Organic compounds as NLRP3 inhibitors

Abstract

Disclosed herein are small molecule compounds capable of inhibiting NLRP3 family proteins and NLRP3 inflammasome function in various disease conditions. Disclosed herein also include pharmaceutical compositions, their uses and preparations.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 478,268, filed January 3, 2023, and U.S. Provisional Application No. 63 / 467,565, filed May 18, 2023, each of which is incorporated by reference in its entirety.

[0002] Background of the Invention FIELD OF THE INVENTION The present disclosure provides a method for the treatment of NLRP3 (NOD-like receptor-, LRR- and The present disclosure relates generally to the field of pyrin domain-containing 3) family proteins and NLRP3 inflammasome function. More specifically, the present disclosure relates to the field of small molecule compounds capable of inhibiting NLRP3 family proteins and NLRP3 inflammasome function in various disease settings. [Background technology]

[0003] 2. Description of Related Art Inflammasomes are large, dynamic multimeric protein complexes that form in the cytosol upon activation by either pathogen-associated molecular patterns (PAMPs) resulting from bacterial infection or endogenous danger signals, danger-associated molecular patterns (DAMPs), released by damaged or dying cells. In 2002, Tschopp and Martinon established a link between inflammasomes and activation of the pro-inflammatory protease caspase-1. Caspase-1 is a proteolytic enzyme responsible for converting inactive precursors, Pro-IL-1β and Pro-IL-18, to their active forms, IL-1β and IL-18, respectively. Both IL-1β and IL-18 belong to the IL-1 family of cytokines, which play key roles in innate and adaptive immune responses that affect a wide range of disease states. Tschopp's discovery placed inflammasomes at the center of immune regulation and homeostasis. Since then, the field has expanded tremendously with new insights accumulating regarding the assembly, regulation, and function of inflammasome complexes as well as their role in inflammatory-related diseases.

[0004] The inflammasome complex is composed of three components: a sensor, an adaptor, and an effector enzyme. The sensor is typically a nucleotide-binding domain and leucine-rich repeat-containing (NLR) protein or an AIM2-like receptor (ALR) protein. Most inflammasomes contain sensors from the NLR family, and importantly, each inflammasome has its own unique sensor protein. The adaptor protein, called ASC (apoptosis-associated speck-like protein containing a CARD), recruits and links the effector enzyme to the sensor. ASC is a common component in many inflammasome complexes. Finally, the effector enzyme is typically pro-caspase-1. During inflammasome assembly and activation, pro-caspase-1 is converted to active caspase-1, which proceeds with the activation of key cytokines, such as IL-1β and IL-18. Summary of the Invention

[0005] The present disclosure provides a compound of formula (1-I): [ka] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein: [ka] is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; W is selected from the group consisting of NH, N-Me, N-Et, and N-iPr, or is a bond; R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1' together with R1 forms a thiophene ring; R2 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R3 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R3 together with R2 may be substituted with -Me or -OH, either at all carbon or with any O or N in the ring. R4 is selected from the group consisting of H, -F, C1-C3 alkyl, and -CF3; R5 is selected from the group consisting of H, Me, and -CF3; R6 and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF3; or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; Y is a bond or a C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3; and n is 1, 2, 3, or 4.

[0006] In some embodiments, the compound of formula (1-I) is further represented by any one of the following: [ka] [ka]

[0007] In some embodiments, the compound of formula (1-I) is further represented by any one of the following: [ka]

[0008] In some embodiments, the compound of formula (1-I) is further represented by any one of the following: [ka]

[0009] The present disclosure also provides a compound of formula (1-II): [ka] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof; wherein: [ka] is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1 together with R1' form a thiophene ring; R2 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R3 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or together with O or N, which may be substituted with -Me or -OH; Y is a bond or is C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3; R4 is selected from the group consisting of H, -F, C1-C3 alkyl, and -CF3; R5 is selected from the group consisting of H, Me, and -CF3; R6 and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF3; or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is 2, 3, or 4.

[0010] In some embodiments, the compound of formula (1-II) is further represented by any one of the following: [ka]

[0011] In some embodiments, the compound of formula (1-II) is further represented by any one of the following: [ka]

[0012] The present disclosure also provides a compound of formula (1-III): [ka] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein: [ka] is a 4- to 7-membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; [ka] is a 4- to 7-membered cycloalkyl ring or a substituted cycloalkyl ring; R is selected from the group consisting of -CN, -H, -F, and -CF; R is H; or R and R 1’ are taken together to form a thiophene ring; R2 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R3 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O or N, which may be substituted with -Me or -OH; R4 is H, -F, C1-C and Y is a bond or a C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0013] In some embodiments, the compound of formula (1-III) is further represented by any one of the following: [ka]

[0014] The present disclosure also provides a compound of formula (1-IV): [ka] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein: [ka] is a 4- to 7-membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; [ka] is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; R is selected from the group consisting of -CN, -H, -F, and -CF; R is H; or R and R together form a thiophene ring; R is selected from the group consisting of H, C-C alkyl, and -CF; R is selected from the group consisting of H, C-C alkyl, and -CF; or R together with R forms a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with an O or N in the ring, which may be substituted with -Me or -OH; Y is a bond or a C-C alkyl optionally substituted with 1, 2, or 3 C-C alkyl or -CF; R is selected from the group consisting of H, -F, C-C alkyl, and -CF; and R is selected from the group consisting of -H, -Me, and -CF.

[0015] In some embodiments, the compound of formula (1-IV) is further represented by any one of the following: [ka]

[0016] The present disclosure also provides a compound of formula (1-V): [ka] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein: [ka] is a 4- to 11-membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; W is NH, N-Me, N-Et, N-iPr, or a bond; R is selected from the group consisting of -CN, -H, -F, and -CF; R is H; or R and R together are thiophene. R2 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R4 is selected from the group consisting of H, -F, C1-C3 alkyl, and -CF3; Y is a bond or a C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3; R5 is selected from the group consisting of -H, -Me, and -CF3; R6 and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is 1, 2, 3, or 4.

[0017] In some embodiments, the compound of formula (1-V) is further represented by any one of the following: [ka]

[0018] The present disclosure also provides a compound of formula (1-VI): [ka] wherein the ring [ka] is an optionally substituted 4- to 7-membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; [ka] is an optionally substituted 4- to 7-membered cycloalkyl ring or a substituted cycloalkyl ring; R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from the group consisting of -H, C1-C3 alkyl, and -CF3; R4 is is selected from the group consisting of -H, -F, C1-C3 alkyl, and -CF3; R5 is selected from the group consisting of -H, -Me, and -CF3; and Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0019] In some embodiments, the compound of formula (1-VI) is further represented by any one of the following: [ka]

[0020] The present disclosure also provides a compound of formula (1-VII): [ka] wherein the ring [ka] is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from the group consisting of -H, C1-C3 alkyl, and -CF3; R4 is selected from the group consisting of -H, -F, C1-C3 alkyl, and -CF3; and R5 is selected from the group consisting of -H, -Me, and -CF3. R6 and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is 0, 1, 2, 3, or 4; and Y is a bond or a C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0021] In some embodiments, the compound of formula (1-VII) is further represented by any one of the following: [ka]

[0022] The present disclosure also provides a compound of formula (1-VIII): [ka] wherein the ring [ka] is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from the group consisting of -H, C1-C3 alkyl, and -CF3; R4 is selected from the group consisting of H, -F, C1-C3 alkyl, and -CF3; R5 is H, Me, and R6 and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is 1, 2, 3, or 4; and Y is a bond or a C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0023] In some embodiments, the compound of formula (1-VIII) is further represented by any one of the following: [ka]

[0024] The present disclosure also provides a compound of formula (1-IX): [ka] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein: [ka] is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring, wherein R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R3 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O or N in the ring, which may be substituted with -Me or -OH; R4 is selected from the group consisting of H, -F, C1-C3 alkyl, and -CF3; R5 is R6 and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl, C1-6 cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is 2, 3, or 4; and Y is a bond or a C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0025] In some embodiments, the compound of formula (1-IX) is further represented by any one of the following: [ka]

[0026] The present disclosure provides a compound of formula (2-I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: [ka] is a 4-11 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring; W is selected from the group consisting of NH, N-Me, N-Et, and N-iPr, or W is a bond; R is selected from the group consisting of -CN, -H, -F, and -CF; R' is -H; or R together with R' forms a thiophene ring; each of R and R is selected from the group consisting of -H, C-C alkyl, and -CF; or R together with R forms a 5- or 6-membered aromatic or non-aromatic ring containing all C or at least one O or N, optionally substituted with -Me or -OH; R is selected from the group consisting of -H, -F, C-C alkyl, and -CF; Y is a bond or C-C alkyl optionally substituted with 1, 2, or 3 C-C alkyl or -CF. R5 is -H, -Me and and -CF3; R6 and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3; or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is 1, 2, 3, or 4; and R7 is -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, [ka] is selected from the group consisting of: In some embodiments, R1 is selected from -CN, -H, -F, -CF3; or may be taken together with R1' to form a thiophene ring (together with the sulfur atom attached to the carbon atom bearing R1) to form a benzothiophene; R1' is -H or may be taken together with R1 to form a thiophene ring (together with the sulfur atom attached to the carbon atom bearing R1) to form a benzothiophene; R2 is selected from -H, C1-C3 alkyl, -CF3, or taken together with R3 to form a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O or N in the ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or taken together with R2 to form a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O or N in the ring, and and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a bond (when Y is a bond, -NH may be directly attached to the ring; similarly, when Y is a bond, -NH-R7 may be directly attached to the ring), or Y may be substituted with 1, 2, or 3 C1-C3 alkyl, or -CF3; C R5 is selected from -H, -Me, and -CF3; R6 and R6' are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 1, 2, 3, and 4; R7 is -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, [ka] is selected from.

[0027] In some embodiments of formula (2-I), the ring [ka] is a 4- to 11-membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic cycloalkyl, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl, and W is selected from NH, N-Me, or a bond; when W is a bond, a carbonyl group (C═O) is not present in the ring. [ka] R is bonded to a nitrogen atom within the ring, such that together they form an amide bond; R is selected from -F, -CF; R' is -H; R is selected from -H, -Me, -CF, or together with R to form a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with O in the ring; R is selected from -H, -Me, or together with R to form a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with O in the ring; R is -H; R is selected from -H and -Me; R and R' are -H; n is 1; and R is -H.

[0028] In some embodiments, the compound of formula (2-I) is further represented by any one of the following: [ka]

[0029] The present disclosure also provides a compound of formula (2-II): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: [ka] is a 4- to 11-membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl W is selected from NH, N-Me, N-Et, and N-iPr, or is a bond; R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 and R3 are each independently selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2 together with R3 form a 5- or 6-membered aromatic ring optionally substituted with -Me or -OH, either all carbon or with any O or N in the ring. R4 is selected from the group consisting of -H, -F, C1-C3 alkyl, and -CF3; R5 is selected from the group consisting of -H, -Me, and -CF3; R6 and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3; or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is 1, 2, 3, or 4.

[0030] In some embodiments of formula (2-II), the ring [ka] is a 4-11 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl, and W is selected from NH, N-Me, or a bond; when W is a bond, a carbonyl group (C=O) is attached to the ring. [ka] R is bonded to a nitrogen atom in the ring such that together they form an amide bond, and R is selected from -F, -CF; R' is -H; R is selected from -H, -Me, -CF, or together with R to form a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with O in the ring; R is selected from -H, -Me, or together with R to form a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with O in the ring; R is -H or -Me; R is selected from -H and -Me; R and R' are -H; and n is 1.

[0031] In some embodiments, the compound of formula (2-II) is further represented by any one of the following: [ka]

[0032] The present disclosure also provides: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: [ka] is a 4-11 membered heterocycloalkyl or substituted heterocycloalkyl ring; R is selected from the group consisting of -CN, -H, -F, and -CF; R is H; or R and R together form a thiophene ring; R is selected from the group consisting of H, C-C alkyl, and -CF; R is selected from the group consisting of H, C-C alkyl, and -CF; or R is taken together with R to form a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with an O or N in the ring, which may be substituted with -Me or -OH; R is selected from the group consisting of -H, -F, C-C alkyl, and -CF; R is selected from the group consisting of -H, -Me, and -CF; W is selected from the group consisting of optionally substituted -CH-, -CHCH-, and -CHCHCH-, or a bond.

[0033] In some embodiments of formula (2-III), the ring [ka] is a 4-9 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl, and W2 is selected from -CH2-, -CH2CH2-, or a bond; R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3, or together with R3, forms a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with endocyclic O; R3 is selected from -H, -Me, or together with R2, forms a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with endocyclic O; R4 is -H or -Me; and R5 is selected from -H and -Me.

[0034] In some embodiments, the compound of formula (2-III) is further represented by any one of the following: [ka]

[0035] The present disclosure also provides a compound of formula (2-IV): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: [ka] is a 4-11 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring; R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R3 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2 together with R3 may be substituted with -Me or -OH, either all at carbon or with any O or N in the ring. R4 is selected from the group consisting of -H, -F, C1-C3 alkyl, and -CF3; R5 is selected from the group consisting of -H, -Me, and -CF3; W3 is selected from the group consisting of optionally substituted -CH2-, -CH2CH2-, and -CH2CH2CH2- or a bond; Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3; and R7 is -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, [ka] is selected from the group consisting of:

[0036] In some embodiments of formula (2-IV), the ring [ka] is a 4-9 membered cycloalkyl or heterocycloalkyl ring, and W3 is selected from -CH2- and -CH2CH2- or a bond; R1 is selected from -F and -CF3; R1' is -H; R2 is selected from -H, -Me, and -CF3, or together with R3, forms an all-carbon or endocyclic O ring, a 5- or 6-membered aromatic or non-aromatic ring; R3 is selected from -H and -Me, or together with R2, forms an all-carbon or endocyclic O ring, a 5- or 6-membered aromatic or non-aromatic ring; R4 is -H or -Me; R5 is selected from -H and -Me; and R7 is -H.

[0037] In some embodiments, the compound of formula (2-IV) is further represented by any one of the following: [ka]

[0038] The present disclosure also provides a compound of formula (2-V): [ka] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer or tautomer thereof, wherein: [ka] is azetidine, pyrrolidine, piperidine, or azepane; R is selected from the group consisting of -CN, -H, -F, and -CF; R' is H; or R and R' together form a thiophene ring; R is selected from the group consisting of H, C-C alkyl, and -CF; R is selected from the group consisting of H, C-C alkyl, and -CF; or R is taken together with R to form a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O or N in the ring, which may be substituted with -Me or -OH; R is selected from the group consisting of -H, -F, C-C alkyl, and -CF; R is selected from the group consisting of -H, -Me, and -CF; and R 12 teeth, [ka] wherein m is 1, 2, or 3, and each R 13 are independently selected from the group consisting of -H, C1-C3 alkyl, and -CF; or two R 13 The groups are joined to form a cyclopropyl or cyclobutyl ring.

[0039] The ring can contain one, two, or three R 13 Each R 13 are independently selected from -H, C1-C3 alkyl, and -CF3. 13 The groups may be joined to form a cyclopropyl or cyclobutyl ring.

[0040] In some embodiments of formula (2-V), the ring [ka] is azetidine or piperidine; R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, and -CF3, or together with R3, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with endocyclic O; R3 is selected from -H, -Me, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with endocyclic O; R4 is -H or -Me; R5 is selected from -H and -Me; R 12 teeth, [ka] is selected from.

[0041] In some embodiments, the compound of formula (2-V) is further represented by any one of the following: [ka]

[0042] The present disclosure also provides a compound of formula (2-VI): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R3 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2 together with R3 form a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O or N in the ring, which may be substituted with -Me or -OH; R5 is selected from the group consisting of -H, -Me, and -CF3; W4 is -CH2-, -CH2CH2-, [ka] R and R are independently selected from the group consisting of -H, C-C alkyl, C-C cycloalkyl, and -CF; and R is -H, C-C alkyl, C-C cycloalkyl, heterocycloalkyl, [ka] is selected from the group consisting of:

[0043] In some embodiments of formula (2-VI), R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3, or together with R3, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R3 is selected from -H, -Me, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R5 is selected from -H and -Me; W4 is -CH2- or [ka] R8 and R8' are -H; n is 1; and R9 is -H.

[0044] In some embodiments of formula (2-VI), R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3, or together with R3, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R3 is selected from -H, -Me, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R5 is selected from -H and -Me; W4 is -CH2- or [ka] R8 and R8' are -H; n is 1; R9 is [ka] is selected from.

[0045] In some embodiments, the compound of formula (2-VI) is further represented by any one of the following: [ka]

[0046] In some embodiments, the compound of formula (2-VI) is further represented by any one of the following: [ka]

[0047] The present disclosure also provides a compound of formula (2-VII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein R1 is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R3 is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2 is together with R3, either all carbon or with O or N in the ring, form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; R5 is selected from the group consisting of H, -Me, and -CF3; R6 and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF3, or R6 and R6', together with the atom to which they are attached, are C1-C6 cycloalkyl or forms a C1-C6 heterocycloalkyl ring; n is 1, 2, 3, or 4; R 14 and R 14 ' is independently selected from the group consisting of H, C1-C5 alkyl (including cycloalkyl), and -CF3; or R 14 and R 14 ' together with the atom to which they are attached form an optionally substituted C3-C6 cycloalkyl or an optionally substituted C3-C6 heterocycloalkyl ring; R10 is -H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl), [ka] and R 11 is selected from the group consisting of H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl.

[0048] In some embodiments of formula (2-VII), R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3, or together with R3, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R3 is selected from -H, -Me, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R5 is selected from -H and -Me; R6 and R6' are -H; n is 1; R9 and R9' are -H; R 10 is -H;R 11 is selected from -H or -Me.

[0049] In one embodiment, the compound of formula (2-VII) is further represented by: [ka]

[0050] The present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound as described herein and a pharmaceutically acceptable excipient.

[0051] The present disclosure further provides methods of preventing, treating, or ameliorating one or more diseases in a subject, comprising administering a compound as described herein or a pharmaceutically acceptable excipient to a subject in need thereof.

[0052] In some embodiments, the disease is characterized by a disease progression involving the activity of IL-1b, IL-18, or both. NLRP3 inflammasome activation has been linked to various inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Various ocular diseases linked to the activation of NLRP3 inflammasome, a part of the immune system involved in responding to cellular stress and injury, can be treated according to the present disclosure. Without being limited to a theory of operation, one possible theoretical explanation behind targeting NLRP3 inflammasome activation in these conditions may be due to the role of inflammasome activation in inflammation and immune responses, which may lead to or exacerbate ocular diseases. Thus, one aspect of the present disclosure is to treat ocular diseases, It is aimed at preventing or ameliorating.

[0053] As a non-limiting example, age-related macular degeneration (AMD), both wet and dry, is accompanied by the deterioration of the central part of the retina, leading to vision loss.NLRP3 inflammasome activation can contribute to the inflammation and angiogenesis seen in AMD.Similarly, diabetic macular edema (DME) and diabetic retinopathy (DR) are complications of diabetes, in which high blood sugar level damages retinal blood vessels, and inflammation plays a crucial role in progression.

[0054] Diseases such as glaucoma, which is characterized by increased pressure within the eye leading to optic nerve damage, and retinopathies, which involve damage to retinal blood vessels, are also associated with inflammatory responses mediated by the NLRP3 inflammasome. Dry eye disease (DED) and bacterial keratitis, infections of the cornea, are associated with inflammation in which NLRP3 may play a role in the response to infection and cellular stress.

[0055] Inflammatory and autoimmune diseases such as Behcet's syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis can have ocular symptoms, including uveitis (inflammation of the middle layer of the eye) and retinal vasculitis (inflammation of the retinal blood vessels). These conditions are often characterized by an excessive immune response, and controlling NLRP3 inflammasome activation can manage inflammation and prevent tissue damage. Targeting NLRP3 inflammasome for patients experiencing or at risk of experiencing the various diseases described above can reduce inflammation, slow disease progression, preserve vision, and improve quality of life by addressing one of the underlying mechanisms contributing to these ocular conditions.

[0056] Consistent with the present disclosure, the compounds of the present disclosure may be used to treat, prevent, or ameliorate diseases affecting the eye. In some embodiments, the disease is selected from the group consisting of, for example, age-related macular degeneration (wet and dry) (AMD), atrophic macular degeneration, bacterial keratitis, Behcet's syndrome, choroidal neovascularization, chronic eye disease, diabetic macular edema (DME), diabetic retinopathy (DR), dry eye disease (DED), glaucoma (acute and non-acute), geographic atrophy (GA), and retinopathies.

[0057] In some embodiments, the disease is selected from the group consisting of, for example, inflammatory eye diseases, ocular inflammation associated with cryopyrin-associated periodic syndromes (CAPS), ocular symptoms of rheumatoid arthritis and systemic lupus erythematosus (SLE), retinitis, retinal vasculitis, retinal vein occlusion (RVO), progressive optic neuropathy, and uveitis (anterior / intermediate / posterior, panuveitis).

[0058] In some embodiments, the disease is age-related macular degeneration (AMD). In some embodiments, the disease is atrophic macular degeneration. In some embodiments, the disease is bacterial keratitis. In some embodiments, the disease is Behcet's syndrome. In some embodiments, the disease is choroidal neovascularization. In some embodiments, the disease is a chronic eye disease. In some embodiments, the disease is diabetic macular edema (DME). In some embodiments, the disease is diabetic retinopathy (DR). In some embodiments, the disease is dry eye disease (DED). In some embodiments, the disease is glaucoma, both acute and non-acute. In some embodiments, the disease is geographic atrophy (GA). In some embodiments, the disease is retinopathy. In some embodiments, the disease is an inflammatory eye disease. In some embodiments, the disease is associated with ocular inflammation from cryopyrin-associated periodic syndromes (CAPS). In some embodiments, the disease is associated with ocular symptoms of rheumatoid arthritis and systemic lupus erythematosus (SLE). In some embodiments, the disease is retinitis. In some embodiments, the disease is retinal vasculitis. In some embodiments, the disease is retinal vein occlusion (RVO). In some embodiments, the disease is uveitis, including anterior, intermediate, posterior, or panuveitis.

[0059] In some embodiments, due to their activity towards NLRP3 inflammasome, the compounds of the present disclosure are expected to have significant biological activity against a wide range of systemic diseases. For example, in diseases such as gout and atherosclerosis, where inflammation is a major factor, the compounds of the present disclosure can reduce symptoms and progression by modulating the inflammatory response. In some embodiments, the disease is selected from the group consisting of atherosclerosis, gout, acute gouty arthritis, rheumatoid arthritis, non-alcoholic steatohepatitis, inflammatory bowel disease, Parkinson's disease, Alzheimer's disease, multiple sclerosis, (acute) glaucoma, wet age-related macular degeneration, dry age-related macular degeneration, diabetic retinopathy, Behcet's syndrome, dry eye disease, and bacterial, viral, fungal, and parasitic infections. [Brief explanation of the drawings]

[0060] [Figure 1] FIG. 1 shows the inhibition of IL-1β release in U937 cells. [Figure 2] FIG. 2 shows the inhibition of IL-1β release in THP-1 cells. [Figure 3] FIG. 3 shows caspase-1 inhibition in THP-1 cells. [Figure 4] FIG. 4 shows a survival assay in THP-1 cells. [Figure 5] FIG. 5 shows ASC-GFP puncta inhibition in THP-1 cells. [Figure 6] FIG. 6 shows the effect of test compounds on TNFα in U937 cells. [Figure 7] FIG. 7 shows toxicity evaluation in human retinal pigment epithelial cells. DETAILED DESCRIPTION OF THE INVENTION

[0061] Detailed Description The compounds disclosed herein are potent inhibitors of NLRP3 inflammasome.Such NLRP3 inhibitory compounds can be useful in treating or preventing inflammatory disorders and diseases associated with the underlying pathology of inflammation, which are associated with NLRP3 inflammasome.The lack of high-resolution crystal structure of the NLRP3 protein complex that binds ligand makes it difficult to apply structure-based design approach to discover NLRP3 inhibitors. A pharmacophore / ligand-based approach was used to identify structural regions where the incorporation of polar amines or amides linked to the terminal hydroxyl group, terminal primary amino group, or secondary amino group was tolerated for activity, while allowing for modulation of the physicochemical properties of the parent compounds of formulas (1-I), (1-II), (1-III), (1-IV), (1-V), (1-VI), (1-VII), (1-VIII), (1-IX), (2-I), (2-II), (2-III), (2-IV), (2-V), (2-VI), and (2-VII).

[0062] Surprisingly, in certain cases, the incorporation of extended linkers containing terminal primary, secondary, and tertiary hydroxyl groups, or amines or amides with terminal primary or secondary amino groups at strategic positions in the molecular structure not only tolerates but also confers robust NLRP3 inhibitory potency or robust inhibition of IL-1β secretion, while also promoting increased solubility and reduced lipophilicity for an enhanced safety profile.

[0063] The surprising terminal primary, secondary, and tertiary hydroxyl-bearing compounds have the overall structure shown by 1A, 1B, 1C, 1D, 1E, 1F, and 1G, where Y′ represents a partial known pharmacophore or analog thereof for NLRP3 inhibitory activity or IL-1β secretion inhibitory activity, such as appropriately substituted (R)-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)phenol, appropriately substituted (R)-5-(6-(piperidin-3-ylamino)pyridazin-3-yl)benzo[b]thiophene-4 -ol, or appropriately substituted (R)-2-(8-(piperidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)phenol;

[0064] X is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring (including substituted and unsubstituted spirocyclic and bicyclic rings), X is a heterocycloalkyl or substituted heterocycloalkyl ring (including spirocyclic and substituted spirocyclic rings), X is a heterocycloalkyl or substituted heterocycloalkyl ring (including substituted and unsubstituted spirocyclic rings), X is a cycloalkyl ring or substituted cycloalkyl ring, and X is a heterocycloalkyl ring or substituted heterocycloalkyl ring (including spirocyclic or substituted spirocyclic rings). X6 is a heterocycloalkyl ring or a substituted heterocycloalkyl ring (including a spirocyclic ring or a substituted spirocyclic ring), X7 is a heterocycloalkyl ring or a substituted heterocycloalkyl ring (including a spirocyclic ring or a substituted spirocyclic ring), X8 is a heterocycloalkyl ring or a substituted heterocycloalkyl ring (including a spirocyclic ring or a substituted spirocyclic ring), R4 is optional, and if present, is -F or -Me, -Et, iPr or cPr, and W is NH, N-Me, N-Et or N-iPr, or W is a bond (if W is a bond, then the ring [ka] is a heterocyclic ring [ka] is bonded directly to the carbonyl through a nitrogen atom embedded in the ring to form an amide); Y is a bond (when Y is a bond, the -OH is directly attached to the ring), or Y is a C1-C3 alkyl, or a C1-C3 alkyl optionally substituted with 1, 2, or 3 -CF3. [ka]

[0065] The surprising terminal primary or secondary amine-bearing compounds have the overall structures shown by 2A, 2B, 2C, 2D, 2E, 2F, and 2G. [ka] wherein Y' is a partially known pharmacophore or analog thereof for NLRP3 inhibitory activity or IL-1β secretion inhibitory activity, such as a suitably substituted (R)-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)phenol, a suitably substituted (R)-5-(6-(piperidin-3-ylamino)pyridazin-3-yl)benzo[b]thiophen-4-ol, or a suitably substituted (R)-2-(8-(piperidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)phenol; ring [ka] is a 4-11 membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl, and W is selected from NH, N-Me, N-Et, and N-iPr, or is a bond; when W is a bond, a carbonyl group (C═O) is not present in the ring. [ka] R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; R6 and R6' are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 1, 2, 3, and 4; R7 is -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, [ka] Selected from; [ka] is a 4-9 membered nitrogen-containing ring, including heterocycloalkyl and substituted heterocycloalkyl rings, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl and substituted spirocyclic and bicyclic heterocycloalkyl, and W is selected from NH, N-Me, N-Et, and N-iPr, or is a bond; when W is a bond, a carbonyl group (C═O) is not present in the ring. [ka] are attached to nitrogen atoms in the ring, so that together they form an amide bond; [ka] is a 4-9 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is a C1-C3 alkyl, or a C1-C3 alkyl optionally substituted with 1, 2, or 3 -CF3; the ring [ka] is a 4-11 membered ring selected from heterocycloalkyl or substituted heterocycloalkyl, including spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl; W2 is selected from optionally substituted -CH2-, -CH2CH2-, -CH2CH2CH2-, or a bond; [ka] is a 4-9 membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl; W3 is selected from optionally substituted -CH2-, -CH2CH2-, -CH2CH2CH2-, or a bond; R7 is -H, C1-C6 alkyl or cycloalkyl, [ka] Selected from; [ka] is azetidine, pyrrolidine, piperidine or azepane; R 12 is selected from the following: [ka]

[0066] The ring can contain one, two, or three R 13 Each R 13 are independently selected from -H, C1-C3 alkyl, and -CF3. 13 The groups may be joined to form a cyclopropyl or cyclobutyl ring; W4 is -CH2-, -CH2CH2-, [ka] R and R 8’ is independently selected from -H, -F, C1-C5 alkyl (including cycloalkyl), and -CF3; R9 is -H, C1-C6 alkyl, or cycloalkyl, [ka] or R and R 9’ together with the atoms to which they are attached form a (substituted) C3-C6 cycloalkyl or (substituted) C3-C6 heterocycloalkyl ring; R 10 is -H, C1-C7 alkyl (including cycloalkyl and methylcycloalkyl), [ka] Selected from; R 11 is selected from H, C1-C7 alkyl (including cycloalkyl and methylcycloalkyl).

[0067] Thus, the disclosed compounds are not only potent inhibitors of the NLRP3 inflammasome or IL-1β secretion, but also possess structural components that can contribute to an enhanced drug safety profile or improved therapeutic utility through better physicochemical properties.

[0068] definition For purposes of the present invention, the following terminology will be used in accordance with the definitions set out below.

[0069] The articles "a" and "an" are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0070] "And / or" is used herein to mean either "and" or "or," unless otherwise indicated.

[0071] "About," as used herein, refers to the variation that may be found in measurements obtained between different instruments, samples, and sample preparations.

[0072] "Administer," "administering," or "administration," as used herein, refers to either administering a disclosed compound or a pharmaceutically acceptable salt of a disclosed compound or a composition thereof directly to a subject, or administering a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt of the compound or a composition thereof to a subject, which is capable of forming an equivalent amount of the active compound in the subject's body.

[0073] "Alkyl" refers to a straight-chain or branched, saturated, aliphatic radical. The number of carbon atoms present in an alkyl group may be specified by indicating the number of carbon atoms in the group (e.g., a C alkyl contains 3 carbon atoms). A size range of alkyl groups may be specified by indicating a range of the number of carbon atoms (e.g., C-C alkyl or (C-C) alkyl or C for alkyl groups containing 1 to 3 carbon atoms). 1-3alkyl). For example, C1-C6 alkyl includes, but is not limited to, methyl (also referred to herein as "-Me"), ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, butyl, pentyl, 1-methylbutyl (i.e., 2-pentyl), 1-ethylpropyl (i.e., 3-pentyl), and 3-methylpentyl, and the like. Alkyl can contain any number of carbons, for example, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6, and 5 to 6. Alkyl groups are typically monovalent but can be divalent, for example, when the alkyl group links two moieties together, and it is understood that "alkyl" includes alkylene when two functional groups are attached through a straight or branched, saturated, aliphatic diradical. Consistent with other groups and substituents, this group may be substituted with other groups.

[0074] "Heteroalkyl" refers to an alkyl group having 1 to 3 heteroatoms, such as N, O, and S. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-, or -N-OH and -N + -O - For example, heteroalkyl can include ethers, thioethers, alkyl-amines, and alkyl-thiols. Heteroalkyl groups are typically monovalent, but can be divalent, for example, when the heteroalkyl group links two or more moieties together, and it is understood that "heteroalkyl" includes heteroalkylene when two functional groups are attached. Consistent with other groups and substituents, this group can be substituted with other groups.

[0075] "Cycloalkyl" or "carbocyclyl" refers to a cyclic hydrocarbon group containing 3 to 12, 3 to 10, 3 to 8, or 3 to 7 ring carbon atoms. A cycloalkyl group can be a fused , bridged, and spiro ring structures. Where a cycloalkyl group can have a range of sizes, the size range can be specified by indicating the number of carbon atoms present in the cycloalkyl group (e.g., a 3- to 10-membered cycloalkyl ring, C3-C10 or (C3-C10) for a cycloalkyl group containing 3 to 10 carbon atoms). 10 ) cycloalkyl or C 3-10 Cycloalkyl). Examples include cyclopropanyl, cyclobutanyl, cyclopentanyl, methylcyclopentanyl, cyclohexanyl, methylcyclohexanyl, cycloheptanyl, and dimethylcyclohexanyl. Cycloalkyls can be substituted. Cycloalkyls can also include spiro rings, such as the non-limiting example of spiro[4.5]decane. Consistent with other groups and substituents, this group can also be substituted with other groups.

[0076] "Heterocyclic" refers to a ring system having from 3 to about 20 ring members and from 1 to about 5 heteroatoms, such as N, O, and S. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-, or -N-OH and -N + -O - Heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, azepanyl, indolinyl, quinuclidinyl, and 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl. Heterocyclic groups include heterocycloalkyl and heteroaryl. Consistent with other groups and substituents, this group may be substituted with other groups.

[0077] "Heterocycloalkyl" refers to a group of cyclic compounds characterized by having at least one non-carbon atom, such as nitrogen, oxygen, or sulfur, in the ring structure. Heterocycloalkyl groups can occur in a variety of forms, including monocyclic, bicyclic, and spirocyclic configurations. Monocyclic heterocycloalkyls have a single ring containing one or more heteroatoms. Examples include pyrrolidine, which has a five-membered ring with one nitrogen atom; tetrahydrofuran (THF), which is a five-membered ring with an oxygen atom; and thiolane, which features a sulfur atom in its five-membered ring. Bicyclic heterocycloalkyls have two connected rings that can both be heterocyclic or a combination of heterocyclic and carbocyclic (all-carbon rings). Spirocyclic heterocycloalkyls are compounds in which two or more rings are connected through a single shared atom, typically a quaternary carbon, known as a spiroatom. Spiro[4.5]decane-7,9'-dione is an example in which the five-membered lactone ring and the six-membered ketone ring share a single carbon atom. Spiropiperidines connect the piperidine ring to another ring structure through a shared spiro atom, and consistent with other groups and substituents, this group may be substituted with other groups.

[0078] "Alkoxy" refers to a straight or branched chain saturated or unsaturated (fully or partially) hydrocarbon containing 1 to 12 carbon atoms containing a terminal "O" in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups. In one embodiment, the "alkoxy" is fully saturated. Consistent with other groups and substituents, this group may be substituted with other groups.

[0079] "Alkoxyalkoxy" refers to an alkoxy group, as defined herein, substituted with an alkoxy group, for example, -O(alkyl)-O-(alkyl). Examples of alkoxyalkoxy groups include, but are not limited to, methoxymethoxy, ethoxyethoxy, propoxymethoxy, or ethoxymethoxy. Consistent with other groups and substituents, this group may be substituted with other groups.

[0080] "Alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. An alkenyl, as defined herein, may be straight- or branched-chain. It is understood that an alkenyl group, as defined herein, can be a pure geometric isomer, e.g., a pure (E) or pure (Z) isomer, or a mixture of geometric isomers, e.g., (E) / (Z) isomers, also known as trans / cis isomers, in any ratio. Consistent with other groups and substituents, this group may be substituted with other groups.

[0081] "Alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted. Consistent with other groups and substituents, this group may be substituted with other groups.

[0082] "Aryl" refers to a monocyclic or fused bicyclic, tricyclic, or larger, aromatic ring assembly containing 6 to 16 ring carbon atoms. For example, aryl may be phenyl, benzyl, or naphthyl, preferably phenyl. "Arylene" refers to a divalent radical derived from an aryl group. The aryl group may be mono-, di-, or tri-substituted with one, two, or more radicals selected from alkyl, alkoxy, aryl, hydroxy, halogen, cyano, amino, amino-alkyl, trifluoromethyl, alkylenedioxy, and oxy-C2-C3-alkylene (all of which may be further substituted, e.g., as previously defined herein); or 1- or 2-naphthyl; or 1- or 2-phenanthrenyl. Consistent with other groups and substituents, this group may be substituted with other groups.

[0083] "Heteroatom" refers to an atom that is not a carbon atom and that is part of the continuous ring structure of a cyclic compound or the continuous structure of a straight or branched chain compound. Consistent with other groups and substituents, this group may be substituted with other groups.

[0084] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, wherein 1 to 4 of the ring atoms are each a heteroatom independently selected from N, O, and S. Non-limiting examples of heteroaryl include pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any other radical substituted, particularly mono- or di-substituted, for example, by alkyl, nitro, or halogen. Pyridyl represents 2-, 3-, or 4-pyridyl, advantageously 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl. Quinolinyl preferably represents 2-, 3-, or 4-quinolinyl. Isoquinolinyl preferably represents 1-, 3-, or 4-isoquinolinyl. Benzopyranyl and benzothiopyranyl preferably represent 3-benzopyranyl or 3-benzothiopyranyl, respectively. Thiazolyl preferably represents 2- or 4-thiazolyl, most preferably 4-thiazolyl. Triazolyl is preferably 1-, 2-, or 5-(1,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl. Consistent with other groups and substituents, this group may be substituted with other groups.

[0085] Substituents for the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are varied and include halogen, —OR′, —OC(O)R′, —NR′R″, —NR′OH, —NR′OR″, —N, in a number ranging from 0 to the total number of open valences on the aromatic ring system. + R'R”-O - , -SR', -R', -CN, -NC, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', - NR"C(O)2R', -NR'-C(O)NR"R"', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -N + (-O- )(═CR′R”), —S(O)R′, —S(O)R′, —S(O)NR′R″, —N3, —CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; and R′, R″, and R′″ are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C1-C4)alkyl, and (unsubstituted aryl)oxy-(C1-C4)alkyl. Consistent with this disclosure, non-limiting examples of substituents may be substituted on the described groups.

[0086] "Carrier," as used herein, encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or body part to another organ or body part of a subject.

[0087] "Compound," as used herein, is intended to encompass not only the specified molecular entity, but also pharmaceutically acceptable, pharmacologically active derivatives thereof, including, but not limited to, salts, prodrugs, metabolites, hydrates, solvates, and the like.

[0088] "Composition," as used herein, means a mixture of substances, including pharmaceutical agents, suitable for administration to a test subject or individual. In some embodiments, the test subject is a mammal. In some embodiments, the test subject is a human.

[0089] "Cyano," as used herein, refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, eg, --C.ident.N.

[0090] "Disorder" is used herein to mean, and is used interchangeably with, a disease, condition, or illness, unless otherwise indicated.

[0091] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0092] As used herein, "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like. In one embodiment, a "haloalkyl" is fully saturated. In embodiments where the haloalkyl group is chiral, such as, but not limited to, -CH(X)-CH, or -CH-CH(X)-CH, and X is a halogen atom, all possible stereoisomers are included. Consistent with other groups and substituents, this group may be substituted with other groups.

[0093] "Haloalkoxy," as used herein, refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, methyl methyl ether, ... In one embodiment, "haloalkoxy" is fully saturated. Consistent with other groups and substituents, this group may be substituted with other groups.

[0094] "Hydroxyalkyl" refers to an alkyl group, as defined above, where the alkyl group is substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HOCH2-, HO-CH2-CH2-, and CH3-CH(OH)-. In one embodiment, a "hydroxyalkyl" is fully saturated. In embodiments where the hydroxyalkyl group is chiral, such as, but not intended to be limiting, -CH(OH)-CH3, or -CH2-CH(OH)-CH3, all possible stereoisomers are included. Consistent with other groups and substituents, this group may be substituted with other groups.

[0095] "Isomers" refer to certain compounds of the invention that possess asymmetrically substituted carbon atoms (stereogenic centers) or double bonds; racemates, diastereomers, atropisomers, geometric isomers, and individual isomers (e.g., separate enantiomers), all of which are encompassed by the term "isomer" within the scope of this disclosure.

[0096] "Optionally substituted" is understood to mean that a given chemical moiety (e.g., alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, aryl, or heteroaryl) can be (but is not required to be) bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (e.g., pure hydrocarbon). Alternatively, the same optionally substituted alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, aryl, or heteroaryl group can have substituents other than hydrogen. For example, it can be bonded at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any additional functional groups. Suitable substituents used in the optional substitution of the groups described are halogen, oxo, -OH, -CN, -COOH, -CHCN, -O-(C-C)alkyl, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)hydroxyalkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, (C-C)cycloalkyl, aryl, heterocycloalkyl, heteroaryl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, These include, but are not limited to, (C-C)alkenyl, (C-C)alkynyl, -OP(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, -NH((C-C)alkyl), -N((C-C)alkyl), -NHC(O)(C-C)alkyl, -C(O)NH(C-C)alkyl, -S(O)(C-C)alkyl, -S(O)NH(C-C)alkyl, and S(O)N((C-C)alkyl). "Optionally substituted," as used herein, also refers to substituted or unsubstituted, the meanings of which are described below.

[0097] "Substituted" means that the specified group or moiety has one or more suitable substituents, and the substituents may be attached to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is attached to one atom of the aryl with a bond or by being fused to the aryl and sharing two or more common atoms.

[0098] "Unsubstituted" means that the specified group bears no substituents.

[0099] "Oxo" as used herein refers to a "=O" group.

[0100] "Patient" or "subject in need thereof" refers to a living organism suffering from or susceptible to a condition that can be prevented or treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, and other non-mammals.

[0101] A "pharmaceutically acceptable composition" or "pharmaceutical composition" refers to a composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients.

[0102] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to an excipient that can be included in the compositions of the present invention and that does not cause significant adverse toxicological effects in patients. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solution, lactated Ringer's solution, normal sucrose, normal glucose, and the like.

[0103] A "prodrug" is a pharmaceutical or compound that is metabolized (i.e., converted within the body of a subject, including, but not limited to, a mammal or human) into a pharmacologically active drug after administration. Instead of administering a drug directly, a corresponding prodrug may be used, for example, but not limited to, to improve how the drug is absorbed, distributed, metabolized, and excreted, or how the drug selectively interacts with cells or processes other than its intended target. The term "prodrug" encompasses a subset of polymeric prodrugs, in which an active drug is attached (typically covalently) to a polymer chain to create a macromolecular carrier system. In some cases, the polymer may improve the solubility and stability of the drug, provide a controlled and / or sustained release mechanism, and can be designed to target the drug to specific tissues, cells, or receptors. The bond between the drug and the polymer is typically cleavable and breaks under specific physiological conditions, releasing the active drug at the desired site of action.

[0104] "Salt" means acid addition salts, including hydrochloride, hydrobromide, phosphate, sulfate, hydrogen sulfate, alkylsulfonate, arylsulfonate, acetate, benzoate, citrate, maleate, fumarate, formate, succinate, lactate, and tartrate; alkali metal cation salts, e.g., Na + , K. + , Li + or alkaline earth metal salts, e.g. Mg ++ Or Ca ++Pharmaceutically acceptable salts of ionizable pharmaceutical compounds are well known in the art and include, for example, those described in Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations, Gupta, et. al., Molecules. 2018, 23(7), 1719, or Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, (Stahl, PH and Wermuth, CM, Editors), Wiley-VCH, 2011, Germany, both of which are incorporated herein in their entirety.

[0105] "Solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For purposes of the present invention, such a solvent may be one that does not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0106] A "spirocycloalkyl" or "spirocyclyl" is a group of cyclic alkyl groups joined together by a single atom. Spirocyclic rings refer to carbon-containing bicyclic ring systems connected by a carbon atom. The rings can be different in size and nature or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spiro ring can be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in a spiro ring can be replaced with a heteroatom (e.g., O, N, S, or P). (C3-C 12A spirocycloalkyl is a spiro ring containing 3 to 12 carbon atoms. One or more of the carbon atoms can be replaced with a heteroatom. In one embodiment, a "spirocycloalkyl" or "spirocyclyl" is fully saturated. The term "spiroheterocycloalkyl" or "spiroheterocyclyl" is understood to mean a spiro ring in which at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperazinyl). In one embodiment, a "spiroheterocycloalkyl" or "spiroheterocyclyl" is fully saturated.

[0107] A "therapeutically effective amount" refers to the amount of a bioactive agent or pharmaceutical composition useful for treating, ameliorating, or preventing an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art.

[0108] "Treating," with respect to a subject, refers to improving at least one symptom of the subject's disorder. Treatment includes curing, improving, or at least partially ameliorating the disorder.

[0109] compound Provided herein are compounds that have the ability to inhibit NLRP3 family proteins and NLRP3 inflammasome function and inhibit IL-1β secretion.Various embodiments of these compounds include the compounds having the structure of formula (1-I), formula (1-II), formula (1-III), formula (1-IV), formula (1-V), formula (1-VI), formula (1-VII), formula (1-VIII), formula (1-IX), formula (2-I), formula (2-II), formula (2-III), formula (2-IV), formula (2-V), formula (2-VI) and formula (2-VII) or its pharmaceutically acceptable salt, solvate, atropisomer, N-oxide or tautomer as described herein.

[0110] The structures of the compounds of formula (1-I), formula (1-II), formula (1-III), formula (1-IV), formula (1-V), formula (1-VI), formula (1-VII), formula (1-VIII), formula (1-IX), formula (2-I), formula (2-II), formula (2-III), formula (2-IV), formula (2-V), formula (2-VI), and formula (2-VII) encompass all stereoisomers and racemic mixtures, including the structures described herein.

[0111] The present disclosure provides a compound of formula (1-I): [ka] wherein the ring [ka] is a 4-11 membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl; and W is selected from -NH, N-Me, N-Et, and N-iPr, or is a bond (when W is a bond, the ring [ka] is a ring [ka] R1 is selected from -CN, -H, -F, -CF3; or forms a thiophene ring together with R1' (to make a benzothiophene together with the sulfur atom attached to the carbon atom bearing R1); R1' may be -H or form a thiophene ring together with R1 (to make a benzothiophene together with the sulfur atom attached to the carbon atom bearing R1); R2 is selected from -H, C1-C3 alkyl, -CF3, or forms a ring, a 5- or 6-membered aromatic or non-aromatic ring together with R3, all carbon or with endocyclic O or N, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or forms an all carbon or with endocyclic O or N together with R2, all carbon or with endocyclic O or together with N form a ring, a 5- or 6-membered aromatic or non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is a C-C alkyl optionally substituted with 1, 2, or 3 C-C alkyl, or -CF; R is -H, -F, C-C alkyl and -CF3; R5 is selected from -H, -Me and -CF3; R5 is selected from -H, -Me and -CF3; R6 and R6' are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is selected from 1, 2, 3, and 4.

[0112] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0113] In some embodiments, R1 together with R1' form a thiophene ring. (The thiophene ring then forms the benzothiophene to which the rings R and R′ are attached.) At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R and where S is attached to the carbon atom bearing R′. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R.

[0114] In some embodiments, the compound of formula (1-I) is further represented by any one of the following: [ka] [ka]

[0115] In some embodiments, the compound of formula (1-I) is further represented by any one of the following: [ka]

[0116] In some embodiments, the compound of formula (1-I) is further represented by any one of the following: [ka]

[0117] The present disclosure also provides a compound of formula (1-II): [ka] wherein the ring [ka] are 4-11 membered nitrogen-containing heterocycloalkyl rings and substituted heterocycloalkyl rings, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl and substituted spirocyclic and bicyclic nitrogen-containing heterocycloalkyl rings, and R is selected from -CN, -H, -F, -CF; or forms a thiophene ring together with R' (to form a benzothiophene together with the sulfur atom bonded to the carbon atom bearing R); R' may be -H or form a thiophene ring together with R (to form a benzothiophene together with the sulfur atom bonded to the carbon atom bearing R); R is selected from -H, C-C alkyl, -CF, or forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, together with R, all carbon or with O or N in the ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R is -H, C R4 is selected from -C3 alkyl, -CF3, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or together with O or N in the ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is selected from 1, R6 and R6' are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is selected from 2, 3, and 4.

[0118] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0119] In some embodiments, R1 is taken together with R1' to form a thiophene ring (which in turn makes up the benzothiophene to which the R1 and R1' rings are attached). At least two isomeric thiophenes are possible for this structure: one where S is attached to the carbon atom bearing R1, and one where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0120] In some embodiments, the compound of formula (1-II) is further represented by any one of the following: [ka]

[0121] In some embodiments, the compound of formula (1-II) is further represented by any one of the following: [ka]

[0122] The present disclosure also provides a compound of formula (1-III): [ka] wherein the ring [ka] is a 4- to 7-membered nitrogen-containing heterocycloalkyl ring and a substituted heterocycloalkyl ring, including spirocyclic nitrogen-containing heterocycloalkyl and substituted spirocyclic nitrogen-containing heterocycloalkyl rings, [ka] are 4-7 membered cycloalkyl and substituted cycloalkyl rings, including spirocyclic and substituted spirocyclic rings, and R1 is selected from -CN, -H, -F, -CF3; or forms a thiophene ring together with R1' (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R1); R1' may be -H or forms a thiophene ring together with R1 (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R1); R2 is -H, C1 R3 is selected from -C3 alkyl, -CF3, or together with R3, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N in the ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N in the ring form a non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl, or -CF3; R5 is selected from -H, -Me, and -CF3.

[0123] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0124] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0125] In some embodiments, the compound of formula (1-III) is further represented by any one of the following: [ka]

[0126] The present disclosure also provides a compound of formula (1-IV): [ka] wherein the ring [ka] are 4- to 7-membered nitrogen-containing heterocycloalkyl rings and substituted heterocycloalkyl rings, including spirocyclic nitrogen-containing heterocycloalkyl and substituted spirocyclic nitrogen-containing heterocycloalkyl rings; [ka] is a 4- to 7-membered nitrogen-containing heterocycloalkyl ring, including spirocyclic nitrogen-containing heterocycloalkyl and substituted spirocyclic nitrogen-containing heterocycloalkyl rings, substituted heterocycloalkyl rings, and R is selected from -CN, -H, -F, -CF; or forms a thiophene ring together with R' (together with the sulfur atom attached to the carbon atom bearing R) to form a benzothiophene; R' may be -H or form a thiophene ring together with R (together with the sulfur atom attached to the carbon atom bearing R) to form a benzothiophene; R is selected from -H, C-C alkyl, -CF, or forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N in the ring, together with R; and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring is selected from -Me. or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or together with R2, form an all-carbon ring, or a 5- or 6-membered aromatic or non-aromatic ring together with O or N in the ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl, or -CF3; R5 is selected from -H, -Me, and -CF3.

[0127] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0128] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0129] In some embodiments, the compound of formula (1-IV) is further represented by any one of the following: [ka]

[0130] The present disclosure also provides a compound of formula (1-V): [ka] wherein the ring [ka] is a 4-11 membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic cycloalkyl rings, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl rings; and W is selected from NH, N-Me, N-Et, and N-iPr, or W is a bond (when W is a bond, the ring [ka] is a ring [ka] and R is selected from -CN, -H, -F, -CF; or forms a thiophene ring together with R' (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R); R' may be -H or forms a thiophene ring together with R (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R); R is selected from -H, C-C alkyl, -CF; R is -H, -F, C-C alkyl, and -CF; Y is a bond (when Y is a bond, -OH is directly bonded to the ring), or Y is a C-C alkyl, or a C-C alkyl optionally substituted with 1, 2, or 3 C-C alkyl, or -CF; R is selected from -H, -Me, and -CF; R and R are independently selected from -H, -F, C-C alkyl, and -CF, or R and R together with the atom to which they are attached form a C-C cycloalkyl or C-C heterocycloalkyl ring; and n is selected from 1, 2, 3, and 4.

[0131] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0132] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0133] In some embodiments, the compound of formula (1-V) is further represented by any one of the following: [ka]

[0134] The present disclosure also provides a compound of formula (1-VI): [ka] wherein the ring [ka] is a 4- to 7-membered nitrogen-containing heterocycloalkyl ring and a substituted heterocycloalkyl ring, including spirocyclic nitrogen-containing heterocycloalkyl and substituted spirocyclic nitrogen-containing heterocycloalkyl rings, [ka] are 4-7 membered cycloalkyl and substituted cycloalkyl rings, including spirocyclic and substituted spirocyclic rings, and R is selected from -CN, -H, -F, -CF; or forms a thiophene ring together with R' (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R); R' may be -H or may form a thiophene ring together with R (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R); R is selected from -H, C-C alkyl, -CF; R is selected from -H, -F, C-C alkyl, and -CF; Y is a bond (when Y is a bond, -OH is directly attached to the ring) or Y is C-C alkyl optionally substituted with 1, 2, or 3 C-C alkyl, or -CF; R is selected from -H, -Me, and -CF.

[0135] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0136] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0137] In some embodiments, the compound of formula (1-VI) is further represented by any one of the following: [ka]

[0138] The present disclosure also provides a compound of formula (1-VII): [ka] wherein the ring [ka] is a 4- to 11-membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic cycloalkyl rings, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl rings, and R is selected from -CN, -H, -F, -CF; or forms a thiophene ring together with R (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R); R is -H or forms a thiophene ring together with R (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R). R2 is selected from -H, C1-C3 alkyl, -CF3; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is C1-C3 alkyl, or C1-C3 alkyl optionally substituted with 1, 2, or 3 -CF3; R5 is selected from -H, -Me, and -CF3; R6 and R6' are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is selected from 0, 1, 2, 3, and 4.

[0139] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and can be selected from the group consisting of aryl, ... In some embodiments, R is present twice and is substituted at any ring position as indicated above. In some embodiments, R is present 3, 4, 5, or 6 times and is substituted at any ring position as indicated above.

[0140] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0141] In some embodiments, the compound of formula (1-VII) is further represented by any one of the following: [ka]

[0142] The present disclosure also provides a compound of formula (1-VIII): [ka]

[0143] wherein the ring [ka] is a 4- to 11-membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic cycloalkyl rings, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl rings, and R is selected from -CN, -H, -F, -CF; or forms a thiophene ring together with R (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R); R is -H or forms a thiophene together with R (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R). R2 is selected from -H, C1-C3 alkyl, -CF3; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is a C1-C3 alkyl, or a C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl, or -CF3; R5 is selected from -H, -Me, and -CF3; R6 and R6' are independently selected from -H, -F, C1-C6 alkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 1, 2, 3, and 4.

[0144] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0145] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0146] In some embodiments, the compound of formula (1-VIII) is further represented by any one of the following: [ka]

[0147] The present disclosure also provides a compound of formula (1-IX): [ka] wherein the ring [ka] are 4-11 membered nitrogen-containing heterocycloalkyl and substituted heterocycloalkyl rings, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl and substituted spirocyclic and bicyclic nitrogen-containing heterocycloalkyl rings, where R1 is selected from -CN, -H, -F, -CF3; or forms a thiophene ring together with R1' (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R1); R1' may be -H or form a thiophene ring together with R1 (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R1); R2 is selected from -H, C1-C3 alkyl, -CF3, or together with R3, forms a ring, 5- or 6-membered aromatic or non-aromatic ring, either all carbon or together with O or N in the ring. R3 is selected from -H, C1-C3 alkyl, -CF3, or together with R2, all carbon or with the O or N in the ring, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; R5 is H, Me, and -CF3 R5 is selected from -H, -Me and -CF3; R6 and R6' are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 2, 3, and 4; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1, 2, or 3 -CF3.

[0148] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0149] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0150] In some embodiments, the compound of formula (1-IX) is further represented by any one of the following: [ka]

[0151] The present disclosure provides a compound of formula (2-I): [ka] wherein the ring [ka] is a 4-11 membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic cycloalkyl, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl, and W is selected from NH, N-Me, N-Et, and N-iPr, or is a bond; when W is a bond, a carbonyl group (C═O) is not present in the ring. [ka] R1 is bonded to a nitrogen atom in the carbon atom bearing R1, so that together they form an amide bond; R1 is selected from -CN, -H, -F, -CF3; or forms a thiophene ring together with R1' (to make a benzothiophene together with the sulfur atom bonded to the carbon atom bearing R1); R1' may be -H or form a thiophene ring together with R1 (to make a benzothiophene together with the sulfur atom bonded to the carbon atom bearing R1); R2 is selected from -H, C1-C3 alkyl, -CF3, or forms together with R3 a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O or N in the ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or forms together with R2 a ring, either all carbon or with O or N in the ring. R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is a C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl, or -CF3. R5 is selected from -H, -Me, and -CF3; R6 and R6' are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 1, 2, 3, and 4; R7 is -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, [ka] is selected from.

[0152] In some embodiments of formula (2-I), the ring [ka] is a 4- to 11-membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic cycloalkyl, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl, and W is selected from NH, N-Me, or a bond; when W is a bond, a carbonyl group (C═O) is not present in the ring. [ka] R is bonded to a nitrogen atom within the ring, such that together they form an amide bond; R is selected from -F, -CF; R' is -H; R is selected from -H, -Me, -CF, or together with R to form a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with O in the ring; R is selected from -H, -Me, or together with R to form a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with O in the ring; R is -H; YI bond; R is selected from -H and -Me; R and R' are -H; n is 1; R is -H.

[0153] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0154] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0155] In some embodiments, the compound of formula (2-I) is further represented by any one of the following: [ka]

[0156] The present disclosure also provides a compound of formula (2-II): [ka] wherein the ring [ka] is a 4-11 membered nitrogen-containing ring, including heterocycloalkyl rings and substituted heterocycloalkyl rings, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyls and substituted spirocyclic and bicyclic heterocycloalkyls, and W is selected from NH, N-Me, N-Et, and N-iPr, or is a bond; when W is a bond, a carbonyl group (C═O) is not present in the ring. [ka] R1 is bonded to a nitrogen atom in the carbon atom bearing R1, so that together they form an amide bond; R1 is selected from -CN, -H, -F, -CF3; or forms a thiophene ring together with R1' (to form a benzothiophene together with the sulfur atom bonded to the carbon atom bearing R1); R1' may be H or form a thiophene ring together with R1 (to form a benzothiophene together with the sulfur atom bonded to the carbon atom bearing R1); R2 is selected from -H, C1-C3 alkyl, -CF3, or together with R3, forms a ring, 5 or 6 carbon, or ... R3 is selected from -H, C1-C3 alkyl, -CF3, or together with R2, all carbon or with O or N in the ring, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or together with R2, all carbon or with O or N in the ring, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; R5 is selected from -H, -Me, and -CF3; R6 and R6' are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is selected from 1, 2, 3, and 4.

[0157] In some embodiments of formula (2-II), the ring [ka] is a 4-11 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl, and W is selected from NH, N-Me, or a bond; when W is a bond, a carbonyl group (C=O) is attached to the ring. [ka] R is bonded to a nitrogen atom in the ring such that together they form an amide bond, and R is selected from -F, -CF; R' is -H; R is selected from -H, -Me, -CF, or together with R to form a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with O in the ring; R is selected from -H, -Me, or together with R to form a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with O in the ring; R is -H or -Me; R is selected from -H and -Me; R and R' are -H; and n is 1.

[0158] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0159] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0160] In some embodiments, the compound of formula (2-II) is further represented by any one of the following: [ka]

[0161] The present disclosure also provides a compound of formula (2-III): [ka] wherein the ring [ka] is a 4- to 11-membered ring selected from heterocycloalkyl or substituted heterocycloalkyl, including spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl; R is selected from -CN, -H, -F, -CF, or forms a thiophene ring together with R' (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R); R' may be -H or form a thiophene ring together with R (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R); R is selected from -H, C-C alkyl, -CF, or forms a ring, 5- or 6-membered aromatic ring, either all carbon or with O or N in the ring, together with R or a non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or together with R2, all carbon or with the O or N in the ring, form a ring, a 5- or 6-membered aromatic or non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; R5 is selected from -H, -Me, and -CF3; W2 is selected from optionally substituted -CH2-, -CH2CH2-, and -CH2CH2CH2-, or a bond.

[0162] In some embodiments of formula (2-III), the ring [ka] is a 4-9 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl, and W2 is selected from -CH2-, -CH2CH2-, or a bond; R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3, or together with R3, forms a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with endocyclic O; R3 is selected from -H, -Me, or together with R2, forms a ring, a 5- or 6-membered non-aromatic ring, either all carbon or with endocyclic O; R4 is -H or -Me; and R5 is selected from -H and -Me.

[0163] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and can be selected from the group consisting of aryl, ... In some embodiments, R is present twice and is substituted at any ring position as indicated above. In some embodiments, R is present 3, 4, 5, or 6 times and is substituted at any ring position as indicated above.

[0164] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0165] In some embodiments, the compound of formula (2-III) is further represented by any one of the following:

[0166] In some embodiments, the compound of formula (2-III) is further represented by any one of the following: [ka]

[0167] The present disclosure also provides a compound of formula (2-IV): [ka] wherein the ring [ka] is a 4- to 11-membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spirocyclic and bicyclic cycloalkyl, substituted spirocyclic and bicyclic cycloalkyl, spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl; R is selected from -CN, -H, -F, -CF, or forms a thiophene ring together with R' (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R'); R' may be -H or form a thiophene ring together with R (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R'); R is selected from -H, C-C alkyl, -CF, or forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, all carbon or with O or N in the ring, together with R each of the C or N atoms in the non-aromatic ring may be substituted with -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or together with R2 forms an all-carbon or, together with the O or N in the ring, a 5- or 6-membered aromatic or non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF 3; Y is a bond (when Y is a bond, -OH is directly attached to the ring), or Y is C1-C3 alkyl, or C1-C3 alkyl optionally substituted with 1, 2, or 3 -CF3; R5 is selected from -H, -Me, and -CF3; W3 is selected from optionally substituted -CH2-, -CH2CH2-, and -CH2CH2CH2-, or a bond; R7 is -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, [ka] is selected from.

[0168] In some embodiments of formula (2-IV), the ring [ka] is a 4- to 9-membered cycloalkyl or heterocycloalkyl ring, and W3 is , -CH2- and -CH2CH2-, or is a bond; R1 is selected from -F and -CF3; R1' is -H; R2 is selected from -H, -Me, and -CF3, or together with R3, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R3 is selected from -H and -Me, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R4 is -H or -Me; Y is a bond; R5 is selected from -H and -Me; and R7 is -H.

[0169] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0170] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0171] In some embodiments, the compound of formula (2-IV) is further represented by any one of the following: [ka]

[0172] The present disclosure also provides a compound of formula (2-V): [ka] wherein the ring [ka] is azetidine, pyrrolidine, piperidine or azepane; R1 is selected from -CN, -H, -F, -CF3; or may be taken together with R1' to form a thiophene ring (together with the sulfur atom attached to the carbon atom bearing R1 to form a benzothiophene); R1' is -H or may be taken together with R1 to form a thiophene ring (together with the sulfur atom attached to the carbon atom bearing R1 to form a benzothiophene); R2 is selected from -H, C1-C3 alkyl, -CF3, or taken together with R3 to form a ring, 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O or N in the ring. R3 is selected from -H, C1-C3 alkyl, -CF3, or together with R2, all carbon or with the O or N in the ring, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; R5 is selected from -H, -Me, and -CF3; R 12 teeth, [ka] m is 1, 2, or 3; and each R 13 are independently selected from -H, C1-C3 alkyl, and -CF3. 13 The groups may be joined to form a cyclopropyl or cyclobutyl ring.

[0173] In some embodiments of formula (2-V), the ring [ka] is azetidine or piperidine; R1 is selected from -F, -CF3; R1' is R2 is selected from -H, -Me, and -CF3, or together with R3 forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with endocyclic O; R3 is selected from -H, -Me, or together with R2 forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with endocyclic O; R4 is -H or -Me; R5 is selected from -H and -Me; R 12 teeth, [ka] is selected from.

[0174] In some embodiments, R4 is present as hydrogen or is otherwise absent in the ring. In some embodiments, R4 is present and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present twice and is substituted at any position on the ring as indicated above. In some embodiments, R4 is present 3, 4, 5, or 6 times and is substituted at any position on the ring as indicated above.

[0175] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0176] In some embodiments, the compound of formula (2-V) is further represented by any one of the following: [ka]

[0177] The present disclosure also provides a compound of formula (2-VI): [ka] wherein R1 is selected from -CN, -H, -F, -CF3; or forms a thiophene ring together with R1' (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R1); R1' may be -H or may form a thiophene ring together with R1 (to form a benzothiophene together with the sulfur atom attached to the carbon atom bearing R1); R2 is selected from -H, C1-C3 alkyl, and -CF3, or forms a ring, 5- or 6-membered aromatic or aryl group together with R3, either all carbon or with O or N in the ring. forms a non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R3 is selected from -H, C1-C3 alkyl, and -CF3, or together with R2, all carbon or with the O or N in the ring, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R5 is selected from -H, -Me, and -CF3; W4 is -CH2-, -CH2CH2-, [ka] R and R are independently selected from -H, C-C alkyl (including cycloalkyl), and -CF; R is -H, C-C alkyl, C-C cycloalkyl, heterocycloalkyl, [ka] is selected from.

[0178] In some embodiments of formula (2-VI), R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3, or together with R3, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R3 is selected from -H, -Me, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R5 is selected from -H and -Me; W4 is -CH2- or [ka] R8 and R8' are -H; n is 1; and R9 is -H.

[0179] In some embodiments of formula (2-VI), R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3, or together with R3, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R3 is selected from -H, -Me, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R5 is selected from -H and -Me; W4 is -CH2- or [ka] R8 and R8' are -H; n is 1; R9 is [ka] is selected from.

[0180] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0181] In some embodiments, the compound of formula (2-VI) is further represented by any one of the following: [ka]

[0182] In some embodiments, the compound of formula (2-VI) is further represented by any one of the following: [ka]

[0183] The present disclosure also provides a compound of formula (2-VII): [ka] wherein R1 is selected from -CN, -H, -F, -CF3; or forms a thiophene ring together with R1' (to make a benzothiophene together with the sulfur atom bonded to the carbon atom bearing R1); R1' may be -H or form a thiophene ring together with R1 (to make a benzothiophene together with the sulfur atom bonded to the carbon atom bearing R1); R2 is selected from -H, C1-C3 alkyl, -CF3, or forms a ring, a 5- or 6-membered aromatic or non-aromatic ring together with R3, all carbon or with endocyclic O or N, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or forms a ring, a 5- or 6-membered aromatic or non-aromatic ring together with R2, all carbon or with endocyclic O or N, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; together with N, form a ring, a 5- or 6-membered aromatic or non-aromatic ring, and each of the C or N atoms in the 5- or 6-membered aromatic or non-aromatic ring may be substituted with -Me or -OH; R5 is selected from -H, -Me, and -CF3; R6 and R6' are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6 and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 1, 2, 3, and 4; R9 and R9' are independently selected from -H, C1-C5 alkyl (including cycloalkyl), -CF3, and R9 and R9' together with the atom to which they are attached form a (substituted) C3-C6 cycloalkyl or (substituted) C3-C6 heterocycloalkyl ring; R 10 is -H, C1-C7 alkyl (including cycloalkyl and methylcycloalkyl), [ka] , and [ka] Selected from: R 11 is selected from -H, C1-C7 alkyl (including cycloalkyl and methylcycloalkyl).

[0184] In some embodiments of formula (2-VII), R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3, or together with R3, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R3 is selected from -H, -Me, or together with R2, forms a ring, a 5- or 6-membered aromatic or non-aromatic ring, either all carbon or with O in the ring; R5 is selected from -H and -Me; R6 and R6' are -H; n is 1; R9 and R9' are -H; R 10 is -H;R 11 is selected from -H or -Me.

[0185] In some embodiments, R1 together with R1' form a thiophene ring (which in turn makes up the benzothiophene to which the rings R1 and R1' are attached). At least two isomeric thiophenes are possible for this structure, where S is attached to the carbon atom bearing R1 and where S is attached to the carbon atom bearing R1'. In some embodiments, preferred benzothiophene moieties may have a sulfur atom attached to the carbon atom bearing R1.

[0186] In one embodiment, the compound of formula (2-VII) is further represented by: [ka]

[0187] Preparation method The compounds disclosed herein may be synthesized by the methods described below or by modifications of these methods. Modifications to the methodology include, among other things, temperatures, solvents, reagents, etc., known to those skilled in the art, and are part of routine reaction modification and optimization. In general, during any process for the preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule of interest. This can be done by conventional protecting group means, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.), both of which are incorporated herein by reference in their entireties. Wiley, New York (1999). Protecting groups may be removed at a convenient subsequent stage using methods known in the art. Synthetic chemical transformations useful in the synthesis of applicable compounds are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Pa, both of which are incorporated herein by reference in their entireties. These and other suitable routes include those described in "Encyclopedia of Reagents for Organic Synthesis," John Wiley and Sons, 1995. The routes shown and described herein are illustrative only and are not intended to, and should not be construed to, limit the scope of the claims in any way. Those skilled in the art will recognize modifications of the disclosed syntheses and will be able to devise alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0188] In the schemes below, protecting groups for oxygen atoms are chosen for their compatibility with the required synthetic steps as well as compatibility of the introduction and deprotection steps with the overall synthetic scheme (P. G. M. Green, T. W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

[0189] When the compounds of the present technology contain one or more stereogenic centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as stereoisomer-enriched mixtures.All such stereoisomers (and enriched mixtures) are within the scope of the present technology unless otherwise indicated.Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents or catalysts well known in the art.Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography and chiral resolving agents.

[0190] The starting materials for the following reactions are generally known or commercially available compounds, or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others can be found in standard references, such as Fieser and Fieser's Reagents for Organic Synthesis. Synthesis, Volumes 1-15 (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), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), as well as Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0191] The methods disclosed herein may involve using standard organic synthesis techniques to construct compounds of general formula (A), as shown in Scheme 1-1. Ar is an appropriately substituted phenol or protected phenol (if a protected phenol is used, a deprotection step is required after amide bond formation). Alternatively, compounds of general formula (A) can be made by starting with Cl instead of Ar and preparing the final compound via Suzuki coupling using an appropriate Ar-boronic acid in the last step. The reagents shown in Scheme 1-1 are commercially available or can be easily synthesized by one skilled in the art using methods well known in the literature.

[0192] General Scheme 1-1 shows a cyclic secondary amino alcohol, such as a substituted or unsubstituted piperidinol, pyrrolidinol, azetidinol, or spirocyclic secondary amino alcohol. However, the same approach can be taken with a primary amino alcohol, such as 4-aminocyclohexanol or 4-aminocyclobutanol, to make the compounds of the invention. Scheme 1-1: [ka]

[0193] Compounds of general formula (B) may be prepared via general schemes 1-2. The phenol on Ar may need to be appropriately protected in the first step of scheme 2. Alternatively, compounds of general formula (B) can be prepared by starting with Cl instead of Ar and preparing the final compound via Suzuki coupling using an appropriate Ar-boronic acid in the last step. The reagents shown in schemes 1-2 are either commercially available or can be easily synthesized by one skilled in the art using methods well known in the literature. Scheme 1-2: [ka]

[0194] Compounds of general formula (C) may be prepared via general schemes 1-3. Ar is an appropriately substituted phenol or protected phenol (if a protected phenol is used, a deprotection step is required after amide bond formation). Alternatively, compounds of general formula (C) can be prepared by starting with Cl instead of Ar and preparing the final compound via Suzuki coupling using an appropriate Ar-boronic acid in the last step. The reagents shown in schemes 1-3 are either commercially available or can be easily synthesized by those skilled in the art using methods well known in the literature. Schemes 1-3: [ka]

[0195] Compounds of general formula (D) may be prepared via general schemes 1-4. Ar is an appropriately substituted phenol or protected phenol (if a protected phenol is used, a deprotection step is required after amide bond formation). Alternatively, compounds of general formula (D) can be prepared by starting with Cl instead of Ar and preparing the final compound via Suzuki coupling using an appropriate Ar-boronic acid in the last step. The reagents shown in schemes 1-4 are either commercially available or can be easily synthesized by those skilled in the art using methods well known in the literature. Schemes 1-4: [ka]

[0196] Compounds of general formula (E) may be prepared via general schemes 1-5. Ar is an appropriately substituted phenol or protected phenol (if a protected phenol is used, a deprotection step is required after amide bond formation). Alternatively, compounds of general formula (E) can be prepared by starting with Cl instead of Ar and preparing the final compound via Suzuki coupling using an appropriate Ar-boronic acid in the last step. The reagents shown in schemes 1-5 are commercially available or can be easily synthesized by those skilled in the art using methods well known in the literature. Scheme 1-5: [ka]

[0197] The methods disclosed herein may involve using standard organic synthesis techniques to construct compounds of general formula (A) and general formula (B), as shown in Scheme 2-1 and Scheme 2-2. Ar is an appropriately substituted phenol or protected phenol (if a protected phenol is used, a deprotection step is required to liberate the protected phenolic hydroxy group in the appropriate synthetic step). Alternatively, compounds of general formula (A) and (B) can be made by starting with Cl instead of Ar and preparing the final compound via Suzuki coupling using an appropriate Ar-boronic acid in the final step. The reagents shown in Scheme 2-1 are commercially available or can be easily synthesized by those skilled in the art using methods well known in the literature.

[0198] General Scheme 2-1 and Scheme 2-2 show the coupling of a protected diamine to a key acid intermediate to form an amide, followed by deprotection of the terminal amine to form the final product. Scheme 2-1: [ka] Scheme 2-2: [ka]

[0199] Compounds of general formula (C) and general formula (D) may be prepared via general schemes 2-3. Ar is an appropriately substituted phenol or protected phenol (if a protected phenol is used, a deprotection step is required to liberate the protected phenolic hydroxy group in the appropriate synthetic step). Alternatively, compounds of general formula (C) can be prepared by starting with Cl instead of Ar and preparing the final compound via Suzuki coupling using an appropriate Ar-boronic acid in the final step. Removal of a protecting group may be required to obtain compounds of formula (D). The reagents shown in schemes 2-3 are commercially available or can be easily synthesized by those skilled in the art using methods well known in the literature. Scheme 2-3: [ka]

[0200] Compounds of general formula (E) may be prepared via general schemes 2-24. Ar is an appropriately substituted phenol or protected phenol (if a protected phenol is used, a deprotection step is required to liberate the protected phenolic hydroxy group in the appropriate synthetic step). Alternatively, compounds of general formula (E) can be prepared by starting with Cl in place of Ar and preparing the final compound via Suzuki coupling using an appropriate Ar-boronic acid in the final step. The reagents shown in schemes 2-4 are either commercially available or can be easily synthesized by one skilled in the art using methods well known in the literature. Scheme 2-4: [ka]

[0201] The above illustrative schemes are provided for guidance to the reader and generally represent exemplary methods for making the compounds encompassed herein. Furthermore, other methods for preparing the compounds described herein will be readily apparent to those of skill in the art in view of the following reaction schemes and examples.

[0202] Treatment method Provided herein are methods capable of inhibiting NLRP3 family proteins and NLRP3 inflammasome function and / or IL-1β secretion. Various embodiments of these methods include compounds having the structures described herein.

[0203] The present disclosure provides methods of preventing, treating, or ameliorating one or more diseases in a subject. In some embodiments, the methods comprise administering to a subject in need thereof at least one compound having a structure as described elsewhere herein. In some embodiments, the methods comprise administering to a subject in need thereof at least one compound having a structure as described elsewhere herein. The method includes administering a pharmaceutically acceptable salt of at least one compound having a structure as described above.

[0204] In some embodiments, the disease is characterized by a disease progression involving activity of at least one member of the IL-1 family of cytokines. In some embodiments, the disease progression involves activity of at least one IL-1 cytokine with agonistic activity, antagonistic activity, anti-inflammatory activity, and any combination thereof. In some embodiments, the disease progression involves activity of at least one IL-1 cytokine with agonistic activity. In some embodiments, the disease progression involves activity of at least one of IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-1Ra, IL-36Ra, IL-38, and IL-37. In some embodiments, the disease progression involves activity of at least one of IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ. In some embodiments, the disease progression involves activity of IL-1b. In some embodiments, the disease progression involves activity of IL-18. In some embodiments, disease progression involves IL-1b and IL-18 activity.

[0205] In some embodiments, the disease is at least one chronic inflammatory disorder. In some embodiments, the disease is characterized by disease progression pathology involving the activation of NLRP3 inflammasome. In some embodiments, the NLRP3 inflammasome comprises at least one mutation.

[0206] As a non-limiting example, age-related macular degeneration (AMD), both wet and dry, is accompanied by the deterioration of the central part of the retina, leading to vision loss.NLRP3 inflammasome activation can contribute to the inflammation and angiogenesis seen in AMD.Similarly, diabetic macular edema (DME) and diabetic retinopathy (DR) are complications of diabetes, in which high blood sugar level damages retinal blood vessels, and inflammation plays a crucial role in progression.

[0207] Diseases such as glaucoma, which is characterized by increased pressure within the eye leading to optic nerve damage, and retinopathies, which involve damage to retinal blood vessels, are also associated with inflammatory responses mediated by the NLRP3 inflammasome. Dry eye disease (DED) and bacterial keratitis, infections of the cornea, are associated with inflammation in which NLRP3 may play a role in the response to infection and cellular stress.

[0208] Inflammatory and autoimmune diseases such as Behcet's syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis can have ocular symptoms, including uveitis (inflammation of the middle layer of the eye) and retinal vasculitis (inflammation of the retinal blood vessels). These conditions are often characterized by an excessive immune response, and controlling NLRP3 inflammasome activation can manage inflammation and prevent tissue damage. Targeting NLRP3 inflammasome for patients experiencing or at risk of experiencing the various diseases described above can reduce inflammation, slow disease progression, preserve vision, and improve quality of life by addressing one of the underlying mechanisms contributing to these ocular conditions.

[0209] In some embodiments, the disease is, for example, age-related macular degeneration (wet and dry) (AMD), atrophic macular degeneration, bacterial endophthalmitis, bacterial infections of the eye, bacterial corneal ulcers including, but not limited to, Pseudomonas aeruginosa and Streptococcus pneumoniae corneal ulcers, bacterial keratitis including, but not limited to, Pseudomonas aeruginosa keratitis, Behcet's syndrome, cataracts, choroidal neovascularization, CMV retinitis, chronic eye diseases, delayed diabetic corneal wound healing and neurodegeneration, diabetic jaundice, Diabetic retinopathy (DR), including but not limited to diabetic macular edema (DME), proliferative diabetic retinopathy, conjunctivitis, corneal allograft rejection, including but not limited to corneal graft failure (CGF), corneal edema, dry eye disease (DED), Graves' disease, Fuchs' endothelial corneal dystrophy, fungal endophthalmitis, fungal keratitis, including but not limited to candida albicans keratitis, fungal infections of the eye, glaucoma (acute and non-acute), geographic atrophy (GA), inflammatory eye diseases, hereditary transient keratitis (keratitis fugax), hereditaria (KFH), LPS-induced ocular inflammation, Mooren's ulcer (MU), neuronal death in retinal ischemia / reperfusion injury, ocular hypertension, ocular inflammation associated with CAPS (including familial cold autoinflammatory syndrome), ocular manifestations of rheumatoid arthritis and systemic lupus erythematosus (SLE), limbal squamous cell carcinoma, optic neuritis, ocular parasitic infections, pathological angiogenesis, excitoretinal hyperstimulation, lipofuscin and A2E-mediated oxidative damage including but not limited to ROS / oxidative stress reduction, ocular hypertension (OHT) retinal ganglion cell (RGC) dysfunction and death in response to ocular inflammatory stress (OHT - glaucoma), retinoblastoma, retinitis, retinal vasculitis, retinal vein occlusion (RVO), Sjogren's syndrome, aseptic corneal inflammation, stroke-induced retinal injury in diabetes, traumatic optic neuropathy / trauma (optic nerve crush) including but not limited to progressive optic neuropathy, ulcerative keratitis, uveal melanoma, uveitis (anterior / intermediate / posterior, panuveitis), and viral infections of the eye including but not limited to inflammatory exanthematous diseases.

[0210] In some embodiments, the disease is selected from the group consisting of, for example, age-related macular degeneration (wet and dry) (AMD), atrophic macular degeneration, bacterial keratitis, Behcet's syndrome, choroidal neovascularization, chronic eye diseases, diabetic macular edema (DME), diabetic retinopathy (DR), dry eye disease (DED), glaucoma (acute and non-acute), geographic atrophy (GA), inflammatory eye diseases, ocular inflammation associated with CAPS, ocular manifestations of rheumatoid arthritis and systemic lupus erythematosus (SLE), retinitis, retinal vasculitis, retinal vein occlusion (RVO), progressive optic neuropathy, and uveitis (anterior / intermediate / posterior, panuveitis).

[0211] Consistent with the present disclosure, the compounds of the present disclosure may be used to treat, prevent, or ameliorate diseases affecting the eye. In some embodiments, the disease is selected from the group consisting of, for example, age-related macular degeneration (wet and dry) (AMD), atrophic macular degeneration, bacterial keratitis, Behcet's syndrome, choroidal neovascularization, chronic eye disease, diabetic macular edema (DME), diabetic retinopathy (DR), dry eye disease (DED), glaucoma (acute and non-acute), geographic atrophy (GA), and retinopathies.

[0212] In some embodiments, the disease is selected from the group consisting of, for example, inflammatory eye diseases, ocular inflammation associated with cryopyrin-associated periodic syndromes (CAPS), ocular symptoms of rheumatoid arthritis and systemic lupus erythematosus (SLE), retinitis, retinal vasculitis, retinal vein occlusion (RVO), progressive optic neuropathy, and uveitis (anterior / intermediate / posterior, panuveitis).

[0213] In some embodiments, the disease is age-related macular degeneration (AMD). In some embodiments, the disease is atrophic macular degeneration. In some embodiments, the disease is bacterial keratitis. In some embodiments, the disease is Behcet's syndrome. In some embodiments, the disease is choroidal neovascularization. In some embodiments, the disease is a chronic eye disease. In some embodiments, the disease is diabetic macular edema (DME). In some embodiments, the disease is diabetic retinopathy (DR). In some embodiments, the disease is dry eye disease (DED).

[0214] In some embodiments, the disease is glaucoma, both acute and non-acute. In some embodiments, the disease is geographic atrophy (GA). In some embodiments, the disease is a retinopathy. In some embodiments, the disease is an inflammatory eye disease. In some embodiments, the disease is associated with ocular inflammation from cryopyrin-associated periodic syndromes (CAPS). In some embodiments, the disease is associated with ocular symptoms of rheumatoid arthritis and systemic lupus erythematosus (SLE). In some embodiments, the disease is retinitis. In some embodiments, the disease is retinal vasculitis. In some embodiments, the disease is retinal vein occlusion (RVO). In some embodiments, the disease is progressive optic neuropathy. In some embodiments, the disease is uveitis, including anterior, intermediate, posterior, or panuveitis.

[0215] In some embodiments, due to the activity of the NLRP3 inflammasome, the compounds of the present disclosure are expected to have significant biological activity against a wide range of systemic diseases.For example, in diseases such as gout and atherosclerosis, where inflammation is a major factor, the compounds of the present disclosure can reduce symptoms and progression by modulating inflammatory responses.Therefore, compounds that inhibit / stimulate NLRP3 inflammasome activation are sought for their potential in treating various systemic conditions.NLRP3 inflammasome plays a role in human immune response, and its dysregulation is involved in many diseases characterized by chronic inflammation and immune system dysfunction.

[0216] In some embodiments, the compounds and methods of the present disclosure can be used to treat or alleviate the systemic symptoms of NLRP3 activation compounds, including autoinflammatory diseases.Conditions such as cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever are directly related to NLRP3 dysregulation.Similarly, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and multiple sclerosis, in which chronic inflammation is sustained through immune response, can benefit from such compounds.

[0217] Metabolic disorders, particularly type 2 diabetes and obesity, are also potential targets for NLRP3 inhibitors. These conditions are associated with chronic low-grade inflammation, in which NLRP3 may contribute to insulin resistance and metabolic complications. In the field of neurodegenerative diseases, conditions such as Alzheimer's disease and Parkinson's disease may benefit from NLRP3 inhibition, given the role of inflammation in neurodegeneration.

[0218] Cardiovascular diseases, including atherosclerosis, are accompanied by chronic inflammation, in which NLRP3 may be involved in plaque formation and cardiac dysfunction.Liver diseases, such as nonalcoholic steatohepatitis (NASH) and alcoholic liver disease, are also accompanied by NLRP3-mediated inflammation.Similarly, kidney diseases such as acute kidney injury and diabetic nephropathy may be affected by NLRP3 activation.Finally, lung diseases with inflammatory components, such as asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis, may also be viable targets for compounds that modulate NLRP3 activity.

[0219] Without being bound by a single theory of operation, NLRP3 inflammasome activation has been linked to a variety of inflammasome-associated diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Non-limiting examples of inflammasome-associated diseases include atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension); autoinflammatory fever syndromes, cryopyrin-associated periodic syndromes (e.g., CAPS); cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis); chronic liver disease; gout; hidradenitis suppurativa; hyperoxaluria; neuroinflammatory-associated disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease); nonalcoholic steatohepatitis (NASH); pseudogout (chondrocalcinosis); sickle cell disease; type I / II diabetes and related complications (e.g., nephropathy, retinopathy); and wound healing and scar formation.

[0220] In some embodiments, the disease is selected from the group consisting of, for example, acute or chronic arthropathy; alcoholic liver disease; alcoholic steatohepatitis; autoinflammatory fever syndromes, such as cryopyrin-associated periodic syndromes (CAPS); chronic liver disease; diabetic nephropathy, a kidney-related complication of diabetes (type 1, type 2, and diabetes mellitus); gout; hemodialysis-associated inflammation; hypertensive nephropathy; inflammatory arthritis-related disorders, such as osteoarthritis and rheumatoid arthritis; kidney-related diseases, such as hyperoxaluria and lupus nephritis; liver-related diseases / disorders, such as viral hepatitis and non-alcoholic steatohepatitis (NASH); pseudogout (chondrocalcinosis); sickle cell disease; and systemic lupus erythematosus (SLE).

[0221] Additionally, increased production of IL-1b and IL-18 by the NLRP3 inflammasome has been implicated in the initiation and progression of various diseases, such as neuroinflammatory-related disorders, such as brain infections, acute injuries, multiple sclerosis, Alzheimer's disease, and neurodegenerative diseases; cardiovascular / metabolic disorders / diseases, such as cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and associated complications (e.g., nephropathy, retinopathy), peripheral arterial disease (PAD), acute heart failure, and hypertension; wound healing and scar formation; inflammatory skin diseases, such as acne, hidradenitis suppurativa, asthma, sarcoidosis, and age-related macular degeneration; and cancer-related diseases / disorders, such as myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer, and colon cancer.

[0222] Administration and Pharmaceutical Compositions Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound having a structure described herein and a pharmaceutically acceptable excipient.

[0223] The compounds are administered in therapeutically effective dosages. While human dosage levels have not yet been optimized for the compounds described herein, in general, daily doses may range from about 0.25 mg to about 120 mg or more per kg of body weight, from about 0.5 mg or less to about 70 mg per kg, from about 1.0 mg to about 50 mg per kg, or from about 1.5 mg to about 10 mg per kg. Thus, for administration to a 70 kg human, dosage ranges would be from about 17 mg / day to about 8000 mg / day, from about 35 mg / day to about 7000 mg / day or more, from about 70 mg / day to about 6000 mg / day, from about 100 mg / day to about 5000 mg / day, or from about 200 mg to about 3000 mg / day. The amount of active compound administered will, of course, depend on the subject and disease state being treated, the severity of the condition, the mode and schedule of administration, and the judgment of the prescribing physician.

[0224] Administration of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be via any of the accepted modes of administration for agents serving similar purposes, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal, or ocular. Oral and parenteral administration are customarily used in the treatment of the indications covered by the preferred embodiments.

[0225] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treating these conditions. Standard pharmaceutical formulation techniques can be used, for example, in accordance with Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005) are used. Thus, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, atropisomers, tautomers, polymorphs, hydrates, and solvates thereof), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

[0226] In addition to the selected compounds useful as described above, some embodiments include compositions containing a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Additionally, various adjuvants, such as those commonly used in the art, may be included. Considerations for including various components in pharmaceutical compositions are found, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0227] Some examples of substances which can serve as pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0228] The choice of pharmaceutically acceptable carrier to be used in conjunction with the subject compounds is basically determined by the way the compound is to be administered.

[0229] The compositions described herein are preferably provided in unit dosage forms. As used herein, a "unit dosage form" is a composition containing an amount of compound suitable for administration to an animal, preferably a mammalian subject, in a single dose, in accordance with principles of good medicine. The preparation of a single or unit dosage form, however, does not imply that the dosage form is administered once per day or once per course of treatment. Such dosage forms are intended to be administered once, twice, or three or more times per day, and may be administered as an infusion over a time period (e.g., from about 30 minutes to about 2-6 hours) or as a continuous infusion, and may be given more than once during a course of treatment, although single administrations are not specifically excluded. Those skilled in the art will recognize that the formulation does not specifically envision an entire course of treatment, and that such decisions are left to those skilled in the art of treatment rather than formulation.

[0230] The compositions useful as described above may be in any of a variety of suitable forms for various routes of administration, such as oral, nasal, rectal, topical (including transdermal), intraocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, intravitreal, subcutaneous, or other parenteral routes of administration. In some embodiments, the compositions may be in a form suitable for subcutaneous administration. Those skilled in the art will understand that oral and nasal compositions, including compositions administered by inhalation, may be prepared using available methodologies. Depending on the specific route of administration desired, various pharmaceutically acceptable carriers known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. These carriers may be used without substantially interfering with the inhibitory activity of the compound. The compound may contain an optional pharmaceutically active material, which is not a pharmaceutical active ingredient. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0231] A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can be compressed, wet-tableted, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-foaming granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings.

[0232] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and croscarmellose; and lubricants such as magnesium stearate, stearic acid, and talc. Lubricants such as silicon dioxide can be used to improve the flow characteristics of powder mixtures. Coloring agents, such as FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents as disclosed above. The selection of carrier components depends on secondary considerations such as taste, cost, and storage stability, which are not essential and can be easily determined by those skilled in the art.

[0233] Oral compositions also include liquid solutions, emulsions, and suspensions. Suitable pharmaceutically acceptable carriers for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more of the components disclosed above, such as sweeteners, flavorings, and coloring agents.

[0234] Such compositions may also be coated by conventional methods, typically with pH or time dependent coatings, so that the subject compounds are released in the vicinity of the desired topical application in the gastrointestinal tract or at various times to prolong the desired effect. Such dosage forms may contain one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac. Typically includes, but is not limited to:

[0235] The compositions described herein may optionally include other active agents.

[0236] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms.Such compositions typically comprise soluble filler materials, such as sucrose, sorbitol and mannitol; and binders, such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose, one or more of which are mentioned above.The above-mentioned glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents may also be included.

[0237] Liquid compositions formulated for external ophthalmic use are formulated so that they can be administered externally to the eye. Comfort should be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may require less than optimal comfort. If comfort cannot be maximized, the liquid should be formulated to be acceptable to patients for external ophthalmic use. Additionally, ophthalmically acceptable liquids should be packaged for single use or contain preservatives to prevent contamination during multiple uses.

[0238] For ophthalmic applications, solutions or medicaments are often prepared using saline solution as the primary medium. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. Formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0239] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.

[0240] A useful surfactant is, for example, Tween 80. Similarly, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, cyclodextrin or derivatives thereof, and purified water.

[0241] Tonicity adjusters may be added as needed or appropriate, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0242] Various buffers and means for adjusting the pH may be used as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH is 4 to 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

[0243] Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0244] Another excipient component that may be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents may also be used instead or in combination therewith.

[0245] For topical use, creams, ointments, gels, solutions or suspensions, etc. containing the compounds disclosed herein are used. Topical formulations may generally include a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0246] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid, may be included to achieve the desired pH. In various embodiments, the pH of the final composition is within the range of 2 to 8, or preferably 4 to 7.

[0247] Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran.

[0248] Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entireties.

[0249] Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0250] Compositions for intravenous administration may be provided to the caregiver in a solid form that is reconstituted with a suitable diluent, such as sterile water, saline, or dextrose in water, immediately prior to administration. In other embodiments, the compositions are provided in a solution ready for parenteral administration. In yet other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments involving administering a combination of a compound described herein and another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0251] The actual dose of the active compounds described herein will depend on the particular compound and the condition to be treated; selection of the appropriate dose is well within the knowledge of one of ordinary skill in the art.

[0252] The compounds and compositions described herein may be provided in a pack or dispenser device containing one or more unit dosage forms containing active ingredients, if desired.Such a pack or device may comprise, for example, metal or plastic foil, such as a blister pack, or glass, and a rubber stopper, for example, in a vial.The pack or dispenser device may be accompanied by instructions for administration.The compounds and compositions described herein may be formulated in a compatible pharmaceutical carrier, and may also be prepared, placed in a suitable container, and labeled for the treatment of the indicated condition.

[0253] The amount of the compound in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation contains, on a weight percent (wt-%) basis, about 0.01 to about 99.99 wt-% of the compound of the present technology based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1 to about 80 wt-%. Representative pharmaceutical formulations are described below.

[0254] Formulation example The following are representative pharmaceutical formulations containing a compound of formula (1-I), (1-II), (1-III), (1-IV), (1-V), (1-VI), (1-VII), (1-VIII), (1-IX), (2-I), (2-II), (2-III), (2-IV), (2-V), (2-VI), or 2-VII.

[0255] Formulation Example 1 -- Tablet Formulation The following ingredients are intimately mixed and pressed into single-score tablets: [Table 1]

[0256] Formulation Example 2 -- Capsule formulation The following ingredients are intimately mixed and loaded into a hard-shell gelatin capsule: [Table 2]

[0257] Formulation Example 3 -- Suspension Formulation The following ingredients are mixed to form a suspension for oral administration: [Table 3]

[0258] Formulation Example 4 -- Injectable formulation The following ingredients are mixed to form an injectable formulation: [Table 4]

[0259] Formulation Example 5 -- Suppository Formulation Suppositories with a total weight of 2.5 g are prepared by mixing a compound of the present technology with Witepsol® H-15 (triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) and have the following composition: [Table 5]

[0260] The following examples are included to further illustrate the present invention. The examples, of course, should not be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the present invention as described and claimed in this application. The reader will recognize that one skilled in the art, armed with this disclosure and the skills in the art, can prepare and use the present invention without the need for exhaustive examples. The following examples further describe the present invention and are used for illustrative purposes only and should not be considered limiting.

[0261] Compounds may be identified by their chemical structure and / or their chemical name. Chemical names are those of PerkinElmer (Waltham, MA 02451, USA). Generated using the ChemDraw® Professional 19.1.1.21 naming program. In the event of a conflict between the chemical structure and the chemical name, the chemical structure is determinative of the compound's identity.

[0262] The compounds of formulas (1-I), (1-II), (1-III), (1-IV), (1-V), (1-VI), (1-VII), (1-VIII), and (1-IX) disclosed herein include any specific compounds within these formulas. Specific compounds within formulas (1-I), (1-II), (1-III), (1-IV), (1-V), (1-VI), (1-VII), (1-VIII), and (1-IX) are shown in Table 1. Example [Table 6-1]

[0263] [Table 6-2]

[0264] Table 6-3

[0265] Table 6-4

[0266] Table 6-5

[0267] Table 6-6

[0268] Table 6-7

[0269] Table 6-8

[0270] Table 6-9

[0271] Table 6-10

[0272] Table 6-11

[0273] Table 6-12

[0274] [Table 6-13]

[0275] [Table 6-14]

[0276] [Table 6-15]

[0277] [Table 6-16]

[0278] [Table 6-17]

[0279] The compounds of formulas (2-I), (2-II), (2-III), (2-IV), (2-V), (2-VI), and (2-VII) disclosed herein include any specific compounds within these formulas. Specific compounds within formulas (2-I), (2-II), (2-III), (2-IV), (2-V), (2-VI), and (2-VII) are shown in Table 2.

[0280] [Table 7-1]

[0281] [Table 7-2]

[0282] [Table 7-3]

[0283] [Table 7-4]

[0284] [Table 7-5]

[0285] [Table 7-6]

[0286] [Table 7-7]

[0287] [Table 7-8]

[0288] [Table 7-9]

[0289] General Procedure It is clear to those skilled in the art that methods for preparing precursors and functional groups for the compounds claimed in this application are generally described in the literature. In these reactions, it is also possible to use variants that are known per se to those skilled in the art, but are not described in more detail. Given the literature and this disclosure, those skilled in the art are fully equipped to prepare any of the compounds.

[0290] Those skilled in the art of organic chemistry will recognize that the manipulations can be readily performed without further instruction, i.e., are well within the scope and practice of one of ordinary skill in the art. These include reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, both electrophilic and nucleophilic aromatic substitutions, etherification, esterification, and saponification. These manipulations are discussed in standard textbooks, such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in its entirety). All intermediate compounds of the present invention were used without further purification unless otherwise specified.

[0291] Those skilled in the art will readily understand that certain reactions are best performed when other functional groups are masked or protected in the molecule, thereby avoiding any undesired side reactions and / or increasing the yield of the reaction. Often, those skilled in the art will utilize protecting groups to achieve such increased yields or to avoid undesired reactions. These reactions can be found in the literature and are also well within the scope of those skilled in the art. Many examples of these operations can be found, for example, in T. Greene and P. Wuts, "Protecting Groups in Organic Synthesis," 4th Ed., John Wiley & Sons (2007), the entire contents of which are incorporated herein by reference.

[0292] The following exemplary schemes are provided for guidance to the reader and represent preferred methods for making the compounds exemplified herein. It will be apparent that these methods are not limiting and that other routes may be used to prepare these compounds. Such methods particularly include solid-phase based chemistry, including combinatorial chemistry. Those skilled in the art are fully equipped to prepare these compounds according to the methods provided in the literature and in this disclosure. The compound numbering used in the synthetic schemes depicted below is meant only for those specific schemes and should not be construed or confused as the same numbering in other sections of this application.

[0293] The trademarks used herein are merely examples and reflect the exemplary materials used at the time of the present invention. Those skilled in the art will recognize that variations in batches, production processes, etc. are to be expected. Therefore, the examples and the trademarks used therein are non-limiting, and they are not intended to be limiting, but merely illustrative of how one skilled in the art may select to perform one or more embodiments of the present invention.

[0294] The following abbreviations have the meanings indicated: 2N = 2 normality solution of a species ACN = acetonitrile AIBN = azobisisobutyronitrile aq. = aqueous Bn = benzyl Boc = tert-butoxycarbonyl Brine = saturated aqueous solution of sodium chloride (NaCl) Bu = butyl CD3OD = deuterated methanol CHCl3 = chloroform CDCl3 = deuterated chloroform CH2Cl2 = methylene chloride, or dichloromethane, or DCM Cs2CO3 = Cesium carbonate DIEA = N,N-diisopropylethylamine DMF = dimethylformamide DMSO = dimethyl sulfoxide EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDC·HCl) Et = ethyl EtOAc or EA = ethyl acetate

[0295] g = grams FA = formic acid h=hour 1 H + = protons H=hydrogen H2O = Water HATU = hexafluorophosphate azabenzotriazole tetramethyluronium HCl = hydrogen chloride HOBt = hydroxybenzotriazole HPLC = High-Performance Liquid Chromatography iPrOH = isopropyl alcohol LCMS = Liquid Chromatography Mass Spectrometry Me = methyl M = molar concentration m=multiplet [M+H] + = molecular ion + 1 proton MeOH = methanol min=minutes mL = milliliters mmol = millimolar MHz = Megahertz m / z=mass-to-charge ratio

[0296] N2 = nitrogen NaCl = sodium chloride Na2SO4 = sodium sulfate NH3 = ammonia NBS = N-bromosuccinimide NH4HCO3 = ammonium bicarbonate NMR=nuclear magnetic resonance NMP = N-methyl-2-pyrrolidone or 1-methyl-2-pyrrolidone o / n or on = all night PBr3 = phosphorus tribromide PCl5 = phosphorus pentachloride PCC = pyridinium chlorochromate PEG = polyethylene glycol Ph = phenyl pH = negative logarithm of hydrogen ion concentration PPh3Cl2 = triphenylphosphine dichloride ppm = parts per million q=Quartet rt=room temperature s = singlet sat.=saturated t = triplet SFC = Supercritical Fluid Chromatography TBSCl = tert-butyldimethylsilyl chloride tBu = tert-butyl TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMS = trimethylsilyl [Example]

[0297] The following exemplary schemes are provided for guidance to the reader and generally represent exemplary methods for making the compounds provided herein. Additionally, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0298] Example 1: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethan-1-one (1) [ka]

[0299] Synthesis scheme: [ka]

[0300] Step 1: Synthesis of tert-butyl (3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidine-1-carboxylate

[0301] A brown solution of 3,6-dichloro-4-methylpyridazine (5.00 g, 30.7 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (6.76 g, 33.7 mmol) and DIEA (16.0 mL, 11.89 g, 92.0 mmol) in NMP (25 mL) was stirred overnight at 150 °C (oil bath). To this solution were added EtOAc (100 mL) and water (100 mL). After phase separation, the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with brine (2 × 200 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. After concentration, the suspension was subjected to silica gel column chromatography purification eluting with a PE / EtOAc gradient (0-50%) to give tert-butyl (3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidine-1-carboxylate as a yellow oil (1.3 g, 13.0% yield). LC / MS: C 15 H 23 Calculated mass of ClN4O2: 326.15, Found mass: m / z = 327.15 [M+H] + .

[0302] Step 2: Synthesis of 6-chloro-5-methyl-N-[(3R)-piperidin-3-yl]pyridazin-3-amine hydrochloride

[0303] To a solution of tert-butyl (3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidine-1-carboxylate (680 mg, 2.08 mmol) in DCM (3 mL) was added hydrogen chloride (HCl) (3 mL, 12.0 mmol, 4 M in 1,4-dioxane) at 0° C. (ice bath). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator to give 6-chloro-5-methyl-N-[(3R)-piperidin-3-yl]pyridazin-3-amine hydrochloride as a colorless solid (550 mg, 90.4% yield). LC / MS: C 10 H 15 Calculated mass of ClN4: 226.10, Found mass: m / z = 227.00 [M+H] + .

[0304] Step 3: Synthesis of tert-butyl (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0305] A brown solution of 6-chloro-5-methyl-N-[(3R)-piperidin-3-yl]pyridazin-3-amine (600 mg, 2.65 mmol), tert-butyl 2-bromoacetate (516 mg, 2.65 mmol, 1.0 equiv.), and DIEA (1.84 mL, 1.37 g, 10.59 mmol) in ACN (7 mL) was stirred at 60 °C for 1 h. The residue was purified on a silica gel column eluted with a PE / EtOAc gradient (0-100%) to give tert-butyl 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]acetate as a yellow solid (650 mg, 68.7% yield). LC / MS: C 16 H 25 Calculated mass of ClN4O2: 340.17, Found mass: m / z = 341.10 [M+H] + .

[0306] Step 4: Synthesis of (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid

[0307] DCM (4 mL) and HCl (4 mL, 16 mmol, 4 M in 1,4-dioxane) A pale yellow suspension of tert-butyl 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]acetate (600 mg, 1.76 mmol) in HCl was stirred overnight at 40° C. The solvent was removed under reduced pressure using a rotary evaporator to give [(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]acetic acid as a pale yellow solid (500 mg, 90.3% yield). LC / MS: C 12 H 17 Calculated mass of ClN4O2: 284.10, Found mass: 285.00 m / z = [M+H] + .

[0308] Step 5: Synthesis of 2-((R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethan-1-one

[0309] A yellow solution of [(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]acetic acid (250 mg, 0.88 mmol), pyrrolidin-3-ol (92 mg, 1.05 mmol, 1.2 equiv), HATU (501 mg, 1.32 mmol, 1.5 equiv) and DIEA (764 μL, 567 mg, 4.39 mmol, 5.0 equiv) in DMF (2 mL) was stirred at room temperature for 2 h. After evaporation of volatiles under reduced pressure in high vacuum, the crude reaction mixture was subjected to reverse-phase column chromatography (10-50% ACN / water (0.05% NH4HCO3)) to afford 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]-1-(3-hydroxypyrrolidin-1-yl)ethanone as a pale yellow oil (200 mg, 57.9% yield). LC / MS: C 16 H 24 Calculated mass of ClN5O2: 353.16, Found mass: m / z = 354.20 [M+H] + .

[0310] Step 6: Synthesis of 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethan-1-one (1)

[0311] A brown suspension of 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]-1-(3-hydroxypyrrolidin-1-yl)ethanone (200 mg, 0.57 mmol, 1.0 equiv), 2-hydroxy-4-(trifluoromethyl)phenylboronic acid (175 mg, 0.85 mmol, 1.5 equiv), Pd(PPh3)4 (20 mg, 0.017 mmol, 0.03 equiv), NaHCO3 (142 mg, 1.70 mmol, 3.0 equiv) in dioxane (3 mL) and water (1.5 mL) was stirred in a sealed tube at 150 °C under an atmosphere of N2 for 1 h. After cooling the reaction mixture to room temperature, the solution was subjected to silica gel column purification eluting with a DCM / MeOH gradient (0-10%) to obtain the pre-purified reaction product (150 mg) as a light brown oil. The material was further purified by preparative RP-HPLC using the following column conditions: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 46% B, 46% B in 7 min; Wavelength: 254 nm; RT1: 5.73 min. After lyophilization of the combined product-containing fractions, the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-1-(3-hydroxypyrrolidin-1-yl)ethenone (1) was obtained as a pale yellow solid (36.0 mg, 13.2% yield). LC / MS: C 23 H 28 Calculated mass of F3N5O3: 479.21, Found mass: m / z = 480.15 [M+H] + . 1H NMR (300 MHz, DMSO-d6): δ 10.51 (s, 1H), 7. 43 - 7.34 (m, 1H), 7.26 - 7.16 (m, 2H), 6.73 - 6.58 (m, 2H), 5.09 - 4.81 (m, 1H), 4.35 - 4.17 (m, 1H), 4.02 (s, 1H), 3.54 - 3.47 (m, 2H), 3.23 - 3.14 (m, 2H), 3.23 - 3.04 (m, 2H), 3.00 - 2.85 (m, 1H), 2.77 - 2.58 (m, 1H), 2.31 - 2.07 (m, 2H), 2.00 (s, 3H), 1.94 - 1.63 (m, 4H), 1.61 - 1.44 (m, 1H), 1.39 - 1.23 (m, 1H) ppm. 19 F NMR (282 MHz, DMSO-d6): δ -61.17 ppm.

[0312] Example 2: 1-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (2) [ka]

[0313] Synthesis scheme: [ka]

[0314] Steps 1a and 1b: Synthesis of 1-(2-((R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol

[0315] A brown suspension of 6-chloro-5-methyl-N-[(3I)-piperidin-3-yl]pyridazin-3-amine hydrochloride (200 mg, 0.76 mmol), 3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)pyrrolidine (221 mg, 0.84 mmol, 1.1 equiv.) (rac-3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)pyrrolidine was added to (3S)-3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)pyrrolidine as described in Example 4. Similar to [(2-chloroethyl)silyloxy]-1-(2-chloroethyl)pyrrolidine, rac-pyrrolidin-3-ol hydrochloride was prepared using NaI (114 mg, 0.76 mmol, 1.0 equiv.) and DIEA (398 μL, 295 mg, 2.28 mmol, 3.0 equiv.) as starting materials in ACN (3 mL) by stirring at 80 °C for 2 h. After evaporation of volatiles under reduced pressure using a rotary evaporator, the suspension was subjected to reverse-phase column purification (5–40% ACN / water + 0.05 vol-% TFA) to give a brown oil, which was dissolved in 2 mL of a DCM-TFA mixture (1:1, v / v) and stirred at room temperature for 1 h. After removal of the solvent at 70°C, the residue was subjected to silica gel column purification eluting with a DCM / MeOH gradient (0-10%) to give 1-{2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]ethyl}pyrrolidin-3-ol as a brown oil (150 mg, 58.1% yield). LC / MS: C 16 H 26 Calculated mass of ClNO: 339.18, Found mass: m / z = 340.10 [M+H] + .

[0316] Step 2: Synthesis of 1-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (2)

[0317] A brown suspension of 1-{2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]ethyl}pyrrolidin-3-ol (150 mg, 0.44 mmol, 1.0 equiv.), 2-hydroxy-4-(trifluoromethyl)phenylboronic acid (145 mg, 0.71 mmol, 1.6 equiv.), Pd(PPh3)4 (15 mg, 0.013 mmol, 0.03 equiv.), and NaHCO3 (111 mg, 1.32 mmol, 3.0 equiv.) in dioxane (2 mL) and HO (1 mL) was stirred in a sealed tube at 150 °C for 1 h under an atmosphere of N2. The reaction mixture was cooled to room temperature. After the reaction, the solvent was removed under reduced pressure using a rotary evaporator, and the residue was subjected to silica gel column purification eluting with a DCM / MeOH gradient (0-10%) to give a brown solid (100 mg). The solid was further purified by preparative RP-HPLC under the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 44% B in 7 min; Wavelength: 254 nm; RT1: 6.07 min. After lyophilization of the combined product-containing fractions, the target material 1-{2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]ethyl}pyrrolidin-3-ol (2) was obtained as a colorless solid (20.3 mg, 9.6% yield). LC / MS: C 23 H 30 Calculated mass of F3N5O2: 465.24, detected mass: m / z = 466.20 [M+H + ]. 1 H NMR (400 MHz, methanol-d4): δ 7.42 - 7.40 (m, 1H), 7.24 - 7.18 (m, 2H), 6.80 (s, 1H), 4.40 - 4.38 (m, 1H), 4.14 - 4.10 (m, 1H), 3.12 - 3.06 (m, 1H), 2.98 - 2.67 (m, 9H), 2.35 - 2.28 (m, 1H), 2.21 - 2.08 (m, 5H), 1.99 - 1.91 (m, 1H), 1.89 - 1.66 (m, 3H), 1.55 - 1.46 (m, 1H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.26 ppm.

[0318] Example 3: (R)-1-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (3) [ka]

[0319] Synthesis scheme: [ka]

[0320] Step 1: Synthesis of N-((R)-1-(2-((R)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)ethyl)piperidin-3-yl)-6-chloro-5-methylpyridazin-3-amine

[0321] (3R)-3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)pyrrolidine (303 mg, 1.15 mmol, 1.4 equiv.) (A brown suspension of (3R)-3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)pyrrolidine was prepared similarly to (3S)-3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)pyrrolidine described in Example 4, but using (3S)-pyrrolidin-3-ol hydrochloride as starting materials, 6-chloro-5-methyl-N-[(3R)-piperidin-3-yl]pyridazin-3-amine (200 mg, 0.88 mmol, 1.0 equiv.), NaI (132 mg, 0.88 mmol, 1.0 equiv.), and DIEA (461 μL, 342 mg, 2.0 equiv.). The reaction mixture was prepared by stirring at 80 °C for 2 hours using a 100% ethanol (65 mmol, 3.0 equiv.). After cooling to room temperature, DCM (20 mL) and water (10 mL) were added to the suspension. After phase separation, the aqueous phase was extracted with DCM (2 × 10 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified on a silica gel column eluting with a DCM / MeOH gradient (0–5%) to give N-[(3R)-1-{2-[(3R)-3-[(tert-butyldimethylsilyl)oxy]pyrrolidin-1-yl]ethyl}piperidin-3-yl]-6-chloro-5-methylpyridazin-3-amine as a colorless oil (180 mg, 44.9% yield). LC / MS: C 22 H 40 Calculated mass of ClN5OSi: 453.27, Found mass: m / z = 454.35 [M+H] + .

[0322] Step 2: Synthesis of (R)-1-(2-((R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol

[0323] A colorless solution of N-[(3R)-1-{2-[(3R)-3-[(tert-butyldimethylsilyl)oxy]pyrrolidin-1-yl]ethyl}piperidin-3-yl]-6-chloro-5-methylpyridazin-3-amine (180 mg, 0.40 mmol) in DCM (2 mL) and HCl (2 mL, 4 M in 1,4-dioxane, 8.0 mmol, 20 equiv.) The mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure using a rotary evaporator, (3R)-1-{2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]ethyl}pyrrolidin-3-ol was obtained as a colorless solid (120 mg, 89.1% yield), which was used without further isolation and characterization. LC / MS: C 16 H 26 Calculated mass of ClNO: 339.18, Found mass: m / z = 340.20 [M+H] + .

[0324] Step 3: Synthesis of (R)-1-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (3)

[0325] A red suspension of (3R)-1-{2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]ethyl}pyrrolidin-3-ol (120 mg, 0.35 mmol), 2-hydroxy-4-(trifluoromethyl)phenylboronic acid (109 mg, 0.53 mmol, 1.5 equiv), NaHCO (60 mg, 0.71 mmol, 2.0) and Pd(PPh) (13 mg, 0.011 mmol, 0.03 equiv) in 1,4-dioxane (1.5 mL) and HO (3 mL) was stirred in a sealed tube at 150 °C for 1 h under an atmosphere of N. After concentration under reduced pressure using a rotary evaporator, the residue was subjected to silica gel column chromatography eluting with a DCM / MeOH gradient (0-5%) to give a white solid, which was subjected to preparative RP-HPLC using the following conditions: Column: XBridge Prep OBD C18 Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 27% B to 57% B in 7 min, 57% B; Wavelength: 254nm; RT: 16min. After lyophilization of the combined fractions, the target material (3R)-1-{2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]ethyl}pyrrolidin-3-ol (3) was obtained as a colorless solid (22.4 mg, 13.6% yield). LC / MS: C 23 H 30 Calculated mass of F3N5O2: 465.24, Found mass: m / z = 466.20 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.44 - 7.37 (m, 1H), 7.26 - 7.14 (m, 2H), 6.79 (s, 1H), 4.43 - 4.33 (m, 1H), 4.20 - 4.08 (m, 1H), 3.16 - 3.03 (m, 1H), 2.97 - 2.80 (m, 2H), 2.79 - 2.66 (m, 4H), 2.65 - 2.51 (m, 3H), 2.39 - 2.26 (m, 1H), 2.25 - 2.06 (m, 5H), 2.03 - 1.91 (m, 1H), 1.90 - 1.61 (m, 3H), 1.59 - 1.41 (m, 1H). 19 F NMR (376 MHz, methanol-d4): δ -64.26 ppm.

[0326] Example 4: (S)-1-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (4) [ka]

[0327] Synthesis scheme: [ka]

[0328] Step 1: Synthesis of (S)-1-(2-(benzyloxy)ethyl)pyrrolidin-3-ol

[0329] To a solution of [(2-bromoethoxy)methyl]benzene (2.00 g, 9.30 mmol, 1.0 equiv.) and (3S)-pyrrolidin-3-ol hydrochloride (1.26 g, 10.23 mmol, 1.1 equiv.) in ACN (30 mL) was added solid K2CO3 (3.86 g, 27.9 mmol, 3.0 equiv.) in a sealed tube. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with saturated aqueous NH4Cl solution (50 mL), and the mixture was extracted with DCM (3 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give (3S)-1-[2-(benzyloxy)ethyl]pyrrolidin-3-ol as a yellow oil (1.00 g, 41.3% yield), which was used without further isolation and characterization. LC / MS: C 13 H 19 Calculated mass of NO2: 221.14, Found mass: m / z = 222.15 [M+H] + .

[0330] Step 2: (S)-1-(2-(benzyloxy)ethyl)-3-((tert-butyl) Synthesis of Dimethylsilyloxypyrrolidine

[0331] To a solution of (3S)-1-[2-(benzyloxy)ethyl]pyrrolidin-3-ol (1.00 g, 4.52 mmol, 1.0 equiv.) in DCM (10 mL) was added solid TBSCl (818 mg, 5.42 mmol, 1.2 equiv.) and 1H-imidazole (616 mg, 9.04 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the residue was subjected to silica gel column purification eluting with a PE / EtO (0-100%) gradient to afford (3S)-1-[2-(benzyloxy)ethyl]-3-[(tert-butyldimethylsilyl)oxy]pyrrolidine as a yellow oil (1.4 g, 83.1% yield) after concentration of the product-containing fractions and evaporation of the solvent under reduced pressure using a rotary evaporator. LC / MS: C 19 H 33Calculated mass of NO2Si: 335.23, detected mass: 336.15 m / z = [M+H] + .

[0332] Step 3: Synthesis of (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)ethan-1-ol

[0333] To a solution of (3S)-1-[2-(benzyloxy)ethyl]-3-[(tert-butyldimethylsilyl)oxy]pyrrolidine (1.4 g, 4.17 mmol) in 30 mL of a mixture of EA / t-BuOH (1:1, v / v) was added 10 wt-% Pd / C (1.4 g, 100 wt-%). The resulting suspension was stirred at 50 °C overnight under an atmosphere of H at atmospheric pressure. After filtration over silica gel, the solution was concentrated under reduced pressure using a rotary evaporator to give 2-[(3S)-3-[(tert-butyldimethylsilyl)oxy]pyrrolidin-1-yl]ethanol as a yellow oil (1.0 g, 85.9% yield), which was used directly in the next step without further isolation and characterization. LC / MS: C 12 H 27 Calculated mass of NO2Si: 245.18, detected mass: m / z = 246.10 [M+H] + .

[0334] Step 4: Synthesis of (S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloroethyl)pyrrolidine

[0335] To a solution of 2-[(3S)-3-[(tert-butyldimethylsilyl)oxy]pyrrolidin-1-yl]ethanol (1.0 g, 4.07 mmol) in DCM (10 mL) was added EtN (1.21 mL, 825 mg, 8.15 mmol, 2.0 equiv.) and solid TsCl (1.17 g, 6.11 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with saturated aqueous NH4Cl solution (30 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give (3S)-3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)-pyrrolidine as a yellow oil (1.0 g, 83.7% yield), which was used directly in the next step without further isolation and characterization. LC / MS:C 12 H 26 Calculated mass of ClNOSi: 263.14, Found mass: m / z = 264.00 [M+H] + .

[0336] Step 5: Synthesis of N-((R)-1-(2-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)ethyl)piperidin-3-yl)-6-chloro-5-methylpyridazin-3-amine

[0337] (R)-6-chloro-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine hydrochloride (200 mg, 0.76 mmol, 1.0 equiv.), (S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloroethene) in ACN (4 mL). A brown suspension of (methyl)pyrrolidine (401 mg, 1.52 mmol, 2.0 equiv.), NaI (228 mg, 1.52 mmol, 2.0 equiv.), and DIEA (398 μL, 295 mg, 2.28 mmol, 3.0 equiv.) was stirred at 80° C. for 2 h. After the reaction mixture was cooled to room temperature, EtOAc (20 mL) and water (10 mL) were added to the crude reaction mixture. After phase separation, the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (2×20 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was subjected to silica gel column chromatography eluting with a DCM / MeOH gradient (0-5%) to afford, after evaporation of the combined product-containing fractions under reduced pressure using a rotary evaporator, N-((R)-1-(2-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)ethyl)piperidin-3-yl)-6-chloro-5-methylpyridazin-3-amine as a yellow oil (160 mg, 36.4% yield). LC / MS: C 22 H 40 Calculated mass of ClN5OSi: 453.27, Found mass: m / z = 454.25 [M+H] + .

[0338] Step 6: Synthesis of (S)-1-(2-((R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol

[0339] A solution of HCl (2 mL, 8.0 mmol, 4 M in 1,4-dioxane) was added to a brown solution of N-((R)-1-(2-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)ethyl)piperidin-3-yl)-6-chloro-5-methylpyridazin-3-amine (200 mg, 0.44 mmol) dissolved in DCM (2 mL), and the reaction mixture was stirred at room temperature for 3 hours to give a suspension. After removal of the solvent under reduced pressure using a rotary evaporator, (S)-1-(2-((R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol was obtained as a brown oil (100 mg, 63.0% yield), which was used directly without further isolation and characterization. LC / MS: C 16 H 26 Calculated mass of ClNO: 339.18, Found mass: m / z = 340.20 [M+H] + .

[0340] Step 7: Synthesis of (S)-1-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (4)

[0341] (S)-1-(2-((R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (310 mg, 0.91 mmol, 1.0 equiv), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (282 mg, 1.37 mmol, 1.5 equiv), Pd(PPh) in dioxane (4 mL) and HO (2 mL). 33A solution of 4 (32 mg, 0.027 mmol, 0.03 equiv.) and NaHCO3 (153 mg, 1.82 mmol, 2.0 equiv.) was stirred in a sealed tube at 150 °C under N2 atmosphere for 1 h. After filtration and concentration of the filtrate under reduced pressure using a rotary evaporator, the residue was subjected to silica gel column purification eluting with a DCM / MeOH gradient (0-10%) to give a yellow oil, which was purified using the following conditions: Column: Xselect CSH C18 OBD Column 30*150 mm Further purification was carried out by preparative RP-HPLC using a 5 μm column; mobile phase A: water (0.1 vol-% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 3% B to 21% B in 7 min, 21% B; wavelength: 254 nm; RT1 (min): 5.38; after lyophilization of the combined fractions, the target compound (S)-1-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (4) formate was obtained as a white solid (26 mg, 5.5% yield). LC / MS: C 24 H 32 Calculated mass of F3N5O4: 465.24, Found mass: m / z = 466.20 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.79 - 7.37 (m, 1H), 7.30 - 7.23 (m, 1H), 7.26 - 7.17 (m, 1H), 6.85 - 6.81 (m, 1H), 4.61 - 4.54 (m, 1H), 4.10 - 4.06 (m, 1H), 3.73 - 3.61 (m, 1H), 3.55 - 3.35 (m, 5H), 3.24 - 3.14 (m, 1H), 2.94 - 2.82 (m, 2H), 2.69 - 2.58 (m, 1H), 2.41 - 2.23 (m, 2H), 2.15 (s, 3H), 2.12 - 1.74 (m, 5H), 1.52 - 1.45 (m, 1H) ppm.

[0342] Example 5: 4-Fluoro-1-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (5) [ka]

[0343] Synthesis scheme: [ka]

[0344] Step 1: Synthesis of 4-fluoropyrrolidin-3-ol hydrochloride

[0345] To a solution of tert-butyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate (3.00 g, 14.62 mmol) in DCM (15 mL) was added HCl (15 mL, 60 mmol, 4 M in 1,4-dioxane) at 0° C. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure using a rotary evaporator to give 4-fluoropyrrolidin-3-ol hydrochloride as a brown solid (2.00 g, 87.0% yield). LC / MS: calculated mass for C4H8FNO: 105.06, found m / z = 106.00 [M+H]. + .

[0346] Step 2: Synthesis of 1-(2-(benzyloxy)ethyl)-4-fluoropyrrolidin-3-ol

[0347] To a solution of [(2-bromoethoxy)methyl]benzene (2.00 g, 9.30 mmol, 1.0 equiv.) and 4-fluoropyrrolidin-3-ol hydrochloride (1.45 g, 10.23 mmol, 1.1 equiv.) in ACN (50 mL) was added K2CO3 (3.86 g, 27.9 mmol). The reaction mixture was stirred at 80°C for 2 h. The reaction mixture was diluted with saturated aqueous NH4Cl solution (50 mL), and the aqueous phase was extracted with DCM (3 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give 1-[2-(benzyloxy)ethyl]-4-fluoropyrrolidin-3-ol as a brown oil (2.00 g, 67.4% yield). LC / MS: C 13 H 18 Calculated mass of FNO2: 239.13, detected mass: m / z = 240.00 [M+H] + .

[0348] Step 3: Synthesis of 1-(2-(benzyloxy)ethyl)-3-((tert-butyldimethylsilyl)oxy)-4-fluoropyrrolidine

[0349] To a solution of 1-[2-(benzyloxy)ethyl]-4-fluoropyrrolidin-3-ol (1.90 g, 7.94 mmol) in DCM (20 mL) was added solid TBSCl (1.44 g, 9.53 mmol) and 1H-imidazole (1.08 g, 15.88 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was subjected to silica gel column purification eluting with PE / ethyl ether (0-50%) to give 1-[2-(benzyloxy)ethyl]-3-[(tert-butyldimethylsilyl)oxy]-4-fluoropyrrolidine as a yellow oil (1.60 g, 51.3% yield). LC / MS: C 19 H 32 Calculated mass of FNO2Si: 353.22, detected mass: m / z = 354.10 [M+H] + .

[0350] Step 4: Synthesis of 2-(3-((tert-butyldimethylsilyl)oxy)-4-fluoropyrrolidin-1-yl)ethan-1-ol

[0351] To a solution of 1-[2-(benzyloxy)ethyl]-3-[(tert-butyldimethylsilyl)oxy]-4-fluoropyrrolidine (800 mg, 2.26 mmol) in ethyl acetate / t-BuOH (16 mL, 1:1, v / v) was added Pd / C (800 mg, 10 wt-% Pd / C). The resulting suspension was stirred at 60 °C overnight under a hydrogen atmosphere at atmospheric pressure. After filtration through silica gel, the solution was concentrated under reduced pressure using a rotary evaporator to give 2-{3-[(tert-butyldimethylsilyl)oxy]-4-fluoropyrrolidin-1-yl}ethanol as a yellow oil (600 mg, 85.6% yield). LC / MS: C 12 H 26 Calculated mass of FNO2Si: 263.17, detected mass: m / z = 264.05 [M+H] + .

[0352] Step 5: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-1-(2-chloroethyl)-4-fluoropyrrolidine

[0353] To a solution of 2-{3-[(tert-butyldimethylsilyl)oxy]-4-fluoropyrrolidin-1-yl}ethanol (580 mg, 2.20 mmol) in DCM (6 mL) was added TEA (614 μL, 446 mg, 4.40 mmol, 2.0 equiv.) and solid TsCl (504 mg, 2.64 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature for 5 hours and diluted with saturated aqueous NH4Cl solution (30 mL). The aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give 3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)-4-fluoropyrrolidine as a yellow oil (600 mg, 77.3% yield). The crude product was used in the next step without further purification or characterization. LC / MS: C 12 H25 Calculated mass of ClFNOSi: 281.14, detected mass: m / z = 282.05 [M+H] + .

[0354] Steps 6 and 7: Synthesis of 1-(2-((R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)-4-fluoropyrrolidin-3-ol

[0355] To a solution of 6-chloro-5-methyl-N-[(3R)-piperidin-3-yl]pyridazin-3-amine hydrochloride (580 mg, 2.20 mmol) and 3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)-4-fluoropyrrolidine (746 mg, 2.65 mmol, 1.2 equiv.) in ACN (6 mL) was added NaI (661 mg, 1.41 mmol, 0.65 equiv.) and DIEA (1.14 mL, 846 mg, 6.612 mmol, 3.0 equiv.). The resulting suspension was stirred at 80 °C for 2 h. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure using a rotary evaporator. The resulting mixture was purified by reverse-phase column chromatography (0-60% ACN / water (0.05% The residue was subjected to HCl (vol-TFA) to give a yellow oil. Under these purification conditions, the TBDMS group was simultaneously removed during lyophilization of the combined product-containing fractions due to the presence of TFA (0.05 vol-%) in the eluent. The resulting oil was subjected to silica gel column chromatography eluting with DCM / MeOH (0-20%) to give 1-{2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]ethyl}-4-fluoropyrrolidin-3-ol as a yellow oil (150 mg, 15.2% yield) after combining the product-containing fractions under reduced pressure using a rotary evaporator. LC / MS: C 16 H 25 Calculated mass of ClFNO: 357.17, Found mass: m / z = 358.05 [M+H] + .

[0356] Step 8: Synthesis of 4-fluoro-1-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (5)

[0357] To a solution of 1-{2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]ethyl}-4-fluoropyrrolidin-3-ol (150 mg, 0.42 mmol) in dioxane / HO (3 mL, 2:1, v / v) was added 2-hydroxy-4-(trifluoromethyl)phenylboronic acid (139 mg, 0.67 mmol, 1.6 equiv), Pd(PPh) (15 mg, 0.013 mmol, 0.03 equiv), and NaHCO (106 mg, 1.26 mmol, 3.0 equiv). The resulting reaction mixture was stirred in a sealed tube at 150 °C for 1 h under an atmosphere of N. After cooling the reaction mixture to room temperature, the solution was evaporated under reduced pressure using a rotary evaporator. The reaction mixture was concentrated. The residue was purified on a silica gel column eluted with DCM / MeOH (0-20%) to give the crude target compound as a yellow oil (70 mg). The oil was further purified by preparative RP-HPLC using the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water + 0.1 vol-% FA, Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 22% B in 7 min; Wavelength: 254 nm; RT1 (min): 4.92. After lyophilization of the combined product-containing fractions, the target compound 4-fluoro-1-{2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]ethyl}pyrrolidin-3-ol (5) formate was obtained as an off-white solid (4.7 mg, 2.3% yield). LC / MS: C 23 H 29 Calculated mass of F4N5O2: 483.23, detected mass: m / z = 484.20 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.43 - 7.40 (m, 1H), 7.27 - 7.20 (m, 2H), 6.87 (s, 1H), 5.08 - 5.04 (m, 1H), 4.88 - 4.83 (m, 1H), 4.42 - 4.24 (m, 2H), 3.57 - 3.37 (m, 2H), 3.28 - 3.08 (m, 7H), 3.02 - 2.56 (m, 2H), 2.17 - 2.01 (m, 5H), 1.93 - 1.88 (m, 1H), 1.70 - 1.62 (m, 1H) ppm. 19 F NMR (376 MHz, methanol-d4): δ −64.26, −180.21 ppm.

[0358] Example 6: (R)-1-(2-(3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidin-1-yl)ethyl)piperidin-4-ol (6) [ka]

[0359] Synthesis scheme: [ka]

[0360] Step 1: Synthesis of 1-(2-(benzyloxy)ethyl)piperidin-4-ol

[0361] To a solution of [(2-bromoethoxy)methyl]benzene (1.47 mL, 2 g, 9.30 mmol, 1.0 equiv) and piperidin-4-ol (1.03 g, 10.2 mmol, 1.1 equiv) in ACN (30 mL) was added K2CO3 (3.86 g, 27.9 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with saturated aqueous NH4Cl solution (50 mL) and extracted with DCM (3 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give 1-[2-(benzyloxy)ethyl]piperidin-4-ol as a yellow oil (2.0 g, 82.3% yield). LC / MS: C 14 H 21 Calculated mass of NO2: 235.16, Found mass: m / z = 236.05 [M+H] + .

[0362] Step 2: Synthesis of 1-(2-(benzyloxy)ethyl)-4-((tert-butyldimethylsilyl)oxy)piperidine

[0363] To a solution of 1-[2-(benzyloxy)ethyl]piperidin-4-ol (2 g, 8.50 mmol) in DCM (25 mL) was added TBSCl (1.54 g, 10.20 mmol, 1.2 equiv.) and 1H-imidazole (1.16 g, 17.0 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the residue was subjected to silica gel column chromatography eluting with a PE / ethyl ether gradient (0-100%) to afford 1-[2-(benzyloxy)ethyl]-4-[(tert-butyldimethylsilyl)oxy]piperidine as a yellow oil (1.2 g, 36.4% yield). LC / MS: C 20 H 35 Calculated mass of NO2Si: 349.24, detected mass: m / z = 350.20 [M+H] + .

[0364] Step 3: Synthesis of 2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)ethan-1-ol

[0365] To a solution of 1-[2-(benzyloxy)ethyl]-4-[(tert-butyldimethylsilyl)oxy]piperidine (1.2 g, 3.43 mmol) in 30 mL of a mixture of EtOAc / t-BuOH (1:1, v / v) was added solid 10 wt% Pd / C (1.2 g). The resulting suspension was stirred at 50 °C overnight under an atmosphere of H at atmospheric pressure. After filtration through silica gel, the filtrate was concentrated under reduced pressure to give 2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-1-yl}ethanol as a yellow oil (900 mg, 88.9% yield). LC / MS: C 13 H 29 Calculated mass of NO2Si: 259.20, detected mass: m / z = 260.10 [M+H] + .

[0366] Step 4: Synthesis of 4-((tert-butyldimethylsilyl)oxy)-1-(2-chloroethyl)piperidine

[0367] To a solution of 2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-1-yl}ethanol (900 mg, 3.47 mmol) in DCM (10 mL) was added EtN (967 μL, 702 mg, 6.94 mmol, 2.0 equiv.) and solid TsCl (794 mg, 4.16 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NH4Cl solution (30 mL), and the aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give 4-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)piperidine as a yellow oil (900 mg, 74.7% yield). LC / MS: C 13 H 28 Calculated mass of ClNOSi: 277.16, Found mass: m / z = 278.10 [M+H] + .

[0368] Step 5: Synthesis of (R)—N-(1-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)ethyl)piperidin-3-yl)-6-chloropyridazin-3-amine

[0369] To a solution of 6-chloro-N-[(3R)-piperidin-3-yl]pyridazin-3-amine hydrochloride (300 mg, 1.20 mmol) and 4-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)piperidine (402 mg, 1.45 mmol, 1.2 equiv) in ACN (5 mL) was added NaI (361 mg, 2.41 mmol, 2.0 equiv) and DIEA (629 μL, 467 mg, 3.61 mmol, 3.0 equiv). The resulting suspension was stirred at 80° C. for 2 h. After the reaction mixture was cooled to room temperature, the reaction mixture was washed with saturated aqueous NH4Cl solution (20 mL) and diluted with DCM (3×50 mL). ). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was subjected to silica gel column purification eluting with a DCM / MeOH gradient (0-20%) to give N-[(3R)-1-(2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-1-yl}ethyl)piperidin-3-yl]-6-chloropyridazin-3-amine as a yellow oil (300 mg, 49.4% yield). LC / MS: C 22 H 40 Calculated mass of ClN5OSi: 453.27, Found mass: m / z = 454.20 [M+H] + .

[0370] Step 6: Synthesis of N-[(3R)-1-(2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-1-yl}ethyl)piperidin-3-yl]-6-[2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-amine

[0371] To a solution of N-[(3R)-1-(2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-1-yl}ethyl)piperidin-3-yl]-6-chloropyridazin-3-amine (150 mg, 0.33 mmol, 1.0 equiv.) in 2.4 mL of a mixture of dioxane / HO (2:1, v / v) was added 2-[2-(ethoxymethoxy)-6-methyl-4-(trimethylsilyl)oxy]piperidin-1-yl]ethyl]-6-chloropyridazin-3-amine.

[0033] [(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared according to WO 2020 / 234715) (238 mg, 0.66 mmol, 2.0 equiv.), Pd(PPh3)4 (12 mg, 0.010 mmol, 0.03 equiv.), and NaHCO3 (84 mg, 0.990 mmol, 3.0 equiv.) were added. The resulting reaction mixture was stirred in a sealed tube at 150 °C for 1 hour under an atmosphere of N2. After cooling the reaction mixture to room temperature, the reaction mixture was concentrated under reduced pressure using a rotary evaporator. The residue was subjected to silica gel column purification eluting with a DCM / MeOH gradient (0-20%) to give N-[(3R)-1-(2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-1-yl}ethyl)piperidin-3-yl]-6-[2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-amine as a yellow oil (100 mg, 41.8% yield). LC / MS: C 33 H 52 Calculated mass of F3N5O3Si: 651.38, Found mass: m / z = 652.40 [M+H] + .

[0372] Step 7: Synthesis of 1-{2-[(3R)-3-({6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl}amino)piperidin-1-yl]ethyl}piperidin-4-ol (6)

[0373] To a solution of N-[(3R)-1-(2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-1-yl}ethyl)piperidin-3-yl]-6-[2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-amine (120 mg, 0.18 mmol) in DCM (1.5 mL) was added TFA (1.5 mL) at 0° C. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator. The following conditions were used: Column: XBridge Prep The resulting residue was subjected to preparative RP-HPLC using an OBD C18 Column, 30*150 mm, 5 μm; mobile phase A: water + 0.1 vol-% FA, mobile phase B: ACN; flow rate: 25 mL / min; gradient: 39% B to 59% B in 7 min; wavelength: 254 nm; RT1: 4.6 min. After lyophilization of the combined product-containing fractions, the target compound 1-{2-[(3R)-3-({6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl}amino)piperidin-1-yl]ethyl}piperidin-4-ol (6) was obtained as a colorless solid (2.6 mg, 2.8% yield). LC / MS: C 24 H 32 Calculated mass of F3N5O2: 479.25, Found mass: m / z = 480.25 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.34 - 7.32 (m, 1H), 7.09 - 7.06 (m, 1H), 7.02 - 6.96 (m, 2H), 4.17 - 4.15 (m, 1H), 3.68 - 3.65 (m, 1H), 3.15 - 3.08 (m, 1H), 2.96 - 2.93 (m, 2H), 2.82 - 2.72 (m, 1H), 2.69 - 2.59 (m, 4H), 2.43 - 2.22 (m, 3H), 2.21 - 2.00(m, 4H), 1.99 - 1.91 (m, 1H), 1.88 - 1.83 (m, 3H), 1.74 - 1.63 (m, 3H), 1.52 - 1.43 (m, 1H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.41 ppm.

[0374] Example 7: (R)-1-(2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)piperidin-4-ol (7) [ka]

[0375] Synthesis scheme: [ka]

[0376] Step 1: Synthesis of (R)-N-(1-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)ethyl)piperidin-3-yl)-6-chloro-5-methylpyridazin-3-amine

[0377] (R)-6-chloro-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine hydrochloride (300 mg, 1.14 mmol, 1.0 equiv.), 4-((tert-butyldimethylsilyl)oxy)-1-(2-chloroethyl)piperidine (634 mg, 2.28 mmol, 2.0 equiv.), NaI (342 mg, 2.2 A brown suspension of (R)-N-(1-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)ethyl)piperidin-3-yl)-6-chloro-5-methylpyridazin-3-amine) ... LC / MS:C 23 H 42 Calculated mass of ClN5OSi: 467.28, Found mass: m / z = 468.30 [M+H] + .

[0378] Step 2: Synthesis of (R)-1-(2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)piperidin-4-ol

[0379] A solution of HCl (3 mL, 12 mmol, 4 HCl in 1,4-dioxane) was added to a brown solution of (R)-N-(1-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)ethyl)piperidin-3-yl)-6-chloro-5-methylpyridazin-3-amine (200 mg, 0.43 mmol) in DCM (3 mL) to give a brown solution, which was stirred at room temperature for 3 hours to form a suspension. After removal of the solvent under reduced pressure using a rotary evaporator, (R)-1-(2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)piperidin-4-ol was obtained as a yellow oil (140 mg, 68.6% yield), which was used without further purification and characterization. LC / MS: C 17 H 28Calculated mass of ClNO: 353.20, Found mass: m / z = 354.25 [M+H] + .

[0380] Step 3: Synthesis of (R)-1-(2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)piperidin-4-ol (7)

[0381] A solution of 1-{2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]ethyl}piperidin-4-ol (250 mg, 0.71 mmol, 1.0 equiv), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (218 mg, 1.06 mmol, 1.5 equiv), Pd(PPh3)4 (24 mg, 0.021 mmol, 0.03 equiv), and NaHCO3 (119 mg, 1.41 mmol, 2.0 equiv) in 4.5 mL of a mixture of 1,4-dioxane and water (2:1, v / v) was stirred in a sealed tube under an atmosphere of N2 at 150 °C for 1 h. After filtration of the solid and concentration under reduced pressure, the residue was subjected to silica gel column chromatography eluting with a DCM / MeOH gradient (0-10%) to give a yellow oil after concentration of the product-containing fractions under reduced pressure using a rotary evaporator, which was further purified by preparative RP-HPLC using the following conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile phase A: water (0.1vol-% FA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3% B to 18% B, 18% B in 7 min; Wavelength: 254nm; RT1: 5.40min. After lyophilization of the product-containing fractions, the target compound (R)-1-(2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)piperidin-4-ol (7) formate was obtained as a colorless solid (27.6 mg, 7.4% yield). LC / MS: C 24 H 32 Calculated mass of F3N5O2: 479.25, Found mass: m / z = 480.2 [M+H]+ . 1 H NMR (400 MHz, methanol-d4): δ 7.42 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 6.84 (s, 1H), 4.20 - 3.86 (m, 2H), 3.46 - 3.36 (m, 4H), 3.28 - 3.24 (m, 1H), 3.16 - 3.09 (m, 3H), 2.94 - 2.90 (m, 2H), 2.75 - 2.67 (m, 1H), 2.40 - 2.35 (m, 1H), 2.15 (s, 3H), 2.08 - 2.01 (m, 3H), 1.97 - 1.72 (m, 4H), 1.55 - 1.47 (m, 1H) ppm.

[0382] Example 8: (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethan-1-one (8) [ka]

[0383] Synthesis scheme: [ka]

[0384] Step 1: Synthesis of (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethan-1-one

[0385] To a yellow suspension of [(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]acetic acid (300 mg, 1.054 mmol), azetidin-3-ol hydrochloride (173 mg, 1.58 mmol, 1.5 equiv.), and DIEA (1.1 mL, 817 mg, 6.32 mmol, 6.0 equiv.) in DMF (3 mL) was added solid HATU (601 mg, 1.58 mmol, 1.5 equiv.) in small portions under stirring to give a yellow suspension. The suspension was stirred at room temperature for 1 h. The reaction progress was monitored by LC / MS. After concentration under reduced pressure, the suspension was subjected to reverse-phase column chromatography eluting with a water (10 mmol / L NH4HCO3) / ACN gradient (5-60%) at 60°C. After concentration of the product-containing fractions on a rotary evaporator under reduced pressure, 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone was obtained as a yellow oil (290 mg, 80.2% yield). LC / MS: C 15 H 22 Calculated mass of ClN5O2: 339.15, Found mass: m / z = 340.30 [M+H] + .

[0386] Step 2: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethan-1-one (8)

[0387] A yellow suspension of 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone (290 mg, 0.85 mmol, 1 equiv.), 2-hydroxy-4-(trifluoromethyl)phenylboronic acid (281 mg, 1.37 mmol, 1.6 equiv.), Pd(PPh3)4 (29.6 mg, 0.026 mmol, 0.03 equiv.), and NaHCO3 (215 mg, 2.56 mmol) in 6.6 mL of a mixture of 1,4-dioxane and HO (2:1, v / v) was stirred at 150 °C for 1 h in a sealed tube. The reaction was monitored by LC / MS. After cooling to room temperature, EtOAc (10 mL) and water (20 mL) were added to the suspension. After phase separation, the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (2 × 40 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was subjected to silica gel column chromatography purification to obtain the crude target compound as a yellow solid (398 mg). The solid was further purified by preparative RP-HPLC using the following conditions: Column: CHIRALPAK IB N-3, 4.6*100 mm, 3 μm; Mobile phase B: MEOH (vol-0.1% DEA); Flow rate: 2 mL / min; Gradient: isocratic 10% B; Wavelength: 220 nm. After lyophilization of the combined product-containing fractions, the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-1-(3-hydroxyazetidin-1-yl)ethenone (8) was obtained (27.5 mg, 6.9% yield). LC / MS: C 22 H 26 Calculated mass of F3N5O3: 465.20, Found mass: m / z = 466.10 [M+H] + . 1H NMR (300 MHz, methanol-d4): δ 7.40 (m, 1H), 7.24 (m, 2H), 6.80 (m, 1H), 4.58 (m, 2H), 4.19 (m, 3H), 3.79 (m, 1H), 3.10 (m, 2H), 2.92 (m, 1H), 2.57 (m, 1H), 2.38 (m, 2H), 2.15 (s, 3H), 1.87 (m, 2H), 1.60 (m, 2H). 19 F NMR (282 MHz, methanol-d4): δ -64.29 ppm.

[0388] Example 9: 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone (9) [ka]

[0389] Synthesis scheme: [ka]

[0390] Step 1: Synthesis of 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone

[0391] HATU (321 mg, 0.84 mmol, 1.2 equiv.) was added to a colorless solution of [(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]acetic acid (200 mg, 0.70 mmol), piperidin-4-ol (71.1 mg, 0.70 mmol, 1.0 equiv.), and DIEA (367 μL, 272 mg, 2.11 mmol, 3.0 equiv.) in DMF (2 mL) to give a yellowish solution, which was stirred overnight at room temperature. EtOAc (20 mL) and water (10 mL) were added to this solution. After phase separation, the aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (1 × 50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography to give 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone as an off-white solid (150 mg, 54.4% yield). LC / MS: C 17 H 26 Calculated mass of ClN5O2: 367.18, Found mass: m / z = 368.10 [M+H] + .

[0392] Step 2: Synthesis of 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone (9)

[0393] A yellow solution of 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone (150 mg, 0.41 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (176.2 mg, 0.61 mmol, 1.5 equiv.), NaHCO (103 mg, 1.22 mmol, 3.0 equiv.) in 3.9 mL of a mixture of 1,4-dioxane / HO (2:1, v / v) was stirred until homogeneous. Then, Pd(PPh3)4 (14.1 mg, 0.012 mmol, 0.03 equiv) was added and the mixture was stirred at 150 °C in a sealed tube under an atmosphere of N2 for 1 h. After cooling to room temperature, the mixture was evaporated under reduced pressure using a rotary evaporator. After concentration, the residue was subjected to silica gel column purification to obtain a yellow solid. The yellow solid was further purified by preparative RP-HPLC using the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 45% B in 9 min, 45% B; Wavelength: 254 nm; RT1: 7 min. After lyophilization of the combined product-containing fractions, the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone (9) was obtained as a pale yellow solid (35 mg, 17.4% yield). LC / MS: C 24 H 30 Calculated mass of F3N5O3: 493.53, Found mass: m / z = 494.40 [M+H] + . 1 H NMR (300 MHz, methanol-d4): δ 7.51 - 7.35 (m, 1H), 7.29 - 7.23 (m, 1H), 7.18 (s, 1H), 6.84 - 6.75 (m, 1H), 4.26 - 3.73 (m, 4H), 3.45 - 3.36 (m, 1H), 3.31 - 3.08 (m, 3H), 3.07 - 2.92 (m, 3H), 2.66 (s, 1H), 2.44 - 2.24 (m, 1H), 2.20 - 2.09 (m, 3H), 2.02 - 1.30 (m, 8H) ppm. 19 F NMR (282 MHz, methanol-d4): δ -64.28 ppm.

[0394] Example 10: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-N-((1r,3R)-3-hydroxycyclobutyl)acetamide (10) [ka]

[0395] Synthesis scheme: [ka]

[0396] Step 1: Synthesis of tert-butyl (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0397] To a solution of tert-butyl 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]acetate (1.00 g, 2.93 mmol, 1.0 equiv.), 2-hydroxy-4-(trifluoromethyl)phenylboronic acid (0.91 g, 4.40 mmol, 1.5 equiv.) in 21 mL of a mixture of 1,4-dioxane / HO (2:1, v / v), NaHCO (0.74 g, 8.80 mmol, 3.0 equiv.) and Pd(PPh) (0.1 g, 0.088 mmol, 0.03 equiv.) were added. The reaction mixture was stirred in a sealed tube at 150 °C under an atmosphere of N for 1 h. After the reaction mixture was cooled to room temperature, it was quenched with an aqueous solution of NaCl (20 mL) and further diluted with water (20 mL). The aqueous phase was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (2 × 80 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography to give tert-butyl 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetate as an off-colorless solid (1.1 g, 75.5% yield). LC / MS: C 23 H 29 Calculated mass of F3N4O3: 466.22, Found mass: m / z = 467.18 [M+H] + .

[0398] Step 2: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid

[0399] To a yellow solution of tert-butyl 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetate (1.1 g, 2.54 mmol) in DCM (4 mL), A 4 M solution in 1,4-dioxane (8 mL, 32 mmol) was added to give a suspension. The suspension was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure using a rotary evaporator to give (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid as a yellow solid (880 mg, 77.3% yield), which was used directly without further purification and characterization. LC / MS: C 19 H 21 Calculated mass of F3N4O3: 410.16, Found mass: m / z = 411.15 [M+H] + .

[0400] Step 3: Synthesis of 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-N-((1r,3R)-3-hydroxycyclobutyl)acetamide (10)

[0401] BOP (129 mg, 0.29 mmol) was added to a colorless solution of [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (100 mg, 0.24 mmol), (1r,3r)-3-aminocyclobutan-1-ol hydrochloride (36 mg, 0.29 mmol), and DIEA (170 μL, 126 mg, 0.98 mmol) in DMF (3 mL) to give a yellowish solution. The solution was stirred at room temperature for 1 h. The solution was subjected to preparative RP-HPLC using the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B in 7 min, 45% B; Wavelength: 254 nm; RT1: 6.05 min. After lyophilization of the combined product-containing fractions, the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-N-[(1r,3r)-3-hydroxycyclobutyl]acetamide (10) was obtained as an off-white solid (10.0 mg, 8.6% yield). LC / MS: C 23 H 28 Calculated mass of F3N5O3: 479.21, Found mass: m / z = 480.20 [M+H] + . 1 H NMR (300 MHz, methanol-d4): δ 7.46 - 7.37 (m, 1H), 7.28 - 7.15 (m, 2H), 6.86 - 6.80 (m, 1H), 4.45 - 4.33 (m, 2H), 4.26 - 4.20 (m, 1H), 3.12 - 2.94 (m, 2H), 2.85 - 2.79 (m, 1H), 2.55 - 2.49 (m, 3H), 2.36 - 2.20 (m, 4H), 2.19 - 2.13 (m, 3H), 1.92 - 1.84 (m, 2H), 1.75 - 1.69 (m, 2H), 1.64 - 1.58 (m, 2H) ppm. 19F NMR (282 MHz, methanol-d4): δ -64.29 ppm.

[0402] Example 11: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one (11) [ka]

[0403] Synthesis scheme [ka]

[0404] Step 1: Synthesis of 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one (11)

[0405] In a flask containing [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 10) (2.00 g, 0.50 mmol, 1.0 equiv.), (S)-pyrrolidin-3-ol hydrochloride (602 mg, 0.50 mmol, 1.0 equiv.), and EDCI (287.4 mg, 1.5 mmol, 3.0 equiv.), pyridine (2.0 mL) was added. The reaction mixture was stirred at 50° C. (heating block) overnight under an atmosphere of N2. After cooling to room temperature, the crude reaction mixture was concentrated under reduced pressure using a rotary evaporator to provide the crude reaction product. The crude reaction product was purified by preparative RP-HPLC using an ACN / water mixture acidified with 0.3 vol-% FA (5-95% gradient in 30 min) to give the target compound 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one (11) formate (30.2 mg, 13.0% yield) as a colorless solid after lyophilization of the combined product-containing fractions. LC / MS: m / z = 480.15 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 8.33 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 1.7 Hz, 1H), 6.83 (s, 1H), 4.45 - 4.39 (m, 1H), 4.29 (s, 1H), 3.70 (s, 1H), 3.60 - 3.56 (m, 4H), 3.46 (d, J = 2.5 Hz, 2H), 3.09 (s, 1H), 2.76 (s, 2H), 2.14 (s, 3H), 1.98 (s, 4H), 1.82 (s, 1H), 1.67 (s, 1H) ppm.

[0406] Example 12: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (12) [ka]

[0407] Synthesis scheme [ka]

[0408] Step 1: Synthesis of 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (12)

[0409] In a flask containing [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 10) (500 mg, 1.2 mmol, 1.0 equiv.), (S)-pyrrolidin-3-ol hydrochloride (151 mg, 1.2 mmol, 1.0 equiv.), and EDCI (690 mg, 3.6 mmol, 3.0 equiv.), pyridine (5.0 mL) was added. The reaction mixture was stirred at 50° C. overnight under an atmosphere of N2. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure using a rotary evaporator to give a crude reaction mixture. The crude reaction mixture was purified by preparative RP-PLC using an ACN / water gradient acidified with 0.3 vol-% FA to give the target compound 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (12) (65.2 mg, 11.2% yield) as a colorless solid after lyophilization of the combined product-containing fractions. LC / MS: m / z=480.40 [M+H] + . 1 H NMR (400 MHz, methanol-d4): 1 H NMR (400 MHz, methanol-d4): δ 7.39 (d, J = 7.9 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.16 (d, J = 1.7 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 4.50 - 4.43 (m, 1H), 4.25 (d, J = 8.7 Hz, 1H), 3.70 - 3.60 (m, 2H), 3.56 (s, 2H), 3.48 (s, 3H), 3.20 - 3.14 (m, 1H), 2.85 (s, 1H), 2.68 - 2.64 (m, 2H), 2.13 (s, 3H), 1.97 - 1.92 (m, 4H), 1.85 - 1.57 (m, 2H) ppm.

[0410] Example 13: (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)- N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (13) [ka]

[0411] Synthesis scheme: [ka]

[0412] Step 1: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (13)

[0413] BOP (228 mg, 0.52 mmol, 1.2 equiv.) was added to a colorless solution of [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 10) (177 mg, 0.43 mmol, 1.0 equiv.), 3-aminobicyclo[1.1.1]pentan-1-ol hydrochloride (70 mg, 0.52 mmol, 2.2 mmol), and DIEA (299 μL, 222 mg, 1.72 mmol, 4.0 equiv.) in DMF (3 mL) to give a yellowish solution. The solution was stirred at room temperature for 1 hour. The solution was subjected to preparative RP-HPLC purification using the following conditions: Column: Xselect CSH C18 OBD Column 30*150 mm 5 μm; Mobile phase A: Water (0.1 vol-% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 18% B in 7 min, 18% B to 18% B in 8 min, 18% B; Wavelength: 254 nm; RT1: 7.4 min. After lyophilization of the combined product-containing fractions, the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-N-{3-hydroxybicyclo[1.1.1]pentan-1-yl}acetamide was obtained as an off-white solid (10 mg, 4.7% yield). LC / MS: C 24 H 28 Calculated mass of F3N5O3: 491.21, Found mass: m / z = 492.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 6.64 - 6.58 (m, 1H), 6.52 - 6.28 (m, 2H), 6.02 (s, 1H), 3.41 (s, 1H), 2.25 - 2.11 (m, 2H), 1.99 - 1.95 (m, 1H), 1.69 (s, 3H), 1.38 - 1.30 (m, 9H), 1.05 (s, 2H), 0.96 - 0.72 (m, 2H) ppm. 19F NMR (376 MHz, DMSO-d6): δ -65.10 ppm.

[0414] Example 14: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-N-((1s,3S)-3-hydroxycyclobutyl)acetamide (14) [ka]

[0415] Synthesis scheme: [ka]

[0416] Step 1: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-N-((1s,3S)-3-hydroxycyclobutyl)acetamide (14)

[0417] BOP (129 mg, 0.29 mmol, 1.2 equiv.) was added to a colorless solution of [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 10) (100 mg, 0.24 mmol, 1.0 equiv.), (1s,3s)-3-aminocyclobutan-1-ol hydrochloride (36 mg, 0.29 mmol, 1.2 equiv.), and DIEA (168 μL, 125 mg, 0.98 mmol, 4.0 equiv.) in DMF (3 mL) to give a yellowish solution. The solution was stirred at room temperature for 1 hour. The solution was subjected to preparative RP-HPLC using the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 46% B in 7 min, 46% B; Wavelength: 254 nm; RT1: 5.87 min. After lyophilization of the combined product-containing fractions, the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-N-[(1s,3s)-3-hydroxycyclobutyl]acetamide (14) was obtained as an off-white solid (20 mg, 17.0% yield). LC / MS: C 23 H 28 Calculated mass of F3N5O3: 479.21, Found mass: m / z = 480.15 [M+H] + . 1 H NMR (300 MHz, methanol-d4) δ: 7.45 - 7.37 (m, 1H), 7.28 - 7 .21 (m, 1H), 7.19 - 7.16 (m, 1H), 6.83 (s, 1H), 4.25 - 4.19 (m, 1H), 4.03 - 3.88 (m, 1H), 3.93 - 3.76 (m, 1H), 3.05 - 2.99 (m, 2H), 2.96 - 2.86 (m, 1H), 2.79 - 2.53 (m, 3H), 2.50 - 2.44 (m, 1H), 2.37 - 2.31 (m, 1H), 2.19 - 2.12 (m, 3H), 2.00 - 1.85 (m, 4H), 1.78 - 1.72 (m, 1H), 1.63 - 1.57 (m, 1H). 19 F NMR (282 MHz, methanol-d4): δ -64.28 ppm.

[0418] Example 15: 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-1-{2-hydroxy-7-azaspiro[3.5]nonan-7-yl}ethanone (15) [ka]

[0419] Synthesis scheme: [ka]

[0420] Step 1: Synthesis of 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-1-{2-hydroxy-7-azaspiro[3.5]nonan-7-yl}ethanone (15)

[0421] EDCI (91 mg, 0.48 mmol, 1.5 equiv.) and HOBT (64 mg, 0.48 mmol, 1.5 equiv.) were added to a yellow solution of [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 10) (130 mg, 0.32 mmol), 7-azaspiro[3.5]nonan-2-ol hydrochloride (113 mg, 0.63 mmol, 2.0 equiv.), and DIEA (221 μL, 164 mg, 1.27 mmol, 4.0 equiv.) in DMF (5 mL) to give a yellowish solution. The solution was stirred at room temperature for 1 hour. To this solution, EtOAc (10 mL) and water (10 mL) were added. mL) was added. After phase separation, the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (3 × 30 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was subjected to preparative RP-HPLC using the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NHHCO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B, 55% B in 7 min; Wavelength: 254 nm; RT1: 6 min. After lyophilization, the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-1-{2-hydroxy-7-azaspiro[3.5]nonan-7-yl}ethenone (15) (19.5 mg, 11.5% yield) was obtained as a pale yellow solid. LC / MS: calculated mass for C27H34F3N5O3: 533.26, found m / z = 534.25 [M+H] + 1H NMR (400 MHz, methanol-d4): δ 7.45 - 7.39 (m, 1H), 7.28 - 7.21 (m, 1H), 7.21 - 7.16 (m, 1H), 6.83 - 6.78 (m, 1H), 4.32 - 4.20 (m, 1H), 4.20 - 4.07 (m, 1H), 3.59 - 3.44 (m, 4H), 3.27 - 3.13 (m, 2H), 2.91 - 2.86 (m, 1H), 2.59 - 2.54 (m, 1H), 2.43 - 2.23 (m, 4H), 2.16 (s, 3H), 1.91 - 1.83 (m, 2H), 1.76 - 1.63 (m, 5H), 1.59 - 1.49 (m, 3H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.28 ppm.

[0422] Example 16: (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)ethan-1-one (16) [ka]

[0423] Synthesis scheme: [ka]

[0424] Step 1: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)ethan-1-one (16)

[0425] A yellow solution of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (prepared as described in Example 10) (130 mg, 0.32 mmol), 2-azaspiro[3.3]heptan-6-ol hydrochloride (95 mg, 0.63 mmol, 2.0 equiv.), EDCI (91 mg, 0.48 mmol, 1.5 equiv.), HOBt (64 mg, 0.48 mmol, 1.5 equiv.), and DIEA (276 μL, 205 mg, 1.59 mmol, 5.0 equiv.) in DMF (3 mL) was stirred overnight at room temperature. EtOAc (50 mL) and water (30 mL) were added to give a biphasic solution. After phase separation, the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phase was washed with (1 x 30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. Conditions: Column: XBridge Prep Phenyl OBD The crude product was purified by preparative RP-HPLC using a column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 60% B in 7 min, 60% B; wavelength: 254 nm; RT1: 6 min. After lyophilization of the combined product-containing fractions, the target compound (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)ethan-1-one (16) (11.2 mg, 6.8% yield) was obtained as a colorless solid. LC / MS: C 25 H 30 Calculated mass of F3N5O3: 505.23, Found mass: m / z = 506.25 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.45 - 7.39 (m, 1H), 7.26 - 7.21 (m, 1H), 7.18 (s, 1H), 6.81 (s, 1H), 4.33 - 4.24 (m, 2H), 4.21 - 4.06 (m, 2H), 4.04 - 3.92 (m, 2H), 3.09 - 3.05 (m, 2H), 2.88 - 2.83 (m, 1H), 2.64 - 2.48 (m, 3H), 2.47 - 2.30 (m, 2H), 2.19 - 2.04 (m, 5H), 1.87 - 1.83 (m, 2H), 1.74 - 1.52 (m, 2H). 19 F NMR (376 MHz, methanol-d4): δ -64.28 ppm.

[0426] Example 17: (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(7-hydroxy-2-azaspiro[3.5]nonan-2-yl)ethan-1-one (17) [ka]

[0427] Synthesis scheme: [ka]

[0428] Step 1: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-(7-hydroxy-2-azaspiro[3.5]nonan-2-yl)ethan-1-one (17)

[0429] A pale yellow solution of [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 10) (120 mg, 0.29 mmol, 1.0 equiv.), 2-azaspiro[3.5]nonan-7-ol hydrochloride (62.3 mg, 0.35 mmol, 1.2 equiv.), EDCI (84.1 mg, 0.44 mmol, 1.5 equiv.), HOBt (59.3 mg, 0.44 mmol, 1.5 equiv.), DIEA (153 μL, 113.4 mg, 0.88 mmol, 3.0 equiv.) in DMF (2 mL) was stirred at room temperature for 2 h. The reaction mixture was subjected to preparative RP-HPLC using the following column conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 54% B in 7 min, 54% B; wavelength: 254 nm; RT1: 5.72 min. After lyophilization of the combined product-containing fractions, the target compound 1-{7-hydroxy-2-azaspiro[3.5]nonan-2-yl}-2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]ethanone (17) (24.1 mg, 15.0%) was obtained as a pale yellow solid. LC / MS: C 27 H 34 Calculated mass of F3N5O3: 533.26, Found mass: m / z = 534.20 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.42 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 6.81 (s, 1H), 4.41 - 4.09 (m, 1H), 4.06 - 3.87 (m, 2H), 3.73 - 3.42 (m, 3H), 3.25 - 2.98 (m, 2H), 2.94 - 2.72 (m, 1H), 2.63 - 2.28 (m, 3H), 2.27 - 2.02 (m, 3H), 2.00 - 1.75 (m, 6H), 1.73 - 1.50 (m, 4H), 1.45 - 1.26 (m, 2H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.27 ppm.

[0430] Example 18: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-N-((1r,4R)-4-hydroxycyclohexyl)-N-methylacetamide (18) [ka]

[0431] Synthesis scheme: [ka]

[0432] Step 1: Synthesis of 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-N-((1r,4R)-4-hydroxycyclohexyl)-N-methylacetamide (18)

[0433] A pale yellow solution of [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 10) (130 mg, 0.32 mmol), (1r,4r)-4-(methylamino)cyclohexan-1-ol (49 mg, 0.38 mmol, 1.2 equiv.), EDCI (91 mg, 0.48 mmol, 1.5 equiv.), HOBt (64 mg, 0.48 mmol, 1.5 equiv.), and DIEA (109 μL, 81 mg, 0.63 mmol) in DMF (2 mL) was stirred overnight at room temperature. EtOAc (50 mL) and water (30 mL) were added to give a biphasic solution. After phase separation, the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phase was washed with brine (1 x 30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. Conditions: Column: XBridge Shield RP18 OBD The crude product was purified by preparative RP-HPLC using a column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 56% B in 7 min, 56% B; wavelength: 254 nm; RT: 1:6 min. After lyophilization of the combined product-containing fractions, the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]-N-methyl-N-[(1r,4r)-4-hydroxycyclohexyl]acetamide (18) (10.1 mg, 5.9%) was obtained as a pale yellow solid. LC / MS: C 26 H 34 Calculated mass of F3N5O3: 521.26, Found mass: m / z = 522.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.47 - 7.31 (m, 1H), 7.27 - 7.13 (m, 2H), 6.75 - 6.67 (m, 1H), 4.29 - 3.76 (m, 2H), 3.41 - 3.24 ( m, 1H), 3.21 - 3.07 (m, 2H), 3.05 - 2.73 (m, 3H), 2.65 - 2.58 (m, 2H), 2.31 - 1.92 (m, 6H), 1.91 - 1.82 (m,2H), 1.80 - 1.72 (m, 1H), 1.67 - 1.56 (m, 2H), 1.55 - 1.38 (m, 3H), 1.32 - 1.18 (m, 3H) ppm. 19 F NMR (376 MHz, DMSO-d6): δ -64.31 ppm.

[0434] Example 19: 1-{2-[(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}amino)piperidin-1-yl]ethyl}piperidin-4-ol (19) [ka]

[0435] Synthesis scheme [ka]

[0436] Step 1: Synthesis of 1-(cyclopent-1-en-1-yl)pyrrolidine

[0437] Pyrrolidine (10.00 g, 140.6 mmol, 1.0 equiv) in toluene (50 mL) To a pale yellow solution of 1-(cyclopent-1-en-1-yl)pyrrolidine (11.83 g, 140.6 mmol, 1 equiv.) was added cyclopentanone (11.83 g, 140.6 mmol, 1 equiv.) and TsOH (0.10 g, 0.56 mmol, 0.004 equiv.). After stirring the reaction mixture for 16 hours at 130° C. (oil bath), the reaction mixture was cooled to room temperature and the residue was concentrated under reduced pressure using a rotary evaporator to give 1-(cyclopent-1-en-1-yl)pyrrolidine (11.0 g, 57.0% yield) as a brown oil. The residue was used directly in the next step without further isolation and characterization.

[0438] Step 2: Synthesis of 1,4-dichloro-5H,6H,7H-cyclopenta[d]pyridazine

[0439] To a red solution of dichloro-1,2,4,5-tetrazine (4.40 g, 29.15 mmol, 0.5 equiv.) in DCM (150 mL) was added 1-(cyclopent-1-en-1-yl)pyrrolidine (8.00 g, 58.3 mmol, 1 equiv.) at 0 °C. After stirring the reaction mixture for 15 min at 0 °C, the reaction mixture was concentrated under reduced pressure at 0 °C using a rotary evaporator. The residue was purified by silica gel column chromatography using a gradient (0 to 45% diethyl ether / PE) to give 1,4-dichloro-5H,6H,7H-cyclopenta[d]pyridazine (2.6 g, 23.6% yield) as a pale yellow solid. LC / MS: calculated mass for C7H6Cl2N2: 187.99, found: m / z = 189.10 [M+H]. + . 1 H NMR (400 MHz, DSMO-d6): δ 3.06 - 3.10 (m, 4H), 2.11 - 2.19 (m, 2H) ppm.

[0440] Step 3: Synthesis of tert-butyl (3R)-3-({4-chloro-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}amino)piperidine-1-carboxylate

[0441] To a pale yellow solution of 1,4-dichloro-5H,6H,7H-cyclopenta[d]pyridazine (900 mg, 4.76 mmol, 1 equiv.) in NMP (10 mL) was added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (1.14 g, 5.71 mmol, 1.2 equiv.) and DIEA (1.66 mL, 1.23 g, 9.52 mmol, 2 equiv.). After stirring in a sealed tube for 12 h at 150 °C, the reaction mixture was cooled to room temperature, and the residue was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with water (3 × 50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography using a (0-45% EA / PE) gradient to give tert-butyl (3R)-3-({4-chloro-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}amino)piperidine-1-carboxylate (0.55 g, 32.7% yield) as a pale yellow solid. LC / MS: C 17 H 25 Calculated mass of ClN4O2: 352.17, Found mass: m / z = 353.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 6.27 (s, 1H), 3.30 - 4.05 (m, 3H), 2.49 - 3.28 (m, 6H), 2.01 - 2.13 (m, 2H), 1.89 - 1.94 (m, 1H), 1.72 (s, 1H), 1.53 (s, 1H), 1.23 - 1.46 (m, 10H) ppm.

[0442] Step 4: Synthesis of tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}amino)piperidine-1-carboxylate

[0443] tert-Butyl (3R)-3-({4-chloro-5H,6H,7H-cyclopenta[d]pyridinyl}-4-methyl-2,4-dioxane in 3.75 mL of a mixture of 1,4-dioxane and water (4:1, v / v) To a solution of ({(2-hydroxy-4-(trifluoromethyl)phenyl)-2-oxazin-1-yl}amino)piperidine-1-carboxylate (250 mg, 0.701 mmol, 1.0 equiv.) and 2-hydroxy-4-(trifluoromethyl)phenylboronic acid (175.1 mg, 0.85 mmol, 1.2 equiv.) was added Pd(PPh3)4 (40.9 mg, 0.035 mmol, 0.05 equiv.) and NaHCO3 (119.0 mg, 1.42 mmol, 2.0 equiv.). After stirring the reaction mixture at 100 °C in a sealed tube under an atmosphere of N2 for 5 h, the resulting reaction mixture was concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography using a (0-50% EA / PE) gradient to give tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}amino)piperidine-1-carboxylate (246 mg, 72.6% yield) as a pale yellow solid. LC / MS: C 24 H 29 Calculated mass of F3N4O3: 478.22, Found mass: m / z = 479.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 6.74 - 6.76 (m, 1H), 7.21 - 7.24 (m, 2H), 6.47 (s, 1H), 3.85 - 4.22 (m, 3H), 3.65 - 3.82 (m, 1H), 3.03 - 3.28 (m, 2H), 2.68 - 2.98 (m, 4H), 2.01 - 2.14 (m, 2H), 1.90 - 1.96 (m, 1H), 1.75 (s, 1H), 1.57 (s, 1H), 1.23 - 1.46 (m, 10H) ppm. 19 F NMR (376 MHz, DMSO-d6): δ -61.35 ppm.

[0444] Step 5: Synthesis of 2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}-5-(trifluoromethyl)phenol

[0445] To a pale yellow solution of tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}amino)piperidine-1-carboxylate (200 mg, 0.42 mmol, 1 equiv.) in DCM (5 mL) was added TFA (1 mL). After stirring for 30 min at room temperature, the suspension was concentrated under reduced pressure using a rotary evaporator. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 60% gradient over 20 min; detector, UV 254 nm, to give 2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}-5-(trifluoromethyl)phenol (71 mg, 44.9% yield) as a pale yellow solid. LC / MS:C 19 H 21 Calculated mass of F3N4O: 378.17, Found mass: m / z = 379.20 [M+H] + .

[0446] Step 6: Synthesis of 1-{2-[(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}amino)piperidin-1-yl]ethyl}piperidin-4-ol (19)

[0447] To a pale yellow solution of 2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}-5-(trifluoromethyl)phenol (100 mg, 0.26 mmol, 1 equiv.) in MeOH (2 mL) were added 2-(4-hydroxypiperidin-1-yl)acetaldehyde (45.4 mg, 0.32 mmol, 1.2 equiv.) (prepared according to the procedure described for Example 21) and NaBH3CN (49.8 mg, 0.79 mmol, 3.0 equiv.). After stirring for 2 hours at room temperature, the suspension was concentrated under reduced pressure using a rotary evaporator. The following conditions were used: Column: Xselect CSH C18 OBD Column 30*150 mm 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min. The residue was purified by reverse-phase flash chromatography using a gradient of 5% B to 30% B in 7 min, 30% B; wavelength: 254 nm; RT1: 5.87 min to give the target compound 1-{2-[(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}amino)piperidin-1-yl]ethyl}piperidin-4-ol (19) (15.3 mg, 11.4% yield) as a pale yellow solid after lyophilization of the combined product-containing fractions. LC / MS: C 26 H 34 MS (ESI) calculation for F3N5O2: 505.27, found: m / z = 506.30 [M+H] + . 1 H NMR (300 MHz, methanol-d4): δ 8.48 - 8.36 (s, 1H), 7.74 - 7.71 (m, 1H), 7.21 - 7.18 (m, 2H), 4.43 - 4.11 (m, 1H), 3.94 - 3.89 (m, 1H), 3.49 - 3.33 (m, 3H), 3.24 - 3.08 (m, 6H), 3.03 - 2.94 (m, 1H), 2.92 - 2.84 (m, 3H), 2.75 - 2.67 (m, 1H), 2.32 - 2.17 (m, 3H), 2.15 - 1.91 (m, 4H), 1.89 - 1.70 (m, 4H), 1.63 - 1.54 (m, 1H) ppm. 19 F NMR (282 MHz, methanol-d4): δ -64.45 ppm.

[0448] Example 20: 2-[(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethenone (20) [ka]

[0449] Synthesis scheme: [ka]

[0450] Step 1: Synthesis of tert-butyl (3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidine-1-carboxylate

[0451] To a solution of tert-butyl (3R)-3-({4-chloro-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}amino)piperidine-1-carboxylate (250 mg, 0.71 mmol, 1 equiv.) and 4-fluoro-2-hydroxyphenylboronic acid (132.6 mg, 0.85 mmol, 1.2 equiv.) in 3.75 mL of a mixture of 1,4-dioxane and water (4:1, v / v) was added Pd(PPh3)4 (40.9 mg, 0.035 mmol, 0.05 equiv.) and NaHCO3 (119.0 mg, 1.42 mmol, 2.0 equiv.). After stirring the reaction mixture in a sealed tube under an atmosphere of N2 at 100 °C for 5 h, the resulting reaction mixture was concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography (0-50% EA / PE) gradient to give tert-butyl (3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidine-1-carboxylate (250 mg, 82.35% yield) as a pale yellow solid after evaporation of the combined product-containing fractions under reduced pressure using a rotary evaporator. LC / MS: C 23 H 29 Calculated mass of FN4O3: 428.22, detected mass: m / z = 429.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.63 - 7.60 (m, 1H), 6.74 - 6.70 (m, 2H), 6.38 (s, 1H), 4.05 - 3.82 (m, 2H), 3.80 - 3.65 (m, 1H), 3.28 - 2.86 (m, 3H), 2.83 - 2.74 (m, 3H), 2.12 - 2.02 (m, 3H), 1.95 - 1.90 (m, 1H), 1.74 (s, 1H), 1.57 (s, 1H), 1.47 - 1.23 (m, 10H) ppm. 19 F NMR (376 MHz, DMSO-d6): δ -111.38 ppm.

[0452] Step 2: Synthesis of 5-fluoro-2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}phenol

[0453] To a pale yellow solution of tert-butyl (3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidine-1-carboxylate (250 mg, 0.58 mmol) in DCM (5 mL) was added TFA (1 mL). After stirring the reaction mixture at room temperature for 30 min, the suspension was concentrated under reduced pressure using a rotary evaporator. The following conditions were used: column, C18 silica gel; mobile phase, ACN in water, 10% to 60% gradient over 20 min; detector, UV The residue was purified by reverse-phase flash chromatography using 254 nm to give, after lyophilization of the combined product-containing fractions, 5-fluoro-2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}phenol (180 mg, 94.0% yield) as a pale yellow solid. LC / MS: C 18 H 21 Calculated mass of FNO: 328.17, Found mass: m / z = 329.15 [M+H] + .

[0454] Step 3: Synthesis of [(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidin-1-yl]acetic acid

[0455] To a pale yellow solution of 5-fluoro-2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}phenol (90 mg, 0.27 mmol, 1 equiv.) in MeOH (2 mL) was added glyoxylate (24.4 mg, 0.33 mmol, 1.2 equiv.) and NaBHCN (51.7 mg, 0.82 mmol, 3.0 equiv.). After stirring for 2 h at room temperature, the suspension was concentrated under reduced pressure using a rotary evaporator. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm to give [(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidin-1-yl]acetic acid (100 mg, 94.4% yield) as a pale yellow solid after lyophilization of the combined product-containing fractions. LC / MS: C 20 H 23 MS (ESI) calculation for FN4O3: 386.18, found: m / z = 387.15 [M+H] + .

[0456] Step 4: Synthesis of 2-[(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone (20)

[0457] To a pale yellow solution of [(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidin-1-yl]acetic acid (90 mg, 0.23 mmol, 1 equiv.) in DMF (2 mL) was added piperidin-4-ol (28.3 mg, 0.28 mmol, 1.2 equiv.), EDCI (89.3 mg, 0.47 mmol, 2.0 equiv.), and HOBt (62.9 mg, 0.47 mmol, 2.0 equiv.) with stirring at room temperature. The suspension was stirred for 4 h at room temperature to give a brown suspension. The reaction was quenched by adding saturated aqueous NH4Cl solution (8 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator under the following conditions: Column: XBridge Prep Phenyl OBD Column, 19*100mm, 5μm; The residue was purified by reverse-phase flash chromatography using mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 95% B in 7 min, 95% B; wavelength: 254 nm; RT 1:6 min to give the target compound 2-[(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone (20) (22.6 mg, 20.6% yield) as a pale yellow solid after lyophilization of the combined product-containing fractions. LC / MS: C 25 H 32 MS (ESI) calculation for FN5O3: 469.25, found: m / z = 470.25 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.61 - 7.56 (m, 1H), 6.67 - 6.63 (m, 2H), 4.36 - 4.25 (m, 1H), 4.19 - 4.02 (m, 1H), 3.98 - 3.78 (m, 2H), 3.43 - 3.39 (m, 1H), 3.41 - 3.12 (m, 4H), 3.11 - 2.93 (m, 2H), 2.90 - 2.88 (m, 2H), 2.75 - 2.56 (m, 1H), 2.38 - 2.11 (m, 4H), 2.08 - 1.88 (m, 4H), 1.78 - 1.53 (m, 3H), 1.50 - 1.37 (m, 1H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -133.28 ppm.

[0458] Example 21: 1-{2-[(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidin-1-yl]ethyl}piperidin-4-ol (21) [ka]

[0459] Synthesis scheme: [ka]

[0460] Step 1: Synthesis of 1-(2,2-dimethoxyethyl)piperidin-4-ol

[0461] A colorless suspension of piperidin-4-ol (2.00 g, 19.77 mmol), 2-bromo-1,1-dimethoxyethane (3.34 g, 19.77 mmol, 1.0 equiv.), and KCO (5.47 g, 39.55 mmol, 2.0 equiv.) in 1,4-dioxane (20 mL) was stirred overnight at 100° C. After cooling to room temperature, EtOAc (60 mL) was added. and water (60 mL) were added. After phase separation, the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give 1-(2,2-dimethoxyethyl)piperidin-4-ol as an off-white solid (1.8 g, 42.3% yield), which was used in the next step without further isolation and characterization. LC / MS: C9H 19 Calculated mass of NO3: 189.14, Found mass: m / z = 190.20 = [M+H] + .

[0462] Step 2: Synthesis of 2-(4-hydroxypiperidin-1-yl)acetaldehyde

[0463] 1-(2,2-Dimethoxyethyl)piperidin-4-ol (1.8 g, 9.51 mmol) in HCl (20 mL, 6 M in water) was stirred at 100° C. overnight. The reaction was concentrated under reduced pressure to give 2-(4-hydroxypiperidin-1-yl)acetaldehyde as a colorless oil (900 mg, 66.2% yield). The product was used directly in the next step without any further isolation or characterization. LCMS: C7H 13 Calculated mass of NO2: 143.09, Found mass: m / z = 144.15 [M+H] + .

[0464] Step 3: Synthesis of 1-{2-[(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidin-1-yl]ethyl}piperidin-4-ol (21)

[0465] To a pale yellow solution of 5-fluoro-2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H-cyclopenta[d]pyridazin-1-yl}phenol (100 mg, 0.31 mmol, 1.0 equiv.) in MeOH (2 mL) was added 2-(4-hydroxypiperidin-1-yl)acetaldehyde (52.3 mg, 0.37 mmol, 1.2 equiv.) and NaBHCN (57.4 mg, 0.92 mmol, 3.0 equiv.) to give a pale yellow solution. After stirring at room temperature for 2 h, the suspension was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column: Xselect CSH C18 OBD Column 30*150 mm 5 μm; mobile phase A: water (0.1 vol-% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 3% B to 20% B, 20% B in 7 min; wavelength: 254 nm; RT1: 5.87 min to obtain the target compound 1-{2-[(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1-yl]amino}piperidin-1-yl]ethyl}piperidin-4-ol (21) (24.6 mg, 17.6% yield) as a pale yellow solid after lyophilization of the combined product-containing fractions. LC / MS: C 25 H 34 MS (ESI) calculation for FN5O2: 455.27, found: m / z = 456.25 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.57 - 7.47 (m, 1H), 6.69 - 6.64 (m, 2H), 4.22 - 4.19 (m, 1H), 3.43 - 3.38 (m, 2H), 3.08 - 2.94 (m, 4H), 3.03 - 2.94 (m, 2H), 2.83 - 2.60 (m, 7H), 2.21 - 1.98 (m, 4H), 1.97 - 1.67 (m, 4H), 1.51 - 1.35 (m, 4H) ppm. 19 F NMR (282 MHz, DMSO-d6): δ -111.39 ppm.

[0466] Example 22: (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethan-1-one (22) [ka]

[0467] Synthesis scheme: [ka]

[0468] Step 1: Synthesis of tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate

[0469] To a solution of tert-butyl (3R)-3-({4-chloro-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate (500 mg, 1.40 mmol, 1 equiv.) and 2-hydroxy-4-(trifluoromethyl)phenylboronic acid (348.2 mg, 1.69 mmol, 1.2 equiv.) in a 5 mL mixture of 1,4-dioxane and water (4:1, v / v), Pd(PPh3)4 (81.4 mg, 0.070 mmol, 0.05 equiv.) and NaHCO3 (355.1 mg, 4.23 mmol, 3.0 equiv.) were added. The reaction mixture was stirred in a sealed tube under an atmosphere of N2 at 100 °C for 5 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography (0–50% EA / PE) gradient to give tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate (373 mg, 55%) after concentration of the combined product-containing fractions under reduced pressure using a rotary evaporator. 0.1% yield) as a pale yellow oil. LC / MS: C 23 H 27 MS (ESI) calculation for F3N4O4: 480.20, found: m / z = 481.25 [M+H] + . 19 F NMR (376 MHz, DMSO-d6): δ -61.43 ppm.

[0470] Step 2: Synthesis of 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol

[0471] To a pale yellow solution of tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate (330 mg, 0.69 mmol, 1 equiv.) in dioxane (1 mL) was added a solution of HCl (3 mL, 12 mmol, 4 M in 1,4-dioxane). After stirring the reaction mixture at room temperature for 30 minutes, the suspension was concentrated under reduced pressure using a rotary evaporator. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 60% gradient in 20 min; detector, UV 254 nm to give 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol (170 mg, 65.1% yield) as a pale yellow solid after lyophilization of the combined product-containing fractions. LC / MS: C 18 H 19 MS (ESI) calculation for F3N4O2: 380.15, found: m / z = 381.20 [M+H] + .

[0472] Step 3: Synthesis of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid

[0473] To a pale yellow solution of 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol (85 mg, 0.22 mmol, 1.0 equiv.) in MeOH (2 mL) was added glyoxylate (33.1 mg, 0.45 mmol, 2.0 equiv.) and NaBHCN (42.1 mg, 0.67 mmol, 3.0 equiv.). After stirring for 2 h at room temperature, the suspension was concentrated under reduced pressure using a rotary evaporator. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm to give [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (80 mg, 81.7% yield) as a pale yellow solid. LC / MS: C 20 H 21 MS (ESI) calculated value for F3N4O4: 438.15, found value: m / z = 439.20 [M+H] + .

[0474] Step 4: Synthesis of 2-[(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone (22)

[0475] To a pale yellow solution of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (100 mg, 0.23 mmol, 1 equiv.) in DMF (2 mL) was added azetidin-3-ol (not the HCl salt?) (25.0 mg, 0.34 mmol, 1.5 equiv.), EDCI (87.5 mg, 0.46 mmol, 2 equiv.), DIEA (119 μL, 88.4 mg, 0.68 mmol, 3.0 equiv.), and HOBT (61.6 mmol). g, 0.46 mmol, 2.0 equiv) was added with stirring at room temperature. The suspension was stirred for 4 h at room temperature to give a brown suspension. The reaction was quenched by adding saturated aqueous NH4Cl solution (8 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified using the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 63% B in 7 min; Wavelength: 254 nm; RT1: 6 min to give the target compound 2-[(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone (16.2 mg, 13.9% yield) as a pale yellow solid after lyophilization of the combined product-containing fractions. LC / MS: C 23 H 26 MS (ESI) calculated value for F3N5O4: 493.20, found value: m / z = 494.20 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.41 - 7.39 (m, 1H), 7.20 - 7.19 (m, 2H), 5.37 (s, 2H), 5.06 (s, 2H), 4.67 - 4.49 (m, 2H), 4.41 - 4.35 (m, 1H), 4.27 - 4.19 (m, 1H), 4.15 - 4.05 (m, 1H), 3.87 - 3.73 (m, 1H), 3.19 - 3.03 (m, 2H), 2.97 - 2.85 (m, 1H), 2.62 - 2.50 (m, 1H), 2.45 - 2.28 (m, 2H), 1.93 - 1.77 (m, 2H), 1.71 - 1.52 (m, 2H) ppm. 19F NMR (376 MHz, methanol-d4): δ -64.53 ppm.

[0476] Example 23: (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one (23) [ka]

[0477] Synthesis scheme: [ka]

[0478] Step 1: Synthesis of 4-(2,5-dihydrofuran-3-yl)morpholine

[0479] To a 200 mL sealed tube equipped with a stir bar was added dihydrofuran-3-one (6.91 g, 80.3 mmol, 1 equiv.), morpholine (4.70 mL, 54.0 mmol, 2.0 equiv.), and MgSO (30.0 g, 249 mmol, 3.1 equiv.) in EtO (150 mL). The resulting reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give 4-(2,5-dihydrofuran-3-yl)morpholine as a pale yellow oil (13.0 g, 98.7% yield), which was used directly in the next step without further isolation and characterization.

[0480] Step 2: Synthesis of 1,4-dichloro-5,7-dihydrofuro[3,4-d]pyridazine

[0481] To a 200 mL sealed tube equipped with a stir bar was added dichloro-1,2,4,5-tetrazine (6.1 g, 40.4 mmol, 1.0 equiv) in DCM (100 mL). The resulting solution was stirred at 0° C. for 0.5 h. 4-(2,5-dihydrofuran-3-yl)morpholine (12.3 g, 79.3 mmol, approximately 2 equiv) was then slowly added to the mixture. The resulting solution was stirred at 0° C. for 2 h with warming to approximately 25° C. The reaction mixture was directly concentrated under reduced pressure using a rotary evaporator to give a brown oil. The conditions were as follows: Column: XSelect CSH Prep C18 OBD Column, 19*150mm, 5μm; Mobile phase A: Water (0.1vol-% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 0% B to 30% B to 40% B in 30 min; Wavelength: 220 The oil was purified by reverse-phase column chromatography using a rotary evaporator at RT 1:23.1 min. After concentration of the combined product-containing fractions under reduced pressure using a rotary evaporator, 1,4-dichloro-5H,7H-furo[3,4-d]pyridazine (3.0 g, 19.8%) was obtained as a yellow solid. LC / MS: MS (ESI) calculated for C6H4Cl2N2O: 191.01. Found: m / z = 192.10 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): δ 5.21 (s, 4H) ppm.

[0482] Step 3: Synthesis of tert-butyl (3R)-3-({4-chloro-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate

[0483] To a solution of 1,4-dichloro-5H,7H-furo[3,4-d]pyridazine (550 mg, 2.88 mmol, 1.0 equiv.) in NMP (2 mL) was added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (577 mg, 2.88 mmol, 1.0 equiv.) and DIEA (1.00 mL, 744.32 mg, 5.76 mmol, 2.0 equiv.). The reaction mixture was stirred at 150 °C for 2 h in a sealed tube and under N2 atmosphere. After completion of the reaction, the reaction mixture was quenched by adding water (10 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic phase was washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give the crude reaction product, which was further purified by silica gel column chromatography using the following column conditions: silica gel column; mobile phase A: PE, mobile phase B: EA; flow rate: 40 mL / min; gradient: 0% B to 50% B in 30 min; wavelength: 254 nm. After concentration of the product-containing fractions under reduced pressure using a rotary evaporator, tert-butyl (3R)-3-({4-chloro-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate (290 mg, 28.4%) was obtained as a solid. LC / MS: C 16 H 23 MS (ESI) calculated for ClN4O3: 354.84. Found: m / z = 355.15 [M+H] + .

[0484] Step 4: Synthesis of tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate

[0485] To a solution of tert-butyl (3R)-3-({4-chloro-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate (290 mg, 0.82 mmol, 1.0 equiv.) and 2-hydroxy-4-(trifluoromethyl)phenylboronic acid (253 mg, 1.23 mmol, 1.5 equiv.) in 3.75 mL of a mixture of 1,4-dioxane and water (4:1, v / v), NaHCO (206 mg, 2.45 mmol, 3 equiv.) and Pd(PPh) (47.2 mg, 0.041 mmol, 0.05 equiv.) were added. After stirring at 100 °C in a sealed tube under an atmosphere of N for 4 h, the reaction was quenched with saturated aqueous NH Cl solution (5 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with HO (2 x 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography using the following conditions: column: silica gel column; mobile phase A: PE, mobile phase B: EA; flow rate: 60 mL / min; gradient: 0% B to 50% B in 30 min; wavelength: 254 nm. After concentration of the combined product-containing fractions, tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate (180 mg, 45.8%) was obtained as a solid. LC / MS: C 23 H 27 MS (ESI) calculated for F3N4O4: 480.40. Found: m / z = 481.10 [M+H] + .

[0486] Step 5: Synthesis of 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4-d]iridazin-1-yl}-5-(trifluoromethyl)phenol

[0487] To a solution of tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate (180 mg, 0.38 mmol, 1 equiv.) in 2.0 mL of 1,4-dioxane was added a 4 M solution of HCl in 1,4-dioxane (2 mL, 8 mmol). The reaction mixture was stirred for 30 minutes at room temperature. The resulting mixture was concentrated under reduced pressure using a rotary evaporator to give 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4-pyridazin-1-yl}-5-(trifluoromethyl)phenol (130 mg, 91.2%) as a solid. LC / MS: C 18 H 19 MS (ESI) calculated for F3N4O2: 380.37. Found: m / z = 381.20 [M+H] + .

[0488] Step 6: Synthesis of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid

[0489] To a stirred solution of glyoxylate (19.0 mg, 0.26 mmol, 1.5 equiv.) in MeOH (2 mL) was added 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol (65 mg, 0.17 mmol, 1.0 equiv.) and NaBHCN (32.2 mg, 0.51 mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure using a rotary evaporator to give [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (50 mg, 66.74%). LC / MS: C 20 H 21 MS (ESI) calculated for F3N4O4: 438.40. Found: m / z = 439.20 [M+H]+ .

[0490] Step 7: Synthesis of 2-[(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethanone (23)

[0491] A solution of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (50 mg, 0.11 mmol, 1.0 equiv.) and piperidin-4-ol (20.8 mg, 0.21 mmol, 1.8 equiv.) in DMF (1 mL) was treated with HOBT (30.8 mg, 0.23 mmol, 2.0 equiv.) and DIEA (59.6 μL, 44.2 mg, 0.34 mmol, 3.0 equiv.). The reaction mixture was stirred for 24 hours at room temperature. The progress of the reaction was monitored by TLC (EA, Rf=0.3). After completion of the reaction, the resulting mixture was concentrated under reduced pressure using a rotary evaporator. The crude reaction mixture was purified by preparative RP-HPLC using the following column conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: 10 mmol NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 58% B in 60 min; Wavelength: 254 nm; RT: 7 min. After lyophilization of the combined product-containing fractions, the target compound 2-[(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d ]pyridazin-1-yl}amino)piperidin-1-yl]-1-(4-hydroxypiperidin-1-yl)ethenone (23) (20.4 mg, 34.0% yield) was obtained as a pale yellow solid. LC / MS: C 25 H 30 Calculated mass of F3N5O4: 521.22, Found mass: m / z = 522.25 [M+H] + . 1H NMR (400 MHz, methanol-d4): δ 7.42 - 7.40 (m, 1H), 7.16 - 7.10 (m, 2H), 5.21 - 5.13 (m, 2H), 4.93 (s, 1H), 4.20 (s, 1H), 3.99 - 3.90 (m, 1H), 3.75 - 3.70 (m, 1H), 3.51 - 2.97 (m, 5H), 2.71 - 2.69 (m, 1H), 2.31 - 1.90 (m, 4H), 1.75 - 1.56 (m, 4H), 1.40 - 1.13 (m, 3H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.39 ppm.

[0492] Example 24: (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)ethan-1-one (24) [ka]

[0493] Synthesis scheme: [ka]

[0494] Step 1: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)ethan-1-one (24)

[0495] To a pale yellow solution of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 23) (60 mg, 0.14 mmol, 1.0 equiv.) in DMF (2 mL) was added 7-azaspiro[3.5]nonan-2-ol (25.1 mg, 0.18 mmol, 1.3 equiv.), EDCI (52.5 mg, 0.274 mmol, 2.0 equiv), HOBT (37.0 mg, 0.274 mmol, 2.0 equiv), and DIEA (71.5 μL, 53.1 mg, 0.41 mmol, 3 equiv) were added with stirring at room temperature. The suspension was stirred for 4 hours at room temperature to give a brown suspension. The reaction was quenched at 0°C through the addition of saturated aqueous NH4Cl solution (8 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator. Column conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L The crude reaction product was purified by preparative RP-HPLC using HCl (NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37% B to 64% B in 10 min, 64% B; wavelength: 254 nm; RT1: 7.18 min; injection volume: 1.6 mL; run number: 1 to give the target compound (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)ethan-1-one (24) (11.8 mg, 14.8% yield) as an off-white solid after lyophilization of the combined product-containing fractions. LC / MS: C 28 H 34 MS (ESI) calculated value for F3N5O4: 561.26, found value: m / z = 562.25 [M+H] + . 1H NMR (300 MHz, methanol-d4): δ 7.41 - 7.33 (m, 1H), 7.22 - 7.18 (m, 2H), 5.39 - 5.37 (s, 2H), 5.04 (s, 2H), 4.45 - 4.13 (m, 2H), 3.73 - 3.38 (m, 4H), 3.26 - 3.24 (m, 1H), 3.19 - 3.15 (m, 1H), 3.10 - 2.92 (m, 1H), 2.69 - 2.57 (m, 1H), 2.42 - 2.19 (m, 4H), 2.03 - 1.44 (m, 10H) ppm. 19 F NMR (282 MHz, methanol-d4): δ -64.55 ppm.

[0496] Example 25: (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-(7-hydroxy-2-azaspiro[3.5]nonan-2-yl)ethan-1-one (25) [ka]

[0497] Synthesis scheme [ka]

[0498] Step 1: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-(7-hydroxy-2-azaspiro[3.5]nonan-2-yl)ethan-1-one (25)

[0499] To a pale yellow solution of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 23) (50 mg, 0.114 mmol, 1.0 equiv.) in DMF (2 mL), 2-azaspiro[3.5]nonan-7-ol (19.3 mg, 0.137 mmol, 1.2 equiv.), EDCI (44 mg, 0.23 mmol, 2 equiv.), HOBt (30.8 mg, 0.23 mmol, 2.0), and DIEA (60 μL, 44.2 mg, 0.342 mmol, 3 equiv.) were added with stirring at room temperature. The suspension was stirred at room temperature for 4 hours to give a brown suspension. The reaction was quenched at 0°C (ice bath) by the addition of saturated aqueous NH4Cl solution (8 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator. The following column conditions were used: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L The residue was purified by preparative RP-HPLC using (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-(7-hydroxy-2-azaspiro[3.5]nonan-2-yl)ethan-1-one (25) (13.0 mg, 20.3% yield) as an off-white solid after lyophilization of the combined product-containing fractions. LC / MS: C 28 H 34 MS (ESI) calculated value for F3N5O4: 561.26, found value: m / z = 562.30 [M+H] + . 1H NMR (300 MHz, methanol-d4): δ 7.40 - 7.32 (m, 1H), 7.20 - 7.16 (m, 2H), 5.37 (s, 2H), 5.05 (s, 2H), 4.63 - 4.59 (m, 1H), 4.41 - 4.33 (m, 1H), 4.13 -3.90 (m, 2H), 3.71 - 3.48 (m, 3H), 3.18 - 3.08 (m, 2H), 2.99 - 2.87 (m, 1H), 2.62 - 2.52 (m, 1H), 2.48 - 2.26 (m, 2H), 2.08 - 1.49 (m, 10H), 1.41 - 1.27 (m, 2H) ppm. 19 F NMR (282 MHz, methanol-d4): δ -64.52 ppm.

[0500] Example 26: 2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl) (phenyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one (26) [ka]

[0501] Synthetic Route: [ka]

[0502] Step 1: Synthesis of 2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one (26)

[0503] To a pale yellow solution of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 23) (100 mg, 0.228 mmol, 1 equiv.) in DMF (2 mL), (3S)-pyrrolidin-3-ol (23.9 mg, 0.274 mmol, 1.2 equiv.), EDCI (88 mg, 0.46 mmol, 2 equiv.), HOBt (61.6 mg, 0.456 mmol, 2 equiv.), and DIEA (119.2 μL, 88.44 mg, 0.684 mmol, 3.0 equiv.) were added with stirring at room temperature. The suspension was stirred at room temperature for 4 hours to give a brown suspension. The reaction was quenched at 0° C. by the addition of saturated aqueous NH4Cl solution (8 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (3×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by preparative RP-HPLC using the following column conditions: Xselect CSH C18 OBD Column 30*150 mm 5 μm; mobile phase A: water (0.1 vol-% FA), mobile phase B: can; flow rate: 60 mL / min; gradient: 10% B to 40% B, 40% B in 7 min; wavelength: 254 nm; RT1: 6.12 min; injection volume: 0.67 mL; number of runs: 3 to give the target compound 2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one (26) (9.3 mg, 8.0% yield) as an off-white solid after lyophilization of the combined product-containing fractions. LC / MS:C 24 H 28 MS(ESI) calculated for F3N5O4: 507.20 Detected value: m / z=508.25 [M+H] + . 1 H NMR (300 MHz, methanol-d4): δ 7.40 - 7.31 (m, 1H), 7.21 - 7.16 (m, 2H), 5.37 (s, 2H), 5.07 (s, 2H), 4.47 - 4.41 (m, 2H), 4.33 - 4.17 (m, 1H), 3.72 - 3.52 (m, 3H), 3.50 - 3.47 (m, 1H), 3.28 - 3.13 (m, 2H), 2.94 - 2.89 (m, 1H), 2.66 - 2.45 (m, 3H), 2.10 - 1.83 (m, 4H), 1.72 - 1.58 (m, 2H) ppm. 19 F NMR (282 MHz, methanol-d4): δ -64.55 ppm.

[0504] Example 27: 2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (27) [ka]

[0505] Synthesis scheme: [ka]

[0506] Step 1: Synthesis of 2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (27)

[0507] To a pale yellow solution of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 23) (100 mg, 0.23 mmol, 1 equiv.) in DMF (2 mL), (3R)-pyrrolidin-3-ol (23.9 mg, 0.27 mmol, 1.2 equiv.), EDCI (87.5 mg, 0.46 mmol, 2.0 equiv.), HOBT (61.6 mg, 0.46 mmol, 2.0 equiv.), and DIEA (119.2 μL, 88.44 mg, 0.68 mmol, 3.0 equiv.) were added with stirring at room temperature. The suspension was stirred at room temperature for 4 hours to give a brown suspension. The reaction was quenched at 0° C. through the addition of saturated aqueous NH4Cl solution (8 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (3×20 mL). The mixture was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator. The column conditions were as follows: XBridge Prep Phenyl OBD Column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L) The residue was purified by preparative RP-HPLC using 2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (27) (12.0 mg, 10.4% yield) as a colorless solid after lyophilization of the combined product-containing fractions. LC / MS: C 24 H 28 MS (ESI) calculated value for F3N5O4: 507.21, found value: m / z = 508.25 [M+H] + . 1H NMR (300 MHz, methanol-d4): δ 7.42 - 7.39 (m, 1H), 7.20 - 7.18 (m, 2H), 5.39 - 5.37 (m, 2H), 5.07 (s, 2H), 4.46 - 4.37 (m, 2H), 3.70 - 3.67 (m, 3H), 3.57 - 3.48 (m, 1H), 3.25 - 3.21 (m, 2H), 2.99 - 2.83 (m, 1H), 2.63 - 2.93 (m, 3H), 2.20 - 1.79 (m, 4H), 1.77 - 1.56 (m, 2H) ppm. 19 F NMR (282 MHz, methanol-d4): δ -64.55 ppm.

[0508] Example 28: 1-((3S,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl)-2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)ethan-1-one (28) [ka]

[0509] Synthesis scheme: [ka]

[0510] Step 1: 1-[(3S,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl]-2-[(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phenyl] Synthesis of [5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]ethenone (28)

[0511] To a pale yellow solution of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 23) (100 mg, 0.228 mmol, 1.0 equiv.) in DMF (2 mL), (3S,4S)-4-fluoropyrrolidin-3-ol (29 mg, 0.27 mmol, 1.2 equiv.), EDCI (88 mg, 0.46 mmol, 2.0 equiv.), HOBt (62 mg, 0.46 mmol, 2.0 equiv.), and DIEA (120 μL, 88.4 mg, 0.68 mmol, 3.0 equiv.) were added with stirring at room temperature. The suspension was stirred at room temperature for 4 hours to give a brown suspension. The reaction was quenched at 0°C through the addition of saturated aqueous NH4Cl solution (8 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator. The following conditions were used: Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5 μm; Mobile phase A: water (10 mmol / L The residue was purified by preparative RP-HPLC using HCl (NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 33% B to 63% B in 7 min, 63% B; wavelength: 254 nm; RT1: 6.63 min; injection volume: 0.9 mL; number of runs: 2 to give the target compound 1-[(3S,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl]-2-[(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]ethanone (28) (15.7 mg, 12.6% yield) as a pale yellow solid after lyophilization of the combined product-containing fractions. LC / MS: C 24 H 27 MS (ESI) calculated value for F4N5O4: 525.20, found value: m / z = 526.20 [M+H] + . 1 H NMR (300 MHz, methanol-d4): 7.42 - 7.39 (m, 1H), 7.20 - 7.18 (m, 2H), 5.37 (s, 2H), 5.08 - 5.06 (m, 2H), 5.01 - 4.89 (m, 1H), 4.52 - 4.27 (m, 2H), 4.05 - 3.83 (m, 1H), 3.79 - 3.51 (m, 3H), 3.23 - 3.20 (m, 2H), 3.17 - 2.88 (m, 1H), 2.82 - 2.79 (m, 3H), 1.85 - 1.90 (m, 2H), 1.76 - 1.54 (m, 2H) ppm. 19 F NMR (282 MHz, methanol-d4): δ -64.54, -185.54 ppm.

[0512] Example 29: 1-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)-2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)ethan-1-one (29) [ka]

[0513] Synthesis scheme: [ka]

[0514] Step 1: Synthesis of 1-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)-2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)ethan-1-one (29)

[0515] To a pale yellow solution of [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]acetic acid (prepared as described in Example 23) (150 mg, 0.34 mmol, 1.0 equiv.) in DMF (2 mL), (3R,4R)-4-fluoropyrrolidin-3-ol (50 mg, 0.514 mmol, 1.5 equiv.), HATU (156 mg, 0.41 mmol, 1.2 equiv.), and DIEA (179.2 μL, 133 mg, 1.03 mmol, 3.0 equiv.) were added with stirring at room temperature. The brown suspension was stirred for 4 hours at room temperature. The reaction was quenched at 0° C. by the addition of saturated aqueous NH4Cl solution (8 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by preparative RP-HPLC using the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NHHCO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 36% B to 51% B, 51% B in 10 min; Wavelength: 254 / 220 nm; RT1: 7.78 min. After lyophilization of the combined product-containing fractions, the target compound 1-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)-2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)ethan-1-one (29) was obtained as a pale yellow solid (14.3 mg, 5.3% yield). LC / MS: C 24 H 27 MS (ESI) calculated value for F4N5O4: 525.20, found value: m / z = 526.25 [M+H] + . 1 H-NMR (400 MHz, methanol-d4): δ 7.42 - 7.32 (m, 1H), 7.22 - 7.10 (m, 2H), 5.35 (s, 2H), 5.10 - 4.90 (m, 3H), 4.50 - 4.25 (m, 2H), 4.00 - 3.51 (m, 4H), 3.27 (s, 2H), 3.01 - 2.85 (m, 1H), 2.65 - 2.40 (m, 3H), 2.00 - 1.80 (m, 2H), 1.80 - 1.50 (m, 2H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.50, -184.62 ppm.

[0516] Example 30: (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one (30) [ka]

[0517] Synthesis scheme [ka]

[0518] Step 1: Synthesis of tert-butyl (R)-3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidine-1-carboxylate

[0519] 3,6-Dichloro-4,5-dimethylpyridazine (5.0 g, 28.2 mmol, 1.0 equiv.), tert-butyl (R)-3-aminopiperidine-1-carboxylate (6.2 g, 28.2 mmol, 1.0 equiv.) and DIEA (14.7 mL, 10.9 g In a sealed tube containing 1,2-dimethyl-3,4-dichloro-2 ... The combined product-containing fractions were concentrated under reduced pressure using a rotary evaporator to give tert-butyl (R)-3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidine-1-carboxylate (1.0 g, 10.4% yield) as a pale yellow solid. LC / MS: m / z=341.15 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 4.32 - 4.29 (m, 1H), 3.63 - 3.59 (m, 1H), 3.45-3.42 (m, 1H), 3.30 - 3.17 (m, 3H), 3.04 - 3.00 (m, 1H), 2.48 (s, 3H), 2.39 (d, J = 0.9 Hz, 3H), 2.23 - 2.05 (m, 2H), 2.00 - 1.81 (m, 2H), 1.44 (s, 9H) ppm.

[0520] Step 2: Synthesis of (R)-6-chloro-4,5-dimethyl-N-(piperidin-3-yl)pyridazin-3-amine

[0521] In a flask containing tert-butyl (R)-3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidine-1-carboxylate (1.0 g, 2.9 mmol, 1.0 equiv.), the chemicals were dissolved in anhydrous dioxane (5.0 mL). To the solution was added a solution of HCl (5.0 mL, 20 mmol, 4 M in 1,4-dioxane), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure using a rotary evaporator to obtain the crude reaction product. The crude reaction product was purified using a Biotage Isolera equipped with a Biotage SFAR (4 g, HC, Duo, 20 μM) and a 0-10% MeOH / DCM gradient. The combined product-containing fractions were concentrated under reduced pressure using a rotary evaporator to give (R)-6-chloro-4,5-dimethyl-N-(piperidin-3-yl)pyridazin-3-amine (580 mg, 82.0% yield) as a colorless solid. LC / MS: m / z=241.15 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 4.27 (td, J = 10.1, 4.9 Hz, 1H), 3.59 (dd, J = 12.5, 4.1 Hz, 1H), 3.38 (dt, J = 12.8, 3.9 Hz, 1H), 3.30 - 3.17 (m, 3H), 3.04 (td, J = 12.1, 3.5 Hz, 1H), 2.48 (s, 3H), 2.39 (d, J = 0.9 Hz, 3H), 2.23 - 2.05 (m, 2H), 2.00 - 1.81 (m, 2H) ppm.

[0522] Step 3: Synthesis of tert-butyl (R)-2-(3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0523] To a flask containing (R)-6-chloro-4,5-dimethyl-N-(piperidin-3-yl)pyridazin-3-amine (570 mg, 2.4 mmol, 1.0 equiv.), t-butyl bromoacetate (462 mg, 2.4 mmol, 1.0 equiv.), and K2CO3 (655 mg, 4.8 mmol, 2.0 equiv.), anhydrous ACN (5 mL) was added. The reaction mixture was stirred overnight at 80 °C in a sealed tube. After cooling to room temperature, the crude reaction mixture was poured into water (100 mL) and the solution was extracted with EtOAc (3 × 20 mL). All All organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give the crude reaction product. The crude reaction product was purified using a Biotage Isolera equipped with a Biotage SFAR (4 g, HC, Duo, 20 μM) using a 0-4% MeOH / DCM gradient. The combined product-containing fractions were concentrated under reduced pressure using a rotary evaporator to give tert-butyl (R)-2-(3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetate (460 mg, 57.1% yield) as a colorless solid. LC / MS: m / z=355.20 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 4.29 (s, 1H), 3.15 (s, 2H), 2.87 (s, 1H), 2.56 (s, 3H), 2.32 (s, 3H), 2.19 (s, 3H), 1.77 (s, 2H), 1.65 (s, 2H), 1.46 (s, 9H) ppm.

[0524] Step 4: Synthesis of tert-butyl (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0525] To a sealed tube containing tert-butyl (R)-2-(3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetate (450 mg, 1.3 mmol, 1.0 equiv), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (392 mg, 1.9 mol, 1.5 equiv), NaCO (787 mg, 5.7 mmol, 3.0 equiv), and Pd(PPh) (231 mg, 0.2 mol, 0.1 equiv), dioxane (4 mL) was added. The reaction mixture was stirred at 110 °C overnight under an atmosphere of N. After cooling to room temperature, the crude reaction mixture was poured into water (100 mL) and the solution was extracted with EtOAc (3 × 20 mL). All organic layers were combined, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give the crude reaction product. The crude product was purified using a Biotage Isolera equipped with a Biotage SFAR (4 g, HC, Duo, 20 μM) using 0-4% MeOH / DCM, then concentrated to give tert-butyl (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetate (500 mg, 82.1% yield) as a pale yellow solid. LC / MS: m / z=481.15 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.34 (s, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 4.41 (s, 1H), 3.63 (s, 2H), 3.29 (s, 1H), 2.57 (s, 3H), 2.16 (s, 3H), 2.07 (s, 3H), 1.78 (s, 2H), 1.66 - 1.62 (m, 2H), 1.60 - 1.55 (m, 4H), 1.45 (s, 9H) ppm.

[0526] Step 5: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid

[0527] In a flask containing tert-butyl (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetate (500 mg, 1.04 mmol, 1.0 equiv.), the chemicals were dissolved in anhydrous DCM (5.0 mL) and TFA (5.0 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure using a rotary evaporator to give the crude reaction product. The mixture was purified using a Biotage SFAR (4 g, HC, Duo, 20 μM) with a 0-40% MeOH / DCM gradient. The crude reaction product was purified using an Isolera. The combined product-containing fractions were concentrated under reduced pressure using a rotary evaporator to give (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (106 mg, 24.0% yield) as a colorless solid. LC / MS: m / z=425.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.34 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.08 - 6.00 (m, 1H), 4.50 (s, 1H), 3.75 (s, 2H), 3.45 - 3.32 (m, 1H), 3.19 (s, 1H), 2.77 - 2.62 (m, 2H), 2.47 (s, 4H), 2.06 (s, 3H), 1.95 (s, 3H), 1.82 (s, 3H), 1.63 - 1.51 (m, 1H) ppm.

[0528] Step 6: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one (30)

[0529] To a flask containing (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (106 mg, 0.3 mmol, 1.0 equiv), 4-hydroxypiperidine (28 mg, 0.3 mmol, 1.0 equiv), and EDCI (93 mg, 0.7 mmol, 3.0 equiv) was added pyridine (2 mL). The reaction mixture was stirred at 50° C. overnight under an atmosphere of N. After cooling to room temperature, the crude reaction mixture was concentrated under reduced pressure using a rotary evaporator to provide the crude reaction product. The crude reaction product was purified by preparative RP-HPLC using an ACN / water mixture acidified with 0.3 vol-% FA (5-95% gradient in 30 min) to give, after lyophilization of the compound-containing fractions, (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one (30) formate (37.9 mg, 29.9% recovery) as a colorless solid. LC / MS: m / z = 508.30 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 8.38 (s, 1H), 7.37 (dd, J = 7.8, 4.4 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 4.47 (s, 1H), 4.10 (s, 2H), 3.85 (d, J = 11.0 Hz, 1H), 3.80 (d, J = 4.1 Hz, 2H), 3.56 (d, J = 14.4 Hz, 1H), 3.37 (s, 1H), 3.17 (s, 2H), 3.05 (d, J = 10.4 Hz, 1H), 2.75 (s, 1H), 2.62 (s, 1H), 2.19 (d, J = 4.1 Hz, 3H), 2.10 (d, J = 2.9 Hz, 3H), 2.02 (s, 2H), 1.92 (d, J = 18.7 Hz, 2H), 1.86 - 1.79 (m, 2H), 1.72 (s, 1H), 1.42 (s, 2H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.31 (s) ppm.

[0530] Example 31: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one (31) [ka]

[0531] Synthesis scheme [ka]

[0532] Step 1: Synthesis of tert-butyl (R)-3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidine-1-carboxylate

[0533] In a sealed tube containing 3,6-dichloro-4-methylpyridazine (5.0 g, 30.7 mmol, 1.0 equiv.), tert-butyl (R)-3-aminopiperidine-1-carboxylate (6.1 g, 30.7 mmol, 1.0 equiv.), and DIEA (16.0 mL, 11.9 g, 92.1 mmol, 3.0 equiv.), anhydrous NMP (50 mL) was added. The reaction mixture was stirred in the sealed tube at 150 °C overnight. After cooling to room temperature, the crude reaction mixture was poured into 500 mL of water, and the solution was diluted with EtOAc (3 x 100 mL). All organic layers were combined, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give the crude reaction product, which was purified by Biotage It was purified using a Biotage Isolera equipped with an SFAR (80 g, HC, Duo, 20 μm) and a 10–33% EtOAc / Hex gradient. The combined fractions were concentrated under reduced pressure using a rotary evaporator to give unreacted 3,6-dichloro-4-methylpyridazine (2.7 g, 55.0% recovery) as the first collected fraction. The desired product, tert-butyl (R)-3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (B) (595 mg, 6.0%), was collected in the second fraction and obtained as a pale yellow foamy solid. tert-Butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (A) (1.5 g, 15.0%) was collected in the last fraction and obtained as an off-white foamy solid. tert-Butyl (R)-3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidine-1-carboxylate) (B): TLC: PE / EA=2:1, 254 nm, R f =0.40. LC / MS: m / z = 327.20 [M+H] + . 1 H NMR (400 MHz, Chloroform-d): δ 7.00 (s, 1H), 4.30 (d, J = 7.5 Hz, 1H), 3.77 - 3.32 (m, 2H), 3.45 (s, 1H), 3.18 - 2.95 (m, 1H), 2.07 (s, 3H), 1.87 (s, 1H), 1.60 - 1.48 (m, 3H), 1.41 (s, 9H) ppm.

[0534] Step 2: Synthesis of (R)-6-chloro-4-methyl-N-(piperidin-3-yl)pyridazin-3-amine hydrochloride

[0535] In a flask containing tert-butyl (R)-3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (B) (400 mg, 1.8 mmol, 1.0 equiv.), the chemical was dissolved in anhydrous dioxane (4.0 mL), followed by the addition of HCl (4.0 mL, 16 mmol, 4 M in 1,4-dioxane). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure using a rotary evaporator to give (R)-6-chloro-4-methyl-N-(piperidin-3-yl)pyridazin-3-amine hydrochloride (approximately 400 mg) as a yellow solid, which was used directly in the next step without further isolation and characterization. LC / MS: m / z = 227.20 [M+H] + .

[0536] Step 3: Synthesis of tert-butyl (R)-2-(3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0537] Anhydrous acetonitrile (4 mL) was added to a flask containing (R)-6-chloro-4-methyl-N-(piperidin-3-yl)pyridazin-3-amine hydrochloride (approximately 400 mg, approximately 1.7 mmol, 1.0 equiv.), tert-butyl bromoacetate (261 μL, 345.1 mg, 1.7 mmol, 1.0 equiv.), and K2CO3 (488 mg, 3.5 mmol, 2.0 equiv.). The reaction mixture was stirred at 80 °C overnight. After cooling to room temperature, the crude reaction mixture was poured into 200 mL of water, and the solution was extracted with EtOAc (3 × 50 mL). All organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure using a rotary evaporator to obtain the crude reaction product. The crude reaction product was purified on a Biotage Isolera using a Biotage SFAR (12 g, HC, Duo, 20 μm) with a 0-38% EA / PE gradient. The combined product-containing fractions were concentrated under reduced pressure using a rotary evaporator to give tert-butyl (R)-2-(3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate (300.0 mg, 49.9% yield) as a pale yellow oil. LC / MS: m / z = 341.10 [M+H] + . 1 H NMR (400 MHz, chloroform-d): δ 7.02 - 6.98 (m, 1H), 4.42 (s, 1H), 3.14 - 3.09 (m, 2H), 2.84 - 2.72 (m, 2H), 2.61 - 2.53 (m, 1H), 2.38 (s, 1H), 2.19 - 2.16 (m, 3H), 1.97 (s, 1H), 1.75 (s, 1H), 1.59 - 1.50 (m, 2H), 1.45 (s, 9H), 0.92 - 0.88 (m, 1H) ppm.

[0538] Step 4: Synthesis of tert-butyl (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0539] To a flask containing tert-butyl (R)-2-(3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate (300 mg, 0.9 mmol, 1.0 equiv), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (278 mg, 1.3 mol, 1.5 equiv), 2 M NaCO (286.2 mg, 2.7 mmol, 3.0 equiv), and Pd(PPh) (104 mg, 0.1 mol, 0.1 equiv), dioxane (3 mL) was added. The reaction mixture was stirred at 110 °C overnight under an atmosphere of N. After cooling to room temperature, the crude solution was poured into 100 mL of water, and the solution was extracted with EtOAc (3 × 50 mL). All organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was then concentrated under reduced pressure using a rotary evaporator to give the crude reaction product, which was purified on a Biotage Isolera using a Biotage SFAR (4 g, HC, Duo, 20 μm) with a 0-6% MeOH / DCM gradient. Compound-containing fractions were combined and concentrated to give tert-butyl (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate (150.0 mg, 36.5% yield) as a pale yellow solid. LC / MS: m / z = 467.20 [M+H] + . 1 H NMR (400 MHz, chloroform-d): δ 7.46 - 7.43 (m, 1H), 7.31 (s, 1H), 7.12 (s, 1H), 6.69 (s, 1H), 4.21 (s, 1H), 3.19 - 3.06 (m, 2H), 2.95 - 2.69 (m, 3H), 2.68 (s, 3H), 1.86 (s, 2H), 1.61 (s, 2H), 1.46 (s, 9H) ppm.

[0540] Step 5: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid

[0541] In a flask containing tert-butyl (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate (150 mg, 0.3 mmol, 1.0 equiv.), the compound was dissolved in anhydrous DCM (2 mL), followed by the addition of TFA (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure using a rotary evaporator to give crude (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (approximately 300 mg) as a yellow solid, which was used directly in the next step without further purification. LC / MS: m / z = 411.30 [M+H] + .

[0542] Step 6: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)-1- Synthesis of ((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one (31)

[0543] Into a flask containing (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (110 mg, 0.3 mmol, 1.0 equiv.), (S)-pyrrolidin-3-ol hydrochloride (33.1 mg, 0.3 mmol, 1.0 equiv.), and EDCI (172.4 mg, 0.9 mmol, 3.0 equiv.), pyridine (2 mL) was added. The reaction mixture was stirred at 50° C. overnight under an atmosphere of N2. After cooling to room temperature, the crude reaction mixture was concentrated under reduced pressure using a rotary evaporator to give the crude reaction product, which was purified by preparative RP-HPLC using an ACN / water mixture acidified with 0.3 vol-% FA (5 to 95% ACN / water gradient in 30 min) to give the target compound 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one (31) (22.7 mg, 17.7% yield) as a yellow solid. LC / MS: m / z = 480.45 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.96 (s, 1H), 7.93 (s, 1H), 7.16 (s, 2H), 4.43 - 3.98 (m, 2H), 3.75 - 3.67 (m, 2H), 3.56 (s, 2H), 3.48 (s, 3H), 3.17 (s, 1H), 2.86 (s, 1H), 2.74 (s, 2H), 2.31 (s, 3H), 2.11 - 1.88 (m, 4H), 1.76 (s, 2H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.55 (s) ppm.

[0544] Example 32: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (32) [ka]

[0545] Synthesis scheme [ka]

[0546] Step 1: Synthesis of 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (32)

[0547] Into a flask containing (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (prepared as disclosed in Example 10) (160 mg, 0.39 mmol, 1.0 equiv.), (S)-pyrrolidin-3-ol hydrochloride (48.2 mg, 0.5 mmol, 1.0 equiv.), and EDCI (224.1 mg, 1.2 mmol, 3.0 equiv.), pyridine (2.0 mL) was added. The reaction mixture was stirred at 50° C. overnight under an atmosphere of N2. After cooling to room temperature, the crude reaction mixture was concentrated under reduced pressure using a rotary evaporator to give a crude mixture, which was purified by preparative RP-HPLC using an ACN / water mixture acidified with 0.3 vol-% FA (5 to 95% ACN / water gradient in 30 min) to give the target compound 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)-1-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (32) (51.8 mg, 27.7% yield) as a colorless solid. LC / MS: m / z = 480.20 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 7.97 (s, 1H), 7.93 (s, 1H), 7.16 (s, 2H), 4.42 - 4.03 (m, 2H), 3.69 (s, 2H), 3.65 (s, 2H), 3.59 - 3.45 (m, 3H), 2.94 (s, 1H), 2.63 (s, 2H), 2.59 (s, 1H), 2.34 - 2.30 (m, 3H), 2.01 (s, 2H), 1.84 (s, 2H), 1.71 (s, 2H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.57 (s) ppm.

[0548] Example 33: (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one (33) [ka]

[0549] Synthesis scheme [ka]

[0550] Step 1: Synthesis of tert-butyl (R)-3-((4-chlorophthalazin-1-yl)amino)piperidine-1-carboxylate

[0551] To a sealed tube containing 1,4-dichlorophthalazine (500 mg, 2.5 mmol, 1.0 equiv.), tert-butyl (R)-3-aminopiperidine-1-carboxylate (503 mg, 2.5 mmol, 1.0 equiv.), and DIEA (1.31 mL, 974 mg, 7.5 mmol, 3.0 equiv.), anhydrous NMP (5.0 mL) was added. The tube was sealed and stirred at 80 °C overnight. After the reaction mixture was cooled to room temperature, the crude solution was poured into water (100 mL), and the solution was extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with 5 wt% aqueous LiCl solution (3 × 10 mL). All organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give the crude reaction product. The crude product was purified by Biotage™ chromatography using 0-5% MeOH / DCM. It was purified using a Biotage Isolera equipped with SFAR (4 g, HC, Duo, 20 μM). The combined product-containing fractions were concentrated to give tert-butyl (R)-3-((4-chlorophthalazin-1-yl)amino)piperidine-1-carboxylate (657 mg, 72.0% yield) as a pale yellow solid. LC / MS: m / z = 363.10 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 8.3 Hz, 1H), 7.86 ( t, J = 7.6 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 4.55 (s, 1H), 3.50 (s, 2H), 3.39 - 3.15 (m, 1H), 3.08 - 2.95 (m, 1H), 2.64 - 2.25 (m, 2H), 1.96 (s, 1H), 1.80 (s, 1H), 1.73 (d, J = 8.3 Hz, 1H), 1.66 - 1.53 (m, 1H), 1.42 (s, 9H) ppm.

[0552] Steps 2 to 5: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid

[0553] (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid was prepared from tert-butyl (R)-3-((4-chlorophthalazin-1-yl)amino)piperidine-1-carboxylate in the same four step sequence as (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (above) and isolated as a yellow solid which was used directly in the next step. LC / MS: m / z = 447.20 [M+H] + .

[0554] Step 6: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one (33)

[0555] To a flask containing (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid (160.0 mg, 0.4 mmol, 1.0 equiv.), 4-hydroxypiperidine (40.0 mg, 0.4 mmol, 1.0 equiv.), and EDCI (230.0 mg, 1.2 mmol, 3.0 equiv.), pyridine (2.0 mL) was added. The reaction mixture was stirred at 50° C. overnight under an atmosphere of N. After cooling to room temperature, the crude solution was concentrated under reduced pressure using a rotary evaporator to give a crude reaction mixture. The crude reaction mixture was purified on preparative RP-HPLC using an ACN / water gradient acidified with 0.3 vol-% FA to give the target compound (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one (33) formate (29.0 mg, 15.3% yield) as an off-white solid after lyophilization of the combined product-containing fractions. LC / MS: 530.25 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 8.39 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.30 (s, 1H), 7.25 (s, 1H), 4.58 (s, 1H), 4.00 (s, 1H), 3.71 (s, 3H), 3.52 (s, 1H), 3.40 (s, 1H), 3.18 (s, 2H), 3.04 (s, 2H), 2.74 (s, 1H), 2.58 - 2.35 (m, 1H), 2.08 (s, 1H), 1.84 (s, 6H), 1.44 (d, J = 3.8 Hz, 2H) ppm. 19 F NMR (376 MHz, Methanol-d4): δ -64.34 (s) ppm.

[0556] Example 34: (R)-2-(3-((4-(2-hydroxy-4-fluorophenyl)phthalazin-1-yl)amino)piperidin-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one (34) [ka]

[0557] Synthesis scheme [ka]

[0558] Steps 1-2: Synthesis of (R)-2-(3-((4-(4-fluoro-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid

[0559] (R)-2-(3-((4-(4-Flu...

Claims

1. Formula (1-I): 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein in formula (1-I): ring 【Chemistry 2】 is a 4- to 11-membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; W is selected from the group consisting of NH, N-Me, N-Et, and N-iPr, or is a bond; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ ' is R １ together with R ２ is H, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, and —CF ３ or selected from the group consisting of: or R ３ is R ２ together with the all-carbon or with the O or N in the ring form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; R ４ is H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is H, Me, and -CF ３ selected from the group consisting of: R ６ and R ６ ' is -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF ３ or independently selected from the group consisting of: or R ６ and R ６ ' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ is C1-C3 alkyl optionally substituted with n is 1, 2, 3, or 4; compound. 【Request Item 2】 【Chemistry 3】 cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, piperidine, 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, 7-aza 2. The compound of claim 1, wherein the compound is selected from the group consisting of spiro[3.5]nonane, spiro[3.3]heptane, and bicyclo[1.1.1]pentane. 【Request Item 3】 【Chemistry 4】 is selected from the group consisting of 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, and 7-azaspiro[3.5]nonane; W is a bond; and Y is a bond; and R ４ The compound of claim 2, wherein is H.

4. R １ Ga-CF ３ and R ２ is methyl; R ３ is H or methyl; or R ２ and R ３ form a five-membered non-aromatic ring either all carbon or together with the O in the ring; R ５ The compound according to claims 1 to 3, wherein is H.

5. below: 【Chemistry 5-1】 【Chemistry 5-2】 2. The compound of claim 1, further represented by any one of:

6. below: 【Transformation 6】 2. The compound of claim 1, further represented by any one of:

7. below: 【Transformation 7】 2. The compound of claim 1, further represented by any one of:

8. Formula (1-II): 【Transformation 8】 or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof; In formula (1-II), the ring 【Chemistry 9】 is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ is R １ ' together with ' form a thiophene ring; R ２ is H, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, and —CF ３ or selected from the group consisting of: or R ２ is R ３ together with all carbon or with O or N to form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ C1-C3 alkyl optionally substituted with R ４ is H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is H, Me, and -CF ３ selected from the group consisting of: R ６ and R ６ ' is -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF ３ or independently selected from the group consisting of: or R ６ and R ６ ' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is 2, 3, or 4; compound.

9. ring 【Chemistry 10】 is selected from pyrrolidine, piperidine and azetidine; R １ Ga-CF ３ and R ２ is methyl; R ３ is H or methyl; or R ２ and R ３ form a five-membered non-aromatic ring either all carbon or together with the O in the ring; R ４ is H or F; Y is a bond; and R ５ The compound of claim 8 , wherein is H.

10. below: 【Chemistry 11】 9. The compound of claim 8, further represented by any one of:

11. below: 【Chemistry 12】 9. The compound of claim 8, further represented by any one of:

12. Formula (1-III): 【Chemistry 13】 or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, In formula (1-III), the ring 【Chemistry 14】 is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; ring 【Chemistry 15】 is a 4- to 7-membered cycloalkyl ring or a substituted cycloalkyl ring; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is H, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, and —CF ３ or selected from the group consisting of: or R ２ is R ３ together with all carbon or with O or N to form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; R ４ is H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ is C1-C3 alkyl optionally substituted with compound.

13. ring 【Chemistry 16】 is piperidine, pyrrolidine or azetidine; 【Chemistry 17】 is cyclobutane, cyclopentane or cyclohexane; R １ Ga-CF ３ and R ２ is methyl; R ３ is H or methyl; or R ２ and R ３ form a five-membered non-aromatic ring either all carbon or together with the O in the ring; R ４ 13. The compound of claim 12, wherein: is H; and Y is a bond.

14. below: [Chemistry 18] 13. The compound of claim 12, further represented by any one of:

15. Formula (1-IV): 【Chemistry 19】 or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, In formula (1-IV), the ring 【Chemistry 20】 is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; In formula (1-IV), the ring 【Chemistry 21】 is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is H, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, and —CF ３ or selected from the group consisting of: or R ２ is R ３ together with the all-carbon or with the O or N in the ring form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ C1-C3 alkyl optionally substituted with R ４ is H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is -H, -Me, and -CF ３ selected from the group consisting of compound.

16. ring 【Chemistry 22】 is selected from azetidine, pyrrolidine and piperidine; 【Chemistry 23】 is selected from the group consisting of azetidine, pyrrolidine, and piperidine; R １ Ga-CF ３ and R ２ is methyl; R ３ is H or methyl; or R ２ and R ３ form a five-membered non-aromatic ring either all carbon or together with the O in the ring; R ４ 16. The compound of claim 15, wherein: is H; and Y is a bond.

17. below: 【Chemistry 24】 16. The compound of claim 15, further represented by any one of:

18. Formula (1-V): 【Chemistry 25】 or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, In formula (1-V), the ring 【Chemistry 26】 is a 4-11 membered cycloalkyl heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; W is NH, N-Me, N-Et, N-iPr, or a bond; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is H, C1-C3 alkyl, -CF ３ selected from the group consisting of: R ４ is H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ C1-C3 alkyl optionally substituted with R ５ is -H, -Me, and -CF ３ selected from the group consisting of: R ６ and R ６ ' is -H, -F, C1-C6 alkyl, and -CF ３ or independently selected from the group consisting of: or R ６ and R ６ ' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is 1, 2, 3, or 4; compound. 【Request Item 19】 【Chemistry 27】 is selected from the group consisting of cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, piperidine, 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, spiro[3.3]heptane, and bicyclo[1.1.1]pentane. 【Request Item 20】 【Chemistry 28】 is selected from the group consisting of 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, and 7-azaspiro[3.5]nonane; W is a bond; and R is —CF ３ and R ２ is methyl; and R ４ 20. The compound of claim 19, wherein: is H; and Y is a bond.

21. below: 【Chemistry 29】 19. The compound of claim 18, further represented by any one of:

22. Formula (1-VI): 【Transformation 30】 In the formula (1-VI), the ring 【Chemistry 31】 is an optionally substituted 4- to 7-membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; ring 【Chemistry 32】 is an optionally substituted 4- to 7-membered cycloalkyl ring or a substituted cycloalkyl ring; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is —H, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ４ is —H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is -H, -Me, and -CF ３ selected from the group consisting of: Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ is C1-C3 alkyl optionally substituted with compound.

23. below: 【Transformation 33】 23. The compound of claim 22, further represented by any one of:

24. Formula (1-VII): 【Transformation 34】 In the formula (1-VII), the ring 【Chemistry 35】 is a 4- to 11-membered cycloalkyl heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is —H, C1-C3 alkyl, —CF ３ selected from the group consisting of: R ４ is —H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is -H, -Me, and -CF ３ selected from the group consisting of: R ６ and R ６ ' is -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF ３ or independently selected from the group consisting of or R ６ and R ６ ' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is 0, 1, 2, 3, or 4; and Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ is C1-C3 alkyl optionally substituted with compound.

25. below: 【Transformation 36】 25. The compound of claim 24, further represented by any one of:

26. Formula (1-VIII): 【Chemistry 37】 In the formula (1-VIII), the ring 【Transformation 38】 is a 4- to 11-membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is —H, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ４ is H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is H, Me, and -CF ３ selected from the group consisting of: R ６ and R ６ ' is -H, -F, C1-C6 alkyl, and -CF ３ or independently selected from the group consisting of: or R ６ and R ６ ' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is 1, 2, 3, or 4; and Y is a bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or —CF3; compound.

27. below: 【Chemistry 39】 27. The compound of claim 26, further represented by any one of:

28. Formula (1-IX): 【Chemistry 40】 or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, In formula (1-IX), the ring 【Chemistry 41】 is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is H, C1-C3 alkyl, -CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, and —CF ３ or selected from the group consisting of: or R ２ is R ３ together with the all-carbon or with the O or N in the ring form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; R ４ is H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is H, Me, and -CF ３ selected from the group consisting of: R ６ and R ６ ' is -H, -F, C1-C6 alkyl, C1-6 cycloalkyl, and -CF ３ or independently selected from the group consisting of or R ６ and R ６ ' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is 2, 3, or 4; and Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ is C1-C3 alkyl optionally substituted with compound.

29. ring 【Chemistry 42】 is selected from pyrrolidine, piperidine and azetidine; R １ Ga-CF ３ and R ２ is methyl; R ３ is H or methyl; or R ２ and R ３ form a five-membered non-aromatic ring either all carbon or together with the O in the ring; R ４ is H or F; R ５ 29. The compound of claim 28, wherein: is H; and Y is a bond.

30. below: 【Chemistry 43】 29. The compound of claim 28, further represented by any one of:

31. Formula (2-I): 【Chemistry 44】 or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, In formula (2-I), the ring 【Chemistry 45】 is a 4- to 11-membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring; W is selected from the group consisting of NH, N-Me, N-Et, and N-iPr, or W is a bond; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is -H; or R １ is R １ ' together with ' form a thiophene ring; Each R ２ and R ３ is —H, C1-C3 alkyl, and —CF ３ or selected from the group consisting of: or R ２ is R ３ together with - to form an all C or at least one O or N containing 5- or 6-membered aromatic or non-aromatic ring, which may be substituted with -Me or -OH; R ４ is —H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ C1-C3 alkyl optionally substituted with R ５ is -H, -Me, and -CF ３ selected from the group consisting of: R ６ and R ６ ' is -H, -F, C1-C6 alkyl or cycloalkyl, and -CF ３ or independently selected from the group consisting of: or R ６ and R ６ ' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is 1, 2, 3, or 4; and R ７ is —H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, 【Chemistry 46】 selected from the group consisting of compound.

32. The ring 【Chemistry 47】 32. The compound of claim 31 , wherein is a spirocyclic or bicyclic cycloalkyl, a substituted spirocyclic or bicyclic cycloalkyl, a spirocyclic or bicyclic heterocycloalkyl, or a substituted spirocyclic and bicyclic heterocycloalkyl.

33. 33. The compound of claim 32, wherein W is NH, N-Me, or a bond; and Y is a bond.

34. R1 is -F or -CF ３ and R1' is -H; R2 is —H, —Me, or —CF ３ and R3 is -H or -Me; or R3 together with R2 form a 5- or 6-membered aromatic or non-aromatic ring containing all C or at least one O; R4 is —H; R5 is selected from -H and -Me; R6 and R6' are each -H; n is 1; and R7 is —H; The compound according to claims 31 to 33.

35. below: 【Chemistry 48】 32. The compound of claim 31, further represented by any one of:

36. Formula (2-II): 【Chemistry 49】 or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, In formula (2-II), the ring [Transformation 50] is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; W is selected from NH, N-Me, N-Et and N-iPr, or is a bond; ； R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ and R ３ is H, C1-C3 alkyl, and —CF ３ or each independently selected from the group consisting of: or R ２ is R ３ together with the all-carbon or with the O or N in the ring form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; R ４ is —H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is -H, -Me, and -CF ３ selected from the group consisting of: R ６ and R ６ ' is -H, -F, C1-C6 alkyl or cycloalkyl, and -CF ３ or independently selected from the group consisting of: or R ６ and R ６ ' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is 1, 2, 3, or 4; compound.

37. ring 【Chemistry 51】 37. The compound of claim 36, wherein is a 4-11 membered spirocyclic or bicyclic nitrogen-containing heterocycloalkyl.

38. 38. The compound of claim 37, wherein W is NH, N-Me, or a bond.

39. R １ is -F or -CF ３ is selected from: R １ ' is -H; R ２ is —H, —Me, or —CF ３ and R ３ is selected from -H, or -Me, or R ２ and R ３ form an all-carbon or 5- or 6-membered aromatic or non-aromatic ring together with the O in the ring; R ４ is —H or —Me; R ５ is selected from —H and —Me; R ６ and R ６ 39. The compound of any one of claims 36 to 38, wherein N' is -H; and n is 1.

40. below: 【Chemistry 52】 37. The compound of claim 36, further represented by any one of:

41. Formula (2-III): 【Chemistry 53】 or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, In formula (2-III), the ring 【Chemistry 54】 is a 4- to 11-membered heterocycloalkyl or substituted heterocycloalkyl ring; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is H, C1-C3 alkyl, -CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, -CF ３ or selected from the group consisting of: or R ２ is R ３ together with the all-carbon or with the O or N in the ring form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; R ４ is —H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is -H, -Me, and -CF ３ selected from the group consisting of: W ２ is an optionally substituted —CH ２ -, -CH ２ CH ２ - and -CH ２ CH ２ CH ２ - or a bond, compound.

42. ring 【Transformation 55】 42. The compound of claim 41, wherein is a 4-9 membered nitrogen-containing spirocyclic or bicyclic nitrogen-containing heterocycloalkyl ring.

43. W ２ 43. The compound of claim 42, wherein is -CH2-, -CH2CH2-, or a bond.

44. R1 is —F or —CF3; R1′ is —H; R2 is —H, —Me, or —CF3, or R ２ and R ３ is, together with the O in the ring, an all-carbon, 5- or 6-membered non-aromatic ring; R4 is -H or -Me; and R5 is selected from -H and -Me.

45. below: 【Transformation 56】 42. The compound of claim 41, further represented by any one of:

46. Formula (2-IV): 【Chemistry 57】 or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: ring 【Chemistry 58】 is a 4- to 11-membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is H, C1-C3 alkyl, -CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, -CF ３ or selected from the group consisting of: or R ２ is R ３ together with the all-carbon or with the O or N in the ring form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; R ４ is —H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is -H, -Me, and -CF ３ selected from the group consisting of: W ３ is an optionally substituted —CH ２ -, -CH ２ CH ２ - and -CH ２ CH ２ CH ２ - or is a bond; Y is a bond or one, two, or three C1-C3 alkyl or -CF ３ is C1-C3 alkyl optionally substituted with R ７ is —H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, 【Chemistry 59】 selected from the group consisting of compound.

47. ring 【Transformation 60】 47. The compound of claim 46, wherein is a 4-6 membered cycloalkyl or heterocycloalkyl ring.

48. W3 is selected from —CH2— and —CH2CH2—, or a bond; Y 48. The compound of claim 47, wherein is a bond.

49. R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3; R ３ is selected from -H, or -methyl, or R ２ and R ３ form an all-carbon or 5- or 6-membered aromatic or non-aromatic ring together with the O in the ring; R ４ is —H or —Me; R ５ is selected from —H and —Me; R ７ The compound of any one of claims 46 to 48, wherein is -H.

50. below: 【Chemistry 61】 47. The compound of claim 46, further represented by any one of:

51. Formula (2-V): 【Transformation 62】 or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein: ring 【Transformation 63】 is azetidine, pyrrolidine, piperidine, or azepane; R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is H, C1-C3 alkyl, -CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, -CF ３ or selected from the group consisting of: or R ２ is R ３ together with the all-carbon or with the O or N in the ring form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; R ４ is —H, —F, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ５ is -H, -Me, and -CF ３ selected from the group consisting of: R １２ teeth, 【Chemistry 64】 is selected from the group consisting of m is 1, 2, or 3, and each R １３ are independently selected from the group consisting of —H, C1-C3 alkyl, and —CF; or two R １３ the groups are joined to form a cyclopropyl or cyclobutyl ring; compound.

52. ring 【Transformation 65】 52. The compound of claim 51, wherein is azetidine or piperidine.

53. R １ is selected from —F, —CF3; R1′ is —H; R2 is selected from —H, -Me, and —CF3; R ３ is selected from -H, or -Me, or R ２ and R ３ form an all-carbon or 5- or 6-membered aromatic or non-aromatic ring together with the O in the ring; R ４ is —H or —Me; R ５ is selected from —H and —Me; R １２ but the following: 【Chemical Formula 66】 53. The compound of claim 52, wherein the compound is selected from any one of:

54. below: 【Transformation 67】 52. The compound of claim 51, further represented by any one of:

55. Formula (2-VI): 【Transformation 68】 or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, In formula (2-VI), R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is H, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, and —CF ３ or selected from the group consisting of: or R ２ is R ３ together with the all-carbon or with the O or N in the ring form a 5- or 6-membered aromatic or non-aromatic ring which may be substituted with -Me or -OH; R ５ is -H, -Me, and -CF ３ selected from the group consisting of: W ４ は、-CH ２ -、-CH ２ CH ２ -、 【Transformation 69】 selected from the group consisting of: R ８ and R ８ ' is -H, C1-C5 alkyl, C1-C5 cycloalkyl, and -CF ３ are independently selected from the group consisting of: R ９ is —H, C1-C6 alkyl, C1-C6 cycloalkyl, heterocycloalkyl, 【Transformation 70】 selected from the group consisting of compound.

56. R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, or -CF3; R3 is selected from -H or -Me, or R ２ and R ３ form an all-carbon or 5- or 6-membered aromatic or non-aromatic ring together with the O in the ring; R ５ 56. The compound of claim 55, wherein is selected from -H and -Me.

57. W4 is -CH ２ -or 【Chemistry 71】 is selected from: R ８ and R ８ ' is -H; n is 1; R ９ 57. The compound of claim 56, wherein is -H.

58. R8 and R8' are -H; n is 1; R9 is 【Chemistry 72】 58. The compound according to claims 55 to 57, selected from:

59. below: 【Transformation 73】 56. The compound of claim 55, further represented by any one of:

60. below: 【Chemistry 74】 56. The compound of claim 55, further represented by any one of:

61. Formula (2-VII): 【Chemistry 75】 or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: R １ represents -CN, -H, -F, and -CF ３ selected from the group consisting of: R １ ' is H; or R １ and R １ ' together form a thiophene ring; R ２ is H, C1-C3 alkyl, and —CF ３ selected from the group consisting of: R ３ is H, C1-C3 alkyl, and —CF ３ or selected from the group consisting of: or R ２ is R ３ together with a 5- or 6-membered aromatic or non-aromatic ring optionally substituted with -Me or -OH either all at carbon or with an O or N in the ring. It forms; R ５ represents H, -Me and -CF ３ selected from the group consisting of: R ６ and R ６ ' is -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF ３ or independently selected from the group consisting of or R ６ and R ６ ' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is 1, 2, 3, or 4; R １４ and R １４ ' is H, C1-C5 alkyl (including cycloalkyl), and -CF ３ or independently selected from the group consisting of: or R １４ and R １４ ' together with the atom to which they are attached form an optionally substituted C3-C6 cycloalkyl or an optionally substituted C3-C6 heterocycloalkyl ring; R １０ is —H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl), 【Transformation 76】 selected from the group consisting of: R １１ is selected from the group consisting of H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl; compound.

62. R １ is -F or -CF ３ and R １ ' is H; R ２ is —H, —Me, or —CF ３ and R ３ is —H or —Me, or R ２ and R ３ form an all-carbon or 5- or 6-membered aromatic or non-aromatic ring together with the O in the ring; R ５ is selected from —H and —Me; R ６ and R ６ ' is -H; n is 1; R １４ and R １４ ' is -H; R １０ is —H; R １１ 62. The compound of claim 61, wherein is selected from -H or -Me.

63. below: 【Chemical 77】 62. The compound of claim 61, further represented by:

64. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 63 and a pharmaceutically acceptable excipient.

65. 64. A method of preventing, treating, or ameliorating one or more diseases in a subject, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof.

66. The disease is age-related macular degeneration (wet and dry) (AMD), atrophic macular degeneration , bacterial endophthalmitis, bacterial infections of the eye, bacterial corneal ulcers, bacterial keratitis, Behçet's syndrome, cataracts, choroidal neovascularization, CMV retinitis, chronic eye diseases, delayed diabetic corneal wound healing and neurodegeneration, diabetic macular edema (DME), diabetic retinopathy (DR), conjunctivitis, corneal allograft rejection, corneal edema, dry eye disease (DED), Graves' disease, Fuchs' endothelial corneal dystrophy, fungal endophthalmitis, fungal keratitis, fungal infections of the eye, glaucoma (acute and non-acute), geographic atrophy (GA), inflammatory eye diseases, hereditary transient keratitis (KFH), LPS-induced ocular inflammation, Mooren's ulcer (MU), neuronal death in retinal ischemia / reperfusion injury, ocular inflammation associated with ocular hypertension, rheumatoid arthritis and systemic lupus erythematosus (SLE) 66. The method of claim 65, wherein the ocular condition is selected from the group consisting of ocular manifestations of glaucoma, limbal squamous cell carcinoma, optic neuritis, ocular parasitic infections, pathological neovascularization, excitoretinal hyperstimulation, lipofuscin and A2E mediated oxidative damage including but not limited to ROS / oxidative stress reduction, retinal ganglion cell (RGC) dysfunction and death in response to ocular hypertension (OHT) induced stress (OHT - glaucoma), retinoblastoma, retinitis, retinal vasculitis, retinal vein occlusion (RVO), Sjogren's syndrome, sterile corneal inflammation, stroke-induced retinal damage in diabetes, traumatic optic neuropathy / trauma including but not limited to progressive optic neuropathy (optic nerve crush), ulcerative keratitis, uveal melanoma, uveitis (anterior / intermediate / posterior, panuveitis), and ocular viral infections.

67. 66. The method of claim 65, wherein the disease is characterized by a disease progression involving activity of IL-1β, IL-18, or both.

68. 68. The method of any one of claims 65 to 67, wherein the disease is selected from the group consisting of age-related macular degeneration (wet and dry) (AMD), atrophic macular degeneration, bacterial keratitis, Behcet's syndrome, choroidal neovascularization, chronic eye diseases, diabetic macular edema (DME), diabetic retinopathy (DR), dry eye disease (DED), glaucoma (acute and non-acute), geographic atrophy (GA), retinopathies, inflammatory eye diseases, ocular inflammation associated with cryopyrin-associated periodic syndromes (CAPS), ocular symptoms of rheumatoid arthritis and systemic lupus erythematosus (SLE), retinitis, retinal vasculitis, retinal vein occlusion (RVO), progressive optic neuropathy, and uveitis (anterior / intermediate / posterior, panuveitis).

69. 69. The method of any one of claims 65 to 68, wherein the disease is at least one chronic inflammatory disorder.

70. 70. The method of claim 69, wherein the disease is characterized by a disease progression pathology involving NLRP3 inflammasome activity or IL-1β secretion, IL-18 secretion, or both.

71. 71. The method of claim 70, wherein the NLRP3 inflammasome comprises at least one mutation.

72. 72. The method of any one of claims 65 to 71, which is a monotherapy.

73. 72. The method of any one of claims 65 to 71, comprising administering at least one other form of treatment.

74. 74. The method of any one of claims 65 to 73, wherein the subject is a human.

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