 8.55 (d, J=1.53 Hz, 1 H) 8.62 (s, 1 H) 8.70 (s, 1 H) 9.35 (s, 1 H) 9.67 (t, J=5.82 Hz, 1 H)397 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 2.17 - 2.36 (m, 2 H) 3.54 - 3.99(m, 4 H) 4.80 (d, J=5.72 Hz, 2 H) 5.42 - 5.65 (m, 1 H) 7.24 - 7.54 (m, 1 H) 7.88 (s, 1 H) 7.96 (t, J=7.87 Hz, 1 H) 8.07 (s, 1 H) 8.15 - 8.21 (m, 1 H) 8.23 (d, J=8.68 Hz, 1 H) 8.37 (dd, J=8.63, 1.57 Hz, 1 H) 8.51 - 8.57 (m, 2 H) 8.62 (s, 1 H) 8.70 (s, 1 H) 9.35 (s, 1 H) 9.61 - 9.73 (m, 1 H) 9.67 (t, J=5.77 Hz, 1 H)398 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.45 (d, J=4.01 Hz, 3 H) 1.48(d, J=4.10 Hz, 3 H) 2.11 (brd, J=11.83 Hz, 1 H) 2.18 - 2.31 (m, 1 H) 2.55 - 2.69 (m, 1 H) 3.41 - 3.64 (m, 2 H) 3.70 - 3.89 (m, 2 H) 4.79 (s, 2 H) 6.57 (d, J=8.39 Hz, 1 H) 7.24 - 7.54 (m, 2 H) 7.66 (t, J=7.87 Hz, 1 H) 7.87 (s, 1 H) 7.95 (t, J=7.82 Hz, 1 H) 8.18 (d, J=8.49 Hz, 2 H) 8.39 (dd, J=8.58, 1.34 Hz, 1 H) 8.53 (brd, J=7.92 Hz, 1 H) 8.55 (s, 1 H) 8.63 (s, 1 H) 9.32 (s, 1 H) 9.65 (br s, 1 H)400 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.30 (s, 1H), 8.70 (t, J = 5.8 Hz, 1H), 8.24 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.98 (dd, J = 8.5, 1.6 Hz, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.71 (s, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 52.5 Hz, 1H), 4.58 - 4.46 (m, 2H), 3.80 (d, J= 12.8 Hz, 1H), 3.69 (d, J = 12.4 Hz, 1H), 3.25 - 3.14 (m, 1H), 3.07 (t, J= 11.5 Hz, 1H), 2.61 - 2.52 (m, 1H), 2.03 (dd, J = 25.8, 13.0 Hz, 1H), 1.81 (d, J = 13.2 Hz, 1H), 1.64 (ddd, J = 15.0, 12.7, 3.4 Hz, 1H), 1.57 - 1.42 (m, 1H).-\T1- Co. No. NMR peaks list401 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.30 (s, 1H), 8.70 (t, J = 5.7 Hz, 1H), 8.24 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.98 (dd, J = 8.5, 1.5 Hz, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.71 (s, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 52.5 Hz, 1H), 4.59 - 4.46 (m, 2H), 3.80 (d, J = 12.8 Hz, 1H), 3.69 (d, J = 12.6 Hz, 1H), 3.19 (dd, J = 18.6, 8.4 Hz, 1H), 3.07 (t, J = 11.5 Hz, 1H), 2.61 - 2.53 (m, 1H), 2.03 (dd, J = 25.8, 13.0 Hz, 1H), 1.81 (d, J = 13.4 Hz, 1H), 1.72 - 1.57 (m, 1H), 1.57 - 1.41 (m, 1H).402 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 11.45 (s, 1H), 9.65 (t, J = 5.8Hz, 1H), 9.33 (s, 1H), 8.54 (dd, J = 18.5, 11.4 Hz, 3H), 8.22 - 8.12 (m, 3H), 7.95 (t, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.39 (t, J = 52.0 Hz, 1H), 6.35 (s, 1H), 5.05 (d, J = 6.1 Hz, 1H), 4.78 (d, J = 5.7 Hz, 2H), 4.11 (s, 2H), 4.06 (s, 2H), 3.98 (dt, J = 13.8, 7.0 Hz, 1H), 2.48 - 2.43 (m, 2H), 2.04 - 1.96 (m, 2H).403 'HNMR (DMSO-de, 400 MHz) 5 (ppm) 9.34 (s, 1H), 9.06 (t, 1H, J=6.0Hz), 8.69 (s, 1H), 8.46 (d, 1H, J=5.2 Hz), 8.33 (dd, 1H, J=1.6, 8.6 Hz), 8.22 (d, 1H, J=8.7 Hz), 7.78 (s, 1H), 7.55 (d, 1H, J=2.1 Hz), 7.50 (dd, 1H, J=2.1, 8.4 Hz), 7.42 (d, 1H, J=5.2 Hz), 6.98 (d, 1H, J=8.5 Hz), 5.09 (t, 1H, J=5.6 Hz), 5.05 (d, 1H, J=6.2 Hz), 4.73 (d, 2H, J=5.7 Hz), 4.40 (dd, 1H, J=2.2, 11.4 Hz), 4.2-4.2 (m, 1H), 4.11 (s, 2H), 4.1-4.1 (m, 1H), 4.0-4.1 (m, 2H), 4.0-4.1 (m, 1H), 3.6-3.7 (m, 2H), 2.4-2.5 (m, 2H), 2.0- 2.1 (m, 2H)404 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 3.97 (s, 3 H) 4.51 (td, J=14.88,3.62 Hz, 2 H) 4.74 (d, J=5.82 Hz, 2 H) 5.79 (s, 1 H) 6.19 - 6.55 (m, 1 H) 6.78 - 7.12 (m, 1 H) 7.66 (s, 1 H) 7.81 - 7.93 (m, 2 H) 8.07 (d, J=8.68 Hz, 1 H) 8.12 - 8.18 (m, 2 H) 8.31 (s, 1 H) 8.40 (d, J=7.82 Hz, 1 H) 8.53 (s, 1 H) 9.19 (s, 1 H) 9.52 (t, J=5.87 Hz, 1 H)405 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 3.28 (s, 3 H) 3.97 (dd, J=9.44,3.43 Hz, 2 H) 4.30 - 4.43 (m, 3 H) 4.78 (br d, J=5.82 Hz, 2 H) 5.79 (s, 1 H) 6.78 - 7.16 (m, 1 H) 7.80 - 7.90 (m, 2 H) 7.94 (s, 1 H) 8.11 - 8.18 (m, 1 H) 8.22 (d, J=8.58 Hz, 1 H) 8.32 (dd, J=8.63, 1.38 Hz, 1 H) 8.41 (d, J=7.82 Hz, 1 H) 8.54 (s, 1 H) 8.62 - 8.67 (m, 2 H) 9.34 (s, 1 H) 9.57 (t, J=5.77 Hz, 1 H)40619F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.30.Co. No. NMR peaks list406 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.58 (t, J = 5.8 Hz, 1H), 9.31(s, 1H), 8.67 - 8.53 (m, 1H), 8.41 - 8.29 (m, 3H), 8.18 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.70 (dd, J = 8.5, 7.4 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.29 (t, J = 52.0 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.77 (d, J = 5.8 Hz, 2H), 4.31 (dd, J = 13.0, 2.4 Hz, 2H), 3.72 - 3.58 (m, 2H), 2.54 (s, 3H), 2.48 - 2.42 (m, 2H), 1.20 (d, J = 6.2 Hz, 6H).40619F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.30.406 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.58 (t, J = 5.8 Hz, 1H), 9.31(s, 1H), 8.62 - 8.54 (m, 1H), 8.38 - 8.33 (m, 3H), 8.18 (d, J = 8.6 Hz, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.70 (dd, J = 8.5, 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 52.0 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.77 (d, J = 5.7 Hz, 2H), 4.31 (dd, J = 13.0, 2.3 Hz, 2H), 3.66 (dtd, J = 12.4, 6.2, 3.7 Hz, 2H), 2.54 (s, 3H), 2.48 - 2.41 (m, 2H), 1.20 (d, J = 6.2 Hz, 6H).407 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 2.20 - 2.38 (m, 2 H) 3.49 - 4.06(m, 4 H) 4.79 (br d, J=5.63 Hz, 2 H) 5.52 (br d, J=53.41 Hz, 1 H) 5.79 (s, 1 H) 6.96 (t, J=53.50 Hz, 1 H) 7.81 - 7.90 (m, 2 H) 8.07 (s, 1 H) 8.11 - 8.18 (m, 1 H) 8.22 (d, J=8.68 Hz, 1 H) 8.32 - 8.47 (m, 2 H) 8.55 (s, 1 H) 8.62 (s, 1 H) 8.69 (s, 1 H) 9.34 (s, 1 H) 9.58 (br t, J=5.72 Hz, 1 H) 408 'HNMR (CDC13, 400 MHz) 5 (ppm) 9.25 (s, 1H), 8.49 (d, 1H, J=1.9 Hz), 8.41 (s, 1H), 8.28 (dd, 1H, J=1.7, 8.6 Hz), 8.10 (dd, 1H, J=1.9, 7.9 Hz), 8.05 (d, 1H, J=8.6 Hz), 7.80 (s, 1H), 7.64 (dd, 1H, J=7.5, 8.4 Hz), 7.54 (br t, 1H, J=5.0 Hz), 7.46 (d, 1H, J=7.9 Hz), 7.29 (s, 1H), 6.68 (d, 1H, J=8.6 Hz), 4.93 (d, 2H, J=5.2 Hz), 4.24 (dd, 2H, J=1.8, 12.8 Hz), 3.80 (ddd, 2H, J=2.5, 6.3, 10.5 Hz), 3.12 (s, 3H), 2.78 (s, 3H), 2.63 (dd, 2H, J=10.7, 12.6 Hz), 1.34 (d, 6H, J=6.3 Hz)409 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 4.02 (s, 3 H) 4.75 (d, J=5.72 Hz, 2 H) 4.92 (dd, J=7.01, 1.57 Hz, 4 H) 5.45 (t, J=7.01 Hz, 1 H) 7.24 - 7.54 (m, 1 H) 7.66 (s, 1 H) 7.90 - 7.98 (m, 2 H) 8.07 (d, J=8.68 Hz, 1 H) 8.13 - 8.15 (m, 1 H) 8.18 (d, J=7.92 Hz, 1 H) 8.46 (s, 1 H) 8.49 - 8.53 (m, 1 H) 8.54 (s, 1 H) 9.19 (s, 1 H) 9.61 (t, J=5.86 Hz, 1 H)410 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 3.97 (s, 3 H) 4.51 (td, J=14.85,3.58 Hz, 2 H) 4.75 (d, J=5.72 Hz, 2 H) 6.19 - 6.55 (m, 1 H) 7.23 - 7.54 (m, 1 H) 7.68 (s, 1 H) 7.88 - 7.92 (m, 1 H) 7.94 (t, J=7.82 Hz, 1 H) 8.04 - 8.10 (m, 1 H) 8.12 - 8.15 (m, 1 H) 8.17 (d, J=7.82 Hz, 1 H) 8.30 (s, 1 H) 8.47 - 8.57 (m, 2 H) 9.19 (s, 1 H) 9.61 (t, J=5.72 Hz, 1 H)Co. No. NMR peaks list411 'HNMR (400 MHz, CDC13) 6 ppm 1.32 (d, J=6.38 Hz, 3 H) 1.33 - 1.35(m, 1 H) 1.42 (br d, J=6.60 Hz, 4 H) 2.98 - 3.10 (m, 1 H) 3.39 (dd, J=13.42, 8.36 Hz, 1 H) 3.56 - 3.67 (m, 1 H) 3.75 - 3.85 (m, 1 H) 4.26 (d, J=18.71 Hz, 1 H) 4.62 (dd, J=13.20, 3.52 Hz, 1 H) 4.85 (br d, J=18.71 Hz, 1 H) 4.95 (d, J=5.50 Hz, 2 H) 6.21 (t, J=54.69 Hz, 1 H) 6.63 - 6.74 (m, 1 H) 7.16 (d, J=5.06 Hz, 1 H) 7.71 (t, J=7.81 Hz, 1 H) 7.86 (s, 1 H) 7.94 (br s, 1 H) 8.05 (d, J=8.58 Hz, 1 H) 8.19 (d, J=7.92 Hz, 1 H) 8.26 (dd, J=8.69, 1.43 Hz, 1 H) 8.30 (d, J=7.92 Hz, 1 H) 8.49 (s, 1 H) 8.48 (d, J=5.28 Hz, 2 H) 8.54 - 8.60 (m, 1 H) 9.26 (s, 1 H)412 'HNMR (400 MHz, CDCI3) 8 ppm 1.32 (d, J=6.38 Hz, 3 H) 1.43 (d, J=6.60 Hz, 3 H) 3.07 (d, J=7.48 Hz, 1 H) 3.39 (dd, J=13.20, 8.36 Hz, 1 H) 3.79 (br dd, J=3.74, 1.76 Hz, 1 H) 4.25 (d, J=18.71 Hz, 1 H) 4.61 (dd, J=13.31, 3.63 Hz, 1 H) 4.84 (d, J=18.71 Hz, 1 H) 4.94 (d, J=5.50 Hz, 2 H) 6.23 (t, J=54.69 Hz, 1 H) 6.69 (s, 1 H) 7.15 (d, J=5.06 Hz, 1 H) 7.70 (t, J=7.81 Hz, 1 H) 7.86 (s, 1 H) 8.03 (d, J=8.58 Hz, 1 H) 8.10 (br t, J=5.28 Hz, 1 H) 8.19 (d, J=8.14 Hz, 1 H) 8.25 (dd, J=8.58, 1.54 Hz, 1 H) 8.31 (dt, J=7.81, 1.27 Hz, 1 H) 8.44 - 8.51 (m, 2 H) 8.56 - 8.62 (m, 1 H) 9.24 (s, 1 H)413 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.20 (br dd, J=13.92, 6.20 Hz,6 H) 2.60 - 2.79 (m, 2 H) 3.55 - 3.67 (m, 2 H) 3.99 (s, 3 H) 4.56 (br d, J=12.87 Hz, 1 H) 4.79 (d, J=5.72 Hz, 2 H) 4.88 (br d, J=12.59 Hz, 1 H) 5.79 (s, 1 H) 6.95 (t, J=53.50 Hz, 1 H) 7.85 (t, J=7.87 Hz, 1 H) 7.99 (s, 1 H) 8.14 (d, J=8.11 Hz, 1 H) 8.24 (d, J=8.68 Hz, 1 H) 8.38 - 8.43 (m, 1 H) 8.51 - 8.57 (m, 2 H) 8.99 (s, 1 H) 9.39 (s, 1 H) 9.56 (s, 1 H)414 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.05 - 1.11 (m, 3 H) 1.16 (d, J=6.10 Hz, 3 H) 2.53 - 2.65 (m, 2 H) 3.20 (s, 3 H) 3.45 - 3.60 (m, 2 H) 4.51 (s, 2 H) 4.80 (d, J=5.82 Hz, 2 H) 5.79 (s, 1 H) 6.74 - 7.19 (m, 1 H) 7.84 - 7.90 (m, 3 H) 8.14 (s, 1 H) 8.27 - 8.33 (m, 2 H) 8.40 (d, J=7.92 Hz, 1 H) 8.51 - 8.55 (m, 1 H) 9.43 (s, 1 H) 9.60 (s, 1 H)415 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 4.02 (s, 3 H) 4.74 (d, J=5.72 Hz, 2 H) 4.86 - 4.96 (m, 4 H) 5.44 (t, J=7.01 Hz, 1 H) 5.79 (s, 1 H) 6.79 - 7.13 (m, 1 H) 7.64 (s, 1 H) 7.86 (t, J=7.87 Hz, 1 H) 7.93 (dd, J=8.58, 1.53 Hz, 1 H) 8.07 (d, J=8.68 Hz, 1 H) 8.11 - 8.17 (m, 2 H) 8.36 - 8.42 (m, 1 H) 8.47 (s, 1 H) 8.53 (t, J=1.57 Hz, 1 H) 9.18 (s, 1 H) 9.53 (t, J=5.82 Hz, 1 H)416 'HNMR (400 MHz, CDCI3) 5 (ppm) 1.32 (d, J=6.3 Hz, 6 H) 1.67 (s, 3H) 2.57 - 2.65 (m, 2 H) 3.73 - 3.83 (m, 2 H) 4.22 (br d, J=12.6 Hz, 2 H) 4.85 - 4.90 (m, 2 H) 5.72 (t, J=56.3 Hz, 1 H) 6.66 (d, J=8.5 Hz, 1 H) 7.24 (br d, J=7.3 Hz, 1 H) 7.38 - 7.46 (m, 1 H) 7.58 - 7.65 (m, 2 H) 7.66 - 7.76 (m, 1 H) 7.78 - 7.83 (m, 2 H) 7.94 - 8.01 (m, 1 H) 8.11 (s, 1 H) 8.23 (br d, J=8.5 Hz, 1 H) 8.37 (br s, 1 H) 9.11 - 9.16 (m, 1 H)Co. No. NMR peaks list417 'HNMR (400 MHz, CDC13) 5 (ppm) 1.32 (d, J=6.5 Hz, 6 H) 2.61 (dd,J=12.6, 10.6 Hz, 2 H) 3.23 (s, 3 H) 3.73 - 3.82 (m, 2 H) 4.22 (dd, J=12.6, 1.6 Hz, 2 H) 4.89 (d, J=4.9 Hz, 2 H) 6.66 (d, J=8.6 Hz, 1 H) 7.22 - 7.27 (m, 1 H) 7.30 (t, J=9.0 Hz, 1 H) 7.56 - 7.65 (m, 1 H) 7.75 (s, 1 H) 7.88 (br t, J=4.9 Hz, 1 H) 7.99 (d, J=8.6 Hz, 1 H) 8.20 - 8.29 (m, 2 H) 8.36 (s, 1 H) 8.45 (dd, J=6.3, 2.2 Hz, 1 H) 9.18 (s, 1 H)418 'HNMR (400 MHz, CDCI3) 5 (ppm) 1.32 (d, J=6.1 Hz, 6 H) 2.61 (dd,J=12.6, 10.6 Hz, 2 H) 3.28 (s, 3 H) 3.74 - 3.82 (m, 2 H) 4.23 (dd, J=12.9, 1.8 Hz, 2 H) 4.89 (d, J=4.9 Hz, 2 H) 6.67 (d, J=8.6 Hz, 1 H) 7.23 - 7.26 (m, 1 H) 7.56 - 7.67 (m, 1 H) 7.77 (s, 1 H) 7.81 - 7.84 (m, 1 H) 7.87 (br t, J=5.1 Hz, 1 H) 7.97 - 8.06 (m, 2 H) 8.26 (dd, J=8.8, 1.4 Hz, 1 H) 8.37 (s, 1 H) 8.62 (d, J=2.0 Hz, 1 H) 9.19 (s, 1 H) 421 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.21 (d, J=6.4 Hz, 7 H) 3.34 (s,4 H) 3.62 - 3.71 (m, 2 H) 4.31 (br d, J=11.2 Hz, 2 H) 4.77 (d, J=5.7 Hz, 2 H) 6.90 (d, J=8.6 Hz, 1 H) 7.45 (d, J=7.5 Hz, 1 H) 7.70 (dd, J=8.4, 7.5 Hz, 1 H) 7.88 (s, 1 H) 8.18 (d, J=8.8 Hz, 1 H) 8.29 (t, J=1.8 Hz, 1 H) 8.34 (dd, J=8.6, 1.5 Hz, 1 H) 8.48 (dt, J=6.8, 1.6 Hz, 2 H) 8.61 (s, 1 H) 9.31 (s, 1 H) 9.59 (t, J=5.7 Hz, 1 H)422 'HNMR (CDCI3, 400 MHz) 5 (ppm) 9.28 (s, 1H), 8.50 (s, 1H), 8.44 (d,1H, J=5.1 Hz), 8.2-8.3 (m, 2H), 8.0-8.1 (m, 2H), 7.8-7.9 (m, 2H), 7.74 (br s, 1H), 7.09 (d, 1H, J=5.1 Hz), 6.25 (t, 1H, J=53.1 Hz), 4.93 (d, 2H, J=5.1 Hz), 4.3-4.4 (m, 1H), 4.22 (d, 4H, J=7.0 Hz), 2.67 (ddd, 2H, J=3.0, 6.9, 9.9 Hz), 2.2-2.3 (m, 2H)423 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 9.51 (t, J = 5.8 Hz, 1H), 8.94 (s, 1H), 8.46 - 8.40 (m, 2H), 8.08 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 6.9 Hz, 1H), 7.84 (d, J = 5.9 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.23 (d, J = 52.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 4.61 (d, J = 5.8 Hz, 2H), 4.02 - 3.72 (m, 4H), 3.62 (dd, J = 11.6, 9.2 Hz, 1H), 2.97 - 2.71 (m, 2H), 1.41 (d, J = 13.4 Hz, 3H), 1.36 (d, J = 13.4 Hz, 3H).424 'HNMR (400 MHz, DMSO-d6) 5 (ppm) 1.19 (d, J=6.20 Hz, 6 H) 2.49(br s, 1 H) 2.55 (s, 1 H) 3.18 (s, 3 H) 3.27 (brt, J=8.68 Hz, 2 H) 3.58 - 3.70 (m, 2 H) 4.10 (t, J=8.68 Hz, 2 H) 4.32 (br d, J=12.02 Hz, 2 H) 4.78 (d, J=6.01 Hz, 2 H) 6.77 (dd, J=12.54, 1.29 Hz, 1 H) 7.38 (dd, J=9.97, 1.38 Hz, 1 H) 7.78 (s, 1 H) 7.92 (s, 1 H) 8.19 (d, J=8.68 Hz, 1 H) 8.35 (dd, J=8.68, 1.43 Hz, 1 H) 8.49 (s, 1 H) 8.61 (s, 1 H) 9.33 (s, 1 H) 9.41 (t, J=6.10 Hz, 1 H)42519F NMR (376 MHz, DMSO-d6) 5 (ppm) -85.20, -124.32.Co. No. NMR peaks list4251H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.80 (t, J = 5.8 Hz, 1H), 9.32 (s, 1H), 8.73 - 8.65 (m, 2H), 8.64 - 8.57 (m, 1H), 8.34 (dd, J = 8.6, 1.7 Hz, 1H), 8.23 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.90 (s, 1H), 7.70 (dd, J = 8.5, 7.5 Hz, 1H), 7.46 (s, 1H), 7.38 (t, J = 45.1 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 5.7 Hz, 2H), 4.31 (dd, J = 13.1, 2.3 Hz, 2H), 3.75 - 3.57 (m, 2H), 2.48 - 2.41 (m, 2H), 2.11 (t, J = 19.2 Hz, 3H), 1.20 (d, J = 6.2 Hz, 6H).42619F NMR (376 MHz, DMSO-d6) 5 (ppm) -124.29 (d, J=52.0 Hz, 1 F)4261H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.28 (s, 3 H) 1.53 - 1.60 (m, 2H) 1.61 - 1.69 (m, 2 H) 1.84 - 1.94 (m, 4 H) 3.79 (br s, 4 H) 4.79 (s, 1 H) 4.80 (d, J=5.7 Hz, 2 H) 7.39 (t, J=52.0 Hz, 1 H) 7.33 (d, J=5.2 Hz, 1 H) 7.91 (s, 1 H) 7.95 (t, J=7.8 Hz, 1 H) 8.19 (d, J=7.9 Hz, 1 H) 8.24 (d, J=8.7 Hz, 1 H) 8.35 (dd, J=8.6, 1.5 Hz, 1 H) 8.48 (d, J=5.1 Hz, 1 H) 8.52 (d, J=7.8 Hz, 1 H) 8.55 (s, 1 H) 8.72 (s, 1 H) 9.37 (s, 1 H) 9.67 (t, J=5.7 Hz, 1 H)4271H NMR (400 MHz, CDCl3) 5 (ppm) 1.32 (d, J=6.38 Hz, 6 H) 2.61 (dd,J=12.54, 10.78 Hz, 2 H) 3.03 (s, 3 H) 3.72 - 3.84 (m, 2 H) 4.22 (dd, J=12.54, 1.54 Hz, 2 H) 4.87 (br d, J=5.28 Hz, 2 H) 4.93 (td, J=10.67, 3.96 Hz, 1 H) 5.77 (td, J=55.73, 3.85 Hz, 1 H) 6.66 (d, J=8.58 Hz, 1 H) 7.23 (d, J=7.48 Hz, 1 H) 7.61 (t, J=8.03 Hz, 1 H) 7.79 (s, 1 H) 7.98 (d, J=8.80 Hz, 1 H) 8.04 (s, 1 H) 8.19 (s, 1 H) 8.24 (dd, J=8.58, 1.32 Hz, 1 H) 8.29 - 8.34 (m, 2 H) 8.36 (s, 1 H) 9.15 (s, 1 H)4281H NMR (400 MHz, CDCl3) 5 (ppm) 1.33 (d, J=6.16 Hz, 6 H) 2.62 (dd,J=12.65, 10.67 Hz, 2 H) 3.13 (s, 3 H) 3.74 - 3.84 (m, 2 H) 4.23 (dd, J=12.76, 1.76 Hz, 2 H) 4.93 (d, J=4.84 Hz, 2 H) 6.68 (d, J=8.36 Hz, 1 H) 7.28 (d, J=6.38 Hz, 1 H) 7.63 (dd, J=8.36, 7.70 Hz, 1 H) 7.81 (s, 1 H) 7.83 - 7.88 (m, 1 H) 8.04 (d, J=8.80 Hz, 1 H) 8.29 (dd, J=8.69, 1.65 Hz, 1 H) 8.33 (s, 1 H) 8.42 (s, 1 H) 8.46 (s, 1 H) 8.62 (s, 1 H) 9.24 (s, 1 H) 4291H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.27 (d, J=6.2 Hz, 3 H) 2.92 - 3.03 (m, 1 H) 3.23 - 3.31 (m, 2 H) 3.32 (s, 4 H) 3.34 (s, 3 H) 3.34 - 3.40 (m, 2 H) 3.41 - 3.47 (m, 1 H) 3.95 - 4.10 (m, 2 H) 4.25 (dd, J=12.8, 4.0 Hz, 1 H) 4.40 (t, J=4.2 Hz, 1 H) 4.79 (d, J=5.7 Hz, 2 H) 6.89 (d, J=8.6 Hz, 1 H) 7.42 - 7.50 (m, 1 H) 7.64 - 7.74 (m, 1 H) 7.82 - 7.94 (m, 3 H) 8.05 - 8.14 (m, 1 H) 8.19 (d, J=8.6 Hz, 1 H) 8.35 (dd, J=8.6, 1.5 Hz, 1 H) 8.40 (t, J=1.4 Hz, 1 H) 8.60 (s, 1 H) 9.32 (s, 1 H) 9.60 (t, J=5.8 Hz, 1H)Co. No. NMR peaks list4301H NMR (400 MHz, CDCl3) 5 (ppm) 1.38 (d, J=6.4 Hz, 3 H) 3.09 (s, 3H) 3.36 (s, 4 H) 3.45 - 3.53 (m, 4 H) 3.82 (dd, J=12.9, 4.1 Hz, 1 H) 3.89 - 4.02 (m, 2 H) 4.09 - 4.18 (m, 1 H) 4.45 (dd, J=5.7, 4.0 Hz, 1 H) 4.91 (d, J=5.1 Hz, 2 H) 6.80 (d, J=8.4 Hz, 1 H) 6.93 - 7.05 (m, 1 H) 7.28 (s, 1 H) 7.63 (dd, J=8.4, 7.5 Hz, 1 H) 7.71 (br t, J=4.8 Hz, 1 H) 7.78 (s, 1 H) 7.99 - 8.09 (m, 2 H) 8.16 (t, J=1.8 Hz, 1 H) 8.24 - 8.33 (m, 2 H) 8.41 (s, 1 H) 9.24 (s, 1 H)4311H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.07 (d, J=6.10 Hz, 3 H) 1.15(d, J=6.20 Hz, 3 H) 2.52 - 2.64 (m, 2 H) 3.20 (s, 3 H) 3.44 - 3.58 (m, 2 H) 4.50 (br t, J=12.97 Hz, 2 H) 4.79 (d, J=5.72 Hz, 2 H) 5.79 (s, 1 H) 6.69 - 7.16 (m, 1 H) 7.83 - 7.90 (m, 3 H) 8.14 (d, J=8.11 Hz, 1 H) 8.28 (d, J=8.58 Hz, 1 H) 8.31 (s, 1 H) 8.39 (d, J=7.92 Hz, 1 H) 8.53 (s, 1 H) 9.42 (s, 1 H) 9.59 (t, J=5.77 Hz, 1 H)4321H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.07 (d, J=6.10 Hz, 3 H) 1.15(d, J=6.10 Hz, 3 H) 2.53 - 2.64 (m, 2 H) 3.20 (s, 3 H) 3.42 - 3.60 (m, 2 H) 4.50 (br t, J=13.07 Hz, 2 H) 4.79 (d, J=5.72 Hz, 2 H) 5.79 (s, 1 H) 6.95 (t, J=53.45 Hz, 1 H) 7.83 - 7.90 (m, 3 H) 8.14 (d, J=7.92 Hz, 1 H) 8.28 (d, J=8.49 Hz, 1 H) 8.31 (s, 1 H) 8.39 (d, J=7.92 Hz, 1 H) 8.52 (s, 1 H) 9.42 (s, 1 H) 9.59 (t, J=5.77 Hz, 1 H)4331H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.08 (d, J=6.10 Hz, 3 H) 1.16(d, J=6.20 Hz, 3 H) 2.53 - 2.68 (m, 2 H) 3.21 (s, 3 H) 3.45 - 3.58 (m, 2 H) 4.51 (br t, J=12.97 Hz, 2 H) 4.80 (d, J=5.72 Hz, 2 H) 5.80 (s, 1 H) 6.79 - 7.12 (m, 1 H) 7.83 - 7.91 (m, 3 H) 8.15 (d, J=8.11 Hz, 1 H) 8.29 (d, J=8.58 Hz, 1 H) 8.31 (s, 1 H) 8.40 (d, J=7.92 Hz, 1 H) 8.53 (s, 1 H) 9.43 (s, 1 H) 9.60 (t, J=5.77 Hz, 1 H)4341H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.17 - 1.24 (m, 6 H) 2.61 - 2.77(m, 2 H) 3.54 - 3.68 (m, 2 H) 3.99 (s, 3 H) 4.56 (br d, J=12.87 Hz, 1 H) 4.75 - 4.83 (m, 2 H) 4.88 (br d, J=12.78 Hz, 1 H) 5.79 (s, 1 H) 6.80 - 7.13 (m, 1 H) 7.85 (t, J=7.82 Hz, 1 H) 7.99 (s, 1 H) 8.09 - 8.19 (m, 1 H) 8.23 (d, J=8.68 Hz, 1 H) 8.40 (d, J=7.92 Hz, 1 H) 8.51 - 8.57 (m, 2 H) 8.99 (s, 1 H) 9.39 (s, 1 H) 9.56 (t, J=5.77 Hz, 1 H)4351H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.19 (d, J=6.20 Hz, 6 H) 2.59(dd, J=12.97, 10.78 Hz, 2 H) 3.18 (s, 3 H) 3.27 (br t, J=8.63 Hz, 2 H) 3.61 (ddd, J=10.37, 6.27, 2.43 Hz, 2 H) 4.09 (t, J=8.68 Hz, 2 H) 4.60 - 4.74 (m, 2 H) 4.78 (d, J=6.10 Hz, 2 H) 7.42 (d, J=5.15 Hz, 1 H) 7.82 (s, 1 H) 7.91 (s, 1 H) 8.23 (d, J=8.68 Hz, 1 H) 8.38 (dd, J=8.63, 1.48 Hz, 1 H) 8.48 (s, 1 H) 8.51 (d, J=5.15 Hz, 1 H) 8.71 (s, 1 H) 9.36 (s, 1 H) 9.39 - 9.44 (m, 1 H)Co. No. NMR peaks list4621H NMR (CDCl3, 400 MHz) 5 (ppm) 9.2-9.3 (m, 1H), 8.43 (s, 1H), 8.31(t, 1H, J=1.4 Hz), 8.29 (dd, 1H, J=1.6, 8.6 Hz), 8.05 (d, 1H, J=8.6 Hz), 7.95 (s, 1H), 7.88 (s, 1H), 7.86 (br s, 1H), 7.83 (s, 1H), 7.64 (dd, 1H, J=7.6, 8.3 Hz), 7.29 (s, 1H), 6.69 (d, 1H, J=8.5 Hz), 6.65 (t, 1H, J=72.2 Hz), 4.92 (d, 2H, J=5.2 Hz), 4.24 (dd, 2H, J=1.8, 12.8 Hz), 4.14 (ddd, 1H, J=3.7, 6.1, 12.8 Hz), 3.92 (ddd, 1H, J=3.6, 6.6, 12.8 Hz), 3.7-3.9 (m, 2H), 3.3-3.4 (m, 2H), 2.63 (dd, 2H, J=10.7, 12.6 Hz), 1.34 (d, 6H, J=6.3 Hz)4631H NMR (CDCl3, 400 MHz) 5 (ppm) 9.2-9.3 (m, 1H), 8.43 (s, 1H), 8.31(t, 1H, J=1.4 Hz), 8.29 (dd, 1H, J=1.6, 8.6 Hz), 8.05 (d, 1H, J=8.6 Hz), 7.95 (s, 1H), 7.88 (s, 1H), 7.86 (br s, 1H), 7.83 (s, 1H), 7.64 (dd, 1H, J=7.6, 8.3 Hz), 7.29 (s, 1H), 6.69 (d, 1H, J=8.5 Hz), 6.65 (t, 1H, J=72.2 Hz), 4.92 (d, 2H, J=5.2 Hz), 4.24 (dd, 2H, J=1.8, 12.8 Hz), 4.14 (ddd, 1H, J=3.7, 6.1, 12.8 Hz), 3.92 (ddd, 1H, J=3.6, 6.6, 12.8 Hz), 3.7-3.9 (m, 2H), 3.3-3.4 (m, 2H), 2.63 (dd, 2H, J=10.7, 12.6 Hz), 1.34 (d, 6H, J=6.3 Hz)4641H NMR (400 MHz, CDCl3) 5 (ppm) 1.24 (t, J=7.0 Hz, 1 H) 1.38 (d, J=6.4 Hz, 3 H) 2.77 (s, 3 H) 3.29 - 3.54 (m, 11 H) 3.78 - 4.01 (m, 4 H) 4.07 - 4.19 (m, 2 H) 4.45 (dd, J=5.7, 4.2 Hz, 1 H) 4.91 (d, J=5.3 Hz, 2 H) 6.80 (d, J=8.6 Hz, 1 H) 6.96 - 7.03 (m, 1 H) 7.28 (s, 1 H) 7.43 (d, J=8.1 Hz, 1 H) 7.63 (dd, J=8.4, 7.5 Hz, 1 H) 7.76 (br s, 1 H) 7.82 (s, 1 H) 8.03 (t, J=7.9 Hz, 2 H) 8.27 (dd, J=8.6, 1.5 Hz, 1 H) 8.42 (s, 1 H) 8.55 (d, J=2.0 Hz, 1 H) 9.23 (s, 1 H)465 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.76 (d, J=5.82 Hz, 2 H) 4.86 - 4.98 (m, 4 H) 5.52 (quin, J=6.91 Hz, 1 H) 7.46 (m, J=1.00, 1.00, 1.00, 1.00, 1.00 Hz, 2 H) 7.71 (s, 1 H) 7.89 (dd, J=8.58, 1.62 Hz, 1 H) 7.94 (t, J=7.87 Hz, 1 H) 8.10 (s, 1 H) 8.12 - 8.20 (m, 2 H) 8.50 (dt, J=7.87, 1.26 Hz, 1 H) 8.53 (d, J=1.53 Hz, 1 H) 8.60 (s, 1 H) 9.24 (s, 1 H) 9.62 (t, J=5.77 Hz, 1 H)4661H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.79 (s, 6 H) 4.78 (d, J=5.82 Hz, 2 H) 6.30 (t, J=7.06 Hz, 1 H) 6.72 (dd, J=7.44, 1.62 Hz, 1 H) 7.21 - 7.53 (m, 2 H) 7.66 (dd, J=8.68, 2.00 Hz, 1 H) 7.84 (s, 1 H) 7.94 (t, J=7.82 Hz, 1 H) 8.02 (d, J=1.81 Hz, 1 H) 8.17 (d, J=8.11 Hz, 1 H) 8.21 (d, J=8.77 Hz, 1 H) 8.47 - 8.52 (m, 1 H) 8.52 (d, J=1.53 Hz, 1 H) 9.38 (s, 1 H) 9.67 (t, J=5.87 Hz, 1 H)4671H NMR (400 MHz, CDCl3) 5 (ppm) 1.65 - 1.67 (m, 2 H) 1.67 - 1.71 (m, 2 H) 4.97 (d, J=5.15 Hz, 2 H) 6.24 (t, J=53.31 Hz, 1 H) 7.62 (br s, 1 H) 7.73 (d, J=5.25 Hz, 1 H) 7.79 (t, J=7.87 Hz, 1 H) 7.86 (s, 1 H) 8.13 (t, J=7.30 Hz, 2 H) 8.29 - 8.37 (m, 2 H) 8.46 (t, J=1.57 Hz, 1 H) 8.57 (s, 1 H) 8.86 (d, J=5.25 Hz, 1 H) 9.32 (s, 1 H)Co. No. NMR peaks list4681H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.71 - 4.83 (m, 4 H) 6.40 (tt,J=54.88, 3.15 Hz, 1 H) 6.70 (d, J=2.96 Hz, 1 H) 7.24 - 7.51 (m, 4 H) 7.66 (dd, J=6.68, 2.29 Hz, 1 H) 7.88 (s, 1 H) 7.91 - 7.98 (m, 2 H) 8.17 (d, J=8.01 Hz, 1 H) 8.21 (s, 1 H) 8.23 (d, J=8.58 Hz, 1 H) 8.50 - 8.53 (m, 1 H) 8.54 (d, J=1.43 Hz, 1 H) 9.34 (s, 1 H) 9.64 (br t, J=5.77 Hz, 1 H)46919F NMR (377 MHz, DMSO-d6) 5 (ppm) -124.25 (d, J=52.2 Hz, 1 F) - 83.19 (s, 1 F)469 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.44 (br d, J=14.0 Hz, 2 H)2.69 (br d, J=14.6 Hz, 2 H) 4.16 (br d, J=16.8 Hz, 4 H) 4.80 (d, J=5.7 Hz, 2 H) 6.54 (s, 1 H) 7.24 - 7.53 (m, 1 H) 7.42 (d, J=5.1 Hz, 1 H) 7.89 (s, 1 H) 7.95 (t, J=7.8 Hz, 1 H) 8.18 (d, J=7.8 Hz, 1 H) 8.24 (d, J=8.7 Hz, 1 H) 8.35 (dd, J=8.6, 1.5 Hz, 1 H) 8.48 (d, J=5.2 Hz, 1 H) 8.52 (d, J=7.9 Hz, 1 H) 8.55 (s, 1 H) 8.71 (s, 1 H) 9.37 (s, 1 H) 9.66 (t, J=5.8 Hz, 1 H)470 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.43 (br d, J=13.9 Hz, 2 H)2.69 (br d, J=14.5 Hz, 2 H) 4.05 (s, 2 H) 4.09 (s, 2 H) 4.79 (d, J=5.7 Hz, 2 H) 6.43 (d, J=8.1 Hz, 1 H) 6.54 (s, 1 H) 7.38 (t, J=52.0 Hz, 1 H) 7.42 (d, J=7.5 Hz, 1 H) 7.65 (t, J=7.8 Hz, 1 H) 7.85 (s, 1 H) 7.95 (t, J=7.8 Hz, 1 H) 8.17 (d, J=3.7 Hz, 1 H) 8.18 - 8.21 (m, 1 H) 8.33 (dd, J=8.6, 1.5 Hz, 1 H) 8.50 - 8.54 (m, 1 H) 8.56 (d, J=6.6 Hz, 2 H) 9.31 (s, 1 H) 9.63 (t, J=5.8 Hz, 1 H)47119F NMR (377 MHz, DMSO-d6) 5 (ppm) -124.27 (d, J=52.2 Hz, 1 F)4711H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.28 (s, 3 H) 1.55 - 1.62 (m, 2H) 1.64 - 1.72 (m, 2 H) 1.82 - 1.94 (m, 4 H) 3.51 - 3.61 (m, 4 H) 4.74 - 4.77 (m, 1 H) 4.79 (d, J=5.7 Hz, 2 H) 6.87 (d, J=8.6 Hz, 1 H) 7.24 - 7.52 (m, 1 H) 7.38 (d, J=3.1 Hz, 1 H) 7.64 (t, J=7.9 Hz, 1 H) 7.86 (s, 1 H) 7.95 (t, J=7.8 Hz, 1 H) 8.17 (d, J=8.6 Hz, 2 H) 8.33 (dd, J=8.6, 1.5 Hz, 1 H) 8.48 - 8.54 (m, 1 H) 8.56 (d, J=11.9 Hz, 2 H) 9.31 (s, 1 H) 9.63 (t, J=5.8 Hz, 1 H)4721H NMR (400 MHz, DMSO-d6) 5 (ppm) 3.19 (s, 3 H) 3.28 (t, J=8.68 Hz, 2 H) 4.02 (s, 3 H) 4.10 (t, J=8.73 Hz, 2 H) 4.74 (d, J=6.10 Hz, 2 H) 4.89 - 4.96 (m, 4 H) 5.45 (t, J=7.01 Hz, 1 H) 7.58 (s, 1 H) 7.90 - 7.95 (m, 2 H) 8.05 - 8.12 (m, 2 H) 8.46 - 8.50 (m, 2 H) 9.19 (s, 1 H) 9.38 (t, J=6.10 Hz, 1 H)Co. No. NMR peaks list4751H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.02 (s, 3 H) 4.74 (br d, J=5.53Hz, 2 H) 4.85 - 5.02 (m, 4 H) 5.37 - 5.54 (m, 1 H) 5.79 (s, 1 H) 6.78 - 7.13 (m, 1 H) 7.64 (s, 1 H) 7.85 (t, J=7.82 Hz, 1 H) 7.93 (br d, J=8.39 Hz, 1 H) 8.07 (d, J=8.68 Hz, 1 H) 8.11 - 8.22 (m, 2 H) 8.40 (br d, J=7.82 Hz, 1 H) 8.46 (s, 1 H) 8.53 (s, 1 H) 9.18 (s, 1 H) 9.52 (br t, J=5.34 Hz, 1 H)4761H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.47 (t, J=13.11 Hz, 6 H) 2.91 - 3.15 (m, 2 H) 3.65 (br t, J=10.54 Hz, 1 H) 3.89 (dt, J=8.85, 2.73 Hz, 1 H) 4.07 (br d, J=10.01 Hz, 1 H) 4.29 (br d, J=13.16 Hz, 1 H) 4.50 (br d, J=12.87 Hz, 1 H) 4.79 (br d, J=5.63 Hz, 2 H) 6.96 (d, J=8.49 Hz, 1 H) 7.22 - 7.56 (m, 2 H) 7.74 (t, J=7.96 Hz, 1 H) 7.84 (s, 1 H) 7.95 (t, J=7.77 Hz, 1 H) 8.12 - 8.25 (m, 2 H) 8.34 (br d, J=8.58 Hz, 1 H) 8.48 - 8.57 (m, 2 H) 8.60 (s, 1 H) 9.32 (s, 1 H) 9.65 (br t, J=5.58 Hz, 1 H)4771H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.71 - 4.83 (m, 4 H) 5.78 (s, 1H) 6.23 - 6.55 (m, 1 H) 6.70 (d, J=3.15 Hz, 1 H) 6.94 (t, J=53.50 Hz, 1 H) 7.29 - 7.35 (m, 2 H) 7.49 (d, J=3.24 Hz, 1 H) 7.66 (dd, J=6.25, 2.62 Hz, 1 H) 7.82 - 7.88 (m, 2 H) 7.95 (dd, J=8.49, 1.53 Hz, 1 H) 8.13 (d, J=8.11 Hz, 1 H) 8.21 (s, 1 H) 8.23 (d, J=8.58 Hz, 1 H) 8.40 (d, J=8.01 Hz, 1 H) 8.53 (s, 1 H) 9.34 (s, 1 H) 9.55 (t, J=5.72 Hz, 1 H)4781H NMR (400 MHz, CDCl3) 5 (ppm) 1.66 (s, 2 H) 1.67 - 1.72 (m, 2 H)3.51 (br s, 1 H) 4.96 (d, J=5.34 Hz, 2 H) 6.19 (s, 1 H) 7.68 (br t, J=4.15 Hz, 1 H) 7.71 - 7.77 (m, 2 H) 7.86 (s, 1 H) 8.11 (d, J=8.68 Hz, 1 H) 8.22 (d, J=7.92 Hz, 1 H) 8.30 (d, J=8.08 Hz, 2 H) 8.55 (d, J=8.11 Hz, 2 H) 8.85 (d, J=5.25 Hz, 1 H) 9.31 (s, 1 H)4791H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.71 - 4.83 (m, 4 H) 5.75 - 5.79(m, 1 H) 6.40 (tt, J=55.02, 3.45 Hz, 1 H) 6.70 (d, J=3.05 Hz, 1 H) 6.94 (t, J=53.50 Hz, 1 H) 7.26 - 7.37 (m, 2 H) 7.49 (d, J=3.34 Hz, 1 H) 7.66 (dd, J=6.34, 2.72 Hz, 1 H) 7.82 - 7.88 (m, 2 H) 7.95 (dd, J=8.44, 1.57 Hz, 1 H) 8.09 - 8.18 (m, 1 H) 8.19 - 8.25 (m, 2 H) 8.40 (d, J=7.92 Hz, 1 H) 8.52 - 8.55 (m, 1 H) 9.34 (s, 1 H) 9.55 (t, J=5.82 Hz, 1 H)4801H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.60 (t, J = 5.8 Hz, 1H), 9.03 (s, 1H), 8.54 (s, 1H), 8.52 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.94 (dd, J = 8.7, 6.4 Hz, 2H), 7.54 (s, 1H), 7.52 - 7.48 (m, 1H), 7.32 (d, J = 52.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 4.70 (d, J = 5.7 Hz, 2H), 4.07 (d, J = 11.4 Hz, 1H), 3.98 - 3.90 (m, 2H), 3.84 (d, J = 12.4 Hz, 1H), 3.71 (dd, J= 11.6, 9.2 Hz, 1H), 3.03 – 2.84 (m, 2H), 1.50 (d, J = 13.4 Hz, 3H), 1.45 (d, J = 13.3 Hz, 3H).Co. No. NMR peaks list481 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.76 (d, J=5.72 Hz, 2 H) 4.88 - 4.97 (m, 4 H) 5.52 (quin, J=6.91 Hz, 1 H) 5.79 (s, 1 H) 6.78 - 7.12 (m, 1 H) 7.33 - 7.69 (m, 1 H) 7.70 (s, 1 H) 7.82 - 7.91 (m, 2 H) 8.10 (s, 1 H) 8.12 - 8.19 (m, 2 H) 8.39 (d, J=7.92 Hz, 1 H) 8.53 (s, 1 H) 8.60 (s, 1 H) 9.24 (s, 1 H) 9.54 (t, J=5.82 Hz, 1 H)482 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.76 (d, J=5.72 Hz, 2 H) 4.86 - 4.99 (m, 4 H) 5.52 (quin, J=6.91 Hz, 1 H) 5.79 (s, 1 H) 6.78 - 7.12 (m, 1 H) 7.32 - 7.69 (m, 1 H) 7.70 (s, 1 H) 7.82 - 7.91 (m, 2 H) 8.10 (s, 1 H) 8.12 - 8.18 (m, 2 H) 8.39 (d, J=7.92 Hz, 1 H) 8.53 (s, 1 H) 8.60 (s, 1 H) 9.24 (s, 1 H) 9.54 (t, J=5.77 Hz, 1 H)4851H NMR (400 MHz, CDCl3) 5 (ppm) 3.31 (s, 3 H) 3.42 - 3.49 (m, 4 H)4.85 - 4.94 (m, 4 H) 6.23 (t, J=53.3 Hz, 1 H) 6.58 (br s, 1 H) 7.63 - 7.79 (m, 4 H) 7.83 - 8.04 (m, 4 H) 8.11 (d, J=8.0 Hz, 1 H) 8.33 (d, J=7.9 Hz, 1 H) 8.44 - 8.47 (m, 1 H) 9.18 (s, 1 H)4881H NMR (DMSO-d6, 400 MHz) 5 (ppm) 9.40 (t, 1H, J=5.8 Hz), 9.36 (s,1H), 8.75 (s, 1H), 8.52 (d, 1H, J=5.1 Hz), 8.38 (dd, 1H, J=1.7, 8.7 Hz), 8.23 (d, 1H, J=8.8 Hz), 8.14 (d, 1H, J=2.2 Hz), 8.00 (dd, 1H, J=2.2, 8.4 Hz), 7.88 (s, 1H), 7.74 (d, 1H, J=8.6 Hz), 7.42 (d, 1H, J=5.3 Hz), 4.77 (d, 2H, J=5.7 Hz), 4.68 (br d, 2H, J=12.8 Hz), 3.75 (t, 2H, J=6.7 Hz), 3.5-3.7 (m, 2H), 3.44 (t, 2H, J=7.4 Hz), 2.60 (dd, 2H, J=10.8, 13.0 Hz), 2.4-2.5 (m, 1H), 1.2-1.2 (m, 6H)48919F NMR (376 MHz, DMSO-d6) 5 (ppm) -81.84.4891H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.30 (s, 1H), 9.25 (t, J = 5.9 Hz, 1H), 8.62 - 8.58 (m, 1H), 8.34 (dd, J = 8.6, 1.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.82 (s, 1H), 7.73 - 7.64 (m, 2H), 7.55 (t, J = 1.8 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.37 (t, J = 68.3 Hz, 1H), 7.22 (t, J = 1.8 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.74 (d, J = 5.8 Hz, 2H), 4.31 (dd, J = 13.1, 2.3 Hz, 2H), 3.71 - 3.56 (m, 2H), 2.48 – 2.43 (m, 2H), 2.40 (s, 3H), 1.20 (d, J = 6.2 Hz, 6H).4901H NMR (400 MHz, DMSO-d6) 5 (ppm) 0.85 - 0.92 (m, 2 H) 1.05 - 1.12(m, 2 H) 1.20 (d, J=6.3 Hz, 6 H) 2.13 - 2.22 (m, 1 H) 2.43 - 2.48 (m, 2 H) 3.26 (s, 3 H) 3.61 - 3.72 (m, 2 H) 4.31 (br d, J=11.4 Hz, 2 H) 4.77 (d, J=5.7 Hz, 2 H) 6.90 (d, J=8.5 Hz, 1 H) 7.46 (d, J=7.4 Hz, 1 H) 7.70 (t, J=8.0 Hz, 1 H) 7.84 (d, J=7.5 Hz, 2 H) 7.94 (s, 1 H) 8.18 (d, J=8.6 Hz, 1 H) 8.24 (s, 1 H) 8.34 (dd, J=8.7, 1.4 Hz, 1 H) 8.61 (s, 1 H) 9.31 (s, 1 H) 9.46 (t, J=5.7 Hz, 1 H)Co. No. NMR peaks list4911H NMR (400 MHz, DMSO-d6) 5 (ppm) 0.88 - 0.95 (m, 2 H) 1.09 - 1.15(m, 2 H) 1.20 (d, J=6.2 Hz, 6 H) 2.21 - 2.29 (m, 1 H) 2.42 - 2.48 (m, 2 H) 3.60 - 3.72 (m, 2 H) 4.31 (br d, J=11.3 Hz, 2 H) 4.77 (d, J=5.6 Hz, 2 H) 6.90 (d, J=8.5 Hz, 1 H) 7.36 (t, J=52.1 Hz, 1 H) 7.45 (d, J=7.4 Hz, 1 H) 7.70 (dd, J=8.4, 7.6 Hz, 1 H) 7.85 - 7.92 (m, 2 H) 8.10 (t, J=1.5 Hz, 1 H) 8.18 (d, J=8.7 Hz, 1 H) 8.28 (t, J=1.6 Hz, 1 H) 8.34 (dd, J=8.6, 1.6 Hz, 1 H) 8.61 (s, 1 H) 9.31 (s, 1 H) 9.58 (t, J=5.8 Hz, 1 H)4921H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.13 - 2.42 (m, 2 H) 3.57 - 4.01(m, 4 H) 4.80 (d, J=5.72 Hz, 2 H) 5.39 - 5.63 (m, 1 H) 5.79 (s, 1 H) 6.77 - 7.17 (m, 1 H) 7.84 - 7.90 (m, 2 H) 8.07 (s, 1 H) 8.15 (d, J=8.01 Hz, 1 H) 8.23 (d, J=8.68 Hz, 1 H) 8.37 (dd, J=8.58, 1.34 Hz, 1 H) 8.42 (d, J=7.92 Hz, 1 H) 8.55 (s, 1 H) 8.62 (s, 1 H) 8.70 (s, 1 H) 9.35 (s, 1 H) 9.58 (s, 1 H)4931H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.17 - 2.38 (m, 2 H) 3.55 - 4.00(m, 4 H) 4.79 (d, J=5.72 Hz, 2 H) 5.40 - 5.61 (m, 1 H) 5.79 (s, 1 H) 6.78 - 7.13 (m, 1 H) 7.83 - 7.89 (m, 2 H) 8.06 (s, 1 H) 8.12 - 8.17 (m, 1 H) 8.22 (d, J=8.68 Hz, 1 H) 8.34 - 8.39 (m, 1 H) 8.41 (d, J=8.01 Hz, 1 H) 8.55 (s, 1 H) 8.62 (s, 1 H) 8.69 (s, 1 H) 9.34 (s, 1 H) 9.57 (t, J=5.72 Hz, 1 H)4941H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.17 - 4.30 (m, 2 H) 4.40 - 4.60(m, 2 H) 4.79 (br d, J=5.63 Hz, 2 H) 5.47 - 5.72 (m, 1 H) 5.79 (s, 1 H) 6.80 - 7.16 (m, 1 H) 7.80 - 7.93 (m, 2 H) 8.00 (s, 1 H) 8.15 (br d, J=7.82 Hz, 1 H) 8.24 (d, J=8.68 Hz, 1 H) 8.33 (d, J=8.49 Hz, 1 H) 8.42 (br d, J=7.82 Hz, 1 H) 8.55 (s, 1 H) 8.68 (d, J=10.30 Hz, 2 H) 9.35 (s, 1 H) 9.58 (brt, J=5.58 Hz, 1 H)4951H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.15 - 4.31 (m, 2 H) 4.42 - 4.57(m, 2 H) 4.79 (d, J=5.72 Hz, 2 H) 5.43 - 5.74 (m, 1 H) 5.79 (s, 1 H) 6.78 - 7.15 (m, 1 H) 7.83 - 7.90 (m, 2 H) 8.00 (s, 1 H) 8.15 (d, J=7.92 Hz, 1 H) 8.21 - 8.26 (m, 1 H) 8.33 (dd, J=8.58, 1.43 Hz, 1 H) 8.42 (d, J=7.92 Hz, 1 H) 8.55 (s, 1 H) 8.66 - 8.71 (m, 2 H) 9.35 (s, 1 H) 9.58 (s, 1 H) 4961H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.58 (s, 1H), 9.35 (s, 1H), 8.72(s, 1H), 8.54 (s, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.34 (dd, J = 1.5, 8.6 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.89 - 7.84 (m, 2H), 7.10 - 6.82 (m, 1H), 6.81 (s, 1H), 5.80 (s, 1H), 5.38 - 5.30 (m, 1H), 4.79 (d, J = 5.7 Hz, 2H), 4.72 - 4.54 (m, 2H), 3.67 - 3.56 (m, 2H), 2.60 (dd, J= 10.7, 13.0 Hz, 2H), 1.34 (d, J = 6.2 Hz, 6H), 1.21 - 1.18 (m, 6H) 4971H NMR (400 MHz, DMSO-d6) 5 (ppm) 4.02 (s, 3 H) 4.74 (d, J=5.72 Hz, 2 H) 4.84 - 4.97 (m, 4 H) 5.36 - 5.51 (m, 1 H) 5.79 (s, 1 H) 6.78 - 7.16 (m, 1 H) 7.64 (s, 1 H) 7.86 (t, J=7.82 Hz, 1 H) 7.93 (dd, J=8.63, 1.57 Hz, 1 H) 8.07 (d, J=8.68 Hz, 1 H) 8.12 - 8.16 (m, 2 H) 8.36 - 8.44 (m, 1 H) 8.47 (s, 1 H) 8.53 (s, 1 H) 9.18 (s, 1 H) 9.53 (t, J=5.87 Hz, 1 H)Co. No. NMR peaks list4981H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.47 (t, J=13.21 Hz, 6 H) 2.96 - 3.11 (m, 2 H) 3.65 (td, J=11.49, 2.29 Hz, 1 H) 3.89 (ddd, J=11.66, 5.46, 2.62 Hz, 1 H) 4.03 - 4.12 (m, 1 H) 4.29 (br d, J=12.78 Hz, 1 H) 4.50 (br d, J=12.68 Hz, 1 H) 4.78 (d, J=5.72 Hz, 2 H) 6.96 (d, J=8.49 Hz, 1 H) 7.22 - 7.54 (m, 2 H) 7.70 - 7.78 (m, 1 H) 7.84 (s, 1 H) 7.95 (t, J=7.82 Hz, 1 H) 8.14 - 8.22 (m, 2 H) 8.34 (dd, J=8.63, 1.57 Hz, 1 H) 8.49 - 8.53 (m, 1 H) 8.54 (d, J=1.53 Hz, 1 H) 8.61 (s, 1 H) 9.32 (s, 1 H) 9.66 (t, J=5.82 Hz, 1 H)4991H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.47 (t, J=13.16 Hz, 6 H) 2.96 - 3.12 (m, 2 H) 3.65 (td, J=11.59, 2.38 Hz, 1 H) 3.89 (ddd, J=11.68, 5.44, 2.62 Hz, 1 H) 4.07 (br d, J=11.44 Hz, 1 H) 4.29 (br d, J=13.07 Hz, 1 H) 4.50 (br d, J=12.78 Hz, 1 H) 4.78 (d, J=5.44 Hz, 2 H) 6.96 (d, J=8.49 Hz, 1 H) 7.21 - 7.54 (m, 2 H) 7.70 - 7.78 (m, 1 H) 7.84 (s, 1 H) 7.95 (t, J=7.82 Hz, 1 H) 8.16 - 8.21 (m, 2 H) 8.34 (dd, J=8.63, 1.57 Hz, 1 H) 8.52 (d, J=7.92 Hz, 1 H) 8.54 (d, J=1.43 Hz, 1 H) 8.61 (s, 1 H) 9.32 (s, 1 H) 9.66 (brt, J=5.67 Hz, 1 H)50019F NMR (377 MHz, DMSO-d6) 5 (ppm) -124.26 (d, J=52.2 Hz, 1 F)5001H NMR (400 MHz, DMSO-d6) 5 (ppm) 1.23 (s, 3 H) 2.19 - 2.29 (m, 4H) 3.99 (s, 2 H) 4.06 (s, 2 H) 4.79 (d, J=5.7 Hz, 2 H) 4.91 (br s, 1 H) 6.40 (d, J=8.1 Hz, 1 H) 7.38 (t, J=52.0 Hz, 1 H) 7.40 (d, J=7.7 Hz, 1 H) 7.64 (t, J=7.8 Hz, 1 H) 7.85 (s, 1 H) 7.95 (t, J=7.8 Hz, 1 H) 8.16 (d, J=4.2 Hz, 1 H) 8.18 - 8.22 (m, 1 H) 8.32 (dd, J=8.6, 1.5 Hz, 1 H) 8.52 (d, J=7.9 Hz, 1 H) 8.56 (d, J=6.8 Hz, 2 H) 9.31 (s, 1 H) 9.64 (t, J=5.7 Hz, 1 H)5011H NMR (400 MHz, DMSO-d6) 5 (ppm) 9.63 - 9.50 (m, 1H), 9.33 (s,1H), 8.59 - 8.46 (m, 2H), 8.43 - 8.36 (m, 1H), 8.22 - 8.10 (m, 3H), 7.92 - 7.76 (m, 2H), 7.15 - 6.80 (m, 2H), 6.52 - 6.37 (m, 1H), 4.82 - 4.75 (m, 2H), 4.69 - 4.54 (m, 2H), 4.20 - 4.02 (m, 1H), 3.65 - 3.50 (m, 2H), 2.49 - 2.43 (m, 2H), 1.17 (dd, J = 4.3, 6.3 Hz, 12H)5031H NMR (400 MHz, CDCl3) 5 (ppm) 1.29 (d, J=6.9 Hz, 3 H) 2.56 (d, J=5.7 Hz, 2 H) 2.94 - 3.03 (m, 1 H) 3.10 (s, 3 H) 3.36 (s, 3 H) 3.41 - 3.58 (m, 4 H) 3.88 - 3.98 (m, 3 H) 4.14 (br d, J=12.2 Hz, 1 H) 4.50 (br d, J=6.5 Hz, 1 H) 4.91 (d, J=4.9 Hz, 2 H) 6.45 - 6.84 (m, 3 H) 7.24 (s, 1 H) 7.62 (dd, J=8.4, 7.5 Hz, 1 H) 7.78 - 7.80 (m, 1 H) 7.82 (t, J=1.8 Hz, 1 H) 7.88 (br t, J=4.9 Hz, 1 H) 7.96 (s, 1 H) 8.02 (d, J=8.6 Hz, 1 H) 8.23 - 8.27 (m, 2 H) 8.39 (s, 1 H) 9.22 (s, 1 H)Co. No. NMR peaks list5061H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.89 (dd, J=12.8, 10.4 Hz, 1 H)3.00 - 3.10 (m, 1 H) 3.25 - 3.26 (m, 3 H) 3.26 - 3.32 (m, 2 H) 3.32 - 3.33 (m, 3 H) 3.37 - 3.42 (m, 2 H) 3.72 (br d, J=2.6 Hz, 1 H) 4.08 (dt, J=10.5, 3.5 Hz, 2 H) 4.20 (br d, J=12.9 Hz, 1 H) 4.47 (dd, J=12.6, 1.7 Hz, 1 H) 4.79 (d, J=5.7 Hz, 2 H) 6.92 (d, J=8.6 Hz, 1 H) 7.46 (t, J=73.1 Hz, 1 H) 7.50 (d, J=7.4 Hz, 1 H) 7.70 - 7.76 (m, 1 H) 7.79 (t, J=5.7 Hz, 1 H) 7.85 (s, 1 H) 7.90 (t, J=1.8 Hz, 1 H) 8.09 (s, 1 H) 8.19 (d, J=8.7 Hz, 1 H) 8.34 (dd, J=8.6, 1.5 Hz, 1 H) 8.40 (t, J=1.4 Hz, 1 H) 8.59 (s, 1 H) 9.32 (s, 1 H) 9.61 (s, 1 H)5071H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.89 (dd, J=12.6, 10.6 Hz, 1 H)3.01 - 3.11 (m, 1 H) 3.26 (s, 3 H) 3.32 (br s, 3 H) 3.36 - 3.44 (m, 4 H) 3.72 (td, J=11.4, 2.4 Hz, 1 H) 4.03 - 4.13 (m, 2 H) 4.20 (br d, J=13.1 Hz, 1 H) 4.47 (br d, J=11.8 Hz, 1 H) 4.79 (d, J=5.7 Hz, 2 H) 6.91 (d, J=8.6 Hz, 1 H) 7.44 (t, J=73.0 Hz, 1 H) 7.49 (d, J=7.3 Hz, 1 H) 7.68 - 7.79 (m, 2 H) 7.84 - 7.87 (m, 1 H) 7.89 (d, J=2.0 Hz, 1 H) 8.08 (s, 1 H) 8.19 (d, J=9.0 Hz, 1 H) 8.34 (dd, J=8.6, 1.6 Hz, 1 H) 8.38 - 8.43 (m, 1 H) 8.58 (s, 1 H) 9.32 (s, 1 H) 9.59 (s, 1 H)5081H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.89 (dd, J=12.9, 10.4 Hz, 1 H)3.00 - 3.10 (m, 1 H) 3.25 (s, 3 H) 3.28 - 3.31 (m, 4 H) 3.36 - 3.37 (m, 3 H) 3.71 (td, J=11.3, 2.7 Hz, 1 H) 4.05 - 4.12 (m, 2 H) 4.19 (br d, J=13.1 Hz, 1 H) 4.47 (dd, J=12.9, 1.8 Hz, 1 H) 4.79 (d, J=5.7 Hz, 2 H) 6.93 (d, J=8.6 Hz, 1 H) 7.51 (d, J=7.8 Hz, 1 H) 7.74 (t, J=8.0 Hz, 1 H) 7.82 (t, J=5.7 Hz, 1 H) 7.87 (s, 1 H) 8.17 - 8.18 (m, 1 H) 8.21 (br d, J=8.6 Hz, 1 H) 8.34 (dd, J=8.8, 1.4 Hz, 1 H) 8.41 (t, J=1.6 Hz, 1 H) 8.49 (t, J=1.4 Hz, 1 H) 8.60 (s, 1 H) 9.33 (s, 1 H) 9.78 (s, 1 H)5091H NMR (400 MHz, DMSO-d6) 5 (ppm) 2.89 (dd, J=12.8, 10.4 Hz, 1 H)2...

Claims

CLAIMS1. A compound having the structure of formula (I):O R2or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope, or prodrug thereof, wherein,R1is any one of the following structures:R2is hydrogen or -CH3;R3is any one of the following structures:O / OHF F2. A compound of any one of the preceding claims, wherein the compound is selected from:■j ’ • <y ' K R d. Z _ V_.-:?V / , <1.©“VTA \ssiSjfit___0 N / _ / 01 v $ / \ "y_r"iiA^X X= / xy. z •**-%Vrrn 1 fi i ©S 4 Ji J,y1 t " $ v’1'- Z X f=A,;NHy / “ u V.0H# y_ NH-Z 1 0 0 ’J-X©| \\. rX■'■ A >x x. 1 J \=NNNH / / f >-A __ / o th) •f—y u ZZ ( \— -'% / / iir 1 ^ yX d3k / X.. X As.’• q M- 7|<□) ■’) — I Q4 d 5 v„ i, - O' f.-^H- f! II 1 ^yjA,-■* [j»•[ 1r.. 11‘■■-XsX K fe z’o- Iff > 11 J I / >ZC 'iJ iJL •**%. ’® '’^h’v1J3. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 or 2; and at least one pharmaceutically acceptable excipient.

4. A compound according to any one of claims 1 or 2 for use in therapy.

5. A compound according to any one of claims 1 or 2 for use in the treatment of a SMARCA4 deficient cancer.

6. The compound for the use of claim 5, wherein the SMARCA4 deficient cancer is SMARCA4 deficient non-small cell lung cancer (NSCLC).

7. A compound according to any one of claims 1 or 2 for use in the treatment of a disease state or condition mediated by the SMARCA2 protein.

8. The compound for the use of claim 7, wherein the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC).

9. Use of a compound as defined in any one of claims 1 or 2 for the manufacture of a medicament for the treatment of cancer or NSCLC.

10. An in vitro method of modulating SMARCA2 activity comprising contacting the SMARCA2 protein, or portion thereof, with a compound according to any one of claims 1 or 2.

11. A method for the treatment of a SMARCA4 deficient cancer, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 or 2.

12. The method of claim 11, wherein the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.

13. A method for the treatment of a disease state or condition mediated by the SMARCA2 protein, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 or 2.

14. The method of claim 13, wherein the disease or condition is selected from a cancer or NSCLC.

15. The method of any one of claims 13 or 14, wherein the subject is a mammal.

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