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 environments. Also disclosed herein are pharmaceutical compositions, uses and formulations thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 478,268, filed on January 3, 2023, and U.S. Provisional Application No. 63 / 467,565, filed on May 18, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure generally relates to the field of NLRP3 (NOD-like receptor-, LRR- and pyrin domain-containing protein 3) family proteins and NLRP3 inflammasome function. More specifically, the present disclosure relates to the field of small molecule compounds that can inhibit NLRP3 family proteins and NLRP3 inflammasome function in various disease settings. Background Art

[0004] Inflammasomes are large, dynamic multimeric protein complexes formed in the cytosol. They are activated by pathogen-associated molecular patterns (PAMPs) produced by bacterial infection or by endogenous danger signals, known as danger-associated molecular patterns (DAMPs), released by damaged or apoptotic cells. In 2002, Tschopp and Martinon established a link between inflammasomes and activation of the proinflammatory protease aspartate-specific cysteine ​​protease-1 (caspase-1). Caspase-1 is a proteolytic enzyme responsible for converting inactive precursors, namely pro-interleukin-1β (Pro-IL-1β) and pro-interleukin-18 (Pro-IL-18), into their activated forms, interleukin-1β (IL-1β) and interleukin-18 (IL-18), respectively. Interleukin-1β (IL-1β) and interleukin-18 (IL-18) are both members of the interleukin-1 (IL-1) family of cytokines. They play key roles in innate and adaptive immune responses and influence a variety of disease states. Tschopp's discovery placed the inflammasome at the core of immune regulation and homeostasis. Since then, the field has advanced significantly, providing new insights into the assembly, regulation, and function of inflammasome complexes and their role in inflammatory diseases.

[0005] The inflammasome complex is composed of three components: a sensor, an adaptor protein, and an effector enzyme. The sensor is typically a nucleotide-binding domain- containing and leucine-rich repeat (NLR)-containing protein or an AIM2-like receptor (ALR) protein. Most inflammasomes contain a sensor from the NLR family, and importantly, each inflammasome has its own unique sensor protein. The adaptor protein is called ASC (apoptosis-associated speck-like protein containing CARD), which is able to recruit and link the effector enzyme to the sensor. ASC is a common component in many inflammasome complexes. Finally, the effector enzyme is typically pro-caspase-1. When the inflammasome is complete and activated, the caspase-1 precursor is converted to activated caspase-1, which in turn activates key cytokines such as interleukin-1 beta (IL-1β) and interleukin-18 (IL-18). SUMMARY

[0006] The present disclosure provides a compound represented by the structure of Formula (1-I):

[0007]

[0008]

[0009] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein the ring is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; W is selected from NH, N-Me, N-Et, and N-iPr, or is a single bond; R1is selected from -CN, -H, -F, and -CF3; R1' is H; or R1' and R1together form a thiophene ring; R2is selected from H, C1-C3 alkyl, and -CF3; R3is selected from H, C1-C3 alkyl, and -CF3; or R3and R2together form a ring, which is a 5- or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, optionally substituted with -Me or -OH; R4is selected from H, -F, C1-C3 alkyl, and -CF3; R5is selected from H, Me, and -CF3; R6and R6' are independently selected from -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF3; or R6and R6' together with the atom to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; Y is a single bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3; and n is 1, 2, 3, or 4.

[0010] In some embodiments, the compound of Formula (1-I) is further represented by any one of:

[0011]

[0012]

[0013] In some embodiments, the compound of Formula (1-I) is further represented by any one of:

[0014]

[0015] In some embodiments, the compound of Formula (1-I) is further represented by any one of:

[0016]

[0017]

[0018] The present disclosure also provides a compound represented by the structure of Formula (1-II):

[0019]

[0020] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof; wherein, ring is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; R1is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1and R1'together form a thiophene ring; R2is selected from the group consisting of H, C1-C3alkyl, and -CF3; R3is selected from the group consisting of H, C1-C3alkyl, and -CF3; or R2and R3together form a ring, which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all-carbocyclic or containing O or N, optionally substituted with -Me or -OH; Y is a single bond or C1-C3alkyl optionally substituted with 1, 2, or 3 C1-C3alkyl or -CF3; R4is selected from the group consisting of H, -F, C1-C3alkyl, and -CF3; R5is selected from the group consisting of H, Me, and -CF3; R6and R6' are independently selected from the group consisting of -H, -F, C1-C6alkyl, C1-C6cycloalkyl, and -CF3; or R6and R6' together with the atom to which they are attached form a C1-C6cycloalkyl or C1-C6heterocycloalkyl ring; and n is 2, 3, or 4.

[0021] In some embodiments, the compound of Formula (1-II) is further represented by any one of:

[0022]

[0023] In some embodiments, the compound of Formula (1-II) is further represented by any one of:

[0024]

[0025] The present disclosure also provides a compound represented by the structure of formula (1-III):

[0026]

[0027] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; ring is a 4-7 membered cycloalkyl ring or substituted cycloalkyl ring; R1is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1and R1' together form a thiophene ring; R2is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R3is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2and R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, optionally substituted with -Me or -OH; R4is selected from the group consisting of H, -F, C1-C3 alkyl, and -CF3; and Y is a single bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0028] In some embodiments, the compound of formula (1-III) is further represented by any one of:

[0029]

[0030] The present disclosure also provides a compound represented by the structure of formula (1-IV):

[0031]

[0032] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; wherein ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; R1is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1and R1' together form a thiophene ring; R2is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R3is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2and R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, optionally substituted with -Me or -OH; Y is a single bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3; R4is selected from the group consisting of H, -F, C1-C3 alkyl, and -CF3; and R5is selected from the group consisting of -H, -Me, and -CF3.

[0033] In some embodiments, the compound of formula (1-IV) is further represented by any one of:

[0034]

[0035] The present disclosure also provides a compound represented by the structure of Formula (1-V):

[0036]

[0037] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein the ring is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; W is NH, N-Me, N-Et, N-iPr, or a single bond; R1is selected from the group consisting of -CN, -H, -F, and -CF3; R1is H; or R1and R1together form a thiophene ring; R2is selected from the group consisting of H, C1-C3 alkyl, and -CF3; R4is selected from the group consisting of H, -F, C1-C3 alkyl, and -CF3; Y is a single bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3; R5is selected from the group consisting of -H, -Me, and -CF3; R6and R6are independently selected from the group consisting of -H, -F, C1-C6 alkyl, and -CF3, or R6and R6together 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.

[0038] In some embodiments, the compound of Formula (1-V) is further represented by any one of:

[0039]

[0040] The present disclosure also provides a compound represented by the structure of Formula (1-VI):

[0041]

[0042] wherein the ring is an optionally substituted 4-7 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; the ring is an optionally substituted 4-7 membered cycloalkyl ring or substituted cycloalkyl ring; R1is selected from the group consisting of -CN, -H, -F, and -CF3; R1is -H; or R1and R1together form a thiophene ring; R2is selected from the group consisting of -H, C1-C3 alkyl, and -CF3; R4is selected from the group consisting of -H, -F, C1-C3 alkyl, and -CF3; R5is selected from the group consisting of -H, -Me, and -CF3; and Y is a single bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0043] In some embodiments, the compound of Formula (1-VI) is further represented by any one of:

[0044]

[0045] The present disclosure also provides a compound represented by the structure of Formula (1-VII):

[0046]

[0047] wherein the ring is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; R1is selected from -CN, -H, -F, and -CF3; R1' is H; or R1and R1' together form a thiophene ring; R2is selected from -H, C1-C3 alkyl, and -CF3; R4is selected from -H, -F, C1-C3 alkyl, and -CF3; R5is selected from -H, -Me, and -CF3; R6and R6' are independently selected from -H, -F, C1-C6 alkyl, and -CF3, or R6and 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 single bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0048] In some embodiments, the compound of Formula (1-VII) is further represented by any one of:

[0049]

[0050] The present disclosure also provides a compound represented by the structure of Formula (1-VIII):

[0051]

[0052] wherein the ring is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; R1is selected from -CN, -H, -F, and -CF3; R1' is H; or R1and R1' together form a thiophene ring; R2is selected from -H, C1-C3 alkyl, and -CF3; R4is selected from -H, -F, C1-C3 alkyl, and -CF3; R5is selected from -H, -Me, and -CF3; R6and R6' are independently selected from -H, -F, C1-C6 alkyl, and -CF3, or R6and 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 single bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0053] In some embodiments, the compound of Formula (1-VIII) is further represented by any one of:

[0054]

[0055] The present disclosure also provides a compound represented by the structure of Formula (1-IX):

[0056]

[0057] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-11 membered nitrogen-containing heterocycloalkyl ring or substituted heterocycloalkyl ring; R1is selected from the group consisting of -CN, -H, -F, and -CF3; R1' is H; or R1and R1'together form a thiophene ring; R2is selected from the group consisting of H, C1-C3 alkyl, -CF3; R3is selected from the group consisting of H, C1-C3 alkyl, and -CF3; or R2and R3together form a ring, which is a 5- or 6-membered aromatic or non-aromatic ring, which is an all-carbocyclic ring or contains O or N within the ring, optionally substituted with -Me or -OH; R4is selected from the group consisting of H, -F, C1-C3 alkyl, and -CF3; R5is selected from the group consisting of H, Me, and -CF3; R6and R6' are independently selected from the group consisting of -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF3, or R6and 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 single bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3.

[0058] In some embodiments, the compound of Formula (1-IX) is further represented by any one of:

[0059]

[0060] The present disclosure also provides a compound represented by the structure of Formula (2-I):

[0061]

[0062] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein ring R1is selected from -CN, -H, -F, and -CF3; R1is -H; or R1and R1together form a thiophene ring; R2and R3are each selected from -H, C1-C3 alkyl, and -CF3; or R2and R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing at least one O or N, optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a single bond or C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3; R5is selected from -H, -Me, and -CF3; R6and R6are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3; or R6and R6together 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 R7is selected from -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl,

[0063] In some embodiments, R1is selected from -CN, -H, -F, -CF3, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1is -H, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3 alkyl, -CF3, or forms a ring with R3which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R3is selected from -H, C1-C3 alkyl, -CF3, or forms a ring with R2which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a single bond (when Y is a single bond, -NH can be directly attached to the ring; similarly, when Y is a single bond, -NH-R7may be directly attached to the ring) or Y is C1-C3 alkyl optionally substituted with 1, 2, or 3 C1-C3 alkyl or -CF3; R5is selected from -H, -Me, and -CF3; R6and R6are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6and R6together 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; R7is selected from -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl,

[0064] In some aspects of Formula (2-I), the ring 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; wherein W is selected from NH, N-Me, or is a single bond; when W is a single bond, the carbonyl (C=0) is bonded to the nitrogen atom within the ring to form an amide bond; R1is selected from -F, -CF3; R1is -H; R2is selected from -H, -Me, -CF3, or together with R3forms a ring which is a 5- or 6-membered non-aromatic ring, the ring being all-carbocyclic or containing O within the ring; R3is selected from -H, -Me, or together with R2forms a ring which is a 5- or 6-membered non-aromatic ring, the ring being all-carbocyclic or containing O within the ring; R4is -H; R5is selected from -H and -Me; R6and R6are -H; n is 1; R7is -H.

[0065] In some embodiments, the compound of Formula (2-I) is further represented by any one of:

[0066]

[0067] The present disclosure also provides a compound represented by the structure of Formula (2-II):

[0068]

[0069] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein the ring 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 single bond; R1is selected from -CN, -H, -F, and -CF3; R1is H; or R1and R1together form a thiophene ring; R2and R3are each independently selected from H, C1-C3 alkyl, and -CF3; or R2and R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all-carbocyclic or containing O or N within the ring, optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3 alkyl, and -CF3; R5is selected from -H, -Me, and -CF3; R6and R6are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3; or R6and R6together 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.

[0070] In some aspects of Formula (2-II), the ring is a 4-11 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl rings; wherein W is selected from NH, N-Me, or is a single bond; when W is a single bond, the carbonyl (C=0) is bonded to the nitrogen atom within the ring to form an amide bond together; R1is selected from -F, -CF3; R1is -H; R2is selected from -H, -Me, -CF3, or R2and R3form a ring together, which is a 5- or 6-membered non-aromatic ring, the ring is a fully carbon ring or contains O within the ring; R3is selected from -H, -Me, or R2and R3form a ring together, which is a 5- or 6-membered non-aromatic ring, the ring is a fully carbon ring or contains O within the ring; R4is -H or -Me; R5is selected from -H and -Me; R6and R6are -H; n is 1.

[0071] In some embodiments, the compound of Formula (2-II) is further represented by any one of:

[0072]

[0073] The present disclosure also provides a compound represented by the following structure:

[0074]

[0075] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein the ring is a 4-11 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl rings; wherein W is selected from NH, N-Me, or is a single bond; when W is a single bond, the carbonyl (C=0) is bonded to the nitrogen atom within the ring to form an amide bond together; R1is selected from -F, -CF3; R1is -H; R2is selected from -H, -Me, -CF3, or R2and R3form a ring together, which is a 5- or 6-membered non-aromatic ring, the ring is a fully carbon ring or contains O within the ring; R3is selected from -H, -Me, or R2and R3form a ring together, which is a 5- or 6-membered non-aromatic ring, the ring is a fully carbon ring or contains O within the ring; R4is -H or -Me; R5is selected from -H and -Me; R6and R6are -H; n is 1.

[0076] In some aspects of Formula (2-III), the ring is a 4-9 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl rings; wherein W2is selected from -CH2-, -CH2CH2-, or is a single bond; R1is selected from -F, -CF3; R1is -H; R2is selected from -H, -Me, -CF3, or R2and R3form a ring together, which is a 5- or 6-membered non-aromatic ring, the ring is a fully carbon ring or contains O within the ring; R3is selected from -H, -Me, or R2and R3form a ring together, which is a 5- or 6-membered non-aromatic ring, the ring is a fully carbon ring or contains O within the ring; R4is -H or -Me; R5is selected from -H and -Me. ​

[0077] In some embodiments, the compound of formula (2-III) is further represented by any one of:

[0078]

[0079] The present disclosure also provides a compound represented by the structure of formula (2-IV):

[0080]

[0081] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: the ring is a 4-11 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring; R1is selected from -CN, -H, -F, and -CF3; R1is H; or R1and R1together form a thiophene ring; R2is selected from H, C1-C3alkyl, -CF3; R3is selected from H, C1-C3alkyl, -CF3; or R2and R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, which is an all-carbocyclic ring or contains O or N within the ring, optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3alkyl, and -CF3; R5is selected from -H, -Me, and -CF3; W3is selected from optionally substituted -CH2-, -CH2CH2-, and -CH2CH2CH2-, or is a single bond; Y is a single bond or C1-C3alkyl optionally substituted with 1, 2, or 3 C1-C3alkyl or -CF3; and R7is selected from -H, C1-C6alkyl, cycloalkyl, heterocycloalkyl,

[0082] In some aspects of formula (2-IV), the ring is a 4-9 membered cycloalkyl or heterocycloalkyl ring, wherein W3is selected from -CH2-, -CH2CH2-, or is a single bond; R1is selected from -F and -CF3; R1is -H; R2is selected from -H, -Me, and -CF3, or together with R3forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, which is an all-carbocyclic ring or contains O within the ring; R3is selected from -H and -Me, or together with R2forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, which is an all-carbocyclic ring or contains O within the ring; R4is -H or -Me; R5is selected from -H and -Me; and R7is -H.

[0083] In some embodiments, the compound of formula (2-IV) is further represented by any one of:

[0084]

[0085] The present disclosure also provides a compound represented by the structure of formula (2-V):

[0086]

[0087] or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein: ring is azetidine, pyrrolidine, piperidine, or azepine; R1is selected from -CN, -H, -F, and -CF3; R1' is H; or R1and R1' together form a thiophene ring; R2is selected from H, C1-C3alkyl, -CF3; R3is selected from H, C1-C3alkyl, -CF3; or R2and R3together form a ring, which is a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon ring or contains O or N within the ring, optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3alkyl, and -CF3; R5is selected from -H, -Me, and -CF3; and R 12 is selected from:

[0088]

[0089] wherein m is 1, 2, or 3, each R 13 is independently selected from -H, C1-C3alkyl, and -CF3; or two R 13 groups are joined to form a cyclopropyl or cyclobutyl ring.

[0090] The ring can have 1, 2, or 3 R 13 groups, wherein each R 13 is independently selected from -H, C1-C3alkyl, and -CF3. Two R 13 groups can be joined to form a cyclopropyl or cyclobutyl ring.

[0091] In some aspects of Formula (2-V), the ring is azetidine or piperidine; R1is selected from -F, -CF3; R1' is -H; R2is selected from -H, -Me, and -CF3, or together with R3forms a ring, which is a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon ring or contains O within the ring; R3is selected from -H, -Me, or together with R2forms a ring, which is a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon ring or contains O within the ring; R4is -H or -Me; R5is selected from -H and -Me; and R 12 is selected from

[0092] In some embodiments, the compound of Formula (2-V) is further represented by any one of:

[0093]

[0094] The present disclosure also provides a compound represented by the structure of Formula (2-VI):

[0095]

[0096] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein R1is selected from -CN, -H, -F, and -CF3; R1is H; or R1and R1together form a thiophene ring; R2is selected from H, C1-C3alkyl, and -CF3; R3is selected from H, C1-C3alkyl, and -CF3; or R2and R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, optionally substituted with -Me or -OH; R5is selected from -H, -Me, and -CF3; W4is selected from -CH2-, -CH2CH2-, R8and R8are independently selected from -H, C1-C5alkyl, C1-C5cycloalkyl, and -CF3; and R9is selected from -H, C1-C6alkyl, C1-C6cycloalkyl, heterocycloalkyl,

[0097] In some aspects of Formula (2-VI), R1is selected from -F, -CF3; R1is -H; R2is selected from -H, -Me, -CF3, or R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R3is selected from -H, -Me, or R2together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R5is selected from -H and -Me; W4is selected from -CH2- or R8and R8are -H; n is 1; R9is -H.

[0098] In some aspects of Formula (2-VI), R1is selected from -F, -CF3; R1is -H; R2is selected from -H, -Me, -CF3, or R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R3is selected from -H, -Me, or R2together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R5is selected from -H and -Me; W4is selected from -CH2- or R8and R8are -H; n is 1; R9is selected from

[0099] In some embodiments, the compound of Formula (2-VI) is further represented by any one of:

[0100]

[0101] In some embodiments, the compound of Formula (2-VI) is further represented by any one of:

[0102]

[0103] The present disclosure also provides a compound represented by the structure of Formula (2-VII):

[0104]

[0105] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: R1is selected from -CN, -H, -F, and -CF3; R1' is H; or R1and R1' together form a thiophene ring; R2is selected from H, C1-C3 alkyl, and -CF3; R3is selected from H, C1-C3 alkyl, and -CF3; or R2and R3together form a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon ring or contains O or N within the ring, optionally substituted with -Me or -OH; R5is selected from -H, -Me, and -CF3; R6and R6' are independently selected from -H, -F, C1-C6 alkyl, C1-C6 cycloalkyl, and -CF3; or R6and 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; R 14 and R 14 ' are independently selected from 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 optionally substituted C3-C6 heterocycloalkyl ring; R 10 is selected from -H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl, and R 11 is selected from H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl.

[0106] In some aspects of Formula (2-VII), R1is selected from -F, -CF3; R1' is -H; R2is selected from -H, -Me, -CF3, or together with R3forms a ring, which is a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon ring or contains O within the ring; R3is selected from -H, -Me, or together with R2forms a ring, which is a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon ring or contains O within the ring; R5is selected from -H and -Me; R6and R6' are -H; n is 1; R9and R9' are -H; R 10 is -H; R 11 is selected from -H or -Me.

[0107] In one embodiment, the compound of Formula (2-VII) is further represented by:

[0108]

[0109] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein and a pharmaceutically acceptable excipient.

[0110] The present disclosure also provides a method of preventing, treating, or ameliorating one or more diseases in a subject comprising administering to a subject in need thereof a compound as described herein or a pharmaceutically acceptable excipient.

[0111] In some embodiments, the disease is characterized by disease progression involving the active role of IL-1β and IL-18 or both. NLRP3 inflammasome activation is implicated in various inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. In accordance with the present disclosure, various ocular diseases associated with NLRP3 inflammasome activation, which is part of the immune system and involved in the response to cellular stress and damage, can be treated. Without being bound to a theory of mechanism of action, one possible rationale behind targeting NLRP3 inflammasome activation in these cases is that inflammasome activation plays a role in inflammation and immune responses, which can trigger or exacerbate ocular diseases. Accordingly, one aspect of the present disclosure relates to treating, preventing, or ameliorating ocular diseases.

[0112] As non-limiting examples, age-related macular degeneration (AMD) (both wet and dry forms) involves the deterioration of the central part of the retina, which in turn leads to vision loss. NLRP3 inflammasome activation can contribute to the inflammation and neovascularization observed in AMD. Similarly, diabetic macular edema (DME) and diabetic retinopathy (DR) are complications of diabetes, in which high blood sugar levels damage retinal blood vessels, and inflammation plays an important role in their progression.

[0113] Diseases like glaucoma, which is characterized by increased eye pressure leading to damage of the optic nerve, and retinopathy, which involves damage to retinal blood vessels, are also associated with inflammatory responses mediated by NLRP3 inflammasome. Dry eye disease (DED) and bacterial keratitis, a corneal infection, both involve inflammation, in which NLRP3 inflammasome can play a role in the response to infection and cellular stress.

[0114] Inflammatory and autoimmune diseases such as Behcet’s syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis can present with ocular manifestations including uveitis (inflammation of the middle layer of the eye) and retinal vasculitis (inflammation of the blood vessels of the retina). These conditions are often characterized by an overactive immune response, where controlling the activation of the NLRP3 inflammasome can control inflammation and prevent tissue damage. Targeting the NLRP3 inflammasome in patients with or at risk of developing the various diseases described above can reduce inflammation, slow disease progression, preserve vision, and improve quality of life by intervening in one of the underlying mechanisms that lead to these ocular conditions.

[0115] Consistent with the present disclosure, the compounds of the present disclosure can be used to treat, prevent, or ameliorate a disease affecting the eye. In several embodiments, the disease is selected from, 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 retinopathy.

[0116] In several embodiments, the disease is selected from, for example, inflammatory eye disease, cold pyrin-related periodic syndrome (CAPS)-associated ocular inflammation, 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 uveitis, panuveitis).

[0117] 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 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 inflammatory eye disease. In some embodiments, the disease is cold urticaria-associated periodic syndrome (CAPS)-associated ocular inflammation. In some embodiments, the disease involves ocular manifestations 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 uveitis, or panuveitis.

[0118] In some embodiments, due to their activity on the NLRP3 inflammasome, the compounds in the present disclosure are expected to exhibit significant biological activity on a range of systemic diseases. For example, in diseases where inflammation is a major causative factor, such as gout and atherosclerosis, the compounds of the present disclosure can alleviate symptoms and slow disease progression by modulating the inflammatory response. In several embodiments, the disease is selected from atherosclerosis, gout, acute gouty arthritis, rheumatoid arthritis, nonalcoholic 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 DESCRIPTION OF DRAWINGS

[0119] Figure 1 Inhibition of IL-1β release in U937 cells is shown.

[0120] Figure 2 Inhibition of IL-1β release in THP-1 cells is shown.

[0121] Figure 3Inhibition of Caspase-1 in THP-1 cells is shown.

[0122] Figure 4 Viability assay of THP-1 cells is shown.

[0123] Figure 5 Inhibition of ASC-GFP speckles in THP-1 cells is shown.

[0124] Figure 6 Effect of test compounds on TNFα in U937 cells is shown.

[0125] Figure 7 Toxicity assessment on human retinal pigment epithelial cells is shown. DETAILED DESCRIPTION

[0126] The compounds disclosed herein are potent inhibitors of the NLRP3 inflammasome. Such NLRP3 inhibiting compounds can be used to treat or prevent inflammatory diseases, as well as diseases with underlying inflammatory pathology associated with the NLRP3 inflammasome. The lack of high resolution crystal structure of the NLRP3 protein complex bound to ligands makes it challenging to apply structure-based design methods in developing NLRP3 inhibitors. Using a pharmacophore / ligand-based approach, a structural region was identified where the introduction of a polar amine or amide attached to a terminal hydroxyl, primary or secondary amino group, neither affects the activity nor allows us to modulate the physicochemical properties of the parent compounds 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), and (2-VII).

[0127] Surprisingly, the introduction of an extended linker comprising an amine or amide at a key position of the molecular structure, as well as a terminal primary, secondary, tertiary hydroxyl or a terminal primary, secondary amino group, in certain cases, not only does not affect the activity, but also produces potent NLRP3 inhibitory potency or potent inhibition of IL-1β secretion, while also contributing to improved solubility, reduced lipophilicity, for enhanced safety.

[0128] The surprisingly compounds with terminal primary, secondary, and tertiary hydroxyl groups have the general structure shown in FIGS. 1A, IB, 1C, ID, IE, IF, and 1G, wherein Y' is a pharmacophore known for NLRP3 inhibitory activity or IL-1 β secretion inhibitory activity or an analog thereof, such as (R)-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)phenol, (R)-5-(6-(piperidin-3-ylamino)pyridazin-3-yl)benzo[b]thiophen-4-ol, or (R)-2-(8-(piperidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)phenol, appropriately substituted.

[0129] X is a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring (including substituted and unsubstituted spirocyclic and bicyclic rings); X2 is a heterocycloalkyl or substituted heterocycloalkyl ring (including spirocyclic and substituted spirocyclic rings); X3 is a heterocycloalkyl or substituted heterocycloalkyl ring (including substituted and unsubstituted spirocyclic rings); X4 is a cycloalkyl ring or substituted cycloalkyl ring; X5 is a heterocycloalkyl ring or substituted heterocycloalkyl ring (including spirocyclic or substituted spirocyclic rings); X6 is a heterocycloalkyl ring or substituted heterocycloalkyl ring (including spirocyclic or substituted spirocyclic rings); X7 is a heterocycloalkyl ring or substituted heterocycloalkyl ring (including spirocyclic or substituted spirocyclic rings); X8 is a heterocycloalkyl ring or substituted heterocycloalkyl ring (including spirocyclic or substituted spirocyclic rings); R4 is optional, if present, is -F or -Me, -Et, iPr, or cPr, W is NH, N-Me, N-Et, or N-iPr, or W is a single bond (when W is a single bond, the ring through a heterocyclic ring through a heterocyclic ring

[0130]

[0131] The surprisingly compounds with terminal primary, secondary, and tertiary hydroxyl groups have the general structure shown in FIGS. 1A, IB, 1C, ID, IE, IF, and 1G, wherein Y' is a pharmacophore known for NLRP3 inhibitory activity or IL-1 β secretion inhibitory activity or an analog thereof, such as (R)-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)phenol, (R)-5-(6-(piperidin-3-ylamino)pyridazin-3-yl)benzo[b]thiophen-4-ol, or (R)-2-(8-(piperidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)phenol, appropriately substituted.

[0132]

[0133] wherein Y' is a known pharmacophore for NLRP3 inhibitory activity or IL-1 beta secretion inhibitory activity or an analog thereof, such as (R)-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)phenol, (R)-5-(6-(piperidin-3-ylamino)pyridazin-3-yl)benzo[b]thiophen-4-ol, or (R)-2-(8-(piperidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)phenol, appropriately substituted, wherein,

[0134] wherein ring 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; wherein W is selected from NH, N-Me, N-Et, and N-iPr, or is a single bond; when W is a single bond, the carbonyl (C=0) is bonded to a nitrogen atom within ring , together forming an amide bond; 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 selected from -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, ring is a 4-9 membered nitrogen-containing ring, including heterocycloalkyl rings and substituted heterocycloalkyl rings, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl; wherein W is selected from NH, N-Me, N-Et, and N-iPr, or is a single bond; when W is a single bond, the carbonyl (C=0) is bonded to a nitrogen atom within ring , together forming an amide bond; ring is a 4-9 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl; Y is a single bond (when Y is a single 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; ring 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 is a single bond; ring R7is selected from -H, C1-C6alkyl or cycloalkyl, ring is azetidine, pyrrolidine, piperidine, or azepane; R 12 is selected from:

[0135]

[0136] The ring can have 1, 2, or 3 R 13 groups, where each R 13 is independently selected from -H, C1-C3alkyl, and -CF3. Two R 13 groups can be joined to form a cyclopropyl or cyclobutyl ring; W4is selected from -CH2-, -CH2CH2-, R8and R8' are independently selected from -H, -F, C1-C5alkyl (including cycloalkyl), and -CF3; R9is independently selected from -H, C1-C6alkyl, or cycloalkyl, or R9and R9' together with the atoms to which they are attached form a (substituted) C3-C6cycloalkyl or (substituted) C3-C6heterocycloalkyl ring; R 10 is selected from -H, C1-C7alkyl (including cycloalkyl and methylcycloalkyl), R 11 is selected from H, C1-C7alkyl (including cycloalkyl and methylcycloalkyl).

[0137] Accordingly, the disclosed compounds are not only potent inhibitors of NLRP3 inflammasome or IL-1β secretion, but also have structural elements that contribute to enhance the safety of the drug or to enhance the therapeutic utility by improving physicochemical properties.

[0138] Definitions

[0139] For purposes of this disclosure, the following terms shall have the following definitions unless otherwise indicated.

[0140] “a” and “an” are used herein to refer to one or more than one (e.g., at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0141] “and / or” is used herein to mean “and”, “or”, or both, unless otherwise indicated.

[0142] As used herein, "about" refers to the variation that may be seen when measurements are made on different instruments, samples, and sample preparations.

[0143] As used herein, "administering," "giving," or "administering" refers to 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 a compound or a pharmaceutically acceptable salt of a compound, or a composition thereof, to a subject, which can form an equivalent amount of active compound in the subject and the body.

[0144] "Alkyl" refers to a straight or branched saturated aliphatic group. The number of carbon atoms present in an alkyl group can be specified by indicating the number of carbon atoms in the group (e.g., a C3 alkyl group contains three carbon atoms). The length range of an alkyl group can be specified by indicating a range of carbon atoms (e.g., C1-C3 alkyl or (C1-C3)alkyl or C 1-3 Alkyl refers to an alkyl group having 1 to 3 carbon atoms. 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, etc. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, butyl, pentyl, 1-methylbutyl (i.e., 2-pentyl), 1-ethylpropyl (i.e., 3-pentyl), 3-methylpentyl, etc. Alkyl groups can include any number of carbon atoms, such as 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6. Alkyl groups are typically monovalent, but may also be divalent, such as when an alkyl group links two moieties together. It should be understood that "alkyl" includes alkylene groups when the two functional groups are linked by a straight or branched saturated aliphatic diradical. As with other groups and substituents, this group may be optionally substituted with other groups.

[0145] "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 groups can include ethers, thioethers, alkylamines, and alkylthiols. Heteroalkyl groups are typically monovalent, but can also be divalent or multivalent, such as when a heteroalkyl group connects two or more moieties together. It should be understood that when two functional groups are connected through a heteroalkyl group, the term "heteroalkyl" includes heteroalkylene groups. Consistent with other groups and substituents, this group may optionally be substituted with other groups.

[0146] "Cycloalkyl" or "carbocyclyl" refers to a cyclic hydrocarbon radical containing 3 to 12, 3 to 10, 3 to 8, or 3 to 7 carbon atoms in the ring. Cycloalkyl includes fused, bridged, and spirocyclic structures. Where a cycloalkyl can have a range of lengths, the range of lengths can be indicated by the number of carbon atoms present in the cycloalkyl (e.g., a 3 to 10 membered cycloalkyl ring, C3-C10, or (C3-C10)). 10 )cycloalkyl or C 3-10 Cycloalkyl represents a cycloalkyl containing 3 to 10 carbon atoms) and is specified. Examples include cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl and dimethylcyclohexyl. Cycloalkyl can be substituted alternatively. Cycloalkyl can include a spirocycle, such as the non-limiting examples of spiro[4.5]decane. Consistent with other groups and substituents, this group can be substituted alternatively by other groups.

[0147] "Heterocycle" refers to a ring system having 3 to about 20 ring members and 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)-, -S(O)2-, or -N-OH, -N + -O-. For example, heterocycle includes but is not limited to tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, morpholinyl, 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 optionally substituted with other groups.

[0148] "Heterocycloalkyl" refers to a group of cyclic compounds characterized by having at least one non-carbon atom in the ring structure, such as nitrogen, oxygen, or sulfur. Heterocycloalkyl groups can occur in various forms, including monocyclic, bicyclic, and spirocyclic configurations. Monocyclic heterocycloalkyl groups have a single ring containing one or more heteroatoms. Examples include pyrrolidine (which has a five-membered ring containing a nitrogen atom), tetrahydrofuran (THF), which has a five-membered ring containing oxygen, and thiazane (which has a sulfur atom in its five-membered ring). Bicyclic heterocycloalkyl groups have two connected rings, both of which can be heterocyclic or a combination of heterocyclic and carbocyclic (all-carbon) rings. Spirocyclic heterocycloalkyl groups are compounds in which two or more rings are connected by a common atom, usually a quaternary carbon, called a spiro atom. An example is spiro[4.5]decane-7,9'-dione, in which the five-membered lactone ring and the six-membered ketone ring share a carbon atom. Spiropiperidine has a piperidine ring connected to another cyclic structure through a shared spiro atom. Consistent with other groups and substituents, this group may be optionally substituted with other groups.

[0149] "Alkoxy" refers to a straight or branched chain saturated or unsaturated (fully or partially unsaturated) hydrocarbon containing 1-12 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, propyloxy, butyloxy, t-butyloxy, or pentyloxy. In one embodiment, the "alkoxy" is fully saturated. Consistent with other groups and substituents, the group can optionally be substituted with other groups.

[0150] "Alkoxyalkoxy" refers to an alkoxy group as defined herein substituted with an alkoxy group, e.g., -O(alkyl)-O-(alkyl). Examples of alkoxyalkoxy groups include, but are not limited to, methoxymethoxy, ethoxyethoxy, propyloxymethoxy, or ethoxymethoxy. Consistent with other groups and substituents, the group can optionally be substituted with other groups.

[0151] "Alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of the alkenyl group can be unconjugated or conjugated with another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. The alkenyl group can be unsubstituted or substituted. The alkenyl groups defined herein can be straight or branched. It is understood that the alkenyl group, as defined herein, can be a pure geometric isomer, e.g., pure (E) isomer or pure (Z) isomer, or a mixture of geometric isomers, e.g., (E) / (Z) isomers, also known as trans / cis isomers, in any proportion. Consistent with other groups and substituents, the group can optionally be substituted with other groups.

[0152] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, or hexynyl. The alkynyl group can be unsubstituted or substituted. Consistent with other groups and substituents, the group can optionally be substituted with other groups.

[0153] "Aryl" refers to a monocyclic or fused bicyclic, tricyclic, and polycyclic aromatic ring system containing 6 to 16 ring carbon atoms. For example, aryl can be phenyl, benzyl, or naphthyl, preferably phenyl. "Arylene" refers to a divalent radical derived from an aryl group. The aryl group can be mono-, di-, tri-, or higher-substituted with one, two, three, or more groups selected from alkyl, alkoxy, aryl, hydroxy, halogen, cyano, amino, aminoalkyl, trifluoromethyl, alkylene dioxy, and oxo-C2-C3-alkylene; all of which groups are optionally further substituted, e.g., as defined previously; or 1- or 2-naphthyl; or 1- or 2-phenanthryl. Consistent with other groups and substituents, the group can optionally be substituted with other groups.

[0154] "Heteroatom" means a non-carbon atom and is part of a contiguous ring structure of a cyclic compound or a contiguous structure of a straight chain or branched chain compound. Consistent with other groups and substituents, the group can optionally be substituted with other groups.

[0155] "Heteroaryl" means a monocyclic or fused bicyclic, tricyclic aromatic ring system containing 5 to 16 ring atoms, of which 1 to 4 ring atoms are heteroatoms independently selected from nitrogen (N), oxygen (O) and sulfur (S). Non-limiting examples of heteroaryl groups include pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiophenyl, or any other group substituted (particularly mono- or di-substituted) with, for example, alkyl, nitro, or halogen. Pyridyl means 2-, 3-, or 4-pyridyl, preferably 2- or 3-pyridyl. Thiophenyl means 2- or 3-thiophenyl. Quinolinyl preferably means 2-, 3-, or 4-quinolinyl. Isoquinolinyl preferably means 1-, 3-, or 4-isoquinolinyl. Benzopyranyl, benzothiopyranyl preferably means 3-benzopyranyl or 3-benzothiopyranyl, respectively. Thiazolyl preferably means 2- or 4-thiazolyl, most preferably 4-thiazolyl. Triazolyl preferably is 1-, 2-, or 5-(1,2,4-triazolyl). Tetrazolyl preferably is 5-tetrazolyl. Consistent with other groups and substituents, the group can optionally be substituted with other groups.

[0156] The substituents for cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are numerous and selected from the following groups: halogen, -OR', -OC(0)R', -NR'R", -NR'OH, -NR'OR", -N + R'R"-O-, -SR', -R', -CN, -NC, -N02, -C02R', -CONR'R", -C(0)R', -OC(0)NR'R", -NR"C(0)R', -NR"C(0)2R', -NR'-C(0)NR"R"', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -N +(-O-)(=CR'R"), -S(O)R', -S(O)2R', -S(O)2NR'R", -N3, -CH(Ph)2, perfluoro(Ci-C4)alkoxy, and perfluoro(Ci-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; wherein R', R", and R'" are independently selected from hydrogen, (Ci-C8)alkyl, and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(Ci-C4)alkyl, and (unsubstituted aryl)oxy-(Ci-C4)alkyl. Non-limiting examples of substituents consistent with the present disclosure can be substituted on the groups of the specification.

[0157] As used herein, "carrier" includes carriers, excipients, and diluents, and refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical from one organ, or portion of the body, to another organ, or portion of the body.

[0158] As used herein, "compound" refers not only to the specified molecular entity, but also to the pharmaceutically acceptable, pharmacologically active derivatives thereof, including, but not limited to, salts, prodrugs, metabolites, hydrates, solvates, and the like.

[0159] As used herein, "composition" refers to a mixture of substances suitable for administration to a test subject or individual that includes a pharmaceutical agent. In some embodiments, the test subject is a mammal. In some embodiments, the test subject is a human.

[0160] As used herein, "cyano" refers to a substituent having a carbon atom connected to a nitrogen atom by a triple bond, e.g., -C≡N.

[0161] As used herein, "disorder" refers to a condition that is the same as "disease," "disorder," or "condition," and can be used synonymously with these terms, unless otherwise indicated.

[0162] "Halo" or "halogen" means fluorine, chlorine, bromine, or iodine.

[0163] As used herein, "haloalkyl" refers to an alkyl group, as defined herein, optionally substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like. In one embodiment, the "haloalkyl" is fully saturated. In embodiments where the haloalkyl is chiral, such as, but not limited to, -CH(X)-CH3, -CH2-CH(X)-CH3, and the like, wherein X is a halogen atom, all possible stereoisomers are included. This group can optionally be substituted with other groups, consistent with other groups and substituents.

[0164] As used herein, "haloalkoxy" refers to an alkoxy group, as defined herein, substituted with one or more halogen. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like. In one embodiment, the "haloalkoxy" is fully saturated. This group can optionally be substituted with other groups, consistent with the other groups and substituents described herein.

[0165] "Heteroalkyl" refers to an alkyl group, as defined herein, wherein one or more carbon atoms are replaced with a heteroatom. Examples of heteroalkyl groups include, but are not limited to, -CH2-O-CH3, -CH2-NH-CH3, and the like. In one embodiment, the "heteroalkyl" is fully saturated. This group can optionally be substituted with other groups, consistent with the other groups and substituents described herein.

[0166] "Isomer" refers to certain compounds in the disclosure that have asymmetrically substituted carbon atoms (chiral centers) or double bonds; racemates, diastereomers, atropisomers, geometric isomers, and individual isomers (e.g., individual enantiomers). All of these are included under the term "isomer" within the scope of the present disclosure.

[0167] "Optionally substituted" is understood to mean that a particular chemical group (e.g., alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, aryl, or heteroaryl) can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, aryl, or heteroaryl group can have a substituent other than hydrogen. For example, it can be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any position on the chain. Thus, the term "optionally substituted" means that the particular chemical group has the potential to contain other functional groups, but need not necessarily have any additional functional groups. Suitable substituents for the above groups optionally substituted include, but are not limited to: halogen, oxo, -OH, -CN, -COOH, -CH2CN, -0-(Ci-C6)alkyl, (Ci-C6)alkyl, (Ci-C6)alkenyl, (Ci-C6)alkynyl, (Ci-C6)hydroxyalkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (C3-C7)cycloalkyl, aryl, heterocycloalkyl, heteroaryl, -0-(C2-C6)alkenyl, -0-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OP(O)(OH)2, -OC(O)(Ci-C6)alkyl, -C(O)(Ci-C6)alkyl, -OC(O)O(Ci-C6)alkyl, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -NHC(O)(Ci-C6)alkyl, -C(O)NH(Ci-C6)alkyl, -S(O)2(Ci-C6)alkyl, -S(O)2NH(Ci-C6)alkyl, and S(O)2N((Ci-C6)alkyl)2. "Optionally substituted" as used herein also means substituted or unsubstituted, as described below.

[0168] "Substituted" means that the specified group or moiety bears one or more suitable substituents, where the substituents can be attached to the specified group or moiety at one or more positions. For example, an aryl group substituted with a cycloalkyl group can mean that the cycloalkyl group is attached to an atom of the aryl group through a bond, or through being fused to the aryl group and sharing two or more shared atoms.

[0169] "Unsubstituted" means that the specified group bears no substituents.

[0170] "Oxo" as used herein means a "=0" group.

[0171] "Patient" or "subject in need thereof means a living organism that has or is susceptible to a disease that can be prevented or treated by administration of a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, and other non-mammals.

[0172] “Pharmaceutically acceptable composition” or “pharmaceutical composition” refers to a composition comprising a compound of the disclosure and one or more pharmaceutically acceptable excipients.

[0173] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to an excipient that can be included in the compositions of the disclosure and that does not produce an adverse, toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s solution, normal sucrose, normal glucose, and the like.

[0174] “Prodrug” is a drug or compound that, upon administration, is metabolized (i.e., converted in vivo, including but not limited to in a mammal or human, into) a drug that is pharmacologically active. Rather than administering the drug directly, a corresponding prodrug can be used, for example, but not limited to, to improve the manner in which the drug is absorbed, distributed, metabolized, and excreted, or to improve the selectivity of the drug when it interacts with cells or processes that are not the intended target. The term “prodrug” encompasses a subset of polymeric prodrugs in which an active drug is attached (typically by a covalent bond) to a polymer chain to form a macromolecular carrier system. In some examples, the polymer can improve the solubility and stability of the drug, provide a controlled and / or sustained release mechanism, and can be designed to target the delivery of the drug to a particular tissue, cell, or receptor. The bond between the drug and the polymer is typically cleavable, and will break down under specific physiological conditions to release the active drug at the desired site of action.

[0175] “Salt” includes, but is not limited to, acid addition salts, including hydrochloride, hydrobromide, phosphate, sulphate, bisulphate, alkylsulphonate, arylsulphonate, acetate, benzoate, citrate, maleate, fumarate, formate, succinate, lactate, and tartrate; alkali metal cation salts such as Na + , K + , Li+salts or alkaline earth metal salts such as Mg 2+ or Ca 2+Salts. Pharmaceutically acceptable salts of ionizable pharmaceutical compounds are well known in the art, including 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, P. H. and Wermuth, C. M., Editors), Wiley-VCH, 2011, Germany, both of which are incorporated by reference in their entireties herein.

[0176] “Solvate” refers to a complex of variable stoichiometry formed from a solute and solvent. For the purpose of this disclosure, such a solvent can 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 wherein water is the solvent molecule are typically known as hydrates. Hydrates include compositions that contain a stoichiometric amount of water, as well as compositions that contain variable amounts of water.

[0177] “Spiroalkyl” or “spirocyclyl” refers to a carbocyclic bicyclic ring system formed by two rings connected through a single atom. The rings can differ in length and nature or be identical in length and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. Either one or both of the rings in the spirocycle can be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spirocycle can be replaced by a heteroatom (e.g., O, N, S, or P). (C3-C 12 )spiroalkyl refers to a spirocycle comprising 3 to 12 carbon atoms. One or more carbon atoms can be replaced by a heteroatom. In one embodiment, “spiroalkyl” or “spirocyclyl” is fully saturated. The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood to refer to a spirocycle in which at least one ring is a heterocyclic ring (e.g., at least one ring is furanyl, morpholinyl, or piperidinyl). In one embodiment, “spiroheterocycloalkyl” or “spiroheterocyclyl” is fully saturated.

[0178] “Therapeutically effective amount” refers to the amount of a biologically active agent or pharmaceutical composition that can be used for treatment, amelioration, or prevention of a particular disease or disorder, or for producing a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art.

[0179] “Treatment” of a subject refers to ameliorating at least one symptom of a subject’s condition. Treatment includes curing, ameliorating, or at least partially ameliorating a condition.

[0180] Compounds

[0181] Provided herein are compounds capable of inhibiting NLRP3 family proteins and NLRP3 inflammasome function and inhibiting IL-1β secretion. Various embodiments of these compounds include 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) described herein, or a pharmaceutically acceptable salt, solvate, epimer, N-oxide, or tautomer thereof.

[0182] 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.

[0183] The present disclosure provides a compound represented by the structure of Formula (1-I):

[0184]

[0185] wherein ring 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; wherein W is selected from -NH, N-Me, N-Et, and N-iPr, or is a single bond (when W is a single bond, ring through ring wherein the thiophene ring is formed by the thiophene group and the thiophene group is directly connected to the carbonyl group by the embedded nitrogen atom to form an amide, and wherein R1 is selected from -CN, -H, -F, -CF3, or can form a thiophene ring with R1' (forming benzothiophene in which the sulfur atom is connected to the carbon atom carrying R1); R1' is -H, or can form a thiophene ring with R1 (forming benzothiophene in which the sulfur atom is connected to the carbon atom carrying R1); R2 is selected from -H, C1-C3 alkyl, -CF3, or forms a ring with R3, which is a 5-membered or 6-membered aromatic ring or non-aromatic ring, the ring is a full carbon ring or contains O or N in the ring, and each C atom or N atom in the 5-membered or 6-membered aromatic ring or non-aromatic ring is optionally substituted by -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or forms a ring with R2, which is a 5-membered or 6-membered aromatic ring or non-aromatic ring. an aromatic or non-aromatic ring, the ring being an all-carbon ring or containing O or N within the ring, and each C atom or N atom in the 5-membered or 6-membered aromatic or non-aromatic ring is optionally substituted by -Me or -OH; Y is a single bond (when Y is a single bond, -OH is directly attached to the ring) or Y is a C1-C3 alkyl group, optionally substituted by 1, 2 or 3 C1-C3 alkyl groups or -CF3; R4 is selected from -H, -F, C1-C3 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 atoms to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 1, 2, 3 and 4.

[0186] In some embodiments, R4 exists in the form of hydrogen, or is not present in the ring. In some embodiments, R4 exists and is substituted as described above at any position of the ring. In some embodiments, R4 exists twice and is substituted as described above at any position of the ring. In some embodiments, R4 exists three times, four times, five times, or six times and is substituted as described above at any position of the ring.

[0187] In some embodiments, R1 and R1' together form a thiophene ring (which then, together with the ring to which R1 and R1' are attached, forms a benzothiophene). For this structure, there may be at least two isomeric thiophenes, one in which S is attached to the carbon atom bearing R1 and one in which S is attached to the carbon atom bearing R1'. In some embodiments, a preferred benzothiophene substructure may have a sulfur atom attached to the carbon atom bearing R1.

[0188] In some embodiments, the compound of formula (I-I) is further represented by any of the following:

[0189]

[0190]

[0191] In some embodiments, the compound of formula (1-I) is further represented by any one of:

[0192]

[0193] In some embodiments, the compound of formula (1-I) is further represented by any one of:

[0194]

[0195]

[0196] The present disclosure also provides a compound as shown in the structure of formula (1-II):

[0197]

[0198] wherein the ring is a 4-11 membered nitrogen-containing heterocycloalkyl ring and substituted heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl and substituted spirocyclic and bicyclic nitrogen-containing heterocycloalkyl ring; and R1is selected from -CN, -H, -F, -CF3; or can form a thiophene ring with R1'(forming a benzothiophene, wherein the sulfur atom is attached to the carbon atom bearing R1); R1'is -H, or can form a thiophene ring with R1'(forming a benzothiophene, wherein the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3 alkyl, -CF3, or forms a ring with R3, which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R3is selected from -H, C1-C3 alkyl, -CF3, or forms a ring with R2, which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a single bond (when Y is a single 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; R5is selected from -H, -Me, and -CF3; R6and R6'are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6and 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.

[0199] In some embodiments, R4is present and substituted as described above at any position on the ring. In some embodiments, R4is present twice and substituted as described above at any position on the ring. In some embodiments, R4is present three, four, five, or six times and substituted as described above at any position on the ring.

[0200] In some embodiments, R1and R1' together form a thiophene ring (which together with the ring to which R1and R1' are attached constitutes a benzothiophene). There can be at least two isomeric thiophenes for this structure, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0201] In some embodiments, the compound of formula (1-II) is further represented by any one of:

[0202]

[0203] In some embodiments, the compound of formula (1-II) is further represented by any one of:

[0204]

[0205] The present disclosure also provides a compound as shown in the structure of formula (1-III):

[0206]

[0207] wherein the ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring and substituted heterocycloalkyl ring, including spirocyclic nitrogen-containing heterocycloalkyl and substituted spirocyclic nitrogen-containing heterocycloalkyl ring; wherein the ring R1is selected from -CN, -H, -F, -CF3, or can be taken together with R1' to form a thiophene ring (forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1' is -H, or can be taken together with R1to form a thiophene ring (forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3alkyl, -CF3, or taken together with R3to form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R3is selected from -H, C1-C3alkyl, -CF3, or taken together with R2to form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3alkyl, and -CF3; Y is a single bond (when Y is a single bond, -OH is directly attached to the ring) or Y is C1-C3alkyl optionally substituted with 1, 2, or 3 C1-C3alkyl or -CF3; R5is selected from -H, -Me, and -CF3.

[0208] In some embodiments, R4is present as hydrogen, or is absent from the ring. In some embodiments, R4is present and substituted as described above at any position on the ring. In some embodiments, R4is present twice and substituted as described above at any position on the ring. In some embodiments, R4is present three, four, five, or six times and substituted as described above at any position on the ring.

[0209] In some embodiments, R1and R1'taken together form a thiophene ring (which, together with the ring to which R1and R1'are attached, constitutes a benzothiophene). There can be at least two isomeric thiophenes for this structure, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0210] In some embodiments, the compound of Formula (1-III) is further represented by any one of:

[0211]

[0212] The present disclosure also provides a compound as shown in the structure of Formula (1-IV):

[0213]

[0214] wherein the ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring and a substituted heterocycloalkyl ring, including a spiro nitrogen-containing heterocycloalkyl ring and a substituted spiro nitrogen-containing heterocycloalkyl ring; wherein the ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring, a substituted heterocycloalkyl ring, including a spiro nitrogen-containing heterocycloalkyl ring and a substituted spiro nitrogen-containing heterocycloalkyl ring; and R1 is selected from -CN, -H, -F, -CF3, or can form a thiophene ring with R1' (forming benzothiophene, wherein the sulfur atom is connected to the carbon atom carrying R1); R1' is -H, or can form a thiophene ring with R1 (forming benzothiophene, wherein the sulfur atom is connected to the carbon atom carrying R1); R2 is selected from -H, C1-C3 alkyl, -CF3, or forms a ring with R3, which is a 5-membered or 6-membered aromatic ring or a non-aromatic ring, the ring is a full carbon ring or contains O or N in the ring, and the 5-membered or 6-membered aromatic ring or non-aromatic ring Each C atom or N atom in the aromatic ring is optionally replaced by -Me or -OH; R3 is selected from -H, C1-C3 alkyl, -CF3, or forms a ring together with R2, which is a 5-membered or 6-membered aromatic ring or non-aromatic ring, the ring is a full carbon ring or contains O or N in the ring, and each C atom or N atom in the 5-membered or 6-membered aromatic ring or non-aromatic ring is optionally replaced by -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a single bond (when Y is a single bond, -OH is directly connected to the ring) or Y is C1-C3 alkyl, optionally substituted by 1, 2 or 3 C1-C3 alkyl or -CF3; R5 is selected from -H, -Me, and -CF3.

[0215] In some embodiments, R4 exists in the form of hydrogen, or is not present in the ring. In some embodiments, R4 exists and is substituted as described above at any position of the ring. In some embodiments, R4 exists twice and is substituted as described above at any position of the ring. In some embodiments, R4 exists three times, four times, five times, or six times and is substituted as described above at any position of the ring.

[0216] In some embodiments, R1 and R1' together form a thiophene ring (which, together with the ring to which R1 and R1' are attached, subsequently forms a benzothiophene). For this structure, there may be at least two isomeric thiophenes, one in which S is attached to the carbon atom bearing R1 and one in which S is attached to the carbon atom bearing R1'. In some embodiments, a preferred benzothiophene substructure may have a sulfur atom attached to the carbon atom bearing R1.

[0217] In some embodiments, the compound of formula (I-IV) is further represented by any of the following:

[0218]

[0219] The present disclosure also provides a compound represented by the structure of formula (I-V):

[0220]

[0221] Among them, the ring is a 4-11 membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spiro and bicyclic cycloalkyl, substituted spiro and bicyclic cycloalkyl rings, spiro and bicyclic heterocycloalkyl, and substituted spiro and bicyclic heterocycloalkyl rings; wherein W is selected from -NH, N-Me, N-Et, and N-iPr, or W is a single bond (when W is a single bond, the ring Through the ring and R1 is selected from -CN, -H, -F, -CF3, or can form a thiophene ring with R1' (forming benzothiophene, wherein the sulfur atom is connected to the carbon atom carrying R1); R1' is -H, or can form a thiophene ring with R1 (forming benzothiophene, wherein the sulfur atom is connected to the carbon atom carrying R1); R2 is selected from -H, C1-C3 alkyl, -CF3; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a single bond (when Y is a single bond, -OH is directly attached to the ring) or Y is C1-C3 alkyl, optionally substituted by 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 atoms to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 1, 2, 3 and 4.

[0222] In some embodiments, R4 exists in the form of hydrogen, or is not present in the ring. In some embodiments, R4 exists and is substituted as described above at any position of the ring. In some embodiments, R4 exists twice and is substituted as described above at any position of the ring. In some embodiments, R4 exists three times, four times, five times, or six times and is substituted as described above at any position of the ring.

[0223] In some embodiments, R1 and R1' together form a thiophene ring (which, together with the ring to which R1 and R1' are attached, subsequently forms a benzothiophene). For this structure, there may be at least two isomeric thiophenes, one in which S is attached to the carbon atom bearing R1 and one in which S is attached to the carbon atom bearing R1'. In some embodiments, a preferred benzothiophene substructure may have a sulfur atom attached to the carbon atom bearing R1.

[0224] In some embodiments, the compound of formula (I-V) is further represented by any of the following:

[0225]

[0226] The present disclosure also provides a compound as shown in the structure of Formula (1-VI):

[0227]

[0228] wherein the ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring and a substituted nitrogen-containing heterocycloalkyl ring, including a spirocyclic nitrogen-containing heterocycloalkyl ring and a substituted spirocyclic nitrogen-containing heterocycloalkyl ring; wherein the ring is a 4-7 membered cycloalkyl ring and a substituted cycloalkyl ring, including a spirocyclic ring and a substituted spirocyclic ring; and R1is selected from -CN, -H, -F, -CF3, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1'is -H, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3alkyl, -CF3; R4is selected from -H, -F, C1-C3alkyl, and -CF3; Y is a single bond (when Y is a single bond, -OH is directly attached to the ring) or Y is C1-C3alkyl, optionally substituted with 1, 2, or 3 C1-C3alkyl or -CF3; R5is selected from -H, -Me, and -CF3.

[0229] In some embodiments, R4is present as hydrogen, or is absent from the ring. In some embodiments, R4is present and substituted at any position on the ring as described above. In some embodiments, R4is present twice and substituted at any position on the ring as described above. In some embodiments, R4is present three times, four times, five times, or six times and substituted at any position on the ring as described above.

[0230] In some embodiments, R1and R1'form a thiophene ring together (which then, along with the ring to which R1and R1'are attached, constitutes a benzothiophene). For this structure, there can be at least two isomeric thiophenes, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0231] In some embodiments, the compound of Formula (1-VI) is further represented by any one of:

[0232]

[0233] The present disclosure also provides a compound as shown in the structure of Formula (1-VII):

[0234]

[0235] wherein the ring R1is selected from -H, -F, -CN, -CF3, or can form a thienyl ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1'is -H, or can form a thienyl ring with R1(forrning a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3alkyl, -CF3; R4is selected from -H, -F, C1-C3alkyl, and -CF3; Y is a single bond (when Y is a single bond, -OH is directly attached to the ring) or Y is C1-C3alkyl, optionally substituted with 1, 2, or 3 C1-C3alkyl or -CF3; R5is selected from -H, -Me, and -CF3; R6and R6'are independently selected from -H, -F, C1-C6alkyl or cycloalkyl, and -CF3, or R6and R6'together with the atoms to which they are attached form a C1-C6cycloalkyl or C1-C6heterocycloalkyl ring; n is selected from 0, 1, 2, 3, and 4.

[0236] In some embodiments, R4is present as hydrogen, or is absent from the ring. In some embodiments, R4is present and substituted as described above at any position on the ring. In some embodiments, R4is present twice and substituted as described above at any position on the ring. In some embodiments, R4is present three times, four times, five times, or six times and substituted as described above at any position on the ring.

[0237] In some embodiments, R1and R1'together form a thienyl ring (which together with the ring to which R1and R1'are attached constitutes a benzothiophene). There can be at least two isomeric thiophenes for this structure, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0238] In some embodiments, the compound of formula (1-VII) is further represented by any one of:

[0239]

[0240] The present disclosure also provides a compound as shown in the structure of formula (1-VIII):

[0241]

[0242] wherein the ring R1is selected from -H, -F, -CN, -CF3, or R1and R1' together can form a thiophene ring (forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1' is -H, or R1and R1' together can form a thiophene ring (forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3alkyl, -CF3; R4is selected from -H, -F, C1-C3alkyl, and -CF3; Y is a single bond (when Y is a single bond, -OH is directly attached to the ring) or Y is C1-C3alkyl optionally substituted with 1, 2, or 3 C1-C3alkyl or -CF3; R5is selected from -H, -Me, and -CF3; R6and R6' are independently selected from -H, -F, C1-C6alkyl, and -CF3, or R6and R6' together with the atoms to which they are attached form a C1-C6cycloalkyl or C1-C6heterocycloalkyl ring; n is selected from 1, 2, 3, and 4.

[0243] In some embodiments, R4is present as hydrogen, or is absent from the ring. In some embodiments, R4is present and substituted as described above at any position on the ring. In some embodiments, R4is present twice and substituted as described above at any position on the ring. In some embodiments, R4is present three times, four times, five times, or six times and substituted as described above at any position on the ring.

[0244] In some embodiments, R1and R1'together form a thiophene ring (which together with the ring to which R1and R1'are attached constitutes a benzothiophene). There can be at least two isomeric thiophenes for this structure, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0245] In some embodiments, the compound of formula (1-VIII) is further represented by any one of:

[0246]

[0247] The present disclosure also provides a compound as shown in the structure of formula (1-IX):

[0248]

[0249] wherein the ring R1is selected from -CN, -H, -F, -CF3; or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1'is H, or can form a thiophene ring with R1(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from H, C1-C3 alkyl, -CF3, or forms a ring with R3, which is a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon or contains O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R3is selected from H, C1-C3 alkyl, -CF3, or forms a ring with R2, which is a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon or contains O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R4is selected from H, -F, C1-C3 alkyl, and -CF3; R5is selected from -H, -Me, and -CF3; R5is selected from -H, -Me, and -CF3; R6and R6'are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6and R6'form, together with the atom to which they are attached, a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 2, 3, and 4; Y is a single bond (when Y is a single 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.

[0250] In some embodiments, R4is present as hydrogen, or is absent from the ring. In some embodiments, R4is present and substituted at any position on the ring as described above. In some embodiments, R4is present twice and substituted at any position on the ring as described above. In some embodiments, R4is present three times, four times, five times, or six times and substituted at any position on the ring as described above.

[0251] In some embodiments, R1and R1'form a thiophene ring together (which then constitutes a benzothiophene with the ring to which R1and R1'are attached). For this structure, there can be at least two isomeric thiophenes, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0252] In some embodiments, the compound of formula (1-IX) is further represented by any one of:

[0253]

[0254] The present disclosure provides compounds represented by the structure of formula (2-I):

[0255]

[0256] wherein ring is a 4-11 membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spiro and bicyclic cycloalkyl, substituted spiro and bicyclic cycloalkyl, spiro and bicyclic heterocycloalkyl, and substituted spiro and bicyclic heterocycloalkyl; wherein W is selected from -NH, N-Me, N-Et, and N-iPr, or is a single bond; when W is a single bond, the carbonyl (C=0) is bonded to the nitrogen atom within ring , together forming an amide bond; R1is selected from -CN, -H, -F, -CF3, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1'is -H, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3 alkyl, -CF3, or together with R3forms a ring that is a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon or contains O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R3is selected from -H, C1-C3 alkyl, -CF3, or together with R2forms a ring that is a 5- or 6-membered aromatic or non-aromatic ring, which is all carbon or contains O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a single bond (when Y is a single 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; R5is selected from -H, -Me, and -CF3; R6and R6'are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6and 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; R7is selected from -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl,

[0257] In some aspects of formula (2-I), ring is a 4-11 membered ring selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl, including spiro and bicyclic cycloalkyl, substituted spiro and bicyclic cycloalkyl, spiro and bicyclic heterocycloalkyl, and substituted spiro and bicyclic heterocycloalkyl; wherein W is selected from NH, N-Me, or is a single bond; when W is a single bond, the carbonyl (C=0) is bonded to the nitrogen atom within ring the nitrogen atom within, together forming an amide bond; R1is selected from -F, -CF3; R1' is -H; R2is selected from -H, -Me, -CF3, or together with R3forms a ring which is a 5- or 6-membered non-aromatic ring, said ring being an all-carbocyclic ring or containing O within the ring; R3is selected from -H, -Me, or together with R2forms a ring which is a 5- or 6-membered non-aromatic ring, said ring being an all-carbocyclic ring or containing O within the ring; R4is -H; Y is a single bond; R5is selected from -H and -Me; R6and R6' are -H; n is 1; R7is -H.

[0258] In some embodiments, R4is present as hydrogen or is absent from the ring. In some embodiments, R4is present and is substituted as described above at any position on the ring. In some embodiments, R4is present twice and is substituted as described above at any position on the ring. In some embodiments, R4is present three, four, five, or six times and is substituted as described above at any position on the ring.

[0259] In some embodiments, R1and R1'together form a thiophene ring (which together with the ring to which R1and R1'are attached constitutes a benzothiophene). For this structure, there can be at least two isomeric thiophenes, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0260] In some embodiments, the compound of formula (2-I) is further represented by any one of:

[0261]

[0262] The present disclosure also provides a compound as shown in the structure of formula (2-II):

[0263]

[0264] wherein the ring 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; wherein W is selected from NH, N-Me, N-Et, and N-iPr, or is a single bond; when W is a single bond, the carbonyl (C=O) is bonded to the ring the nitrogen atom within the ring to form an amide bond; R1is selected from -CN, -H, -F, -CF3, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1'is H, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3 alkyl, -CF3, or together with R3forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R3is selected from -H, C1-C3 alkyl, -CF3, or together with R2forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3 alkyl, and -CF3; R5is selected from -H, -Me, and -CF3; R6and R6'are independently selected from -H, -F, C1-C6 alkyl or cycloalkyl, and -CF3, or R6and R6' together with the atoms to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; n is selected from 1, 2, 3, and 4.

[0265] In some aspects of Formula (2-II), the ring is a 4-11 membered nitrogen-containing heterocycloalkyl ring, including spirocyclic and bicyclic nitrogen-containing heterocycloalkyl rings; wherein W is selected from NH, N-Me, or is a single bond; when W is a single bond, the carbonyl (C=0) is bonded to the nitrogen atom within the ring to form an amide bond; R1is selected from -F, -CF3; R1'is -H; R2is selected from -H, -Me, -CF3, or together with R3forms a ring which is a 5- or 6-membered non-aromatic ring, the ring being all carbon or containing O within the ring; R3is selected from -H, -Me, or together with R2forms a ring which is a 5- or 6-membered non-aromatic ring, the ring being all carbon or containing O within the ring; R4is -H or -Me; R5is selected from -H and -Me; R6and R6'are -H; n is 1. In some embodiments, R4is present in the form of hydrogen, or is absent from the ring. In some embodiments, R4is present and substituted at any position on the ring as described above. In some embodiments, R4is present twice and substituted at any position on the ring as described above. In some embodiments, R4is present three, four, five, or six times and substituted at any position on the ring as described above.

[0266]

[0267] ​In some embodiments, R1and R1' together form a thiophene ring (which together with the ring to which R1and R1' are attached constitutes a benzothiophene). For this structure, there can be at least two isomeric thiophenes, one in which the S is attached to the carbon atom bearing R1and one in which the S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0268] In some embodiments, the compound of formula (2-II) is further represented by any one of:

[0269]

[0270] The present disclosure also provides a compound as shown in the structure of formula (2-III):

[0271]

[0272] wherein the ring is a 4-11 membered ring selected from heterocycloalkyl or substituted heterocycloalkyl, including spirocyclic and bicyclic heterocycloalkyl, and substituted spirocyclic and bicyclic heterocycloalkyl; R1is selected from -CN, -H, -F, -CF3, or can together with R1' form a thiophene ring (forming a benzothiophene in which the sulfur atom is attached to the carbon atom bearing R1); R1' is -H, or can together with R1form a thiophene ring (forming a benzothiophene in which the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3alkyl, -CF3, or together with R3forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring being optionally substituted with -Me or -OH; R3is selected from -H, C1-C3alkyl, -CF3, or together with R2forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring being optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3alkyl, and -CF3; Y is a single bond (when Y is a single bond, -NH can be directly attached to the ring; similarly, when Y is a single bond, -NH-R7may be directly attached to the ring) or Y is C1-C3alkyl, optionally substituted with 1, 2, or 3 C1-C3alkyl or -CF3; R5is selected from -H, -Me, and -CF3; and wherein W2is selected from -CH2-, -CH2CH2-, and -CH2CH2CH2-, optionally substituted, or is a single bond.

[0273] In some aspects of formula (2-III), the ring R1is selected from -F, -CF3; R1is -H; R2is selected from -H, -Me, -CF3, or together with R3forms a ring which is a 5- or 6-membered non-aromatic ring, said ring being all-carbocyclic or containing O within the ring; R3is selected from -H, -Me, or together with R2forms a ring which is a 5- or 6-membered non-aromatic ring, said ring being all-carbocyclic or containing O within the ring; R4is -H or -Me; R5is selected from -H and -Me.

[0274] In some embodiments, R4is present and substituted as described above at any position on the ring. In some embodiments, R4is present twice and substituted as described above at any position on the ring. In some embodiments, R4is present three, four, five, or six times and substituted as described above at any position on the ring.

[0275] In some embodiments, R1and R1together form a thiophene ring (which together with the ring to which R1and R1are attached constitutes a benzothiophene). For this structure, there can be at least two isomeric thiophenes, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0276] In some embodiments, the compound of formula (2-III) is further represented by any one of:

[0277] In some embodiments, the compound of formula (2-III) is further represented by any one of:

[0278]

[0279] The present disclosure also provides a compound as shown in the structure of formula (2-IV):

[0280]

[0281] wherein the ring R1is selected from -H, -F, -CF3, or can be taken together with R1' to form a thienyl ring (forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1' is -H, or can be taken together with R1to form a thienyl ring (forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3alkyl, -CF3, or taken together with R3to form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R3is selected from -H, C1-C3alkyl, -CF3, or taken together with R2to form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3alkyl, and -CF3; Y is a single bond (when Y is a single bond, -OH is directly attached to the ring) or Y is C1-C3alkyl optionally substituted with 1, 2, or 3 C1-C3alkyl or -CF3; R5is selected from -H, -Me, and -CF3; wherein W3is selected from optionally substituted -CH2-, -CH2CH2-, and -CH2CH2CH2-, or is a single bond; R7is selected from -H, C1-C6alkyl, cycloalkyl, heterocycloalkyl,

[0282] In some aspects of Formula (2-IV), the ring is a 4-9 membered cycloalkyl or heterocycloalkyl ring, wherein W3is selected from -CH2- and -CH2CH2-, or is a single bond; R1is selected from -F and -CF3; R1' is -H; R2is selected from -H, -Me, and -CF3, or taken together with R3to form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R3is selected from -H and -Me, or taken together with R2to form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R4is -H or -Me; Y is a single bond; R5is selected from -H and -Me; R7is -H.

[0283] In some embodiments, R4is present as hydrogen or is absent from the ring. In some embodiments, R4is present and substituted as described above at any position on the ring. In some embodiments, R4is present twice and substituted as described above at any position on the ring. In some embodiments, R4is present three, four, five, or six times and substituted as described above at any position on the ring.

[0284] In some embodiments, R1and R1' together form a thiophene ring (which together with the ring to which R1and R1' are attached constitutes a benzothiophene). For this structure, there can be at least two isomeric thiophenes, one in which the S is attached to the carbon atom bearing R1and one in which the S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0285] In some embodiments, the compound of formula (2-IV) is further represented by any one of:

[0286]

[0287] The present disclosure also provides a compound as shown in the structure of formula (2-V):

[0288]

[0289] wherein the ring is azetidine, pyrrolidine, piperidine, or azepine; R1is selected from -CN, -H, -F, -CF3, or can together with R1' form a thiophene ring (forming a benzothiophene in which the sulfur atom is attached to the carbon atom bearing R1); R1' is -H, or can together with R1form a thiophene ring (forming a benzothiophene in which the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3alkyl, -CF3, or together with R3forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring being optionally substituted with -Me or -OH; R3is selected from -H, C1-C3alkyl, -CF3, or together with R2forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring being optionally substituted with -Me or -OH; R4is selected from -H, -F, C1-C3alkyl, and -CF3; R5is selected from -H, -Me, and -CF3; R 12 is selected from:

[0290]

[0291] wherein m is 1, 2, or 3, and each R 13 is independently selected from -H, C1-C3alkyl, and -CF3. Two R 13 groups can be joined to form a cyclopropyl or cyclobutyl ring.

[0292] In some aspects of formula (2-V), the ring is azetidine or piperidine; R1is selected from -F, -CF3; R1is -H; R2is selected from -H, -Me, and -CF3, or together with R3forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, said ring being all-carbocyclic or containing O within the ring; R3is selected from -H, -Me, or together with R2forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, said ring being all-carbocyclic or containing O within the ring; R4is -H or -Me; R5is selected from -H and -Me; R 12 is selected from

[0293] In some embodiments, R4is present as hydrogen or is absent from the ring. In some embodiments, R4is present and substituted as described above at any position on the ring. In some embodiments, R4is present twice and substituted as described above at any position on the ring. In some embodiments, R4is present three, four, five, or six times and substituted as described above at any position on the ring.

[0294] In some embodiments, R1and R1together form a thiophene ring (which together with the ring to which R1and R1are attached constitutes a benzothiophene). For this structure, there can be at least two isomeric thiophenes, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0295] In some embodiments, the compound of formula (2-V) is further represented by any one of:

[0296]

[0297] The present disclosure also provides a compound as shown in the structure of formula (2-VI):

[0298]

[0299] wherein R1is selected from -CN, -H, -F, -CF3, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R1'is -H, or can form a thiophene ring with R1'(forming a benzothiophene where the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3 alkyl, and -CF3, or together with R3forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R3is selected from -H, C1-C3 alkyl, and -CF3, or together with R2forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R5is selected from -H, -Me, and -CF3; W4is selected from -CH2-, -CH2CH2-, R8and R8'are independently selected from -H, C1-C5 alkyl (including cycloalkyl), and -CF3; R9is selected from -H, C1-C6 alkyl, C1-C6 cycloalkyl, heterocycloalkyl,

[0300] In some aspects of Formula (2-VI), R1is selected from -F, -CF3; R1'is -H; R2is selected from -H, -Me, -CF3, or together with R3forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R3is selected from -H, -Me, or together with R2forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R5is selected from -H and -Me; W4is selected from -CH2- or R8and R8'are -H; n is 1; R9is -H.

[0301] In some aspects of Formula (2-VI), R1is selected from -F, -CF3; R1'is -H; R2is selected from -H, -Me, -CF3, or together with R3forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R3is selected from -H, -Me, or together with R2forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R5is selected from -H and -Me; W4is selected from -CH2- or R8and R8'are -H; n is 1; R9is selected from

[0302] In some embodiments, R1and R1' together form a thiophene ring (which together with the ring to which R1and R1' are attached constitutes a benzothiophene). For this structure, there can be at least two isomeric thiophenes, one in which the S is attached to the carbon atom bearing R1and one in which the S is attached to the carbon atom bearing R1'. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0303] In some embodiments, the compound of formula (2-VI) is further represented by any one of:

[0304]

[0305] In some embodiments, the compound of formula (2-VI) is further represented by any one of:

[0306]

[0307] The present disclosure also provides a compound as shown in the structure of formula (2-VII):

[0308]

[0309] wherein R1is selected from -CN, -H, -F, -CF3, or can together with R1' form a thiophene ring (forming a benzothiophene in which the sulfur atom is attached to the carbon atom bearing R1); R1' is -H, or can together with R1form a thiophene ring (forming a benzothiophene in which the sulfur atom is attached to the carbon atom bearing R1); R2is selected from -H, C1-C3alkyl, -CF3, or together with R3forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R3is selected from -H, C1-C3alkyl, -CF3, or together with R2forms a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O or N within the ring, and each C or N atom in the 5- or 6-membered aromatic or non-aromatic ring is optionally substituted with -Me or -OH; R5is selected from -H, -Me, and -CF3; R6and R6' are independently selected from -H, -F, C1-C6alkyl or cycloalkyl, and -CF3, or R6and R6' together with the atom to which they are attached form a C1-C6cycloalkyl or C1-C6heterocycloalkyl ring; n is selected from 1, 2, 3, and 4; R9and R9' are independently selected from -H, C1-C5alkyl (including cycloalkyl), -CF3; and R9and R9' together with the atom to which they are attached form a (substituted) C3-C6cycloalkyl or (substituted) C3-C6heterocycloalkyl ring; R 10 selected from -H, C1-C7alkyl (including cycloalkyl and methylcycloalkyl), R11 selected from -H, C1-C7 alkyl (including cycloalkyl and methylcycloalkyl).

[0310] In some aspects of Formula (2-VII), R1is selected from -F, -CF3; R1is -H; R2is selected from -H, -Me, -CF3, or R2and R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R3is selected from -H, -Me, or R2and R3together form a ring which is a 5- or 6-membered aromatic or non-aromatic ring, the ring being all carbon or containing O within the ring; R5is selected from -H and -Me; R6and R6are -H; n is 1; R9and R9are -H; R 10 is -H; R 11 is selected from -H or -Me.

[0311] In some embodiments, R1and R1together form a thiophene ring (which together with the ring to which R1and R1are attached constitutes a benzothiophene). For this structure, there can be at least two isomeric thiophenes, where S is attached to the carbon atom bearing R1and where S is attached to the carbon atom bearing R1. In some embodiments, the preferred benzothiophene substructure can have the sulfur atom attached to the carbon atom bearing R1.

[0312] In one embodiment, the compound of Formula (2-VII) is further represented by:

[0313]

[0314] Methods of preparation

[0315] The compounds disclosed herein can be synthesized by the methods described below, or by modifications thereof. Ways of modifying the methodology include, but are not limited to, temperature, solvent, reagents, and the like, which are well known to those skilled in the art and are part of routine reaction modification and optimization. Generally, it can be necessary and / or desirable to protect sensitive or reactive groups of molecules on which the compounds disclosed herein are prepared during their synthesis. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973) and in P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), the entire contents of which are incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage by methods known in the art. Synthetic chemistry transformation methods that can be used to synthesize suitable compounds are known in the art, for example those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989 or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, the entire contents of which are incorporated herein by reference. The routes shown and described herein are merely illustrative examples and are not intended to limit the scope of the claims in any way, nor should they be construed as limiting the scope of the claims in any way. Those skilled in the art will be able to modify the disclosed synthetic methods and devise alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0316] In the following schemes, the choice of oxygen atom protecting group needs to take into account compatibility with the necessary 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)).

[0317] If the compounds of the present technology contain one or more stereocenters, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as stereoisomerically enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present technology unless indicated otherwise. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials, stereoselective reagents or catalysts, which are well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0318] The starting materials used in the following reactions are generally known compounds, commercially available compounds, or can be prepared by known methods or by obvious modifications of known methods. For example, many of the starting materials can be obtained from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Emka-Chemce, or Sigma (St. Louis, MO). Other starting materials can be prepared by methods described in, or modifications of, standard reference texts such as Fieser and Fieser’s Reagents for Organic 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), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0319] As shown in Scheme 1-1, the methods disclosed herein can include the use of standard organic synthesis techniques to build compounds of general formula (A). Ar is an appropriately substituted phenol or a protected phenol (if a protected phenol is used, a deprotection step will be required after amide bond formation). Alternatively, compounds of general formula (A) can be prepared starting from Cl rather than Ar, and the final compound is prepared in the last step by Suzuki coupling with the appropriate Ar-boronic acid. The reagents shown in Scheme 1-1 are commercially available or can be readily synthesized by one skilled in the art using well-known literature methods.

[0320] General Scheme 1-1 shows cyclic secondary amino alcohols, such as substituted or unsubstituted piperidinol, pyrrolidinol, azetidinol, or spirocyclic secondary amino alcohols. However, the same methods can be employed to prepare compounds of the disclosure for primary amino alcohols, such as 4-aminocyclohexanol or 4-aminocyclobutanol.

[0321] Scheme 1-1:

[0322]

[0323] Compounds of general formula (B) can be prepared by General Scheme 1-2. In the first step of Scheme 2, the phenol on Ar can need to be appropriately protected. Alternatively, compounds of general formula (B) can be prepared starting from Cl rather than Ar, and the final compound is prepared in the last step by Suzuki coupling with the appropriate Ar-boronic acid. The reagents shown in Scheme 1-2 are commercially available or can be readily synthesized by one skilled in the art using well-known literature methods.

[0324] Scheme 1-2:

[0325]

[0326] Compounds of general formula (C) can be prepared by General Scheme 1-3. Ar is an appropriately substituted phenol or a protected phenol (if a protected phenol is used, a deprotection step will be required after amide bond formation). Alternatively, compounds of general formula (C) can be prepared starting from Cl rather than Ar, and the final compound is prepared in the last step by Suzuki coupling with the appropriate Ar-boronic acid. The reagents shown in Scheme 1-3 are commercially available or can be readily synthesized by one skilled in the art using well-known literature methods.

[0327] Scheme 1-3:

[0328]

[0329] Compounds of general formula (D) can be prepared by general schemes 1-4. Ar is an appropriately substituted phenol or a protected phenol (if a protected phenol is used, a deprotection step will be required after amide bond formation). Alternatively, compounds of general formula (D) can be prepared starting from CI instead of Ar, and the final compound is prepared in the last step by Suzuki coupling with the appropriate Ar-boronic acid. The reagents shown in schemes 1-4 are commercially available or can be readily synthesized by a person skilled in the art using well-known literature methods.

[0330] Schemes 1-4:

[0331]

[0332] Compounds of general formula (E) can be prepared by general scheme 1-5. Ar is an appropriately substituted phenol or a protected phenol (if a protected phenol is used, a deprotection step will be required after amide bond formation). Alternatively, compounds of general formula (E) can be prepared starting from CI instead of Ar, and the final compound is prepared in the last step by Suzuki coupling with the appropriate Ar-boronic acid. The reagents shown in scheme 1-5 are commercially available or can be readily synthesized by a person skilled in the art using well-known literature methods.

[0333] Schemes 1-5:

[0334]

[0335] As shown in Scheme 2-1 and Scheme 2-2, the methods disclosed herein can include the use of standard organic synthesis techniques to build compounds of general formula (A) and general formula (B). Ar is an appropriately substituted phenol or a protected phenol (if a protected phenol is used, a deprotection step will be required at an appropriate synthesis step to release the protected phenolic hydroxyl group). Alternatively, compounds of general formula (A) and general formula (B) can be prepared starting from CI instead of Ar, and the final compound is prepared in the last step by Suzuki coupling with the appropriate Ar-boronic acid. The reagents shown in Scheme 2-1 are commercially available or can be readily synthesized by a person skilled in the art using well-known literature methods.

[0336] General Scheme 2-1 and Scheme 2-2 show the coupling of a protected diamine with a key acid intermediate to form an amide, followed by deprotection of the terminal amine to generate the final product.

[0337] Scheme 2-1:

[0338]

[0339] Scheme 2-2:

[0340]

[0341] Compounds of general formula (C) and general formula (D) can be prepared by general scheme 2-3. Ar is an appropriately substituted phenol or a protected phenol (if a protected phenol is used, a deprotection step to release the protected phenolic hydroxyl group will be required at an appropriate synthetic step). Alternatively, compounds of general formula (C) can be prepared starting from Cl instead of Ar, and the final compound is prepared in the last step by Suzuki coupling with the appropriate Ar-boronic acid. Removal of the protecting group can be required to obtain compounds of general formula (D). The reagents shown in scheme 2-3 are commercially available or can be readily synthesized by a person skilled in the art using well-known literature methods.

[0342] Scheme 2-3:

[0343]

[0344] Compounds of general formula (E) can be prepared by general scheme 2-4. Ar is an appropriately substituted phenol or a protected phenol (if a protected phenol is used, a deprotection step to release the protected phenolic hydroxyl group will be required at an appropriate synthetic step). Alternatively, compounds of general formula (E) can be prepared starting from Cl instead of Ar, and the final compound is prepared in the last step by Suzuki coupling with the appropriate Ar-boronic acid. The reagents shown in scheme 2-4 are commercially available or can be readily synthesized by a person skilled in the art using well-known literature methods.

[0345] Scheme 2-4:

[0346]

[0347] The above example schemes are intended to provide guidance to the reader and collectively represent example methods of preparing the compounds encompassed herein. In addition, other methods of preparing the compounds described herein will be readily apparent to one of ordinary skill in the art in view of the reaction schemes and examples below.

[0348] Methods of treatment

[0349] 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.

[0350] The present disclosure provides a method of preventing, treating, or ameliorating one or more diseases in a subject. In several embodiments, the method comprises administering to a subject in need thereof at least one compound having a structure described elsewhere herein. In several embodiments, the method comprises administering to a subject in need thereof at least one pharmaceutically acceptable salt of a compound having a structure described elsewhere herein.

[0351] In several embodiments, the disease is characterized by disease progression comprising active roles of at least one of the IL-1 cytokine family members. In several embodiments, the disease progression comprises active roles of at least one IL-1 cytokine having agonistic activity, antagonistic activity, anti-inflammatory activity, and any combination of the above activities. In several embodiments, the disease progression comprises active roles of at least one IL-1 cytokine having agonistic activity. In several embodiments, the disease progression comprises active roles of at least one of IL-1a, IL-1b, IL-18, IL-33, IL-36a, IL-36b, IL-36y, IL-1Ra, IL-36Ra, IL-38, and IL-37. In several embodiments, the disease progression comprises active roles of at least one of IL-1a, IL-1b, IL-18, IL-33, IL-36a, IL-36b, and IL-36y. In several embodiments, the disease progression comprises active roles of IL-1b. In several embodiments, the disease progression comprises active roles of IL-18. In several embodiments, the disease progression comprises active roles of IL-1b and IL-18.

[0352] In several embodiments, the disease is at least one chronic inflammatory disease. In several embodiments, the disease is characterized by disease progression pathology comprising active roles of NLRP3 inflammasome. In several embodiments, the NLRP3 inflammasome comprises at least one mutation.

[0353] As non-limiting examples, age-related macular degeneration (AMD), both wet and dry forms, involves deterioration of the central part of the retina, which in turn leads to vision loss. NLRP3 inflammasome activation can contribute to the inflammation and neovascularization observed in AMD. Similarly, diabetic macular edema (DME) and diabetic retinopathy (DR) are complications of diabetes in which high blood sugar levels damage retinal blood vessels, and inflammation plays an important role in their progression.

[0354] Diseases like glaucoma, which is characterized by increased eye pressure leading to damage of the optic nerve, and retinopathies, which involve damage to blood vessels in the retina, are also associated with inflammatory responses mediated by the NLRP3 inflammasome. Dry eye disease (DED) and bacterial keratitis, a corneal infection, both involve inflammation in which the NLRP3 inflammasome can play a role in the response to infection and cellular stress.

[0355] Inflammatory and autoimmune diseases like Behcet’s syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis can have ocular manifestations, including uveitis, inflammation of the middle layer of the eye, and retinal vasculitis, inflammation of blood vessels in the retina. These conditions are often characterized by an overactive immune response, in which controlling activation of the NLRP3 inflammasome can control inflammation and prevent tissue damage. Targeting the NLRP3 inflammasome in patients with or at risk of developing the various diseases described above can reduce inflammation, slow disease progression, preserve vision, and improve quality of life by intervening in one of the underlying mechanisms that leads to these ocular conditions.

[0356] In several embodiments, the disease is selected from, for example, age-related macular degeneration (wet and dry) (AMD), atrophic macular degeneration, bacterial keratitis, ocular bacterial infection, bacterial corneal ulcer (including, but not limited to, Pseudomonas aeruginosa and Streptococcus pneumoniae corneal ulcer), bacterial keratitis (including, but not limited to, Pseudomonas aeruginosa keratitis), Behcet's syndrome, cataract, choroidal neovascularization, cytomegalovirus retinitis, chronic eye disease, delayed corneal wound healing and neurodegeneration in diabetes, diabetic macular edema (DME), diabetic retinopathy (DR) (including, but not limited to, 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 dystrophy of the cornea, fungal endophthalmitis, fungal keratitis (including, but not limited to, Candida albicans keratitis), ocular fungal infection, glaucoma (acute and non-acute), geographic atrophy (GA), inflammatory eye disease, keratoconjunctivitis filiformis hereditaria (KFH), lipopolysaccharide-induced ocular inflammation, melting ulcer (MU), neuronal death in retinal ischemia / reperfusion injury, ocular hypertension, CAPS-associated ocular inflammation (CAPS includes cryopyrin-associated periodic syndromes), ocular manifestations of rheumatoid arthritis and systemic lupus erythematosus (SLE), ocular surface squamous neoplasia, optic neuritis, ocular parasitic infection, pathological neovascularization, retinal excitatory overstimulation, lipofuscin and A2E-mediated oxidative damage (including, but not limited to, ROS / oxidative stress reduction), retinal ganglion cell (RGC) dysfunction and death due to stress induced by ocular hypertension (OHT), retinoblastoma, retinitis, retinal vasculitis, retinal vein occlusion (RVO), syndrome, sterile corneal inflammation, diabetic-induced retinal damage, traumatic optic neuropathy / trauma (optic nerve crush injury, including, but not limited to, progressive optic neuropathy), ulcerative keratitis, uveal melanoma, uveitis (anterior / intermediate / posterior uveitis, panuveitis), and ocular viral infection (including, but not limited to, inflammatory herpetic disease).

[0357] In several embodiments, the disease is selected from, 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), inflammatory eye disease, CAPS-related ocular inflammation, 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 uveitis, panuveitis).

[0358] Consistent with the present disclosure, the compounds of the present disclosure can be used to treat, prevent, or ameliorate a disease affecting the eye. In several embodiments, the disease is selected from, 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 retinopathy.

[0359] In several embodiments, the disease is selected from, for example, inflammatory eye disease, CAPS-related ocular inflammation, 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 uveitis, panuveitis).

[0360] 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 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).

[0361] 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 cold urticaria-associated periodic syndrome (CAPS)-associated ocular inflammation. In some embodiments, the disease involves ocular manifestations 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 uveitis, or panuveitis.

[0362] In some embodiments, due to their activity on the NLRP3 inflammasome, the compounds in the present disclosure are expected to exhibit significant biological activity on a range of systemic diseases. For example, in diseases where inflammation is a major pathogenic factor, such as gout and atherosclerosis, the compounds of the present disclosure can alleviate symptoms and slow disease progression by modulating the inflammatory response. Thus, compounds that inhibit / stimulate NLRP3 inflammasome activation are of interest for their potential in treating a variety of systemic indications. The NLRP3 inflammasome plays a role in the human immune response, and its dysregulation is associated with a variety of diseases characterized by chronic inflammation and abnormal immune system function.

[0363] In some embodiments, the compounds and methods of the present disclosure can be used to treat or ameliorate systemic diseases associated with NLRP3 activation compounds, including autoinflammatory diseases. Diseases such as cold urticaria-associated periodic syndrome (CAPS) and familial Mediterranean fever are directly associated with NLRP3 dysregulation. Similarly, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and multiple sclerosis, in which chronic inflammation is sustained through the immune response, can benefit from such compounds.

[0364] Metabolic diseases, 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 can exacerbate insulin resistance and metabolic complications. In the area of neurodegenerative diseases, given the role of inflammation in neurodegeneration, diseases such as Alzheimer’s disease and Parkinson’s disease can benefit from NLRP3 inhibition.

[0365] Cardiovascular diseases, including atherosclerosis, involve chronic inflammation, in which NLRP3 can be implicated in plaque formation and cardiac dysfunction. Liver diseases, such as nonalcoholic steatohepatitis (NASH) and alcoholic liver disease, are also associated with NLRP3-mediated inflammation. Similarly, kidney diseases, such as acute kidney injury and diabetic nephropathy, can be affected by NLRP3 activation. Finally, lung diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis, have an inflammatory component that can also be a potential target for compounds that modulate NLRP3 activity.

[0366] Without being limited to a single mechanism of action theory, NLRP3 inflammasome activation is implicated in various 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 syndrome (MDS), myelofibrosis); chronic liver disease; gout; hidradenitis suppurativa; hyperoxaluria; neuroinflammation-associated diseases (e.g., multiple sclerosis, brain infections, acute injury, 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 scarring.

[0367] In several embodiments, the disease is selected from, 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, including type 1 diabetes, type 2 diabetes, and diabetes mellitus); gout; hemodialysis-related inflammation; hypertensive nephropathy; inflammatory arthritis-associated diseases, such as osteoarthritis and rheumatoid arthritis; kidney-related diseases, such as hyperoxaluria and lupus nephritis; liver-related diseases, such as viral hepatitis and nonalcoholic steatohepatitis (NASH); pseudogout (chondrocalcinosis); sickle cell disease; systemic lupus erythematosus (SLE).

[0368] In addition, the increase of IL-1 β and IL-18 produced by NLRP3 inflammasome is associated with the occurrence and development of various diseases, such as neuroinflammatory related diseases, for example, brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases; cardiovascular / metabolic diseases, such as cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications (such as 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, age-related macular degeneration; cancer related diseases, such as myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis, lung cancer, colon cancer.

[0369] Administration and pharmaceutical compositions

[0370] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound having a structure described herein and a pharmaceutically acceptable excipient.

[0371] The compounds are administered in therapeutically effective doses. While human dosage levels of the compounds described herein have not been optimized, generally speaking, daily dosages can range from about 0.25 mg / kg to about 120 mg / kg or more, from about 0.5 mg / kg or less to about 70 mg / kg, from about 1.0 mg / kg to about 50 mg / kg, or from about 1.5 mg / kg to about 10 mg / kg, relative to body weight. Thus, for administration to a 70 kg person, the dosage range can be from about 17 mg / day to about 8000 mg / day, from about 35 mg / day or less 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 / day to about 3000 mg / day. Of course, the amount of active compound administered will depend on the subject and disease state being treated, the severity of the disease state, the manner and schedule of administration and the judgment of the prescribing physician.

[0372] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be administered in any form of administration acceptable to those in the art, including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarily, vaginally, rectally, or intraocularly. Oral and parenteral administration are the most common modes of administration in treating the indications that are the subject of the preferred embodiments.

[0373] The compounds for use as described above can be formulated into pharmaceutical compositions for the treatment of these disorders. Standard pharmaceutical formulation techniques are employed, such as those described in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), which is incorporated herein by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereomers, atropisomers, tautomers, polymorphs, hydrates, and solvates thereof), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0374] In addition to the selected compounds for use as described above, some embodiments include compositions comprising 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 that are physiologically compatible. 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 the therapeutic compositions is contemplated. Furthermore, various adjuvants can be included in the compositions. Considerations for inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0375] Some examples of materials that can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, dextrose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, 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 castor oil; polyols, such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such as sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0376] The choice of a pharmaceutically acceptable carrier to be used in conjunction with the subject compounds is essentially dependent on the way the compound is to be administered.

[0377] The compositions described herein are preferably provided in unit dosage form. As used herein, "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably a mammalian subject, in a single dose, according to good medical practice. 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, thrice or more per day, and can be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or as a continuous infusion, and can be administered multiple times during a course of treatment, although single administration is not specifically excluded. Those of skill in the art will recognize that the formulation does not specifically include the entire course of treatment, such decisions being made by those skilled in the therapeutic arts, not the formulation arts.

[0378] The compositions for use as described above can be any of a variety of suitable forms for a variety of routes of administration, for example, for oral, intranasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, intravitreal, subcutaneous, or other parenteral routes of administration. In some embodiments, the composition can be in a form suitable for subcutaneous administration. Those of skill in the art will appreciate that oral and nasal compositions include compositions for administration by inhalation, and are made using existing methodologies. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well-known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, excipients, surfactants, and encapsulating substances. Pharmaceutically active materials can optionally be added, so long as they do not significantly interfere with the inhibitory activity of the compounds. The amount of carrier employed in conjunction with the compounds is sufficient to provide for the desired amount of material for actual administration per unit dosage. Techniques for preparation of dosage forms for use in the methods described herein and compositions are described in detail in the following references, 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).

[0379] A variety of oral dosage forms can be used, including solid dosage forms such as tablets, capsules, granules, and powders. Tablets can be compressed, scored, uncoated, plain or coated tablets. Capsules can be hard or soft shelled, gelatin or non-gelatin. Liquid dosage forms include solutions, suspensions, emulsions, and elixirs. The choice of the most suitable solid or liquid dosage form depends on the specific pharmaceutical compound, the method of administration, and the therapeutic effect desired.

[0380] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically include conventional pharmaceutically acceptable ingredients such as binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents, glidants, and melting agents. Suspending agents, wetting agents, and preservatives can also be included. Capsules typically include one or more of the above-described solid diluents. The choice of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the therapeutic effect, and can be readily made by a person skilled in the art.

[0381] Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Carriers for syrup, elixir, emulsion, and suspension formulations typically include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, common suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth, and sodium alginate; common wetting agents include lecithin and polysorbate 80; and common preservatives include methyl paraben and sodium benzoate. Oral liquid compositions can also include one or more of the above-described ingredients such as sweeteners, flavoring agents, and colorants.

[0382] Such compositions can also be coated by conventional methods, typically using pH-dependent or time-dependent coatings, to release the subject compound at the desired local site of action in the gastrointestinal tract, or at different times to extend the desired pharmaceutical effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coating materials, waxes, and shellac.

[0383] The compositions described herein can optionally include other pharmaceutically active ingredients.

[0384] Other compositions for achieving systemic delivery of the compounds of interest include sublingual, buccal, and nasal dosage forms. Such compositions typically include one or more soluble filler substances such as sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. The flow agents, lubricants, sweeteners, colorants, antioxidants, and flavorings disclosed above can also be included.

[0385] Liquid compositions formulated for ophthalmic topical use are such that they can be applied topically to the eye. Suitability should be maximized as much as possible, although at times optimal suitability can not be achieved due to formulation considerations (e.g., drug stability). In cases where maximal suitability cannot be achieved, the liquid should be formulated to ensure that the patient can tolerate ophthalmic topical use. Additionally, ophthalmically acceptable liquids should be in single-use packaging or should contain a preservative to prevent contamination during multiple uses.

[0386] For ophthalmic applications, solutions or suspensions are typically prepared in physiological saline. Ophthalmic solutions should preferably be maintained at the appropriate pH value by an appropriate buffer system. The formulation can also contain conventional, pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0387] Preservatives for use in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, polyhexamethylene biguanide (PHMB), chlorobutanol, thiomersal, phenylmercuric acetate, and phenylmercuric nitrate.

[0388] Useful surfactants, for example, are Tween 80. Likewise, a variety of useful carriers can be used in the ophthalmic formulations disclosed herein. These include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, cyclodextrin or derivatives thereof, and purified water.

[0389] Osmotic pressure adjusting agents can be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerol, or any other suitable ophthalmically acceptable osmotic pressure adjusting agent.

[0390] A variety of buffers and methods of adjusting pH can be used, as long as the resulting formulation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases can be used as needed to adjust the pH of these formulations.

[0391] Likewise, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0392] Other adjuvant ingredients that can be included in the ophthalmic formulations are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents can be used in place of or in combination with it.

[0393] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing a compound disclosed herein are employed. Topical formulations can generally consist of a pharmaceutically acceptable carrier, a solubilizer, an emulsifier, a penetration enhancer, a preservative system, and an emollient.

[0394] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent such as normal saline or dextrose solution. Suitable adjuvants can be added to achieve the desired pH, including but not limited to sodium hydroxide, sodium carbonate, sodium acetate, hydrochloric acid, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.

[0395] Antioxidant adjuvants can include sodium bisulfite, acetone sodium bisulfite, formaldehyde sodium bisulfite, thiourea, and ethylenediaminetetraacetic acid (EDTA). Other non-limiting examples of suitable excipients found in final intravenous compositions can include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran.

[0396] Other acceptable adjuvants 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 by reference in their entirety.

[0397] Antibacterial agents can also be added to obtain a solution with bacteriostatic or fungistatic action, including but not limited to phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzalkonium bromide, phenol, cresol, and chlorobutanol.

[0398] Compositions for intravenous administration can be provided to the caregiver in one or more solid forms that need to be reconstituted shortly before administration with a suitable diluent such as sterile water, normal saline or glucose in water. In other embodiments, the composition is provided as a solution ready for parenteral administration. In other embodiments, the composition is provided in a solution that is further diluted prior to administration. In embodiments that include administration of a compound described herein in combination with another agent, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents prior to administration, or the two agents can be administered separately.

[0399] The actual dose of an active compound described herein depends on the particular compound as well as the condition to be treated; the selection of an appropriate dose is well within the knowledge of the skilled artisan.

[0400] If desired, the compounds and compositions described herein can be presented in a pack or dispenser device which can contain one or more unit dosage forms containing the active ingredient. Such a pack or device can for example comprise metal or plastic foil, such as a blister pack, or glass and rubber stoppers such as vials. The pack or dispenser device can be accompanied by instructions for administration. Compounds and compositions described herein are formulated into compatible pharmaceutical carriers, and also can be prepared into a galenical dosage form, packaged, and labeled in a conventional manner using tamper resistant or otherwise abuse resistant closure / containers.

[0401] The amount of the compound in the formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain from about 0.01 wt-% to about 99.99 wt-% of the compound of the technology, based on the total weight of the formulation, the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present in an amount of about 1 wt-% to about 80 wt-%. Representative pharmaceutical formulations are described below.

[0402] Formulation embodiments

[0403] 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).

[0404] Formulation Embodiment 1 - Tablets

[0405] The following ingredients are thoroughly mixed and compressed into single- scored tablets.

[0406]

[0407] Formulation Embodiment 2 - Capsules

[0408] The following ingredients are mixed thoroughly and filled into hard shell gelatin capsules.

[0409]

[0410] Formulation Embodiment 3 - Suspensions

[0411] The following ingredients are mixed to make an oral suspension.

[0412]

[0413] Formulation Embodiment 4 - Injectables

[0414] The following ingredients are mixed to make an injectable.

[0415]

[0416]

[0417] Formulation Embodiment 5 - Suppositories

[0418] Suppositories of total weight 2.5 grams are prepared by mixing the compound of the present technology with H-15 (saturated vegetable fatty acid triglyceride; Riches-Nelson, Inc., New York) to have the following composition:

[0419] Ingredient Amount

[0420] Compound disclosed herein 500 mg

[0421] H-15 to make up the balance

[0422] To further illustrate the disclosure, the following examples are included. Of course, these examples should not be construed as specific limitations on the scope of the present disclosure. Modifications can be made to these examples within the scope of the claims and those skilled in the art, and it is contemplated to fall within the scope of the present disclosure as set forth herein. It will be understood by the reader that those skilled in the art, with the knowledge gained from the disclosure and with the relevant expertise, can make and use the present disclosure without the aid of the detailed examples. The following examples will further illustrate the present disclosure and are intended only to exemplify and not limit the disclosure.

[0423] Compounds can be identified by chemical structure and / or chemical name. Chemical names are generated using ChemDraw® from PerkinElmer (Waltham, MA 02451 USA). Professional 19.1.1.21 naming program generated. When there is a conflict between the chemical structure and the chemical name, the chemical structure is used as the basis for determining the compound.

[0424] The compounds of Formula (1-I), (1-II), (1-III), (1-IV), (1-V), (1-VI), (1-VII), (1-VIII), and (1-IX) disclosed herein include any specific compound within these formulas. Specific compounds within Formula (1-I), (1-II), (1-III), (1-IV), (1-V), (1-VI), (1-VII), (1-VIII), and (1-IX) are shown in Table 1.

[0425] Examples

[0426] Table 1

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441] The compounds of formula (2-I), (2-II), (2-III), (2-IV), (2-V), (2-VI), and (2-VII) disclosed herein include any specific compound of these formulas. Specific compounds of formula (2-I), (2-II), (2-III), (2-IV), (2-V), (2-VI), and (2-VII) are shown in Table 2.

[0442] Table 2:

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450] General procedure

[0451] Methods for preparing precursors and functional groups related to the compounds claimed herein are readily apparent to one skilled in the art and are generally described in the literature. Variations on these reactions can also be employed by one of ordinary skill in the art without departing from the scope of the present disclosure. A person of ordinary skill in the art, armed with the relevant literature and the present disclosure, would be able to prepare any of the compounds described.

[0452] One skilled in the art of organic chemistry will recognize that these manipulations are readily performed without further guidance, that is, they are well within the ability and skill of one of ordinary skill in the art. These reactions include reduction of carbonyl compounds to their corresponding alcohols, oxidation reactions, acylation reactions, electrophilic and nucleophilic aromatic substitution reactions, etherification reactions, esterification and saponification reactions, and the like. These manipulations are described in standard textbooks such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (the entire contents of which are incorporated herein by reference). Unless otherwise indicated, all intermediate compounds of the present disclosure are used directly without further purification.

[0453] Those skilled in the art will readily appreciate that when other functional groups in the molecule are masked or protected, certain reactions can achieve optimal results, thereby avoiding any unnecessary side reactions and / or improving reaction yields. Those skilled in the art will typically utilize blocking groups to achieve such as improving yields or avoiding undesirable reactions. These reactions can be found in the literature and are fully within the capabilities of those skilled in the art. Examples of many such operations can be found in, for example, T.Greene and P.Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), which is incorporated herein by reference in its entirety.

[0454] The following embodiments are provided for the reader's reference and represent preferred methods for preparing the exemplary compounds described herein. These methods are not limiting, and it is apparent that other routes can be used to prepare these compounds. Such methods specifically include solid-phase chemical methods, including combinatorial chemistry. In conjunction with the relevant literature and this disclosure, those skilled in the art are fully capable of preparing these compounds by these methods. The compound numbers used in the following synthetic schemes apply only to these specific schemes and should not be confused with or interpreted as the same numbering in other parts of this application.

[0455] The trademarks used herein are illustrative only and reflect the exemplary materials used in this disclosure at a particular time. Those skilled in the art will recognize that batch variations, manufacturing process variations, and the like are unavoidable. Therefore, these embodiments and the trademarks used therein are not intended to be limiting and are not intended to be limiting. Instead, they are intended to illustrate how one skilled in the art may implement one or more embodiments of this disclosure.

[0456] The following abbreviations have the following meanings:

[0457] 2N = 2 times the equivalent of a substance

[0458] ACN = acetonitrile

[0459] AIBN = azobisisobutyronitrile

[0460] aq.=water-based

[0461] Bn=benzyl

[0462] Boc = tert-butyloxycarbonyl

[0463] Brine = saturated aqueous solution of sodium chloride (NaCl)

[0464] Bu=butyl

[0465] CD3OD = deuterated methanol

[0466] CHCl3= chloroform

[0467] CDCl3= deuterated chloroform

[0468] CH2Cl2= methylene chloride, or dichloromethane, or DCM

[0469] Cs2CO3= cesium carbonate

[0470] DIEA = N,N-diisopropylethylamine

[0471] DMF = dimethylformamide

[0472] DMSO = dimethyl sulfoxide

[0473] EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDC-HCl)

[0474] Et = ethyl

[0475] EtOAc or EA = ethyl acetate

[0476] g = gram

[0477] FA = formic acid

[0478] h = hour

[0479] 1 H + = proton

[0480] H = hydrogen

[0481] H2O = water

[0482] HATU = hexafluorophosphate azide benzotriazole tetramethyluronium

[0483] HC1 = hydrogen chloride

[0484] HOBt = hydroxybenzotriazole

[0485] HPLC = high performance liquid chromatography

[0486] iPrOH = isopropyl alcohol

[0487] LCMS = liquid chromatography mass spectrometry

[0488] Me = methyl

[0489] M = molarity

[0490] m = multiplet

[0491] [M+H] + = molecular ion plus one proton

[0492] MeOH = methanol

[0493] min = minutes

[0494] mL = milliliters

[0495] mmol = millimoles

[0496] MHz = megahertz

[0497] m / z = mass-to-charge ratio

[0498] N2 = nitrogen

[0499] NaCl = sodium chloride

[0500] Na2SO4 = sodium sulfate

[0501] NH3 = ammonia

[0502] NBS = N-bromosuccinimide

[0503] NH4HCO3 = ammonium bicarbonate

[0504] NMR = nuclear magnetic resonance

[0505] NMP = N-methyl-2-pyrrolidone or 1 -methyl-2-pyrrolidone

[0506] o / n or o.n. = overnight

[0507] PBr3 = phosphorus tribromide

[0508] PCl5 = phosphorus pentachloride

[0509] PCC = pyridinium chlorochromate

[0510] PEG = polyethylene glycol

[0511] Ph = phenyl

[0512] pH = negative logarithm of the hydrogen ion concentration

[0513] PPh3Cl2 = triphenylphosphine dichloride

[0514] ppm = parts per million

[0515] q = quartet

[0516] rt = room temperature

[0517] s = singlet

[0518] sat. = saturated

[0519] t = triplet

[0520] SFC = supercritical fluid chromatography

[0521] TBSCl = tert-butyldimethylsilyl chloride

[0522] tBu = tert-butyl

[0523] TFA = trifluoroacetic acid

[0524] THF = tetrahydrofuran

[0525] TLC = thin layer chromatography

[0526] TMS = trimethylsilyl

[0527] Examples

[0528] The following example schemes are intended to provide guidance to the reader and together represent example methods of preparing the compounds provided herein. Furthermore, given the following reaction schemes and examples, one of ordinary skill in the art will readily perceive other methods of preparing the compounds described herein. Unless otherwise indicated, all variable factors are as defined above.

[0529] Example 1: 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-l-yl)-l-(3-hydroxypyrrolidin-l- yl)ethan-l-one (1)

[0530]

[0531] Synthetic Route:

[0532]

[0533] Step 1: Synthesis of tert-butyl (3R)-3-[(6-chloro-5-methylpyridazin-3- yl)amino]piperidine-l-carboxylate.

[0534] A brown solution of 3,6-dichloro-4-methylpyridazine (5.00 g, 30.7 mmol), (3R)-3- aminopiperidine-1-carboxylic acid tert-butyl ester (6.76 g, 33.7 mmol), and DIEA (16.0 mL, 11.89 g, 92.0 mmol) in NMP (25 mL) was stirred at 150 °C (oil bath) overnight. To this solution was added EtOAc (100 mL) and water (100 mL). After separation, the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (2 x 200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. After concentration, the suspension was purified by column chromatography on silica gel eluting with a gradient of PE / EtOAc (0-50%) to give (3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (1.3 g, 13.0% yield). LC / MS: C 15 H 23 ClN4O2 mass calcd: 326.15, found: m / z = 327.15 [M+H] + .

[0535] Step 2: Synthesis of 6-chloro-5-methyl-N-[(3R)-piperidin-3-yl]pyridazin-3-amine hydrochloride

[0536] To a solution of (3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (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 ClN4 mass calcd: 226.10, found: m / z = 227.00 [M+H] + .

[0537] Step 3: Synthesis of (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid tert-butyl ester

[0538] 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 (DIEA) (1.84 mL, 1.37 g, 10.59 mmol) in ACN (7 mL) was stirred at 60 °C for 1 h. The crude product was purified by silica gel column with petroleum ether / ethyl acetate gradient elution (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, yield 68.7%). LC / MS: C 16 H 25 ClN4O2 mass calcd: 340.17, found: m / z = 341.10 [M+H] + .

[0539] Step 4: Synthesis of (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid

[0540] A light 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 DCM (4 mL) and HCl (4 mL, 16 mmol, 4 M HCl in 1,4-dioxane) was stirred at 40 °C overnight. The solvent was removed under reduced pressure with a rotary evaporator to give [(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]acetic acid as a light yellow solid (500 mg, yield 90.3%). LC / MS: C 12 H 17 ClN4O2 mass calcd: 284.10, found: 285.00 m / z = [M+H] + .

[0541] 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

[0542] A solution of [(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-l-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 μί, 567 mg, 4.39 mmol, 5.0 equiv) in DMF (2 mL) was stirred at room temperature for 2 h. After removal of volatiles under reduced pressure on high vacuum, the crude reaction mixture was purified by reverse phase column chromatography (10-50% ACN / water (0.05% NH4HCO3)) to give 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-l-yl]-l-(3- hydroxypyrrolidin-l-yl)ethanone as a light yellow oil (200 mg, 57.9% yield). LC / MS: C 16 H 24 ClN5O2 mass calcd: 353.16, found: m / z = 354.20 [M+H] + .

[0543] Step 6: Synthesis of 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-l-yl)-l-(3-hydroxypyrrolidin-l-yl)ethan-l-one (1)

[0544] 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 placed under N2 atmosphere and stirred in a sealed tube at 150°C for 1 hour. After the reaction mixture was cooled to room temperature, the solution was purified on a silica gel column using a DCM / MeOH gradient elution (0-10%) to give the pre-purified product (150 mg) as a light brown oil. The substance was further purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) under the following conditions: chromatographic column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 46% B (7 minutes), 46% B; wavelength: 254 nm; RT1: 5.73 minutes. The combined fractions containing the product were lyophilized to obtain 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)ethanone (1) as a light yellow solid (36.0 mg, yield 13.2%). LC / MS: C 23 H 28 Calculated mass of F3N5O3: 479.21, found: m / z = 480.15 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): δ

[0545] 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.

[0546] Example 2: l-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-l-yl)ethyl)pyrrolidin-3-ol (2)

[0547]

[0548] Synthetic route:

[0549]

[0550] Steps la and lb: Synthesis of l-(2-((R)-3-((6-chloro-5-methylpyridazin-3- yl)amino)piperidin-l-yl)ethyl)pyrrolidin-3-ol

[0551] A brown suspension of 6-chloro-5-methyl-N-[(3l)-piperidin-3-yl]pyridazin-3-amine hydrochloride (200 mg, 0.76 mmol), 3-[(tert-butyldimethylsilyl)oxy]-l-(2- chloroethyl)pyrrolidine (221 mg, 0.84 mmol, 1.1 eq) (racemic 3-[(tert- butyldimethylsilyl)oxy]-l-(2-chloroethyl)pyrrolidine was prepared as described for (3S)-3-[(tert-butyldimethylsilyl)oxy]-l-(2-chloroethyl)pyrrolidine in Reference Example 4, but racemic pyrrolidin-3-ol hydrochloride was used as starting material), Nal (114 mg, 0.76 mmol, 1.0 eq), and DIEA (398 μL, 295 mg, 2.28 mmol, 3.0 eq) in ACN (3 mL) was stirred at 80 °C for 2 h. After removal of volatiles under reduced pressure using a rotary evaporator, the suspension was subjected to reverse phase column purification (5-40% ACN / water + 0.05 volume% TFA) to give a brown oil. The oil was dissolved in 2 mL of DCM-TFA mixture (1 : 1, v / v) and stirred at room temperature for 1 h. After removal of solvent at 70 °C, the residue was subjected to silica gel column purification eluting with a gradient of DCM / MeOH (0-10%) to give l-{2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-l-yl]ethyl}pyrrolidin-3-ol as a brown oil (150 mg, 58.1% yield). LC / MS: C 16 H 26 ClN5O mass calcd: 339.18, found: m / z = 340.10 [M+H] + .

[0552] Step 2: Synthesis of l-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-l-yl)ethyl)pyrrolidin-3-ol (2)

[0553] A brown suspension of l-{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)benzoic acid (145 mg, 0.71 mmol, 1.6 equiv), Pd(PPh3)4(15 mg, 0.013 mmol, 0.03 equiv), and NaHC03(111 mg, 1.32 mmol, 3.0 equiv) in dioxane (2 mL) and water (1 mL) was stirred in a sealed tube at 150 °C under N2atmosphere for 1 h. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure with a rotary evaporator, and the residue was subjected to silica gel column purification eluted with a gradient of DCM / MeOH (0-10%) to give a brown solid (100 mg). The solid was further purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) with the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HC03), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 44% B (7 min), 44% B; wavelength: 254 nm; RT1: 6.07 min. After the combined product-containing fractions were lyophilized, the target compound, l-{2-[(3R)-3-({6-[2-hydroxy-4- (trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-l-yl]ethyl}pyrrolidin-3- ol (2), was obtained as a colorless solid (20.3 mg, 9.6% yield). LC / MS: C 23 H 30 F3N5O2 mass calcd: 465.24, found: m / z = 466.20 [M+H+]. 1 H NMR (400 MHz, Methanol-d4): δ

[0554] 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.

[0555] 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)

[0556]

[0557] Synthesis route:

[0558]

[0559] 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

[0560] A brown suspension of (3R)-3-[(tert-butyldimethylsilyl)oxy]-1-(2-chloroethyl)pyrrolidine (303 mg, 1.15 mmol, 1.4 eq) ((3R)-3-[(tert-butyldimethylsilyl)oxy]-1-(2- chloroethyl)pyrrolidine was prepared as described for (3S)-3-[(tert-butyldimethylsilyl)oxy]- 1-(2-chloroethyl)pyrrolidine in Reference Example 4, but using (3S)-pyrrolidin-3-ol hydrochloride as starting material), 6-chloro-5-methyl-N-[(3R)-piperidin-3-yl]pyridazin-3-amine (200 mg, 0.88 mmol, 1.0 eq), Nal (132 mg, 0.88 mmol, 1.0 eq), and DIEA (461 μL, 342 mg, 2.65 mmol, 3.0 eq) in ACN (5 mL) was stirred at 80 °C for 2 h. After the reaction mixture was cooled to room temperature, DCM (20 mL) and water (10 mL) were added to the suspension. After the mixture was partitioned, the aqueous phase was extracted with DCM (2 x 10 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over Na2S04, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by column chromatography on silica gel eluting with a gradient of DCM / MeOH (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 ClN5OSi mass calcd: 453.27, found: m / z = 454.35 [M+H] + .

[0561] Step 2: Synthesis of (R)-1-(2-((R)-3-((6-chloro-5-methylpyridazin-3- yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol

[0562] 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 HC1 (2 mL, 4 M in 1,4-dioxane, 8.0 mmol, 20 equiv) was stirred at room temperature for 3 h. After concentration under reduced pressure with 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 directly without further isolation and characterization. LC / MS: C 16 H 26 ClN5O mass calcd: 339.18, found: m / z = 340.20 [M+H] + .

[0563] 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)

[0564] 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), NaHCO3 (60 mg, 0.71 mmol, 2.0 equiv), and Pd(PPh3)4 (13 mg, 0.011 mmol, 0.03 equiv) in 1,4-dioxane (1.5 mL) and water (3 mL) was stirred in a sealed tube at 150°C under N2 atmosphere for 1 h. After concentration under reduced pressure using a rotary evaporator, the residue was purified by silica gel column chromatography using a DCM / MeOH gradient elution (0-5%) to give a white solid, which was purified by preparative reverse-phase high performance liquid chromatography (RP-HPLC) under the following conditions: chromatographic column: XBridge PrepOBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 27% B to 57% B, 7 minutes, 57% B; wavelength: 254 nm; RT1: 6 minutes. The combined fractions were lyophilized to obtain the target product (3R)-1-{2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]ethyl}pyrrolidin-3-ol (3) as a colorless solid (22.4 mg, yield 13.6%). LC / MS: C 23 H 30 Calculated mass of F3N5O2: 465.24, found: m / z = 466.20 [M+H] + . 1 H NMR (400MHz, methanol-d4): δ7.44-7.37(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.

[0565] 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)

[0566]

[0567] Synthetic route:

[0568]

[0569] Step 1: Synthesis of (S)-1-(2-(benzyloxy)ethyl)pyrrolidin-3-ol

[0570] In a sealed tube, 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). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with saturated aqueous NH4Cl (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 (3S)-1-[2-(benzyloxy)ethyl]pyrrolidin-3-ol as a yellow oil (1.00 g, 41.3% yield) which was used directly without further isolation and characterization. LC / MS: C 13 H 19 NO2 mass calcd: 221.14, found: m / z = 222.15 [M+H] + .

[0571] Step 2: Synthesis of (S)-1-(2-(benzyloxy)ethyl)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine

[0572] To a solution of (3S)-1-[2-(benzyloxy)ethyl]pyrrolidin-3-ol (1.00 g, 4.52 mmol, 1.0 eq) in DCM (10 mL) was added solid TBSCl (818 mg, 5.42 mmol, 1.2 eq) and 1H-imidazole (616 mg, 9.04 mmol, 2.0 eq). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure with a rotary evaporator and the residue was purified by column chromatography on silica gel eluting with a gradient of petroleum ether / ethyl ether (0-100%) and the product containing fractions were concentrated and the solvent was evaporated under reduced pressure with a rotary evaporator to give (3S)-1-[2-(benzyloxy)ethyl]-3-[(tert-butyldimethylsilyl)oxy]pyrrolidine as a yellow oil (1.4 g, 83.1% yield). LC / MS: C 19 H 33 NO2Si mass calcd: 335.23, found: 336.15 m / z = [M+H] + .

[0573] Step 3: Synthesis of (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)ethan-1-ol

[0574] 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 ethyl acetate / tert-butanol (1:1, v / v) was added 10 wt% Pd / C (1.4 g, 100 wt%). The resulting suspension was stirred at 50 °C under an atmosphere of hydrogen at atmospheric pressure overnight. After filtration through celite, the solution was concentrated under reduced pressure with 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 without further isolation and characterization. LC / MS: C 12 H 27 NO2Si mass calcd: 245.18, found: m / z = 246.10 [M+H] + .

[0575] Step 4: Synthesis of (S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloroethyl)pyrrolidine

[0576] To a solution of (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- chloroethyl)pyrrolidine (401 mg, 1.52 mmol, 2.0 equiv), Nal (228 mg, 1.52 mmol, 2.0 equiv), and DIEA (398 μL, 295 mg, 2.28 mmol, 3.0 equiv) in ACN (4 mL) was stirred at 80 °C for 2 h. After the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) and water (10 mL) were added to the crude reaction mixture. After the mixture was partitioned, the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with brine (2 x 20 mL), dried over Na2S04, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by column chromatography on silica gel eluting with a gradient of DCM / MeOH (0-5%) to give 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 12 H 26 ClNOSi mass calcd: 263.14, found: m / z = 264.00 [M+H] + .

[0577] 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

[0578] To a solution of (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- chloroethyl)pyrrolidine (401 mg, 1.52 mmol, 2.0 equiv), Nal (228 mg, 1.52 mmol, 2.0 equiv), and DIEA (398 μL, 295 mg, 2.28 mmol, 3.0 equiv) in ACN (4 mL) was stirred at 80 °C for 2 h. After the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) and water (10 mL) were added to the crude reaction mixture. After the mixture was partitioned, the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with brine (2 x 20 mL), dried over Na2S04, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by column chromatography on silica gel eluting with a gradient of DCM / MeOH (0-5%) to give 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 40CIN5OSi mass calcd: 453.27, found: m / z = 454.25 [M+H] + .

[0579] Step 6: Synthesis of (S)-1-(2-((R)-3-((6-chloro-5-methylpyridazin-3- yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol

[0580] HCl solution (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) in DCM (2 mL) and the reaction mixture was stirred at room temperature for 3 hours to form a suspension. After removal of the solvent under reduced pressure with 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 CIN5O mass calcd: 339.18, found: m / z = 340.20 [M+H] + .

[0581] 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)

[0582] A solution of (S)-l-(2-((R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-l- 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(PPh3)4(32 mg, 0.027 mmol, 0.03 equiv), and NaHC03(153 mg, 1.82 mmol, 2.0 equiv) in dioxane (4 mL) and water (2 mL) was stirred in a sealed tube at 150 °C under N2atmosphere for 1 h. The filtrate was concentrated under reduced pressure using a rotary evaporator and the residue was purified by silica gel column chromatography eluting with a gradient of DCM / MeOH (0-10%) to give a yellow oil which was further purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) with the following conditions: column: Xselect CSH C18 OBD column 30*150 mm 5 pm; mobile phase A: water (containing 0.1% formic acid), 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. The combined fractions were lyophilized to give the target compound (S)-l-(2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-l-yl)ethyl)pyrrolidin-3-ol (4) as a formate salt as a white solid (26 mg, 5.5% yield). LC / MS: C 24 H 32 F3N5O4 mass calcd: 465.24, found: 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.

[0583] 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)

[0584]

[0585] Synthetic route:

[0586]

[0587] Step 1: Synthesis of 4-fluoropyrrolidin-3-ol hydrochloride

[0588] 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 solution 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, yield 87.0 %). LC / MS: C4H8FNO mass calcd: 105.06, found: m / z = 106.00 [M+H] + .

[0589] Step 2: Synthesis of 1-(2-(benzyloxy)ethyl)-4-fluoropyrrolidin-3-ol

[0590] To a solution of [(2-bromoethoxy)methyl]benzene (2.00 g, 9.30 mmol, 1.0 eq) and 4-fluoropyrrolidin-3-ol hydrochloride (1.45 g, 10.23 mmol, 1.1 eq) 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 (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, yield 67.4 %). LC / MS: C 13 H 18 FNO2 mass calcd: 239.13, found: m / z = 240.00 [M+H] + .

[0591] Step 3: Synthesis of 1-(2-(benzyloxy)ethyl)-3-((tert-butyldimethylsilyl)oxy)-4- fluoropyrrolidine

[0592] 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 purified by column chromatography on silica gel eluting with petroleum ether / 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 FNO2Si mass calcd: 353.22, found: m / z = 354.10 [M+H] + .

[0593] Step 4: Synthesis of 2-(3-((tert-butyldimethylsilyl)oxy)-4-fluoropyrrolidin-1-yl)ethan-1-ol

[0594] To a solution of 1-[2-(benzyloxy)ethyl]-3-[(tert-butyldimethylsilyl)oxy]-4- fluoropyrrolidine (800 mg, 2.26 mmol) in ethyl acetate / tert-butanol (16 mL, 1 : 1, v / v) was added Pd / C (800 mg, 10 wt-% Pd / C). The resulting suspension was stirred at 60 °C under an atmosphere of hydrogen overnight at atmospheric pressure. After filtration through celite, 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 FNO2Si mass calcd: 263.17, found: m / z = 264.05 [M+H] + .

[0595] Step 5: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-1-(2-chloroethyl)-4- fluoropyrrolidine

[0596] To a solution of 2-{3-[(tert-butyldimethylsilyl)oxy]-4-fluoropyrrolidin-1- yl}ethanol (580 mg, 2.20 mmol) in dichloromethane (6 mL) was added triethylamine (614 μL, 446 mg, 4.40 mmol, 2.0 eq) and solid p-toluenesulfonyl chloride (504 mg, 2.64 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 5 h, diluted with saturated aqueous NH4Cl (30 mL). The aqueous phase was extracted with DCM (3 x 50 mL), and the combined organic phases were dried over anhydrous 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 directly in the next step without further purification and characterization. LC / MS: C 12 H 25 ClFNOSi mass calcd: 281.14, found: m / z = 282.05 [M+H] + .

[0597] Step 6 and 7: Synthesis of 1-(2-((R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1- yl)ethyl)-4-fluoropyrrolidin-3-ol

[0598] 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 eq) in ACN (6 mL) was added Nal (661 mg, 1.41 mmol, 0.65 eq) and DIEA (1.14 mL, 846 mg, 6.612 mmol, 3.0 eq). The resulting suspension was stirred at 80 °C for 2 h, and after the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure using a rotary evaporator. The residue was subjected to reverse phase column chromatography (0-60% ACN / water (containing 0.05% volume TFA)) to give a yellow oil. Under these purification conditions, due to the presence of TFA (0.05% volume) in the eluent, the TBDMS protecting group was simultaneously removed during the lyophilization of the pooled product-containing fractions. The obtained oil was subjected to silica gel column chromatography eluted with DCM / MeOH (0-20%), and after the pooled product-containing fractions were concentrated under reduced pressure using a rotary evaporator, 1-{2-[(3R)-3-[(6-chloro-5- methylpyridazin-3-yl)amino]piperidin-1-yl]ethyl}-4-fluoropyrrolidin-3-ol was obtained as a yellow oil (150 mg, 15.2% yield). LC / MS: C 16 H 25ClFN5O mass calcd.: 357.17, found: m / z = 358.05 [M+H] + .

[0599] Step 8: Synthesis of 4-fluoro-l-(2-((R)-3-((6-(2-hydroxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-l- yl)ethyl)pyrrolidin-3-ol (5)

[0600] To a solution of l-{2-[(3R)-3-[(6-chloro-5-methylpyridazin-3- yl)amino]piperidin-l-yl]ethyl}-4-fluoropyrrolidin-3-ol (150 mg, 0.42 mmol) in dioxane / water (3 mL, 2: 1, v / v) was added 2-hydroxy-4- (trifluoromethyl)benzeneboronic acid (139 mg, 0.67 mmol, 1.6 eq), Pd(PPh3)4(15 mg, 0.013 mmol, 0.03 eq), and NaHC03(106 mg, 1.26 mmol, 3.0 eq). The resulting reaction mixture was stirred at 150 °C in a sealed tube under N2atmosphere for 1 h. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure with a rotary evaporator. The residue was subjected to silica gel column purification eluted with DCM / MeOH (0-20%) to give the crude target product as a yellow oil (70 mg). The resulting oil was further purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) under the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water + 0.1% formic acid, mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 22% B in 7 min; wavelength: 254 nm; RTi(min): 4.92. After lyophilization of the combined product-containing fractions, the target compound, 4-fluoro-l-{2-[(3R)-3-({6-[2-hydroxy-4- (trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-l- yl]ethyl}pyrrolidin-3-ol (5) formate salt, was obtained as a off-white solid (4.7 mg, 2.3% yield). LC / MS: C 23 H 29 F4N5O2 mass calcd.: 483.23, found: 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.

[0601] 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)

[0602]

[0603] Synthetic route:

[0604]

[0605] Step 1: Synthesis of 1-(2-(benzyloxy)ethyl)piperidin-4-ol

[0606] To a solution of [(2-bromoethoxy)methyl]benzene (1.47 mL, 2 g, 9.30 mmol, 1.0 eq) and piperidin-4-ol (1.03 g, 10.2 mmol, 1.1 eq) 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 (50 mL) and extracted with DCM (3 x 100 mL). The combined organic phase was 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 NO2 mass calcd: 235.16, found: m / z = 236.05 [M+H] + .

[0607] Step 2: Synthesis of 1-(2-(benzyloxy)ethyl)-4-((tert-butyldimethylsilyl)oxy)piperidine

[0608] To a solution of 1-[2-(benzyloxy)ethyl]piperidin-4-ol (2 g, 8.50 mmol) in DCM (25 mL) was added TBSC1 (1.54 g, 10.20 mmol, 1.2 eq) and 1H-imidazole (1.16 g, 17.0 mmol, 2.0 eq). 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 column chromatography on silica gel eluting with a gradient of petroleum ether / ethyl ether (0-100%) to give 1-[2-(benzyloxy)ethyl]-4-[(tert-butyldimethylsilyl)oxy]piperidine as a yellow oil (1.2 g, yield 36.4%). LC / MS: C 20 H 35 NO2Si mass calcd: 259.20, found: m / z = 260.10 [M+H] + .

[0609] Step 3: Synthesis of 2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)ethan-1-ol

[0610] To a solution of 1-[2-(benzyloxy)ethyl]-4-[(tert-butyldimethylsilyl)oxy]piperidine (1.2 g, 3.43 mmol) in a mixture of ethyl acetate / tert-butanol (30 mL, 1:1, v / v) was added solid 10 wt% Pd / C (1.2 g). The resulting suspension was stirred at 50 °C under an atmosphere of hydrogen at atmospheric pressure overnight. After filtration through celite, the filtrate was concentrated under reduced pressure to give 2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-1-yl}ethanol as a yellow oil (900 mg, yield 88.9%). LC / MS: C 13 H 29 NO2Si mass calcd: 259.20, found: m / z = 260.10 [M+H] + .

[0611] Step 4: Synthesis of 4-((tert-butyldimethylsilyl)oxy)-1-(2-chloroethyl)piperidine

[0612] To a solution of 2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-l-yl}ethanol (900 mg, 3.47 mmol) in DCM (10 mL) was added triethylamine (967 μL, 702 mg, 6.94 mmol, 2.0 eq) and solid p-toluenesulfonyl chloride (794 mg, 4.16 mmol, 1.2 eq). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NH4Cl (30 mL) and the aqueous phase was extracted with DCM (3 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give 4-[(tert-butyldimethylsilyl)oxy]-l-(2-chloroethyl)piperidine as a yellow oil (900 mg, 74.7% yield). LC / MS: C 13 H 28 ClNOSi mass calcd: 277.16, found: m / z = 278.10 [M+H] + .

[0613] Step 5: Synthesis of (R)-N-(l-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-l- yl)ethyl)piperidin-3-yl)-6-chloropyridazin-3-amine

[0614] To a solution of 6-chloro-N-[(3R)-piperidin-3-yl]pyridazin-3-amine hydrochloride (300 mg, 1.20 mmol), 4-[(tert-butyldimethylsilyl)oxy]-l-(2-chloroethyl)piperidine (402 mg, 1.45 mmol, 1.2 eq) in ACN (5 mL) was added NaI (361 mg, 2.41 mmol, 2.0 eq) and DIEA (629 μL, 467 mg, 3.61 mmol, 3.0 eq). The resulting suspension was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature, washed with saturated aqueous NH4Cl (20 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. The residue was subjected to silica gel column purification eluting with a gradient of DCM / MeOH (0-20%) to give N-[(3R)-l-(2-{4-[(tert-butyldimethylsilyl)oxy]piperidin-l-yl}ethyl)piperidin-3-yl]-6-chloropyridazin-3-amine (300 mg, 49.4% yield) as a yellow oil. LC / MS: C 22 H 40 ClN5OSi mass calcd: 453.27, found: m / z = 454.20 [M+H] + .

[0615] 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

[0616] 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 dioxane / water mixture (2.4 mL, 2:1, v / v) was added 2-[2-(ethoxymethoxy)-6-methyl-4- (trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared according to International Patent Application WO2020 / 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). The reaction mixture was stirred at 150 °C in a sealed tube under N2atmosphere for 1 h. After cooling to room temperature, it was concentrated under reduced pressure with a rotary evaporator. The residue was purified by column chromatography on silica gel eluted with a gradient of DCM / MeOH (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 F3N5O3Si Mass calc: 651.38, found: m / z = 652.40 [M+H] + .

[0617] 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)

[0618] 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) was dissolved in dichloromethane (1.5 mL) and TFA (1.5 mL) was added 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 and the resulting residue was purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) with the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water + 0.1% formic acid, 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. The product containing fractions were combined and lyophilized to give 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) as a colorless solid (2.6 mg, 2.8% yield). LC / MS: C 24 H 32 F3N5O2 mass calcd: 479.25, found: 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.

[0619] 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)

[0620]

[0621] Synthetic route:

[0622]

[0623] Step 1: Synthesis of (R)-N-(l-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-l- yl)ethyl)piperidin-3-yl)-6-chloro-5-methylpyridazin-3-amine

[0624] A brown suspension of (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)-l-(2- chloroethyl)piperidine (634 mg, 2.28 mmol, 2.0 equiv), Nal (342 mg, 2.28 mmol, 2.2 equiv) and DIEA (593 μί, 440 mg, 3.42 mmol, 3.0 equiv) in ACN (3 mL) was stirred at 80 °C for 2 h. After the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) and water (10 mL) were added to the suspension. After the separation of the layers, the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over Na2S04, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by column chromatography on silica gel eluted with a gradient of ethyl acetate / petroleum ether (0-70%) to give (R)-N-(l-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-l- yl)ethyl)piperidin-3-yl)-6-chloro-5-methylpyridazin-3-amine as a yellow oil (200 mg, 37.5% yield). LC / MS: C 23 H 42 ClN5OSi mass calcd: 467.28, found: m / z = 468.30 [M+H] + .

[0625] Step 2: Synthesis of (R)-l-(2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-l- yl)ethyl)piperidin-4-ol

[0626] HCI solution (3 mL, 12 mmol, 4 HCI 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 form a brown suspension, which was stirred at room temperature for 3 hours. After removal of the solvent by rotary evaporator under reduced pressure, (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 directly without further purification and characterization. LC / MS: C 17 H 28 ClN5O mass calcd: 353.20, found: m / z = 354.25 [M+H] + .

[0627] 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)

[0628] 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 a 1,4-dioxane / water mixture (4.5 mL, 2:1, v / v) was stirred in a sealed tube at 150 °C under N2atmosphere for 1 h. After filtration of the solid and concentration under reduced pressure, the residue was purified by silica gel column chromatography eluting with a gradient of DCM / MeOH (0-10%) and the fractions containing the product were concentrated under reduced pressure on a rotary evaporator and further purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) with the following conditions: Column: Xselect CSH C18 OBD 30*150mm 5μm; Mobile Phase A: water (with 0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 18% B (7 min), hold 18% B; Wavelength: 254 nm; RT1: 5.40 min. The fractions containing the product were lyophilized to give 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 as a colorless solid (27.6 mg, 7.4% yield). LC / MS: C 24 H 32 F3N5O2 mass calcd: 479.25, found: 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

[0629] 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)

[0630]

[0631] Synthesis route:

[0632]

[0633] 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

[0634] 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 eq) and DIEA (1.1 mL, 817 mg, 6.32 mmol, 6.0 eq) in DMF (3 mL), solid HATU (601 mg, 1.58 mmol, 1.5 eq) was added portionwise and the yellow suspension was stirred. The suspension was stirred at room temperature for 1 h and the reaction progress was monitored by LC / MS. After concentration under reduced pressure, the suspension was subjected to reverse phase column chromatography eluted with a gradient of water (containing 10 mmol / L NH4HCO3) / ACN (5-60%) and the fractions containing the product were collected and concentrated under reduced pressure at 60 °C to give 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]-1-(3- hydroxyazetidin-1-yl)ethanone as a yellow oil (290 mg, 80.2% yield). LC / MS: C 15 H 22 ClN5O2 mass calcd: 339.15, found: m / z = 340.30 [M+H] + .

[0635] 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)

[0636] 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)benzoic 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 a mixture of 1,4-dioxane and H2O (6.6 mL, 2:1, v / v) was stirred at 150 °C in a sealed tube for 1 h. 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 separation, the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine (2 x 40 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by column chromatography on silica gel to give the crude product as a yellow solid (398 mg). This solid was further purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) with the following conditions: column: CHIRALPAK IBN-3, 4.6*100 mm, 3 μm; mobile phase B: MeOH (containing 0.1% diethylamine); flow rate: 2 mL / min; gradient: isocratic 10% B; wavelength: 220 nm. After lyophilization of the fractions containing the product, 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)ethanone (8) (27.5 mg, 6.9% yield) was obtained. LC / MS: C 22 H 26 F3N5O3mass calcd: 465.20, found: m / z = 466.10 [M+H] + . 1 HNMR (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.

[0637] 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)

[0638]

[0639] Synthetic route:

[0640]

[0641] Step 1: Synthesis of 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1- yl]-1-(4-hydroxypiperidin-1-yl)ethanone

[0642] 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 eq) and DIEA (367 μL, 272 mg, 2.11 mmol, 3.0 eq) in DMF (2 mL) was added HATU (321 mg, 0.84 mmol, 1.2 eq) to give a light yellow solution, which was stirred at room temperature overnight. To this solution was added ethyl acetate (20 mL) and water (10 mL). After separation, the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with brine (1 x 50 mL), dried over Na2S04, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by column chromatography on silica gel to give 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-1-yl]-1-(4- hydroxypiperidin-1-yl)ethanone as off-white solid (150 mg, 54.4% yield). LC / MS: C 17 H 26 ClN5O2 mass calcd: 367.18, found: m / z = 368.10 [M+H] + .

[0643] 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)

[0644] A solution of 2-[(3R)-3-[(6-chloro-5-methylpyridazin-3-yl)amino]piperidin-l-yl]-l- (4-hydroxypiperidin-l-yl)ethanone (150 mg, 0.41 mmol), 2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (176.2 mg, 0.61 mmol, 1.5 eq), NaHC03(103 mg, 1.22 mmol, 3.0 eq) in 1,4-dioxane / H20 mixture (3.9 mL, 2:1, v / v) was stirred until homogeneous. Pd(PPh3)4(14.1 mg, 0.012 mmol, 0.03 eq) was then added and the reaction was stirred in a sealed tube at 150 °C under N2atmosphere for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography to give a yellow solid. The yellow solid was further purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: water (containing 10 mmol / L NH4HC03), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 45% B in 9 min, hold at 45% B; Wavelength: 254 nm; RT1: 7 min. The fractions containing the target product were combined and lyophilized to give the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5- methylpyridazin-3-yl}amino)piperidin-l-yl]-l-(4-hydroxypiperidin-l-yl)ethanone (9) as a light yellow solid (35 mg, 17.4% yield). LC / MS: C 24 H 30 F3N5O3mass calcd: 493.53, found: 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.

[0645] 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)

[0646]

[0647] Synthetic route:

[0648]

[0649] Step 1: Synthesis of tert-butyl (R)-2-(3-((6-(2-hydroxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0650] 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 eq), 2-hydroxy-4- (trifluoromethyl)benzeneboronic acid (0.91 g, 4.40 mmol, 1.5 eq) in 1,4- dioxane / H2O mixture (21 mL, 2:1, v / v) was added NaHCO3(0.74 g, 8.80 mmol, 3.0 eq) and Pd(PPh3)4(0.1 g, 0.088 mmol, 0.03 eq). The reaction mixture was stirred at 150 °C in a sealed tube under N2atmosphere for 1 h. After cooling to room temperature, the reaction was quenched with aqueous NaCl solution (20 mL) and diluted with water (20 mL). The aqueous phase was extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with brine (2 x 80 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by column chromatography on silica gel to give tert-butyl 2-[(3R)-3-({6-[2-hydroxy-4- (trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetate as a colorless solid (1.1 g, 75.5% yield). LC / MS: C 23 H 29 F3N4O3 mass calcd: 466.22, found: m / z = 467.18 [M+H] + .

[0651] Step 2: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid

[0652] 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 dichloromethane (4 mL) was added 4 M 1,4-dioxane solution (8 mL, 32 mmol) to form a suspension. The suspension was stirred at room temperature for 4 hours. The solvent was removed by rotary evaporator under reduced pressure 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 in the next step without purification characterization. LC / MS: C 19 H 21 F3N4O3 Mass calcd: 410.16, Found: m / z = 411.15 [M+H] + .

[0653] 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)

[0654] 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- aminocyclobutane-1-ol hydrochloride (36 mg, 0.29 mmol) and DIEA (170 μL, 126 mg, 0.98 mmol) in DMF (3 mL) was added BOP (129 mg, 0.29 mmol) to form a light yellow solution. The solution was stirred at room temperature for 1 hour. Purification was performed by preparative reverse phase high performance liquid chromatography (RP-HPLC) with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 45% B (7 min), hold 45% B; wavelength: 254 nm; RT1: 6.05 min. After lyophilization of the fractions containing the target product, 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 a white solid (10.0 mg, 8.6% yield). LC / MS: C 23 H 28F3N5O3 mass calcd: 479.21, found: m / z = 480.20 [M+H] + . 1 H NMR (300 MHz, Methanol-d4): δ

[0655] 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. 19 F NMR (282 MHz, Methanol-d4): δ 64.29 ppm.

[0656] 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)

[0657]

[0658] Synthesis route

[0659]

[0660] 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)

[0661] To a reaction flask containing [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (prepared according to 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) was added pyridine (2.0 mL). The reaction mixture was stirred at 50°C (heat block) under an N2 atmosphere overnight. After cooling to room temperature, the crude reaction mixture was concentrated under reduced pressure on a rotary evaporator to provide the crude product. The crude product was purified by preparative reverse-phase high performance liquid chromatography (RP-HPLC) (ACN / water mixed solvent containing 0.3% formic acid, gradient elution from 5% to 95% over 30 minutes). The product-containing fractions were combined and lyophilized to obtain the formate salt of 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), as a colorless solid (30.2 mg, 13.0% yield). LC / MS: m / z = 480.15 [M+H] + . 1 H NMR (400MHz, methanol-d4): δ8.33(s,1H),7.38(d,J=7.9Hz,1H),7.22(d,J=7.9Hz,1H),7.16(d,J=1.7Hz,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=2.5Hz,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.

[0662] 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)

[0663]

[0664] Synthesis route

[0665]

[0666] Step 1 : Synthesis of 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-l-yl)-l-((R)-3-hydroxypyrrolidin-l-yl)ethan-l- one (12)

[0667] To a flask containing [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5- methylpyridazin-3-yl}amino)piperidin-l-yl]acetic acid (prepared according to the procedure of 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) was added pyridine (5.0 mL). The reaction mixture was stirred at 50 °C under N2atmosphere overnight. After cooling to room temperature, it was concentrated under reduced pressure using a rotary evaporator to give the crude product. The crude product was purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) (ACN / water gradient with 0.3% formic acid) and the fractions containing the product were combined and lyophilized to give the target compound 2-((R)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidin-l-yl)-l-((R)-3-hydroxypyrrolidin-l-yl)ethan-l-one (12) as a colorless solid (65.2 mg, 11.2% yield). LC / MS: m / z = 480.40 [M+H] + . 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.

[0668] Example 13: (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidin-l-yl)-N-(3-hydroxybicyclo[l. l. l]pentan-l-yl)acetamide (13)

[0669]

[0670] Synthesis route:

[0671]

[0672] Step 1 : Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-l-yl)-N-(3-hydroxybicyclo[l. l. l]pentan- 1- yl)acetamide (13)

[0673] 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 per the method of Example 10) (177 mg, 0.43 mmol, 1.0 equiv), 3-aminobicyclo[l. l. l]pentan-l -ol hydrochloride (70 mg, 0.52 mmol, 2.2 mmol) and DIEA (299 μί, 222 mg, 1.72 mmol, 4.0 equiv) in DMF (3 mL) to give a light yellow solution. After stirring at room temperature for 1 h, purification by preparative reverse phase high performance liquid chromatography (RP-HPLC) with the following conditions: Column: Xselect CSH C18 OBD 30*150mm 5μm; Mobile Phase A: Water (with 0.1% formic acid), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 5% B to 18% B (7 min), 18% B for 8 min; Wavelength: 254 nm; RT1 : 7.4 min). The product containing fractions were combined and lyophilized to give the target compound 2-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3- yl}amino)piperidin-l-yl]-N-{3-hydroxybicyclo[l. l. l]pentan-l-yl}acetamide as a off-white solid (10 mg, 4.7% yield). LC / MS: C 24 H 28 F3N5O3 Mass calculated: 491.21, found: 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. 19 F NMR (376 MHz, DMSO-d6): δ 65.10 ppm.

[0674] 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)

[0675]

[0676] Synthetic route:

[0677]

[0678] 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)

[0679] To a colorless solution of [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5- methylpyridazin-3-yl}amino)piperidin-1-yl]acetic acid (prepared according to the method of 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) was added BOP (129 mg, 0.29 mmol, 1.2 equiv) to give a light yellow solution. The solution was stirred at room temperature for 1 h. Subsequent preparative reverse phase high performance liquid chromatography (RP-HPLC) purification was performed with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150mm, 5μm; Mobile Phase A: water (containing 10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 46% B in 7 min, hold 46% B; Wavelength: 254 nm; RT1: 5.87 min. The combined product containing fractions were lyophilized to give 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) as a off-white solid (20 mg, 17.0% yield). LC / MS: C 23 H 28 F3N5O3 Mass calcd: 479.21, found: m / z = 480.15 [M+H] + . 1H 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.

[0680] 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)

[0681]

[0682] Synthetic route:

[0683]

[0684] 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)

[0685] To a yellow solution of [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5- methylpyridazin-3-yl}amino)piperidin-l-yl]acetic acid (prepared according to the procedure of 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 μί, 164 mg, 1.27 mmol, 4.0 equiv) in DMF (5 mL) was added EDCI (91 mg, 0.48 mmol, 1.5 equiv) and HOBT (64 mg, 0.48 mmol, 1.5 equiv) to give a light yellow solution. The solution was stirred at room temperature for 1 h. To this solution was added EtOAc (10 mL) and water (10 mL). After separation, the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine (3 x 30 mL), dried over Na2S04, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) under the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μιη; mobile phase A: water (containing 10 mmol / L NH4HC03), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B (7 min), 55% B; 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-l-yl]-l-{2-hydroxy-7- azaspiro[3.5]nonan-7-yl}ethanone (15), was obtained as a light yellow solid (19.5 mg, 11.5% yield). LC / MS: C 27 H 34 F3N5O3mass calcd: 533.26, found: m / z = 534.25 [M+H] + H 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. 19F NMR (376 MHz, Methanol-d4): d -64.28 ppm.

[0686] Example 16: (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-l-yl)-l-(6-hydroxy-2-azaspiro[3.3]heptan-2- yl)ethan-l-one (16)

[0687]

[0688] Synthetic route:

[0689]

[0690] Step 1: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-l-yl)-l-(6-hydroxy-2-azaspiro[3.3]heptan-2- yl)ethan-l-one (16)

[0691] A yellow solution of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (prepared according to the procedure of 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 at room temperature overnight. Ethyl acetate (50 mL) and water (30 mL) were added to form a two-phase solution. After separation, the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine (1 x 30 mL), dried over Na2S04, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product was purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) under the following conditions: column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HC03), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 60% B (7 min), hold at 60% B; wavelength: 254 nm; RT1: 6 min. After lyophilization of the fractions containing product, 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) was obtained as a colorless solid (11.2 mg, 6.8% yield). LC / MS: C 25 H 30 F3N5O3mass calcd: 505.23, found: 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

[0692] 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)

[0693]

[0694] Synthetic route:

[0695]

[0696] 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)

[0697] [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin- 1-yl]acetic acid (prepared according to the method of Example 10) (120 mg, 0.29 mmol, 1.0 eq), 2-azaspiro[3.5]nonan-7-ol hydrochloride (62.3 mg, 0.35 mmol, 1.2 eq), EDCI (84.1 mg, 0.44 mmol, 1.5 eq), HOBt (59.3 mg, 0.44 mmol, 1.5 eq), DIEA (153 μL, 113.4 mg, 0.88 mmol, 3.0 eq) were dissolved in DMF (2 mL) to form a light yellow solution, which was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative reverse-phase high performance liquid chromatography (RP-HPLC) with the following conditions: column: XBridge Prep OBD C18, 30*150 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 54% B in 7 minutes; wavelength: 254 nm; RT1: 5.72 minutes. The product-containing fractions were combined and lyophilized to give 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) as a light yellow solid (24.1 mg, 15.0% yield). LC / MS: C 27 H 34 F3N5O3 mass calcd: 533.26, found: m / z = 534.20 [M+H] + .1 H NMR (400 MHz, Methanol-d4): d 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): d 64.27 ppm.

[0698] 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)

[0699]

[0700] Synthesis route:

[0701]

[0702] 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)

[0703] [(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)piperidin- 1 -yl] acetic acid (prepared according to the procedure of Example 10) (130 mg, 0.32 mmol), (1r,4r)-4-(methylamino)cyclohexan-1-ol (49 mg, 0.38 mmol, 1.2 eq), EDCI (91 mg, 0.48 mmol, 1.5 eq), HOBt (64 mg, 0.48 mmol, 1.5 eq), DIEA (109 μί, 81 mg, 0.63 mmol) were dissolved in DMF (2 mL) and stirred at room temperature overnight. Ethyl acetate (50 mL) and water (30 mL) were added to form a two-phase solution. After separation, the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic phase was washed with brine (1 x 30 mL), dried over Na2S04, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product was purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) under the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150mm, 5μm; mobile phase A: water (containing 10 mmol / L NH4HC03), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 56% B (7 min), 56% B; wavelength: 254 nm; RT1 : 6 min. The fractions containing the target product were combined and lyophilized to give 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) as a light yellow solid (10.1 mg, 5.9% yield). LC / MS: C 26 H 34 F3N5O3mass calcd: 521.26, found: m / z = 522.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.47-7.31 (m, 1 H), 7.27-7.13 (m, 2 H), 6.75-6.67 (m, 1 H), 4.29-3.76 (m, 2 H), 3.41-3.24 (m, 1 H), 3.21-3.07 (m, 2 H), 3.05-2.73 (m, 3 H), 2.65-2.58 (m, 2 H), 2.31-1.92 (m, 6 H), 1.91-1.82 (m, 2 H), 1.80-1.72 (m, 1 H), 1.67-1.56 (m, 2 H), 1.55-1.38 (m, 3 H), 1.32-1.18 (m, 3 H) ppm. 19FNMR (376 MHz, DMSO-d6): δ 64.31 ppm.

[0704] 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)

[0705]

[0706] Synthetic route

[0707]

[0708] Step 1: Synthesis of 1-(cyclopent-1-en-1-yl)piperidine

[0709] To a light yellow solution of piperidine (10.00 g, 140.6 mmol, 1.0 eq) in toluene (50 mL) was added cyclopentanone (11.83 g, 140.6 mmol, 1 eq) and p-toluenesulfonic acid (0.10 g, 0.56 mmol, 0.004 eq). After the reaction mixture was stirred at 130 °C (oil bath) for 16 h, it was cooled to room temperature and the residue was concentrated under reduced pressure with a rotary evaporator to give 1-(cyclopent-1-en-1-yl)piperidine as a brown oil (11.0 g, yield 57.0%). The crude product was used directly in the next step without further purification and characterization.

[0710] Step 2: Synthesis of 1,4-dichloro-5H,6H,7H-cyclopenta[d]pyridazine

[0711] To a red solution of dichloro-1,2,4,5-tetrazine (4.40 g, 29.15 mmol, 0.5 eq) in DCM (150 mL) was added 1-(cyclopent-1-en-1-yl)piperidine (8.00 g, 58.3 mmol, 1 eq) at 0 °C. After the reaction mixture was stirred at 0 °C for 15 min, it was concentrated under reduced pressure with a rotary evaporator at 0 °C. The residue was purified by silica gel column chromatography (0-45% ethyl ether / petroleum ether gradient elution) to give 1,4-dichloro-5H,6H,7H-cyclopenta[d]pyridazine as a light yellow solid (2.6 g, yield 23.6%). LC / MS: mass calcd 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.

[0712] Step 3: Synthesis of (3R)-3-({4-chloro-5H,6H,7H-cyclopenta[d]pyridazin-l- yl}amino)piperidine-l-carboxylic acid tert-butyl ester

[0713] To a light yellow solution of l,4-dichloro-5H,6H,7H-cyclopenta[d]pyridazine (900 mg, 4.76 mmol, 1 eq) in NMP (10 mL) was added (3R)-3-aminopiperidine-l-carboxylic acid tert-butyl ester (1.14 g, 5.71 mmol, 1.2 eq) and DIEA (1.66 mL, 1.23 g, 9.52 mmol, 2 eq). The reaction mixture was stirred at 150 °C in a sealed tube for 12 h, cooled to room temperature, and the residue was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with water (3 x 50 mL), dried over Na2S04, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography (0-45% EA / PE gradient elution) to give (3R)-3-({4-chloro-5H,6H,7H-cyclopenta[d]pyridazin-l-yl}amino)piperidine-l- carboxylic acid tert-butyl ester as a light yellow solid (0.55 g, 32.7% yield). LC / MS: C 17 H 25 ClN4O2 mass calcd: 352.17, found 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.

[0714] Step 4: Synthesis of (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,6H,7H- cyclopenta[d]pyridazin-l-yl}amino)piperidine-l-carboxylic acid tert-butyl ester

[0715] To a solution of (3R)-3-({4-chloro-5H,6H,7H-cyclopenta[d]pyridazin-l- yl}amino)piperidine-l-carboxylate tert-butyl ester (250 mg, 0.701 mmol, 1.0 eq), 2- hydroxy-4-(trifluoromethyl)benzoic acid (175.1 mg, 0.85 mmol, 1.2 eq) in 1,4- dioxane / water mixture (4:1, v / v, 3.75 mL) was added Pd(PPh3)4(40.9 mg, 0.035 mmol, 0.05 eq) and NaHC03(119.0 mg, 1.42 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C in a sealed tube under N2atmosphere for 5 h, concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (0-50% EA / PE gradient elution) to give (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,6H,7H- cyclopenta[d]pyridazin-l-yl}amino)piperidine-l-carboxylate tert-butyl ester as a light yellow solid (246 mg, 72.6% yield). LC / MS: C 24 H 29 F3N4O3 mass calcd: 478.22, found 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.

[0716] Step 5: Synthesis of 2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H- cyclopenta[d]pyridazin-1-yl}-5-(trifluoromethyl)phenol To a light 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 eq) in dichloromethane (5 mL) was added TFA (1 mL). After stirring at room temperature for 30 min, the suspension was concentrated under reduced pressure using a rotary evaporator. The residue was purified by reverse phase flash chromatography with the following conditions: C18 silica gel; mobile phase: ACN / water, 10% to 60% gradient elution for 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 as a light yellow solid (71 mg, 44.9% yield). LC / MS: C 19 H 21 F3N4O mass calcd: 378.17, found: m / z = 379.20 [M+H] + .

[0717] 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)

[0718] To a light 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 eq) in MeOH (2 mL) was added 2-(4-hydroxypiperidin-1-yl)acetaldehyde (45.4 mg, 0.32 mmol, 1.2 eq) (prepared as described in Example 21) and sodium cyanoborohydride (49.8 mg, 0.79 mmol, 3.0 eq). After stirring at room temperature for 2 h, the suspension was concentrated under reduced pressure using a rotary evaporator. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Xselect CSH C18 OBD 30*150mm 5μm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 30% B over 7 min, hold at 30% B; Wavelength: 254 nm; RT1: 5.87 min. After lyophilization of the fractions containing the product, 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) was obtained as a light yellow solid (15.3 mg, 11.4% yield). LC / MS: MS (ESI): C 26 H 34 F3N5O2 calculated: 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.

[0719] 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)

[0720]

[0721] Synthesis route:

[0722]

[0723] 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

[0724] 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 eq) and 4-fluoro-2- hydroxybenzeneboronic acid (132.6 mg, 0.85 mmol, 1.2 eq) in 1,4-dioxane / water mixture (3.75 mL, 4:1, v / v) was added Pd(PPh3)4 (40.9 mg, 0.035 mmol, 0.05 eq) and NaHC03 (119.0 mg, 1.42 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C in a sealed tube under N2atmosphere for 5 h, then concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (0-50% EA / PE elution), the fractions containing the product were combined and concentrated under reduced pressure to give tert-butyl (3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H-cyclopenta[d]pyridazin-1 - yl]amino}piperidine-1 -carboxylate as a light yellow solid (250 mg, 82.35% yield). LC / MS: C 23 H 29 FN4O3 mass calcd: 428.22, found m / z = 429.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.63-7.60 (m, 1 H), 6.74-6.70 (m, 2H), 6.38 (s, 1 H), 4.05-3.82 (m, 2H), 3.80-3.65 (m, 1 H), 3.28-2.86 (m, 3H), 2.83-2.74 (m, 3H), 2.12-2.02 (m, 3H), 1.95-1.90 (m, 1 H), 1.74 (s, 1 H), 1.57 (s, 1 H), 1.47-1.23 (m, 10H) ppm. 19 F NMR (376 MHz, DMSO-d6): δ 111.38 ppm.

[0725] Step 2: Synthesis of 5-fluoro-2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H- cyclopenta[d]pyridazin-l-yl}phenol To a light yellow solution of (3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H- cyclopenta[d]pyridazin-l-yl]amino}piperidine-l-carboxylate (250 mg, 0.58 mmol) in dichloromethane (5 mL) was added TFA (1 mL). 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 with the following conditions: C18 silica gel as the column; ACN / water as the mobile phase, 10% to 60% gradient elution for 20 minutes; UV 254 nm as the detector. After lyophilization of the fractions containing product, 5-fluoro-2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H- cyclopenta[d]pyridazin-l-yl}phenol was obtained as a light yellow solid (180 mg, 94.0% yield). LC / MS: MS (ESI): C 18 H 21 FN4O mass calcd: 328.17, found: m / z = 329.15 [M+H] + .

[0726] Step 3: Synthesis of [(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H- cyclopenta[d]pyridazin-l-yl]amino}piperidin-l-yl]acetic acid

[0727] To a light yellow solution of 5-fluoro-2-{4-[(3R)-piperidin-3-ylamino]-5H,6H,7H- cyclopenta[d]pyridazin-l-yl}phenol (90 mg, 0.27 mmol, 1 equiv) in MeOH (2 mL) was added glyoxylic ester (24.4 mg, 0.33 mmol, 1.2 equiv) and sodium cyanoborohydride (51.7 mg, 0.82 mmol, 3.0 equiv). After stirring at room temperature for 2 hours, the suspension was concentrated under reduced pressure using a rotary evaporator. The residue was purified by reverse phase flash chromatography with the following conditions: C18 silica gel as the column; ACN / water as the mobile phase, 10% to 50% gradient elution for 20 minutes; UV 254 nm as the detector. After lyophilization of the fractions containing product, [(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H- cyclopenta[d]pyridazin-l-yl]amino}piperidin-l-yl]acetic acid was obtained as a light yellow solid (100 mg, 94.4% yield). LC / MS: MS (ESI): C 20 H 23 FN4O3 calcd: 386.18, found: m / z = 387.15 [M+H] + .

[0728] Step 4: Synthesis of 2-[(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H- cyclopenta[d]pyridazin-l-yl]amino}piperidin-l-yl]-l-(4-hydroxypiperidin-l- yl)ethanone (20)

[0729] To a light yellow solution of [(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H- cyclopenta[d]pyridazin-l-yl]amino}piperidin-l-yl]acetic acid (90 mg, 0.23 mmol, 1 eq) in DMF (2 mL), piperidin-4-ol (28.3 mg, 0.28 mmol, 1.2 eq), EDCI (89.3 mg, 0.47 mmol, 2.0 eq) and HOBt (62.9 mg, 0.47 mmol, 2.0 eq) were added under stirring at room temperature. The reaction suspension turned brown after stirring at room temperature for 4 h. The reaction was quenched by the addition of saturated aqueous NH4C1 (8 mL) at 0 °C and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with water (3 x 20 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator and the residue was purified by reverse phase flash chromatography with the following conditions: column: XBridge Prep Phenyl OBD Column, 19*100 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 95% B in 7 min, hold at 95% B; wavelength: 254 nm; RT1: 6 min. The fractions containing the target product were combined and lyophilized to give 2-[(3R)-3-{[4-(4-fluoro-2-hydroxyphenyl)-5H,6H,7H- cyclopenta[d]pyridazin-l-yl]amino}piperidin-l-yl]-l-(4-hydroxypiperidin-l- yl)ethanone (20) as a light yellow solid (22.6 mg, 20.6% yield). LC / MS: MS (ESI): C 25 H 32 FN5O3 calculated: 469.25, found: m / z = 470.25 [M+H] + . 1H 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.

[0730] 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)

[0731]

[0732] Synthesis route:

[0733]

[0734] Step 1 : Synthesis of 1-(2,2-dimethoxyethyl)piperidin-4-ol

[0735] 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 K2CO3(5.47 g, 39.55 mmol, 2.0 equiv) in 1,4-dioxane (20 mL) was stirred at 100 °C overnight. After cooling to room temperature, EtOAc (60 mL) and water (60 mL) were added, the phases were separated and 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 a off-white solid (1.8 g, yield 42.3%) which was used directly without further isolation and characterization. LC / MS: C9H 19 NO3 mass calcd: 189.14, found: m / z = 190.20 = [M+H] + .

[0736] Step 2: Synthesis of 2-(4-hydroxypiperidin-1-yl)acetaldehyde

[0737] Dissolve 1-(2,2-dimethoxyethyl)piperidin-4-ol (1.8 g, 9.51 mmol) in aqueous HC1 (20 mL, 6 M) and stir at 100 °C overnight. Concentrate the reaction under reduced pressure to give 2-(4-hydroxypiperidin-1-yl)acetaldehyde as a colorless oil (900 mg, yield 66.2 %), which was used directly in the next step without further purification. C7H 13 NO2 LCMS: Calculated: 143.09, Found: m / z = 144.15 [M+H] + .

[0738] 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)

[0739] To a light 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 NaBH3CN (57.4 mg, 0.92 mmol, 3.0 equiv) to give a light yellow solution. After stirring at room temperature for 2 h, the suspension was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1% Formic Acid), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 3% B up to 20% B over 7 min, hold at 20% B; Wavelength: 254 nm; RT1: 5.87 min. The product containing fractions were combined and lyophilized to give 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) as a light yellow solid (24.6 mg, yield 17.6 %). LC / MS: MS (ESI): C 25 H 34 FN5O2 Calculated: 455.27, Found: m / z = 456.25 [M+H] + . 1H 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.

[0740] Example 22: (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7- dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin-l-yl)-l-(3-hydroxyazetidin-l- yl)ethan-l-one (22)

[0741]

[0742] Synthesis route:

[0743]

[0744] Step 1: Synthesis of tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]- 5H,7H-furo[3,4-d]pyridazin-l-yl}amino)piperidine-l-carboxylate

[0745] To a solution of (3R)-3-({4-chloro-5H,7H-furo[3,4-d]pyridazin-l- yl}amino)piperidine-l-carboxylic acid tert-butyl ester (500 mg, 1.40 mmol, 1 equiv) and 2-hydroxy-4-(trifluoromethyl)benzoic acid (348.2 mg, 1.69 mmol, 1.2 equiv) in 1,4-dioxane and water (4:1, v / v) (5 mL) was added Pd(PPh3)4 (81.4 mg, 0.070 mmol, 0.05 equiv) and NaHC03 (355.1 mg, 4.23 mmol, 3.0 equiv). After the reaction mixture was stirred at 150 °C in a sealed tube for 5 h under N2atmosphere and cooled 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% ethyl acetate / petroleum ether) gradient, and the fractions containing the product were combined and concentrated under reduced pressure to give (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H-furo[3,4- d]pyridazin-l-yl}amino)piperidine-l-carboxylic acid tert-butyl ester as a light yellow oil (373 mg, 55.1% yield). LC / MS: MS (ESI): C 23 H 27 F3N4O4 calculated: 480.20, found: m / z = 481.25 [M+H] + . 19 F NMR (376 MHz, DMSO-d6): δ 61.43 ppm.

[0746] Step 2: Synthesis of 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4- d]pyridazin-l-yl}-5-(trifluoromethyl)phenol To a light yellow solution of (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]- 5H,7H-furo[3,4-d]pyridazin-l-yl}amino)piperidine-l-carboxylic acid tert-butyl ester (330 mg, 0.69 mmol, 1 equiv) in dioxane (1 mL) was added a solution of HC1 (3 mL, 12 mmol, 4 M in 1,4-dioxane). After the reaction mixture was stirred at room temperature for 30 min, the suspension was concentrated under reduced pressure using a rotary evaporator. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN / water, 10% to 60% gradient elution for 20 min; detector, UV 254 nm. After the fractions containing the product were combined and lyophilized, 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4-d]pyridazin-l-yl}-5- (trifluoromethyl)phenol was obtained as a light yellow solid (170 mg, 65.1% yield). LC / MS: MS (ESI): C 18 H 19F3N4O2 calculated: 380.15, found: m / z = 381.20 [M+H] + .

[0747] 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

[0748] To a light 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 glyoxylic ester (33.1 mg, 0.45 mmol, 2.0 equiv) and sodium cyanoborohydride (42.1 mg, 0.67 mmol, 3.0 equiv). After stirring at room temperature for 2 h, the suspension was concentrated under reduced pressure using a rotary evaporator. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN / water, 10% to 50% gradient elution for 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 as a light yellow solid (80 mg, 81.7% yield). LC / MS: MS (ESI): C 20 H 21 F3N4O4 calculated: 438.15, found: m / z = 439.20 [M+H] + .

[0749] 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)

[0750] To a light 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 eq) in DMF (2 mL), azetidin-3-ol (non-hydrochloride?) (25.0 mg, 0.34 mmol, 1.5 eq), EDCI (87.5 mg, 0.46 mmol, 2 eq), DIEA (119 μL, 88.4 mg, 0.68 mmol, 3.0 eq) and HOBT (61.6 mg, 0.46 mmol, 2.0 eq) were added with stirring at room temperature. The suspension was stirred at room temperature for 4 h to form a brown suspension. The reaction was quenched by the addition of saturated aqueous NH4Cl (8 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 20 mL), and the combined organic phase was 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 residue was purified by the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150mm, 5μm; Mobile Phase A: water (containing 10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 63% B (7 min), hold 63% B; Wavelength: 254 nm; RT1: 6 min. After lyophilization of the fractions containing the product, 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 was obtained as a light yellow solid (16.2 mg, yield 13.9%). LC / MS: MS (ESI): C 23 H 26 F3N5O4 calculated: 493.20, found: 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): d 64.53 ppm.

[0751] Example 23: (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7- dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin-l-yl)-l-(4-hydroxypiperidin-l- yl)ethan-l-one (23)

[0752]

[0753] Synthetic route:

[0754]

[0755] Step 1: Synthesis of 4-(2,5-dihydrofuran-3-yl)morpholine

[0756] 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), MgS04(30.0 g, 249 mmol, 3.1 equiv) in Et20 (150 mL). The reaction mixture was stirred at room temperature for 48 h. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator to give 4-(2,5-dihydrofuran-3-yl)morpholine as a light yellow oil (13.0 g, 98.7% yield), which was used directly in the next step without further purification and characterization.

[0757] Step 2: Synthesis of l,4-dichloro-5,7-dihydrofuro[3,4-d]pyridazine

[0758] To a 200 mL sealed tube equipped with a stir bar was added a solution of 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. Then 4-(2,5-dihydrofuran-3-yl)morpholine (12.3 g, 79.3 mmol, ~2 equiv) was added slowly. The reaction was stirred at 0 °C and gradually warmed to ~25 °C for 2 h. The mixture was concentrated directly by rotary evaporator under reduced pressure to give a brown oil. The oil was purified by reverse phase column chromatography with the following conditions: Column: XSelect CSH Prep C18 OBD, 19*150 mm, 5 μm; Mobile Phase A: water (with 0.1% TFA), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 0% to 30% B over 30 min, final 40% B; Wavelength: 220 nm; RT1: 23.1 min). The fractions containing the product were concentrated by rotary evaporator under reduced pressure to give 1,4-dichloro-5H,7H-furo[3,4-d]pyridazine as a yellow solid (3.0 g, 19.8% yield). LC / MS: MS (ESI): C6H4Cl2N2O calculated: 191.01, found: m / z = 192.10 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): δ 5.21 (s, 4H) ppm.

[0759] Step 3: Synthesis of tert-butyl (3R)-3-({4-chloro-5H,7H-furo[3,4-d]pyridazin-l- yl}amino)piperidine-l-carboxylate

[0760] To a solution of 1,4-dichloro-5H,7H-furo[3,4-d]pyridazine (550 mg, 2.88 mmol, 1.0 eq) in NMP (2 mL) was added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (577 mg, 2.88 mmol, 1.0 eq) and DIEA (1.00 mL, 744.32 mg, 5.76 mmol, 2.0 eq). The reaction mixture was stirred at 150 °C in a sealed tube under N2atmosphere for 2 h. After completion of the reaction, the reaction was quenched by the addition of water (10 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL) and 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 obtain the crude product. The crude product was purified by silica gel column chromatography with the following conditions: column: silica gel column; mobile phase A: petroleum ether, mobile phase B: ethyl acetate; flow rate: 40 mL / min; gradient: 0% to 50% B phase in 30 min; wavelength: 254 nm. The product containing fractions were concentrated under reduced pressure using a rotary evaporator to obtain tert-butyl (3R)-3-({4-chloro-5H,7H-furo[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate as a solid (290 mg, 28.4% yield). LC / MS: MS (ESI): C 16 H 23 ClN4O3 calculated: 354.84; found: m / z = 355.15 [M+H] + .

[0761] 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

[0762] To a solution of (3R)-3-({4-chloro-5H,7H-furo[3,4-d]pyridazin-l- yl}amino)piperidine-l-carboxylate (290 mg, 0.82 mmol, 1.0 equiv), 2-hydroxy-4- (trifluoromethyl)benzoic acid (253 mg, 1.23 mmol, 1.5 equiv) in 1,4-dioxane / water mixture (3.75 mL, 4: 1, v / v) was added NaHC03(206 mg, 2.45 mmol, 3 equiv) and Pd(PPh3)4(47.2 mg, 0.041 mmol, 0.05 equiv). After stirring at 100 °C in a sealed tube under N2atmosphere for 4 h, the reaction was quenched with saturated aqueous NH4C1 (5 mL). The mixture was extracted with EtOAc (3 x 10 mL), and the combined organic phase was washed with H20 (2 x 5 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure on a rotary evaporator, and the residue was purified by silica gel column chromatography (chromatography conditions: column: silica gel column; mobile phase A: petroleum ether, mobile phase B: ethyl acetate; flow rate: 60 mL / min; gradient: 0% to 50% B phase over 30 min; wavelength: 254 nm). Concentration of the fractions containing the product gave (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H- furo[3,4-d]pyridazin-l-yl}amino)piperidine-l-carboxylate as a solid (180 mg, 45.8%). LC / MS: MS (ESI): C 23 H 27 F3N4O4calc: 480.40, found: m / z = 481.10 [M+H] + .

[0763] Step 5: Synthesis of 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4-d]pyridazin-l- yl}-5-(trifluoromethyl)phenol

[0764] To a solution of (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5H,7H- furo[3,4-d]pyridazin-l-yl}amino)piperidine-l-carboxylate (180 mg, 0.38 mmol, 1 equiv) in 1,4-dioxane (2.0 mL) was added a solution of 4 M HC1 in 1,4-dioxane (2 mL, 8 mmol). After stirring at room temperature for 30 min, the reaction was concentrated under reduced pressure on a rotary evaporator to give 2-{4-[(3R)-piperidin-3-ylamino]-5H,7H-furo[3,4-d]pyridazin-l-yl}-5- (trifluoromethyl)phenol as a solid (130 mg, 91.2%). LC / MS: MS (ESI): C 18 H 19C26H25F3N4O4 Calculated: 438.40. Found: m / z = 439.20 [M+H] + .

[0765] 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

[0766] To a stirred solution of methyl glyoxylate (19.0 mg, 0.26 mmol, 1.5 eq) 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 eq) and sodium cyanoborohydride (32.2 mg, 0.51 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, it was concentrated under reduced pressure using a rotary evaporator to get [(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: MS (ESI): C 20 H 21 C26H25F3N4O4 Calculated: 438.40. Found: m / z = 439.20 [M+H] + .

[0767] 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)

[0768] To 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 added 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 at room temperature for 24 hours. The progress of the reaction was monitored by TLC (EA, Rf = 0.3). After completion of the reaction, the mixture was concentrated under reduced pressure using a rotary evaporator. The crude product was purified by preparative reverse-phase high performance liquid chromatography (RP-HPLC) under the following conditions: column: 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 (60 min), 58% B; wavelength: 254 nm; RT1: 7 min. The fractions containing the product were combined and lyophilized to obtain 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)ethanone (23) as a light yellow solid (20.4 mg, yield 34.0%). LC / MS: C 25 H 30 Calculated mass of F3N5O4: 521.22, found: m / z = 522.25 [M+H] + . 1 H NMR (400MHz, methanol-d4): δ7.42-7.40(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,1 H),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.

[0769] Example 24: (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7- dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin-l-yl)-l-(2-hydroxy-7- azaspiro[3.5]nonan-7-yl)ethan-l-one (24)

[0770]

[0771] Synthetic Route:

[0772]

[0773] Step 1: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7- dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin-l-yl)-l-(2-hydroxy-7- azaspiro[3.5]nonan-7-yl)ethan-l-one (24)

[0774] To a light 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 according to the procedure of Example 23) (60 mg, 0.14 mmol, 1.0 eq) in DMF (2 mL), 7-azaspiro[3.5]nonan-2-ol (25.1 mg, 0.18 mmol, 1.3 eq), EDCI (52.5 mg, 0.274 mmol, 2.0 eq), HOBT (37.0 mg, 0.274 mmol, 2.0 eq) and DIEA (71.5 μL, 53.1 mg, 0.41 mmol, 3 eq) were added with stirring at room temperature. The suspension turned into a brown suspension after stirring at room temperature for 4 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (8 mL) at 0 °C and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases 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 and the crude product was purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) under the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37% B to 64% B (10 min), 64% B; wavelength: 254 nm; RT1: 7.18 min; injection volume: 1.6 mL; number of runs: 1. The product-containing fractions were combined and lyophilized to give the title 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) as a off-white solid (11.8 mg, 14.8% yield). LC / MS: MS (ESI): C 28 H 34 F3N5O4 calculated: 561.26, found: m / z = 562.25 [M+H] + . 1H NMR (300 MHz, Methanol-d4): d 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): d -64.55 ppm.

[0775] Example 25: (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7- dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin-l-yl)-l-(7-hydroxy-2- azaspiro[3.5]nonan-2-yl)ethan-l-one (25)

[0776]

[0777] Synthetic route

[0778]

[0779] Step 1: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7- dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin-l-yl)-l-(7-hydroxy-2- azaspiro[3.5]nonan-2-yl)ethan-l-one (25)

[0780] To a light 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 according to the procedure of Example 23) (50 mg, 0.114 mmol, 1.0 eq) in DMF (2 mL) was added 2-azaspiro[3.5]nonan-7-ol (19.3 mg, 0.137 mmol, 1.2 eq), EDCI (44 mg, 0.23 mmol, 2 eq), HOBt (30.8 mg, 0.23 mmol, 2.0 eq) and DIEA (60 μL, 44.2 mg, 0.342 mmol, 3 eq) with stirring at room temperature. The suspension turned into a brown suspension after 4 h stirring at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl solution (8 mL) at 0 °C (ice bath) and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases 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 and the residue was purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) under the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient program: 31% B to 61% B linear gradient elution for 7 min, hold at 61% B; wavelength: 254 nm; RT1: 6.15 min; injection volume: 1 mL; run number: 2. The product-containing fractions were combined and lyophilized to give the title compound (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) as a off-white solid (13.0 mg, 20.3% yield). LC / MS: MS (ESI): C 28 H 34 F3N5O4 calculated: 561.26, found: m / z = 562.30 [M+H] + . 1HNMR (300 MHz, Methanol-d4): d 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): d -64.52 ppm.

[0781] Example 26: 2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7- dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin-l-yl)-l-((S)-3-hydroxypyrrolidin-l- yl)ethan-l-one (26)

[0782]

[0783] Synthesis route:

[0784]

[0785] Step 1: Synthesis of 2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7- dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin-l-yl)-l-((S)-3-hydroxypyrrolidin-l- yl)ethan-l-one (26)

[0786] To a light 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 according to the procedure of Example 23) (100 mg, 0.228 mmol, 1 eq) in DMF (2 mL), (3S)-pyrrolidin-3-ol (23.9 mg, 0.274 mmol, 1.2 eq), EDCI (88 mg, 0.46 mmol, 2 eq), HOBt (61.6 mg, 0.456 mmol, 2 eq) and DIEA (119.2 μL, 88.44 mg, 0.684 mmol, 3.0 eq) were added at room temperature with stirring. The suspension turned brown after 4 h stirring at room temperature. The reaction was quenched at 0 °C by the addition of saturated aqueous NH4Cl (8 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with pure water (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator and the residue was purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) under the following conditions: column: Xselect CSH C18 OBD 30*150mm 5μm; mobile phase A: water (with 0.1% formic acid), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 40% B in 7 min; wavelength: 254 nm; RT1: 6.12 min; injection volume: 0.67 mL; number of runs: 3. The fractions containing the desired product were combined and lyophilized to give 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) as an off-white solid (9.3 mg, 8.0% yield). LC / MS: MS (ESI): C 24 H 28 F3N5O4 calculated: 507.20, found: 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. 19F NMR (282 MHz, methanol-d4): δ 64.55 ppm.

[0787] 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)

[0788]

[0789] Synthesis route:

[0790]

[0791] 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)

[0792] To a light 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 according to the procedure of Example 23) (100 mg, 0.23 mmol, 1 eq) in DMF (2 mL), (3R)-pyrrolidin-3-ol (23.9 mg, 0.27 mmol, 1.2 eq), EDCI (87.5 mg, 0.46 mmol, 2.0 eq), HOBT (61.6 mg, 0.46 mmol, 2.0 eq) and DIEA (119.2 μL, 88.44 mg, 0.68 mmol, 3.0 eq) were added with stirring at room temperature. The suspension turned into a brown suspension after stirring at room temperature for 4 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (8 mL) at 0 °C and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with water (3 x 20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) under the following conditions: column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 33% to 63% B over 7 min, hold at 63% B; wavelength: 254 nm; RT1: 6.63 min; injection volume: 0.9 mL; number of runs: 2). The fractions containing the desired product were combined and lyophilized 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-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one (27) as a colorless solid (12.0 mg, 10.4% yield). LC / MS: MS (ESI): C 24 H 28 F3N5O4 calculated: 507.21, found: m / z = 508.25 [M+H] + . 1H NMR (300 MHz, Methanol-d4): d 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): d 64.55 ppm.

[0793] 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)

[0794]

[0795] Synthesis route:

[0796]

[0797] Step 1: Synthesis of 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]ethenone (28)

[0798] To a light 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 according to the procedure of Example 23) (100 mg, 0.228 mmol, 1.0 eq) in DMF (2 mL), (3S,4S)-4-fluoropyrrolidin-3-ol (29 mg, 0.27 mmol, 1.2 eq), EDCI (88 mg, 0.46 mmol, 2.0 eq), HOBt (62 mg, 0.46 mmol, 2.0 eq) and DIEA (120 μL, 88.4 mg, 0.68 mmol, 3.0 eq) were added under stirring at room temperature. The suspension turned brown after 4 h stirring at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl solution (8 mL) at 0 °C and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with pure water (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure using a rotary evaporator and the residue was purified by preparative reverse phase high performance liquid chromatography (RP-HPLC) (chromatography conditions: column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient elution: 33% B to 63% B (7 min), hold 63% B; wavelength: 254 nm; RT1: 6.63 min; injection volume: 0.9 mL; number of runs: 2). The fractions containing the desired product were combined and lyophilized to give the title 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) as a light yellow solid (15.7 mg, 12.6% yield). LC / MS: MS (ESI): C 24 H 27 F4N5O4 calculated: 525.20, found: m / z = 526.20 [M+H] + . 1H NMR (300 MHz, Methanol-d4): d 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): d 64.54, 185.54 ppm.

[0799] Example 29: l-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-l-yl)-2-((R)-3-((4-(2-hydroxy-4- (trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin-l-yl)ethan- 1 -one (29)

[0800]

[0801] Synthesis route:

[0802]

[0803] Step 1: Synthesis of l-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-l-yl)-2-((R)-3-((4-(2- hydroxy-4-(trifluoromethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyridazin-l-yl)amino)piperidin- 1 -yl)ethan- 1 -one (29)

[0804] To a light 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 according to the procedure of Example 23) (150 mg, 0.34 mmol, 1.0 eq) in DMF (2 mL), (3R,4R)-4-fluoropyrrolidin-3-ol (50 mg, 0.514 mmol, 1.5 eq), HATU (156 mg, 0.41 mmol, 1.2 eq) and DIEA (179.2 μL, 133 mg, 1.03 mmol, 3.0 eq) were added with stirring at room temperature. The brown suspension was stirred at room temperature for 4 h. The reaction was quenched at 0 °C by the addition of saturated aqueous NH4Cl (8 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL) and the combined organic phases 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 residue was purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) under the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (containing 10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 36% B to 51% B (10 min), 51% B; wavelength: 254 / 220 nm; RT1: 7.78 min. After lyophilization of the fractions containing the product, 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 light yellow solid (14.3 mg, 5.3% yield). LC / MS: MS (ESI): C 24 H 27 F4N5O4 calculated: 525.20, found: m / z = 526.25 [M+H] + .1H-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.

[0805] 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)

[0806]

[0807]

[0808]

[0809] Step 1: Synthesis of tert-butyl (R)-3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidine-1-carboxylate

[0810] To a sealed tube, 3,6-dichloro-4,5-dimethylpyridazine (5.0 g, 28.2 mmol, 1.0 equiv), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (6.2 g, 28.2 mmol, 1.0 equiv), and DIEA (14.7 mL, 10.9 g, 84.6 mmol, 3.0 equiv) were added, along with anhydrous NMP (50.0 mL). The reaction tube was sealed and stirred at 150°C overnight. After cooling to room temperature, the crude reaction mixture was poured into water (300 mL), extracted with ethyl acetate (3 × 100 mL), and washed with 5 wt% aqueous lithium chloride solution (3 × 50 mL). All organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was purified using a Biotage Isolera system (equipped with a Biotage SFAR column, 40 g, HC, Duo, 20 μM) with a 0-5% MeOH / DCM gradient elution. Product-containing fractions were combined and concentrated on a rotary evaporator under reduced pressure to afford (R)-tert-butyl 3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidine-1-carboxylate as a pale yellow solid (1.0 g, 10.4% yield). LC / MS: m / z = 341.15 [M+H] + . 1 H NMR (400MHz, methanol-d4): δ4.32-4.29(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=0.9Hz,3H),2.23-2.05(m,2H),2.00-1.81(m,2H),1.44(s,9H)ppm.

[0811] Step 2: Synthesis of (R)-6-chloro-4,5-dimethyl-N-(piperidin-3-yl)pyridazin-3- amine

[0812] (R)-tert-butyl 3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidine-1- carboxylate (1.0 g, 2.9 mmol, 1.0 equiv) was placed in a flask and dissolved in anhydrous dioxane (5.0 mL). To the solution was added hydrogen chloride in dioxane (5.0 mL, 20 mmol, 4 M) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator to give the crude product. The crude product was purified by a Biotage Isolera purification system (equipped with a Biotage SFAR column, 4 g, HC, Duo, 20 μM) eluting with a gradient of 0-10% MeOH / dichloromethane. The product containing fractions were combined and concentrated under reduced pressure using a rotary evaporator to give (R)-6-chloro-4,5-dimethyl-N-(piperidin-3-yl)pyridazin-3-amine as a colorless solid (580 mg, 82.0% yield). 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.

[0813] Step 3: Synthesis of (R)-tert-butyl 2-(3-((6-chloro-4,5-dimethylpyridazin-3- yl)amino)piperidin-1-yl)acetate

[0814] To a reaction vial containing (R)-6-chloro-4,5-dimethyl-N-(piperidin-3-yl)pyridazin-3-amine (570 mg, 2.4 mmol, 1.0 eq), tert-butyl bromoacetate (462 mg, 2.4 mmol, 1.0 eq) and K2CO3(655 mg, 4.8 mmol, 2.0 eq) was added anhydrous ACN (5 mL). The reaction mixture was stirred at 80 °C in a sealed tube overnight. After cooling to room temperature, the crude reaction was poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator to give the crude product. The crude product was purified by a Biotage Isolera purification system (equipped with a Biotage SFAR column, 4 g, HC, Duo, 20 μM) eluting with a gradient of 0-4% MeOH / dichloromethane. Fractions containing product were combined and concentrated under reduced pressure using a rotary evaporator to give (R)-tert-butyl 2-(3-((6-chloro-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetate as a colorless solid (460 mg, 57.1% yield). 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.

[0815] Step 4: Synthesis of (R)-tert-butyl 2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0816] In a sealed tube was added (R)-tert-butyl 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), Na2CO3(787 mg, 5.7 mmol, 3.0 equiv) and Pd(PPh3)4(231 mg, 0.2 mol, 0.1 equiv) and dioxane (4 mL). The reaction mixture was stirred at 110 °C under N2atmosphere overnight. After cooling to room temperature, the crude reaction was poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator to give the crude product. The crude product was purified by Biotage Isolera purification system (equipped with Biotage SFAR column, 4 g, HC, Duo, 20 μM) eluting with 0-4% MeOH / dichloromethane gradient and concentrated to give (R)-tert-butyl 2-(3-((6-(2-hydroxy-4- (trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)amino)piperidin-1-yl)acetate as a light yellow solid (500 mg, 82.1% yield). 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.

[0817] Step 5: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5- dimethylpyridazin-3-yl)amino)piperidin-l-yl)acetic acid + . 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.

[0818] Step 6: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5- dimethylpyridazin-3-yl)amino)piperidin-l-yl)-l-(4-hydroxypiperidin-l-yl)ethan-l-one (30)

[0819] In 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 under N2atmosphere overnight. After cooling to room temperature, the crude reaction mixture was concentrated under reduced pressure by rotary evaporator to give the crude product. The crude product was purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) (using a gradient elution of ACN / water mixed solvents containing 0.3% formic acid, 5-95% gradient, 30 min), and the fractions containing the target compound were lyophilized to give (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 as a colorless solid (37.9 mg, 29.9% recovery yield). 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.

[0820] 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)

[0821]

[0822] Synthesis route

[0823]

[0824] Step 1: Synthesis of (R)-tert-butyl 3-((6-chloro-4-methylpyridazin-3- yl)amino)piperidine-1-carboxylate

[0825] To a sealed tube was added 3,6-dichloro-4-methylpyridazine (5.0 g, 30.7 mmol, 1.0 equiv), (R)-tert-butyl 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) followed by anhydrous NMP (50 mL). The reaction mixture was stirred at 150 °C in a sealed tube overnight. After cooling to room temperature, the crude reaction mixture was poured into 500 mL of water and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator to give the crude product. The crude product was purified on a Biotage Isolera system (equipped with a Biotage SFAR column, 80 g, HC, Duo, 20 pm) eluting with a gradient of 10-33% EtOA / Hex. The first fraction was unreacted 3,6-dichloro-4-methylpyridazine (2.7 g, 55.0% recovery). The second fraction gave the target product (R)-tert-butyl 3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (B) as a light yellow foamy solid (595 mg, 6.0% yield). The last fraction gave (R)-tert-butyl 3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (A) as an off-white foamy solid (1.5 g, 15.0% yield). (R)-tert-butyl 3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (B): TLC: RE / EA = 2:1, 254 nm, Rf = 0.40. LC / MS: m / z = 327.20 [M+H] f . + . 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.

[0826] Step 2: Synthesis of (R)-6-chloro-4-methyl-N-(piperidin-3-yl)pyridazin-3-amine hydrochloride

[0827] To a flask containing (R)-tert-butyl 3-((6-chloro-4-methylpyridazin-3- yl)amino)piperidine-l-carboxylate (B) (400 mg, 1.8 mmol, 1.0 equiv) was dissolved in anhydrous dioxane (4.0 mL) followed by the addition of HC1 (4.0 mL, 16 mmol, 4M in 1,4-dioxane). The reaction mixture was stirred at room temperature for 1 h. Concentrated under reduced pressure using a rotary evaporator to give (R)-6-chloro-4-methyl-N-(piperidin-3-yl)pyridazin-3-amine hydrochloride as a yellow solid (ca. 400 mg) which was used directly in the next step without further purification and characterization. LC / MS: m / z = 227.20 [M+H] + .

[0828] Step 3: Synthesis of (R)-tert-butyl 2-(3-((6-chloro-4-methylpyridazin-3- yl)amino)piperidin-l-yl)acetate

[0829] To a flask containing (R)-6-chloro-4-methyl-N-(piperidin-3-yl)pyridazin-3-amine hydrochloride (ca. 400 mg, ca. 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) was added anhydrous ACN (4 mL). The reaction mixture was stirred at 80 °C overnight. After cooling to room temperature, the crude reaction was poured into 200 mL of water and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4and concentrated under reduced pressure using a rotary evaporator to give the crude product. The crude product was purified by Biotage Isolera purification system (Biotage SFAR 12 g HC Duo 20 μm column) eluting with a gradient of 0-38% ethyl acetate / petroleum ether. The product containing fractions were combined and concentrated under reduced pressure to give (R)-tert-butyl 2-(3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidin-l-yl)acetate as a light yellow oil (300.0 mg, 49.9% yield). 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.

[0830] Step 4: Synthesis of (R)-tert-butyl 2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)- 4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0831] To a flask containing (R)-tert-butyl 2-(3-((6-chloro-4-methylpyridazin-3- yl)amino)piperidin-1-yl)acetate (300 mg, 0.9 mmol, 1.0 equiv) was added (2- hydroxy-4-(trifluoromethyl)phenyl)boronic acid (278 mg, 1.3 mmol, 1.5 equiv), 2M Na2CO3(286.2 mg, 2.7 mmol, 3.0 equiv), Pd(PPh3)4(104 mg, 0.1 mmol, 0.1 equiv) and dioxane (3 mL). The reaction mixture was stirred at 110 °C under N2atmosphere overnight. After cooling to room temperature, the crude product solution was poured into 100 mL of water and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product was purified by a Biotage Isolera system using a Biotage SFCR 4g HC Duo 20 pm column with a gradient of 0-6% MeOH / DCM. The fractions containing the desired compound were collected and concentrated to yield (R)-tert-butyl 2-(3-((6-(2-hydroxy-4- (trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate as a light yellow solid (150.0 mg, 36.5% yield). LC / MS: m / z = 467.20 [M+H] + . 1 H NMR (400 MHz, Chloroform-d): d 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.

[0832] Step 5: Synthesis of (R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4- methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid

[0833] To a solution of (R)-tert-butyl 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) in anhydrous DCM (2 mL) was added TFA (2.0 mL). The reaction mixture was stirred at room temperature for 1 h. 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 as a yellow solid (ca. 300 mg), which was used directly in the next step without purification. LC / MS: m / z = 411.30 [M+H] + .

[0834] Step 6: Synthesis of 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)

[0835] To a reaction vial 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) was added (S)-pyrrolidin-3-ol hydrochloride (33.1 mg, 0.3 mmol, 1.0 equiv), EDCI (172.4 mg, 0.9 mmol, 3.0 equiv), and pyridine (2 mL). The reaction mixture was stirred at 50 °C under N2atmosphere overnight. After cooling to room temperature, the crude product was concentrated under reduced pressure using a rotary evaporator and purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) using ACN / water mixed solvents containing 0.3% formic acid with gradient elution ratio 5-95% for 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) as a yellow solid (22.7 mg, yield 17.7%). LC / MS: m / z = 480.45 [M+H] + . 1 H NMR (400 MHz, Methanol-d4): δ

[0836] 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): d -64.55 (s) ppm.

[0837] 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)

[0838]

[0839] Synthetic Route

[0840]

[0841] 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)

[0842] To a reaction vial containing (R)-2-(3-((6-(2-hydroxy-4- (trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (prepared according to the procedure of 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) was added pyridine (2.0 mL). The reaction mixture was stirred at 50 °C under N2atmosphere overnight. After cooling to room temperature, the crude reaction was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product was purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) (using ACN / water mixtures containing 0.3% formic acid, eluting with a gradient of 5-95% ACN / water over 30 minutes) 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) as a colorless solid (51.8 mg, 27.7% yield). 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.

[0843] 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)

[0844]

[0845] Synthetic Route

[0846]

[0847] Step 1: Synthesis of (R)-tert-butyl 3-((4-chlorophthalazin-1-yl)amino)piperidine-1- carboxylate

[0848] To a sealed tube was added 1,4-dichlorophthalazine (500 mg, 2.5 mmol, 1.0 equiv), (R)-tert-butyl 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) followed by anhydrous NMP (5.0 mL). The reaction tube was sealed and stirred at 80 °C overnight. After the reaction mixture was cooled to room temperature, the crude product solution was poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with 5 wt% aqueous lithium chloride solution (3 times). After all the organic layers were combined, they were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to give the crude product, which was then purified by a Biotage Isolera purification system (equipped with a Biotage SFAR column, 4 g, HC, Duo, 20 μM) eluting with a gradient of 0-5% MeOH / dichloromethane. After the product containing fractions were concentrated, (R)-tert-butyl 3-((4-chlorophthalazin-1-yl)amino)piperidine-1-carboxylate was obtained as a light yellow solid (657 mg, 72.0% yield). LC / MS: m / z = 363.10 [M+H] + . 1HNMR (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.

[0849] Step 2-5: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)piperidin-1-yl)acetic acid

[0850] (R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)piperidin-1- yl)acetic acid was prepared from (R)-tert-butyl 3-((4-chlorophthalazin-1-yl)amino)piperidine-1- carboxylate by the exact same four-step reaction sequence as described above for (R)-2-(3-((6-(2- hydroxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid. The product was a yellow solid and was used directly in the next reaction. LC / MS: m / z = 447.20 [M+H] + .

[0851] 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)

[0852] To a reaction 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) was added pyridine (2.0 mL). The reaction was stirred at 50°C under a nitrogen atmosphere overnight. After cooling to room temperature, the crude reaction solution was concentrated under reduced pressure on a rotary evaporator, and the crude product was purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) using an ACN / water gradient (acidified with 0.3 vol% formic acid). The product-containing fractions were combined and lyophilized to obtain 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 as an off-white solid (29.0 mg, 15.3% yield). LC / MS: 530.25 [M+H] + . 1 H NMR (400MHz, methanol-d4): δ8.39(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 = 3.8Hz, 2H) ppm. 19 F NMR (376 MHz, methanol-d4): δ -64.34 (s) ppm.

[0853] 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)

[0854]

[0855] Synthesis route

[0856]

[0857] Step 1-2: Synthesis of (R)-2-(3-((4-(4-fluoro-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid

[0858] The product (196.0 mg, yield 52.5%) was prepared as a light yellow solid according to the method for preparing (R)-2-(3-((4-(2-hydroxy-4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid (Example 33) with (4-fluoro-2-hydroxyphenyl)boronic acid as the starting material. LC / MS: (ESI): C 21 H 21 FN4O3Calcd: 396.16; Found: m / z = 397.15 [M+H] + . 1 H 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), 7.28 (t, J = 7.7 Hz, 1H), 6.77 - 6.42 (m, 2H), 4.55 (s, 1H), 3.50 (s, 2H), 3.39 - 3.28 (m, 1H), 3.08 - 2.85 (m, 1H), 2.64 - 2.35 (m, 2H), 1.96 (s, 1H), 1.80 (s, 1H), 1.73 (d, J = 8.3 Hz, 1H), 1.66 - 1.53 (m, 1H) ppm. 19 F NMR (376 MHz, DMSO-d6): δ -110.52 - -110.61 (m) ppm.

[0859] Step 3: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-fluorophenyl)phthalazin-1- yl)amino)piperidin-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one (34)

[0860] (R)-2-(3-((4-(4-fluoro-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid (90.0 mg, 0.2 mmol, 1.0 equiv), 4-hydroxypiperidine (48.0 mg, 0.5 mmol, 1.0 equiv) and EDCI (276.0 mg, 1.4 mmol, 3.0 equiv) were placed in a reaction vial, and pyridine (2.0 mL) was added. The reaction mixture was stirred at 50 °C under N2atmosphere overnight. After cooling to room temperature, the crude product was concentrated under reduced pressure with a rotary evaporator. Purification was performed by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) (ACN / water mixed solvent with 0.3% formic acid, gradient elution 5-95% ACN / water, 30 min), and the fractions containing the product were lyophilized to give the target compound (R)-2-(3-((4-(2-hydroxy-4-fluorophenyl)phthalazin-1-yl)amino)piperidin-1-yl)-1-(4- hydroxypiperidin-1-yl)ethan-1-one (34) as a light yellow solid (81.6 mg, 35.5% yield). LC / MS: (ESI): C 26 H 30 FN5O3 calculated: 479.23; found: m / z = 480.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.38-8.30 (m, 1H), 7.82 (d, J = 9.7 Hz, 1H), 7.74 (s, 1H), 7.56-7.49 (m, 1H), 7.18 (s, 2H), 7.03 (d, J = 6.3 Hz, 1H), 6.59 (s, 2H), 4.38 (s, 1H), 4.06 (d, J = 26.1 Hz, 1H), 3.85 (s, 1H), 3.71 (s, 1H), 3.54 (s, 1H), 3.43 (s, 2H), 3.17 (s, 2H), 3.06 (s, 1H), 3.08-2.95 (m, 1H), 2.80 (s, 2H), 2.01 (s, 4H), 1.78 (s, 2H), 1.63-1.38 (m, 4H), 1.23 (s, 1H) ppm. 19 F NMR (376 MHz, DMSO-d6): δ -117.74 - -112.96 (m) ppm.

[0861] Example 35: (S)-1-(2-((R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,7- dihydrofuro[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)ethyl)pyrrolidin-3-ol (35)

[0862]

[0863] Synthesis route:

[0864]

[0865] Step 1: Synthesis of (S)-1-(2,2-dimethoxyethyl)pyrrolidin-3-ol

[0866] To a solution of (S)-pyrrolidin-3-ol (500 mg, 5.75 mmol, 1.0 eq) in 1,4-dioxane (10 mL) was added 2-bromo-1,1-dimethoxyethane (1.05 mL, 1.5 g, 8.62 mmol, 1.5 eq) and K2CO3(2.40 g, 17.24 mmol, 3.0 eq). The reaction mixture was stirred at 100 °C for 24 h. After filtration, the suspension was concentrated under reduced pressure using a rotary evaporator to give crude (S)-1-(2,2-dimethoxyethyl)pyrrolidin-3-ol (500 mg), which was used directly in the next step without purification and characterization.

[0867] Step 2: Synthesis of (S)-2-(3-hydroxypyrrolidin-1-yl)acetaldehyde

[0868] The crude (S)-1-(2,2-dimethoxyethyl)pyrrolidin-3-ol (500 mg) was dissolved in 5 mL of 6 M hydrochloric acid (aqueous HCl). After stirring at 100 °C for 24 h, the suspension was concentrated under reduced pressure using a rota...

Claims

1. A compound represented by the structure of formula (1-I): or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; W is selected from NH, N-Me, N-Et, and N-iPr, or is a single bond; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1' and R1 together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, and -CF3; R3 is selected from H, C1-C3 alkyl, and -CF3; or R3 and R2 together form a 5-membered or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, and is optionally substituted with -Me or -OH; 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, C1-C6 cycloalkyl, and -CF3; or R6 and R6' together with the atoms to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; Y is a single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups or -CF3; and n is 1, 2, 3 or 4.

2. The compound according to claim 1, wherein Selected from 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.

3. The compound according to claim 2, wherein is selected from 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, and 7-azaspiro[3.5]nonane, W is a single bond, Y is a single bond, and R4 is H.

4. The compound according to claim 1-3, wherein R1 is -CF3; R2 is methyl; R3 is H or methyl; or R2 and R3 form a 5-membered non-aromatic ring, which is an all-carbon ring or contains O; R5 is H.

5. The compound according to claim 1, further represented by any one of the following:

6. The compound according to claim 1, further represented by any one of the following:

7. The compound according to claim 1, further represented by any one of the following:

8. A compound represented by the structure of formula (I-II): or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-11 membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, and -CF3; R3 is selected from H, C1-C3 alkyl, and -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, said ring being an all-carbon ring or containing O or N, optionally substituted by -Me or -OH; Y is a single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups or -CF3; 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, C1-C6 cycloalkyl, and -CF3; or R6 and R6' together with the atoms to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is 2, 3 or 4.

9. The compound according to claim 8, wherein ring Selected from pyrrolidine, piperidine, and azetidine; R1 is -CF3; R2 is methyl; R3 is H or methyl; or R2 and R3 form a 5-membered non-aromatic ring, which is an all-carbon ring or contains O; R4 is H or F; Y is a single bond; and R5 is H.

10. The compound according to claim 8, further represented by any one of the following:

11. The compound according to claim 8, further represented by any one of the following:

12. A compound represented by the structure of formula (I-III): or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; ring is a 4-7 membered cycloalkyl ring or a substituted cycloalkyl ring; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, and -CF3; R3 is selected from H, C1-C3 alkyl, and -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, said ring being an all-carbon ring or containing O or N, optionally substituted by -Me or -OH; R4 is selected from H, -F, C1-C3 alkyl, and -CF3; as well as Y is a single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups or -CF3.

13. The compound according to claim 12, wherein ring is piperidine, pyrrolidine, or azetidine; is cyclobutane, cyclopentane, or cyclohexane; R1 is -CF3; R2 is methyl; R3 is H or methyl; or R2 and R3 form a 5-membered non-aromatic ring, which is an all-carbon ring or contains O; R4 is H; and Y is a single bond.

14. The compound according to claim 12, further represented by any one of the following:

15. A compound represented by the structure of formula (I-IV): or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; ring is a 4-7 membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, and -CF3; R3 is selected from H, C1-C3 alkyl, and -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, and is optionally substituted with -Me or -OH; Y is a single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups or -CF3; R4 is selected from H, -F, C1-C3 alkyl, and -CF3; and R5 is selected from -H, -Me, and -CF3.

16. The compound according to claim 15, wherein ring selected from azetidine, pyrrolidine, and piperidine; Selected from azetidine, pyrrolidine, and piperidine; R1 is -CF3; R2 is methyl; R3 is H or methyl; or R2 and R3 form a 5-membered non-aromatic ring, which is an all-carbon ring or contains O; R4 is H; Y is a single bond.

17. The compound according to claim 15, further represented by any one of the following:

18. A compound represented by the structure of formula (I-V): or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; W is NH, N-Me, N-Et, N-iPr, or a single bond; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, -CF3; R4 is selected from H, -F, C1-C3 alkyl, and -CF3; Y is a single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups 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 atoms to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is 1, 2, 3 or 4.

19. The compound according to claim 18, wherein Selected from 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.

20. The compound according to claim 19, wherein is selected from 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, and 7-azaspiro[3.5]nonane, W is a single bond, R1 is -CF3; R2 is methyl; R4 is H; and Y is a single bond.

21. The compound of claim 18, further represented by any one of the following:

22. A compound represented by the structure of formula (I-VI): in, ring is an optionally substituted 4-7 membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; ring is an optionally substituted 4-7 membered cycloalkyl ring or a substituted cycloalkyl ring; R1 is selected from -CN, -H, -F, and -CF3; R1' is -H; or R1 and R1' together form a thiophene ring; R2 is selected from -H, C1-C3 alkyl, and -CF3; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; R5 is selected from -H, -Me, and -CF3; as well as Y is a single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups or -CF3.

23. The compound of claim 22, further represented by any one of the following:

24. A compound represented by the structure of formula (I-VII): in, ring is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from -H, C1-C3 alkyl, -CF3; 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, C1-C6 cycloalkyl, and -CF3, or R6 and R6' together with the atoms 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 single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups or -CF3.

25. The compound of claim 24, further represented by any one of the following:

26. A compound represented by the structure of formula (I-VIII): in, ring is a 4-11 membered cycloalkyl, heterocycloalkyl, substituted cycloalkyl, or substituted heterocycloalkyl ring; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from -H, C1-C3 alkyl, and -CF3; 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, and -CF3, or R6 and R6' together with the atoms 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 single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups or -CF3.

27. The compound of claim 26, further represented by any one of the following:

28. A compound represented by the structure of formula (I-IX): or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-11 membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, -CF3; R3 is selected from H, C1-C3 alkyl, and -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, and is optionally substituted with -Me or -OH; 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, C1-C6 cycloalkyl, and -CF3, or R6 and R6' together with the atoms 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 single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups or -CF3.

29. The compound according to claim 28, wherein ring Selected from pyrrolidine, piperidine, and azetidine; R1 is -CF3; R2 is methyl; R3 is H or methyl; or R2 and R3 form a 5-membered non-aromatic ring, which is an all-carbon ring or contains O; R4 is H or F; R5 is H; and Y is a single bond.

30. The compound of claim 28, further represented by any of the following:

31. A compound represented by the structure of formula (2-1): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-11 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring; W is selected from NH, N-Me, N-Et, and N-iPr, or W is a single bond; R1 is selected from -CN, -H, -F, and -CF3; R1' is -H; or R1 and R1' together form a thiophene ring; R2 and R3 are each selected from -H, C1-C3 alkyl, and -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring containing all carbon or at least one O or N, optionally substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; Y is a single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups 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 atoms 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 selected from -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, 32. The compound according to claim 31, wherein The ring is spiro or bicyclic cycloalkyl, substituted spiro or bicyclic cycloalkyl, spiro or bicyclic heterocycloalkyl, or substituted spiro and bicyclic heterocycloalkyl.

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

34. The compound according to claims 31 to 33, wherein R1 is -F or -CF3; R1' is -H; R2 is -H, -Me, or -CF3; R3 is -H or -Me; or R3 and R2 together form a 5-membered or 6-membered aromatic or non-aromatic ring containing all carbon atoms 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.

35. The compound of claim 31 , further represented by any of the following:

36. A compound represented by the structure of formula (2-II): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-11 membered nitrogen-containing heterocycloalkyl ring or a substituted heterocycloalkyl ring; W is selected from NH, N-Me, N-Et, and N-iPr, or is a single bond; R1 is selected from -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 H, C1-C3 alkyl, and -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, and is optionally substituted with -Me or -OH; 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 atoms to which they are attached form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl ring; and n is 1, 2, 3 or 4.

37. The compound according to claim 36, wherein ring It is a 4-11 membered spiro or bicyclic nitrogen-containing heterocycloalkyl group.

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

39. A compound according to any one of claims 36 to 38, wherein R1 is selected from -F or -CF3; R1' is -H; R2 is -H, -Me, or -CF3; R3 is selected from -H or -Me, or R2 and R3 form a 5-membered or 6-membered aromatic ring or non-aromatic ring, which is an all-carbon ring or contains O; R4 is -H or -Me; R5 is selected from -H and -Me; R6 and R6' are -H; n is 1.

40. The compound of claim 36, further represented by any of the following:

41. A compound represented by the structure of formula (2-III): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein ring is a 4-11 membered heterocycloalkyl or substituted heterocycloalkyl ring; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, -CF3; R3 is selected from H, C1-C3 alkyl, -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, and is optionally 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 is a single bond.

42. The compound according to claim 41, wherein ring It is a 4-9 membered nitrogen-containing spiro ring or a bicyclic nitrogen-containing heterocycloalkyl ring.

43. The compound according to claim 42, wherein W2 is -CH2-, -CH2CH2-, or a single bond.

44. A compound according to any one of claims 41 to 43, wherein R1 is -F or -CF3; R1' is -H; R2 is -H, -Me, or -CF3, or R2 and R3 form a 5-membered or 6-membered non-aromatic ring, which is an all-carbon ring or contains O; R4 is -H or -Me; R5 is selected from -H and -Me.

45. The compound of claim 41 , further represented by any of the following:

46. ​​A compound represented by the structure of formula (2-IV): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: ring is a 4-11 membered cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, -CF3; R3 is selected from H, C1-C3 alkyl, -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, and is optionally substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; R5 is selected from -H, -Me, and -CF3; W3 is selected from optionally substituted -CH2-, -CH2CH2- and -CH2CH2CH2-, or is a single bond; Y is a single bond or a C1-C3 alkyl group optionally substituted with 1, 2 or 3 C1-C3 alkyl groups or -CF3; and R7 is selected from -H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, 47. The compound according to claim 46, wherein ring is a 4-6 membered cycloalkyl ring or a heterocycloalkyl ring.

48. The compound according to claim 47, wherein W3 is selected from -CH2- and -CH2CH2-, or is a single bond; Y is a single bond.

49. A compound according to any one of claims 46 to 48, wherein R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, -CF3; R3 is selected from -H or -methyl, or R2 and R3 form a 5-membered or 6-membered aromatic ring or non-aromatic ring, which is a full carbon ring or contains O; R4 is -H or -Me; R5 is selected from -H and -Me; R7 is -H.

50. The compound of claim 46, further represented by any of the following:

51. A compound represented by the structure of formula (2-V): or a pharmaceutically acceptable salt, solvate, isomer, atropisomer, or tautomer thereof, wherein: ring is azetidine, pyrrolidine, piperidine, or azepane; R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, -CF3; R3 is selected from H, C1-C3 alkyl, -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, and is optionally substituted with -Me or -OH; R4 is selected from -H, -F, C1-C3 alkyl, and -CF3; R5 is selected from -H, -Me, and -CF3; and R 12 Selected from: Where m is 1, 2 or 3, each R 13 Independently selected from -H, C1-C3 alkyl, and -CF3; or two R 13 The groups are linked to form a cyclopropyl or cyclobutyl ring.

52. The compound according to claim 51, wherein ring is azetidine or piperidine.

53. The compound according to claim 52, wherein R1 is selected from -F, -CF3; R1' is -H; R2 is selected from -H, -Me, and -CF3; R3 is selected from -H or -Me, or R2 and R3 form a 5-membered or 6-membered aromatic ring or non-aromatic ring, the ring is a full carbon ring or contains O; R4 is -H or -Me; R5 is selected from -H and -Me; R 12 Select any one of the following:

54. The compound of claim 51 , further represented by any of the following:

55. A compound represented by the structure of formula (2-VI): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, and -CF3; R3 is selected from H, C1-C3 alkyl, and -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, and is optionally substituted with -Me or -OH; R5 is selected from -H, -Me, and -CF3; W4 is selected from -CH2-, -CH2CH2-, R8 and R8' are independently selected from -H, C1-C5 alkyl, C1-C5 cycloalkyl, and -CF3; and R9 is selected from -H, C1-C6 alkyl, C1-C6 cycloalkyl, heterocycloalkyl, 56. The compound according to claim 55, wherein 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 R2 and R3 form a 5-membered or 6-membered aromatic ring or non-aromatic ring, which is a full carbon ring or contains O; R5 is selected from -H and -Me.

57. The compound according to claim 56, wherein W4 is selected from -CH2- or R8 and R8' are -H; n is 1; and R9 is -H.

58. The compound according to claims 55 to 57, wherein R8 and R8' are -H; n is 1; R9 is selected from 59. The compound of claim 55, further represented by any of the following:

60. The compound of claim 55, further represented by any of the following:

61. A compound represented by the structure of formula (2-VII): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, atropisomer, or tautomer thereof, wherein: R1 is selected from -CN, -H, -F, and -CF3; R1' is H; or R1 and R1' together form a thiophene ring; R2 is selected from H, C1-C3 alkyl, and -CF3; R3 is selected from H, C1-C3 alkyl, and -CF3; or R2 and R3 together form a 5-membered or 6-membered aromatic or non-aromatic ring, which is an all-carbon ring or contains O or N within the ring, and is optionally 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, C1-C6 cycloalkyl, and -CF3; or R6 and R6' together with the atoms 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 'Independently selected from H, C1-C5 alkyl (including cycloalkyl), and -CF3; or R 14 and R 14 'Together with the atoms to which they are attached, they form an optionally substituted C3-C6 cycloalkyl or an optionally substituted C3-C6 heterocycloalkyl ring; R 10 Selected from -H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl, as well as R 11 Selected from H, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 methylcycloalkyl.

62. The compound according to claim 61, wherein R1 is -F or -CF3; R1' is H; R2 is -H, -Me, or -CF3; R3 is -H or -Me, or R2 and R3 form a 5-membered or 6-membered aromatic ring or non-aromatic ring, which is a full carbon ring or contains O; R5 is selected from -H and -Me; R6 and R6' are -H; n is 1; R 14 and R 14 ' is -H; R 10 -H; R 11 Selected from -H or -Me.

63. The compound of claim 61 , further represented by any of the following:

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. A method for 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 method of claim 65, wherein The disease is selected from the group consisting of: age-related macular degeneration (wet and dry) (AMD), atrophic macular degeneration, bacterial keratitis, bacterial infection of the eye, bacterial corneal ulcer, bacterial keratitis, Behçet's syndrome, cataract, choroidal neovascularization, cytomegalovirus retinitis, chronic eye disease, 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' corneal endothelial dystrophy, fungal endophthalmitis, fungal keratitis, fungal infection of the eye, glaucoma (acute and non-acute), geographic atrophy (GA), inflammatory eye disease, hereditary Ocular keratitis (KFH), lipopolysaccharide-induced ocular inflammation, Mooren's ulcer (MU), neuronal death in retinal ischemia / reperfusion injury, ocular hypertension, related ocular inflammation, ocular manifestations of rheumatoid arthritis and systemic lupus erythematosus (SLE), limbal squamous cell carcinoma, optic neuritis, ocular parasitic infection, pathological neovascularization, retinal hyperexcitability, lipofuscin and A2E-mediated oxidative damage (including, but not limited to, ROS / oxidative stress reduction), retinal ganglion cell (RGC) dysfunction and stress-induced death induced by ocular hypertension (OHT) (OHT-type glaucoma), retinoblastoma, retinitis, retinal vasculitis, retinal vein occlusion (RVO), syndrome, sterile corneal inflammation, diabetic stroke-induced retinal damage, traumatic optic neuropathy / trauma (optic nerve crush, including, but not limited to, progressive optic neuropathy), ulcerative keratitis, uveal melanoma, uveitis (anterior / middle / posterior uveitis, panuveitis), and viral infections of the eye.

67. The method of claim 65, wherein The disease is characterized by disease progression involving the active effects of IL-1β and IL-18, or both.

68. The method according to 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, Behçet's syndrome, choroidal neovascularization, chronic eye diseases, diabetic macular edema (DME), diabetic retinopathy (DR), dry eye (DED), glaucoma (acute and non-acute), geographic atrophy (GA), retinopathy, inflammatory eye disease, ocular inflammation associated with cryopyrin-associated periodic syndrome (CAPS), ocular manifestations of rheumatoid arthritis and systemic lupus erythematosus (SLE), retinitis, retinal vasculitis, retinal vein occlusion (RVO), progressive optic neuropathy, and uveitis (anterior / middle / posterior uveitis, panuveitis).

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

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

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

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

73. The method according to any one of claims 65 to 71, wherein The method comprises administering at least one other form of therapy.

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

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