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

[0001] SMARCA2 INHIBITORS USEFUL FOR THE TREATMENT

[0002] OF SMARCA4 DEFICIENT CANCERS

[0003] CROSS-REFERENCE

[0004] This application claims benefit of US Application No. 63 / 743073, filed on January 8, 2025, which is herein incorporated by reference in its entirety.

[0005] FIELD OF THE INVENTION

[0006] [1] 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).

[0007] BACKGROUND OF THE INVENTION

[0008] [2] The Switch / Sucrose Non-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.

[0009] [3] 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).[4] 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 co-occurrence 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.

[0010] [5] 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.

[0011] [6] An objective of the present invention is to provide compounds that are selective on SMARCA2 over SMARCA 4.

[0012] [7] An objective of the present invention is to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient cancers.

[0013] [8] An objective of the present invention is to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient NSCLC.

[0014] SUMMARY OF THE INVENTION

[0015] [9] The present invention relates to a compound having the structure of formula (I):

[0016] O

[0017]

[0018] R2(I)

[0019] or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope, or prodrug thereof, wherein,

[0020] R1ais a 6-membered heterocycle containing one nitrogen atom as heteroatom, said nitrogen atom substituted with -SO2-Ci-4haloalkyl, said heterocycle optionally substituted with one, two, or three substituents selected from halo, Ci-4alkyl, or haloCi-4alkyl; a 9-membered spiro-heterocycle containing one nitrogen atom as heteroatom, said nitrogen atom substituted with −SO2−C1-4haloalkyl; or a 6-to 8-membered fused-heterocycle containing one nitrogen atom as heteroatom, said nitrogen atom substituted with -SO2-Ci-4haloalkyl;

[0021] R1bis hydrogen, C1-4alkyl, -C(O)-O-CH2-O-C(O)-R1c; or

[0022] -C(O)-O-CH(CH3)-O-C(O)-R1c;

[0023] R1cis C1-6alkyl optionally substituted with -O-CH2-CH2-O-CH3, piperazinyl, or phenyl, said phenyl optionally substituted with -0-P(0)(0H)2; C2-6alkenyl optionally substituted with -COOH; C3-6cycloalkyl; phenyl; or pyridinyl;

[0024] R2is hydrogen, -OH, or halo;

[0025] R3is hydrogen, -CH3, or -CH2-O-CH3;

[0026] R4is a structure of formula (II)

[0027]

[0028] wherein,

[0029] Z1is C or N;

[0030] Z2is C or N;

[0031] Z3is C orN;

[0032] Z4is C or N;

[0033] Z5is C or N;

[0034] R11is hydrogen, or amino;

[0035] R12is hydrogen, or halo;

[0036] R13is hydrogen, halo, C1-4alkyl, haloC1-4alkyl, -CN, -O-C1-4alkyl, -NH-C1-4alkyl, amino, hydroxy;

[0037] R14is hydrogen, or fluoro;

[0038] R15is hydrogen, or halo;

[0039] R16is Ci-4alkyl, haloCi-4alkyl, -O-Ci-4alkyl, C3-6cycloalkyl, azetidinyl, -N(C1-4alkyl)2;

[0040] R17is hydrogen, halo, hydroxy, -O-C1-4alkyl, -CN;

[0041] R18is − C1-4alkyl, haloC1-4alkyl, C3-6cycloalkyl, -N(C1-4alkyl)2;or R17and R18form, together with the ring to which they are attached, a 5- or 6- membered heterocycle with an oxygen or nitrogen atom;

[0042] provided that Z1and Z2cannot be both nitrogens;

[0043] provided that when Z1, Z2, Z3, Z4, or Z5, is, each independently, nitrogen, then R12, R13, R14, R15, R17is, each independently, absent.

[0044]

[0010] In one embodiment, R1ais a structure of formula (III)

[0045]

[0046] wherein,

[0047] R5is hydrogen, halo, Ci-4alkyl, or haloCi-4alkyl;

[0048] R6is hydrogen or halo.

[0049]

[0011] In one embodiment, the compound has the structure of Formula (IV):

[0050] wherei

[0051]

[0052] n substituents Rlb, R2, R3, R5, R6, Z1, Z2, Z3, Z4, Z5, R11, R12, R13, R14, R15, R16, R17, R18are as defined above.

[0053]

[0012] In one embodiment, the substituents of the structure of formula (II) are:

[0054] R11is H, or NH2;

[0055] R12is H, F, or Cl;

[0056] R13is H, F, Cl, -CH3, -CHF2, -CN, -O-CH3, -NH-CH3, -NH2, or -OH;

[0057] R14is H, or F;

[0058] R15is H, or F;

[0059] R16is -CH3, — CH2CH3, — CHF2, -CF3, -OCH3, cyclopropyl, azetidinyl, -N(CH3)2; R17is H, F, -OH, -OCH3, or -CN;

[0060] R18is -CH3, — CHF2, cyclopropyl, or -N(CH3)2;or R17and R18form, together with the ring to which they are attached, a 5-membered heterocycle with an oxygen or nitrogen atom; preferably said 5-membered heterocycle is not aromatic;

[0061] provided that when Z1, Z2, Z3, Z4, or Z5, is each, independently, nitrogen, then R12, R13, R14, R15, R17are, each independently, absent.

[0062]

[0013] In one embodiment, R1ais selected from:

[0063]

[0064] F

[0014] In one embodiment, R1bis selected from:

[0065]

[0066]

[0015] If R1bis either -C(O)-O-CH2-O-C(O)-R1cor

[0067] -C(O)-O-CH(CH3)-O-C(O)-R1c, then the resulting compound is a prodrug. This means that its metabolite is the compound that exhibits pharmacological activity.

[0068]

[0016] In one embodiment, R4is selected from:HH Tr VNy / Z^- bNt ANh M >h FA n-g H-C> HQ- / HHQ- HQ^Fyh yh >hFyh yH i-^ Kh H> K>^Nyh C " )h H M

[0069]

[0070] -7- JAB7149WOPCT1

[0071]

[0072]

[0073]

[0017] In one embodiment, the compound is selected from those depicted in the claims.

[0074]

[0018] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds disclosed herein and at least one pharmaceutically acceptable excipient.

[0075]

[0019] The compounds disclosed herein are meant for use in therapy.

[0076]

[0020] The compounds disclosed herein are meant for use in the treatment of a SMARCA4 deficient cancer.

[0077]

[0021] In one embodiment, the SMARCA4 deficient cancer is SMARCA4 deficient non-small cell lung cancer (NSCLC).

[0078]

[0022] The compounds disclosed herein are meant for use in the treatment of a disease state or condition mediated by the SMARCA2 protein.

[0079]

[0023] In one embodiment, the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC).

[0080]

[0024] The present invention further relates to the use of a compound disclosed herein for the manufacture of a medicament for the treatment of cancer or NSCLC.

[0081]

[0025] 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 disclosed herein.

[0082]

[0026] 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 disclosed herein.

[0083]

[0027] In one embodiment, the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.

[0028] 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.

[0084]

[0029] In one embodiment, the disease or condition is selected from a cancer or NSCLC.

[0085]

[0030] In one embodiment, the subject is a mammal.

[0086] INCORPORATION BY REFERENCE

[0087]

[0031] 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.

[0088] DETAILED DESCRIPTION OF THE INVENTION

[0089] Definitions

[0090]

[0032] 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.

[0091] 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.

[0092]

[0033] 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.

[0093]

[0034] 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.

[0094]

[0035] 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.”

[0095]

[0036] 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.

[0096]

[0037] 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.

[0097]

[0038] Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0098]

[0039] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0099]

[0040] 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.

[0100]

[0041] 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 optional substituents). Thus, a Ci-ealkyl group contains from 1 to 6 carbon atoms, a C3-6cycloalkyl group contains from 3 to 6 carbon atoms, a Ci-4alkyl group contains from 1 to 4 carbon atoms, and so on.

[0101]

[0042] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.

[0102]

[0043] 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.

[0103]

[0044] 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 “C2-6alkenyl”.

[0104]

[0045] 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 haloC1-4alkyl or haloC1-6alkyl may have one, two, three or more halogens. The halogens may be 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.

[0105]

[0046] “Amino” refers to a –NH2group.

[0106]

[0047] 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 of

[0107] . OH N

[0108] bioisosteres of a carboxylic acid include, but are not limited to,

[0109]

[0110] H H

[0111]

[0112] like.

[0113]

[0048] 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.

[0114]

[0049] 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).

[0115]

[0050] The term “non-aromatic group” embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and fully saturated heterocycles or heterocyclyl ring systems.

[0116]

[0051] 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.

[0052] The term “fully saturated” refers to rings where there are no multiple bonds between ring atoms. Saturated heterocycles include piperidine, morpholine, thiomorpholine, piperazine. Partially saturated heterocycles include pyrazolines, for example 2-pyrazoline and 3-pyrazoline.

[0117]

[0053] 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).

[0118]

[0054] 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 “C3-6cycloalkyl”. 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,

[0119]

[0120]

[0055] 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 heterocycle or 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

[0121]

[0122]

[0056] 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).

[0123]

[0057] The heterocyclyl ring systems can be heteroaryl ring systems having from 5 to 12 ring members, more usually from 5 to 10 ring members.

[0124]

[0058] The term “heteroaryl” is used herein to denote a heterocyclyl ring system having aromatic character. The term “heteroaryl” embraces polycyclic (e.g. bicyclic) ring systemswherein 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 five to 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.

[0125]

[0059] 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; afuran 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 five membered 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.

[0126]

[0060] 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.

[0127]

[0061] 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.

[0128]

[0062] 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.

[0129]

[0063] Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

[0130]

[0064] Examples of non-aromatic heterocycles or 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). Particular examples include morpholinyl, thiomorpholinyl, piperidinyl (e.g.

[0131] 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.

[0132]

[0065] In a nitrogen-containing non-aromatic heterocycle or heterocyclyl ring the ring must contain at least one ring nitrogen atom.

[0133]

[0066] Particular examples of nitrogen-containing non-aromatic heterocycles or 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.

[0134]

[0067] Particular examples of 3 to 6 membered monocyclic saturated heterocycles or 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.

[0135]

[0068] Particular examples of 3 to 6 membered monocyclic heterocycles or 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.

[0136]

[0069] Particular examples of 3 to 12 membered heterocycles include morpholinyl, thiomorpholinyl, piperidinyl (e.g. 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl and

[0137] 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-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, imidazopyridinyl and 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-dihydro-benzo[l,4]dioxinyl, benzofl, 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.

[0138]

[0070] 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.

[0139]

[0071] 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 example

[0140] 3.6-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.

[0141]

[0072] Lines drawn into ring systems indicate that the bond may be attached to any of the suitable and available ring atoms.

[0142]

[0073] 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.

[0143]

[0074] 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 arethose 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 and purification 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.

[0144]

[0075] 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.

[0145]

[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.

[0146]

[0077] 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 a pure 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.

[0147]

[0078] 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.

[0079] 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.

[0148]

[0080] 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 at least partially ameliorate or to at least partially prevent diseases, disorders or conditions described herein.

[0149]

[0081] 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.

[0150]

[0082] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0151]

[0083] 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.

[0152]

[0084] 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.

[0153]

[0085] 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.

[0154]

[0086] 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.

[0155]

[0087] 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 whichreduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0156]

[0088] 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.

[0157]

[0089] 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.

[0158]

[0090] 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.

[0159] 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.

[0160]

[0091] As used herein, the term “cancer” refers to a malignant neoplasm.

[0161]

[0092] 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).

[0162]

[0093] 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 whole organisms (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.

[0163] Isomers, salts, N-oxides, isotopically labeled derivatives

[0164]

[0094] 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.

[0165]

[0095] In certain embodiments, the compound presented herein possesses one or more stereocenters and each center independently exists in either the R or S configuration. Thecompound 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.

[0166]

[0096] In some situations, the compound may exist as tautomers. All tautomers are included within the scope of the compound presented herein.

[0167]

[0097] 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.

[0168] H+\ OH H+xo’

[0169] — c-czc=czc=cz

[0170]

[0171] | \Z XH+ / \

[0172] keto enol enolate

[0173]

[0098] 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.

[0174]

[0099] 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.

[0175]

[0100] The present disclosure includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

[0176]

[0101] 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.

[0102] 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.

[0177]

[0103] 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.

[0178]

[0104] 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.

[0179]

[0105] 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.

[0180]

[0106] 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.

[0181]

[0107] 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.

[0182]

[0108] 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+, NR.4+); 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.

[0183]

[0109] Conversely said salt forms can be converted by treatment with an appropriate acid into the free form.

[0184]

[0110] 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 thearomatic ring to metabolic reactions is, by way of example only, a halogen, deuterium or an alkyl group.

[0185]

[0111] 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, references to 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 of2H,3H,11C,18F,122I,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of2H,3H,11C and18F. More preferably, the radioactive isotope is2H. In particular, deuterated compounds are intended to be included within the scope of the present invention. In some embodiments, metabolic sites on the compounds described herein are deuterated.

[0186]

[0112] 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.

[0113] 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.

[0187] 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 after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.

[0188] Synthesis of Compounds

[0189]

[0114] 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.

[0190]

[0115] The starting materials and reagents used for the synthesis of the compound described herein may be synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

[0191]

[0116] In the reactions described herein, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where theseare 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 moi eties 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.

[0192]

[0117] 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 Cbz groups, 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.

[0193]

[0118] 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), and

[0194] 9-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.

[0195]

[0119] 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.

[0196]

[0120] Typically blocking / protecting groups may be selected from:Fmoc

[0197]

[0198] TBDPS

[0199]

[0121] 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.

[0200] General synthetic pathways

[0201]

[0122] Compounds of Formula (I), wherein R7is an aromatic 6 membered ring aryl or heteroaryl and all other substituents are defined as in the general scope, could be prepared according to General Scheme 1.General scheme 1

[0202] (Ha)X4=tBu r* (Hla)X4=tBu (IVa) X4=tBu (llb)X4=Me (lllb) X4=Me (IVb) X4=Me (He) X4=Et (Nile) X4=Et (IVc) X4=Et (lid) X4=HL(Hid) X4=H

[0203]

[0204]

[0123] According to General Scheme 1, a compound of Formula (Illa-d) can be obtained reacting a compound of Formula (Ila-d) or an acceptable salt of thereof, wherein X4is an hydrogen or an alkyl substituent such as / Butyl, Methyl or Ethyl and R3is a hydrogen or an alkyl substituent, such as Methyl, with a di -halogenated 5 membered ring heterocycle such as, 2,4-dibromothiazole [4175-77-3], in the presence of a suitable base such as DIPEA, in a suitable solvent such as DMF at a suitable temperature such as, 60 °C. Alternatively compound of Formula (Illa) can be obtained reacting a compound of Formula (Hid), or an acceptable salt of thereof, wherein X4is an hydrogen, with a reagent such as POCh in the presence of a suitable alcohol such as t-BuOH and a suitable base such as pyridine, in a suitable solvent such as acetonitrile at a suitable temperature such as room temperature.

[0205]

[0124] A compound of Formula (IVa-c) can be obtained in two steps by reacting first a compound of Formula (Illa-c) wherein X is a suitable halide such as Br with a boron source such as bis(pinacolato)diboron [73183-34-3] in the presence of a suitable base such as, potassium pivalate [19455-23-3] in the presence of a suitable catalyst such as, cataCXium Pd G4 [2230788-67-5] in a suitable solvent such as, 1,4-dioxane, at a suitable temperature such as, 90 °C and in a second step, reacting the formed intermediate with a compound of Formula(VII) wherein X2is a suitable halide such as Br, Cl or I in the presence of a suitable base such as potassium carbonate in the presence of a suitable catalyst such as, Pd(dppf)C12. CH2C12 [95464-05-4] in a suitable solvent such as, a mixture of 1,4-di oxane and water, at a suitable temperature such as, 100 °C. Alternatively a compound of Formula (IVa-c) can be obtained via the same sequence of reactions inverting the roles of X2and X. A compound of Formula (VII) wherein X2is a suitable halide such as Br, Cl or I could be prepared reacting a compound of Formula (VI) wherein X1and X2are suitable halides, such as Br, Cl or I with a suitable aryl- or heteroaryl- boronic acid or boronate such as, (2,6-dimethylpyridin-4-yl)boronic acid [846548-44-5], in the presence of a suitable base such as, Sodium carbonate, in the presence of a suitable catalyst such as, Pd(dppf)C12. CH2C12 [95464-05-4], in a suitable solvent such as a mixture of 1,4-di oxane and water at a suitable temperature such as, 80 °C. Alternatively, a compound of Formula (VII) wherein X2is a suitable halide such as Br, Cl or I could be prepared reacting a compound of Formula (VI) wherein X1is a suitable boronic acid or boronate functional group and X2is a suitable halide such as Cl or Br with a suitable aryl-or heteroaryl- halide such, 4-bromo-2,6-dimethylpyrimidine [354574-56-4] in the presence of a suitable base such as aqueous Sodium carbonate, in the presence of a suitable catalyst such as, tetrakis(triphenylphosphine)palladium(0) [14221-01-3], in a suitable solvent such as, toluene at a suitable temperature such as, 100 °C.

[0206]

[0125] A compound of Formula (V), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (IVa), with a suitable deprotecting agent such as, TFA, in a suitable solvent such as, DCM, at a suitable temperature such as, room temperature.

[0207] Alternatively a compound of Formula (V), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (IVb) or (IVc) with a suitable deprotecting agent such as, LiOH, in a suitable solvent such as, a mixture of THF and water, at a suitable temperature such as, room temperature.

[0208]

[0126] A compound of Formula (I) can be obtained by reacting a compound of Formula (V) or an acceptable salt of thereof, with a suitable amine or as salt of thereof, such as (3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine, in the presence of a suitable coupling agent such as, HATU, HBTU, or 1-propanephosphonic anhydride; in the presence of a suitable base such as, DIPEA; in a suitable solvent such as DCM or DMF, at a suitable temperature such as room temperature. A suitable amine, such as (3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine can be readily prepared reacting tertbutyl ((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)carbamate withdifluoromethanesulfonyl chloride [1512-30-7], followed by treatment of the resulting compound with a suitable deprotecting agent such as HC1 in a suitable solvent such as 1,4-di oxane.

[0209]

[0127] Compounds of Formula (VIII), wherein all the substituents are defined as in the general scope, could be prepared according but not limited to General Scheme 2.

[0210] General Scheme 2

[0211] R12

[0212] (XI)

[0213] (lllb) X4=Me (IXb)X4=Me (lllc) X4=Et (IXc)X4=Et

[0214]

[0215]

[0128] According to General Scheme 2, a compound of Formula (IXa-c) can be obtained in two steps by reacting first respectively a compound of Formula (Illa-c) wherein X is a suitable halide such as Br with a boron source such as bis(pinacolato)diboron [73183-34-3] in the presence of a suitable base such as potassium pivalate [19455-23-3] in the presence of a suitable catalyst such as cataCXium Pd G4 [2230788-67-5] in a suitable solvent such as 1,4-dioxane, at a suitable temperature such as 90 °C and in a second step, reacting the formed intermediate with a compound of Formula (XIV) wherein X2 is a suitable halide such as Br or Cl in the presence of a suitable base such as potassium carbonate in the presence of a suitable catalyst such as, Pd(dppf)C12. CH2C12 [95464-05-4] in a suitable solvent such as, a mixture of 1,4-di oxane and water, at a suitable temperature such as, 100 °C. Alternatively a compound ofFormula (IXa-c) can be obtained via the same sequence of reactions inverting the roles of X2 and X.

[0216]

[0129] An intermediate compound of Formula (XIV) wherein X2 is a suitable halide such as Br or Cl can be obtained in two steps by reacting first a compound of Formula (XI) wherein XI is a suitable halides such as Br, Cl or I and X2 is a suitable halide such as Cl or Br with a organometallic reagent such as iPrMgCl in a suitable solvent such as THF, at a suitable temperature such as 0 °C followed by 25 °C, followed by the addition of a suitable Zinc reagent such as ZnC12, at a suitable temperature such as 25 °C and reacting the resulting compound of Formula (XII) with a compound of Formula (XIII) wherein X3 is a suitable halide such as Br or Cl in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium(0) [14221-01-3] in a suitable solvent such as THF, at a suitable temperature such as 80 °C.

[0217]

[0130] A compound of Formula (X), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (IXa), with a suitable deprotecting agent such as, TFA, in a suitable solvent such as, DCM, at a suitable temperature such as, room temperature.

[0218] Alternatively a compound of Formula (X), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (IXb) or (IXc) with a suitable deprotecting agent such as, LiOH, in a suitable solvent such as, a mixture of THF and water, at a suitable temperature such as, room temperature.

[0219]

[0131] A compound of Formula (VIII) can be obtained by reacting a compound of Formula (X) or an acceptable salt of thereof, with a suitable amine or as salt of thereof, such as (3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine, in the presence of a suitable coupling agent such as, HATU, HBTU, or 1-propanephosphonic anhydride; in the presence of a suitable base such as, DIPEA; in a suitable solvent such as, DCM or DMF, at a suitable temperature such as, room temperature. A suitable amine, such as (3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine can be readily prepared reacting tertbutyl ((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)carbamate with difluoromethanesulfonyl chloride [1512-30-7], followed by treatment of the resulting compound with a suitable deprotecting agent such as HC1 in a suitable solvent such as 1,4-di oxane.

[0220]

[0132] Compounds of Formula (I), wherein R7 is an aromatic 6 membered ring aryl or heteroaryl and all other substituents are defined as in the general scope, could be prepared according to General Scheme 3.General Scheme 3

[0221] R7X2

[0222]

[0223]

[0133] A compound of Formula (XV) wherein X1is a suitable halide such as Br or Cl could be prepared reacting a compound of Formula (lllb) wherein X4 is a suitable alkyl substituent such as Methyl and wherein X is a suitable halide, such as Br with a suitable aryl- or heteroaryl- boronic acid or boronate such as 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine [1146615-89-5], in the presence of a suitable base such as,

[0224] Sodium carbonate, in the presence of a suitable catalyst such as, Pd(dppf)C12. CH2C12

[0225] [95464-05-4], in a suitable solvent such as, 1,4-di oxane and water at a suitable temperature such as, 100 °C, followed by treatment with a suitable acidic solution such as aqueous HC1.

[0226]

[0134] Alternatively a compound of Formula (XV), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (XIXa), with a suitable deprotecting agent such as, TFA, in a suitable solvent such as, DCM, at a suitable temperature such as, room

[0227] temperature. Alternatively a compound of Formula (XV), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (XlXb) or (XIXc) with a suitable deprotecting agent such as, LiOH, in a suitable solvent such as, a mixture of THF and water, at a suitable temperature such as room temperature.

[0228]

[0135] A compound of Formula (XIXa-c) wherein XI is a suitable halide such as Br or

[0229] Cl can be obtained in two steps by reacting first a compound of Formula (Illa-c) wherein X is a suitable halide such as Br with a boron source such as bis(pinacolato)diboron [73183-34-3] in the presence of a suitable base such as potassium pivalate [19455-23-3] in the presence of asuitable catalyst such as, cataCXium Pd G4 [2230788-67-5] in a suitable solvent such as, 1,4-dioxane, at a suitable temperature such as, 90 °C and in a second step, reacting the formed intermediate with a suitable bis-halogenated aryl- or heteroaryl ring such as 2,6-dichloropyridine in the presence of a suitable base such as potassium carbonate in the presence of a suitable catalyst such as, cataCXium Pd G4 [2230788-67-5] in a suitable solvent such as 1,4-di oxane, or a mixture of dioxane and water at a suitable temperature such as, 100 °C.

[0230]

[0136] Alternatively a compound of Formula (XIXa-c) wherein XI is a suitable halide such as Br or Cl can be obtained by reacting a compound of Formula (Illa-c) wherein X is a suitable halide such as Br with a suitable with a suitable halogenated aryl- or heteroaryl-Boronic acid or ester such as 2-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine [652148-92-0] in the presence of a suitable base such as potassium carbonate in the presence of a suitable catalyst such as Xantphos Pd G4 [1621274-19-8] in a suitable solvent such as, a mixture of 1,4-di oxane and water, at a suitable temperature such as, 80 °C.

[0231]

[0137] A compound of Formula (V), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (XV) wherein XI is a suitable halide such as Br or Cl with a suitable aryl- or heteroaryl- boronic acid or boronate such as, (2,6-dimethylpyridin-4-yl)boronic acid [846548-44-5], in the presence of a suitable base such as sodium carbonate in the presence of a suitable catalyst such as, Pd(dppf)C12. CH2C12 [95464-05-4] in a suitable solvent such as, a mixture of 1,4-di oxane and water, at a suitable temperature such as, 100 °C. A compound of Formula (V), or an acceptable salt of thereof, can be also obtained reacting a compound of Formula (XlXb) or Formula (XIXc) wherein X4 is a suitable alkyl substituent such as Methyl or Ethyl and XI is a suitable halide such as Cl, with a suitable aryl- or heteroaryl- boronic acid or boronate such as, (2,6-dimethylpyridin-4-yl)boronic acid [846548-44-5], in the presence of a suitable base such as sodium carbonate in the presence of a suitable catalyst such as, Pd(dppf)C12. CH2C12 [95464-05-4] in a suitable solvent such as, a mixture of 1,4-di oxane and water, at a suitable temperature such as, 100 °C.

[0232]

[0138] A compound of Formula (IVa-c) can be obtained by reacting a compound of Formula (XIXa-c) wherein XI is a suitable halide such as Cl, Br or a suitable substituted hydroxy group such as Tritiate with a suitable aryl- or heteroaryl- boronic acid or boronate such as, (2,6-dimethylpyridin-4-yl)boronic acid [846548-44-5], in the presence of a suitable base such as potassium carbonate in the presence of a suitable catalyst such as, cataCXium Pd G4 [2230788-67-5] in a suitable solvent such as, a mixture of 1,4-dioxane and water, at asuitable temperature such as 90°C. Alternatively a compound of Formula (IVa-c) can be obtained by reacting a compound of Formula (XIXa-c) wherein XI is a suitable halide such as Cl, Br or a suitable leaving group such as Triflate with a suitable aryl- or heteroaryl- trialkyl stannane such as, 2,4-Dimethyl-6-(trimethylstannyl)pyrimidine [169259-05-6], in the presence of a suitable catalyst such as, tetrakis(triphenylphosphine)palladium(0) [14221-01-3] in a suitable solvent such as 1,4-di oxane at a suitable temperature such as 100°C.

[0233]

[0139] A compound of Formula (IVa-c) can be also obtained in two steps by reacting first a compound of Formula (XIXa-c) wherein XI is a suitable halide such as Br or Cl with a boron source such as bis(pinacolato)diboron [73183-34-3] in the presence of a suitable base such as, potassium 2 -ethylhexanoate [3164-85-0] in the presence of a suitable catalyst such as, cataCXium Pd G4 [2230788-67-5] in a suitable solvent such as, 1,4-dioxane, at a suitable temperature such as, 100 °C and in a second step, reacting the formed intermediate with a suitable aryl- or heteroaryl- halide such as 4-bromo-2,6-dimethylpyrimidine [354574-56-4] in the presence of a suitable base such as, potassium carbonate in the presence of a suitable catalyst such as, cataCXium Pd G4 [2230788-67-5] in a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as, 100 °C. Alternatively a compound of Formula (IVa-c) can be obtained in two steps by reacting first a compound of Formula (XlXa-c) wherein XI is a suitable halide such as Br or Cl with a hexa-alkly di stannane such as hexamethylditin [661-69-8] in the presence of a catalyst such as, tetrakis(triphenylphosphine)palladium(0) [14221-01-3] in a suitable solvent such as, 1,4-dioxane, at a suitable temperature such as, 100 °C and in a second step, reacting the formed intermediate with a suitable aryl- or heteroaryl- halide such as 4-bromo-2,6-dimethylpyrimidine [354574-56-4] in the presence of a suitable catalyst such as, bis(tri-tert-butylphosphine)palladium(O) [53199-31-8] in a suitable solvent such as 1,4-dioxane at a suitable temperature such as, 100 °C.

[0234]

[0140] A compound of Formula (XVI) can be obtained by reacting a compound of Formula (XV) or an acceptable salt of thereof, with a suitable amine or as salt of thereof, such as (3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine, in the presence of a suitable coupling agent such as, HATU, HBTU, or 1-propanephosphonic anhydride; in the presence of a suitable base such as, DIPEA; in a suitable solvent such as, DCM or DMF, at a suitable temperature such as, room temperature. A suitable amine, such as (3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine can be readily prepared reacting tertbutyl ((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)carbamate withdifluoromethanesulfonyl chloride [1512-30-7], followed by treatment of the resulting compound with a suitable deprotecting agent such as HC1 in a suitable solvent such as 1,4-di oxane.

[0235]

[0141] A compound of Formula (XVI) wherein XI is a suitable halide such as Br or Cl could be prepared by reacting a compound of Formula (XVIII) wherein X is a suitable halide, such as Br, with a suitable aryl- or heteroaryl-halogenated boronic acid or boronate such as 2-(3-bromo-2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane [1400220-51-0] in the presence of a suitable base such as, potassium carbonate, in the presence of a suitable catalyst such as, Xantphos Pd G4 [1621274-19-8], in a suitable solvent such as a mixture of 1,4-dioxane and water at a suitable temperature such as, 80 °C.

[0236]

[0142] A compound of Formula (XVIII) can be obtained by reacting a compound of Formula (XVII) or an acceptable salt of thereof, with a suitable amine or as salt of thereof, such as (3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine, in the presence of a suitable coupling agent such as, HATU, HBTU, or 1-propanephosphonic anhydride; in the presence of a suitable base such as, DIPEA; in a suitable solvent such as, DCM or DMF, at a suitable temperature such as, room temperature. A suitable amine, such as (3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine can be readily prepared reacting tertbutyl ((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)carbamate with difluoromethanesulfonyl chloride [1512-30-7], followed by treatment of the resulting compound with a suitable deprotecting agent such as HC1 in a suitable solvent such as 1,4-di oxane.

[0237]

[0143] A compound of Formula (XVII), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (Illa), with a suitable deprotecting agent such as, TFA, in a suitable solvent such as, DCM, at a suitable temperature such as, room temperature.

[0238] Alternatively a compound of Formula (XVII), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (Illb) or (IIIc) with a suitable deprotecting agent such as, LiOH, in a suitable solvent such as, a mixture of THF and water, at a suitable temperature such as room temperature.

[0239]

[0144] A compound of Formula (I), or an acceptable salt of thereof, can be obtained reacting a compound of Formula (XVI) wherein XI is a suitable halide such as Br or Cl with a suitable aryl- or heteroaryl- boronic acid or boronate such as, (2,6-dimethylpyridin-4-yl)boronic acid [846548-44-5], in the presence of a suitable base such as potassium phosphate in the presence of a suitable catalyst such as, XPhos Pd G4 [1599466-81-5] in a suitablesolvent such as, a mixture of 1,4-dioxane and water, at a suitable temperature such as, 80 °C.

[0240] A compound of Formula (I), or an acceptable salt of thereof, can be also obtained in two steps by reacting first a compound of Formula (XVI) wherein XI is a suitable halide such as Br or Cl with a boron source such as bis(pinacolato)diboron [73183-34-3] in the presence of a suitable base such as, potassium phosphate in the presence of a suitable catalyst such as, XPhos Pd G4 [1599466-81-5] in a suitable solvent such as, 1,4-dioxane, at a suitable temperature such as, 80 °C and in a second step, reacting the formed intermediate with a suitable aryl- or heteroaryl- halide such as 4-bromo-2,6-dimethylpyrimidine [354574-56-4] in the presence of a suitable base such as, potassium phosphate in the presence of a suitable catalyst such as, XPhos Pd G4 [1599466-81-5] in a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as, 80 °C.

[0241]

[0145] Alternatively, a compound of Formula (I) can be obtained from a compound of Formula (V) or from a compound of Formula (IVa), (IVb) or (IVc) following General

[0242] Scheme 1.

[0243]

[0146] Compounds of Formula (XXIII), wherein R7 is an aromatic 6 membered ring aryl or heteroaryl and all other substituents are defined as in the general scope, could be prepared according to General Scheme 4.

[0244] General Scheme 4

[0245]

[0246] (XXII) (XXIII)

[0247]

[0147] A compound of Formula (XX) wherein XI is a suitable halide such as Br or Cl could be prepared reacting a compound of Formula (Illb) wherein X4 is a suitable alkyl substituent such as Methyl and wherein X is a suitable halide, such as Br with a suitable aryl-or heteroaryl- boronic acid or boronate such as 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine [1146615-89-5], in the presence of a suitable base such as, Na2CO3 in the presence of a suitable catalyst such as, Pd(dppf)C12. CH2C12 [95464-05-4], in a suitable solvent such as, 1,4-di oxane and water at a suitable temperature such as, 100 °C.

[0248]

[0148] A compound of Formula (XXI), or an acceptable salt of thereof, can be obtained by reacting a compound of Formula (XX) or an acceptable salt of thereof wherein XI is a suitable halide such as Br or Cl with a suitable amine or as salt of thereof, such as (3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine, in the presence of a suitable coupling agent such as, HATU, HBTU, or 1-propanephosphonic anhydride; in the presence of a suitable base such as, DIPEA; in a suitable solvent such as, DCM or DMF, at a suitable temperature such as, room temperature. A suitable amine, such as (3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine can be readily prepared reacting tertbutyl ((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)carbamate with difluoromethanesulfonyl chloride [1512-30-7], followed by treatment of the resulting compound with a suitable deprotecting agent such as HC1 in a suitable solvent such as 1,4-di oxane.

[0249]

[0149] A compound of Formula (XXII), or an acceptable salt of thereof, can be obtained by reacting a compound of Formula (XXI) wherein XI is a suitable halide such as Br or Cl with a boron source such as bis(pinacolato)diboron [73183-34-3] in the presence of a suitable base such as potassium 2-ethylhexanoate [3164-85-0] in the presence of a suitable catalyst such as cataCXium Pd G4 [2230788-67-5] in a suitable solvent such as, 1,4-dioxane, at a suitable temperature such as 100 °C.

[0250]

[0150] A compound of Formula (XXIII), or an acceptable salt of thereof, can be obtained by reacting a compound of Formula (XXII) with a suitable aryl- or heteroaryl- halide such as 5-chloro-7-methyl-2,3-dihydrobenzofuran in the presence of a suitable base such as, potassium carbonate in the presence of a suitable catalyst such as, cataCXium Pd G4

[0251] [2230788-67-5] in a suitable solvent such as a mixture of 1,4-dioxane and water, at a suitable temperature such as, 105 °C.

[0252]

[0151] Compounds of Formula (XXVIII), wherein R7 is an aromatic 6 membered ring aryl or heteroaryl and all other substituents are defined as in the general scope, could be prepared according to General Scheme 5.General Scheme 5

[0253] (XXIV) (XXVI)

[0254] (XXVa) PG = Boc (XXVb) PG =benzhydryl

[0255]

[0256]

[0152] A compound of Formula (XXVa) or an acceptable salt of thereof, wherein PG is defined as a suitable N-protecting group such as Boc or benzhydryl, can be obtained by

[0257] reacting a compound of Formula (XXIV) or an acceptable salt of thereof wherein R2 can be a hydrogen, an alkyl, a fluorine or a heteroatom substituent such as OH and R3 is a hydrogen or an alkyl substituent such as methoxymethyl and with a suitable protecting group PG such as benzhydryl or tert-butyl carbammate with a suitable amine or as salt of thereof, such as

[0258] (3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine s, in the presence of a

[0259] suitable coupling agent such as, HATU, HBTU, or 1-propanephosphonic anhydride; in the presence of a suitable base such as, DIPEA; in a suitable solvent such as, DCM or DMF, at a suitable temperature such as, room temperature. A suitable amine, such as (3R,5S)-1-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine can be readily prepared reacting tertbutyl ((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)carbamate with difluoromethanesulfonyl chloride [1512-30-7], followed by treatment of the resulting compound with a suitable deprotecting agent such as HC1 in a suitable solvent such as 1,4-di oxane.

[0260]

[0153] A compound of Formula (XXVI) or an acceptable salt of thereof, can be obtained by reacting a compound of Formula (XXVa) or an acceptable salt of thereof wherein R2 can be a hydrogen, an alkyl, a fluorine or a heteroatom substituent such as OH and R3 is a hydrogen or an alkyl substituent such as methoxymethyl with a suitable deprotecting agent such as, TFA, in a suitable solvent such as, DCM, at a suitable temperature such as, roomtemperature. Alternatively a compound of Formula (XXVI) or an acceptable salt of thereof, can be obtained by reacting a compound of Formula (XXVb) or an acceptable salt of thereof wherein R2 can be a hydrogen, an alkyl, a fluorine or a heteroatom substituent such as OH and R3 is a hydrogen or an alkyl substituent such as methoxymethyl with a suitable deprotecting agent such as, hydrogen gas, in the presence of a suitable catalyst such as Pd(OH)2 / C [12135-22-7] in a suitable solvent such as, Ethanol and TFA, at a suitable temperature such as room temperature.

[0261]

[0154] A compound of Formula (XXVII) can be obtained reacting a compound of Formula (XXVI) or an acceptable salt of thereof with a di -halogenated 5 membered ring heterocycle such as, 2,4-dibromothiazole [4175-77-3], in the presence of a suitable base such as DIPEA, in a suitable solvent such as 1,4-dioxane at a suitable temperature such as, 85 °C.

[0262]

[0155] A compound of Formula (XXVIII) can be obtained in two steps by reacting first a compound of Formula (VII) that can be synthesized accordingly to General Scheme 1 wherein X2 is a suitable halide such as Br or Cl with a boron source such as bis(pinacolato)diboron [73183-34-3] in the presence of a suitable base such as, potassium pivalate [19455-23-3] in the presence of a suitable catalyst such as, XPhos Pd G3 [1445085-55-1] in a suitable solvent such as, 1,4-dioxane, at a suitable temperature such as, 90 °C and in a second step, reacting the formed intermediate with a compound of Formula (XXVII) wherein X is a suitable halide such as Br in the presence of a suitable base such as sodium carbonate in the presence of a suitable catalyst such as, XPhos Pd G3 [1445085-55-1] in a suitable solvent such as, a mixture of 1,4-dioxane and water, at a suitable temperature such as, 90 °C. Alternatively a compound of Formula (XXVIII) can be obtained via the same sequence of reactions inverting the roles of X2 and X.

[0263]

[0156] Compounds of Formula (XXXII), wherein all the substituents are defined as in the general scope, could be prepared according to General Scheme 6.General Scheme 6

[0264] (XXIX)

[0265]

[0266]

[0157] A compound of Formula (XXX) can be obtained reacting a compound of Formula (XXIX) or an acceptable salt of thereof with a suitable chloroalkyl chloroformate such as chloromethyl chloroformate [22128-62-7] in the presence of a suitable base such as LiHMDS, in a suitable solvent such as THF at a suitable temperature such as, -78 °C.

[0267]

[0158] A compound of Formula (XXXI) can be obtained reacting a compound of Formula (XXX) or an acceptable salt of thereof with a suitable source of nucleophilic halide such as Nal, in suitable solvent such as acetone at a suitable temperature, for example ranging from room temperature to 65 °C.

[0268]

[0159] A compound of Formula (XXXII) can be obtained reacting a compound of Formula (XXXI) or an acceptable salt of thereof with a suitable commercially available or synthetically accessible alkyl, aryl or heteroaryl carbonyloxy silver reagent, which can contain suitable variable functional groups such as phosphonates or protected amines, such as Silver acetate, in suitable solvent such as acetone at a suitable temperature such as, 60 °C or room temperature. Non commercially available alkyl, aryl or heteroaryl carbonyloxy silver reagents which can contain suitable variable functional groups such as phosphonates or protected amines, can be obtained by reacting a suitable alkyl, aryl or heteroaryl carbonyloxy sodium salt, which can contain suitable variable functional groups such as phosphonates or protected amines, such as XX with a suitable silver source such as AgNO3. Alternatively, a compoundof Formula (XXXII) could be also obtained reacting a compound of Formula (XXX) or an acceptable salt of thereof with a suitable commercially available or synthetically accessible alkyl, aryl or heteroaryl, carbonyloxy sodium reagent, which can contain suitable variable functional groups such as phosphonates or protected amines, such as Sodium Hydrogen Fumarate [5873-57-4], in suitable solvent such as DMF at a suitable temperature, such as 105 °C.

[0269]

[0160] Compounds of Formula (XXXIV), wherein all the substituents are defined as in the general scope, could be prepared according to General Scheme 8.

[0270] General Scheme 7

[0271] F

[0272]

[0273] (XXXIII)

[0274]

[0161] A compound of Formula (XXXIV) can be obtained reacting a compound of Formula (XXXIII) or an acceptable salt of thereof wherein R12 can be a suitable substituent such as hydrogen or a fluorine with a suitable commercially available or synthetically

[0275] accessible alkyl, aryl or heteroaryl chloroformate, such as 2,2-Dimethyl-propanoyloxymethyl carbonochloridate [133217-74-0] in the presence of a suitable base such as LiHMDS, in a suitable solvent such as THF at a suitable temperature such as, -78 °C.

[0276]

[0162] Compounds of Formula (XXXVI), wherein all the substituents are defined as in the general scope, could be prepared according to General Scheme 8.General Scheme 8

[0277]

[0278] (XXXV) (XXXVI)

[0279]

[0163] A compound of Formula (XXXVI) can be obtained reacting a compound of Formula (XXXV) or an acceptable salt of thereof with a suitable deprotecting agent such as, hydrogen gas, in the presence of a suitable catalyst such as Pd / C (10%) [7440-05-3], in a suitable solvent such as, MeOH, at a suitable temperature such as, room temperature.

[0280]

[0164] Compounds of Formula (XXXVIII), wherein all the substituents are defined as in the general scope, could be prepared according to General Scheme 9.

[0281] General Scheme 9

[0282]

[0283] (XXXVII) (XXXVIII)

[0284]

[0165] A compound of Formula (XXXVIII) can be obtained reacting a compound of Formula (XXXVII) or an acceptable salt of thereof with a suitable deprotecting agent such as, TFA, in a suitable solvent such as, DCM, at a suitable temperature such as, room temperature.

[0285]

[0166] Wherein a compound of Formula (I) has a protecting group such as, for example, Boc, 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.

[0167] Wherein a compound of Formula (I) has a protecting group such as, for example, Boc or THP, the protecting group can be removed by reaction with a suitable reagent such as, for example, HC1, pTsOH, or pyridinium p-toluenesulfonate, in a suitable solvent such as, for example, 1,4-dioxane, or EtOH, at a suitable temperature such as, for example, room temperature. Wherein when the protecting group is an ester, a compound of Formula (I) can be reacted with a suitable hydrolyzing agent such as, for example, LiOH or NaOH, in a suitable solvent such as, for example, THF, MeOH, water, or a mixture thereof, at a suitable temperature such as, for example, room temperature.

[0286]

[0168] The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of Formula (I).

[0287] The skilled person will realize that intermediates and final compounds shown in the schemes below may be further functionalized according to methods well-known by the person skilled in the art.

[0288]

[0169] The compounds of Formula (I) may also be converted into each other via art-known reactions or functional group transformations. For instance, substituents like -C(=O)-O-C1-6alkyl can be converted into a carboxylic acid in the presence of lithium hydroxide, and in the presence of a suitable solvent, such as for example tetrahydrofuran or an alcohol, e.g. methanol.

[0289]

[0170] 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.

[0290]

[0171] 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.

[0291]

[0172] 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.

[0292]

[0173] 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 chiralacid. 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.

[0293]

[0174] 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. The purity of the reaction products may be determined according to methodologies generally known in the art such as for example LC-MS, TLC, HPLC.

[0294]

[0175] 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. The purity of the reaction products may be determined according to methodologies generally known in the art such as for example LC-MS, TLC, HPLC.

[0295] Methods of Treatment and Medical Uses, Pharmaceutical compositions, and combinations

[0296]

[0176] 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.

[0297]

[0177] 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. Thesubject 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.

[0298]

[0178] 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.

[0299]

[0179] 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.

[0300]

[0180] In certain embodiments, the proliferative disease to be treated or prevented using the compounds of the present disclosure is cancer.

[0301]

[0181] 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.

[0302]

[0182] In another aspect, the present invention provides methods of downregulating the expression of SMARCA2 in a biological sample or subject.

[0303]

[0183] 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.

[0184] 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.

[0304]

[0185] 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, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

[0305]

[0186] 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.

[0306]

[0187] 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 inunitary 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 any significant 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.

[0307]

[0188] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage.

[0308] 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.

[0309]

[0189] 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 knownto 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.

[0310]

[0190] 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.

[0311]

[0191] 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 dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

[0312]

[0192] 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.

[0313]

[0193] 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 bythose skilled in the art using conventional methods and in view of the information set out herein.

[0314]

[0194] 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.

[0315]

[0195] Compounds of the present disclosure are:

[0316] o

[0317]

[0318] o

[0319]

[0320] o

[0321]

[0322]

[0323] O

[0324]

[0325]

[0326]

[0327] 

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335] o

[0336]

[0337] 82 83

[0338]

[0339]

[0340] 91 93

[0341]

[0342] 98

[0343] O

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355] 158

[0356] 159

[0357] 160

[0358] 161

[0359]

[0360] EXAMPLES

[0361]

[0196] 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, Acros Organics, Fluka, and Fischer Scientific.

[0362]

[0197] When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained.

[0363]

[0198] 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.

[0199] Hereinafter, DCM and CH2Cl2means dichloromethane; r.t. means room temperature; Boc means tert-butoxycarbonyl; CH3CNand ACN means acetonitrile; MeOH means methanol; EtOH means ethanol; iPrOH means isopropanol; DMF means dimethylformamide; iPrNH₂ means isopropylamine; SOCI2 means thionylchloride; Et3N means triethylamine; NH4OAC means ammonium acetate; NH4OH means ammonium hydroxide; NH4CI means ammonium chloride; NaBH(OAc)3means sodium triacetoxyborohydride; POCI3 means phosphorus oxychloride; RuPhos Pd G3 means (2-Dicyclohexylphosphino-2',6'-diisopropoxy- 1,1’ -biphenyl)(2-(2’ -amino- 1,1’-biphenyl))palladium(II) methanesulfonate; Na2CO3means sodium carbonate; KHSO4 means potassium hydrogenasulfate, HBTU means 2-(lH-Benzotriazole-l-yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate; EA means ethylamine; NH4HCO3 means ammonium bicarbonate; TFA means trifluoroacetic acid; THF means tetrahydrofuran; h means hours; RM means reaction mixture; SFC means Supercritical fluid chromatography; Bredereck’s reagent means tert-Butoxy bis(dimethylamino)methane; AcOEt means ethyl acetate; K2CO3 means potassium carbonate; MgSO₄ means magnesium sulfate; BOC2O means di -tert-butyl decarbonate.

[0364] Example 1: Preparation of the Intermediates and the final Compounds, and characterization thereof

[0365]

[0200] 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.

[0366] In the following table, abbreviations of the most used terms are listed:

[0367] Abbreviation Meaning

[0368] ACN acetonitrile

[0369] AcOH acetic acid

[0370] Celite® diatomaceous earth

[0371] Co Compound

[0372] Co. No. Compound Number

[0373] DCE 1,2-di chloroethane

[0374] DCM dichloromethane

[0375] DEA diethylamine

[0376] DIPEA N,N-diisopropylethylamine

[0377]

[0378] Abbreviation Meaning

[0379] DMF N,N-dimethylformamide

[0380] eq. equivalent(s)

[0381] Et3N or TEA triethylamine

[0382] EtOAc ethyl acetate

[0383] EtOH ethanol

[0384] HATU hexafluorophosphate azabenzotriazole tetramethyl uronium HPLC high performance liquid chromatography

[0385] iPrNH₂ isopropylamine

[0386] iPrOH isopropanol

[0387] LED light-emitting diode

[0388] mCPBA meta-chloroperoxybenzoic acid

[0389] Me methyl

[0390] MeOH methanol

[0391] MTBE Methyl tertiary butyl ether

[0392] NMP N -Methyl -2-py rroli done

[0393] PIDA phenyliodine(III) diacetate

[0394] PPh3triphenylphosphine

[0395] quant. quantitative

[0396] rac racemic

[0397] RP reversed phase

[0398] Selectfluor l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)

[0399] SFC supercritical fluid chromatography

[0400] TFA trifluoroacetic acid

[0401] THF tetrahydrofuran

[0402]

[0403]

[0201] As understood by a person skilled in the art, Compounds synthesized using the protocols as indicated may contain residual solvent or minor impurities.

[0404]

[0202] 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.

[0203] In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context.

[0405]

[0204] 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.

[0406] 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 MgSO₄ Where mixtures, solutions, and extracts were concentrated, they were typically concentrated on a rotary evaporator under reduced pressure.

[0407]

[0206] 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.

[0408]

[0207] 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 (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.

[0409] Preparation of intermediates

[0410]

[0208] 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.

[0411]

[0209] Chemical names were generated using ChemDraw Ultra 21.0 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0412]

[0210] Compounds designated as R* or S* are enantiopure compounds where the absolute configuration was not determined.

[0413] Synthesis of Intermediate 1-1 tert-butyl l-(4-bromothiazol-2-yl)azetidine-3-carboxylate.

[0414]

[0415] DMF

[0211] 2,4 -dibromothiazole [4175-77-3] (5.44 g, 22.1 mmol, 1 eq) was added in a sealed vessel, to a homogeneous solution of tert-butyl azetidine-3 -carboxylate hydrochloride [53871-08-2] (5.0 g, 25.0 mmol, 1.1 eq) and N, N-diisopropylethylamine (7.3 mL, 44.3 mmol, 2 eq) in dimethylformamide (50 mL). The mixture was stirred for 16 h at 60 °C and then concentrated to dryness. The crude was purified by silica gel column chromatography (0:100 to 20:80, EtOAc / heptane) to yield 1-1 as a white solid (4.65 g, 62%).

[0416]

[0212] Additional analogues were synthesized in an analogous manner starting from 2,4-dibromothiazole [4175-77-3] using the reagents as appropriate.

[0213]

[0417] Resulting Int.

[0418] Reagent Structure

[0419] No.

[0420] -O IRS

[0421] >RSO

[0422] Intermediate

[0423] methyl trans-2- — o IRSN^BR

[0424] 1-2

[0425] J

[0426] methylazetidine-3- O RSVS-^ carboxylate, hydrochloride

[0427] [2733987-47-6]

[0428] O

[0429] \ ( NH Intermediate

[0430] O / . N^ / Br

[0431] 1-3

[0432] )> — \n~ I

[0433] ethyl azetidine-3- o s-^ carboxylate [405090-31-5]

[0434]

[0435] Synthesis of Intermediate 1-4 rac-(2R,3S)-2-methylazetidine-3-carboxylic acid

[0436] O^OH

[0437]

[0438]

[0214] Two batches were carried out in parallel. Each batch 72.5 g of -[(tert-butoxy)carbonyl]-2-methylazetidine-3 -carboxylic acid was used. To a solution of 1 -[(tert-butoxy)carbonyl]-2-methylazetidine-3 -carboxylic acid [1638760-82-3] (72.5 g, 336 mmol, 1.00 eq) in DCM (544 mL) was added TFA (278 g, 2.44 mol, 181 mL, 7.24 eq) at 20 °C and the colorless mixture stirred at 20 °C for 2 h to obtain white suspension. TLC

[0439] (Di chloromethane: Methanol = 5:1, SM (Rf) = 0.60, DP (Rf) = 0.1, Ninhydrin) showed that the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to remove solvent. The mixture was co-evaporated three times with DCE (500 mL) to remove TFA. The crude product was without further purification. 1-4 (163.2 g, crude, TFA) was obtained as white solid.

[0440] Synthesis of Intermediate 1-5 rac-(2R,3S)-l-(4-bromothiazol-2-yl)-2-methylazetidine-3-carboxylic acidOH

[0441] Cs2CO3, t-BuOH

[0442]

[0443] Br

[0444]

[0215] 2 batches were carried out in parallel. Each batch 82.5g of 1-4 was used. A solution of 1-4 (82.5 g, 360 mmol, 1.00 eq, TFA) in t-BuOH (825 mL) was added CS2CO3 (351.90 g, 1.08 mol, 3.00 eq) and 2,4-dibromo-l,3-thiazole [4175-77-3] (105 g, 432 mmol, 1.20 eq) at 20 °C. The white mixture was stirred at 85 °C for 16 hours under N2 atmosphere. The reaction mixture was cooled to 20 °C. The mixture was filtered and the solid was washed with MeCN (1.00 L). The liquid was concentrated under reduced pressure to remove solvent. The crude product was without further purification. 1-5 (510 g, 71.2% purity, crude) was obtained as yellow gum.

[0445] Synthesis of Intermediate 1-6 tert-butyl rac-(2R,3S)-l-(4-bromothiazol-2-yl)-2-methylazetidine-3-carboxylate

[0446] POCI3, pyridine, t-BuOH

[0447] ACN

[0448]

[0449]

[0216] 4 batches were carried out in parallel. Each batch 108.6 g of 1-5 was used. To a solution of 1-5 (108.6 g, 279 mmol, 71.2% purity, 1.00 eq), pyridine (227 g, 2.87 mol, 232 mL, 10.3 eq) and t-BuOH (186 g, 2.51 mol, 240 mL, 9.00 eq) in MeCN (760 mL) was added POCI3 (60.7 g, 396 mmol, 36.9 mL, 1.42 eq) at 0-5 °C over 30 min under N2 atmosphere. The white mixture was stirred at 20 °C for 5 min under N2 atmosphere to give yellow mixture. The mixture was cooled to 0 °C and poured into ice water (500 mL) at 0-5 °C, the organic phase was separated, the aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic layer was washed with NaHCO₃ solution (350 mL x 2). The combined organic layer was washed with water (500 mL) and brine (500 mL), dried over Na2SO4, and concentrated to dryness under reduce pressure to afford the crude product. 4 reactions were combined for the purification. The residue was purified by flash silica gel chromatography (ISCO®; 660 g Sepa Flash ® Silica Flash Column, Eluent of 2~5% Ethyl acetate: Petroleumether gradient @120 mL / min). TLC (Petroleum ether: Ethyl acetate = 10: 1, product (Rf) = 0.50, UV = 254 nm). 1-6 (224 g, 544 mmol, 48.7% yield, 81.0% purity) was obtained as yellow oil.

[0450] Synthesis of Intermediate rel-tert-hutyl (2R,3S)-l-(4-bromothiazol-2-yl)-2-methylazetidine-3-carboxylate 1-7 and rel-tert-butyl (2S,3R)-l-(4-bromothiazol-2-yl)-2-methylazetidine-3-carboxylate 1-8

[0451]

[0452]

[0217] The crude product 1-6 was purified by SFC separation (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 urn); mobile phase: [CO2-MeOH]; B%: 10%, isocratic elution mode). Compound 1-7 (78.0 g, 232.42 mmol, 37.9% yield, 99.3% purity) was obtained as yellow solid (SFC: RT = 0.473 min, AP = 100% ee value. Compound 1-8 (80.0 g, 236.70 mmol, 38.6% yield, 98.6% purity) was obtained as yellow solid (SFC: RT = 0.369 min, AP = 99.7% ee value).

[0453] Flow

[0454] mobile Run

[0455] column gradient

[0456] phase time

[0457] Col T

[0458] A:CO2

[0459] Chiralpak® B: 5%-40% B in

[0460] 4.0

[0461] AD 50A MeOH+0.05 1.5 min, hold for 2 min (4.6 mm ID % 0.3 min, then 5%

[0462] 35

[0463] 3 urn) diethylamin B for 0.2 min

[0464]

[0465] e

[0466] Synthesis of Intermediate 1-9 4-Chloro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile

[0467] Pd(dppf)CI2. CH2CI2

[0468] AcOK

[0469]

[0470] 1,4 dioxane

[0218] To a flask containing a nitrogen-sparged solution of 2-bromo-4-chlorobenzonitrile [57381-49-4] (2.0 g, 9.24 mmol, 1 eq), bis(pinacolato)diboron [73183-34-3] (2.82 g, 11.1 mmol, 1.2 eq), AcOK (2.72 g, 27.8 mmol, 3 eq) in 1,4-dioxane (28 mL), was added Pd(dppf)Cl2.CH2Cl2[95464-05-4] (227 mg, 0.28 mmol, 0.03 eq) at room temperature. The reaction mixture was stirred at 85 °C for 5 h. The reaction was allowed to cool to room temperature, filtered through a pad of Celite that was further rinsed with DCM (30 mL). The filtrate was diluted with H2O (20 mL) and extracted with DCM (2 x 40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to a dark oil. The oil was subjected to silica gel chromatography (0: 100 to 30:70, DCM / heptane) to yield 1-9 as a withe solid (843 mg, 33%).

[0471] Synthesis of Intermediate 1-11 tert-butyl l-[4-(2-chloropyridin-4-yl)-l,3-thiazol-2-yl]azetidine-3-carboxylate

[0472]

[0473]

[0219] A mixture of 1-1 (95 g, 297.60 mmol, 1 eq) and K2CO3 (82.26 g, 595.20 mmol, 2.0 eq), 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine [458532-84-8] (51.51 g, 327.36 mmol, 1.1 eq), Xantphos Pd G4 [1621274-19-8] (28.64 g, 29.76 mmol, 0.1 eq) in 1,4-dioxane (760 mL) and H2O (190 mL) was stirred for overnight at 80°C. The mixture was allowed to cool down to RT. The resulting mixture was diluted with ice water (1 L). The resulting mixture was extracted with EA (3x1 L). The combined organic layers were washed with brine (2x1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with PE: EtOAc=5: 1 to afford 1-11 (46.5 g, 44%) as a white solid.

[0474]

[0220] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. Catalyst can vary between Xantphos Pd G4 [1621274-19-8], cataCXium Pd G4 [2230788-67-5], P(t-Bu)3Pd G4 [1621274-11-0] and Pd(dppf)Cl2·CH2Cl2[95464-05-4] while the base can vary between K2CO3, Na2CO3, NaHCO3and CS2CO3.Resulting

[0475] Reagent A Reagent B

[0476] Int. No.

[0477] e y— BXJ _

[0478] / =N O y - Cl Br Cl 2-chl oro-6-(4, 4,5,5- Intermedi

[0479] n

[0480] tetram ethyl- 1,3,2- 0 ate 1-12

[0481] — i_ A / A J dioxaborolan-2- 1-1 — 0 s yl)pyridine [652148- 92-0]

[0482] F.

[0483] / A 'OHBr

[0484] \ 5= / / B' OH \ Intermedi

[0485] Br

[0486] \ [[ ate 1-13

[0487] (3-bromo-5- 0

[0488] —

[0489] fluoropheny l)b oroni c 1-1

[0490] acid [849062-37-9]

[0491] 1

[0492] <( y— BXJ

[0493] / \ ° \ "

[0494] Br F Br °°x Br z

[0495] Intermedi

[0496] 2-(3-bromo-2- ^Z cz /

[0497] ate 1-14

[0498] fluorophenyl)-4,4, 5,5- 0

[0499] i_ AANA j tetram ethyl- 1,3,2- 1-1 — — 0 s OT dioxaborolane T1 [1400220-51-0]

[0500] °H

[0501] F\ / B\ Br

[0502] \= / OH

[0503] Cl Intermedi O Cl (3-chloro-4- w? ate 1-15

[0504] 0

[0505] fluoropheny l)b oroni c

[0506] 1-1

[0507] acid [144432-85-9]

[0508] Br

[0509] O

[0510] < VB'OHIntermedi

[0511] \= / OH c > AA / ClCl 0 ate 1-16 \ / =<

[0512] 1-1 s-#

[0513]

[0514] ,— >- Z Resulting ZA o- / \- co-^ Reagent A Reagent B

[0515] Int. No.

[0516] (3- chlorophenyl)boronic Z Z

[0517] acid [63503-60-6]

[0518] \40- A A ° °

[0519] Br

[0520] \= / OH

[0521] Br Intermedi 0

[0522] ate 1-17,Br(3- 0

[0523] bromophenyl)boronic

[0524] 1-1 s-#

[0525] acid [89598-96-9]

[0526] F\

[0527] z°4- N )>— BsJ

[0528] \= / O' \

[0529] Cl Br

[0530] Cl Intermedi

[0531] 2-chloro-6-fluoro-4- w? ate 1-18 \ VN(4,4,5,5-tetramethyl- 0

[0532] l,3,2-dioxaborolan-2- 1-1

[0533] yl)pyridine [1146615- 89-5]

[0534] Br

[0535] \= / OH

[0536] Cl Intermedi

[0537] (3-chloro-4- w? ate 1-19

[0538] 0

[0539] methy Ipheny l)b oroni c

[0540] 1-1

[0541] acid [175883-63-3]

[0542] Br Br

[0543] Intermedi

[0544] 2-bromo-4-(4, 4,5,5- ate 1-20

[0545] tetram ethyl- 1,3,2- 0

[0546] dioxaborolan-2- 1-1

[0547] yl)pyridine [458532- 82-6]

[0548]

[0549] Resulting

[0550] Reagent A Reagent B

[0551] Int. No.

[0552] F.

[0553] z°4- N y— BsJ

[0554] \= / O' \

[0555] Cl. Br

[0556] Cl Intermedi

[0557] 2-chloro-6-fluoro-4- 4 n% s ate 1-21

[0558] (4,4,5,5-tetramethyl- 0 -4— Q 1R*

[0559] 4 c

[0560] l,3,2-dioxaborolan-2- /

[0561] 1 oSC S J

[0562] -7 -^ yl)pyridine [1146615- 89-5]

[0563] CD — I

[0564] °

[0565] N / BxH

[0566] \=z OH

[0567] Cl. N-^ / BrIntermedi z^N ate 1-22 \ \ L (2-chloropyridin-4- ^0. N^^^CI yl)boronic acid 1-3 0 s j [458532-96-2]

[0568] Cl\.

[0569] ,°H

[0570] Cl \= / OH. N^ / BrIntermedi

[0571] Cl

[0572] a e 1- 3 \ z

[0573] t 2

[0574] (2,6-dichloropyridin- 4.° 1. ft 1-3

[0575] 4-yl)boronic acid

[0576] [1072951-54-2] % Q7 >— N^x OHz\ F— (zy— B

[0577] / = / OH

[0578] Cl O. N-_z-Br

[0579] (5-chloro-6- Intermedi

[0580] fluoropyri din-3 - 1-3 ate 1-24

[0581] yl)boronic acid

[0582] [1366482-32-7]

[0583] N- A OH

[0584] p— (zy— B Cl )= / OH Intermedi

[0585] ZZ4 / FCl ate 1-25 \ I \ " (5-Chloro-6- -4-o JR*

[0586] / N— |] fluoropyri din-3 -yl) oz

[0587]

[0588] Resulting

[0589] Reagent A Reagent B

[0590] Int. No.

[0591] boronic acid

[0592] [1366482-32-7]

[0593]

[0594] Synthesis of Intermediate 1-26 tert-butyl (3-bromo-5-chloropyrazin-2-yl)carbamate

[0595]

[0596]

[0221] 2 -amino-3-bromo-5 -chloropyrazine (500 mg, 2.399 mmol) was dissolved in DCM (15.4 mL). Bis(tert-butyl) decarbonate [24424-99-5] (575.6 mg, 2.639 mmol) and DMAP [1122-58-3] (14.7 mg, 0.12 mmol) was added, and the reaction was stirred at RT for 2h. The reaction mixture was diluted with DCM, washed with NaHCO₃ sat. and dried over MgSO4. The volatile was removed under reduced pressure to afford 1-26 (700 mg, 94%) as a white powder.

[0597] Synthesis of Intermediate 1-27 rac-(2R,3S)-l -(4-(2-chloro-6-fluoropyridin-4-yl)thiazol-2-yl)- 2-methylazetidine-3-carboxylic acid

[0598]

[0599] 1M Na2CO3

[0600] 1,4-dioxane

[0601]

[0222] In a sealed vessel, under nitrogen atmosphere, 2-chloro-6-fluoro-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine [1146615-89-5] (529 mg, 2.05 mmol, 1.3 eq), IM aqueous ISfeCCh (5.0 mL, 5.00 mmol, 3 eq), 1-2 (460 mg, 1.58 mmol, 1 eq) and Pd(dppf)C12. CH2C12 [95464-05-4] (103 mg, 0.13 mmol, 0.08 eq) were combined in 1,4- di oxane (15 mL). The resulting mixture was stirred at 100 °C for 3 h and then allowed to cool to room temperature. IM aqueous HC1 solution was added until pH ~ 3, and the mixture was extracted with EtOAc (2 x 50 mL). The organic layers were dried over MgSO4, filtered andconcentrated. The crude residue was subjected to silica gel chromatography (0 / 100 to 100 / 0, EtOAc / heptane) to give 1-27 (298 mg, 44%) as brownish solid.

[0602]

[0223] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. Catalyst can vary between Pd(dppf)C12. CH2C12 [95464-05-4] and Xantphos Pd G4 [1621274-19-8], and the base can vary between ISfeCCh and K2CO3.

[0603] Resulting

[0604] Reagent A Reagent B Structure

[0605] Int. No.

[0606] F

[0607] A

[0608] ' z\

[0609] O- / HO Cl0)-O^8T Intermedia

[0610] 2-Chloro-6-fluoro-4- te 1-28 1-3

[0611] (4,4,5,5-tetramethyl- 1, 3, 2 -di oxab orol an-2 - yl)pyridine [1146615- 89-5]

[0612] — 0 IRSN^BRClCIXXB. OH

[0613] J

[0614] 0 RSVS-^ OH Intermedia

[0615] te 1-29HO\ RS / X

[0616] 1-2 3 -chi oropheny lb oroni c N— <( J

[0617] ° £ RS

[0618] acid [63503-60-6]S

[0619]

[0620] Synthesis of Intermediate 1-30 Ethyl l-(4-(6-chloropyridin-2-yl)thiazol-2-yl)azetidine-3- carboxylate.

[0621] 1 ) CataCXium Pd G4 PivOK 1,4-dioxane 2) K2CO31,4-dioxane

[0622]

[0623]

[0224] 1-3 (600 mg, 2.06 mmol, 1 eq), bis(pinacolato)diboron [73183-34-3] (576 mg, 2.27 mmol, 1.1 eq), potassium pivalate [19455-23-3] (582 mg, 4.12 mmol, 2 eq), cataCXium Pd G4 [2230788-67-5] (75 mg, 0.10 mmol, 0.05 eq) and nitrogen-sparged 1,4-dioxane (30 mL) were combined in a sealed reactor. The reaction was stirred at 90 °C for 2 h. After cooling to 75 °C, the reaction mixture was kept under nitrogen atmosphere while 2,6- dichloropyridine [2402-78-0] (396 mg, 2.68 mmol, 1.3 eq), K2CO3 (570 mg, 4.12 mmol, 2 eq) and 1,4-dioxane (19 mL) were added. The reaction was then continued for 16 h at 100 °C. At room temperature, the mixture was filtered through a pad of Celite, and filtrate concentrated to a black oil. The crude was subjected to silica gel chromatography (0:100 to 45:55, EtOAc / heptane) to give 1-30 (314 mg, 46%) as a white solid.

[0624]

[0225] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. The catalyst can vary between cataCXium Pd G4 [2230788-67-5] and XPhos Pd G4 [1599466-81-5] and the base can vary between potassium pivalate and potassium 2-ethylhexanoate.

[0625] Resulting

[0626] Reagent A Regent B Structure

[0627] Int. No.

[0628] Cl

[0629] N= / Br

[0630] Br — d A — =N

[0631] Intermedixz

[0632] 6-bromo-2- 0 ate 1-3101 11 chloronicotinonitril

[0633] 1-1

[0634] e [1171919-79-1] Ko \ / I _ z. N \\

[0635] Br z Xi

[0636] Br^^ TDH Intermedi

[0637] 4-bromo-2- ate 1-32

[0638] 0

[0639] hydroxybenzonitril

[0640] 1-1

[0641] e [288067-35-6]

[0642] CI^N Cl

[0643] Cl w. N^ / BrIntermedi

[0644] >> — XN~ T NKN 2,4- 0 s-^ ate 1-33

[0645] dichloropyrimidine 1-3 \ \ N— T

[0646] 0v

[0647] [3934-20-1]

[0648]

[0649] / =z Resulting

[0650] Reagent A Regent B Structure Z <—

[0651] Int. No.

[0652] 1

[0653] YX^F Br Cl ( Y Intermedi

[0654] ^N^CI

[0655] ate 1-34

[0656] 2-chl oro-3 -fluoro- 0 1, VA NJU 4-iodopyridine 1-1

[0657] [148639-07-0]

[0658] Br

[0659] Br Jl NNX Cl Intermedi

[0660] 2-bromo-6- ate 1-35

[0661] 0

[0662] chloropyrazine

[0663] 1-1

[0664] [916791-07-6]

[0665] Cr N Br Cl Intermedi

[0666] tert-butyl (6- r<^N i ~^ O° II ate 1-36

[0667] chloro-4- ( / ):

[0668] 0

[0669] iodopyri din-3 - ^“ z

[0670] 1-1 * I 0 yl)carbamate

[0671] [400777-00-6]

[0672] Xvo \ / I _. Br Cl \\ Intermedi z B< N Cl IN11 A

[0673] 2-bromo-6- N-YJ ate 1-37

[0674] O O S*^

[0675] chloropyrazine

[0676] 1-7

[0677] [916791-07-6]

[0678] . Br

[0679] JOL

[0680] Br^^^OH Intermedi

[0681] A N-YJ

[0682] 4-bromo-2- ate 1-38

[0683] O

[0684] hydroxybenzonitril

[0685] 1-7

[0686] e [288067-35-6]

[0687]

[0688] Resulting

[0689] Reagent A Regent B Structure

[0690] Int. No.

[0691] 1

[0692] . Br Br A Intermedi

[0693] XN^Br \ V

[0694] e - 9 _ I i r N at 13

[0695] 2-bromo-4- \s

[0696] 0

[0697] iodopyridine 1-7

[0698] [100523-96-4]

[0699] Cl

[0700] Cl Intermedi

[0701] XA — 0 IRS

[0702] N IN^

[0703] CBRJ N^N a

[0704] 2,4- O RSVS-^ te 1-40

[0705] o' IRS

[0706] dichloropyr 1-2 Jj imidine o7RS"7

[0707] [3934-20-1]

[0708] Cl / Br 0\\ V Br

[0709] N=y / -OxIntermedi

[0710] Cl — < NH N il ate 1-41

[0711] 0

[0712] 1-26 HN^Ox /

[0713] 1-1 0 Cl F

[0714] N=— / V- Br Br

[0715] Intermedi

[0716] 4-bromo-2-chloro- ate 1-42 ° 1 T 3- 0

[0717] fluorob enzonitril e 1-1

[0718] [1427439-32-4]

[0719]

[0720] Synthesis of Intermediate 1-434-Chloro-N, N,6-trimethylpyridin-2-amine

[0721] Me2NH

[0722] Pd(OAc)2

[0723]

[0724] Cl JohnPhos

[0725]

[0726] tBuONa

[0727] Toluene

[0728]

[0226] Pd(OAc)2[3375-31-3] (56 mg, 0.25 mmol, 0.1 eq) and JohnPhos [224311-51-7] (74 mg, 0.27 mmol, 0.1 eq) were added to a sealed vessel containing a nitrogen-spargedtoluene (8 mL) solution of 2,4-dichloro-6-methylpyridine [42779-56-6] (400 mg, 2.47 mmol, 1 eq), 33% dimethylamine in EtOH [124-40-3](0.53 mL, 2.96 mmol, 1.2 eq) and sodium tert-butoxide (239 mg, 2.47 mmol, 1 eq). The reaction was stirred at 100 °C for 16 h. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (100 mL) and washed with H2O (50 mL). The organic layer was dried under MgSO4, filtered, and concentrated to obtain an orange oil. The oil was subjected to silica gel chromatography (0:100 to 100:0, EtOAc / heptane) to give 1-43 (130 mg, 28%).

[0729]

[0227] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[0730] Resulting Int.

[0731] Reagent Amine Structure

[0732] No.

[0733] Cl

[0734] ONHCI^%T^ Intermediate

[0735] Azetidine

[0736] 2,4-dichloro-6- 1-44

[0737] [503-29-7]

[0738] methylpyridine

[0739] ^z

[0740] [42779-56-6]

[0741]

[0742] 0

[0743] Synthesis of Intermediate 1-45 4-Chloro-2-ethyl-6-methylpyridine

[0744]

[0745] Cl Cui

[0746] THF

[0747]

[0228] To a solution of 2,4-dichloro-6-methylpyridine [42779-56-6] (600 mg, 3.63 mmol, 1 eq) in tetrahydrofuran (18 mL) under nitrogen atmosphere, were added Pd(dppf)C12. CH2C12 [95464-05-4] (297 mg, 0.36 mmol, 0.1 eq) and Cui (70 mg, 0.36 mmol, 0.1 eq). IM diethylzinc solution in hexanes [557-20-0] (2.90 mL, 2.90 mmol, 0.8 eq) was then added via syringe at room temperature and reaction vessel sealed. The mixture was stirred at 70 °C for 2.5 h and allowed to cool to room temperature. EtOAc (30 mL), H2O (30 mL) and 35% aqueous NH3 (1 mL) were added. The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude was subjected to silica gel chromatography (0:100 to 45:55, EtOAc / heptane) to give 1-45 (335 mg, 59%) as a colorless oil.

[0229] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[0748] Resulting

[0749] Reagent Zincate Structure

[0750] Int. No.

[0751] \, N Br [>- Zn+HBr

[0752] XT Cyclopropylzinc

[0753] Intermedia

[0754] Br bromide solution 0.5

[0755] te 1-46

[0756] 2,4-dibromo-6- M in THF [126403- Br methylpyridine 68-7]

[0757] [79055-52-0]

[0758]

[0759] Synthesis of Intermediate 1-47 4-Chloro-6-cyclopropyl-2-methylpyrimidine

[0760] OH

[0761]

[0762]

[0230] Pd(dppf)C12. CH2C12 [95464-05-4] (966 mg, 1.18 mmol, 0.1 eq), cyclopropylboronic acid [411235-57-9] (1.07 g, 12.4 mmol, 1.05 eq) andKaPCU (6.29 g, 29.6 mmol) were added to a solution of 2-methyl-4,6-dichloropyrimidine [1780-26-3] (1.93 g, 11.8 mmol, 1 eq) in THF (30 mL) in flask equipped with a condenser, under light nitrogen stream, at room temperature. The mixture was stirred at 75 °C for 16 h and allowed to cool to room temperature. H2O (100 mL) was added. The organics were extracted with EtOAc (2 x 200 mL), dried over MgSO4, filtered and concentrated. The crude was subjected to silica gel chromatography (0:100 to 50:50, EtOAc / heptane) to give 1-47 (1.18 g, 58%) as a white solid.

[0763] Synthesis of Intermediate 1-48 N, N,6-Trimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-aminePd(dppf)Cl2. CH2Cl2

[0764] AcOK

[0765]

[0766] 1,4-dioxane

[0767]

[0231] In a sealed reaction vessel, under nitrogen atmosphere, a mixture of 1-43 (130 mg, 0.76 mmol, 1 eq), bis(pinacolato)diboron [73183-34-3] (232 mg, 0.91 mmol, 1.2 eq), AcOK (227 mg, 2.29 mmol, 3 eq) and Pd(dppf)C12. CH2C12 [95464-05-4] (16 mg, 0.02 mmol, 0.025 eq) in 1,4-dioxane (1.5 mL) was stirred at 100 °C for 16 h. Upon cooling to room temperature, EtOAc (10 mL) was added, and the mixture was filtered through a pad of Celite. The filtrate was concentrated to dryness in vacuo to give 1-48 (199 mg, 90%) as a dark crystalline solid. The product was used as such in the next step.

[0768]

[0232] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. The catalyst can vary between Pd(dppf)C12. CH2C12 [95464-05-4], cataCXium Pd G4 [2230788-67-5] and XPhos Pd G3 [1445085-55-1],

[0769] Resulting Int.

[0770] Reagent Structure

[0771] No.

[0772] Br

[0773] F\ / =(

[0774] / — V #

[0775] F N— F.

[0776] y-F

[0777] Intermediate

[0778] 4-bromo-2- HO / =\

[0779] 1-49 B -4 N

[0780] (difluoromethyl)- HO ' — (

[0781] 6-methylpyridine

[0782] [1226800-12-9]

[0783] Cl

[0784] A Intermediate

[0785] 1-50 -Uo J3

[0786] 1-44

[0787]

[0788] Resulting Int.

[0789] Reagent Structure

[0790] No.

[0791] Intermediate

[0792] Cl 1-51 ~A-q B— z=\ N

[0793] 1-45

[0794] Intermediate

[0795] Br 1-52

[0796] 1-46

[0797]

[0798] Synthesis of Intermediate 1-53 tert-butyl l-(4-{2',6'-dimethyl-[2,4'-bipyridin]-4-yl}-l,3- thiazol-2-yl)azetidine-3-carboxylate 00

[0799] HO^^OH LU J

[0800]

[0801]

[0233] A flask was charged with 2,6-dimethylpyridin-4-ylboronic acid [846548-44-5] (22.66 g, 150.06 mmol, 1.2 equiv), 1-11 (44 g, 125.05 mmol, 1.0 equiv), K2CO3 (34.57 g, 250.10 mmol, 2.0 equiv), cataCXiumPdG4 [2230788-67-5] (7.7 g, 7.31 mmol, 0.0830 equiv) in H2O (66 mL) and 1,4-dioxane (440 mL) at 25°C. The flask was purged with nitrogen and stirred at 90°C for 2 h. The reaction was cooled to RT. The resulting mixture was extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with

[0802] EtOAc: PE (60:40) to afford 1-53 (36 g, 68%) as a yellow oil.

[0803]

[0234] Additional analogues were synthesized in an analogous manner using the

[0804] reagents as appropriate. The catalyst can vary between], cataCXium Pd G4 [2230788-67-5],tetrakis(triphenylphosphine)palladium(0) [14221-01-3], XPhos Pd G4 [1599466-81-5], XPhos 1

[0805] Pd G3 [1445085-55-1] and Pd(dppf)C12. CH2C12 [95464-05-4], and the base can vary between Na2CO3, K2CO3K3PO4, and NaHCO3.

[0806] A

[0807] z Resultin

[0808] Reagent A ^ / czz Reagent B g Int. Structure

[0809] No.

[0810] CT

[0811] Cl \— N

[0812] Tl ( / \\ _

[0813] HO-B

[0814] nx

[0815] Interme

[0816] OH / 0 — I J

[0817] 2,6- diate

[0818] — 0

[0819] V-N^N / MN—=\ I dimethylpyridin- 1-54

[0820] u U

[0821] 1-1 1

[0822] 4-ylboronic acid

[0823] [846548-44-5]

[0824] N

[0825] ( / \\ _

[0826] HO-BxInterme

[0827] OH diate

[0828] \°=

[0829] 2,6- 1-55

[0830] dimethylpyridin- 1-1

[0831] 4-ylboronic acid I z [846548-44-5]

[0832] N

[0833] ( / \\ _

[0834] HO-B Interm

[0835] 0 ITxe

[0836] OH diate0\=^ 2,6- 1-56

[0837] 1-31 dimethylpyridin- yyvp 4-ylboronic acid

[0838] [846548-44-5]

[0839] Cl

[0840] N Interme

[0841] r^N ( / \\ _

[0842] ( JH- \ I 1 k diate

[0843] —4—0 IR* HO- Bx

[0844] OH 1-57

[0845] 0s vS-^

[0846] s- /

[0847] 1-21 F

[0848]

[0849] Resultin

[0850] j Y Reagent A Reagent B g Int. Structure

[0851] No.

[0852] p w

[0853] 2,6- ^ ^zz- dimethylpyridin- \\

[0854] o oo= o=

[0855] 4-ylboronic acid

[0856] [846548-44-5]

[0857] N

[0858] # \\ _

[0859] 0 Cl

[0860] HO-Bx

[0861] OH Interme

[0862] S-U 2,6- diate

[0863] 1-15

[0864] dimethylpyridin- 1-58

[0865] 4-ylboronic acid

[0866] [846548-44-5]

[0867] \-N

[0868] Cl # \\ _

[0869] sA HO-BxInterme

[0870] . VA -UJ OH diate

[0871] 2,6- 1-59

[0872] 1-34 dimethylpyridin- 4-ylboronic acid

[0873] [846548-44-5]

[0874] N

[0875] # \\ _

[0876] 0

[0877] cr A-A CI HO-BxInterme

[0878] NOH O

[0879] ^'x^N\ Z ') diate

[0880] s- / V_7 2,6- 1-60 / =\ 1-16 dimethylpyridin- s—

[0881] 4-ylboronic acid

[0882] [846548-44-5]

[0883]

[0884] Resultin u X- XJI Reagent A Reagent B g Int. Structure 1 I

[0885] No.

[0886] OT

[0887] ^Z.

[0888] Cl \-N

[0889] ( / \\ _ 3

[0890] * 'N\ O w — '

[0891] I il te oO='

[0892] HO-BxIn rme

[0893] v °~

[0894] OH diate

[0895] \ 2,6- 1-61

[0896] dimethylpyridin- 1-37

[0897] 4-ylboronic acid

[0898] [846548-44-5]

[0899] N

[0900] Cl ( / \\ _

[0901] HO-BxInterme

[0902] OH diate

[0903] o 2,6- 1-62

[0904] 1-36 dimethylpyridin- 4-ylboronic acid

[0905] [846548-44-5]

[0906] N

[0907] Cl ( / \\ _

[0908] \ f^N HO-BxInterme L \-N ( / - °\ / \ OH diate

[0909] o v 2,6- 1-63 N 1-23 dimethylpyridin- Cl 4-ylboronic acid

[0910] [846548-44-5]

[0911] Cl r^N

[0912] r^N VSAJQ Interme

[0913] 0. zx NXX < V6 FF

[0914] I KH J diate

[0915] - 0 S"^ 2-methyl-4- 1-64

[0916] (4, 4,5,5- ° U

[0917] 1-11

[0918] tetramethyl- 1,3,2-

[0919]

[0920] Resultin

[0921] wwzReagent A Reagent B g Int. Structure

[0922] No.

[0923] z dioxaborolan-2- yl)-6- (trifluoromethyl)

[0924] pyridine

[0925] [1321518-03-9]

[0926] A~N

[0927] \ \ L Interme

[0928] ?H)=N \ \ N— T diate

[0929] ovs-^0Tn W A 1-65 V \ / A

[0930] 1-22

[0931] 1-51

[0932] Cl \-N

[0933] / / \\ _

[0934] HO-BxInterme XJJ 0 S-VHNK r, OH diate

[0935] 0^ 2,6- 1-66 / K^

[0936] sMA

[0937] Ox-udimethylpyridin- 1-41 0^^

[0938] 4-ylboronic acid

[0939] [846548-44-5]

[0940] \— N

[0941] / / \\ _

[0942] C'|

[0943] HO-BxInterme

[0944] OH diate

[0945] 0 T

[0946] 2,6- 1-67

[0947] 1-42 dimethylpyridin- 4-ylboronic acid

[0948] [846548-44-5]

[0949]

[0950] Synthesis of Intermediate 1-68 l-(4-(2'-(Dimethylamino)-6'-methyl-[2,4'-bipyridin]-4- yl) thiazol-2-yl) azetidine-3-carboxylic acid.r

[0951] z ^ zoc

[0952] ^ / z cz

[0953] ZA 1 i

[0954] X

[0955] w

[0956] 0 Pd(dppf)Cl2. CH2Cl2

[0957] 1M Na2CO3

[0958] 1,4-dioxane

[0959]

[0235] In a sealed vessel, under nitrogen atmosphere, a mixture of 1-22 (81 mg, 0.25 mmol, 1 eq), 1-48 (200 mg, 0.50 mmol, 2 eq), 1M aqueous Na2CO3(0.75 mL, 0.75 mmol, 3 eq) and Pd(dppf)C12. CH2C12 [95464-05-4] (16 mg, 0.02 mmol, 0.08 eq) in 1,4-dioxane (4 mL) was stirred at 100 °C for 3 h. The mixture was allowed to cool to room temperature, diluted with H2O (20 mL) and washed EtOAc (15 mL). The aqueous phase was brought to pH ~ 3 and washed with DCM (2 x 80 mL). The aqueous solution was then concentrated to the crude yellowish oil, 1-68 (142 mg, 143%, crude).

[0960]

[0236] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[0961] Resulting Int. 0

[0962] Reagent Structure

[0963] No. / z

[0964] 1' z- 0

[0965] _ JL ci L z

[0966] ' 0 yA _ / ^0 J3X Intermediate OH 5=N S-# '= / 1-69 o^\-^

[0967] 1-22 LH1-50 1 / ) — \ N S-<7 \— /

[0968] 0

[0969] 0XN N T'® / X Intermediate

[0970] 1-70

[0971] 1-22

[0972] 1-52

[0973] Intermediate

[0974] 1-71

[0975]

[0976] Resulting Int.

[0977] Reagent Structure

[0978] No.

[0979] 1-33 (2,6- dimethylpyridin-4- yl)boronic acid

[0980] [846548-44-5]

[0981] -V-q / X

[0982] Cl

[0983] o N^N 7%'

[0984] Intermediate

[0985] —6 RSVN^ (2,6- 1-72

[0986] 1-40 dimethylpyridin-4- yl)boronic acid

[0987] [846548-44-5]

[0988] F 7-0 / =(

[0989] r^N W\,,N\^N i I if r'd

[0990] HO 1RS Intermediateh°? r 0 ^'RSCM J ’ (2,6-RSVS 1-73 o

[0991] dimethylpyridin-4-Q / RSORS N V / N 1-27 *

[0992] yl)boronic acid XTMbF [846548-44-5] V «\^ z

[0993] «

[0994] HO Cl / =( zz^

[0995] ,B~(\,N\-N 7%'

[0996] N A OH # —

[0997] Intermediate x x S-4 (2,6- 7

[0998] 1-74tNYNyX N 1-28 dimethylpyridin-4- F yl)boronic acid

[0999] [846548-44-5]

[1000]

[1001] Synthesis of Intermediate 1-75 tert-butyl l-(4-(2'-(difluoromethyl)-3-fluoro-6'-methyl-[2,4'- bipyridin]-4-yl)thiazol-2-yl)azetidine-3-carboxylateBr

[1002]

[1003]

[0237] XPhos Pd G4 [1599466-81-5] (66.77 mg, 0.078 mmol) was added to a stirred mixture of 4-bromo-2-(difluoromethyl)-6-methylpyridine [1226800-12-9] (720.4 mg, 3.24 mmol), bis(pinacolato)diboron [73183-34-3] (823.94 mg, 3.24 mmol) and potassium 2- ethyl hexanoate [3164-85-0] (1626.63 mg, 8.92 mmol) in 1,4-dioxane (55 mL). The air in the reaction system was replaced with nitrogen, and under the saturation of nitrogen, the reaction mixture was heated at 100 °C and stirred for 30 minutes, then cooled to 25 °C. Then, 1-34 (1000 mg, 2.7 mmol) and K2CO3 (1121.05 mg, 8.11 mmol), 1,4-dioxane (25 mL) and water (29 mL) were added. The air in the reaction system was replaced with nitrogen, and under the saturation of nitrogen, the reaction mixture was heated at 100 °C and stirred for 2 h. Then, the L z

[1004] mixture was cooled and evaporated in vacuo till water. The aqueous phase was extracted with EtOAc twice and the combined organic layer were washed with Brine, dried on MgSO4,

[1005] JML M

[1006] filtered and evaporated. The residue was purified by silica gel chromatography (Heptane: EtOAc 100:0 to 70:30). The pure fractions were evaporated, yielding 1-75 (682 mg, yield 52.93%) as an orange sticky oil.

[1007]

[0238] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. The catalyst can vary between XPhos Pd G4 [1599466-81-5], Pd(dppf)C12. CH2C12 [95464-05-4] and cataCXium Pd G4 [2230788-67-5] and the base of the first step can vary between potassium 2-ethylhexanoate and potassium acetate.

[1008] Resultin

[1009] Reagent A Reagent B Structure

[1010] g Int. No.

[1011] Interme

[1012] \=N

[1013] FA J* — diate

[1014] Br 1-76

[1015]

[1016] Resultin

[1017] Reagent A Reagent B Structure

[1018] g Int. No.

[1019] Cl

[1020] r^N

[1021] - 1 o KK SJ

[1022] 1-11

[1023]

[1024]

[0239] Additional analogues were synthesized in an analogous manner using the reagents as appropriate and using 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan- 2-yl)-l,3,2-dioxaborolane rather than bis(pinacolato)diboron [73183-34-3],

[0240]

[1025] Resultin

[1026] Reagent Reagent B Structure

[1027] g Int. No.

[1028] A

[1029] A) Br

[1030] J l

[1031] A^ N Br

[1032] F Interme o

[1033] o A #N4-brom diate \\ _ / Fo-2- 1-20 )=N F (difluoromethyl)- 1-77 VN^_N / =\ 6- methylpyrimidine

[1034] [2248359-57-9]

[1035] Br Br

[1036] N' A / 1

[1037] A T°\ A N I;

[1038] JI Interme

[1039] o diate

[1040] 4-bromo-2,6- 1-39 1-78

[1041] dimethylpyrimidi

[1042] ne [354574-56-4]

[1043] A

[1044] Br

[1045] F L z

[1046] N' A

[1047] A JI Interme

[1048] o

[1049] diate

[1050] 4-bromo-2,6- 1-42 00^

[1051] 1-79 Y ]i dimethylpyrimidiH HIIv I Z ne [354574-56-4]

[1052]

[1053] -HISynthesis of Intermediate 1-80 tert-butyl rel-(2R,3S)-l-(4-(2-(2,6-dimethylpyrimidin-4-yl)-6- fluoropyridin-4-yl)thiazol-2-yl)-2-methylazetidine-3-carboxylate

[1054] 1 ) CataCXium Pd G4 potassium 2-ethylhexanoate 1,4-dioxane 2) K2CO3, CataCXium Pd G4 1,4-dioxane, water Br

[1055]

[1056]

[0241] A mixture of 1-21 (700 mg, 1.477 mmol), Bis(pinacolato) diboron [73183-34-3] (450.098 mg, 1.772 mmol), potassium 2-ethylhexanoate [3164-85-0] (434.885 mg, 2.385 mmol) in 1,4-dioxane (17 mL) was degassed with nitrogen for 5 min. CataCXium Pd G4 [2230788-67-5] (30.154 mg, 0.0406 mmol) was added and the mixture was heated at 100°C for 1 h. The mixture was cooled to RT and kept under nitrogen. Then, 4-bromo-2,6- dimethylpyrimidine [354574-56-4] (359.145 mg, 1.92 mmol), K2CO3 [584-08-7] (408.273 mg, 2.954 mmol), dioxane (7.6 mL) and water (6.5 mL) was added and the mixture was degassed with nitrogen for 5 min. CataCXium Pd G4 [2230788-67-5] (30.697 mg, 0.0414 mmol) was added and the mixture was heated at 100°C for 2 h. The mixture was cooled to RT. LC / MS showed complete conversion. The mixture was poured out in water, extracted with EtOAc two times, the combined organic layers were washed with brine, dried on MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography (Heptane: EtOAc 100:0 to 50:50) to give 1-80 (614 mg, 83%).

[1057]

[0242] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. The catalyst can vary between CataCXium Pd G4 [2230788-67-5] and XPhos Pd G4 [1599466-81-5] and the base in the first step can vary between potassium 2- ethyl hexanoate and potassium pivalate. Water might not be added in the second step.

[1058] Resulting

[1059] Reagent A Reagent B Structure

[1060] Int. No.

[1061] Br

[1062] Intermedi

[1063] Y Y ate 1-81

[1064] Br VN N / \

[1065]

[1066] Resulting

[1067] Reagent A Reagent B Structure

[1068] Int. No.

[1069] 1-14 4-bromo-2,6- dimethylpyrimidi

[1070] ne [354574-56-4]

[1071] Cl

[1072] Y

[1073] \ rNY / =N Br Intermedi

[1074] <7O-p 4-bromo-2,6- ate 1-82 OA-AN1-18 dimethylpyrimidi

[1075] F ne [354574-56-4]

[1076] F

[1077] Cl

[1078] WF

[1079] \ rN

[1080] Br Intermedi / 0 / / — ( 7 dK>-p 4-bromo-2- ate 1-83F1-18 (difluoromethyl)- F

[1081] 6-methylpyridine

[1082] [1226800-12-9]

[1083] F

[1084] Cl YA

[1085] \ rNCl

[1086] Intermedi

[1087] M A / "-A^F 4-chloro-6- / ° F cH>-V ate 1-84

[1088] (difluoromethyl)- VN_N

[1089] 1-18

[1090] 2- methylpyrimidine

[1091] [1706452-87-0]

[1092] Br

[1093] Y Y O OKNYUA Br Intermedi

[1094] i >-O-< YoV'N)=X - o s 1

[1095] 4-bromo-2,6- ate 1-85

[1096] ^NVNM

[1097] 1-13 dimethylpyrimidi

[1098] F

[1099] ne [354574-56-4]

[1100]

[1101] Resulting

[1102] Reagent A Reagent B Structure

[1103] Int. No.

[1104] Cl

[1105] Y y «

[1106] q [ T

[1107] Br Intermedi

[1108] 4-bromo-2,6- ate 1-86

[1109] o

[1110] 1-15 dimethylpyrimidi

[1111] ne [354574-56-4]

[1112] \_, N. /

[1113] Y Y

[1114] Br Intermedi

[1115] 0 Cl 4-bromo-2,6- ate 1-87

[1116] 1-31

[1117] dimethylpyrimidi

[1118] ne [354574-56-4]

[1119] F

[1120] Cl YA

[1121] Cl O Q

[1122] \ I 1 k Intermedi

[1123] —4—0 IR* NY^F 4-chloro-6- \ 1 r ate \o=S: R*

[1124] zX. X / Y J 1-88

[1125] 0SS-^ ° /

[1126] (difluoromethyl)- \^N 1-21 2- F ( Zjs. methylpyrimidine

[1127] [1706452-87-0]

[1128] I

[1129] Clzziiy Tl z B Intermedi

[1130] -7—0 IR* r

[1131] / J 4-bromo-2- ate 1-89

[1132] (difluoromethyl)- 1-21

[1133] 6-methylpyridine

[1134] [1226800-12-9]

[1135]

[1136] Synthesis of Intermediate 1-90 Ethyl l-(4-(6-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-3-yl)thiazol-2-yl)azetidine-3-carboxylate

[1137]

[1138]

[0243] In a sealed reaction vessel, under nitrogen atmosphere, a mixture of 1-24 (850 mg, 2.49 mmol, 1 eq), bis(pinacolato)diboron [73183-34-3] (1.58 g, 6.22 mmol, 2.5 eq), AcOK (488 mg, 4.97 mmol, 3 eq) and XPhos Pd G3 [1445085-55-1] (211 mg, 0.25 mmol, 0.1 eq) in 1,4-di oxane (24 mL) was stirred at 90 °C for 16 h. Upon cooling to room temperature, H2O (50 mL) was added, and organics extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The crude was subjected to silica gel chromatography (EtOAc / heptane 0:100 to 45:55) to give 1-90 (1.08 g, 98%) as a yellow sticky solid.

[1139] Synthesis of Intermediate 1-91 l-(4-(5-(2,6-Dimethylpyrimidin-4-yl)-6-fluoropyridin-3-yl) thiazol-2-yl) azetidine-3-carboxylic acid

[1140]

[1141] 1,4-dioxane

[1142]

[0244] In a sealed vessel, under nitrogen atmosphere, a mixture of 1-90 (200 mg, 0.46 mmol, 1 eq), 4-chloro-2,6-dimethylpyrimidine [4472-45-1] (0.164 mL, 1.38 mmol, 3 eq), 1M aqueous Na2CO3(1.4 mL, 1.40 mmol, 3 eq) and XPhos Pd G3 [1445085-55-1] (31 mg, 0.04 mmol, 0.08 eq) in 1,4-dioxane (2 mL) was stirred at 100 °C for 6 h. The mixture was allowed to cool to room temperature, diluted with H2O (40 mL) and washed with EtOAc (2 x 50 mL). The aqueous solution was brought to pH ~ 3 with 1M aqueous KHSO4and extracted with DCM (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give I-91 (178 mg, 70%) as a brown solid.

[1143] Synthesis of Intermediate 1-92 tert-butyl l-(4-(6-(tributylstannyl)pyrazin-2-yl)thiazol-2-yl) azetidine-3-carboxylate

[1144]

[1145]

[0245] In a 2-5 mL microwave tube and under nitrogen, a solution of hexa-N-butyl ditin [813-19-4] (0.32 mL, 0.63 mmol) in dry 1,4-dioxane (2.5 mL) was added to a mixture, previously flushed 3 times with nitrogen / vacuum, of 1-35 (12 mg, 0.034 mmol), tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (2.4 mg, 0.0021 mmol; yellow one) and lithium chloride [7447-41-8] (119.6 mg, 2.82 mmol). The reaction mixture was stirred 3 h at 120 °C. The reaction mixture was poured out in a mixture of KF, KOH in water and EtOAc. The water phase was extracted with EtOAc (3 times). The different organic layers were combined, dried over MgSO4, filtered off and concentrated under reduced pressure. The crude was purified by column chromatography on a 25 g Sfar Silica HC in a Biotage system using at the beginning an isocratic method of 100% heptane (5 CV) and then a gradient from 0 till 100% EtOAc in heptane (20 CV). The different product fractions were combined and concentrated under reduced pressure to afford 1-92 (113 mg, 42%).

[1146] Synthesis of Intermediate 1-93 2,4-Dimethyl-6-(trimethylstannyl)pyrimidine.

[1147] Me3SnSnMe3

[1148] - - l 'L /

[1149] Pd(PPh

[1150]

[1151] 3)4

[1152]

[1153] 1,4-dioxane I

[1154]

[0246] In a sealed glass reactor, tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (1.26 g, 1.10 mmol, 0.1 eq) was added to a solution of 4-chloro-2,6-dimethylpyrimidine [4472-45-1] (1.30 mL, 10.9 mmol, 1 eq), and hexamethylditin [661-69-8] (2.95 mL, 14.2 mmol, 1.3 eq) in dry 1,4-dioxane (50 mL), under nitrogen atmosphere. The resulting solution was stirred at 100 °C for 16 h. The dark mixture was filtered through a pad of Celite, that was further washed with EtOAc (30 mL). The filtrate was concentrated to dryness. The crude dark oil was triturated 5 times with heptane (15 mL) separating the phases by decantation. The heptane solutions were combined and concentrated to give 1-93 (3.09 g, 65%) as a yellow oil.

[1155]

[0247] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[1156]

[1157] Synthesis of Intermediate 1-96 tert-butyl l-(4-(6-(2,6-dimethylpyriniidin-4-yl)pyrazin-2- yl) thiazol-2-yl) azetidine-3-carboxylate

[1158]

[1159]

[0248] In a 2-5 mL microwave tube and under nitrogen, 1-92 (113 mg, 0.19 mmol) and dry 1,4-dioxane (1.8 mL) were added to a mixture, previously flushed 3 times with nitrogen / vacuum, of 4-bromo-2,6-dimethylpyrimide [354574-56-4] (55.2 mg, 0.3 mmol) and bis(tri-tert-butylphosphine)palladium(0) [53199-31-8] (22.2 mg, 0.043 mmol). The reaction mixture was stirred 3 h at 100 °C. The reaction mixture was poured out in a mixture of a solution of NaHCO3sat. in water (10 mL), KF solution in water (20 mL) and EtOAc (10 mL). The product was extracted with EtOAc (3 x 10 mL). The different organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure at 40 °C. The crude was purified by column chromatography on a 25 g Sfär Silica HC in a Biotage system using a gradient from 0 till 50% EtOAc in heptane (25 CV) and an isocrtic method with 50%EtOAc in heptane (5 CV). The different product fractions were combined and concentrated under reduced pressure to afford 1-96 (33.5 mg, 31%).

[1160]

[0249] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[1161] Resulti

[1162] Reagent A Reagent B ng Int. Structure

[1163] No.

[1164] _ S-, Cl

[1165] i KHV j

[1166] — Ho II A Interm o Cl

[1167] 1

[1168] ediate

[1169] 4,6-dichloro-2- Y 1-95 1-97

[1170] methylpyrimidinexCl [1780-26-3]

[1171]

[1172] Synthesis of Intermediate 1-98 Ethyl l-(4-(2',6'-dimethyl-[2,4'-bipyrimidin]-4-yl)thiazol-2- yl) azetidine-3-carboxylate

[1173]

[1174] 1,4-dioxane

[1175]

[0250] XPhos Pd G3 [1445085-55-1] (201 mg, 0.24 mmol, 0.1 eq) was added to a sealed vessel containing a solution of 1-33 (830 mg, 2.38 mmol, 1 eq), 1-93 (1.53 mg, 3.56 mmol, 1.5 eq), LiCl (294 mg, 6.94 mmol, 3 eq), Cui (45 mg, 0.24 mmol, 0.1 eq) in nitrogen-sparged 1,4- dioxane (7 mL). The mixture was heated at 100 °C for 16 h. At room temperature, the mixture was diluted with EtOAc (20 mL), filtered through a pad of Celite, and concentrated to dryness. The brown residue was purified by silica gel chromatography (0:100 to 10:90, MeOH / DCM) to obtain 1-98 (122 mg, 13%) as a brown solid.

[0251]

[1176] Resulting Int.

[1177] Reagent Structure

[1178] No.

[1179] \R* / S1\ / -^CI

[1180] L-oN FIntermediate - o

[1181] 1-99

[1182] 1-25 yMhT

[1183]

[1184] Synthesis of Intermediate 1-100 tert-Butyl l-(4-(2-(2,6-dimethylpyrimidin-4-yl)-3- fluoropyridin-4-yl)thiazol-2-yl)azetidine-3-carboxylate.

[1185]

[1186]

[0252] Tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (51 mg, 0.05 mmol, 0.05 eq) was added to a solution of 1-34 (330 mg, 0.89 mmol, 1 eq) and 1-93 (316 mg, 0.98 mmol, 1.1 eq) in nitrogen-sparged 1,4-di oxane in a glass reactor. The solution was stirred at 100 °C for 48 h. The mixture was allowed to cool to room temperature and filtered through a pad of Celite. The filtrate was concentrated to a brownish oil. The crude was subjected to silica gel chromatography (0:100 to 30:70, EtOAc / heptane) to give 1-100 (333 mg, 80%) as light yellow solid.

[1187]

[0253] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. The catalyst can vary between Tetrakis(triphenylphosphine)palladium(0) [14221-01-3] and XPhos Pd G4 [1599466-81-5],

[0254]

[1188] Resulting

[1189] Reagent A Reagent B Structure

[1190] Int. No.

[1191] \ \ L -Sn—

[1192] . N^Z^^CI Intermediat

[1193] o A e 1-101

[1194] r V 1-22

[1195] 1-94

[1196]

[1197] Synthesis of Intermediate 1-102 l-(4-(6-(2,6-Dimethylpyrimidin-4-yl)pyridin-2-yl)thiazol-2- yl)azetidine-3-carboxylic acid.

[1198]

[1199]

[0255] Tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (62 mg, 0.05 mmol, 0.1 eq) was added to a solution l-(4-(6-chloropyridin-2-yl)thiazol-2-yl)azetidine-3-carboxylate I- 30 (174 mg, 0.54 mmol, 1 eq) and 2,4-dimethyl-6-(trimethylstannyl)pyrimidine 1-93 (320 mg, 1.18 mmol, 2.2 eq) in nitrogen-sparged toluene in a glass reactor. The solution was stirred at 100 °C for 16 h. The mixture was allowed to cool to room temperature and IM aqueous Na2CC>3 (10 mL) was added. The aqueous solution was washed with EtOAc (3 x 15 mL) and concentrated. The solid was triturated in dimethylformamide (10 mL) and filtered through a sintered funnel. The filtrate was concentrated dry to give the crude 1-102 (150 mg, 72%) as an orange solid

[1200] Synthesis of Intermediate 1-103 tert-Butyl l-(4-(2-(6-(dimethylamino)-2-methylpyrimidin-4- yl)pyridin-4-yl)thiazol-2-yl)azetidine-3-carboxylate

[1201]

[1202]

[0256] To a solution of 1-97 (325 mg, 0.73 mmol, 1 eq) in tetrahydrofuran (2 mL) in flask, was added 40% dimethylamine in H2O (0.092 mL, 0.72 mmol, 1 eq) and N, N-diisopropylethylamine (0.153 mL, 0.87 mmol, 1.2 eq) under a nitrogen atmosphere to give

[1203] pale red solution. The mixture was heated at 60 °C for 16 h. Then, the mixture was recharged with 40% dimethylamine in H2O (0.092 mL, 0.72 mmol, 1 eq) and reaction continued at 60

[1204] °C for 16 h. The mixture was concentrated to give an orange oil. The oil was subjected to

[1205] silica gel chromatography (0:100 to 55:45, EtOAc / heptane) to give 1-103 (238 mg, 64%) as

[1206] an orange foam.

[1207] Synthesis of Intermediate 1-104 tert-butyl l-(4-(4-cyano-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)thiazol-2-yl)azetidine-3-carboxylate

[1208]

[1209]

[0257] At 0 °C, N,N-bis(trifluoromethylsulfonyl)aniline [37595-74-7] (1.87 g, 4.77

[1210] mmol, 1.30 eq.) was added to a mixture of 1-32 (1.31 g, 3.67 mmol, 1.00 eq.), DIPEA [7087-68-5] (2.00 mL, 0.750 g / mL, 11.6 mmol, 3.17 eq.), and 4-dimethylaminopyridine [1122-58-3] (0.179 g, 1.47 mmol, 0.400 eq.) in DCM (24.0 mL). The mixture was warmed to 21 °C and

[1211] stirred for 72 h. LCMS analysis of a reaction aliquot revealed full consumption of the starting material. A saturated solution of NaHCO3(100 mL) and EtOAc (15.0 mL) were added to the mixture, and the aqueous phase was extracted with EtOAc (4 x 15.0 mL). The combined

[1212] organic layers were washed with brine (60.0 mL), dried (MgSO4), filtered, and concentrated

[1213] under reduced pressure. The crude material was purified by silica gel chromatography (24 g column) eluting with heptane and EtOAc (0-80%) to provide 1-104 (832 mg, 46%) as a white solid.

[1214]

[0258] Additional analogues were synthesized in an analogous manner using the

[1215] reagents as appropriate.

[0259]

[1216] Resulting z Reagent Structure

[1217] Int. No. _ [O

[1218] 7 / Z- "

[1219] Intermediat

[1220] \ w— J \

[1221] e 1-105 jjO C tx

[1222] 1-38 ^O / ' '

[1223]

[1224] Synthesis of Intermediate 1-106 tert-butyl l-(4-(4-cyano-3-(2-(difluoromethyl)-6-methylpyridin-4-yl)phenyl)thiazol-2-yl)azetidine-3-carboxylate

[1225]

[1226]

[0260] Dry N2 was bubbled through a mixture of 4-bromo-2-(difluoromethyl)-6-methylpyridine [1226800-12-9] (177 mg, 0.797 mmol, 1.00 eq), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane [2247367-07-1] (425 mg, 1.16 mmol, 1.46 eq), potassium pivalate [19455-23-3] (370 mg, 2.64 mmol, 3.31 eq), and cataCXium Pd G4 [2230788-67-5] (70.0 mg, 0.0943 mmol, 12 mol%) in 1,4-dioxane (16.0 mL). The mixture was sealed and heated at 85 °C for 1.5 h with vigorous stirring (1200 rpm), then 1-104 (200 mg, 0.409 mmol, 0.513 eq) and potassium carbonate [584-08-7] (370 mg, 2.68 mmol, 3.36 eq) were added, then the mixture was heated to 85 °C for 16 h. LCMS analysis of a reaction aliquot revealed full consumption of the starting material, and the formation of the desired product mass. An analogous reaction was conducted on 39 mg of 4-bromo-2-(difluoromethyl)-6-methylpyridine and combined with this reaction mixture. A scoop ofSiliCycle MetS DMT was added, the mixture was stirred for 10 min at 21 °C, then filtered through a short pad of Celite, washing with EtOAc (3 x 15.0 mL). Water (160 mL) was added to the filtrate and the aqueous phase was extracted with EtOAc (4 x 20.0 mL). The combined organic layers were washed with brine (60.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (40 g column) eluting with heptane and EtOAc (0-80%) to provide 1-106 (100 mg, 26%) as a white solid.

[1227]

[0261] Additional analogues were synthesized in an analogous manner starting from I-104 using the reagents as appropriate.

[1228] Resultin

[1229] Reagent g Int. Structure

[1230] No.

[1231] Cl

[1232] ^0

[1233] / >=N F Interme

[1234] diate I- 4-chloro-6-(difhioromethyl)-2- 107

[1235] methylpyrimidine [1706452-87- / = / \ z —

[1236] 0]

[1237]

[1238] \ )\ —0

[1239] ZT|

[1240] Synthesis of Intermediate 1-108 tert-butyl rel-(2R,3S)-l-(4-(4-cyano-3-(2,6-dimethylpyridin- 4-yl)phenyl)thiazol-2-yl)-2-methylazetidine-3-carboxylate

[1241] HO.^OH

[1242]

[1243]

[0262] A mixture of 1-105 (578 mg, 1.15 mmol, 1.00 eq), (2,6-dimethylpyridin-4-yl)boronic acid [846548-44-5] (225 mg, 1.49 mmol, 1.30 eq), CS2CO3 [534-17-8] (1.12 g,

[1244] 3.45 mmol, 3.01 eq), and cataCXium Pd G4 [2230788-67-5] (64.0 mg, 0.00862 mmol, 8

[1245] mol%) in dioxane (20.0 mL) was stirred at 80 °C for 16 h. LCMS revealed the clean

[1246] formation of the desired product. A scoop of SiliCycle MetS DMT was added, the mixture

[1247] was stirred for 10 min, then filtered through a short pad of Celite, washing with EtOAc (3 x15.0 mL). Water (200 mL) was added to the filtrate, and the product was extracted with EtOAc (3 x 25.0 mL). The combined organic layers were washed with brine (50.0 mL), dried (MgSO4) filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (40 g column) eluting with heptane and EtOAc (0-80%) to provide 1-108 (543 mg, quant.) as a brown oil.

[1248] Synthesis of Intermediate 1-1093,5-Dichloro-2-fluoropyrazine

[1249] Cl Cl

[1250] k. N py. HF U. N

[1251] c

[1252]

[1253] r cr

[1254]

[0263] In a Teflon flask under ice cooling, NaNO? (631 mg, 9.15 mmol, 1.5 eq) was added portion wise to a solution of 2-amino-3,5-dichloropyrazine [873-42-7] (1 g, 6.10 mmol, 1 eq) in pyridine hydrofluoride [32001-55-1] (6.5 mL, 73.2 mmol, 12 eq). The resulting mixture was stirred and slowly warmed to room temperature over 16 h. The reaction was poured onto H2O (50 mL) and extracted with DCM (4 x 40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated give 1-109 (614 mg, 60%) as a pale, yellow oil.

[1255] Synthesis of Intermediate 1-110 4-Chloro-3 -fluor o-2 6 '-dimethyl-2, 4 '-bipyridine

[1256] OH

[1257]

[1258]

[0264] Pd(dppf)C12. CH2C12 [95464-05-4] (202 mg, 0.25 mmol, 0.08 eq) was added to a sealed vessel containing a stirred solution of 2-bromo-4-chl oro-3 -fluoropyridine [1155847-42-9] (650 mg, 3.09 mmol, 1 eq), (2,6-dimethylpyridin-4-yl)boronic acid [846548-44-5] (466 mg, 3.09 mmol, 1 eq) and CS2CO3 (2.21 g, 6.80 mmol, 2.2 eq) in 1.4-dioxane (39 mL) and H2O (10 mL), under nitrogen atmosphere. The heterogeneous brown reaction mixture was stirred at 80 °C for 6 h and then allowed to cool to room temperature. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to a brown oil. The oil was subjected to silica gel chromatography (0:100 to 40:60, EtOAc / heptane) to yield 1-110 (474 mg, 64%) as a brown solid.

[0265] Additional analogues were synthesized in an analogous manner from (2,6- dimethylpyridin-4-yl)boronic acid [846548-44-5] using the reagents as appropriate. The catalyst can vary between Pd(PPh3)C12 [13965-03-2], tetrakis(triphenylphosphine)palladium(0) [14221-01-3] and Pd(dppf)C12. CH2C12 [95464-05- 4], and the base can vary between Na2CO3, K2CO3 and CS2CO3.

[1259] Z=z

[1260] Resulting Int.

[1261] Reagent Structure (\ / ) z —

[1262] No. / / /

[1263] CIVNYCI

[1264] Intermediate r^N

[1265] V 0

[1266] 2,6-dichloropyrazine [4774- 1-111 T jj

[1267] N

[1268] 14-5]

[1269] 0

[1270] Intermediate

[1271] NO21-112 11 ]

[1272] |T z n -n —

[1273] / (—T\ \

[1274] 2,6-dibromo-4-nitropyridine

[1275] NO

[1276] [175422-04-5]2

[1277] — A V

[1278] Z / Intermediate

[1279] UL

[1280] 1-113

[1281] 2-bromo-4-chlorobenzonitrile

[1282] [57381-49-4]

[1283] CI^N^Sr

[1284] Intermediate

[1285] 1-114

[1286] 2-bromo-6-chloropyridine

[1287] [5140-72-7]

[1288] F

[1289] Intermediate

[1290] V

[1291] 1-115

[1292] 3, 5 -di chi oro-4-fluoropy ri dine

[1293] [916791-62-3]

[1294]

[1295] Resulting Int.

[1296] Reagent Structure No.

[1297] Y T Intermediate

[1298] 1-116 [I l 2-bromo-4-chloro- 1 - I T methoxybenzene [60633-25-2]

[1299] Intermediate

[1300] 1-117

[1301] 2,6-dichloro-3-fluoropyridine

[1302] [52208-50-1]

[1303] c|^^Br

[1304] Intermediate

[1305] o o O

[1306] 1-118 Il 1 2-bromo-4-chlorophenol [695- A / A

[1307] z zZ\

[1308] 96-5]

[1309] UGZ / F Intermediate

[1310] 2-bromo-4-chloro- 1 - 1-119

[1311] (difluoromethyl)benzene

[1312] [1261476-50-9]

[1313] CI^N Cl

[1314] Intermediate

[1315] XI,

[1316] 1-120

[1317] 1-109

[1318] CI^^^Br

[1319] \ II

[1320] Intermediate

[1321] L! L 2-Bromo-4-chloropyridine 1-121

[1322] \ [1

[1323] [22918-01-0]

[1324]

[1325] Resulting Int.

[1326] Reagent Structure

[1327] No.

[1328] Br^x ^l

[1329] Intermediate 1 1

[1330] 4-bromo- 1 -chloro-2- 1-122

[1331] XI

[1332] iodobenzene [774608-49-0]

[1333]

[1334] Synthesis of Intermediate 1-123 4-(4-chloropyridin-2-yl)-2,6-dimethylpyrimidine

[1335] iPrMgCI, ZnCI2

[1336] THF Pd(PPh3)4|THF

[1337]

[1338]

[0266] To a solution of 2-bromo-4-chloropyridine [22918-01-0] (64.8 g, 336 mmol, 1.00 eq) in THF (650 mL) was added dropwise iPrMgCI (2.00 M, 202 mL, 1.20 eq) under N2 atmosphere at 0 °C. After addition, the mixture was stirred at 25 °C for 1 h, and then ZnCL (2 M, 202 mL, 1.20 eq) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 2 hrs. LC-MS showed that the starting material was consumed completely and one main peak with desired m / z was detected. 4-Bromo-2,6-dimethylpyrimidine [354574-56-4] (81.9 g, 437 mmol, 1.30 eq) andPd(PPh3)4(38.9 g, 33.6 mmol, 0.100 eq) in THF (650 mL) were added dropwise to the solution under N2 atmosphere at 25 °C. The resulting mixture was stirred at 80 °C for 12 hrs. LC-MS showed that one main peak with desired m / z was detected. The mixture was cooled to 25 °C and poured into water (800 mL), the organic phase was separated, the aqueous phase was extracted with EtOAc (500 mL x 2), dried over Na2SO4, and concentrated to dryness under reduce pressure to afford the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 220 g *2 Sepa Flash® Silica Flash Column, Eluent of 0~20 % Ethyl acetate / Petroleum ether gradient at 200 mL / min). TLC (Petroleum ether: Ethyl acetate = 3: 1, product (Rf) = 0.41, 254 nm). 1-123 (30.1 g, 137 mmol, 41% yield) was obtained as a yellow solid.

[1339]

[0267] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[0268]

[1340] Resulting

[1341] Reagent A Reagent B Structure

[1342] Int. No.

[1343] F

[1344] Br

[1345] Intermedia 11\ / V\^zz

[1346] z / z

[1347] 2,6-dibromo-4- te 1-124

[1348] fluoropyridine [1214344- o LL A JL

[1349] Br^'^' T

[1350] 15-6]

[1351] Br

[1352] F

[1353] lb1F^NY'Intermedia

[1354] te 1-125

[1355] 2-bromo-4- Cl

[1356] chloropyridine [22918- 01-0]

[1357] Br

[1358] XJ Intermedia

[1359] y te 1-126

[1360] 2-bromo-4- Cl

[1361] chloropyridine [22918- 01-0]

[1362]

[1363] Synthesis of Intermediate 1-127 4-(5-chloro-2-(difluoromethyl)phenyl)-2,6- dimethylpyrimidine

[1364] Br 1 ) CataCXium Pd G4

[1365] PivOK

[1366] 1,4-dioxane

[1367]

[1368]

[0269] Dry N2 was bubbled through a mixture of 2-bromo-4-chloro-l- (difluoromethyl)benzene [1261476-50-9] (0.40 g, 1.66 mmol, 1 eq), bis(pinacolato)diboron [73183-34-3] (505 mg, 1.99 mmol, 1.20 eq), potassium pivalate [19455-23-3] (698 mg, 4.98 mmol, 3.01 eq), and cataCXium Pd G4 [2230788-67-5] (126 mg, 0.170 mmol, 10 mol%) in dioxane (20.0 mL). The mixture was sealed and heated at 70 °C for 1 h, then cooled. 4- Bromo-2,6-dimethylpyrimidine [354574-56-4] (0.420 g, 2.25 mmol, 1.36 eq) was added, followed by potassium carbonate [584-08-7] (504 mg, 3.65 mmol, 2.20 eq). The mixture was heated to 70 °C for 16 h. LCMS analysis of a reaction aliquot revealed full consumption of the starting material, and the formation of the desired product. A scoop of SiliCycle MetS DMT was added, the mixture was stirred for 10 min, then filtered through a short pad of Celite. Water was added to the filtrate (100 mL) and the aqueous phase was extracted with EtOAc (4 x 20.0 mL). The combined organic layers were washed with brine (80.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (24 g column) eluting with heptane and EtOAc (0-60%) to provide 1-127 (87.0 mg, 20%) as an orange solid.

[1369]

[0270] Additional analogues were synthesized in an analogous manner starting from 4- Bromo-2,6-dimethylpyrimidine [354574-56-4] using the reagents as appropriate.

[1370] Resulting Int.

[1371] Reagent Structure

[1372] No.

[1373] HCI

[1374] Br

[1375] Cl — / )— NH Intermediate T T

[1376] \

[1377] 1-128 T H

[1378] 2-bromo-4-chloro-n- methylaniline hydrochloride JLJ

[1379] [1199773-47-1]

[1380]

[1381] Synthesis of Intermediate 1-1294-Chloro-2-(2,6-dimethylpyrimidin-4-yl)benzonitrile

[1382] Br

[1383] Pd(PPh3)4Na2CO3

[1384]

[1385] Toluene

[0271] In a sealed reactor, tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (174 mg, 0.27 mmol, 0.1 eq) was added to a suspension of 4-bromo-2,6-dimethylpyrimidine [354574-56-4] (500 mg, 2.63 mmol, 1 eq), 1-9 (845 mg, 3.21 mmol, 2 eq) and Na2CO3(740 mg, 5.35 mmol, 2 eq) in nitrogen-sparged toluene (7 mL). The resulting mixture was stirred at 100 °C for 16 h and allowed to cool to room temperature. The reaction was recharged with tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (174 mg, 0.27 mmol, 0.1 eq) and continued for 24 h. The yellow suspension was diluted with H2O (10 mL) at room temperature and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to a yellow solid. The solid was subjected to silica gel chromatography (0:100 to 30:70, EtOAc / heptane) to give 1-129 (222 mg, 34%) as a white solid.

[1386] Synthesis of Intermediate 1-1306-bromo-4-fluoro-2',6'-dimethyl-2,4'-bipyridine

[1387]

[1388] O

[1389]

[0272] In a 2-5 mL microwave tube, tetramethylammonium fluoride [373-68-2] (1.99 g, 21.36 mmol) was weighted and dried at 120 °C under vacuum. The tube was cooled down with nitrogen atmosphere. A solution of 1-112 (3.21 g, 10.42 mmol) in dry DMF (55 mL) was added and the reaction was stirred overnight at 65 °C. The reaction mixture was quenched with water (-200 mL). The product was extracted with EtOAc (50 mL x 3). The different organic layers were combined, dried over MgSO4, filtered off and concentrated under reduced pressure at 40 °C. The crude was purified by column chromatography on a 100 g Sfar Silica HC in a Biotage system using a gradient from 0 till 50% EtOAc in heptane (20 CV). The different product fractions were combined and concentrated under reduced pressure to afford 1-130 (2.51 g, 77%) as a light yellow solid.Synthesis of Intermediate 1-1312-(2,6-Dimethylpyrinndin-4-yl)-4-(4,4,5,5-tetramethyl-

[1390] XPhos Pd G3 XPhos AcOK 1,4 dioxane

[1391] l,3

[1392]

[1393] ,2-dioxaborolan-2-yl)benzonitrile

[0273] In a sealed reaction vessel, under nitrogen atmosphere, a mixture of 1-129 (282 mg, 1.56 mmol, 1 eq), bis(pinacolato)diboron [73183-34-3] (592 mg, 2.33 mmol, 2 eq), AcOK (351 mg, 3.57 mmol, 3.1 eq), XPhos Pd G3 [1445085-55-1] (98 mg, 0.12 mmol, 0.1 eq) and XPhos [564483-18-7] (110 mg, 0.23 mmol, 0.2 eq) in 1,4-dioxane (3 mL) was stirred at 70 °C for 16 h. Upon cooling to room temperature, H2O (10 mL) was added. The mixture CD

[1394] was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give a brown oil. The oil was subjected to silica gel

[1395] X j

[1396] chromatography (0: 100 to 50:50, EtOAc / heptane) to afford 1-131V YZ(382 mg, 69%) as a yellow solid.

[1397]

[0274] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[1398] Resulting Int.

[1399] Reagent Structure

[1400] No.

[1401] r^N

[1402] _ A I-0' B— / (\=\ / ) — =N

[1403] Intermediate

[1404] XX

[1405] 1-132

[1406] 1-113 / N

[1407] r^N

[1408] 1! L Intermediate

[1409] \ II 1-133

[1410] 1-121

[1411]

[1412] Synthesis of Intermediate 1-134 Ethyl l-(4-(4-cyano-3-(2,6-dimethylpyrimidin-4- yl)phenyl)thiazol-2-yl)azetidine-3-carboxylate.

[1413]

[1414]

[0275] In a sealed vessel, under nitrogen atmosphere, a mixture of 1-3 (214 mg, 0.73 mmol, 1 eq), 1-131 (352 mg, 0.73 mmol, 1 eq), K2CO3 (254 mg, 1.84 mmol, 2.5 eq) and Pd(dppf)C12. CH2C12 [95464-05-4] (48 mg, 0.06 mmol, 0.08 eq) in 1,4-dioxane (2.2 mL) and 0

[1415] H2O (0.8 mL), was stirred at 85 °C for 16 h. The mixture w \o=as allowed to cool to room temperature and filtered through a pad of Celite, that was further^" z rinsed with EtOAc (30 mL) and DCM / MeOH (9 / 1, v / v, 20 mL). The filtrate was concentrated dry to a dark brown solid.

[1416] 1 z

[1417] The solid was subjected to silica gel chromatography (0:100 to 50:50, EtOAc / heptane) to afford 1-134 (130 mg, 39%) as a brown solid.

[1418]

[0276] Additional analogues were synthesized in an analogous manner starting from 1-3

[1419] using the reagents as appropriate.

[1420] Resulting

[1421] Reagent Structure

[1422] Int. No.

[1423] _ A / '0' B— < / \=\ / ) — =N

[1424] Intermedia

[1425] te 1-135

[1426] / N

[1427] 1-132

[1428]

[1429] Synthesis of Intermediate 1-136 tert-butyl l-(4-(2-(2,6-dimethylpyrimidin-4-yl)pyridin-4- yl) thiazol-2-yl) azetidine-3-carboxylate

[1430]

[1431]

[0277] CataCXium Pd G4 [2230788-67-5] (19.599 mg, 0.0264 mmol) was added to a solution of 1-1 (98.004 mg, 0.264 mmol), potassium pivalate [19455-23-3] (111.069 mg, 0.792 mmol), bis(pinacolato)diboron [73183-34-3] (100.572 mg, 0.396 mmol) in dry 1,4- dioxane (2.6 mL) and the mixture was degassed by bubbling nitrogen. The vial was sealed, and the reaction mixture was stirred at 90°C for 2 h.

[1432] After cooling to 75°C, the vial was opened and kept under nitrogen atmosphere while 1-123 (145 mg, 0.66 mmol), Potassium carbonate [584-08-7] (72.981 mg, 0.528 mmol) and dry 1,4- dioxane (1 mL) were added. The vial was sealed again, and the reaction mixture was stirred at 75°C overnight. After cooling, 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 crude was purified by column chromatography (heptane: EtOAc 100:0 to 0:100) yielding 1-136 (52 mg, yield 46%).

[1433] Synthesis of Intermediate 1-137 tert-Butyl l-(4-(6-(2,6-dimethylpyridin-4-yl)-5-fluoropyrazin-2-yl)thiazol-2-yl)azetidine-3-carboxylate.

[1434]

[1435]

[0278] 1-1 (220 mg, 0.69 mmol, 1 eq), bis(pinacolato)diboron [73183-34-3] (757 mg, 0.76 mmol, 1.1 eq), potassium pivalate [19455-23-3] (192 mg, 1.38 mmol, 2 eq), cataCXium Pd G4 [2230788-67-5] (25 mg, 0.03 mmol, 0.05 eq) and nitrogen-sparged 1,4-dioxane (10 mL) were combined in a sealed glass reactor. The reaction was stirred at 90 °C for 2 h. After cooling to 75 °C, the reaction mixture was kept under nitrogen atmosphere while I-120 5-chloro-3-(2,6-dimethylpyridin-4-yl)-2-fluoropyrazine (180 mg, 0.76 mmol, 1.1 eq), K2CO3 (190 mg, 1.38 mmol, 2 eq) and 1,4-dioxane (6.5 mL) were added. The reaction was then continued for 16 h at 75 °C and finally allowed to cool to room temperature. H2O (20 mL) and EtOAc (50 mL) were added. The organic layer was separated, dried over MgSO4, filtered, and concentrated to a black oil. The oil was subjected to silica gel chromatography (0:100 to 100:0, EtOAc / heptane) to give 1-137 (215 mg, 70%) as a white solid.

[1436]

[0279] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. CuCl can be added in the second step.

[1437] Resulti

[1438] Reagent A Reagent B ng Int. Structure

[1439] No.

[1440] (Rj

[1441] “Vo N^Br

[1442] Interm

[1443] NA, \ y —

[1444] ediate

[1445] 1-1 CI^^N / N=\

[1446] 1-138 w

[1447] 1-111 S-^ ^-N

[1448] / w

[1449] — O I RS N-~Y'Br(TT Interm

[1450] N— 1]

[1451] 0 RS^ S-^ NA ediate

[1452] d^^-N

[1453] 1-2 1-139 R

[1454] 1-111

[1455] . Br TJ Interm

[1456] X

[1457] ediate

[1458] -A.3X7 O^-fAR*

[1459] JUL 1-140 UN N N=f 1-7 1-130 F

[1460]

[1461] Resulti =Z z.1 Reagent A Reagent B ng Int. Structure £ jzA1

[1462] No.

[1463] ^x

[1464] A / z wH

[1465] — Q! RS N-^ / BrInterm ^x Q w

[1466] Q H r\oM o J ediate \ z °

[1467] ^3

[1468] 1-2 Br ^ T 1-141 y / °“

[1469] 1-130

[1470] \zNx /

[1471] — Vo N^ / BrII Interm / VI \-N 9 / \> — / / OyJ A ediate Cr \--\ \=N A JL 1-142 X-M N N= / I-l Br ^A

[1472] s-A

[1473] 1-124 F

[1474] F A I X / F-Vo N^BrAN nterm Z\ F— ( / y-c^y ediate J >~N I-l XJ 1-143

[1475] / =< ' 1-125 s-->~W

[1476] -4-0. N-^ / BrTT Interm

[1477] / yo^ y ediate

[1478] I-l JL J 1-144

[1479] 1-126

[1480] . Br

[1481] F ANInterm

[1482] \ V*

[1483] ediate

[1484] ' >"s^s

[1485] 0 1 H 1-145

[1486]

[1487] Resulti

[1488] Reagent A Reagent B ng Int. Structure I J J I L

[1489] No.

[1490] 1-7 1-110

[1491] p

[1492] JZ—

[1493] / o- -4-C) N~_ / Brfl 1 Interm „ O / / N \\ _ HX y ediate

[1494] / V-N^N N=< I-l 1-146

[1495] F

[1496] 1-130 F

[1497] Br rA^N

[1498] Cl\ / NW \ Interm OKAS* / S-> J X ediate

[1499] 0Kj ^O R*^N'Xj"N'^X^Z\

[1500] 1-114 1-147

[1501] 1-8

[1502] . Br Interm

[1503] 0 IR*

[1504] Jr°\ 4 NCl\ / NW \ ediate S-^ 1 AJJ

[1505] \ ) / "sZ s Xj ^|'ZN— jl I 'lf ^-0 S*^ NA / N

[1506] 0 1-148

[1507] 1-114

[1508] 1-7

[1509] Br Interm

[1510] ci^XjtX ediate

[1511] 0K1-149 xZKuA

[1512] 1-8 1-115

[1513] — Vo N-_xBrInterm

[1514] / y< Msy ClykX< ediate

[1515] I-l 1-150

[1516] ^NT

[1517] 1-115

[1518]

[1519] Resulti

[1520] Reagent A Reagent B ng Int. Structure i xll AX J

[1521] No.

[1522] “Vo N-^ / BrInterm

[1523] Il 1

[1524] 0 / N\ ediate V X

[1525] o o

[1526] I-l 1-151 AN / =(

[1527] 1I )> — (\ / )— O 1-116 S^Z v / / \

[1528] r^N Interm

[1529] O. N-_x CI^N^ X I zZ NOM)N^8Br

[1530] T ediate

[1531] T IT \ S-a VJV 1-10 °vXNN^t 1 1-3 1-117 II

[1532] 0

[1533] — O IRS N- / BrX'N

[1534] Interm

[1535] O RS^ S-^ t o ZNT T ediate / \RS / S~\\ L JL °\ AN A

[1536] 1-2

[1537] 1-152nX L

[1538] 1-117 o AZ'f

[1539] “Vo N^BrInterm

[1540] Il 1

[1541] / yoxj ediate

[1542] x x

[1543] ^^'OH

[1544] I-l 1-153

[1545] 1-118

[1546] X^N

[1547] — Vo N-_xBrInterm

[1548] 1 L

[1549] ediate

[1550] ^' TII

[1551] I-l 1-154

[1552] 1-122

[1553]

[1554] Resulti

[1555] Reagent A Reagent B ng Int. Structure 21 111

[1556] No. y0^ ^ NV

[1557] — Vo N-_xBr~ (zJ / Interm

[1558] N\

[1559] F ediate

[1560] / — \ / Cl1- V V

[1561] I-l 155 o o

[1562] 1-127

[1563] -Vo N^BrIl 1

[1564] Interm

[1565] / yOyJ

[1566] uy

[1567] ediate

[1568] I-l F 1-156

[1569] 1-119

[1570] W - * A

[1571] Br yV Interm T *

[1572] 1 £ ^ Wz

[1573] ediate

[1574] \ n

[1575] Y Y?

[1576] 0RV-N1-157 cAky Oj Y ^Ssjrz1-8 1-121

[1577] . Br yV Interm

[1578] 1 L

[1579] Jr°\ AVJ ediate

[1580] \ II

[1581] 0 1-158

[1582] 1-7 1-121

[1583] \ T

[1584] -4-0. N^BrInterm

[1585] / y-c^y T H ediate0 / N\

[1586] VNz1. V-N^N^ / =y I-l 1-159

[1587] V" sJW 'NxH1-128

[1588]

[1589] Resulti

[1590] Reagent A Reagent B ng Int. Structure

[1591] No.

[1592]

[1593] Synthesis of Intermediate 1-160 tert-butyl l-(4-(3-(2,6-dimethylpyridin-4-yl)-4- (((trifluoromethyl)sulfonyl)oxy)phenyl)thiazol-2-yl)azetidine-3-carboxylate

[1594]

[1595]

[0280] At 0 °C, N, N-bis(trifluoromethylsulfonyl)aniline [37595-74-7] (44.0 mg, 0.123 mmol, 1.24 eq) was added to a mixture of 1-153 (197 mg, 0.315 mmol, 1.00 eq), DIPEA

[1596] [7087-68-5] (0.0855 mL, 0.750 g / mL, 0.496 mmol, 1.57 eq), and 4-dimethylaminopyridine

[1597] [1122-58-3] (15.0 mg, 0.123 mmol, 0.39 eq) in DCM (3.00 mL). The mixture was warmed to

[1598] 21 °C and stirred for 16 h. LCMS analysis of a reaction aliquot revealed partial consumption of the starting material. The mixture was left for an additional 7 h before LCMS analysis of a reaction aliquot revealed full consumption of the starting material. A saturated solution of NaHCO₃ (60.0 mL) and EtOAc (5.00 mL) were added to the mixture, and the aqueous phase was extracted with EtOAc (4 x 10.0 mL). The combined organic layers were washed with

[1599] brine (40.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (24 g column) eluting with heptane and EtOAc (0-100%) to provide 1-160 (139 mg, 77%) as a yellow oil.

[1600] Synthesis of Intermediate 1-161 tert-butyl l-(4-(3-(2,6-dimethylpyridin-4-yl)-4- ((diphenylmethylene)amino)phenyl)thiazol-2-yl)azetidine-3-carboxylate

[1601]

[1602]

[0281] A mixture of 1-160 (25.0 mg, 0.0439 mmol, 1.00 eq), XantPhos Pd G3

[1603] [1445085-97-1] (4.00 mg, 0.00422 mmol, 10 mol%), benzophenone imine [1013-88-3] (0.0111 mL, 1.08 g / mL, 0.0662 mmol, 1.51 eq), Cs2CO3 [534-17-8] (45.0 mg, 0.138 mmol, 3.15 eq) in toluene (1.00 mL) was stirred at 100 °C for 16 h. LCMS analysis of a reaction aliquot revealed full consumption of the starting material. A scoop of SiliCycle MetS DMT was added, the mixture was stirred for 10 min, then filtered through a short pad of Celite.

[1604] Water (60.0 mL) and EtOAc (10.0 mL) were added to the filtrate, and the aqueous phase was extracted with EtOAc (4 x 15.0 mL). The combined organic layers were washed with brine (60.0 mL), dried on MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (12 g column) eluting with heptane and EtOAc (0-60%) to provide 1-161 as a yellow solid.

[1605] Synthesis of Intermediate 1-162 l-(4-(4-amino-3-(2,6-diniethylpyridin-4-yl)phenyl)thiazol-2-yl) azetidine-3-carboxylic acid

[1606]

[1607]

[0282] TFA [76-05-1] (0.260 mL, 1.49 g / mL, 3.40 mmol, 30.0 eq) was added to a solution of 1-161 (68.0 mg, 0.113 mmol, 1.00 eq) in DCM (1.00 mL) and the solution was stirred at 65 °C for 5 h. LCMS analysis of a reaction aliquot revealed partial consumption of the starting material. The mixture was left to stir for another 16 h at 37 °C, before LCMS analysis revealed almost full consumption of the starting material. More TFA [76-05-1] (0.260 mL, 1.49 g / mL, 3.40 mmol, 30.0 eq) was added and the mixture was warmed to 45 °C for an additional 4 h. The mixture was cooled to 21 °C and quenched by dropwise addition ofDIPEA [7087-68-5] (1.20 mL, 0.75 g / mL, 6.96 mmol, 61.5 eq). The mixture was concentrated under reduced pressure to provide 1-162 as a yellow residue (assumed quantitative yield).

[1608] Synthesis of Intermediate 1-163 l-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-3 -carboxylic acid

[1609]

[1610]

[0283] To a solution of compound 1-53 (26.0 g, 61.5 mmol, 1.00 eq) in DCM (130 mL) was added TFA (79.8 g, 700 mmol, 52.0 mL, 11.4 eq) at 25 °C. The yellow solution was stirred at 25 °C for 16 hrs. LC-MS showed compound 1-53 was consumed completely and one main peak with desired m / z was detected. Then DCM (20.0 ml) was added and reconcentrated on the rotavapor. This process was repeated 2 additional times to give the desired product. The crude product was used to next step without further purification. 1-163 (70.0 g, crude) was obtained as a yellow oil.

[1611]

[0284] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. The products can be obtained in neutral or in salt form.

[1612] Resulting

[1613] Reagent Structure

[1614] Int. No.

[1615] / o / —

[1616] _ N=< Intermediate

[1617] Q. Z\

[1618] S — 1-164 KOH / j

[1619] HOVS-^ \

[1620] 1-54

[1621] >5° j Xv

[1622] t-N N N=< Intermediate I D* S — -i

[1623] 1-165 7Nii I

[1624] HO F

[1625] F

[1626]

[1627] Resulting

[1628] Reagent Structure

[1629] Int. No.

[1630] Intermediate

[1631] 1-166 V>-CXJJ6L 1-81

[1632] A >y_

[1633] oA-"\ / nIntermediate

[1634] '-'NS^N N=Z

[1635] 1-167 HONA N \ F

[1636] F

[1637] 1-142

[1638] Intermediate

[1639] °w rN1-168

[1640] HO H l

[1641] 1-56

[1642] F

[1643] \ ^N 1

[1644] MfF

[1645] Intermediate

[1646] 1-169

[1647] A~° vN"^

[1648] s-7>> W y 1-106 A

[1649] TX

[1650] Intermediate OH y-N 1 r 'N

[1651] — T~O |l 1-170 UN

[1652] s •N / > — <\,Ns-^ ^Z A / / 1-136

[1653]

[1654] Resulting

[1655] Reagent Structure

[1656] Int. No.

[1657] 0 / / \\ _

[1658] yr

[1659] / t-N^N N=< Intermediate

[1660] 1-171

[1661] FH0ll J 1-146 F

[1662] >y

[1663] Intermediate

[1664] 1-172 HO ||

[1665] F

[1666] F

[1667] 1-55

[1668] 0 \ —

[1669] Intermediate

[1670] / N=\ S^, r^N 1-173

[1671] ^-N

[1672] H0<1 J

[1673] I-138

[1674] x / O N

[1675] X. II / / \\ _

[1676] UNNFx W >= / Intermediate

[1677] OK / S"n F r^N LH^N1-174 A — < N— % JI I L II 1-59

[1678] o

[1679] xH

[1680] ozYl y70 VNA ^NV'N / =\ Intermediate

[1681] HCT V'A

[1682] 1-175 VNI M / =< I-60

[1683]

[1684] Resulting

[1685] Reagent Structure

[1686] Int. No.

[1687] °\ As*

[1688] ^-O7 rA / NA, N Intermediate

[1689] HO? a* [ I]

[1690] 1-176 Cr

[1691] O

[1692] 1-147

[1693] z W

[1694] oKIR* S-^ 1

[1695] \ " \ / N— Jl ^ IN Intermediate

[1696] s*^NooA A

[1697] 1-177

[1698] 1-148

[1699] i o yy_

[1700] / ''0zY7 Z Intermediate °°v

[1701] t-N N / =<70 VNA W:

[1702] LZ vJ^F1-178 HO^X *\ / r-A X7t5"-o zM * 1^M / =\ 1-58 kZ vxF

[1703] OzXi

[1704] Intermediate o y y_Nll

[1705] 1-179 HO^ ^r-A / NXK> XXN\ _ N., N N=\

[1706] T s-y XA

[1707] 1-96

[1708] Intermediate

[1709] 1-180

[1710] 1-149

[1711]

[1712] A o -o- Resulting

[1713] Reagent Structure

[1714] \O= Int. No.

[1715] ^" Z

[1716] \=N

[1717] 4- w

[1718] 1 z

[1719] 0n Intermediate

[1720] 1-181

[1721] 1-150 Yy

[1722] o / N\

[1723] A UNN / =( Intermediate

[1724] 1s IX )> — ( v\ / / ')— o \ 1-182

[1725] 1-151 z

[1726] o

[1727] \°=

[1728] r z

[1729] ° y~N ^ z- j, r C y- ^^ y5WZ

[1730] i s*r ' Intermediate L z UNR*NN=Z )= /

[1731] I AX 1-183

[1732] 0^^ 1-61

[1733] XXX

[1734] o

[1735] / =\ Intermediate o

[1736] S-J^ A ■ / 1-184 / =NUN^N^ y=y F

[1737] s-J>

[1738] 1-85 F

[1739] Intermediate o

[1740] 1-185 HO^ A'-'A AN N^, N / =< ln / F

[1741]

[1742] V O Resulting

[1743] Reagent Structure

[1744] A S°\-- r Int. No.

[1745] \ z o 9^^ <zx 5=NJJL J< ■ y ” Intermediate 0 VNALVN / r~C 1-186 HO^YA

[1746] YY I V-N^, M / =< -Z- V / ) — (\ / )— OH x / j -n n S-~! /

[1747] 1-153

[1748] \ °

[1749] o

[1750] T

[1751] \=N

[1752] 0rn v / ~ Intermediate

[1753] NVN1-187

[1754] S-Y^ \ _ / Cl

[1755] I I

[1756] 1-154 o o

[1757] ^ y°°==

[1758] 9^'ZzH H

[1759] ' \=NZ ZX Xss

[1760] o% W~

[1761] Intermediate

[1762] LNYNV^C / F1-188 Y T Y 7 iri 1 Y Yzz / ^x"ri-n 1-155

[1763] Intermediate

[1764] 1-189

[1765] \-N

[1766] J # \\ Intermediate o y~N ii ( / \\ _ °^ VA v= /

[1767] '— N N N- / 1-190 Hcr ^y-A 7= / XM3- \--N N N-7 b-V \=NF

[1768] TbJ^ / Y \=NV 1-137

[1769]

[1770] Resulting

[1771] Reagent Structure

[1772] Int. No.

[1773] z Xv

[1774] Intermediate

[1775] s* ^=n1-191

[1776] « 1

[1777] Z. - 1-108

[1778] % 0"

[1779] 0 \=N

[1780] 1 M / -N Intermediate

[1781] ■^KL"NSS;N N- /

[1782] 1T y^N 1-192

[1783] O-^y \— /

[1784] 1-87 I

[1785] o S'A ^ Z- pN ANNH ' —J \HN

[1786] \ / =\ f Intermediate

[1787] / I H NK / > — ( I0 N / — \ ’ 0 'F1-193 HCr 'Y^ \=J FUNy\ / y-=N 1-107 S-# \= /

[1788] x

[1789] I z 0 / \\ _

[1790] >=NIntermediate

[1791] HO J p* 1 H S*V-N^. N / =\

[1792] 1-194

[1793] Xrw

[1794] 1-78

[1795] 0^ F-^ —

[1796] Intermediate

[1797] O’iA V^N _ N F, _=\ I OF-W"

[1798] 1-195 HO^ YX /

[1799] V-N. _ N / =\ 1-76

[1800]

[1801] Resulting

[1802] Reagent Structure

[1803] Int. No.

[1804] Intermediate VN 7

[1805] 0K O^“F° U FF1-196 JL \= / F HO _ / VN. _ N f=\

[1806] 1-64 XzO

[1807] k k /

[1808] O X F

[1809] Intermediate

[1810] HO J 1D. ||

[1811] 1-197 \, AR

[1812] O

[1813] 1-88 F^F

[1814] X H -< F A * Intermediate

[1815] ° / S*VNR^N O\

[1816] 1-198H0> >•

[1817] / 'A<rXY 1-89 F^F

[1818] oW X Intermediate XN° \X) -?vsiN1-199 HO vA \ _ /

[1819] V-N. _ N / =\ 1-100 XZON

[1820] . Xkzx

[1821] 0O,N NN /

[1822] — N Intermediate

[1823] Ox X / ^NXN\ v / 1-2000\X) —

[1824] )=N ' O / NHO VA _ /

[1825] / n\ V-N. _ N / =\

[1826] 1-103 TzO

[1827]

[1828] / \ 00— Resulting

[1829] Rea / O og. ent Structure

[1830] VO- Int. No.

[1831] w- -A ♦-z

[1832] 0'*zS ' / ^x

[1833] JL -, 4- w V A

[1834] c ) VA 1 z Z-N Intermediate 0 )=N V-N^N^ / ==\

[1835] 1-201

[1836] sl# W^H0^VAK

[1837] c\ / z^NxHV-N,^N / = /

[1838] \ #—NH I-159

[1839] . >=N

[1840] >=N c An >n

[1841] VNYNV-O Intermediate N (\ A HO^YA JNs ' J M 1-202

[1842] F

[1843] I-82 F

[1844] A

[1845] ^0 / \ —NIntermediate

[1846] A °Hy - 1-203

[1847] s—

[1848] F

[1849] s< / M

[1850] 1-57 F

[1851] x /

[1852] X F— (F

[1853] F

[1854] J >N

[1855] \X) — Intermediate

[1856] J0H" A V- NNyN, { / " / 7.

[1857] = ~N = 1-2040r

[1858] s7 Ln

[1859] ~W -N C > N^~

[1860] X-N

[1861] 1-143 s^ V_?N

[1862] \- M Intermediate °H x) —

[1863] J- / , V >=N 1-205

[1864] S< N N / =\Ns-~?

[1865] F

[1866]

[1867] Resulting

[1868] Reagent Structure

[1869] Int. No.

[1870] / O^ ^r- \=N Intermediate

[1871] / =< 9 >NWs 1 ~A / >—< V\ J / ,'N1-206 Hcr X-A V=N / =< 1-144 s-A VA \-N f

[1872] J / FIntermediate

[1873] 1-207

[1874] F

[1875] 1-83

[1876] I I I

[1877] o o o

[1878] \ \°°==

[1879] / VO )

[1880] ° \ J Fo==

[1881] ^^ z z-- Intermediate * 1

[1882] VN T^JN-H 1-208 ( ( Z Zss..

[1883] z

[1884] 1-84 n A Z. Cl / Xz’i VN,F

[1885] / ° CM

[1886] TXF>< Intermediate

[1887] 1-209

[1888] 1-75

[1889] Cl 1R*c1

[1890] \ X° UH " lYf n Intermediate 0 1R* s^, 1

[1891] ANA- 1-210

[1892] 1-145

[1893] Intermediate

[1894] A o^CAN~< JJOA TJ 1-211

[1895] o ^sr ’

[1896]

[1897] Resulting

[1898] Reagent Structure

[1899] Int. No.

[1900] 1-157

[1901] A,,

[1902] Intermediate I

[1903] o HO lR. II

[1904] 1-212

[1905] O

[1906] 1-158

[1907] \~N F

[1908] 0 # \\_ /

[1909] ( / N FIntermediate OH _< / FV-N^N / =\

[1910] TJH^N1-213 O^YA >=N F / =\

[1911] I-77

[1912] Xy- (

[1913] V-N^, N / =\

[1914] Intermediate OH

[1915] HN 1-214 V— N N / ==\ >=°

[1916] q^ TJ -JH } y J H2N

[1917] I-62

[1918] A Xjy- ( y ''X"\ z7

[1919] L-N^N / N=\

[1920] OH

[1921] X a— / 7v / “? N Intermediate

[1922] HN 1-215 O^^ Y-A f7>=° V-N^N / N=\ q^

[1923] X a—Z7v y—? N H2N

[1924] I-66

[1925]

[1926]

[1927] Resulting

[1928] Reagent Structure

[1929] Int. No.

[1930] K i GF

[1931] N^F Intermediate

[1932] 1-216H°>„ > „N

[1933] O

[1934] 1-99

[1935] 1 \=N

[1936] Intermediate

[1937] 1-217

[1938] 1-67

[1939] o i.

[1940] yo- ^ Z

[1941] 0# \\ —

[1942] \=N

[1943] 1 z

[1944] 0F NIntermediate

[1945] A \ / <\

[1946] V-N^N / =\ HO y-N

[1947] 1-218

[1948] v / >-< / r^

[1949] S-#N

[1950] QYv

[1951] Gz\.

[1952] 1-79 \\ \ \ ' z

[1953]

[1954] Synthesis of Intermediate 1-219 l-(4-(2-chloropyridin-4-yl)thiazol-2-yl)azetidine-3- carboxylic acid

[1955] Cl

[1956] TFA DCM

[1957]

[1958]

[0285] TFA (5.5 mL, 1.49 g / mL, 69.59 mmol) was added to a solution of 1-11 (1.06 g, 2.32 mmol) in DCM (12 mL) and the solution was stirred RT overnight. The solvent was removed in vacuo. The residue was dissolved in MeOH and concentrated in vacuo (x3) to afford 1-219 considering theoretical yield.

[1959]

[0286] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.Resultin

[1960] Reagent g Int. Structure

[1961] No.

[1962] Interme Cl

[1963] diate I- HO

[1964] 220

[1965] V \. N— ( / T

[1966] 1-19

[1967] 0

[1968] C / ClO

[1969] Interme

[1970] \ / ==\ Hcr ^r-A /

[1971] s- / V^Z diate I- V-N^N / =<Cl1-1 6 221 S-# V2Z

[1972] O

[1973] c ZVABRInterme 0

[1974] diate I- HO^VA,

[1975] S-27BR

[1976] 222 / =\

[1977] 1-1 7 s-# V^Z

[1978]

[1979] Synthesis of Intermediate 1-223 l-(4-(4-Cyano-3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol- 2-yl) azetidine-3-carboxylic acid.

[1980]

[1981]

[0287] Lithium hydroxide monohydrate (20 mg, 0.48 mmol, 2 eq) was added to flask containing a stirred solution of 1-135 (100 mg, 0.24 mmol, 1 eq) in tetrahydrofuran (2 mL) and H2O (0.5 mL). The mixture was stirred for 16 h at 50 °C. At room temperature, the mixture was acidified with 1M aqueous KHSO4until pH ~ 6, and concentrated dry to ayellow oil. The oil was subjected to silica gel chromatography (0:100 to 5:95, MeOH / DCM) to yield 1-223 (86 mg, 91%) as a yellow solid.

[1982]

[0288] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. Methanol can be added as a solvent to THF and H2O.

[1983] p i Resulting Int.

[1984] Reagent Structure No.

[1985] \o==

[1986] o

[1987] I

[1988] \ RS ki —

[1989] uRS VN _ NK / \ Intermediate o 1RS / s%

[1990] 4 JjLN12 IL S-_# ^-N 1-224HO> RsS / N

[1991] ^i\r

[1992] 1-139

[1993] \-N

[1994] o f - Intermediate

[1995] °

[1996] 1-225

[1997] S-~# \= / II H tHO

[1998] 1-134

[1999] Intermediate

[2000] rQ v 1-226

[2001] 1-101

[2002] L VA

[2003] \ "

[2004] V\ — \ J Intermediate

[2005] 0\ — 1-227 HO^ V-A }

[2006] Cl N

[2007] 1-63 Cl

[2008] zZ N S—, ri^N \ S-a LJk- Intermediate

[2009] V HkA °vXN1 1-228

[2010] II0L I

[2011] 0

[2012]

[2013] Resulting Int.

[2014] Reagent Structure

[2015] No.

[2016] 1-10

[2017] i A

[2018] / \RS S-n f Intermediate

[2019] o. AN A HO IRS J.

[2020] N — [1

[2021] 1-229 $ RS^7f

[2022] 1-152

[2023] Intermediate

[2024] / -O y T o / v A

[2025] 1-230 HONy yv\

[2026] 1-98 X^N

[2027] o 1RSJL

[2028] —Q RS ^ Intermediate o 1RSL

[2029] 1-231 HOZRA

[2030] F

[2031] 1-141 F

[2032]

[2033] Synthesis of Intermediate 1-232 tert-butyl ((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl) carbamate

[2034] 1 -Methylimidazole

[2035]

[2036] DCM

[2037]

[0289]

[2038]

[2039] solution consisting of difluoromethanesulfonyl chloride [1512-30-7 ] (1.64 mL, 17.50 mmol) and dry DCM (10 mL) was added over 5-10 min to a 100 mL flask containing a solution consisting of tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate [1270019-92-5] (2.50 g, 11.67 mmol), 1 -Methylimidazole [616-47-7] (1.41 mL, 17.50 mmol) and dry DCM (20 mL) at 0°C and under nitrogen atmosphere. The reaction was allowed to stir at room temperature gradually for 2h. The reaction was diluted with aq. std. NaHCO₃ (10 mL) andextracted with DCM (3x 20mL). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (40g, 40-60um irregular, 0-100% EtOAc / heptane). The desired fractions >° ° were concentrated in vacuo to obtain 1-232 (2.0 g, 50%) as a white solid. rz

[0290] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.,.p

[2040] Reagent Resulting Int. No. Stcr -u°cture

[2041] O

[2042] H< / N^ Y''N / H ° F

[2043] A '? H

[2044] F Intermediate 1-233f / -n''NXY tert-butyl ((3R,5S)-5- F^F (difluorom ethyl)piperi din-3 - yl)carbamate [2306254-30-6]

[2045] v H

[2046] X1F o^

[2047] ° I P H F F Intermediate 1-234

[2048] f / n"NYV tert-butyl (R)-(5,5- ” Q k J °

[2049] z — difluoropiperi din-3 -yl)carbamate F F [2089320-98-7] O H /

[2050] HNX^II'N'y'°7\

[2051] Intermediate 1-235

[2052] tert-butyl (R)-piperi din-3 - ylcarbamate [309956-78-3]

[2053] o Intermediate 1-236

[2054] tert-butyl (R)-methyl(piperidin- 3-yl)carbamate [309962-67-2]

[2055]

[2056] Reagent Resulting Int. No. Structure

[2057] k J 0z

[2058] Intermediate 1-237

[2059] F

[2060] tert-butyl ((3R,5R)-5- fluoropiperi din-3 -yl)carbamate

[2061] [1363378-07-7]

[2062] H

[2063] F

[2064] ° u A ' / ° H

[2065] H Intermediate 1-238

[2066] tert-butyl ((3R,5S)-5-0fluoropiperi din-3 -yl)carbamate F

[2067] [1363378-08-8]

[2068]

[2069] Synthesis of Intermediate 1-239 (3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-amine hydrochloride c / K

[2070] HCI / dioxane

[2071] ZI

[2072] dioxane

[2073]

[2074] O

[0291] To a solution of compound 1-232 (23.2 g, 70.7 mmol, 1.00 eq) in dioxane (90.0 mL) was added HCI / dioxane (2 M, 141 mL, 4.00 eq) at 25 °C. The white suspension mixture was stirred at 25°C for 3 hrs. LC-MS showed compound 1-232 was consumed completely and one main peak with desired m / z was detected. The reaction was concentrated in vacuo then DCM (50.0 ml) was added and re-concentrated on the rotovap. This process was repeated 2 additional times to give the desired product. The crude product was used to next step without further purification. Intermediate 1-239 (18.5 g, crude, HC1) was obtained as a white solid.Flow Analytical mobile Run column Gradient

[2075] Result phase time Col T Daicel

[2076] 10%-50% B in 6

[2077] Retention Chiralpak® A:CO2

[2078] min, hold 3.5 2.5 10.0 time: IG3 column B:

[2079] min, to 20% B in

[2080] 2.17 min; (3.0 pm, 4.6 MeOH+O.2

[2081] O.lmin and hold 40 130 100% ee mm x 150 % iPrNH₂

[2082] 0.4min

[2083]

[2084] mm)

[2085]

[0292] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[2086] Resulting Int.

[2087] Reagent Structure

[2088] No.

[2089] F

[2090] A 'P H F

[2091] f / -n"NvY

[2092] 0JUP IntermediateF / 'N^"NH2

[2093] 1-240 HCI F^F

[2094] 1-233 F^F

[2095] F I P H F

[2096] Intermediate

[2097] F / Q "lY A> P

[2098] 1-241

[2099] F FF

[2100] 1-234 F F

[2101] F

[2102] A 'P H F

[2103] FIntermediate

[2104] / HNY oV 1-242 A> P

[2105] F

[2106] 1-235 HCI

[2107] F I P H F

[2108] Intermediate

[2109] FA'P

[2110] / f k YJ A o11-243F / 'O HCI F

[2111] F

[2112] 1-237

[2113]

[2114] Ab t Resulting Int.

[2115] Rea " H / Ckg 00.ent Structure

[2116] C / K No.

[2117] O ’"

[2118] ZI

[2119] o Intermediate

[2120] 1-244

[2121] F

[2122] A -P I

[2123] F

[2124] F / 'O'Nv 0 V Intermediate

[2125] 1A 'p H

[2126] F

[2127] 1-245 6ZY J

[2128] 1-236

[2129]

[2130] ex

[2131] Synthesis of Intermediate 1-246 (3R,5S)-l-((difluoromethyl-d)sulfonyl)-5-methylpiperidin-3-amine

[2132] z

[2133] I I

[2134] Mo

[2135]

[2136]

[0293] Ni Raney [7440-02-0] (4.434 mg, 0.0756 mmol) was added to a stirred solution of 1-239 (200 mg, 0.756 mmol) and Deuterium oxide [7789-20-0] (3 mL, 1.105 g / mL, 165.522 mmol) under N2 atmosphere. The mixture was stirred at 80°C for 16h. The solvent was removed in vacuo to give 1-246 (180 mg, 90%).

[2137] Synthesis of Intermediate 1-247 rac-(2R,3S)-l-benzhydryl-2-(methoxymethyl)azetidin-3-ol

[2138]

[2139]

[0294] Sodium borohydride (332 mg, 8.78 mmol, 2 eq) was added in small portions to a stirred white suspension of l-benzhydryl-2-(methoxymethyl)azeti din-3 -one (prepared according to A. Salgado et al. Tetrahedron, 2002, 5S, 2763-2775) (1.31 g, 4.44 mmol, 1 eq) in EtOH (240 mL) at 0 °C under nitrogen atmosphere. The resulting homogeneous reaction mixture was allowed to come to room temperature and stirred for 1 h. H₂O (400 mL) was added and stirring maintained for 1 h. Organics were extracted with diethyl ether (3 x 300 mL), dried over MgSO4, filtered, and concentrated to a yellow oil. The oil was subjected to silica gel chromatography (0:100 to 25:75, EtOAc / heptane) to give 1-247 (655 mg, 51%). nthesis of Intermediate 1-248 rac-(2R,3S)-l-benzhydryl-2-(methoxymethyl)azetidin-3-yl methanesulfonate

[2140]

[2141]

[0295] To an ice-cold stirred solution of 1-247 (642 mg, 2.27 mmol, 1 eq) and tri ethylamine (0.475 mL, 3.41 mmol, 1.5 eq) in dry DCM (25 mL), was added methanesulfonyl chloride [124-63-0] (0.295 mL, 3.81 mmol, 1.7 eq). Cooling was removed and reaction continued for 1 h. DCM (150 mL) was added, and the solution was washed with H2O (2 x 150 mL). The organic layer was dried over MgSO₄, filtered, and concentrated to the crude white solid 1-248 (846 mg, 99%).

[2142] Synthesis of Intermediate 1-249 rac-(2R,3R)-l-benzhydryl-2-(methoxymethyl)azetidine-3-carbonitrile

[2143] NaCN

[2144] DMF / H₂O

[2145]

[2146]

[0296] Sodium cyanide (287 mg, 5.86 mmol, 2.5 eq) in H₂O (6 mL) was added dropwise to a flask containing a stirred solution of 1-248 (845 mg, 2.34 mmol, 1 eq) in dimethylformamide (15 mL) at room temperature under nitrogen atmosphere. The reaction was stirred at 65 °C for 20 h. The mixture was diluted with H₂O (50 mL) and extracted with diethyl ether (3 x 75 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated to a yellow oil. The oil was subjected to silica gel chromatography (0: 100 to 20:80, EtOAc / heptane) to give 1-249 (432 mg, 63%) as yellow oil.Synthesis of Intermediate 1-250 rac-(2R,3R)-l-benzhydryl-2-(methoxymethyl)azetidine-3-carboxylic acid

[2147]

[2148]

[0297] In a round bottomed flask, 3.5M aqueous NaOH (7.0 mL, 24.5 mmol, 17 eq) was added to solution of 1-249 (428 mg, 1.46 mmol, 1 eq) in EtOH (7 mL) at room temperature. The colorless solution was stirred at 90 °C for 3 h and allowed to cool to room temperature. The mixture was diluted with H₂O (30 mL) and DCM (50 mL). Then, 1M aqueous KHSO4was added dropwise within 10 minutes with vigorous stirring till the pH reached the value of 2-3. The aqueous phase was extracted with DCM (3 x 20 mL). The extracts were combined, dried over MgSO4, filtered, and concentrated to give 1-250 (400 mg, 86%) as a white solid.

[2149] Synthesis of Intermediate 1-251 rac-(2R,3R)-l-benzhydryl-N-((3R,5S)-l- ((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-2-(methoxymethyl)azetidine-3-

[2150]

[2151]

[0298] In a round bottom flask, 50% propylphosphonic anhydride solution in EtOAc [68957-94-8] (1.0 mL, 1.68 mmol, 1.31 eq) was added to a stirred solution of 1-250 (400 mg, 1.29 mmol, 1 eq), 1-239 (400 mg, 1.29 mmol, 1 eq) and N, N-diisopropylethylamine (1.0 mL, 6.05 mmol, 4.7 eq) in dimethylformamide (10 mL) at room temperature. The reaction was continued for 3 h and then quenched with 1M aqueous Na₂CO₃ (75 mL). The organics were extracted with EtOAc (3 x 50 mL), dried over MgSO₄, filtered, and concentrated to give an oil. The crude was subjected to silica gel chromatography (0:100 to 35:65, EtOAc / heptane) to give 1-251 (538 mg, 76%) as a white solid.

[2152]

[0299] Additional analogues were synthesized in an analogous manner starting from I-239 using the reagents as appropriate. The base can vary between DIPEA and TEA, and the solvent can vary between DCM and DMF.Resulting

[2153] Reagent Structure

[2154] Int. No.

[2155] HO. O F

[2156] ovo- O IntermediaF>

[2157] O 'N^o- l-(tert- te 1-252

[2158] ( )" NH. p

[2159] \

[2160] butoxycarbonyl)a zetidine-3- '' IZ ovo - carboxylic acid [1 42253-55-2] ) X „ o —

[2161] HO F. O <

[2162] J _ \I \ I

[2163] / O U- ovo—

[2164] Intermedia

[2165] 1 -(tert-butoxycarl ionyl)-3- te 1-253

[2166] fluoroazetidine-3- carboxylic

[2167] acid [1126650-67 -6]

[2168]

[2169] Synthesis of Intermediate 1-254 rac-(2S,3S)-N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-2-(methoxymethyl)azetidine-3-carboxamide

[2170]

[2171]

[0300] 1-251 (530 mg, 1.02 mmol, 1 eq) and trifluoroacetic acid (0.17 mL, 2.22 mmol, 2.2 eq) were combined in MeOH (15 mL) in flask, under nitrogen atmosphere. The reaction was charged with 20% Pd(OH)2 [12135-22-7] (170 mg, 0.24 mmol, 0.24 eq) and then stirred at 30 °C for 16 h under atmospheric pressure of hydrogen. The suspension was filtered through a pad of Celite that was further rinsed with MeOH (2 x 10 mL), The filtrate was concentrated to afford 1-254 (495 mg, 99%) as a yellow solid.

[2172] Synthesis of Intermediate 1-255 l-Benzhydryl-3-hydroxyazetidine-3-carbonitrile

[2173]

[2174]

[0301] Potassium cyanide (2.2 g, 33.7 mmol, 1 eq) was added to a flask containing a stirred solution of l-(diphenylmethyl)azeti din-3 -one [40320-60-3] (8.0 g, 33.7 mmol, 1 eq), NaHCO3(5.7 g, 67.4 mmol, 2 eq), H2O (150 mL) and tetrahydrofuran (150 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h, and then diluted with EtOAc (200 mL). The aqueous layer was separated and further extracted and with EtOAc (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to a colorless oil. The oil was subjected to silica gel column chromatography (0:100 to 100:0, EtOAc / heptane) to give 1-255 (3.84 g, 43%) as a clear oil.

[2175] Synthesis of Intermediate 1-256 l-Benzhydryl-3-hydroxyazetidine-3-carboxylic acid

[2176]

[2177]

[0302] A stirred mixture of 1-255 (3.84 g, 12.5 mmol, 1 eq), 30% aqueous H2SO4 (50 mL, 153 mmol, 12 eq), and 1,4-dioxane (50 mL) was heated at 90 °C for 2 h. The reaction was allowed to cool to room temperature and most of the organic solvent remove in vacuo. The solution was neutralized carefully with 12M aqueous NaOH to pH 7 and filtered. The filtrate was extracted with CHCh / iso-propanol (7 / 3, v / v, 4 x 25 mL). The combined extracts were concentrated in vacuo to give the crude 1-256 (3.84 g, 90%) as an orange solid.

[2178] Synthesis of Intermediate 1-257 1-Benzhydryl-N-((3R, 5S)-l-((difluoromethyl)sulfonyl)-5- methylpiperidin-3-yl)-3-hydroxyazetidine-3-carboxamide

[2179] F

[2180]

[2181]

[0303] 1-239 (2.06 g, 8.48 mmol, 1.2 eq) was added to a flask containing a stirred solution of 1-256 (2.0 g, 7.06 mmol, 1 eq), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride [25952-53-8] (2.20 g, 14.2 mmol, 2 eq), 1 -hydroxybenzotriazole [123333-53-9] (1.90 g, 14.1 mmol), and N, N-diisopropylethylamine (4.6 mL, 27.8 mmol, 3.9 eq) in dimethylformamide (90 mL). The reaction was continued for 16 h. Brine (20 mL) and EtOAc (30 mL) were added. The organic layer was separated, washed with brine (3 x 20 mL) and concentrated in vacuo to an oil. The residue was subjected to silica gel columnchromatography (0:100 to 100:0, EtOAc / Heptane) to give 1-257 (1.70 g, 48%) as a white solid.

[2182] Synthesis of Intermediate 1-258 N-((3R, 5S)-l-((Difluoromethyl)sulfonyl)-5-niethylpiperidin-3-yl)-3-hydroxyaz.etidine-3-carboxamide trifluoroacetate

[2183] H2(1 atm) Pd(OH)2TFA

[2184] MeOH

[2185]

[2186]

[0304] To a solution of 1-257 (1.70 g, 3.44 mmol, 1 eq) and trifluoroacetic acid (0.57 mL, 7.44 mmol, 2.1 eq) in MeOH (45 mL), was added 20% Pd(OH)2[12135-22-7] (604 mg, 0.86 mmol, 0.25 eq) under nitrogen atmosphere. The resulting suspension was placed under hydrogen atmosphere and stirred for 2 h. The mixture was filtered through a pad of Celite that further rinsed with EtOH (3 x 50 mL). The filtrate was concentrated to a grey oil. Triturating in a mixture diisopropyl ether / MeCN (9 / 1, v / v, 100 mL) led to a suspension. The solid was filtered through a sintered funnel and dried under high vacuum to give 1-258 (1.65 mg, 97%) as a grey solid.

[2187] Synthesis of Intermediate 1-259 N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl) azetidine-3-carboxamide

[2188] TFA DCM

[2189]

[2190]

[0305] In a round bottom flask equipped with a magnetic stir bar, 1-252 (601 mg, 1.46 mmol) was dissolved in DCM (10.3 mL) and TFA (2.2 mL, 28.73 mmol) was added. The reaction mixture was stirred at rt for 3h. After 3h, the reaction mixture was diluted with MeOH and concentrated under reduced pressure to yield 1-259 (0.62 g, yield 99%) as a sticky oil.

[2191]

[0306] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[0307]

[2192] Resulting Int.

[2193] Reagent Structure

[2194] No.

[2195] F

[2196] F>

[2197] O N

[2198] Intermediate I- ( >'" NHR O0N— \

[2199] V / XH 1 260 / >'" NH f

[2200] ' 0 o \ _ / P\ NH

[2201] O

[2202] 1-253

[2203]

[2204] Synthesis of Intermediate 1-261 l-(4-bromothiazol-2-yl)-N-((3R,5S)-l- ((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)azetidine-3-carboxamide

[2205]

[2206]

[0308] In a pressure vial equipped with a magnetic stir bar, crude 1-259 (310.11 mg, 1 mmol) and 2,4-dibromothiazole (242 mg, 1 mmol) were dissolved in 1,4-di oxane (3 mL) and N, N-diisopropylethylamine [7087-68-5] (700 pL, 0.742 g / mL, 4.019 mmol) was added. The reaction mixture was then stirred at 85°C overnight. The reaction mixture was cooled down to rt and quenched with NaHCO3(aq) / brine and EtOAc was added. The layers were separated and the aqueous phase was extracted with EtOAc (2x). Combined organic layers were then dried over MgSO4, filtered and concentrated under reduced pressure to give a crude oil. The residue was then purified by column chromatography over silica gel (biotage on 25 g Sfar column, 100% n-heptane to 30 / 70 n-heptane / EtOAc). The desired fractions were combined and concentrated under reduced pressure to give 1-261 (175 mg, yield 37%) as a white solid.

[2207]

[0309] Additional analogues were synthesized in an analogous manner starting from 2,4-dibromothiazole using the reagents as appropriate. The solvent can vary between 1,4-di oxane and MeCN.

[0310]

[2208] Resulting

[2209] Reagent Structure

[2210] Int. No.

[2211] ->Sx / O

[2212] IntermediateF-X <° I

[2213] 'A

[2214] 1-262

[2215] 0 ° I RS

[2216] w > / - O NBr1-254 / Ro

[2217]

[2218] Synthesis of Intermediate 1-263 l-(4-Bromothiazol-2-yl)-N-((3R, 5S)-1- ((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-3-fluoroazetidine-3-carboxamide

[2219]

[2220] 1,4-dioxane

[2221]

[0311] In a sealed reactor, XantPhos Pd G3 [1445085-97-1] (5 mg, 0.005 mmol, 0.01 eq) was added to a nitrogen-sparged suspension of 1-260 (221 mg, 0.50 mmol, 1.1 eq), 2,4- dibromothiazole [4175-77-3] (110 mg, 0.45 mmol, 1 eq) and CS2CO3 (443 mg, 1.36 mmol, 3 eq) in 1,4-di oxane (7 mL). The mixture was stirred for 16 h at 100 °C and allowed to cool to room temperature. H2O (40 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to a dark oil. The oil was subjected to silica gel chromatography (0:100 to 100:0, EtOAc / heptane) to afford 1-263 (100 mg, 44%) as a yellow solid.

[2222]

[0312] Additional analogues were synthesized in an analogous manner starting from 2,4- dibromothiazole using the reagents as appropriate.

[0313]

[2223] Resulting Int.

[2224] Reagent Structure

[2225] No.

[2226] F

[2227] F~V OHO. F

[2228] °X / Y" N VH CNHIntermediate

[2229] 1-264 ° / NO -NHR / X A ^Br

[2230] / ) 06 N N

[2231] / °Z

[2232] 1-258

[2233]

[2234] Synthesis of Intermediate 1-265 l-(4-(3-bromo-2-fluorophenyl)thiazol-2-yl)-N-((3R,5S)-l- ((difluorometbyl)sulfonyl)-5-metbylpiperidin-3-yl)azetidine-3-carboxamide

[2235] F

[2236] XantPhos Pd G4K2CO31,4-dioxane, water

[2237]

[2238]

[0314] In a vial equipped with a magnetic stir bar, 1-261 (100 mg, 0.21 mmol), 2-(3- bromo-2-fhiorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane [1400220-51-0] (50 mg, 0.17 mmol), XantPhos Pd G4 [1621274-19-8] (22 mg, 0.023 mmol) and Potassium carbonate (60 mg, 0.43 mmol) were placed under aN2 atm and 1,4-dioxane (2 mL) and water, distilled

[2239] (0.32 mL) were added. The reaction mixture was then stirred at 80°C for 1 h. The reaction mixture was cooled down to RT, poured out in water, extracted with EtOAc. The organic layer was washed with Brine, dried on MgSO4, filtered and evaporated. The residue was purified on a column with silicagel, eluent EtOAc in Heptane from 0 to 100%. The pure fractions were evaporated, yielding 1-265 (40 mg, yield 33%) as a white foam.

[2240]

[0315] Additional analogues were synthesized in an analogous manner starting from I- 261 using the reagents as appropriate:

[0316]

[2241] Resulting Int.

[2242] Reagent Structure

[2243] No.

[2244] Cl

[2245] F HO.BX)N IntermediateF4, O 91OH 1-266O< S'N

[2246] ( > " NH *

[2247] 5-chloropyridine-3-boronic acid T [872041-85-5]

[2248]

[2249] Synthesis of Intermediate 1-267 l-(4-(3-bromophenyl)thiazol-2-yl)-N-((3R,5S)-l- ((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)azetidine-3-carboxamide

[2250] F

[2251]

[2252] Br

[0317] In a 1000 mL round-bottom flask, 1-propanephosphonic anhydride, 50 % in EtOAc [68957-94-8] (26.25 mL, 88.19 mmol) was added to a solution of 1-222 (9.9 g, 29.18 mmol), 1-239 (8.12 g, 30.68 mmol) and TEA (20.42 mL, 146.88 mmol) in DCM (350 mL). The reaction was stirred at rt for 2 h. LC / MS showed complete reaction.

[2253]

[0318] The reaction mixture was poured out in a solution of NaHCO3sat. (-300 mL) and DCM (500 mL). The water phase was extracted with DCM (3 x 200 mL). The combined organic layers were washed with water and then dried on MgSO4. The solvents were evaporated. The residue was crystalized from MeCN to yield 1-267 (12.31 g, yield 77%) as a white solid.

[2254]

[0319] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.[3 £O2 IA0]

[2255] V O oo- Resulting

[2256] Reagent A Reagent B Structure

[2257] r -z Int. No.

[2258] Cl

[2259] 1 z F

[2260] HO. JU?

[2261] JFAQ"™2Intermedi ( \-NH.

[2262] o S-^ L v

[2263] ^ > Q-Zo U 1

[2264] ate 1-268

[2265] ■n F— <0T V 1-219 y VN 1-239

[2266] F F JUP IntermediF^°

[2267] FO^NQ"NH2ate 1-269 O'.™ / X / S V y- C ON^ 1

[2268] N^x^x -CI o 1-239 F o

[2269] F HCT > — \ZC|Intermedi

[2270] V--N., N / =\ JUP

[2271] F6' 'Q"2ate 1-270 X -n

[2272] 1-221 Q'°

[2273] 1-242 z z

[2274] o F X X11z z HOUA ci JUP Intermedi ^^ zw zw

[2275] V-'N^. N / =\

[2276] F6' 'Q"NH2

[2277] ate 1-271

[2278] 1-221 F F o o 1-241

[2279] o F

[2280] HO^ A'-'A A.° F

[2281] P1F— ( Cl L-N N / =\

[2282] FAQ ''™2Intermedi

[2283] ate 1-272 ' n.„ O

[2284] 1-221

[2285] '' 0 s-^

[2286] 1-239

[2287]

[2288] Resulting

[2289] Reagent A Reagent B Structure

[2290] Int. No.

[2291] Cl

[2292] F A P Intermedi

[2293] F^

[2294] H0\ RSARSANV^0N°

[2295] Fo- 'Q2ate 1-273 ( \"NHIRS S

[2296] o

[2297] ORS

[2298] 1-29 1-242

[2299] Cl

[2300] F JUP

[2301] Intermedi

[2302] F6^NQ"NH2Fi°

[2303] H0\ RSARSANV^ °

[2304] t 1-N-A I

[2305] a e 274

[2306] oF

[2307] F^F F~A ORS XZ

[2308] F

[2309] 1-29

[2310] 1-240

[2311] Cl

[2312] F HO r T JUP Intermedi T o

[2313] # — \ 'N— « HFd's'Q"NH2

[2314] ate 1-275 ' o

[2315] 1-220 ex z

[2316] 1-239

[2317] p

[2318]

[2319] z Synthesis of Intermediate 1-276 rac-(2R,3S)-N-((3R,5S)-l-((difluoromethyl)sulf^on zwyl)-5-methylpiperidin-3-yl)-2-methyl-l-(4-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)azetidine-3-carboxamide o

[2320] o

[2321]

[2322]

[0321] 1-273 (387 mg, 0.746 mmol) was dissolved in 1,4-dioxane [123-91-1] (6.359 mL, 1.033 g / mL, 74.561 mmol) and potassium phosphate tribasic [7778-53-2] (474.806 mg, 2.237 mmol), bis(pinacolato)diboron [73183-34-3] (473.356 mg, 1.864 mmol) and XPhos Pd G4

[2323] [1599466-81-5] (64.159 mg, 0.0746 mmol) were added. The solution was stirred to 80 °C during Ih. The solution was filtered over dicalite and washed with EtOAc and evaporated.Then the crude was purified by means of column chromatography using heptane / EtOAc: 100 / 0 to 0 / 100 gradient elution to give 1-276 (530 mg, yield 91%).

[2324]

[0322] Additional analogues were synthesized in an analogous manner using the reagents as appropriate. The catalyst can vary between XPhos Pd G4 [159946p6-81- ■5] and cataCXium Pd G4 [2230788-67-5], and the base can vary between potass 4ium phosphate ^ z

[2325] tribasic, potassium acetate and potassium 2-ethylhexanoate.

[2326] )o=

[2327] Z I

[2328] Resulting

[2329] Reagent Structure

[2330] Int. No. P o.

[2331] U _O "

[2332] F

[2333] Fp

[2334] Intermediat,FB F— / 1 V°

[2335] e 1-277

[2336] ° V N

[2337] 1-270

[2338] Wx F

[2339] ° Q.

[2340] ZI

[2341] Z o=

[2342] Intermediat ^Z

[2343] e 1-278 h z

[2344] y

[2345] F

[2346] Xi

[2347] 1-269 °z'V | / \ o^

[2348] F^ O \|°

[2349] - A. Intermediat

[2350] irj e 1-279

[2351] 1-272

[2352]

[2353] Synthesis of Intermediate 1-2805-chloro-7-methyl-2,3-dihydrobenzofuran

[2354] Cl

[2355] dimethyl carbonate,

[2356] Pd(OAc), KOAc

[2357]

[2358] I

[2359]

[0323] A vial was charged with Pd(OAc)2 (21 mg, 0.0935 mmol), KOAc (366 mg, 3.729 mmol) Bu₄NBr (1.5 g, 4.56 mmol), 4-chloro-2-iodoanisole [52807-27-9] (250 mg, 0.931 mmol), and NMP (7 mL). The vial was purged with nitrogen for 5 minutes, dimethyl carbonate [616-38-6] (1 mL, 1.07 g / mL, 11.878 mmol) was added. The reaction mixture was purged with nitrogen for 5 minutes again. Then the mixture was stirred at 105 °C for 18 hours. After being cooling to room temperature, the reaction mixture was diluted with ethyl acetate (15 mL), washed with water (3 times), dried over MgSO4, and concentrated in vacuo. The residue was purified by normal phase chromatography (24 g cartridge, 0-20% ethyl acetate in heptane) to afford 1-280 (157 mg, yield assumed quantitative) as a white colorless liquid (almost a solid).

[2360] Synthesis of Intermediate 1-281 rac-(2R,3S)-N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(6-fluoro-2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-2-methylazetidine-3-carboxamide

[2361]

[2362] DMF

[0324] In a round bottom flask, 50% propylphosphonic anhydride in EtOAc [68957-94-8] (0.344 mL, 0.58 mmol, 1.25 eq) was added to a solution of 1-73 (184 mg, 0.46 mmol, 1 eq), 1-239 (135 mg, 0.51 mmol, 1.1 eq) and N, N-diisopropylethylamine (0.306 mL, 1.85 mmol, 3 eq) in dimethylformamide (7 mL) at room temperature. The mixture was stirred for 2.5 h. EtOAc (20 mL) and 1M aqueous Na2CO3(15 mL) were added. The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude was purified by chromatography over silica gel (0:100 to 100:0, EtOAc / heptane) to yield 1-281 as a white solid (110 mg, 37%).Synthesis of Intermediate 1-282 methyl 2-(4-((bis(benzyloxy)phosphoryl)oxy)phenyl)acetate

[2363]

[2364]

[0325] To a solution of methyl 4-hydroxyphenylacetate [14199-15-6] (1.89 g, 11.37 mmol) in acetonitrile (90 mL) at -10 °C was added CCU (5.5 mL, 57.0 mmol), DIPEA (4.16 mL, 23.9 mmol), and DMAP (139 mg, 1.14 mmol).

[2365]

[0326] The mixture was stirred for 10 min before dibenzyl phosphite (3.7 mL, 16.5 mmol) was slowly added to keep the temperature below -10 °C. The resulting mixture was stirred at -10 °C for 1 h, quenched with aqueous K2HPO4(0.5 M, 20 mL) in acetonitrile (60 mL), allowed to warm to rt, and extracted with ethyl acetate (3 × 150 mL). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The residue was subjected to chromatography (120 g silica gel, 30-50% ethyl acetate / hexanes) to give the title compound 1-282 (4.05 g, yield 83%) as a colorless oil.

[2366] Synthesis of Intermediate 1-2832-(4-((bis(benzyloxy)phosphoryl)oxy)phenyl)acetic acid

[2367]

[2368]

[0327] To a solution of 1-282 (4 g, 9.38 mmol) in THF (38 mL) and MeOH (12 mL) at 0 °C was added a solution of LiOH.H2O (590.73 mg, 14.08 mmol) in water (12 mL) over 15 min. The mixture was stirred at 0 °C for 2 h before it was acidified with 1 N HC1 to pH 2. The mixture was concentrated under vacuum and then extracted with ethyl acetate (3 x 30 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. The residue was purified on a column with silicagel, eluent MeOH in DCM, from 0 to 10 %. The pure fractions were collected and removal of solvent under vacuum provided the title compound I-283 (3.6 g, yield 93%) as a colorless oil.

[2369] Synthesis of Intermediate 1-284 silver pentanoateo UAg+Na+II AgNO3

[2370]

[2371] Water, Et2O

[0328] To a solution of sodium pentanoate [6106-41-8] (500 mg, 4.03 mmol) in water (15 mL) at 0 °C was added a solution of silver nitrate (787.69 mg, 4.64 mmol) in water (4.43 mL) over 10 min. The resulting mixture was stirred at 0 °C for 40 min. To the mixture was added diethyl ether (3 mL), and the title compound 1-284 was collected by suction filtration (725 mg, yield 86%) as white solid.

[2372]

[0329] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[2373] Resulting

[2374] Reagent Structure

[2375] Int. No.

[2376] O

[2377] Intermediate

[2378] Na+O

[2379] 1-285 Ag+

[2380] O

[2381] O

[2382] sodium (E)-3-carboxyacrylate

[2383] / =\ O Intermediate

[2384] N / =\ 0

[2385] x0- Na+ 1-286

[2386] x0- Ag+

[2387] sodium isonicotinate

[2388]

[2389] Synthesis of Intermediate 1-287 silver cyclopropanecarboxylate

[2390] O,

[2391] NaOH 1M, AgNO3

[2392] Ag

[2393]

[2394] Water, Et2O+O

[2395]

[0330] To a suspension of cyclopropanecarboxylic acid [1759-53-1] (1 g, 11.62 mmol) in water (34 mL) at 0 °C was added NaOH (1M in H2O) (12.56 mL, 1 M, 12.56 mmol) over 10 min. The mixture was stirred at 0 °C for 30 min before a solution of silver nitrate [7761 - 88-8] (2.27 g, 13.37 mmol) in water (13 mL) was added over 10 min. The resulting mixture was stirred at 0 °C for 40 min. To the mixture was added diethyl ether (3 mL), and the title compound precipitated, filtered off, washed with water and dried in the oven to give 1-287 (2g, yield 89%) as a brown solid.

[2396]

[0331] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.Resulting

[2397] Reagent Structure

[2398] Int. No.

[2399] Intermediate

[2400] OH

[2401] 1-288

[2402] 3-(2-methoxyethoxy)propanoic °' Ag+

[2403] acid [149577-05-9]

[2404] °Y-o— Intermediate

[2405] OH

[2406] 1-289

[2407] 2-(2-methoxyethoxy)acetic acid O’ Ag+

[2408] [16024-56-9]

[2409] 0 / — \

[2410] 1 N N— \

[2411] X—ZVoH Intermediate

[2412] / 0 1 O

[2413] N N^.

[2414] 1-290

[2415] 2-(4-(tert- / ° o^°‘Ag+butoxycarbonyl)piperazin- 1 - yl)acetic acid [156478-71-6]

[2416] Intermediate \Ag1-291

[2417] 0

[2418] 1-283 l

[2419] 0

[2420] Intermediate

[2421] Ag+ 0

[2422] 1-292

[2423] (E)-pent-2-enoic acid [13991-37- Ag+

[2424] 2]

[2425]

[2426] Synthesis of Intermediate 1-293 chloromethyl ((3R,5S)-l-((difluoromethyl)sulfonyl)-5- methylpiperidin-3-yl) (l-(4-(2 6 '-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-3- carbonyl) carbamate

[2427]

[2428]

[0332] To a solution of Compound 2 (2 g, 3.47 mmol) in THF (dry, 140 mL) at -78 °C under a nitrogen atmosphere was added Hexamethyldisilazane lithium salt, 1 M in THF

[2429] [4039-32-1] (5.55 mL, 1 M, 5.55 mmol) over 30 min with a syringe pump. The reaction mixture was stirred at -78°C for 45 min. Then chloromethyl chloroformate [22128-62-7] (715.49 mg, 5.55 mmol) in THF (10 mL) was added and the mixture was stirred another hour at -78°C and then allowed slowly to warm to RT. The mixture was decomposed with water and then EtOAc was added. The layers were separated, and the organic layer was washed with brine and dried over MgSO4. After the solvent was removed under vacuum, the residue was applied to silicagel chromatography, eluent MeOH in DCM from 0 to 10 %. The pure fractions were evaporated, to give 1-293 (1 g, yield 43%) as a yellow foam.

[2430]

[0333] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[2431] Resulting

[2432] Reagent A Reagent B Structure

[2433] Int. No.

[2434] o Cl

[2435] F

[2436] 1 P H / '"'N X NW \= / N

[2437] F \

[2438] 6' Y T Z=\

[2439] O0IntermediF

[2440] i / N1 -chloroethyl 7> S*° O Rs)— Cl o;NZ-N ate 1-294

[2441] Compound 2 < )" N - chloroformate

[2442] NA I

[2443] '' 0

[2444] [50893-53-3]

[2445] o Cl

[2446] r / \

[2447] A «° H / ~~N^N \= / N

[2448] F, S.1XN. \ CI^O^

[2449] o' V 1 V / =\ Intermedi X o YV £ / ~NxOZ ” Z chloromethyl ate 1-295

[2450] Compound 1 I0 / / Nchloroformate

[2451] S-V [22128-62-7]

[2452]

[2453] Resulting

[2454] Reagent A Reagent B Structure

[2455] Int. No.

[2456] PN 0 Cl

[2457] vz-Fi / \ KI

[2458] AP H rN N Intermedi

[2459] chloromethyl

[2460] ate 1-296F>° Ox^Cl I °; NAy< T nj chloroformate

[2461] Compound 18 [22128-62-7]

[2462]

[2463] Synthesis of Intermediate 1-297 iodomethyl ((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl) (l-(4-(2 6 '-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-3-carbonyl) carbamate

[2464] Nal acetone dry

[2465]

[2466]

[0334] A mixture of 1-293 (1000 mg, 1.49 mmol) and sodium iodide [7681-82-5] (895.99 mg, 5.98 mmol) in dry acetone (14 mL) was heated at 60°C in a pressure tube for 1 h. LC / MS showed almost no starting material anymore. The insoluble material generated during the reaction was removed by suction filtration. The filtrate was concentrated to remove acetone. The residue was diluted with ethyl acetate (200 mL), washed with saturated sodium thiosulfate solution (100 mL) and brine. The organic layer was dried on MgSO4, filtered and evaporated under vacuum provided crude product 1-297 as a yellow sticky oil which was directly used in the next step.

[2467]

[0335] Additional analogues were synthesized in an analogous manner using the reagents as appropriate.

[2468] Reagent Resulting Int. No. Structure F Y T \ zN. / H2O \RST

[2469] F XX

[2470] Intermediate 1-298 O RS>—1

[2471] 0

[2472] 1-294

[2473]

[2474] -\T1-

[2475] Reagent Resulting Int. No. Structure / XX

[2476] F>° Ox^Cl I / XX < >'" N Intermediate 1-299

[2477] y^ y^y TF0NAy< F y 1-296

[2478] X 0 Yv

[2479] / xx Y0X TZ / NIntermediate 1-300o, J s-^0NAyr

[2480] 1-295 y^ y-<y TF

[2481]

[2482] Synthesis of Intermediate 1-301 ((((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin- 3-yl) (l-(4-(2 6 '-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-3-carbonyl) carbamoyl) oxy) methyl 2-(4-( (bis (benzyloxy)phosphoryl) oxy)phenyl)acetate

[2483]

[2484]

[0336] A mixture of 1-297 (645 mg, 0.85 mmol) and 1-291 (748.52 mg, 1.44 mmol) in THF, dry (30.5 mL) was heated at 65 °C for 30 min and then cooled to RT. The solid phase was removed by suction filtration through Celite 545. The filtrate was concentrated. A purification was performed via column with silicagel, eluent MeOH in DCM, from 0 to 8 %. The fractions were evaporated and repurified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-lOpm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeCN). The pure fractions were evaporated till water at RT. NaHCO3(0.2 g) was added and then the aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried on MgSO4, filtered and evaporated at room temp to yield 1-301 (240 mg, yield 27%) as a white sticky solid.

[0337] Additional analogues were synthesized in an analogous manner starting from I-297 using the reagents as appropriate.

[2485] Resulting Int.

[2486] Reagent Structure

[2487] No.

[2488] O / — \

[2489] w

[2490] F N N— v |l J Intermediate I- H2O

[2491] / ° o^°'Ag+>° T 302 °" V A

[2492] 1-290

[2493]

[2494] Preparation of final compounds

[2495] Synthesis of Compound 1 N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)- l-(4-(2-(2,6-dimethylpyrimidin-4-yl)pyridin-4-yl)thiazol-2-yl)azetidine-3-carboxamide

[2496]

[2497]

[0338] 1-Propanephosphonic anhydride [68957-94-8] (0.689 mL, 0.92 g / mL, 0.996 mmol, 50 wt. % in ethyl acetate) was added to a solution of Intermediate 1-239 (421.77 mg, 1.59 mmol), Intermediate 1-170 (659 mg, 1.33 mmol), triethylamine [121-44-8] (0.92 mL, 0.728 g / mL, 6.64 mmol) in DCM (14 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with satd aq NH4CI and DCM. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried on MgSO4, filtered, and concentrated to dryness. The crude was purified on silicagel column chromatography (DCM MeOH 100:0 to 95:5), concentrated to dryness and the resulting residue was stirred in Et2O, filtered and dried to give Compound 1 (354 mg, yield 46%) as a white solid.

[2498] Synthesis of Compound 2 N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-3-carboxamide

[2499]

[2500]

[0339] Intermediate 1-163 mlecomte_1089_l (0.097 mmol) and Intermediate 1-239 pmathie1_1363_2 (27 mg, 0.102 mmol) were dissolved in DCM (2 mL). To this stirring solution at rt, triethylamine [121-44-8] (100 pL, 0.726 g / mL, 0.717 mmol) and then 1-Propanephosphonic anhydride solution [68957-94-8] (150 pL, 1.069 g / mL, 0.252 mmol; 50 wt. % in ethyl acetate) were added and the reaction mixture was stirred at rt for 2h. The reaction mixture was quenched with NaHCO3(aq) and DCM was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were then dried over MgSO4, filtered and concentrated under reduced pressure to give Compound 2 as a crude which was purified by column chromatography over silica gel (biotage on a 10 g Sfar column, 100% n-heptane to 70 / 30 n-heptane / EtOAc). The desired fractions were combined, concentrated under reduced pressure and dried overnight to give Compound 2 (34 mg, 61% yield) as a white solid.

[2501] Synthesis of Compound 5 rel-(2R,3S)-N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5- methylpiperidin-3-yl)-l-(4-(4-fluoro-2',6'-dimethyl-[2,4'-bipyridin]-6-yl)thiazol-2-yl)-2- methylazetidine-3-carboxamide

[2502]

[2503]

[0340] 1-Propanephosphonic anhydride [68957-94-8] (2 mL, 2.891 mmol, 50 wt. % in ethyl acetate) was added to a solution of Intermediate 1-239 (453.12 mg, 1.71 mmol), Intermediate 1-165 (731 mg, 1.43 mmol) and triethylamine [121-44-8] (1.6 mL, 11.51 mmol) in DCM (12 mL). The reaction was stirred 2 h 30 min at R. T. The reaction mixture was purified on silicagel column chromatography using a gradient from 0 till 70% EtOAc in heptane and 70% EtOAc in heptane. The product fractions were combined, concentrated under reduced pressure and dried overnight in the vacuo at 50°C to afford the Compound 5 (505 mg, yield 58%) as a white solid.

[2504] Synthesis of Compound 18 N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3- yl)-l-(4-(2-(2,6-dimethylpyrimidin-4-yl)-6-fluoropyridin-4-yl)thiazol-2-yl)azetidine-3-carboxamide

[2505]

[2506]

[0341] 1-Propanephosphonic anhydride solution [68957-94-8] (8.32 mL, 0.92 g / mL, 12.02 mmol, 50 wt. % in ethyl acetate) was added to a solution of Intermediate 1-239 (1.75 g, 6.61 mmol), Intermediate 1-202 (3 g, 6.01 mmol) and triethylamine [121-44-8] (7.51 mL, 54.06 mmol) in dry DCM (193 ml). The reaction was stirred 2 h at R. T. The reaction mixture was quenched with sat aq NaHCO₃ solution and more DCM was added. The organic layer was separated and the aqueous phase was extracted with DCM / MeOH 9 / 1. The combined organic layer was concentrated to dryness and purified over silicagel with MeOH in DCM, from 0 to 10 %. The final compound was obtained and crystalized from MeCN to yield Compound 18 (3.13 g, yield 88%) as a white solid.

[2507] '° 0 Q..

[2508]

[0342] Additional final compounds were synthesized in an analog zz zzous manner using ^ / 0 o== 7 Intermediate 1-239 and the corresponding starting material reagent as indic ^-zated in the following table. The following compounds have been synthesized using DIPE 0°A?

[2509] 00 z or Et3N as base and DCM or DMF as solvent. The compounds can be purified via silicagel, SFC or HPLC chromatography. rj * ur Resulting

[2510] Reagent* Structure Compound.

[2511] HO [1 J Compound 3

[2512] ^i\r

[2513] Intermediate 1-173

[2514] HO H 1 Compound 4

[2515] Intermediate 1-174

[2516]

[2517] Resulting

[2518] Reagent* Structure Compound. vx! LT i'^^ M

[2519] °hv y —

[2520] ^^o OT w c-—- oArA* y *

[2521] Compound 6

[2522] )o=

[2523] sA TZ IZ

[2524] F

[2525] Intermediate 1-203 X„ «pb.. '

[2526] x W

[2527] (u__O '

[2528] < Xu-—°'

[2529] O. / P / X A” LL

[2530] V-K N-A X N X X

[2531] HO II J Compound 8

[2532] F

[2533] Intermediate 1-171

[2534] \-N

[2535] OH # )=N vX cr X'-'A 2

[2536] FXX / AVNYNyXT<N Compound 10 X? H r~Nn\= / ' X 'X ' F

[2537] Intermediate 1-74

[2538] o

[2539] F nC' VAFFixA PNN / =< X P H / " N^N Compound 11

[2540] sX V-4;60 s X F i / =NF Intermediate 1-207

[2541] A NXX

[2542] Hcr X--^ ) — 'FF XMN / =<

[2543] r / )—£, N A P H rN-VXNS<7 Compound 12

[2544] FFA A

[2545] £ / =NF Intermediate 1-208

[2546] o. / S>1

[2547] / - \ zNA 11 \N

[2548] h°v

[2549] Compound 13

[2550] Intermediate 1-164

[2551]

[2552] Resulting

[2553] Reagent* Structure Compound.

[2554] QCZ^ ^0 (- H vO o o Y u ] di

[2555] Compound 17

[2556] Intermediate 1-166 20=

[2557] IZ

[2558] F x.

[2559] x W

[2560] LN / =N

[2561] Compound 20

[2562] Intermediate 1-204

[2563] IX

[2564] " Fl ■n 71

[2565] > ) " H " H““ O O O Oxxxx

[2566] XN W W W Wxxxx

[2567] Compound 21

[2568] HO IR* / NVKAF°'°'° q O o o....

[2569] ZI zx zx zx0> s< MsJ / / £ o= o o==

[2570] w

[2571] / ^ / *0 / z Intermediate 1-205 ^ ^ *zz■

[2572] y y y y°i°°°?ii A z A J A z z z Z=^N X O XJ H Y JOi Xx / Compound 22 Z / n-,"rCN" x~®« o Vr Intermediate 1-223

[2573] o

[2574] 7 — <XN— ( / Il II J

[2575] HOJX Compound 23

[2576] Intermediate 1-225

[2577] z^N

[2578] HQ 1R* NO^ Il f

[2579] >"sXNXsJ L^NCompound 29

[2580] Intermediate 1-212

[2581]

[2582] Resulting

[2583] Reagent* Structure Compound.

[2584] o VNA

[2585] HO^ YY

[2586] 0N N / =\ Compound 30

[2587] Intermediate 1-178

[2588] o

[2589] S-^. / =N F L >— < \ Hcr v-'A /

[2590] \ _NY / ? H rNNNY Compound 31 °' i1] V o iN / T. Y —

[2591] : >=N Intermediate 1-179

[2592] r^N

[2593] HO\F.

[2594] rzZ' \\ KI K / M J O 1 o |_| / "-N N M__ 4 o s y Compound 32 ■n

[2595] 0O ex. 0 s O- r e i t 1 7 Wx £ >=N Inte m d a e - 1

[2596] '°'° 0 Q o...

[2597] zi ZI zz

[2598] o V'v ^£^ o o °===

[2599] XWA-o JLp H £7 ^ ^z" Z N \=( \ HOZ\A

[2600] V-N^. N / =< / Compound 36 y y^°?- A J A z z z

[2601] s ' -# > W\ / / “°

[2602] Intermediate 1-182 JlJ I 0^NrffH°\ < Z\R*N.?2 zS —

[2603] Compound 39

[2604] Intermediate 1-194

[2605] S—, r^N F XY-fL A,? H p-N N N=Y w x»A Compound 40

[2606] 0L 11'-o' / r -: YNIntermediate 1-228

[2607] o

[2608] V-N N / =\ Compound 42

[2609] F

[2610]

[2611] Intermediate 1-184Resulting

[2612] Reagent* Structure Compound.

[2613] 0F— / — F

[2614] F— ( *0

[2615] / , S'

[2616] V-N.. N / =\ Compound 430Q C v 0 zu I In Intermediate 1-195

[2617] — l /

[2618] OH \=N

[2619] '-'NN / / -k Compound 45

[2620] LZA= / N

[2621] Intermediate 1-68

[2622] OH 5=N ■n

[2623] FOx. I’V / ^ A WPx H nNMN / r-C Compound 46

[2624] 10'° Q

[2625] / ) Q 0 Q.

[2626] — ( / N i.. Z £ O >=N S-# \— / Z zz ZZ -o / / o °== Intermediate 1-69

[2627] ^z

[2628] Z0?

[2629] J z A z V / X N. JI

[2630] / — \,N~Z HNH 1 HO V ~\sJ |l II Il 7 z J Z - Vzlj Compound 48 J Z -Z-x Intermediate 1-230

[2631] A

[2632] w HO H JNA H PN N 'N== / Compound 49 0 v h_ F

[2633] : / ~N Intermediate 1-167

[2634] 0 1 II Compound 50

[2635] A / N

[2636] Intermediate 1-65

[2637]

[2638] Resulting

[2639] Reagent* Structure Compound.

[2640] \=N >1

[2641] ohc?Fryy=\

[2642] _ I XP H AnvyVNVNK J^N Compound 51

[2643] S-#F^'0 Y TA £ / NIntermediate 1-70

[2644] o

[2645] HO^YA / =N

[2646] AN N / =\ Compound 52

[2647] Intermediate 1-185

[2648] YN 7

[2649] 0\ vy-F

[2650] Ff'W^' HO Y7 _ /

[2651] VN^, N / =\ A P H ry A / \== / NCompound 55

[2652] T O~" / — • A"

[2653] " Fl °' O' 0 CW i / =NF F

[2654] Intermediate 1-196 O-0" H o Ck. C / k

[2655] '° q Q..

[2656] o >NWZT zx O^A / o=>

[2657] H — \ \=N °

[2658] A F =

[2659] -P H S ' c por-- XV-O / =< ^Hz N A / ”

[2660] Compound 57 ^z

[2661] 1 / >— <\ / z d' 'i 1 y°?- Z=Nv SA wN

[2662] M0J z

[2663] 1 y Z VNz^~<? / Intermediate 1-206

[2664] O XZJ - j? Tk

[2665] \=N F n-r\ AN. M N-K A -p H N~y Compound 58

[2666] r^crT K XHJ £. / NIntermediate 1-102

[2667] F

[2668] > A 'N

[2669] HO JD* II

[2670] \ A\RN. /

[2671] O S*^ \SJ / IIN

[2672] Compound 59

[2673] F^ T

[2674] Intermediate 1-197

[2675]

[2676] Resulting

[2677] Reagent* Structure Compound. z —

[2678] I 1I F

[2679] z!s « I KN

[2680] F w—

[2681] F \R* XV- / ~ 0 S*vN A P H z. N A^ / N Compound 601)°=

[2682] ‘ O TZ / ov=

[2683] F^ T £ TZ m / -NF Intermediate 1-198

[2684] XOT.s WSps„ o.

[2685] u-O u_—

[2686] (—°X

[2687] v

[2688] / X.. _ / SAl I^N

[2689] HO H | \

[2690] Compound 61

[2691] Intermediate 1-168

[2692] 0 5=N

[2693] HO'JVnF| 'V- / =XA '? H / ---N Aj' V?1LHLy Compound 62

[2694] )■"“ Ck

[2695] C / k O oNO~< \ Z~NIntermediate 1-226

[2696] Q.

[2697] ZT

[2698] / °=

[2699] V\

[2700] 0^-z

[2701] \ —

[2702] y°?- HO^ V'A } J zUYVT N Compound 63

[2703] Cl r y Intermediate 1-227

[2704] F

[2705] 9 ' fVFrw^

[2706] A H 7~N^N Y- / 1HO^ rA F Compound 64

[2707] N )=< ° O 0 OA i Z=NF s-~# VJ'

[2708] Intermediate 1-209

[2709] 0)=\_

[2710] HOA^ / —

[2711] UNY\ #'CCI Compound 67

[2712] sA \= /

[2713] Intermediate 1-187

[2714]

[2715] Resulting

[2716] Reagent* Structure V Z"

[2717] Compound.

[2718] o 1R* 1 F

[2719] Compound 69 y ^ o o-— j A ^_ Z Z~- /

[2720] Intermediate 1-210 ) )oo== PN IZ IZ

[2721] \-N

[2722] 0\X) —o0.

[2723] P o.

[2724] R 7=N xx O O

[2725] HO VA \ _ / (

[2726] V-N. _ N / =\ LLu-—° "

[2727] Compound 70

[2728] Intermediate 1-199

[2729] /

[2730] — N

[2731] \-N

[2732] 0\X) —Frv / ^

[2733] )=N

[2734] HO VA _ / A,9 H / " N N M" V-N.. N / =\ Compound 71 o' i i PA / XHJ" k / 1 0 N\\ / >-N £ PN XOx

[2735] Ox

[2736] Intermediate 1-200

[2737] ° Q.

[2738] ZI

[2739] o p KO=

[2740] A W- Hcr X-Y / F zv / ~w P z ^NYNy- / y-< Compound 72 d' Q M sP \= / F / NIntermediate 1-188 Y

[2741] °

[2742] HCr X---^ / —

[2743] Compound 73

[2744] ^NYNy- / y-<

[2745] Sx / \= / F

[2746] Intermediate 1-189

[2747] ° y~N

[2748] ji ( / \\ _

[2749] HO^r--\ \= /

[2750] \--N N N- /

[2751] T Compound 74

[2752] b--H / \=NV

[2753] Intermediate 1-190

[2754]

[2755] Resulting

[2756] Reagent* Structure Compound.

[2757] OH

[2758] H2N?' W=\ X 'P H y cnZ ^7 — / / -" N N V / - Compound 75

[2759] ° ij IZ I fy_ H2N / =N Intermediate 1-214

[2760] x WOo.

[2761] (u_—° "

[2762] HONH ]T

[2763] Compound 88

[2764] F

[2765] Intermediate 1-172

[2766] HO c* \ ||

[2767] V / \S

[2768] nNH i

[2769] Compound 93 ■n

[2770] Ws

[2771] Intermediate 1-176

[2772] '° d Q..

[2773] zz

[2774] X'N ZI

[2775] ^^ ° °==

[2776] = L /

[2777] HO IS* NXA / YY -.s*

[2778] r-N^-N V / 1y F \ C A TR* y y°?- ompound 94 °i A z A z AAF / 'QNHyr- Intermediate 1-211

[2779] AJ V\HO\ A NXI^. Z

[2780] Compound 95

[2781] Intermediate 1-177

[2782] . ISk

[2783] HV> " X -zzz FXF<.0 / VLN;::::\ y~~y d^ZN~<gjr j iQT Compound 97

[2784] 0p

[2785] Intermediate 1-180

[2786] FH-fi X / P H r~N^N \= / Compound 98

[2787] r^crr

[2788] £ / NIntermediate 1-181

[2789]

[2790] Resulting

[2791] Reagent* Structure Compound.

[2792] 0HFrw^ CT Y V'-AM^N )=N F A 'P H / Y

[2793] r=\N\=

[2794] Compound 99

[2795] V / X \\ AN°N0 v t v i / N fIntermediate 1-213

[2796] OH H2N (r Y s 'S'A_V==N / N=\ A 'P H / Y A Compound 131

[2797] I o~- / / u y— N

[2798] H2N ° 0 I <y~

[2799] : YNIntermediate 1-215

[2800] N^F

[2801] HO / D* 1 II M F

[2802] / '" CNY y Y Y

[2803] o s*^ \SJ Il N o*sY

[2804] Compound 132 Z ~ / • UH I R- < / NYFA > YJ V 1-216

[2805] r H

[2806] X. FF?yn A? H / "hrnA / Compound 133 F, S,kl / \ANxAJV HH WI0O s h~ o: / ==NIntermediate 1-91

[2807] \=N

[2808] HO V

[2809] 0YVN Y Y Compound 134

[2810] N J 9C >— E f Y 4 1 o \ -Ny / - n F H V t-N »NF\ \ / tACY 1-217

[2811] 0

[2812] ZN X

[2813] HoYY F. < > N Y- o I ] 9 ANNY L\ H7 Compound 136

[2814] ZO ^NF°HY.NFy>NW -

[2815]

[2816] 1-218Resulting

[2817] Reagent* Structure

[2818] Compound.

[2819]

[2820] * Reagent can be used as TFA salt or TFA adduct, increasing the equivalents of EbN or DIPEA to neutralize the eccess of acid.

[2821] Synthesis of Compound 27 rel-(2R,3S)-N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(6-(2,6-dimethylpyridin-4-yl)pyrazin-2-yl)thiazol-2-yl)-2-methylazetidine-3-carboxamide and Compound 28 rel-(2S,3R)-N-((3R,5S)-l- ((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(6-(2,6-dimethylpyridin-4-yl)pyrazin-2-yl)thiazol-2-yl)-2-methylazetidine-3-carboxamide

[2822]

[2823] F F

[0343] 1-Propanephosphonic anhydride solution [68957-94-8] (0.22 mL, 0.92 g / mL, 0.31 mmol, 50 wt. % in ethyl acetate) was added to a solution of Intermediate 1-239 (132.4 mg, 0.5 mmol), Intermediate 1-224 (159 mg, 0.42 mmol), Et3N [121-44-8] (0.29 mL, 2.08 mmol) in DCM (3.3 mL) and the reaction mixture was stirred at room temperature for Ih. The reaction mixture was diluted with water and DCM, the layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried on MgSO4, filtered, and evaporated to dryness. The crude was purified by silica chromatography (DCM MeOH 100:0 to 95:5). A purification was performed via Prep SFC (Stationary phase:

[2824] Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4% iPrNH₂) yielding Compound 28 (38 mg, 15%) and Compound 27 (35 mg, 14%).

[2825]

[0344] Additional final compounds were synthesized in an analogous manner using Intermediate 1-239 and the corresponding starting material reagent as indicated in the following table. The following compounds have been synthesized using DIPEA or Et3N as base and DCM or DMF as solvent and afforded the final compounds after SFC separation.

[2826] Resulting

[2827] Reagent Structure Compound.

[2828] x '? H y N

[2829] Compound 19

[2830] F°'O'N□ o-

[2831]

[2832] Resulting

[2833] Reagent Structure Compound. rS HO IRS 1

[2834] A P H AN^N / ^N=AFCompound 106 ^ w-F^O""^

[2835] : » ml K / ~N Intermediate 1-229 )°=

[2836] IZ S— \ / ==\ OH VN F \R* A z - < N?A P H rAN * 1 ( / \\ _ F \

[2837] Compound 37 6ZxO CP o 7. 7 71 * ZA o AVARS AA os

[2838] \ 2 —RS^N.NN-Z A "°

[2839] XZZ= / N

[2840] Intermediate 1-72 A P H Y Compound 38 o i o ITK\ p— -

[2841] F4r ty<( Compound 92

[2842] 0IRS s--. A'A-sA" "N=C 6' 7 T YR* / =\ M o

[2843] HORS NOx; / -N «x F '° o.

[2844] Intermediate 1-231 h- zz i A Y / o=

[2845] Compound 5 °.< A v V F^ '° S 'r w-- Qi - 1 F

[2846] V0? A z

[2847] Compound 44

[2848] < AN

[2849] I 'L

[2850] Q. IRS

[2851] ^„.z \_z / y

[2852] HO RS^ s-^ Compound 6

[2853] Intermediate 1-73

[2854]

[2855] Synthesis of Compound 24 l-(4-(4-cyano-3-(2-(difluoromethyl)-6-methylpyridin-4- yl)phenyl)thiazol-2-yl)-N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3- yl)azetidine-3-carboxamide

[2856]

[2857]

[0345] HATU [148893-10-1] (101 mg, 0.27 mmol, 1.17 eq) was added to a mixture of Intermediate 1-169 (97.0 mg, 0.227 mmol, 1.00 eq), Intermediate 1-239 (72.0 mg, 0.27

[2858] A A11 A mmol, 1.20 eq), N, N-diisopropylethylamine [7087-68-5] (0.28 mL, 0.75 g / mL, 1.63 mmol, 7.14 eq) in DMF (3.0 mL). The mixture was stirred at rt for 3 h. A saturated solution of A a>

[2859] NaHCO3(30.0 mL) was added and the mixture was allowed to stir for 10 min. DCM (20.0 mL) was added, and the aqueous phase was extracted with DCM. The combined organic layer was washed with a saturated solution of NH4Cl (50.0 mL), brine (50.0 mL), dried (MgSO₄),

[2860] Kc / Xfiltered, and concentrated under reduced pressure. The crude material was purified by silica <u_—

[2861] gel chromatography eluting with DCM and MeOH (0-7%) to provide Compound 24 as a white solid (73 mg, 50%).

[2862]

[0346] Additional final compounds were synthesized in an analogous manner using Intermediate 1-239 and the corresponding starting material reagent as indicated in the following table. The following compounds have been synthesized using HATU or TBTU [CAS: 125700-67-6] as coupling reagent. ■Fl

[2863] 0^

[2864] OK

[2865] Resulting

[2866] Reagent Structure Q.

[2867] Compound. zi

[2868] KO=

[2869] 0 VNA

[2870] HO^ A'-'A F D- / V

[2871] A P H ANAA z

[2872] \--N., N Compound N / \= / 0H / =<FA

[2873] o' 7 1’ / =\ 660HM0A- = A-N Intermediate 1-186 Yl il z

[2874] O )=N

[2875] V-N^N^ / =■( Compound

[2876] \ #~~NH 76

[2877] Intermediate 1-201

[2878] IHO>TA / 'F

[2879] Compound

[2880] Y _ <! 7 — =N

[2881] sA \= / 78

[2882] Intermediate 1-193

[2883]

[2884] Resulting

[2885] Reagent Structure 1 X CM 1

[2886] Compound.

[2887] O )=N

[2888] HcAn

[2889] V-N^N^ / =( Compound w—

[2890] S-# V#"NH2 _ Z- 113

[2891] Intermediate 1-162 /

[2892] z xo=

[2893] ^. N P o.

[2894] L__O '

[2895] HO JR* f || F \R.

[2896] °sA / Lp CompoundF, S., N -L / — (

[2897] d -Q" y.

[2898] 114 o e _ i pN Intermediate 1-191

[2899] \=N

[2900] ° <\

[2901] tNYNo / Compound X " H” CX

[2902] ¥^N "cx /

[2903] S<7 \= / 117

[2904] ° Q.

[2905] Intermediate 1-192 zx

[2906] ^ o=

[2907]

[2908] ^z

[2909] P z Synthesis of Compound 25 N-((3R,5S)-5-(difluoromethyl)-l- ((difluoromethyl)sulfonyl)piperidin-3-yl)-l-(4-(2',6'-dimethyl-[2,4'-bipyridin]-6-yl)thiazol- T T T

[2910] -yl)azetidine-3-carboxamide Ji 1 z

[2911]

[2912]

[0347] Intermediate 1-164 (46 mg, 0.125 mmol) and Intermediate 1-240 (39 mg, 0.13 mmol) were dissolved in DCM (1 mL). To this stirring solution at rt, triethylamine [121-44-8] (130 pL, 0.726 g / mL, 0.933 mmol) and then 1-Propanephosphonic anhydride solution [68957-94-8] (190 pL, 1.069 g / mL, 0.319 mmol; 50 wt. % in ethyl acetate) were added and the reaction mixture was stirred at rt for 3h. The reaction mixture was quenched with a mixture of NaHCO3(aq) / K2CO3(aq) and DCM was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified via PrepSFC (Stationary phase: Torus Diol 30 x 150 mm, Mobile phase: CO2, MeOH + 20mM NH4OH) to give Compound 25 (28 mg, 0.046 mmol, 37%).

[2913]

[0348] Additional final compounds were synthesized in an analogous manner using Intermediate 1-240 and the corresponding starting material reagent as indicated in the following table.

[2914] Resulting

[2915] Reagent Structure Compound.

[2916] A

[2917] H0N^X-" X f / /

[2918] Compound

[2919] X^N 1. P „ JW

[2920] 33

[2921] Intermediate 1-163FMM

[2922] F^F

[2923] F

[2924] A,p H rNn\==f Compound

[2925] 0I JL

[2926] 47FM"NX K Intermediate 1-178 i / NFX~S'F

[2927] 0FXWY Compound F X, / \,. NVA / \ / =< 6' 7 1 T / =\ sY 82 M o M>— V— y i / NIntermediate 1-175 F" A

[2928] / =N F L >- 4,\ A -P H Cfr NXN / Compound

[2929] H0IL J

[2930] 1010O K fy.

[2931] Intermediate 1-173 i. / NF^F

[2932] N

[2933] » / =N> oXwjnvY F \ FR* X z— v A P H AN V / Compound

[2934] 6' 7 ] Tf s* / ==\ 103 M o V M Intermediate 1-183 i / N

[2935] F^F

[2936]

[2937]

[0349] Additional final compounds were synthesized in an analogous manner as Compound 25 using Reagent A in place of Intermediate 1-164 and Reagent B in place of Intermediate 1-240 as indicated in the following table.Resulting

[2938] Reagent A Reagent B Structure Compound.

[2939] F

[2940] A 'P

[2941] F

[2942] H0VX-A AF / 'NQ"NfF— (

[2943] L / /

[2944] V°

[2945] X^N Compound 340A V-Y Intermediate 1-163 Intermediate

[2946] 1-242

[2947] FyF

[2948] o v* O^'N^Y 'NH2

[2949] HCF AX O 7 JFXWA VN N / =< A / ? H r~Nn\= / LZ VY F Compound 87

[2950] ■ -A"’ k Intermediate 1-175 Intermediate

[2951] Fz1-243

[2952] v

[2953] o v* OAN^X'NH2

[2954] o 7 JFXWA Hcr AX A 'P H r-Nn\= / YN N / \

[2955] F Compound 91

[2956] 1-W k Intermediate - / -N Intermediate 1-175 Fz1-244

[2957] F AP

[2958] 9\ z\ /

[2959] H / H 1 ANF / 'Q''NH2

[2960] Fi 'V / ==\ HONrkAJ. A 'P H rYNM X^N F F Compound 96 A.

[2961] Intermediate 1-163 Intermediate0Q I 0- A / =N F F / 1-241

[2962] F N X 'P

[2963] HOI2

[2964] \ X* VF / 'NQ'NfF /

[2965] o s*\ / 11 1

[2966] Compound 100 < S*° °x AR* Intermediate0NX J Y / \" NH A \NIntermediate 1-183

[2967] 1-242

[2968]

[2969] Resulting

[2970] Reagent A Reagent B Structure Compound.

[2971] F A P

[2972] F / 'NQ "Nf

[2973] HO U J Intermediate Compound 102

[2974] Intermediate 1-173 1-242

[2975] F N A P

[2976] F / 'NQ ''NH*

[2977] H°\ A* N^ X

[2978] AO-e / rNiTA

[2979] °S X / AN F F

[2980] Compound 104

[2981] Intermediate

[2982] Intermediate 1-183

[2983] 1-241

[2984] F A P

[2985] „,s~n AF / 'Q ''NH2S^ / = " Fl TlNyX>\\NyV< o

[2986] °A A A.. P H PN N N A HO 0 J F Fm-" Z f\ \

[2987] ^hT Compound 105FA % / / J ° J °NVA A Intermediate0Q I fA Intermediate 1-173 A >=N F F / 1-241 CO:

[2988] 1 X°

[2989] ^ ^" T z zz F ^^^ M WZZ WZ

[2990] o A°

[2991] o \|X=3z zzy\ y_ Hcr V^ A7

[2992] \-N N / \ / ( A y " N / H

[2993] Compound 11 O- - L / w 8 K z— Intermediate 1-175 Intermediate

[2994] 1-245

[2995] q,. / DA P

[2996] Fx yHOr< K 2 YND F Y AA IjFA A Compound 135 V° r O* ' o N II Intermediate 1-163 Intermediate

[2997]

[2998] 1-246Synthesis of Compound 109 N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-N-methylazetidine-3-carboxamide

[2999]

[3000]

[0350] To a solution of Compound 2 (100 mg, 0.17 mmol) in DMF (dry, 2 mL) at 0 °C under a nitrogen atmosphere was added NaH (60% dispersion in mineral oil) (9.02 mg, 0.23 mmol) and stirred at the temperature for 10 min. Mel [74-88-4] (0.011 mL, 2.28 g / mL, 0.17 mmol) in DMF (1 mL) was then added and the mixture was left stirring for 24 h. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layer was dried over MgSO4, filtered and evaporated to dryness. Purification via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10μm, 30x150mm, Mobile phase: acetonitrile) afforded Compound 109 (5.5 mg, 9.3 pmol, 11%).

[3001] Synthesis of Compound 77 ((((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)(l-(4-(2-(2,6-dimethylpyrimidin-4-yl)-6-fluoropyridin-4-yl)thiazol-2-yl)azetidine-3-carbonyl) carbamoyl) oxy) methyl pivalate

[3002]

[3003]

[0351] A solution of Compound 18 (100 mg, 0.16 mmol) in dry THF (6.5 mL) was sonicated for 15 min until complete dissolution. This solution was cooled to -78°C under a nitrogen atmosphere and LiHMDS, 1 M in THF [4039-32-1] (0.26 mL, 1 M, 0.26 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 45 min. Then 2,2-Dimethyl-propanoyloxymethyl carbonochloridate [133217-74-0] (50.1 mg, 0.26 mmol) in THF (0.5 mL) was added and the mixture was stirred another hour at -78°C before being allowed to warm to rt slowly. Water was then added followed by EtOAc. The layers were separated, and the organic layer was washed with brine, dried over MgSO4, filtered and evaporated till dryness. A purification was performed via Prep HPLC (Stationary phase: RP CSH Prep C18 OBD-5μm, 50x150mm, Mobile phase: Formic acid, MeCN) and afforded Compound 77 (35 mg, 0.046 mmol, 28%).

[0352] Compound 130 was synthesized in an analogous manner using as starting material Compound 1:

[3004] Resulting

[3005] Reagent Compoun Structure

[3006] d.

[3007] z=N

[3008] c —

[3009] Q-XN\=N F A P H A o V —

[3010] Compoun

[3011] A A P °Y°

[3012] d 130

[3013] Compound 1 ZQ-A

[3014]

[3015] Synthesis of Compound 124 ((((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)(l-(4-(2',6'-dimethyl-l2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-3-carbonyl) carbamoyl) oxy) methyl cyclopropanecarboxylate

[3016]

[3017]

[0353] A mixture of Intermediate 1-297 (495 mg, 0.65 mmol) and Intermediate 1-287 (144.25 mg, 0.75 mmol) in dry THF (12 mL) was stirred at RT for 45 min. The mixture was then cooled to rt and filtered over dicalite. The filtrate was evaporated to dryness and purified via Prep HPLC (Stationary phase: RP CSH Prep C18 OBD-5pm, 50x150mm, Mobile phase: Formic acid, MeCN) to give Compound 124 (134 mg, 0.19 mmol, 29%) as a white foam.

[3018]

[0354] Additional final compounds were synthesized in an analogous manner as Compound 124 using Intermediate 1-297 and the reagents indicated in the following table instead of 1-287. The reaction mixtures in some cases could have been stirred at 65 °C.

[3019] Resulting

[3020] Reagent Structure

[3021] Compound.

[3022] O OK Z\ fl A9.OA^XX Compound 110

[3023] Intermediate 1-292

[3024]

[3025] A-0PAResulting

[3026] Reagent Structure Compound.

[3027] O

[3028] 0 if^N

[3029] 0. V z\ NAI A _ 0

[3030] Silver Compound 120 hr Y 0 r v Benzoate [532-31- W 0 y

[3031] 10]

[3032] 0 0 0 0 / / y — A0, ASX X X

[3033] -'' X) 0 [ Compound 121 ~ \^N. _N / ==\

[3034] Y \ _ 6, N Silver Acetate [563- 0 ' I S— y

[3035] FANA

[3036] 63-3] Y 'b

[3037] F O

[3038] Compound 122

[3039] Vo4'0X^ ° / Intermediate 1-284

[3040] / =\ / °

[3041] O-Ag Compound 123 tnr° H fl F1Intermediate 1-286

[3042] N-^

[3043] \-N O^. - 0 0 0 / / y —

[3044] 0 I I I \= /

[3045] ' 0 — 0 0 N Y"\ _ /

[3046] °Ag Compound 125 i V-NYN Z=\

[3047] 0 1 1

[3048] Intermediate 1-288 1 '0

[3049] F

[3050] 0

[3051] NVS-^ ] Compound 126 °K°

[3052] Intermediate 1-289 X7°F

[3053]

[3054] — 0

[3055] Synthesis of Compound 129 ((((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)(l-(4-(2-(2,6-dimethylpyrimidin-4-yl)pyridin-4-yl)thiazol-2-yl)azetidine-3-carbonyl) carbamoyl) oxy) methyl cyclopropanecarboxylate

[3056]

[3057]

[0355] A solution of 1-300 (79 mg, 0.104 mmol) in dry THF (2 mL) under a N2 atmosphere was added to Intermediate 1-287 (25.5 mg, 0.132 mmol), previously backfilled with nitrogen / vacuum. The reaction mixture was stirred 45 min at R. T. and then filtered overa mixture of dicalite and MgSO4. The filtrate was concentrated under reduced pressure to dryness and the residue was purified via Prep HPLC (Stationary phase: RP XB ridge Prep Cl 8

[3058] OBD-10μm, 50x150mm, Mobile phase: 0.1% FA solution in water, MeCN). The different product fractions were combined and freeze-dried to afford Compound 129 (8>d °

[3059] , O< °=

[3060] o mg, yield 10%) as a white solid. p < °

[3061] op

[3062]

[0356] Additional final compounds were synthesized in an analogous manner as

[3063] / °

[3064] o

[3065] X

[3066] Compound 129 using Reagent A in place of Intermediate 1-300 and Reagent B in place of Intermediate 1-287 as indicated in the following table. The reaction mixtures in some cases could have been stirred at 50 or 65 °C.

[3067] Resulting Structure Reagent A Reagent B

[3068] Compound

[3069] o O O 0

[3070] j XX ^O-A9V I CN N zriNfl Intermediate I- Compound o' 1 hk / /

[3071] F ^-N 115

[3072] O 287

[3073] Intermediate 1-299

[3074] 0

[3075] j XX HO^^A. Ag

[3076] >° » JO+

[3077] O

[3078] I l Compound

[3079] / KpA Intermediate I- 116

[3080] 285

[3081] Intermediate 1-299

[3082] O

[3083] p-_ / nN— L N X<F

[3084] yX X X< vw X CA "' / \'*N

[3085] Compound X >=0 X r Silver Benzoate

[3086] 128 RS)

[3087] O

[3088] [532-31-10] y=° Intermediate 1-298

[3089]

[3090] oSynthesis of Compound 108 (E)-4-(((((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl) (l-(4-(2 6 '-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-3-carbonyl)carbamoyl)oxy)methoxy)-4-oxobut-2-enoic acid

[3091]

[3092]

[0357] A mixture of 1-293 (500 mg, 0.75 mmol) and Sodium hydrogen fumarate [5873-57-4] (180.5 mg, 1.31 mmol) in DMF, dry (13.2 mL) was stirred at 105°C for 5 h. The mixture was cooled down, poured out in 100 ml water, and extracted with EtOAc. The combined organic layer was washed with brine, dried on MgSO4, filtered and concentrated to dryness. The residue was purified via Prep HPLC (Stationary phase: RP CSH Prep C18 OBD-5μm, 50x150mm, Mobile phase: 0.1% FA solution in water, MeCN) yielding Compound

[3093] 108 (68.9 mg, yield 12.31%) as a white foam.

[3094] Synthesis of Compound 83 reZ-(2R,3S)-N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)-2-methylazetidine-3-carboxamide and Compound 84 re / -(2S,3R)-N-((3R,5S)-l- ((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)-2-methylazetidine-3-carboxamide

[3095]

[3096]

[0358] Intermediate 1-276 (270 mg, 0.345 mmol) was dissolved in 1,4-di oxane (4.413 mL, 1.033 g / mL, 51.74 mmol)) and water (0.625 mL, 0.998 g / mL, 34.493 mmol ) and Potassium phosphate tribasic [7778-53-2] (219.7 mg, 1.035 mmol) and 4-Bromo-2,6-dimethylpiridine [5093-70-9] (64.2 mg, 0.345 mmol) were added and the solution was bubbled through with N2 before P(t-Bu)s Pd G4 [1621274-11-0] (20.216 mg, 0.0345 mmol) was added. The solution was stirred for 80 °C for Ih. The solution was then washed with water, extracted with EtOAc, and the combined organics were dried with MgSO4, filtered and concentrated in vacuo to dryness the residue was purified via Prep SFC (Stationary phase:Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4% iPrNH2) Compound 83 (40 mg, yield 20%) and Compound 84 (40 mg, yield 20%).

[3097] Synthesis of Compound 81 (R)-l-(4-(3-(2-(difluoromethyl)-6-methylpyrimidin-4-yl)phenyl)thiazol-2-yl)-N-(l-((difluoromethyl)sulfonyl)piperidin-3-yl)azetidine-3-carboxamide

[3098]

[3099]

[0359] To a vial containing 4-chloro-2-(difluoromethyl)-6-methylpyrimidine [2302807-98-1] (0.15 mmol) were added 0.5 mL of a stock solution Intermediate 1-277 (58.25 mg, 0.1 mmol) in dry dioxane. The catalyst, XPhos Pd G4 [1599466-81-5] (0.01 mmol, 8.6 mg) was added as 0.5 mL of a stock solution in dry dioxane. Potassium phosphate [7778-53-2] (0.4 mmol, 85 mg) was added as an aqueous stock solution (0.2 mL). The reactions were stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated to < 0.5 mL and aq 0.1 M citric acid was added. The aqueous phase was extracted with Ethyl acetate and the organic layer was evaporated to dryness. The residue was re-dissolved in DMSO / MeOH and purified via Prep HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD- 10pm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeCN or MeOH) to give Compound 81.

[3100] Synthesis of Compound 68 re / -(2R,3R)-N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-2-(methoxymethyl)azetidine-3-carboxamide and Compound 112 re / -(2S,3S)-N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-2-(methoxymethyl)azetidine-3-carboxamide

[3101]

[3102]

[0360] In a sealed vessel, Intermediate 1-133 (260 mg, 0.67 mmol, 1.7 eq) and Na2CO3 (120 mg, 1.13 mmol, 2.9 eq) were added to a stirred solution of Intermediate 1-262 (202 mg, 0.39 mmol, 1 eq) in a nitrogen-sparged mixture of 1,4-dioxane (6 mL) and H2O (1.5 mL) atroom temperature. Then XPhos Pd G3 [1445085-55-1] (35 mg, 0.04 mmol, 0.11 eq) was added, and the reaction was heated at 90 °C for 4 h. The mixture was allowed to cool to / z— room temperature. H2O (40 mL) was added, and the mixture was extracted with EtOAc (2 x 100

[3103] mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to a black oil. The crude oil was purified by silica gel chromatography (0: 100 to 3:97, MeOH / CH2C12) to give a mixture of stereoisomers as a grey amorphous solid (181 mg, IZ

[3104] 62%). The racemate was subjected to chiral separation via SFC (i-Amylose-3 column, 5 pm, 250 mm x 30 mm, at 30 °C, 20 min isocratic 45:55, CO2 / (EtOH +0.1% Et2NH)) to yield IL0

[3105] Compound 68 as a white solid (70 mg, 29%). and Compound 112 as white solid (62 mg, 25%).

[3106]

[0361] Additional final compounds were synthesized in an analogous manner as Compound 68 or Compound 112 using Intermediate 1-133 and the reagent indicated in the following table.

[3107] Resulting

[3108] Reagent Structure Compound.

[3109] 0- Q r- Compound 56

[3110] Intermediate 1-263

[3111] / ? HH0\ / \ / S>i

[3112] Fo' O'" S0 nX* Compound 65 O = O T If Intermediate 1-264

[3113]

[3114] Synthesis of Compound 85 reZ-(2R,3S)-N-((3R,5S)-5-(difluoromethyl)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-l-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)-2-methylazetidine-3-carboxamide and Compound 86 rc / -(2S.3R)-N-((3R,5S)-5-(difluoromethyl)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-l-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)-2-methylazetidine-3-carboxamide

[3115]

[3116]

[0362] Intermediate 1-274 (142 mg, 0.256 mmol) was dissolved in 1,4-dioxane (2.182 mL, 1.033 g / mL, 25.59 mmol) and water (0.7 mL, 0.998 g / mL, 38.4 mmol) and Potassium phosphate [7778-53-2] (162.9 mg, 0.77 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine [325142-95-8] (71.571 mg, 0.307 mmol) were added. The solution was bubbled with N2 before XPhos Pd G4 [1599466-81-5] (22 mg, 0.026 mmol) was added and the resultant solution was stirred for 80 °C for Ih. The solution was washed with water, extracted with EtOAc, and the combined organic layer was dried with MgSO4, filtered and concentrated in vacuo to dryness. This residue was purified via Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4% iPrNH2) to give Compound 85 (45 mg, yield 28%) and Compound 86 (30 mg, yield 19%).

[3117] Synthesis of Compound 7 N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)azetidine-3-carboxamide

[3118]

[3119]

[0363] A solution of Intermediate 1-267 (1500 mg, 2.73 mmol), 2,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine [325142-95-8] (954.602 mg, 4.095 mmol), CS2CO3 [534-17-8] (2223.7 mg, 6.8 mmol) in dioxane (25 mL) and water (5 mL) was flushed with nitrogen for 2 minutes and then APhos Pd G3 [1820817-64-8] (173.384 mg, 0.273 mmol) was added. The solution stirred for 80 °C for 4h. Water was added to the solution and the aqueous layer was extracted with EtOAc, and the combined organic layer was dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Heptane: EtOAc 100:0 to 0: 100) yielding Compound 7 (1100 mg, yield 70%).

[3120]

[0364] Additional final compounds were synthesized in an analogous manner as Compound 7 using 2,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine [325142-95-8] or 2,6-Dimethyl-pyridine-4-boronic acid [846548-44-5] and the reagent indicated in the following table. Other variations in the conditions may include but not belimited to the use of a different Palladium catalyst such as XPhos Pd G4 [1599466-81-5] or cataCXium Pd G4 [2230788-67-5], a different base such as triethylamine or potassium phosphate [7778-53-2], variation of temperature up to 100 degrees and reaction time can be increased up to 16 hours.

[3121] Resulting

[3122] Reagent Structure Compound.

[3123] FXV-O

[3124] 1zp H / "'N N \= /

[3125] F FBr

[3126] °

[3127] Compound 14

[3128] Intermediate 1-265

[3129] F 1,pHr~N X NV / \=A / -F- ° 1 F,pHr~N i Nw \= /

[3130] Compound 41 o' 7 1 n Ax Intermediate 1-275 )_n_o* O0v A Ws = / ~N° O.

[3131] F zi

[3132] F— / / o=

[3133] X° y

[3134] °V / JlX,

[3135] / \ \, N— ^

[3136] / " H XclAz C

[3137] \ ’ M V JJHCompound 79 A z Intermediate 1-270 yy

[3138] Fjyn A V 7A

[3139] FX,pHr NNw p..«K>-xjr^ci

[3140] Compound 80

[3141] F

[3142] Intermediate 1-271 F F /

[3143] Cli

[3144] FXA I *1Xzp H r~<^NGV HOWSJ! Compound 90 o i i n V O ° V A Intermediate 1-266 = XN

[3145]

[3146] Synthesis of Compound 16 l-(4-(2'-(difluoromethyl)-6'-methyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)azetidine-3-carboxamide

[3147]

[3148]

[0365] A solution of Intermediate 1-268 (237.92 mg, 0.47 mmol), Intermediate 1-49 (190 mg, 1.02 mmol) and Potassium carbonate [7778-53-2] (194.95 mg, 1.41 mmol) in dioxane (8.2 mL) and water (1.6 mL) was purged with nitrogen. Then cataCXium Pd G4

[3149] [2230788-67-5] (34.9 mg, 0.047 mmol) was added and the mixture was stirred for Ih at 80°C. The mixture was filtered over an extralute filter and evaporated to dryness in vacuo. A purification was performed via Prep HPLC (Stationary phase: RP XB ridge Prep Cl 8 OBD-10pm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeCN) followed by Prep SFC (Stationary phase: Torus Diol 30 x 150 mm, Mobile phase: CO2, MeOH + 20mM NH4OH) to afford Compound 16 (51 mg, 18%).

[3150]

[0366] Additional final compounds were synthesized in an analogous manner as Compound 16 using the reagents indicated in the following table. Other variations in the conditions may include but not be limited to the use of a different Palladium catalyst such as XPhos Pd G4 [1599466-81-5] or cataCXium Pd G4 [2230788-67-5], a different base such as triethylamine or potassium phosphate [7778-53-2], variation of temperature up to 100 degrees and reaction time can be increased up to 16 hours.

[3151] Resulting

[3152] Reagent A Reagent B Compoun Structure d.

[3153] B

[3154] A / P H / ^NN

[3155] f\=z - Compoun

[3156] l

[3157] ° 2-methoxy-6- d 35F0Intermediate 1-268 methyl-4-F^9^

[3158] (4, 4,5,5- tetramethyl-

[3159]

[3160] 1,3,2-Resulting

[3161] Reagent A Reagent B Compoun Structure d.

[3162] dioxaborolan-2- yl)pyridine

[3163] [1083168-87-9]

[3164] HO,XOH

[3165] B F

[3166] A / ? H fN N \=Z

[3167] FX°

[3168] F ClCompoun

[3169] OH

[3170] (4-hydroxy-3,5- d 53 ( X " NH iCxf 2 — 'bOH Intermediate 1-268 dimethylphenyl

[3171] )boronic acid

[3172] [934826-20-7]

[3173] ( /

[3174] B

[3175] F

[3176] A, P H / " N N \== /

[3177] FFX°

[3178] F 7 ClCompoun

[3179] / 'O^T 2-(4-fluoro-3,5- ° N-x °WX

[3180] ( ^■"NH \ / N'Y J XX, dimethylphenyl d 54 — / b y r Intermediate 1-268 )-4, 4,5,5- tetramethyl- 1,3,2- dioxaborolane

[3181] [1147894-98-1]

[3182] B

[3183] 1

[3184] FXV--O

[3185] _X H / " N^N \= / 2-methoxy-6-Fxvo A P H / " N N VVF cmethyl-4- Compoun

[3186] k _ > 0i

[3187] °' i X / A / (4, 4,5,5- d 890\ Z~~O: >=N Intermediate 1-272 tetramethyl- 1,3,2- dioxaborolan-2- yl)pyridine

[3188]

[3189] [1083168-87-9]Resulting w Reagent A Reagent B Compoun Structure d.

[3190] HO,XOH

[3191] B

[3192] l oi

[3193] JyL n

[3194] A / P H / ^N N Vy CN

[3195] f- Compoun

[3196] 0

[3197] d 107

[3198] (4-cyano-3,5- Intermediate 1-268

[3199] dimethylphenyl

[3200] )boronic acid

[3201] [911210-53-2]

[3202] HO,XOH

[3203] B

[3204] FfA-7^

[3205] A P H CN N \=== / N

[3206] / -0

[3207] F ClCompoun

[3208] V V VvV ° (4-methoxy-3,5- d 111

[3209] Intermediate 1-268 dimethylphenyl

[3210] )boronic acid

[3211]

[3212] [301699-39-8]

[3213] Synthesis of Compound 119 ((((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)(l-(4-(2\6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-3-carbonyl) carbamoyl) oxy) methyl 2- (4- (phosphonooxy)phenyl) acetate

[3214]

[3215]

[0367] A mixture of Intermediate 1-301 (240 mg, 0.23 mmol) and Pd / C (10%) [7440-05-3] (40.15 mg, 0.038 mmol) in MeOH (20 mL) was stirred under H2 atmosphere for ~48 h. The catalyst was filtered and washed well with MeOH and the filtrate was evaporated to dryness. A purification was performed via Prep HPLC (Stationary phase: RP CSH Prep C18 OBD-5μm, 50x150mm, Mobile phase: 0.1% FA solution in water, MeCN) yielding a white foam as Compound 119 (18 mg, yield 9%).Synthesis of Compound 127 ((((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)(l-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-3-carbonyl) carbamoyl) oxy) methyl 2- (piperazin-1 -y I) acetate

[3216] 20=

[3217] IZ

[3218]

[3219] P o.

[3220]

[0368] To a solution of Intermediate 1-302 (250 mg, 0.29 mmol) in 2 mL of DCM was added 1 mL TFA. The mixture was stirred at room temperature for Ih. The solvents were then evaporated at low temperature and the residue was purified via Prep HPLC (Stationary phase: RP CSHPrep C18 OBD-lOpm, 30x150mm, Mobile phase: 0.1% FA solution in water, MeCN) to afford Compound 127 (145 mg, 65%).

[3221] Synthesis of Compound 9 N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)~ l-(4-(3-(2,6-dimethylpyrimidin-4-yl)phenyl)thiazol-2-yl)azetidine-3-carboxamide

[3222]

[3223]

[0369] A solution of Intermediate 1-279 (45 mg, 1 Eq, 75 pmol) in 1,4-dioxane (1.6 mL) with XPhos Pd G4 [1599466-81-5] (6.5 mg, 0.1 eq, 7.5 pmol) was added to 4-Bromo-2,6-dimethylpirymidine [354574-56-4] (9.0 mg, 1.5 Eq, 0.11 mmol). Then a solution of potassium phosphate (96 mg, 6 Eq, 0.45 mmol) in water (0.4 mL) was then added. And the reaction mixture was heated at 80°C overnight. The reaction mixture was concentrated and extracted with EtOAc from 2 mL 50% brine solution. The mixture was concentrated, redissolved in MeOH and purified via Prep HPLC to afford Compound 9 (6.5 mg, 15%).

[3224]

[0370] Additional final compounds were synthesized in an analogous manner as Compound 9 using Intermediate 1-279 and the reagent indicated in the following table.

[3225] Resulting

[3226] Reagent Structure Compound.

[3227] Br

[3228] Compound 15

[3229] r'Y N

[3230] F

[3231]

[3232] Resulting

[3233] Reagent Structure Compound.

[3234] 4-bromo-2-(difluoromethyl)- 6-methylpyrimidine

[3235] [2248359-57-9]

[3236] Br

[3237] Compound 26

[3238] l-bromo-3,5-

[3239]

[3240] dimethylbenzene [556-96-7]

[3241] Synthesis of Compound 137 N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-l-(4-(2-fluoro-6-(7-methyl-2,3-dihydrobenzofuran-5-yl)pyridin-4-yl)thiazol-2-yl) azetidine-3-carboxamide

[3242] "" Ox

[3243] Q.

[3244]

[3245] ZI

[3246] ^ O=

[3247]

[0371] A solution of Intermediate 1-278 (117 mg, 0.19 mmol), Intermediate I-280 (50 mg, 0.297 mmol) K2CO3 (52 mg, 0.38 mmol) and cataCXium Pd G4 [2230788-67-5] (7 mg, 0.00943 mmol) in 1,4-di oxane (2 mL) and water (0.5 mL) was purged with nitrogen. The reaction was stirred at 105 °C for 1 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, filtered over a pad of celite, rinsed with ethyl acetate. The filtrate was evaporated and a purification was performed via Silica column chromatography (eluent 0-10% MeOH in DCM) followed by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-lOpm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeCN) and Prep SFC (Stationary phase: Torus Diol 30 x 150 mm, Mobile phase: CO2, MeOH + 20mM NH4OH) to give Compound 137 (2 mg, 2%).

[3248]

[0372] Synthesis of Compounds 138-160

[3249] Compounds numbered from 138 to 160 can be synthesized according to similar procedures as described for Compound 25, reacting either Intermediate 1-175 or Intermediate 1-164 with the corresponding difluoromethyl sulfonated amines.

[3250]

[0373] Synthesis of Compound 161

[0374] Compound 161 can be synthesized following for example a similar procedure as for the synthesis of Compound 46.

[3251]

[3252] characterization methods of Intermediates and

[3253]

[3254] LC-MS methods

[3255]

[0375] 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).

[3256]

[0376] 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.

[3257]

[0377] 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.

[3258]

[0378] Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane / silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica.

[3259]

[0379] LCMS Method Codes: Flow expressed in mL / min; column temperature (T) in °C; Run time

[3260] Table 1. LCMS MethodsMethod Instrument column mobile gradient Flow Run Code phase time Col T From 100% A to

[3261] A: 0.1%

[3262] 5% A in Waters: Waters

[3263] NH4HCO3

[3264] Acquity®: BEH 2.10min, 0.6

[3265] in 95% H2O

[3266] 1 (1.7pm, to 0% A in 3.5 UPLC® - + 5%

[3267] DAD and 2.1* 100mm 0.9min, 55

[3268] CH3CN SQD to 5% A in ) B: CH3CN 0.5min

[3269] A: lOmM

[3270] Waters: CH3COON

[3271] From 100% A to Waters

[3272] H4 0.8 Acquity®

[3273] : BEH 5% Ain 1.3

[3274] 2 in 95% H2O 2 UPLC® - (1.7pm, min,

[3275] DAD and + 5% 55

[3276] 2.1*50mm) hold 0.7min

[3277] SQD2 CH3CN

[3278] B: CH3CN

[3279] Agilent

[3280] 1260 YMC-pack From 95% A to

[3281] A: 0.1% 2.6

[3282] ODS-AQ 5% Ain 4.8 min, Infinity

[3283] HCOOH in mL / min 3 DAD C18 (3 pm, held for 1.0 min, 6.8

[3284] H2O

[3285] TOF- 50x 4.6 to 95% A in 0.2

[3286] B: CH3CN 35 °C mm) min. LC / MS

[3287] G6224A

[3288] A: lOmM

[3289] Waters: CH3COON

[3290] From 100% A to Waters

[3291] H4 Acquity®

[3292] 4: BEH 5% Ain 1.3

[3293] in 95% H2O 0.8 55 UPLC® - min, (1.7pm,

[3294] DAD and + 5%

[3295] 2.1*50mm) hold 0.7min

[3296] SQD2 CH3CN

[3297] B: CH3CN

[3298] Agilent

[3299] 1290

[3300] Infinity

[3301] DAD YMC-pack From 95% A to A: 0.1%

[3302] TOF- ODS-AQ 5% A in 5 min, 2.6 HCOOH in

[3303] LC / MS 5 C18 (50 x held for 1.0 min, 7 H2O

[3304] G6230B 4.6 mm, 3 to 95% A in 0.2 35

[3305] B: CH3CN pm) min. ISET

[3306] emulating

[3307] G1311C /

[3308] G1329B

[3309] A: 0.1%

[3310] Waters:

[3311] NH4HCO3 From 100% A to Waters Acquity® 0.8 in 95% H2O: BEH 5% Ain 1.3 UPLC® - 6 2 + 5% (1.8pm, min, DAD and 55 CH3CN 2.1*50mm) hold 0.7min SQD

[3312] B: CH3CN

[3313]

[3314] A: 0.1% From 100% A to Waters: Waters NH4HCO3 5% A in

[3315] Acquity®: BEH in 95% H2O 2.10min, 0.6 UPLC® - (1.8qm, + 5% to 0% A in 3.5 DAD and 2.1* 100mm 0.9min, 55

[3316] SQD CH3CN

[3317] ) B: CH3CN to 5% A in

[3318] 0.5min

[3319] A: 0.1% From 100% A to

[3320] Waters: Waters NH4HCO3 5% A in

[3321] Acquity®: BEH in 95% H2O 2.10min, 0.6 UPLC® - 3.5

[3322] (1.7pm, + 5% to 0% A in

[3323] DAD and 2.1* 100mm CH3CN 0.9min, 55

[3324] SQD

[3325] ) B: CH3CN to 5% A in

[3326] 0.5min

[3327] A: 10 mM

[3328] Waters: From 100 % A

[3329] Waters CH3COON

[3330] Acquity® to 5 % A in 2.10 0.6

[3331] UP: BEH(1.7 H4in 95 %

[3332] LC® - min, to 0 % A in 3.5 DAD a pm, 2.1 * H2O + 5 %

[3333] nd

[3334] AC 0.9 min, to 5 % 55

[3335] SQD 100 mm) N

[3336] B: ACN A in 0.5 min

[3337] A: 0.1%

[3338] Waters:

[3339] NH4HCO3 From 100% A to Acquity® Waters

[3340] : BEH in 95% H2O

[3341] UPLC® - 5% Ain 1.3

[3342] (1. + 5% 0.8 55 DAD and 7pm, min,

[3343] CH3CN 2.1*50mm) hold 0.7min SQD2

[3344] B: CH3CN

[3345] From 100% A to A: 0.1% Waters:

[3346] 5% A in Waters NH4HCO3 Acquity®

[3347] : BEH 2.10min, in 95% H2O UPLC® - (1.7pm, to 0% A in 0.6 55 DAD and + 5%

[3348] 2.1* 100mm 0.9min, SQD2 and CH3CN

[3349] to 5% A in ) ELSD B: CH3CN

[3350] 0.5min

[3351] From 100% A to A: 0.1%

[3352] Waters: 5% A in Waters NH4HCO3

[3353] Acquity®: BEH 2.10min, in 95% H2O

[3354] UPLC® - (1.7pm, to 0% A in 0.6 55 + 5%

[3355] DAD and 2.1* 100mm 0.9min, CH3CN

[3356] SQD2 to 5% A in ) B: CH3CN

[3357] 0.5min

[3358] A: lOmM From 100% A to

[3359] Waters: CH3C00N 5% A in Waters

[3360] H4 Acquity®: BEH 2.10min,

[3361] in 95% H20 UPLC® - (1.7pm, to 0% A in 0.6 55 DAD and + 5% 2.1* 100mm 0.9min,

[3362] SQD2 CH3CN to 5% A in )

[3363] B: CH3CN 0.5min

[3364]

[3365] A: lOmM

[3366] Waters: CH3C00N

[3367] Acquity® Waters H4 From 100% A to 14 UPLC® -: BEH in 95% H20 5% Ain 1.3

[3368] 0.8 55 DAD and (1.7pm, + 5% min,

[3369] SQD2 2.1*50mm) CH3CN hold 0.7min

[3370] B: CH3CN

[3371] A: lOmM

[3372] Waters: From 100% A to Acquity® Waters CH3C00N 5% A in

[3373] : BEH H4

[3374] UPLC® - 2.10min,

[3375] 15 in 95% H20

[3376] DAD and (1.7pm, to 0% A in 0.6 55 S 2.1* 100mm + 5%

[3377] QD2 and 0.9min,

[3378] CH3CN

[3379] ELSD ) to 5% A in

[3380] B: CH3CN 0.5min

[3381] A: 0.1%

[3382] Waters:

[3383] NH4HCO3

[3384] Acquity® Waters From 100% A to

[3385] in 95% H2

[3386] UPLC: BEH 0

[3387] 16 ® - 5% Ain 1.3

[3388] + 5% 0.8 55 DAD and (1.7pm, min,

[3389] S 2.1*50mm) CH3CN

[3390] QD2 hold 0.7min

[3391] B: CH3CN

[3392]

[3393] Table 2: LC-MS Results

[3394] Monoisot

[3395] Compound number LCMS result Method opic MW

[3396] Compound 1 577.2 confirms the MW; RT = 0.99 min; [M+H]+= 578.2 6 Compound 2 576.2 confirms the MW; RT = 1.86 min; [M+H]+= 577.4 7 Compound 3 577.2 confirms the MW; RT = 2.02 min; [M+H]+= 578.4 1 Compound 4 594.2 confirms the MW; RT = 1.97 min; [M+H]+= 595.6 8 Compound 5 608.2 confirms the MW; RT = 2.22 min; [M+H]+= 609.3 1 Compound 6 608.2 confirms the MW; RT = 2.18 min; [M+H]+= 609.3 1 Compound 7 575.2 confirms the MW; RT = 2.16 min; [M+H]+= 576.2 1 Compound 8 594.2 confirms the MW; RT = 2.21 min; [M+H]+= 595.4 1 Compound 9 576.2 confirms the MW; RT = 1.06 min; [M+H]+= 577.5 2 Compound 10 594.2 confirms the MW; RT = 2.90 min; [M+H]+= 595.2 3 Compound 11 630.2 confirms the MW; RT = 2.09 min; [M+H]+= 631.3 1 Compound 12 631.1 confirms the MW; RT = 2.18 min; [M+H]+= 632.3 1 Compound 13 576.2 confirms the MW; RT = 2.11 min; [M+H]+= 577.3 1 Compound 14 593.2 confirms the MW; RT = 2.06 min; [M+H]+= 594.4 7 Compound 15 612.2 confirms the MW; RT = 1.13 min; [M+H]+= 613.4 2 Compound 16 612.2 confirms the MW; RT = 1.99 min; [M+H]+= 613.5 13

[3397]

[3398] Monoisot

[3399] Compound number LCMS result Method opic MW

[3400] Compound 17 594.2 confirms the MW; RT = 1.98 min; [M+H]+= 595.3 1 Compound 18 595.2 confirms the MW; RT = 2.09 min; [M+H]+= 596.3 1 Compound 19 608.2 confirms the MW; RT = 2.72 min; [M+H]+= 609.2 3 Compound 20 613.2 confirms the MW; RT = 1.1 min; [M+H]+= 614.5 10 Compound 21 609.2 confirms the MW; RT = 2.2 min; [M+H]+= 610.4 12 Compound 22 600.2 confirms the MW; RT = 2.67 min; [M+H]+= 601.1 3 Compound 23 601.2 confirms the MW; RT = 3.57 min; [M+H]+= 602.0 3 Compound 24 636.2 confirms the MW; RT = 2.04 min; [M+H]+= 637.3 1 Compound 25 612.2 confirms the MW; RT = 1.92 min; [M+H]+= 613.3 1 Compound 26 574.2 confirms the MW; RT = 1.33 min; [M+H]+= 575.5 2 Compound 27 591.2 confirms the MW; RT = 2.13 min; [M+H]+= 592.3 1 Compound 28 591.2 confirms the MW; RT = 2.14 min; [M+H]+= 592.3 1 Compound 29 590.2 confirms the MW; RT = 1.96 min; [M+H]+= 591.4 1 Compound 30 593.2 confirms the MW; RT = 2.22 min; [M+H]+= 594.4 1 Compound 31 578.2 confirms the MW; RT = 2.03 min; [M+H]+= 579.4 1 Compound 32 577.2 confirms the MW; RT = 2.56 min; [M+H]+578.1 3 Compound 33 612.2 confirms the MW; RT = 1.80 min; [M+H]+= 613.5 1 Compound 34 562.2 confirms the MW; RT = 1.70 min; [M+H]+= 563.6 8 Compound 35 592.2 confirms the MW; RT = 1.10 min; [M+H]+= 593.5 2 Compound 36 605.2 confirms the MW; RT = 1.96 min; [M+H]+= 606.5 1 Compound 37 591.2 confirms the MW; RT = 2.65 min; [M+H]+= 592.2 3 Compound 38 591.2 confirms the MW; RT = 2.67 min; [M+H]+= 592.2 3 Compound 39 591.2 confirms the MW; RT = 1.96 min; [M+H]+= 592.4 1 Compound 40 594.2 confirms the MW; RT = 2.54 min; [M+H]+= 595.2 3 Compound 41 589.2 confirms the MW; RT = 2.15 min; [M+H]+= 590.4 12 Compound 42 594.2 confirms the MW; RT = 2.11 min; [M+H]+= 595.3 1 Compound 43 594.2 confirms the MW; RT = 1.99 min; [M+H]+= 595.3 1 Compound 44 608.2 confirms the MW; RT = 2.80 min; [M+H]+= 609.2 3 Compound 45 605.2 confirms the MW; RT = 2.76 min; [M+H]+= 606.2 5 Compound 46 617.2 confirms the MW; RT = 2.57 min; [M+H]+= 618.2 3 Compound 47 629.2 confirms the MW; RT = 2.08 min; [M+H]+= 630.3 1 Compound 48 578.2 confirms the MW; RT = 3.23 min; [M+H]+= 579.2 5 Compound 49 595.2 confirms the MW; RT = 2.17 min; [M+H]+= 596.3 1

[3401]

[3402] Monoisot

[3403] Compound number LCMS result Method opic MW

[3404] Compound 50 590.2 confirms the MW; RT = 2.54 min; [M+H]+= 591.2 3 Compound 51 602.2 confirms the MW; RT = 2.59 min; [M+H]+= 603.2 3 Compound 52 594.2 confirms the MW; RT = 2.00 min; [M+H]+= 595.4 13 Compound 53 591.2 confirms the MW; RT = 1.97 min; [M+H]+= 592.3 1 Compound 54 593.2 confirms the MW; RT = 2.26 min; [M+H]+= 594.4 12 Compound 55 630.2 confirms the MW; RT = 2.17 min; [M+H]+= 631.3 12 Compound 56 594.2 confirms the MW; RT = 2.60 min; [M+H]+= 595.1 3 Compound 57 603.2 confirms the MW; RT = 2.17 min; [M+H]+= 604.3 1 Compound 58 577.2 confirms the MW; RT = 3.64 min; [M+H]+= 578.2 3 Compound 59 645.2 confirms the MW; RT = 2.22 min; [M+H]+= 646.3 1 Compound 60 644.2 confirms the MW; RT = 2.20 min; [M+H]+= 645.3 1 Compound 61 601.2 confirms the MW; RT = 1.04 min; [M+H]+= 602.4 10 Compound 62 603.2 confirms the MW; RT = 4.08 min; [M+H]+= 604.2 5 Compound 63 611.1 confirms the MW; RT = 3.01 min; [M+H]+= 611.1 5 Compound 64 630.2 confirms the MW; RT = 2.07 min; [M+H]+= 631.2 1 Compound 65 592.2 confirms the MW; RT = 2.58 min; [M+H]+= 593.2 3 Compound 66 591.2 confirms the MW; RT = 1.79 min; [M+H]+= 592.3 1 Compound 67 609.1 confirms the MW; RT = 2.14 min; [M+H]+= 610.3 12 Compound 68 620.2 confirms the MW; RT = 2.56 min; [M+H]+= 621.1 3 Compound 69 608.2 confirms the MW; RT = 2.72 min; [M+H]+= 609.0 3 Compound 70 595.2 confirms the MW; RT = 3.36 min; [M+H]+= 596.0 3 Compound 71 606.2 confirms the MW; RT = 2.70 min; [M+H]+= 607.2 3 Compound 72 626.2 confirms the MW; RT = 2.00 min; [M+H]+= 627.3 9 Compound 73 625.2 confirms the MW; RT = 2.06 min; [M+H]+= 626.7 13 Compound 74 595.2 confirms the MW; RT = 2.80 min; [M+H]+= 596.2 5 Compound 75 591.2 confirms the MW; RT = 1.85 min; [M+H]+= 592.3 1 Compound 76 605.2 confirms the MW; RT = 2.05 min; [M+H+= 606.3 1 Compound 77 753.2 confirms the MW; RT = 2.49 min; [M+H]+= 754.7 15 Compound 78 637.2 confirms the MW; RT = 2.02 min; [M+H]+= 638.5 1 Compound 79 561.2 confirms the MW; RT = 1.04 min; [M+H]+= 562.5 2 Compound 80 597.1 confirms the MW; RT = 1.07 min; [M+H]+= 598.3 6 Compound 81 598.1 confirms the MW; RT = 1.12 min; [M+H]+= 599.2 2 Compound 82 611.2 confirms the MW; RT = 1.96 min; [M+H]+= 612.5 9

[3405]

[3406] Monoisot

[3407] Compound number LCMS result Method opic MW

[3408] Compound 83 589.2 confirms the MW; RT = 2.09 min; [M+H]+= 590.3 1 Compound 84 589.2 confirms the MW; RT = 2.09 min; [M+H]+= 590.3 1 Compound 85 625.2 confirms the MW; RT = 2.06 min; [M+H]+= 626.3 1 Compound 86 625.2 confirms the MW; RT = 2.06 min; [M+H]+= 626.3 1 Compound 87 579.2 confirms the MW; RT = 1.87 min; [M+H]+= 580.2 1 Compound 88 593.2 confirms the MW; RT = 2.22 min; [M+H]+= 594.3 1 Compound 89 591.2 confirms the MW; RT = 1.21 min; [M+H]+= 592.5 2 Compound 90 576.2 confirms the MW; RT = 1.78 min; [M+H]+= 577.3 1 Compound 91 579.2 confirms the MW; RT = 1.90 min; [M+H]+= 580.3 1 Compound 92 608.2 confirms the MW; RT = 2.28 min; [M+H]+= 609.4 1 Compound 93 590.2 confirms the MW; RT = 2.23 min; [M+H]+= 591.3 1 Compound 94 590.2 confirms the MW; RT = 2.15 min; [M+H]+= 591.3 1 Compound 95 590.2 confirms the MW; RT = 2.23 min; [M+H]+= 591.3 1 Compound 96 598.1 confirms the MW; RT = 1.76 min; [M+H]+= 599.5 8 Compound 97 608.2 confirms the MW; RT = 1.95 min; [M+H]+= 609.4 1 Compound 98 594.2 confirms the MW; RT = 1.85 min; [M+H]+= 595.4 1 Compound 99 613.2 confirms the MW; RT = 1.98 min; [M+H]+= 614.4 1 Compound 100 577.2 confirms the MW; RT = 1.94 min; [M+H]+= 578.3 1 Compound 101 613.2 confirms the MW; RT = 1.88 min; [M+H]+= 614.3 1 Compound 102 563.2 confirms the MW; RT = 1.75 min; [M+H]+= 564.3 1 Compound 103 627.2 confirms the MW; RT = 1.94 min; [M+H]+= 628.3 1 Compound 104 613.2 confirms the MW; RT = 1.95 min; [M+H]+= 614.5 13 Compound 105 599.1 confirms the MW; RT = 1.83 min; [M+H]+= 600.4 13 Compound 106 608.2 confirms the MW; RT=:2.95 min; [M+H]+= 609.2 3 Compound 107 600.2 confirms the MW; RT = 2.17 min; [M+H]+= 601.3 1 Compound 108 748.2 confirms the MW; RT = 1.65 min; [M+H]+= 749.4 12 Compound 109 590.2 confirms the MW; RT = 1.10 min; [M+H]+= 591.5 4 Compound 110 732.2 confirms the MW; RT = 2.32 min; [M+H]+= 733.3 1 Compound 111 605.2 confirms the MW; RT = 2.12 min; [M+H]+= 606.6 11 Compound 112 620.2 confirms the MW; RT = 2.57 min; [M+H]+= 621.0 3 Compound 113 590.2 confirms the MW; RT = 0.98 min; [M+H]+= 591.4 10 Compound 114 614.2 confirms the MW; RT = 2.04 min; [M+H]+= 615.3 1

[3409]

[3410] Monoisot

[3411] Compound number LCMS result Method opic MW

[3412] Compound 115 737.2 confirms the MW; RT = 2.37 min; [M+H]+= 738.4 12 Compound 116 767.2 confirms the MW; RT = 1.76 min; [M+H]+= 768.4 12 Compound 117 602.2 confirms the MW; RT = 1.78 min; [M+H]+= 603.3 11 Compound 118 575.2 confirms the MW; RT = 2.03 min; [M+H]+= 576.3 1 Compound 119 864.2 confirms the MW; RT = 1.62 min; [M+H]+= 865.3 1 Compound 120 754.2 confirms the MW; RT = 2.32 min; [M+H]+= 755.4 12 Compound 121 692.2 confirms the MW; RT = 2.13 min; [M+H]+= 693.3 1 Compound 122 734.2 confirms the MW; RT = 2.35 min; [M+H]+= 735.3 1 Compound 123 755.2 confirms the MW; RT = 2.13 min; [M+H]+= 756.6 13 Compound 124 718.2 confirms the MW; RT = 2.25 min; [M+H]+= 719.3 1 Compound 125 780.2 confirms the MW; RT = 2.17 min; [M+H]+= 781.4 1 Compound 126 766.2 confirms the MW; RT = 2.09 min; [M+H]+= 767.7 11 Compound 127 776.2 confirms the MW; RT = 2.01 min; [M+H]+= 777.3 14 Compound 128 768.2 confirms the MW; RT = 2.39 min; [M+H]+= 769.3 1 Compound 129 719.2 confirms the MW; RT = 2.24 min; [M+H]+= 720.4 12 Compound 130 735.2 confirms the MW; RT = 1.34 min; [M+H]+= 736.5 16 Compound 131 592.2 confirms the MW; RT = 1.86 min; [M+H]+= 593.3 1 Compound 132 609.2 confirms the MW; RT = 3.82 min; [M+H]+= 610.0 3 Compound 133 595.2 confirms the MW; RT = 3.61 min; [M+H]+= 596.3 3 Compound 134 618.2 confirms the MW; RT = 1.98 min; [M+H]+= 619.5 11 Compound 135 577.2 confirms the MW; RT = 1.85 min; [M+H]+= 578.5 1 Compound 136 619.2 confirms the MW; RT = 1.88 min; [M+H]+= 620.6 11 Compound 137 621.2 confirms the MW; RT = 2.23 min; [M+H]+= 622.4 12 Compound 138 575.2 confirms the MW; RT = 1.98; [M+H]+= 576.3 1 Compound 139 575.2 confirms the MW; RT = 1.96; [M+H]+= 576.3 1 Compound 140 597.1 confirms the MW; RT = 1.96; [M+H]+= 598.3 1 Compound 141 597.1 confirms the MW; RT = 1.96; [M+H]+= 598.4 1 Compound 142 575.2 confirms the MW; RT = 1.08; [M+H]+= 576.5 2 Compound 143 629.2 confirms the MW; RT = 1.12; [M+H]+= 630.5 2 Compound 144 601.2 confirms the MW; RT = 1.15; [M+H]+= 602.5 2 Compound 145 589.2 confirms the MW; RT = 1.13; [M+H]+= 590.5 2 Compound 146 589.2 confirms the MW; RT = 1.14; [M+H]+= 590.5 2 Compound 147 559.2 confirms the MW; RT = 1.05; [M+H]+= 560.4 2

[3413]

[3414] Monoisot

[3415] Compound number LCMS result Method opic MW

[3416] Compound 148 579.2 confirms the MW; RT = 1.06; [M+H]+= 580.4 2 Compound 149 579.2 confirms the MW; RT = 1.87; [M+H]+= 580.5 8 Compound 150 579.2 confirms the MW; RT = 1.87; [M+H]+= 580.5 8 Compound 151 579.2 confirms the MW; RT = 1.87; [M+H]+= 580.6 8 Compound 152 579.2 confirms the MW; RT = 1.87; [M+H]+= 580.6 8 Compound 153 575.2 confirms the MW; RT = 2.12; [M+H]+= 576.3 1 Compound 154 575.2 confirms the MW; RT = 2.15; [M+H]+= 576.3 1 Compound 155 575.2 confirms the MW; RT = 2.12; [M+H]+= 576.3 1 Compound 156 575.2 confirms the MW; RT = 2.15; [M+H]+= 576.3 1 Compound 157 589.2 confirms the MW; RT = 2.22; [M+H]+= 590.4 1 Compound 158 589.2 confirms the MW; RT = 2.22; [M+H]+= 590.3 1 Compound 159 560.1 confirms the MW; RT = 1.99; [M+H]+= 561.3 1 Compound 160 560.1 confirms the MW; RT = 1.99; [M+H]+= 561.3 1 Compound 161 577.2 confirms the MW; RT = 2.40; [M+H]+= 578.1 3

[3417]

[3418] SFC data

[3419]

[0380] The SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). 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. Analytical SFC-MS Methods (Flow expressed in mL / min; column temperature (Col T) in °C; Run time in minutes, Backpressure (BPR) in bars. “iPrNEh ” means isopropylamine, “iPrOH” means 2-propanol, “EtOH” means ethanol, “min” mean minutes, “DEA” means diethylamine.Table 3. SFC Methods

[3420] Method column mobile gradient Flow Run Code phase time Col T Daicel

[3421] 10%-50% B in 6

[3422] Chiralpak® A:CO2

[3423] min, hold 3.5 2.5 10.0 AD3 B:

[3424] Method 1 min, to 20% B in

[3425] column (3.0 EtOH+O.2%

[3426] O.lmin and hold 40 130 pm, 4.6 mm iPrNH₂

[3427] 0.4min

[3428] x 150 mm)

[3429] Phenomene A:CO2

[3430] From 5% B to

[3431] x Lux i- B: EtOH 2.5 13 Method 2 60% B in 7 min,

[3432] Amylose-3 +0.1%

[3433] hold 2 min. To

[3434] 100 x4.6 Diethylamin 35 100

[3435] 5% B in 1 min.

[3436] mm, 3 mm e

[3437] Regis

[3438] A:CO2

[3439] Technologic From 5% B to

[3440] B: 2.5 13 Method 3 s Whelk-Ol 60% B in 7 min,

[3441] EtOH+0.1%

[3442] 100 x4.6 hold 2 min. To

[3443] Diethylamin 35 100 mm, 3.5 5% B in 1 min.

[3444] e

[3445] mm

[3446] A:CO2

[3447] Phenomene

[3448] B: From 5% B to

[3449] x Lux i- 2.5 13 Method 4 MeOH+0.1 60% B in 7 min,

[3450] Amylose-3

[3451] % hold 2 min. To

[3452] 100x 4.6 35 100

[3453] Diethylamin 5% B in 1 min.

[3454] mm, 3 mm

[3455] e

[3456] Daicel

[3457] A: CO 10%-50% B in 6 Chiralpak®2

[3458] B: EtOH- min, hold 3.5 2.5 10.0 OD3

[3459] Method 5 iPrOH (50- min, to 20% B in

[3460] column (3.0

[3461] 50)+0.2% O.lmin and hold 40 130 pm, 4.6 mm

[3462] iPrNH₂ 0.4min

[3463] x 150 mm)

[3464] Daicel

[3465] 10%-50% B in 6

[3466] Chiralpak® A:CO2

[3467] min, hold 3.5 2.5 10.0 ID3 column B:

[3468] Method 6 min, to 20% B in

[3469] (3.0 pm, 4.6 EtOH+O.2%

[3470] O.lmin and hold 40 130 mm x 150 iPrNH₂

[3471] 0.4min

[3472] mm)

[3473] Daicel

[3474] 10%-50% B in 6

[3475] Chiralpak® A:CO2

[3476] min, hold 3.5 2.5 10.0 IG3 column B:

[3477] Method 7 min, to 20% B in

[3478] (3.0 pm, 4.6 EtOH+O.2%

[3479] O.lmin and hold 40 130 mm x 150 iPrNH₂

[3480] 0.4min

[3481] mm)

[3482] Daicel A:CO2

[3483] 10%-50% B in 6 2.5 10.0 Chiralpak® B:

[3484] Method 8 min, hold 3.5

[3485] OJ3 column EtOH+O.2%

[3486] min, to 20% B in 40 130

[3487]

[3488] (3.0 pm, 4.6 iPrNH₂mm x 150mm) 0.1min and hold0.4min

[3489]

[3490] Table 4. SFC data for separated final compounds:

[3491] SFC Method

[3492] Compound Rt Purity [M+H]+code

[3493] Compound 5 Method 1 5.15 100 609.2 Compound 6 Method 4 5.69 99

[3494] Compound 19 Method 3 6.38 99

[3495] Compound 27 Method 1 5.78 100 592.4 Compound 28 Method 1 7.46 100 592.4 Compound 37 Method 2 5.68 99

[3496] Compound 38 Method 2 6.33 99

[3497] Compound 44 Method 4 6.25 99

[3498] Compound 68 Method 2 6.07 99 - Compound 83 Method 1 4.74 100 590.2 Compound 84 Method 1 5.22 100 590.2 Compound 85 Method 1 4.72 100 626.5.0 Compound 86 Method 1 5.53 100 626.5 Compound 92 Method 1 4.32 100 609.2 Compound 106 Method 3 5.64 99

[3499] Compound 112 Method 2 7.31 99 - Compound 140 Method 5 5.04 100 598.4 Compound 141 Method 5 5.57 100 598.4 Compound 149

[3500] Method 1 6.85 100 580.2 Compound 150

[3501] Method 1 7.56 100 580.2 Compound 151

[3502] Method 1 6.47 100 580.2 Compound 152

[3503] Method 1 5.20 100 580.2 Compound 153

[3504] Method 6 5.20 100 576.2

[3505]

[3506] SFC Method

[3507] Compound Rt Purity [M+H]+

[3508] code

[3509] Compound 154

[3510] Method 6 5.98 100 576.2 Compound 155

[3511] Method 6 5.03 100 576.2 Compound 156

[3512] Method 6 5.40 100 576.2 Compound 157

[3513] Method 7 6.19 100 590.5 Compound 158

[3514] Method 7 6.93 100 590.5 Compound 159

[3515] Method 8 6.29 100 561.2 Compound 160

[3516] Method 8 7.05 100 561.2

[3517]

[3518] NMR data:

[3519]

[0381] 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 (d) 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, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets. 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.

[3520] Table 5 NMR resultsCompound number NMR data

[3521] 'HNMR (400 MHz, DMSO-J6) d ppm 0.90 (d, J= 6.6 Hz, 3 H) 1.04 - 1.14 (m, 1 H) 1.70 (br s, 1 H) 1.87 - 1.96 (m, 1 H) 2.54 (s, 3 H) 2.63 (td, J= 11.9, 6.5 Hz, 2H) 2.71 (s, 3 H) 3.54 - 3.75 (m, 3 H) 3.84 - Compound 1

[3522] 3.93 (m, 1 H) 4.07 - 4.29 (m, 4 H) 7.11 (t, J= 52.5 Hz, 1 H) 7.78 (s, 1 H) 7.94 (dd, J=5.1, 1.8 Hz, 1 H) 8.08 (s, 1 H) 8.12 (d, J= 7.3 Hz, 1

[3523] H) 8.73 (dd, J=5.1, 0.7 Hz, 1 H) 8.78 (s, 1 H) 'HNMR (400 MHz, DMSO-J6) d ppm 0.89 (d, J= 6.6 Hz, 3 H) 1.00 - 1.14 (m, 1 H) 1.61 - 1.78 (m, 1 H) 1.90 (brd, J= 12.6 Hz, 1 H) 2.53 (s, 6 H) 2.62 (td, J= 11.9, 4.9 Hz, 2 H) 3.52 - 3.60 (m, 1 H) 3.64 (br Compound 2 dd, J= 13.2, 3.7 Hz, 1 H) 3.68 - 3.77 (m, 1 H) 3.87 (brdd, J= 12.1,

[3524] 4.6 Hz, 1 H) 4.06 - 4.15 (m, 2 H) 4.18 - 4.27 (m, 2 H) 7.11 (t, J=52.5 Hz, 1 H) 7.76 (s, 2 H) 7.83 (dd, J= 5.1, 1.5 Hz, 1 H) 7.86 (s, 1 H) 8.12 (d, J= 7.2 Hz, 1 H) 8.38 (s, 1 H) 8.70 (d, J= 5.1 Hz, 1 H) ’HNMR (400 MHz, DMSO-J6) d ppm 0.90 (d, J= 6.6 Hz, 3 H) 1.08 (q, J= 12.3 Hz, 1 H) 1.21 - 1.37 (m, 2 H) 1.64 - 1.75 (m, 1 H) 1.91 (brd, J= 12.8 Hz, 1 H) 2.55 (s, 6 H) 2.63 (td, J= 11.8, 6.3 Hz, 2 H) Compound 3

[3525] 3.55 - 3.74 (m, 3 H) 3.88 (brdd, J= 12.3, 4.6 Hz, 1 H) 4.07 - 4.28 (m, 4 H) 7.11 (t, J= 52.4 Hz, 1 H) 7.86 - 7.91 (m, 3 H) 8.12 (d, J=7.3

[3526] Hz, 1 H) 9.09 (s, 1 H) 9.23 (s, 1 H)

[3527] ’H NMR (400 MHz, DMSO-J6) d ppm 0.89 (br d, J= 6.38 Hz, 3 H) 1.07 (q, J= 12.18 Hz, 1 H) 1.70 (br d, J= 5.94 Hz, 1 H) 1.85 - 1.97 (m, 1 H) 2.52 (s, 6 H) 2.56 -2.65 (m, 1 H) 2.62 (td, J= 11.72, 5.83 Hz, 1 H) 3.27 - 3.29 (m, 1 H) 3.50 - 3.61 (m, 1 H) 3.61 - 3.68 (m, 1 H) 3.70 (br dd, J= 11.11, 4.51 Hz, 1 H) 3.83 - 3.93 (m, 1 H) 4.05 - Compound 4

[3528] 4.15 (m, 2 H) 4.22 (br t, J= 8.14 Hz, 2 H) 7.10 (t, J= 52.38 Hz, 1 H) 7.53 (s, 2 H) 7.59 (brd, J = 1.98 Hz, 1 H) 8.01 (br t, J= 5.17 Hz, 1 H) 8.11 (brd, J = 7.26 Hz, 1 H) 8.53 - 8.60 (m, 1 H); 19FNMR(377 MHz, DMSO-d6) d ppm -126.49 (s, 1 F) -123.09 (br d, J= 52.20 Hz,

[3529] 2 F)

[3530] ’H NMR (400 MHz, DMSO-J6) d ppm 0.90 (d, J= 6.58 Hz, 3 H) 1.09 (q, J= 12.19 Hz, 1 H) 1.53 (d, J= 6.27 Hz, 3 H) 1.63 - 1.77 (m, 1 H) 1.91 (brd, J= 12.75 Hz, 1 H) 2.54 (s, 6 H) 2.63 (td, J= 11.76, 7.11 Hz, 2 H) 3.19 (q, J= 7.21 Hz, 1 H) 3.59 - 3.67 (m, 1 H) 3.67 - 3.76 (m, 1 H) 3.87 (brdd, J= 12.02, 3.87 Hz, 1 H) 3.97 (t, J= 7.32 Compound 5

[3531] Hz, 1 H) 4.13 (t, J= 7.94 Hz, 1 H) 4.32 (quin, J = 6.27 Hz, 1 H) 7.11 (t, J= 52.47 Hz, 1 H) 7.67 (br d, J= 9.72 Hz, 1 H) 7.86 (s, 3 H) 7.94 (brd, J= 10.14 Hz, 1 H) 8.13 (br d, J= 7.32 Hz, 1 H); 19FNMR (376 MHz, DMSO-d6) d ppm -123.13 (br d, J= 52.02 Hz, 2 F) - 101.93 (brt, J= 10.40 Hz, 1 F)

[3532] ’HNMR (400 MHz, DMSO-J6) d ppm 0.89 (d, J= 6.6 Hz, 3 H) 1.08 (q, J= 12.3 Hz, 1 H) 1.53 (d, J= 6.2 Hz, 3 H) 1.69 (br d, J= 4.0 Hz, 1 H) 1.90 (brd, J = 12.3 Hz, 1 H) 2.53 (s, 6 H) 2.62 (td, J= 11.9, 5.9 Compound 6 Hz, 2 H) 3.15 - 3.22 (m, 1 H) 3.60 - 3.74 (m, 2 H) 3.85 (br dd, J =

[3533] 12.1, 4.4 Hz, 1 H) 3.97 (t, J =7.4 Hz, 1 H) 4.14 (t, J= 8.0 Hz, 1 H) 4.32 (quin, J = 6.3 Hz, 1 H) 6.95 - 7.25 (m, 1 H) 7.54 (s, 1 H) 7.73 (s, 2H) 8.01 (s, 1 H) 8.12 (d, J= 7.3 Hz, 1 H) 8.39 (s, 1 H) ’HNMR (400 MHz, DMSO-J6) d ppm 0.89 (d, J= 6.6 Hz, 3 H) 1.02 - 1.20 (m, 1 H) 1.70 (brdd, J= 10.6, 4.0 Hz, 1 H) 1.85 - 2.01 (m, 1 Compound 7 H) 2.50 (s, 6 H) 2.62 (td, J= 11.8, 6.2 Hz, 2 H) 3.51 - 3.75 (m, 3 H)

[3534] 3.87 (br dd, J= 12.3, 4.4 Hz, 1 H) 4.00 - 4.25 (m, 4 H) 7.10 (t, J=

[3535]

[3536] 52.5 Hz, 1 H) 7.37 - 7.42 (m, 2 H) 7.45 - 7.48 (m, 1 H) 7.49 - 7.56(m, 1 H) 7.66 (d, J= 7.9Hz, 1 H) 7.92 (d, J= 7.9 Hz, l H) 8.10 (d, J = 7.3 Hz, l H) 8.15 (s, 1 H)

[3537] 1H NMR (400 MHz, DMSO-J6) d ppm 0.90 (d, J= 6.60 Hz, 3 H) 1.08 (q, J= 12.10Hz, 1 H) 1.62 - 1.78 (m, 1 H) 1.91 (brd, J= 12.98 Hz, 1 H) 2.53 (s, 6 H) 2.57 - 2.72 (m, 2 H) 3.51 - 3.61 (m, 1 H) 3.61 - 3.68 (m, 1 H) 3.68 - 3.77 (m, 1 H) 3.88 (brdd, J= 12.21, 4.51 Hz, 1 Compound 8 H) 4.10 (ddd, J= 7.59, 6.05, 3.74 Hz, 2 H) 4.18 - 4.24 (m, 2 H) 7.11

[3538] (t, J= 52.49 Hz, 1 H) 7.66 (dd, J= 9.68, 2.20 Hz, 1 H) 7.85 (s, 2 H) 7.85 (s, 1 H) 7.94 (dd, J= 10.12, 2.20 Hz, 1 H) 8.13 (d, J= 7.26 Hz, 1 H); 19F NMR (377 MHz, DMSO-d6) d ppm -123.10 (br d, J= 52.20

[3539] Hz, 1 F) -101.98 (t, J= 10.04 Hz, 1 F)

[3540] 'HNMR (600 MHz, DMSO-de) d = 8.57 (s, 1H), 8.14 (br d, J= 7.3 Hz, 1H), 8.08 (br d, J= 7.7 Hz, 1H), 7.99 (d, J= 7.7 Hz, 1H), 7.83 (s, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.11 (t, J= 52.5 Hz, 1H), 4.23 - 4.19 (m, 2H), 4.11 -4.06 (m, 2H), 3.87 (brd, J= 12.5 Hz, 1H), Compound 9

[3541] 3.74 - 3.67 (m, 1H), 3.64 (br d, J= 9.2 Hz, 1H), 3.59 - 3.54 (m, 1H), 3.43 - 3.38 (m, 1H), 3.17 (d, J= 4.8 Hz, 1H), 2.65 (s, 3H), 2.64 - 2.60 (m, 2H), 1.90 (brd, J= 12.5 Hz, 1H), 1.69 (br s, 1H), 1.11 - 1.04 (m,

[3542] 1H), 0.89 (d, J = 6.6 Hz, 3H)

[3543] 'H NMR (400 MHz, DMSO-J6) dppm 8.38 (s, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.99 (s, 1H), 7.73 (s, 2H), 7.54 (s, 1H), 7.12 (t, J = 52.5 Hz, 1H), 4.23 (t, J = 8.2 Hz, 2H), 4.15 - 4.08 (m, 2H), 3.88 (dd, J = 12.1, Compound 10 4.3 Hz, 1H), 3.77 - 3.68 (m, 1H), 3.65 (dd, J = 13.0, 3.4 Hz, 1H),

[3544] 3.61 - 3.52 (m, 1H), 2.63 (td, J = 12.0, 3.7 Hz, 2H), 2.53 (s, 6H), 1.90 (d, J = 12.7 Hz, 1H), 1.78 - 1.63 (m, 1H), 1.08 (q, J = 12.2 Hz, 1H),

[3545] 0.90 (d, J = 6.5 Hz, 3H).

[3546] 1H NMR (400 MHz, DMSO-J6) d ppm 0.89 (d, J= 6.60 Hz, 3 H) 1.08 (q, J= 12.18 Hz, 1 H) 1.61 - 1.78 (m, 1 H) 1.90 (brd, J= 12.54 Hz, 1 H) 2.57 - 2.71 (m, 5 H) 3.52 - 3.61 (m, 1 H) 3.61 - 3.68 (m, 1 H) 3.68 - 3.78 (m, 1 H) 3.87 (br dd, J= 12.10, 3.96 Hz, 1 H) 4.06 - Compound 11 4.16 (m, 2 H) 4.18 - 4.30 (m, 2 H) 7.01 (t, J= 55.02 Hz, 1 H) 7.10 (t,

[3547] J= 52.38 Hz, 1 H) 7.59 (s, 1 H) 8.03 (s, 1 H) 8.12 (brd, J= 7.26 Hz, 1 H) 8.16 (s, 2 H) 8.50 (s, 1 H); 19F NMR (377 MHz, DMSO-d6) d ppm -123.09 (br d, J= 52.20 Hz, 2 F) -115.41 (d, J= 54.21 Hz, 2 F) - 67.19 (br s, 1 F)

[3548] 'H NMR (400 MHz, DMSO-J6) d ppm 0.90 (br d, J= 6.48 Hz, 3 H) 1.08 (q, J= 12.33 Hz, 1 H) 1.65 - 1.74 (m, 1 H) 1.91 (brd, J= 12.23 Hz, 1 H) 2.63 (td, J= 11.68, 6.64 Hz, 2 H) 2.83 (s, 3 H) 3.51 - 3.61 (m, 1 H) 3.65 (brd, J= 11.91 Hz, 1 H) 3.71 (brdd, J= 10.82, 4.23 Hz, 1 H) 3.88 (brdd, J= 12.12, 3.66 Hz, 1 H) 4.06 - 4.18 (m, 2 H) Compound 12

[3549] 4.25 (brt, J= 8.05 Hz, 2 H) 7.06 (t, J= 54.24 Hz, 1 H) 7.10 (t, J = 52.47 Hz, 1 H) 7.77 (s, 1 H) 7.95 (s, 1 H) 8.14 (br d, J= 7.21 Hz, 1 H) 8.24 (s, 1 H) 8.77 (s, 1 H); 19F NMR (376 MHz, DMSO-d6) d ppm -123.13 (br d, J= 52.02 Hz, 2 F) -120.19 (d, J= 53.75 Hz, 2 F) - 67.87 (br s, 1 F)

[3550] 1H NMR (400 MHz, DMSO-J6) d ppm 0.90 (d, J= 6.60 Hz, 3 H) 1.08 (q, J= 12.18 Hz, 1 H) 1.61 - 1.77 (m, 1 H) 1.91 (brd, J= 12.98 Hz, 1 H) 2.53 (s, 6 H) 2.56 - 2.63 (m, 1 H) 2.63 - 2.70 (m, 1 H) 3.49 - 3.60 (m, 1 H) 3.65 (brd, J= 11.44 Hz, 1 H) 3.68 - 3.79 (m, 1 H) 3.88 Compound 13 (brdd, J= 11.99, 4.29 Hz, 1 H) 4.07 -4.13 (m, 2 H) 4.16 - 4.25 (m, 2

[3551] H) 7.11 (t, J= 52.38 Hz, 1 H) 7.76 (s, 1 H) 7.81 (s, 1 H) 7.81 - 7.83 (m, 1 H) 7.91 - 7.96 (m, 1 H) 7.94 - 7.98 (m, 1 H) 7.95 - 7.99 (m, 1 H) 8.12 (brd, J= 7.26 Hz, 1 H); 19F NMR (377 MHz, DMSO-d6) d

[3552]

[3553] ppm -123.09 (br d, J= 52.20 Hz, 2 F)1H NMR (400 MHz, DMSO-J6) d ppm 0.90 (d, J= 6.6 Hz, 3 H),

[3554] 1.07 (q, J= 12.2 Hz, 1 H), 1.69 (brs, 1 H), 1.90 (brd, J= 12.6 Hz, 1 H), 2.50 - 2.52 (m, 6 H), 2.54 (br s, 1 H), 2.62 (td, J= 11.9, 5.0 Hz, 2 Compound 14 H), 3.51 - 3.76 (m, 1 H), 3.52 - 3.72 (m, 2 H), 3.82 - 3.90 (m, 1 H),

[3555] 4.04 - 4.13 (m, 2 H), 4.13 - 4.23 (m, 2 H), 6.92 - 7.39 (m, 1 H), 7.24 - 7.39 (m, 3 H), 7.47 (t, J= 7.0 Hz, 1 H), 8.05 - 8.11 (m, 1 H), 8.12 (d,

[3556] J= 7.3 Hz, 1 H)

[3557] ’H NMR (600 MHz, DMSO-de) d = 8.63 (s, 1H), 8.23 (s, 1H), 8.15 (br d, J= 1.3 Hz, 2H), 8.05 (br d, J= 7.7 Hz, 1H), 7.61 (t, J= 7.7 Hz, 1H), 7.47 (s, 1H), 7.12 (brs, 1H), 7.00 (br t, J= 54.1 Hz, 1H), 4.21 (brt, J= 8.1 Hz, 2H), 4.14 - 4.05 (m, 2H), 3.87 (brd, J= 12.1 Hz, Compound 15 1H), 3.70 (br s, 1H), 3.64 (br d, J= 9.9 Hz, 1H), 3.57 (br d, J= 6.2

[3558] Hz, 1H), 3.17 (d, J = 5.1 Hz, 1H), 2.66 - 2.63 (m, 3H), 2.63 - 2.60 (m, 1H), 1.90 (brd, J= 12.8 Hz, 1H), 1.69 (brs, 1H), 1.13 - 1.03 (m, 1H),

[3559] 0.90 (br d, J = 6.6 Hz, 3H)

[3560] 'HNMR (400 MHz, DMSO-J6) d ppm 0.90 (d, J= 6.6 Hz, 3 H) 1.08 (q, J= 12.3 Hz, 1 H) 1.62 - 1.78 (m, 1 H) 1.90 (brd, J= 12.5 Hz, 1 H) 2.56 - 2.63 (m, 1 H) 2.64 (s, 3 H) 3.54 - 3.60 (m, 1 H) 3.60 - 3.78 Compound 16 (m, 3 H) 3.87 (br dd, J= 12.1, 4.4 Hz, 1 H) 4.07 - 4.15 (m, 2 H) 4.19

[3561] - 4.26 (m, 2 H) 6.84 - 7.25 (m, 2 H) 7.89 (dd, J= 5.1, 1.5 Hz, 1 H) 7.91 (s, 1 H) 8.12 (d, J= 7.5 Hz, 1 H) 8.18 (s, 1 H) 8.22 (s, 1 H) 8.50

[3562] (s, 1 H) 8.75 (d, J=5.1 Hz, 1 H)

[3563] 'H NMR (400 MHz, DMSO-J6) d ppm 8.15 (td, J= 7.5, 1.9 Hz, 1 H) 8.11 (d, J= 7.3 Hz, 1 H) 7.85 (td, J= 7.4, 1.9 Hz, 1 H) 7.60 (d, J= 2.0 Hz, 1 H) 7.41 (t, J = 7.7 Hz, 1 H) 7.30 (d, J = 2.9 Hz, 1 H) 7.11 (t, J= 52.5 Hz, 1 H) 4.16 - 4.24 (m, 2 H) 4.08 ...

Claims

CLAIMS1. A compound having the structure of formula (I):OR2(I)or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope, or prodrug thereof, wherein,R1ais a 6-membered heterocycle containing one nitrogen atom as heteroatom, said nitrogen atom substituted with -SO2-Ci-4haloalkyl, said heterocycle optionally substituted with one, two, or three substituents selected from halo, Ci-4alkyl, or haloCi-4alkyl; a 9-membered spiro-heterocycle containing one nitrogen atom as heteroatom, said nitrogen atom substituted with −SO2−C1-4haloalkyl; or a 6-to 8- membered fused-heterocycle containing one nitrogen atom as heteroatom, said nitrogen atom substituted with -SO2-Ci-4haloalkyl;R1bis hydrogen, C1-4alkyl, -C(O)-O-CH2-O-C(O)-R1c; or-C(O)-O-CH(CH3)-O-C(O)-R1c;R1cis C1-6alkyl optionally substituted with -O-CH2-CH2-O-CH3, piperazinyl, or phenyl, said phenyl optionally substituted with -0-P(0)(0H)2; C2-6alkenyl optionally substituted with -COOH; C3-6cycloalkyl; phenyl; or pyridinyl;R2is hydrogen, -OH, or halo;R3is hydrogen, -CH3, or -CH2-O-CH3;R4is a structure of formula (II)wherein,Z1is C or N;Z2is C or N;Z3is C or N;Z4is C or N;Z5is C or N;R11is hydrogen, or amino;R12is hydrogen, or halo;R13is hydrogen, halo, C1-4alkyl, haloC1-4alkyl, -CN, -O-C1-4alkyl, -NH-C1-4alkyl, amino, hydroxy;R14is hydrogen, or fluoro;R15is hydrogen, or halo;R16is Ci-4alkyl, haloCi-4alkyl, -O-Ci-4alkyl, C3-6cycloalkyl, azetidinyl, -N(Ci-4alkyl)2; R17is hydrogen, halo, hydroxy, -O-C1-4alkyl, -CN;R18is - Ci-4alkyl, haloCi-4alkyl, C3-6cycloalkyl, -N(Ci-4alkyl)2;or R17and R18form, together with the ring to which they are attached, a 5- or 6- membered heterocycle with an oxygen or nitrogen atom;provided that Z1and Z2cannot be both nitrogens;provided that when Z1, Z2, Z3, Z4, or Z5, is, each independently, nitrogen, then R12, R13, R14, R15, R17is, each independently, absent.

2. A compound of claim 1, wherein R1ais the structure of formula (III)>5wherein,R5is hydrogen, halo, C1-4alkyl, haloC1-4alkyl;R6is hydrogen or halo.A compound of claim 1, having the structure of Formula (IV):wherein substituents R1b, R2, R3, R5, R6, Z1, Z2, Z3, Z4, Z5, R11, R12, R13, R14, R15, R16, R17, R18are as defined in claim 1 or 2.

4. A compound of any one of the preceding claims, wherein:R11is H, or NH2;R12is H, F, or Cl;R13is H, F, Cl, -CH3, -CHF2, -CN, -O-CH3, -NH-CH3, -NH2, or -OH;R14is H, or F;R15is H, or F;R16is -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, cyclopropyl, azetidinyl, -N(CH3)2; R17is H, F, -OH, -OCH3, or -CN;R18is -CH3, — CHF2, cyclopropyl, or -N(CH3)2;or R17and R18form, together with the ring to which they are attached, a 5-membered heterocycle with an oxygen or nitrogen atom; preferably said 5-membered heterocycle is not aromatic;provided that when Z1, Z2, Z3, Z4, or Z5, is each, independently, nitrogen, then R12, R13, R14, R15, R17are, each independently, absent.

5. A compound of any one of the preceding claims, wherein R1ais selected from:F 6. A compound of any one of the preceding claims, wherein R1bis selected from:

7. A compound of any one of the preceding claims, wherein R4is selected from:-259- JAB7149WOPCT18. A compound of any one of the preceding claims, wherein the compound is selected from:compoundnrOOF-277-O1591601619. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 8; and at least one pharmaceutically acceptable excipient.

10. A compound according to any one of claims 1 to 8 for use in therapy.

11. A compound according to any one of claims 1 to 8 for use in the treatment of a SMARCA4 deficient cancer.

12. The compound for the use of claim 11, wherein the SMARCA4 deficient cancer is SMARCA4 deficient non-small cell lung cancer (NSCLC).

13. A compound according to any one of claims 1 to 8 for use in the treatment of a disease state or condition mediated by the SMARCA2 protein.

14. The compound for the use of claim 13, wherein the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC).

15. Use of a compound as defined in any one of claims 1 to 8 for the manufacture of a medicament for the treatment of cancer or NSCLC.

16. 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 to 8.

17. 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 to 8.

18. The method of claim 17, wherein the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.

19. 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 to 8.

20. The method of claim 19, wherein the disease or condition is selected from a cancer or NSCLC.

21. The method of any one of claims 17 to 20, wherein the subject is a mammal.

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