Cot modulators and methods of use thereof

Abstract

To provide a method for treating a disease.SOLUTION: The present disclosure relates generally to modulators of Cot (cancer Osaka thyroid) of general formula (I) and methods of use and manufacture thereof. The present disclosure provides compounds that modulate the expression or activity of Cot. The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds. The compounds provided herein can be useful in treating diseases, disorders, or conditions that are mediated by Cot. The disclosure also provides compounds for use in therapy. The disclosure further provides compounds for use in a method of treating a disease, disorder, or condition that is mediated by Cot. Moreover, the disclosure provides uses of compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by (or mediated, at least in part, by) Cot.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 861,390, filed June 14, 2019, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to modulators of Cot (cancer Osaka thyroid) and methods of use and production thereof. [Background technology]

[0003] The Cot (Osaka-type thyroid carcinoma) protein is a serine / threonine kinase that is a member of the MAP kinase kinase kinase (MAP3K) family. The Cot protein is also known as "TPL2" (tumor progression locus), "MAP3K8" (mitogen-activated protein kinase kinase kinase 8), or "EST" (Ewing's sarcoma transforming element). Cot was identified by its tumorigenic transforming activity in cells and has been shown to regulate tumorigenic and inflammatory pathways.

[0004] Cot is known to be upstream in the MEK-ERK pathway and is essential for LPS-induced production of tumor necrosis factor-α (TNF-α). Cot has been shown to be involved in both TNFα production and signal transduction. TNFα is a proinflammatory cytokine that plays an important role in inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), diabetes, sepsis, psoriasis, misregulation of TNFα expression, and transplant rejection.

[0005] Therefore, agents and methods that modulate the expression or activity of Cot may be useful in preventing or treating such diseases. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides compounds that modulate the expression or activity of Cot. The disclosure also provides compositions, including pharmaceutical compositions, kits, including the compounds, as well as methods of using (or administering) the compounds and methods of producing the compounds. The compounds provided herein may be useful in treating a disease, disorder, or condition mediated by Cot. The disclosure also provides compounds for use in therapy. The disclosure further provides compounds for use in methods of treating a disease, disorder, or condition mediated by Cot. Additionally, the disclosure provides the use of a compound in the manufacture of a medicament for the treatment of a disease, disorder, or condition mediated by Cot (or at least partially mediated by Cot).

[0007] In one aspect, Formula I: [ka] A compound having the structure: R 1 But hydrogen, -OR 7 , -N(R 8 )(R 9 ), -C(O)-R 7 , -S(O)2-R 7 , -C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, and heteroaryl each optionally have 1 to 4 Z 1 may be substituted with R 2 is hydrogen, -C(O)-R 7 , -C(O)OR 7 , -C(O)N(R 7 )2, C 1~9 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 2 may be substituted with or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains 1 to 4 Z 2 is replaced by R 3 is heterocyclyl or heteroaryl, wherein each heterocyclyl or each heteroaryl optionally has 1 to 4 Z 3 is replaced by R 4 is aryl, heterocyclyl, or heteroaryl, wherein each aryl, each heterocyclyl, or each heteroaryl is optionally joined to one to four Z 4 is replaced by R 5 But hydrogen, halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R7 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 5 may be substituted with R 6 But -C(O)OR 16 -OP(O)(OR 12 )2-C(O)-R 16 -OP(O)(OR 12 )2, -R 16 -OP(O)(OR 12 )2, -C(O)OR 16 -OR 17 ;-C(O)OR 16 -OH;-C(O)OR 16 -OC(O)R 17 ;-C(O)-C(O)OR 12 ; or -C(O)OR 16 -OC(O)R 17 NH2, Each R 7 are independently hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 7 may be substituted with R 8 and R 9 independently at each occurrence, hydrogen, -S(O)R 10 , -C(O)-R 10 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl each optionally having 1 to 4 Z 8 may be substituted with R 10 and R 11 independently at each occurrence: hydrogen, C 1~9 Alkyl, C 2~6 Arkeny Lu, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 1b is replaced by Z 1 , Z 2 , Z 3 , Z 4 , Z 5, Z 6 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -NR 12 S(O)2N(R 13 )(R 14 ), -NR 12 S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)-N(R 13 )(R 14 ), -P(O)(OR 12 )2, -OP(O)(OR 12 )2, -CH2P(O)(OR 12 )2, -OCH2P(O)(OR 12 )2, -C(O)OCH2P(O)(OR 12 )2, -P(O)(R 12 )(OR 12 ), -OP(O)(R 12 )(OR 12 ), -CH2P(O)(R 12 )(OR 12 ), -OCH2P(O)(R 12)(OR 12 ), -C(O)OCH2P(O)(R 12 )(OR 12 ), -P(O)(N(R 12 )2)2, -OP(O)(N(R 12 )2)2, -CH2P(O)(N(R 12 )2)2, -OCH2P(O)(N(R 12 )2)2, -C(O)OCH2P(O)(N(R 12 )2)2, -P(O)(N(R 12 )2)(OR 12 ), -OP(O)(N(R 12 )2)(OR 12 ), -CH2P(O)(N(R 12 )2)(OR 12 ), -OCH2P(O)(N(R 12 )2)(OR 12 ), -C(O)OCH2P(O)(N(R 12 )2)(OR 12 ), -P(O)(R 12 )(N(R 12 )2), -OP(O)(R 12 )(N(R 12 )2), -CH2P(O)(R 12 )(N(R 12 )2), -OCH2P(O)(R 12 )(N(R 12 )2), -C(O)OCH2P(O)(R 12 )(N(R 12 )2), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR 12 , -OC(O)-N(R 13 )(R 14 ), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, Each R 12 are independently hydrogen, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15cycloalkyl, aryl, heteroaryl, or heterocyclyl; Among these, any of alkyl, alkenyl, alkynyl, cycloalkyl, aryl aryl, heteroaryl or heterocyclyl optionally having 1 to 4 Z 1b is substituted with a group, R 13 and R 14 each occurrence independently represents hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b or R 13 and R 14 together with the nitrogen to which they are attached form a heterocyclyl, wherein the heterocyclyl optionally contains 1 to 4 Z 1b is replaced by Each R 15 are independently halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R 7 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; R 16 However, in some cases, 1 to 4 C 1~3 alkyl- or cyclopropyl-substituted, -C 1~3 alkyl or cyclopropyl; R 17 However, in some cases, 1 to 3 R 16 Replaced by C 1~9 alkyl, cycloalkyl, or heterocyclyl; and Z 1 , Z 2 , Z 4 , Z 5 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -NR 12 S(O)2N(R 13 )(R 14 ), -NR 12 S(O)2O(R 12 ), -OC(O)R 12、-OC(O)-N(R 13 )(R 14 )、-P(O)(OR 12 )2、-OP(O)(OR 12 )2、-CH2P(O)(OR 12 )2、-OCH2P(O)(OR 12 )2、-C(O)OCH2P(O)(OR 12 )2、-P(O)(R 12 )(OR 12 )、-OP(O)(R 12 )(OR 12 )、-CH2P(O)(R 12 )(OR 12 )、-OCH2P(O)(R 12 )(OR 12 )、-C(O)OCH2P(O)(R 12 )(OR 12 )、-P(O)(N(R 12 )2)2、-OP(O)(N(R 12 )2)2、-CH2P(O)(N(R 12 )2)2、-OCH2P(O)(N(R 12 )2)2、-C(O)OCH2P(O)(N(R 12 )2)2、-P(O)(N(R 12 )2)(OR 12 )、-OP(O)(N(R 12 )2)(OR 12 )、-CH2P(O)(N(R 12 )2)(OR 12 )、-OCH2P(O)(N(R 12 )2)(OR 12 )、-C(O)OCH2P(O)(N(R 12 )2)(OR 12 )、-P(O)(R 12 )(N(R 12 )2)、-OP(O)(R 12 )(N(R 12 )2)、-CH2P(O)(R 12 )(N(R 12 )2)、-OCH2P(O)(R 12 )(N(R 12 )2)、-C(O)OCH2P(O)(R 12 )(N(R 12)2), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, Z 9 is hydrogen, halo, -CN, or -OR 12 and each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR12 , -OC(O)-N(R 13 )(R 14 ), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, each Z 1b are independently oxo, thioxo, hydroxy, halo, -NO2, -N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(C 1~8 haloalkyl), -N(aryl), -N(heteroaryl), -N(heterocyclyl), -N(C 1~9Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 alkyl)(aryl), -N(C 1~9 alkyl)(heteroaryl), -N(C 1~9 alkyl)(heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8haloalkyl), -C(O)N(aryl), -C(O)N(heteroaryl), -C(O)N(heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC (O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl optionally contains 1 to 4 halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9alkyl), -S(O)(NH)(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl) 2、 -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or -O(C 1~9 alkyl), a compound wherein m is 0, 1, or 2; or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. Some embodiments provide methods of using (or administering) a compound of Formula I or an additional formula described throughout, suitable for treatment with a Cot modulator, in the treatment of a disease or condition in a mammal, such as a human.

[0008] In certain embodiments, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I or an additional formula described throughout) and at least one pharmaceutically acceptable excipient. [Brief explanation of the drawings]

[0009] [Figure 1] 1 illustrates the plasma concentration of Compound A over time following oral administration of Compound B compared to oral administration of Compound A to dogs. [Figure 2] 1 illustrates the plasma concentrations of Compound A and Compound D over time following oral administration of Compound C to dogs. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present disclosure relates to Cot or TPL2 inhibitors. The present disclosure also relates to compositions and methods relating to inhibitors of TPL2 and the use of such compounds for the treatment and prevention of diseases and conditions mediated by TPL2 binding. The present disclosure also relates to compositions and methods for treating and preventing cancer, diabetes, inflammatory diseases, or liver diseases, including TPL2 inhibitors in combination with one or more additional therapeutic agents.

[0011] Several Cot inhibitors are known and are being studied in relation to several physiological conditions, including inflammatory diseases. Cot or TPL2 has been shown to regulate oncogenic and inflammatory pathways. TPL2 was identified by its oncogenic transformation activity in cells and has been shown to regulate oncogenic and inflammatory pathways. TPL2 is expressed in a wide range of immune cells and regulates ERK-mediated gene expression downstream of multiple stimuli, including LPS and bacterial products such as bacterial peptidoglycan, TNFα, and IL-1β. In inflammatory bowel disease, for example, intestinal inflammation reflects the loss of homeostatic association between the intestinal microbiota and the host immune system. In IBD, the homeostatic response to commensal bacteria is overwhelmed by persistent and exacerbated immune signaling. TPL2 inhibition may offer an opportunity to restore immune homeostasis by attenuating exacerbated inflammatory signaling, for example, in IBD patients.

[0012] Embodiments of the present disclosure provide compounds that provide inhibition of TPL2. In some embodiments, the compounds disclosed herein exhibit desirable pharmacokinetic properties. In some embodiments, the compounds disclosed herein are cleaved, e.g., cleaved in the intestine, to provide compounds that inhibit TPL2. In some embodiments, the compounds disclosed herein have improved solubility compared to known inhibitors of TPL2. In some embodiments, the compounds disclosed herein provide improved systemic exposure of the TPL2 inhibitor compared to known compounds.

[0013] Definitions and general parameters The following description sets forth example methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of example embodiments.

[0014] As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0015] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes at the front or end of a chemical group are for convenience, and chemical groups can be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0016] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~6 "Alkyl group" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0017] Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, for that term, "about X" includes the description of "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1~20 alkyl), having 1 to 8 carbon atoms (i.e., C 1~8 alkyl), having 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or having 1 to 4 carbon atoms (i.e., C 1~4 alkyl). Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbon atoms is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), having 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), having 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or having 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an alkyl group. Examples of alkenyl groups are ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0020] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), having 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), having 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or having 2 to 4 carbon atoms (i.e., C 2~4 "alkynyl" refers to an alkyl group. The term "alkynyl" also includes those alkynyl groups having one triple bond and one double bond.

[0021] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0022] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms has been replaced by a halogen.

[0023] "Alkylthio" refers to the group "alkyl-S-".

[0024] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is It may be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0025] "Amide" is -C(O)NR y R z "C-amido" refers to the group, and -NR y C(O)R z "N-amide group" refers to both the N-amide group and the N-amide group. y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which may be optionally substituted.

[0026] "Amino" is -NR y R z refers to a group, wherein R y and R z is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl, each of which may be optionally substituted.

[0027] "Amidino" refers to -C(NH)(NH2).

[0028] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to a group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), having 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), or having 6 to 10 carbon ring atoms (i.e., C 6~10(aryl). Examples of aryl groups include phenyl, naphthylenyl, fluorenyl, and anthracenyl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

[0029] "Azido" refers to -N3.

[0030] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group refers to the group, and -NR y C(O)OR z "N-carbamoyl group" refers to both the "N-carbamoyl group" and the "N-carbamoyl group" y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which may be optionally substituted.

[0031] "Carboxyl" refers to -C(O)OH.

[0032] "Carboxyl ester" refers to both -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0033] "Cyano" or "carbonitrile" refers to the group --CN.

[0034] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), having 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6 Cycloalkyl). Cycloa Examples of alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0035] "Guanidino" refers to -NHC(NH)(NH).

[0036] "Hydrazino" refers to -NHNH2.

[0037] "Imino" refers to the group -C(NR)R, where each R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0038] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms are replaced by halogen. For example, if a residue is substituted with two or more halogens, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0039] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)-, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted. Examples of heteroalkyl groups include -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which is optionally substituted. As used herein, heteroalkyl contains 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0040] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or multiple rings fused with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group containing 1 to 20 ring carbon atoms (i.e., C 1~20 heteroaryl), containing 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), or containing 3 to 8 carbon ring atoms (i.e., C 3~8 Heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be attached via any ring of the fused system. Any aromatic ring having a single ring or multiple fused rings containing at least one heteroatom is considered heteroaryl regardless of attachment to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryl Heteroaryl does not encompass or overlap with aryl as defined above.

[0041] "Heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, in which case the polycyclic rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of attachment (i.e., it can be attached via a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to encompass rings in which any non-aromatic ring containing at least one heteroatom may be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2~20 heterocyclyl), having 2 to 12 ring carbon atoms (i.e., C 2~12 heterocyclyl), having 2 to 10 ring carbon atoms (i.e., C 2~10 heterocyclyl), having 2 to 8 ring carbon atoms (i.e., C 2~8 heterocyclyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 heterocyclyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 heterocyclyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6Heterocyclyl; having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. The heterocyclyl may contain one or more oxo and / or thioxo groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged heterocyclyl" refers to a 4- to 10-membered ring moiety in which each heteroatom is independently connected to at least one heteroatom selected from nitrogen, oxygen, and sulfur at two non-adjacent atoms of a heterocyclyl having one or more (e.g., one or two) 4- to 10-membered ring moieties. As used herein, bridged heterocyclyl includes bicyclic and tricyclic ring systems. As used herein, the term "spiroheterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, wherein the one or more additional rings is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl, and wherein a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached via either ring of the fused system.

[0042] "Hydroxy" or "hydroxyl" refers to the group -OH. "Hydroxyalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms have been replaced by hydroxyl.

[0043] "Oxo" refers to the (=O) or (O) radical.

[0044] "Nitro" refers to the -NO2 group.

[0045] "Sulfonyl" refers to the radical -S(O)R, where R is alkyl, haloalkyl, Heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0046] "Alkylsulfonyl" refers to the group -S(O)R where R is alkyl.

[0047] "Alkylsulfinyl" refers to the group --S(O)R where R is alkyl.

[0048] "Thiocyanate" -SCN.

[0049] "Thiol" refers to the group --SR, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl.

[0050] "Thioxo" or "thione" refers to the (=S) group or the (S) group.

[0051] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups, or "arylenyl" groups, respectively. Also, unless expressly indicated otherwise, combinations of groups are referred to herein as one moiety; for example, the last-mentioned group, arylalkyl, contains the atom by which the moiety is attached to the remainder of the molecule.

[0052] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be replaced by a non-hydrogen moiety.

[0053] Some of the compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0054] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. 3 H, 13 C and 14and those into which a radioactive isotope such as C is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.

[0055] The present disclosure also provides "deuterated analogs" of compounds of formula wherein 1 to n hydrogens bonded to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. Deuterium isotope compounds also include deuterated analogs, which are compounds of formula I. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of formula I when administered to a mammal, such as a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0056] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0057] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have that hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0058] In some cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0059] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human medicine.

[0060] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt such as a pharmaceutically acceptable addition salt can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines

[0033] Suitable amines include, but are not limited to, primary, secondary, and tertiary amines such as mono-, di-, or tri-cycloalkylamines (i.e., N(substituted alkenyl)s), mono-, di-, or tri-cycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)s), mono-, di-, or tri-arylamines (i.e., NH(aryl), HN(aryl), N(aryl)s), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0061] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanato, thiol, thione, or combinations thereof. Polymers or similar amorphous structures resulting from defining the substituents with an infinite number of additional substituents (e.g., substituted aryls with substituted alkyls, which themselves are substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of ordinary skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. Unless otherwise specified, if a group is described as optionally substituted, any substituents on the group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0062] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0063] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0064] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0065] compound Provided herein are compounds that function as modulators of Cot. In one aspect, compounds of Formula I: [ka] A compound having the structure: R 1 But hydrogen, -OR 7 , -N(R 8 )(R 9 ), -C(O)-R 7 , -S(O)2-R 7 , -C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, and heteroaryl each optionally have 1 to 4 Z 1 may be substituted with R 2 is hydrogen, -C(O)-R 7 , -C(O)OR 7 , -C(O)N(R 7 )2, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 2 may be substituted with or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains 1 to 4 Z 2 is replaced by R3 is heterocyclyl or heteroaryl, wherein each heterocyclyl or each heteroaryl optionally has 1 to 4 Z 3 is replaced by R 4 is aryl, heterocyclyl, or heteroaryl, wherein each aryl, each heterocyclyl, or each heteroaryl is optionally joined to one to four Z 4 is replaced by And, R 5 But hydrogen, halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R 7 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 5 may be substituted with R 6 But -C(O)OR 16 -OP(O)(OR 12)2-C(O)-R 16 -OP(O)(OR 12 )2, -R 16 -OP(O)(OR 12 )2, -C(O)OR 16 -OR 17 ;-C(O)OR 16 -OH;-C(O)OR 16 -OC(O)R 17 ;-C(O)-C(O)OR 12 ; or -C(O)OR 16 -OC(O)R 17 NH2, Each R 7 are independently hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 7 may be substituted with R 8 and R 9 independently at each occurrence, hydrogen, -S(O)R 10 , -C(O)-R 10 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl each optionally having 1 to 4 Z 8 may be substituted with R 10 and R 11 independently at each occurrence: hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 1b is replaced by Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12、-N(R 12 )C(O)N(R 13 )(R 14 )、-N(R 12 )S(O)2(R 12 )、-NR 12 S(O)2N(R 13 )(R 14 )、-NR 12 S(O)2O(R 12 )、-OC(O)R 12 、-OC(O)-N(R 13 )(R 14 )、-P(O)(OR 12 )2、-OP(O)(OR 12 )2、-CH2P(O)(OR 12 )2、-OCH2P(O)(OR 12 )2、-C(O)OCH2P(O)(OR 12 )2、-P(O)(R 12 )(OR 12 )、-OP(O)(R 12 )(OR 12 )、-CH2P(O)(R 12 )(OR 12 )、-OCH2P(O)(R 12 )(OR 12 )、-C(O)OCH2P(O)(R 12 )(OR 12 )、-P(O)(N(R 12 )2)2、-OP(O)(N(R 12 )2)2、-CH2P(O)(N(R 12 )2)2、-OCH2P(O)(N(R 1 2 )2)2、-C(O)OCH2P(O)(N(R 12 )2)2、-P(O)(N(R 12 )2)(OR 12 )、-OP(O)(N(R 12 )2)(OR 12 )、-CH2P(O)(N(R 12 )2)(OR 12 )、-OCH2P(O)(N(R 12 )2)(OR 12 )、-C(O)OCH2P(O)(N(R 12 )2)(OR12 ), -P(O)(R 12 )(N(R 12 )2), -OP(O)(R 12 )(N(R 12 )2), -CH2P(O)(R 12 )(N(R 12 )2), -OCH2P(O)(R 12 )(N(R 12 )2), -C(O)OCH2P(O)(R 12 )(N(R 12 )2), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR 12 , -OC(O)-N(R 13 )(R 14 ), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, Each R 12 are independently hydrogen, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, R 13 and R 14 each occurrence independently represents hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b or R 13 and R 14together with the nitrogen to which they are attached form a heterocyclyl, wherein the heterocyclyl optionally contains 1 to 4 Z 1b is replaced by Each R 15 are independently halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R 7 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; R 16 However, in some cases, 1 to 4 C 1~3 alkyl- or cyclopropyl-substituted, -C 1~3 alkyl or cyclopropyl; R 17 However, in some cases, 1 to 3 R 16 Replaced by C 1~9 Alkyl, cycloalkenyl alkyl, or heterocyclyl; and Z 1 , Z 2 , Z 4 , Z 5 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -NR 12 S(O)2N(R 13 )(R 14 ), -NR 12 S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)-N(R 13 )(R 14 ), -P(O)(OR 12 )2, -OP(O)(OR 12 )2, -CH2P(O)(OR 12 )2, -OCH2P(O)(OR 12 )2, -C(O)OCH2P(O)(OR 12 )2, -P(O)(R 12 )(OR 12 ), -OP(O)(R 12 )(OR 12 ), -CH2P(O)(R 12 )(OR 12 ), -OCH2P(O)(R 12 )(OR 12 ), -C(O)OCH2P(O)(R 12 )(OR 12 ), -P(O)(N(R 12 )2)2, -OP(O)(N(R 12)2)2, -CH2P(O)(N(R 12 )2)2, -OCH2P(O)(N(R 12 )2)2, -C(O)OCH2P(O)(N(R 12 )2)2, -P(O)(N(R 12 )2)(OR 12 ), -OP(O)(N(R 12 )2)(OR 12 ), -CH2P(O)(N(R 12 )2)(OR 12 ), -OCH2P(O)(N(R 12 )2)(OR 12 ), -C(O)OCH2P(O)(N(R 12 )2)(OR 12 ), -P(O)(R 12 )(N(R 12 )2), -OP(O)(R 12 )(N(R 12 )2), -CH2P(O)(R 12 )(N(R 12 )2), -OCH2P(O)(R 12 )(N(R 12 )2), -C(O)OCH2P(O)(R 12 )(N(R 12 )2), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, Z 9 is hydrogen, halo, -CN, or -OR 12 and each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR 12 , -OC(O)-N(R 13 )(R 14 ), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, each Z 1b are independently oxo, thioxo, hydroxy, halo, -NO2, -N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1~9 alkyl) , -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(C 1~8 haloalkyl), -N(aryl), -N(heteroaryl), -N(heterocyclyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 alkyl)(aryl), -N(C 1~9 alkyl)(heteroaryl), -N(C 1~9 alkyl)(heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl), -C(O)N(aryl), -C(O)N(heteroaryl), -C(O)N(heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl optionally contains 1 to 4 halo, C 1~9 Alkyl, C1~8 Haloalkyl , -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl) 2、 -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or -O(C 1~9 alkyl), a compound wherein m is 0, 1, or 2; or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. Some embodiments provide methods of using (or administering) a compound of Formula I or an additional formula described throughout, suitable for treatment with a Cot modulator, in the treatment of a disease or condition in a mammal, such as a human.

[0066] In one aspect, formula IA: [ka] A compound having the structure: R 1 But hydrogen, -OR 7 , -N(R 8 )(R 9 ), -C(O)-R 7 , -S(O)2-R 7 , -C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, and heteroaryl each optionally have 1 to 4 Z 1 may be substituted with R 2 is hydrogen, -C(O)-R 7 , -C(O)OR 7 , -C(O)N(R 7 )2, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 2 may be substituted with or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains 1 to 4 Z 2 is replaced by R 3 is heterocyclyl or heteroaryl, wherein each heterocyclyl or each heteroaryl optionally has 1 to 4 Z 3 is replaced by R 4 is aryl, heterocyclyl, or heteroaryl, wherein each aryl, each heterocyclyl, or each heteroaryl is optionally joined to one to four Z 4 is replaced by R 5 But hydrogen, halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R 7 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 5 may be substituted with R 6 But -C(O)OR 16 -OP(O)(OR 12 )2-C(O)-R 16 -OP(O)(OR 12 )2, -C(O)OR 16 -OP(O)(OR 12 )2, -R 16 -OP(O)(OR 12 )2, -C(O)OR 16 -OR 17 ;-C(O)OR 16 -OH;-C(O)OR 16 -OC(O)R 17 ; or -C(O)OR 16 -OC(O)R 17 NH2, Each R 7 are independently hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 7 may be substituted with R 8 and R 9 independently at each occurrence, hydrogen, -S(O)R 10 , -C(O)-R 10 , -C(O)OR10 , -C(O)N(R 10 )(R 11 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl each optionally having 1 to 4 Z 8 may be substituted with R 10 and R 11 independently at each occurrence: hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 1b is replaced by Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -NR 12 S(O)2N(R 13 )(R 14 ), -NR 12 S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)-N(R 13 )(R 14 ), -P(O)(OR 12 )2, -OP(O)(OR 12 )2, -CH2P(O)(OR 12 )2, -OCH2P(O)(OR 12 )2, -C(O)OCH2P(O)(OR 12 )2, -P(O)(R 12 )(OR 12 ), -OP(O)(R 12 )(OR 12 ), -CH2P(O)(R 12 )(OR 12 ), -OCH2P(O)(R 12 )(OR 12 ), -C(O)OCH2P( O)(R 12 )(OR 12 ), -P(O)(N(R 12 )2)2, -OP(O)(N(R 12 )2)2, -CH2P(O)(N(R 12 )2)2, -OCH2P(O)(N(R12 )2)2, -C(O)OCH2P(O)(N(R 12 )2)2, -P(O)(N(R 12 )2)(OR 12 ), -OP(O)(N(R 12 )2)(OR 12 ), -CH2P(O)(N(R 12 )2)(OR 12 ), -OCH2P(O)(N(R 12 )2)(OR 12 ), -C(O)OCH2P(O)(N(R 12 )2)(OR 12 ), -P(O)(R 12 )(N(R 12 )2), -OP(O)(R 12 )(N(R 12 )2), -CH2P(O)(R 12 )(N(R 12 )2), -OCH2P(O)(R 12 )(N(R 12 )2), -C(O)OCH2P(O)(R 12 )(N(R 12 )2), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR 12 , -OC(O)-N(R 13 )(R 14 ), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, Each R 12 are independently hydrogen, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, R 13 and R14 each occurrence independently represents hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b or R 13 and R 14 together with the nitrogen to which they are attached form a heterocyclyl, wherein the heterocyclyl optionally contains 1 to 4 Z 1b is replaced by Each R 15 are independently halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R 7 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; R 16 However, in some cases, 1 to 4 C 1~2 or cyclopropyl-substituted, -C 1~ 2 alkyl, R 17However, in some cases, 1 to 3 R 16 Replaced by C 1~9 alkyl, cycloalkyl, or heterocyclyl; and Z 1 , Z 2 , Z 4 , Z 5 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -NR 12 S(O)2N(R 13 )(R 14 ), -NR 12 S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)-N(R 13 )(R 14 ), -P(O)(OR 12 )2, -OP(O)(OR 12 )2, -CH2P(O)(OR 12 )2, -OCH2P(O)(OR 12 )2, -C(O)OCH2P(O)(OR 12) 2, -P(O)(R 12 )(OR 12 )、 -OP(O)(R 12 )(OR 12 )、 -CH2P(O)(R 12 )(OR 12 )、 -OCH2P(O)(R 12 )(OR 12 )、 -C(O)OCH2P(O)(R 12 )(OR 12 )、 -P(O)(N(R 12 )2)2、 -OP(O)(N(R 12 )2)2、 -CH2P(O)(N(R 12 )2)2、 -OCH2P(O)(N(R 12 )2)2、 -C(O)OCH2P(O)(N(R 12 )2)2、 -P(O)(N(R 12 )2)(OR 12 )、 -OP(O)(N(R 12 )2)(OR 12 )、 -CH2P(O)(N(R 12 )2)(OR 12 )、 -OCH2P(O)(N(R 12 )2)(OR 12 )、 -C(O)OCH2P(O)(N(R 12 )2)(OR 12 )、 -P(O)(R 12 )(N(R 12 )2)、 -OP(O)(R 12 )(N(R 12 )2)、 -CH2P(O)(R 12 )(N(R 12 )2)、 -OCH2P(O)(R 12 )(N(R 12 )2)、 -C(O)OCH2P(O)(R 12 )(N(R 12 )2)、 -Si(R 12 )3、 -S-R 12 、 -S(O)R 12 、 -S(O)(NH)R 12 、 -S(O)2R 12 or -S(O)2N(R 13 )(R 14 ) and, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, Z 9 is hydrogen, halo, -CN, or -OR 12 and each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR 12 , -OC(O)-N(R 13 )(R 14 ), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, each Z 1b are independently oxo, thioxo, hydroxy, halo, -NO2, -N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O( C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(C 1~8 haloalkyl), -N(aryl), -N(heteroaryl), -N(heterocyclyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8haloalkyl), -N(C 1~9 alkyl)(aryl), -N(C 1~9 alkyl)(heteroaryl), -N(C 1~9 alkyl)(heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl), -C(O)N(aryl), -C(O)N(heteroaryl), -C(O)N(heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl optionally contains 1 to 4 halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C1~9 alkyl) 2、 -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or -O(C 1~9 alkyl), a compound wherein m is 0, 1, or 2; Alternatively, a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided.

[0067] In certain embodiments, the compound of formula IB has the formula IB: [ka] where R 1 -R 6 , R 15 and m is as described herein.

[0068] In certain embodiments, the compound of formula I has formula IC: [ka] where R 1 -R 6 , R 15 and m is as described herein.

[0069] In certain embodiments, m is 0. In certain embodiments, R 2 is hydrogen.

[0070] In certain embodiments, the compound of formula I has formula II: [ka] where R 1 But hydrogen, -OR 7 , -N(R 8 )(R 9 ), -C(O)-R 7 , -S(O)2-R 7, -C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, and heteroaryl each optionally have 1 to 4 Z 1 may be substituted with R 2 is hydrogen, -C(O)-R 7 , -C(O)OR 7 , -C(O)N(R 7 )2, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 2 may be substituted with or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains 1 to 4 Z 2 is replaced by R 3a However, hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -NR 12 S(O)2N(R 13 )(R 14 ), -NR 12 S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)-N(R 13 )(R 14 ), -P(O)(OR 12 )2, -OP(O)(OR 12 )2, -CH2P(O)(OR 12 )2, -OCH2P(O)(OR 12 )2, -C(O)OCH2P(O)(OR 12 )2, -P(O)(R 12 )(OR 12 ), -OP(O)(R 12 )(OR 12 ), -CH2P(O)(R 12 )(OR 12 ), -OCH2P(O)(R 12 )(OR 12 ), -C(O)OCH2P(O)(R 12 )(OR 12 ), -P(O)(N(R 12 )2)2, -OP(O)(N(R 12 )2)2, -CH2P(O)(N(R 12 )2)2, -OCH2P(O)(N(R 12)2)2, -C(O)OCH2P(O)(N(R 12 )2)2, -P(O)(N(R 12 )2)(OR 12 ), -OP(O)(N(R 12 )2)(OR 12 ), -CH2P(O)(N(R 12 )2)(OR 12 ), -OCH2P(O)(N(R 12 )2)(OR 12 ), -C(O)OCH2P(O)(N(R 12 )2)(OR 12 ), -P(O)(R 12 )(N(R 12 )2), -OP(O)(R 12 )(N(R 12 )2), -CH2P(O)(R 12 )(N(R 12 )2), -OCH2P(O)(R 12 )(N(R 12 )2), -C(O)OCH2P(O)(R 12 )(N(R 12 )2),- Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, R 4 is aryl, heterocyclyl, or heteroaryl, wherein each aryl, each heterocyclyl, or each heteroaryl is optionally joined to one to four Z 4 is replaced by R 5 But hydrogen, halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R 7 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 5 may be substituted with R 6 But -C(O)OR 16 -OP(O)(OR 12 )2, Each R 7 are independently hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z7 may be substituted with R 8 and R 9 independently at each occurrence, hydrogen, -S(O)R 10 , -C(O)-R 10 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl each optionally having 1 to 4 Z 8 may be substituted with R 10 and R 11 independently at each occurrence: hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 1b is replaced by Each R 12 are independently hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, R 13 and R 14 each occurrence independently represents hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b or R 13 and R 14 together with their attached nitrogen atoms to form heterocyclic and forming a heterocyclyl, wherein the heterocyclyl is optionally joined to one to four Z 1b is replaced by R 16 However, in some cases, 1 to 4 C 1~2 or cyclopropyl-substituted -C 1~2 is alkyl, and Z 1 , Z 2 , Z 4 , Z 5 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R14 )、-N(R 13 )2(R 14 ) + 、-N(R 12 )C(O)-R 12 、-N(R 12 )C(O)O-R 12 、-N(R 12 )C(O)N(R 13 )(R 14 )、-N(R 12 )S(O)2(R 12 )、-NR 12 S(O)2N(R 13 )(R 14 )、-NR 12 S(O)2O(R 12 )、-OC(O)R 12 、-OC(O)-N(R 13 )(R 14 )、-P(O)(OR 12 )2、-OP(O)(OR 12 )2、-CH2P(O)(OR 12 )2、-OCH2P(O)(OR 12 )2、-C(O)OCH2P(O)(OR 12 )2、-P(O)(R 12 )(OR 12 )、-OP(O)(R 12 )(OR 12 )、-CH2P(O)(R 12 )(OR 12 )、-OCH2P(O)(R 12 )(OR 12 )、-C(O)OCH2P(O)(R 12 )(OR 12 )、-P(O)(N(R 12 )2)2、-OP(O)(N(R 12 )2)2、-CH2P(O)(N(R 12 )2)2、-OCH2P(O)(N(R 12 )2)2、-C(O)OCH2P(O)(N(R 12 )2)2、-P(O)(N(R 12 )2)(OR 12 )、-OP(O)(N(R 12 )2)(OR 12 )、-CH2P(O)(N(R 12)2)(OR 12 ), -OCH2P(O)(N(R 12 )2)(OR 12 ), -C(O)OCH2P(O)(N(R 12 )2)(OR 12 ), -P(O)(R 12 )(N(R 12 )2), -OP(O)(R 12 )(N(R 12 )2), -CH2P(O)(R 12 )(N(R 12 )2), -OCH2P(O)(R 12 )(N(R 12 )2), -C(O)OCH2P(O)(R 12 )(N(R 12 )2), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, Z 9 is hydrogen, halo, -CN, or -OR 12 and each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13)2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR 12 , -OC(O)-N(R 13 )(R 14 ), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, each Z 1b are independently oxo, thioxo, hydroxy, halo, -NO2, -N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(C 1~8 haloalkyl), -N(aryl), -N(heteroaryl), -N(heterocyclyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 alkyl)(aryl), -N(C 1~9 alkyl)(heteroaryl), -N(C 1~9 alkyl)(heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl), -C(O)N(aryl), -C(O)N(heteroaryl), -C(O)N(heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl optionally contains 1 to 4 halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl) 2、 -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or -O(C 1~9 alkyl), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

[0071] In certain embodiments, R 3a is hydrogen, C 1~9 Alkyl, C 3~15 cycloalkyl, heterocyclyl, aryl, or heteroaryl, and 1~9 Alkyl, C 3~15Cycloalkyl, aryl, or heterocyclyl may be substituted with cyano, halo, -OR 12 , -C(O)-R 12 , -OC(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -S(O)2-R 12 , -Si(R 12 )3, C 1~9 Alkyl, C 1~8 Haloalkyl, C 3~15 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein C 1~9 Alkyl, C 3~15 The cycloalkyl, heterocyclyl, or aryl may optionally be selected from halo, —O(C 1~9 alkyl), -C(O)N(C 1~9 Alkyl)2, C 1~9 It may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and heterocyclyl.

[0072] In some embodiments, R 3a is hydrogen or C 1~9 alkyl, wherein the C 1~9 The alkyl is optionally selected from cyano, halo, -OR 12 , -C(O)-R 12 , -OC(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -S(O)2-R 12 , -Si(R 12 )3, C 1~8 Haloalkyl, C 3~15and optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein 3~15 The cycloalkyl, aryl, heterocyclyl, or heteroaryl may optionally be selected from halo, —O(C 1~9 alkyl), -C(O)N(C 1~9 Alkyl)2, C 1~9 It may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and heterocyclyl, or a pharmaceutically acceptable salt thereof.

[0073] In certain embodiments, R 3a is C 3~15 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein 1~9 Alkyl, C 3~15 The cycloalkyl, aryl, or heterocyclyl may optionally be selected from the group consisting of cyano, halo, -OR 12 , -C(O)-R 12 , -OC(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -S(O)2-R 12 , -Si(R 12 )3, C 1~9 Alkyl, C 1~8 Haloalkyl, C 3~15 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein 1~9 Alkyl, C 3~15 The cycloalkyl, heterocyclyl, or aryl may optionally be selected from halo, —O(C 1~9 alkyl), -C(O)N(C 1~9 Alkyl)2, C 1~9It may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and heterocyclyl.

[0074] In some embodiments, R 3a Cyano, halo, -OR 12 , -C(O)OR 12 , -OC(O)-R 12 , -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , C 1~9 Alkyl, C 1~8 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl, heterocyclyl, and heteroaryl 3~15 It is cycloalkyl.

[0075] In certain embodiments, R 4 -CN, Halo, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -S(O)2-R 12 , -N(R 12 )C(O)-R 12 , -N(R 12 )S(O)2R 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), C 1~9 Alkyl, C 3~15 aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein 1~9 Alkyl, C 3~15 The cycloalkyl or heteroaryl may optionally be selected from halo, -CN, -OR 12 , -N(R 13 )(R 14 ), C 1~9 It may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and heterocyclyl.

[0076] In some embodiments, R 4 teeth, [ka] [ka] [ka] is.

[0077] In some embodiments, R 4 is heterocyclyl, or cyano, halo and C 1~9 and heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl.

[0078] In certain embodiments, R 4 is heterocyclyl or heteroaryl, and the heterocyclyl or heteroaryl is optionally selected from -CN, halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 It is substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl and heterocyclyl.

[0079] In certain embodiments, R 4 -CN, Halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 and heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl and heterocyclyl.

[0080] In some embodiments, R 4 -CN, Halo, -OR 12 , -C(O)-R12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 Heterocyclyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl and heterocyclyl, or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, R 4 teeth, [ka] and q is 0, 1, 2, 3, or 4; In the formula, Z 4 -CN, Halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 is independently selected from the group consisting of haloalkyl, and heterocyclyl.

[0082] In some embodiments, R 4 teeth, [ka] and q is 0, 1, 2, 3, or 4; In the formula, Z 4 -CN, Halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 is independently selected from the group consisting of haloalkyl, and heterocyclyl.

[0083] In some embodiments, R 4 teeth, [ka] and In the formula, Z 4 -CN, Halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 is independently selected from the group consisting of haloalkyl, and heterocyclyl.

[0084] In certain embodiments, R 4 teeth, [ka] [ka] [ka] [ka] is.

[0085] In certain embodiments, R 5 is hydrogen, halo, -CN, -OR 7 , -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 5 may be substituted with

[0086] In certain embodiments, R5 is hydrogen, halo, -CN, -C(O)R 7 or heteroaryl. In one embodiment, R 5 is -CN, halo, or -OR 7 In certain embodiments, R 5 is hydrogen, halo, -CN, -C(O)R 7 , -OR 7 , -S(O)2R 7 or heteroaryl. In one embodiment, R 5 is a halo.

[0087] In certain embodiments, R 5 is 1H-pyrazol-4-yl, 1-hydroxyethyl, 1-methyl-1H-pyrazol-4-yl, 4-(acetylamino)phenyl, 6-fluoropyridin-3-yl, methylacetyl, bromo, chloro, cyano, cyclopropyl, dimethylaminocarbonyl, ethynyl, fluoro, iodo, methoxy, methyl, hydroxyl, phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, acetyl, methylsulfonyl, or trifluoromethyl. 5 teeth , Chloro.

[0088] In some embodiments, R 6 is -C(O)OR 16 -OP(O)(OH)2.

[0089] In some embodiments, R 6 teeth, [ka] is.

[0090] In some embodiments, R 6 teeth, [ka] is.

[0091] In some embodiments, R 6 teeth, [ka] is.

[0092] In some embodiments, R 6 teeth, [ka] is.

[0093] In some embodiments, R 16 is C 2~3 In some embodiments, R 16 is methyl. In some embodiments, R 16 is ethyl. In some embodiments, R 16 is unsubstituted. In some embodiments, R 16 is substituted with 1, 2, 3, or 4 methyl groups. In some embodiments, R 16 is substituted with one or two methyl groups. In some embodiments, R 16 is substituted by one or two cyclopropyl groups.

[0094] In some embodiments, Z 9 is hydrogen.

[0095] Some embodiments are of the formula: [ka] [ka] The present invention provides a compound of the formula:

[0096] In one embodiment, m is 0. In another embodiment, m is 1.

[0097] Some embodiments of the present disclosure include compounds of the following formula III: [ka] A compound of the formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 15 and m are as described herein; and R 18 is hydrogen, -C(O)-R 7 , -C(O)OR 7 , -C(O)N(R 7 )2, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 6 a compound optionally substituted with or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof.

[0098] Generally, the specific compounds exemplified herein are named using ChemBioDraw Ultra. However, it is understood that other names may be used to identify compounds of the same structure. For example, compounds may also be listed in, for example, Chemical Abstract Service (CAS) and International Union of Chemical Substances. Other nomenclature systems and symbols generally recognized in the field of chemistry, including the International Union for the Study of Pure and Applied Chemistry (IUPAC), may also be used. Other compounds or radicals may be designated using common names, or systematic or non-systematic names.

[0099] In certain embodiments, optical isomers, racemates, or other mixtures or mixtures thereof of the compounds described herein or pharmaceutically acceptable salts thereof are provided. In these situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution. Resolution can be accomplished by conventional methods such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high-performance liquid chromatography (HPLC) column.

[0100] The compositions provided herein can include compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof, which may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer, or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0101] Also provided herein are compositions comprising mixtures of enantiomers (or diastereomers) of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises a single enantiomer of the compound and is substantially free of other enantiomers. In certain embodiments, the compound of Formula I (or another formula described herein) may be a compound of Formula I (e.g., R 1 and / or R 3 containing one or more additional stereogenic atoms In such cases, the composition may contain a mixture of diastereomers. In some embodiments, the composition comprises a single enantiomer of the compound and is substantially free (i.e., has less than about 40%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01%) of one or more diastereomers.

[0102] Thus, in certain embodiments, compositions are provided that include a mixture of formula IA-1, or a pharmaceutically acceptable salt thereof, and formula IB-1, or a pharmaceutically acceptable salt thereof. [ka] In the formula, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 15 is as defined herein.

[0103] In one embodiment, the mixture is a racemic mixture. In another embodiment, the composition comprises a mixture of Formula IA-1, or a pharmaceutically acceptable salt thereof, and a mixture of Formula IB-1, or a pharmaceutically acceptable salt thereof, wherein Formula IA-1 is present in excess of Formula IB-1, or a pharmaceutically acceptable salt thereof. In certain embodiments, compositions are provided that are substantially free of Formula IB-1, i.e., have about 40%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01% or less of a compound of Formula IB-1.

[0104] In other embodiments, the mixture comprises the compounds of formulae IA-1 and IB-1, respectively, in a molar ratio of at least or about 3:1, at least or about 4:1, at least or about 5:1, at least or about 6:1, at least or about 7:1, at least or about 8:1, at least or about 9:1, at least or about 10:1, at least or about 11:1, at least or about 12:1, at least or about 20:1, at least or about 30:1, at least or about 40:1, at least or about 80:1, at least or about 160:1, or at least or about 320:1.

[0105] In certain embodiments, chelates, noncovalent complexes, and mixtures thereof of the compounds described herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, are also provided. A "chelate" is formed by coordinating a compound to a metal ion at two (or more) points. A "noncovalent complex" is formed by the interaction of a compound with another molecule where no covalent bond is formed between the compound and the molecule. For example, complex formation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).

[0106] Therapeutic Uses of the Compounds "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition, and / or a) reducing one or more symptoms resulting from a disease or condition; b) slowing or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating the disease or condition, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0107] "Prevention" or "preventing" means treating any disease or condition such that the clinical symptoms of the disease or condition do not develop. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0108] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0109] The terms "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment and provide a therapeutic benefit, such as amelioration of symptoms or slowing of disease progression, when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to reduce symptoms of a disease or condition in response to inhibition of Cot activity. A therapeutically effective amount may vary depending on the subject, the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art.

[0110] The term "inhibition" refers to a decrease in baseline activity of a biological activity or process. "Inhibition of the activity of Cot" or variations thereof refers to a decrease in the activity of Cot as a direct or indirect response to the presence of a compound described herein relative to the activity of Cot in the absence of the compound described herein. "Inhibition of Cot" refers to a decrease in Cot activity as a direct or indirect response to the presence of a compound described herein relative to the activity of Cot in the absence of the compound described herein. In some embodiments, the inhibition of Cot activity may be compared in the same subject prior to treatment or in another subject not receiving treatment.

[0111] The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and their biopsies. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine the optimal schedule and / or dosing of Cot inhibitor administration for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used for experimental purposes or to design protocols for in vivo treatment in the clinic. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. Selected compounds may be used in the treatment of human The compound may be further characterized to determine its safety or tolerability in human or non-human subjects. Such properties may be determined using methods commonly known to those skilled in the art.

[0112] The compounds disclosed herein are useful for treating diseases or conditions mediated by Cot, including, but not limited to, cancer, diabetes, and inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis, misregulated TNF expression, transplant rejection, and liver disease.

[0113] In further embodiments, methods are provided for alleviating symptoms of a Cot-mediated disease or disorder. In some embodiments, the methods include identifying a mammal having symptoms of a Cot-mediated disease or disorder and providing the mammal with a compound described herein in an amount effective to ameliorate the symptoms (i.e., reduce the severity of the symptoms).

[0114] In some embodiments, the Cot-mediated disease or condition is cancer. In some embodiments, the cancer is Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, multiple myeloma (MM), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell ALL, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), mantle cell lymphoma (MCL), follicular lymphoma (FL), Waldenstrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or marginal zone lymphoma (MZL). In one embodiment, the cancer is minimal residual disease (MRD). In additional embodiments, the cancer is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), and refractory iNHL. In certain embodiments, the cancer is indolent non-Hodgkin's lymphoma (iNHL). In some embodiments, the cancer is refractory iNHL. In one embodiment, the cancer is chronic lymphocytic leukemia (CLL). In other embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0115] In certain embodiments, the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, including metastatic breast cancer, prostate cancer, including androgen-dependent and androgen-independent prostate cancer, kidney cancer or renal cancer, including metastatic renal cell carcinoma, hepatocellular carcinoma, e.g., For example, lung cancer, including non-small cell lung cancer (NSCLC), alveolar epithelial carcinoma (BAC), and lung adenocarcinoma, including advanced epithelial carcinoma or primary peritoneal carcinoma, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, including squamous cell carcinoma of the head and neck, melanoma, neuroendocrine cancer, including metastatic neuroendocrine tumors, brain tumor, bone cancer, and soft tissue sarcoma, hepatic carcinoma, rectal cancer, penile cancer, vulvar cancer, thyroid cancer, salivary gland cancer, endometrial or uterine cancer, hepatoma, hepatocellular carcinoma, liver cancer, gastrointestinal cancer, The cancer is a solid tumor selected from the group consisting of gastric cancer or stomach cancer, peritoneal cancer, lung squamous cell carcinoma, gastroesophageal cancer, biliary tract cancer, gallbladder cancer, colorectal / appendix cancer, squamous cell carcinoma (e.g., epithelial squamous cell cancer).

[0116] Any of the provided treatment methods can be used to treat cancer at various stages, including, but not limited to, early stage, advanced stage, locally advanced stage, remission stage, treatment-resistant stage, relapsed stage after remission, and recurrent / advanced stage.

[0117] In some embodiments, the Cot-mediated disease or condition is diabetes, which includes any metabolic disorder characterized by impaired insulin production and glucose tolerance. In some embodiments, diabetes includes type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting glucose, and impaired glucose tolerance. Type 1 diabetes is also known as insulin-dependent diabetes mellitus (IDDM). Type 2 is also known as non-insulin-dependent diabetes mellitus (NIDDM).

[0118] In some embodiments, the Cot-mediated disease or condition is an inflammatory disease or LPS-induced endotoxic shock, hi some embodiments, the disease is an autoimmune disease.

[0119] In some embodiments, the inflammatory disease is selected from the group consisting of acid-induced lung injury, Addison's disease, adrenal hyperplasia, adrenal insufficiency, adult-onset Still's disease, adult respiratory distress syndrome (ARDS), age-related macular degeneration, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, allergic conjunctivitis, allergic contact dermatitis, allergy, allergic encephalomyelitis, allergic neuritis, allograft rejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, angiofibroma, anhidrotic ectodermal dysplasia, antiglomerular basement membrane disease, antigen-antibody complex-dependent disease, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, Ascites, aspergillosis, asthma, atherosclerosis, atherosclerotic plaque, atopic dermatitis, atrophic thyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune polyendocrine syndrome, autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders, autoinflammatory diseases, back pain, anthrax infection, Behçet's disease, bee-sting-induced inflammation, Behçet's syndrome, Bell's palsy, beryllium disease, Blau syndrome, bone pain, bronchiolitis, bullous pemphigoid (BP) asthma, burns, bursitis, cardiomegaly, carpal tunnel syndrome, Castleman's disease, catabolic disorders disorder), cataracts, celiac disease, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic atypical neutrophilic dermatosis with lipodystrophy and fever (CANDLE) syndrome, chronic heart failure, chronic lung disease of prematurity, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic prostatitis, chronic recurrent multifocal osteomyelitis, cicatricial alopecia, colitis, complex regional pain syndrome, organ transplant complications, conjunctivitis, connective tissue disease, contact dermatitis, corneal graft neovascularization, corneal ulcer, Crohn's disease, cryopyrin-associated periodic fever syndrome, cutaneous lupus erythematosus (CLE), cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist deficiency (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diabetic macular edema, Diverticulitis, eczema, encephalitis, endometriosis, endotoxemia, eosinophilic pneumonia, epicondylitis, epidermolysis bullosa, erythema multiforme, erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, fibromyalgia, fistulizing Crohn's disease, food allergy, giant cell arteritis, glaucoma, glioblastoma, glomerular disease, glomerulonephritis, glomerulonephritis, Rutten-sensitive enteropathy, gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatous hepatitis, Graves' disease, epiphyseal plate injury, Guillain-Barré syndrome, intestinal disease, hair loss, Hashimoto's thyroiditis, head trauma, headache, hearing loss, heart disease, hemangiomas, hemolytic anemia, hemophilic arthropathy, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndromes, hereditary disorders of connective tissue, shingles and herpes simplex, hidradenitis suppurativa (HS), hip replacement surgery, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperactive inflammatory response, hyperammonemia , hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES), hyperimmunoglobulin D syndrome with relapsing fever (HIDS), hypersensitivity pneumonitis, hypertrophic bone formation, aplastic anemia and other anemias, aplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy, idiopathic inflammatory myopathy (dermatomyositis, polymyositis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, immunoglobulin nephropathy, immune complex nephritis, immune thrombocytopenic purpura (ITP), incontinentia pigmenti Infectious diseases including viral diseases such as (IP) (Bloch-Siemens syndrome), infectious mononucleosis, acquired immune deficiency syndrome (HIV infection), hepatitis A, B, C, D and E, herpes; inflammation, inflammation of the central nervous system, inflammatory bowel disease (IBD), inflammatory diseases of the lower respiratory tract including bronchitis or chronic obstructive pulmonary disease, inflammatory diseases of the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis, inflammatory diseases of the airways, inflammatory-ischemic events such as stroke or cardiac arrest, inflammatory lung diseases, inflammatory myopathies such as myocarditis, inflammatory liver diseases, inflammatory neuropathy, inflammatory pain, insect sting-induced inflammation, interstitial cystitis, interstitial lung disease, iritis, irritant-induced inflammation, ischemia / reperfusion, joint replacement surgery, juvenile arthritis, juvenile rheumatoid arthritisrheumatoid), keratitis, kidney damage caused by parasitic infections, kidney transplant rejection, leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS), Lambert-Eaton myasthenic syndrome, Löffler syndrome, lupus, lupus nephritis, Lyme disease, Marfan syndrome (MFS), mast cell activation syndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria, hearing loss, amyloidosis) , mucositis, multisystem dysfunction syndrome, multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG), myelodysplastic syndrome, myocarditis, myositis, rhinosinusitis, necrotizing enterocolitis, neonatal-onset multisystem inflammatory disease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, ocular allergy, optic neuritis, organ transplant rejection, Osler-Weber syndrome, osteoarthritis, Osteogenesis imperfecta, osteonecrosis, osteoporosis, osteoarthritis, otitis, pachyonychia congenita, Paget's disease, Paget's disease of bone, pancreatitis, Parkinson's disease, childhood rheumatism, pelvic inflammatory disease, pemphigus, pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pernicious anemia (Addison's disease), whooping cough, PFAPA (periodic fever with aphthous pharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPA syndrome), implantation Physical irritant-induced inflammation, Pneumocystis infection, pneumonia, pneumonitis, poison ivy / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyalgia rheumatica, giant cell arteritis, polymyositis, pouchitis, preperfusion injury and graft rejection, primary biliary cirrhosis, primary pulmonary hypertension, primary sclerosing cholangitis (PSC), proctitis, psoriasis, plaque psoriasis, psoriatic arthritis, epidermal psoriasis (psoriaticepidermis), psychosocial stress disorders, lung diseases, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenic granulomatous retrolental fibroplasia, suppurative aseptic arthritis, Raynaud's syndrome, Reiter's disease, reactive arthritis, kidney diseases, renal transplant rejection, reperfusion injury, respiratory distress syndrome, retinal diseases, retrolental fibroplasia, Raynaud's syndrome, rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoid arthritis, rhinitis, psoriasis, rosacea, sarcoidosis, Schnitzler's syndrome, scleritis, sclerosis, scleroderma, scoliosis, seborrhea, sepsis, septic syndrome shock, severe pain, Sézary syndrome, sickle cell anemia, silica-induced disease (silicosis), Sjögren's syndrome, skin disease, skin irritation, skin rash, skin sensitization (contact dermatitis or allergic contact dermatitis), spinal cord injury, spinal stenosis, spondyloarthropathy, Stevens-Johnson syndrome (SJS), stroke, subarachnoid hemorrhage, sunburn, synovial inflammation, systemic inflammatory response syndrome (SIRS), systemic lupus erythematosus, systemic mastocytosis (SMCD), systemic vasculitis, systemic-onset juvenile idiopathic arthritis, temporal arteritis, tendonitis, tenosynovitis , thrombocytopenia, thyroiditis, thyroiditis, tissue transplant, toxoplasmosis, trachoma, transplant rejection, traumatic brain injury, tuberculosis, tubulointerstitial nephritis, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), type 1 diabetes, type 2 diabetes, complications of type 1 or type 2 diabetes, ulcerative colitis, urticaria, uterine fibroids, uveitis, vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener's granulomatosis, or Whipple's disease.

[0120] In some embodiments, the autoimmune disease is systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic Thrombocytopenic purpura, multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis, Sjögren's syndrome, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD), ankylosing spondylitis, acute gout and ankylosing spondylitis, reactive arthritis, monoarthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile onset rheumatoid arthritis In another embodiment, the disease is inflammation. In yet another embodiment, the disease is an excessive or destructive immune response, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.

[0121] In some embodiments, the Cot-mediated disease or condition is inflammatory bowel disease (IBD). As used herein, the term "inflammatory bowel disease" or "IBD" is a collective term describing inflammatory disorders of the gastrointestinal tract, the most common forms of inflammatory disorders of the gastrointestinal tract being ulcerative colitis and Crohn's disease. Other forms of IBD that can be treated using the compounds, compositions, and methods of the disclosure include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behcet's disease, gastroduodenal colitis, and ulcerative colitis. These include CD, jejunoileitis, ileitis, ileocolitis, Crohn's disease (granulomatous colitis), irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, pouchitis, proctitis, and chronic diarrhea.

[0122] Treating or preventing IBD may also include improving or reducing one or more symptoms of IBD. As used herein, the term "symptoms of irritable bowel syndrome (IBD)" refers to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications such as dehydration, anemia, and malnutrition. Some such symptoms are subject to quantitative analysis (e.g., weight loss, fever, anemia, etc.). Some symptoms are easily determined from blood tests (e.g., anemia) or tests that detect the presence of blood (e.g., rectal bleeding). The term "reducing the symptom" refers to a qualitative or quantitative reduction in a detectable symptom, including, but not limited to, a detectable effect on the rate of recovery from the disease (e.g., weight gain rate). Diagnosis is typically determined by endoscopic observation of the mucosa and pathological examination of an endoscopic biopsy sample.

[0123] The course of IBD can vary and can be associated with intermittent periods of disease remission and disease exacerbation.Various methods have been described to characterize the disease activity and severity of IBD and the response to treatment in subjects suffering from IBD.Treatment by this method is generally applicable to subjects suffering from IBD with any level or degree of disease activity.

[0124] In some embodiments, diseases or conditions treated by administration of a compound of the compositions described herein include acute gout and ankylosing spondylitis, allergic disorders, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis and multiple sclerosis, atherosclerosis, bacterial infections, bone cancer pain and pain due to endometriosis, BRAF-resistant melanoma, brainstem glioma or pituitary adenoma, burns, bursitis, cancer of the anal region, cancer of the endocrine system, kidney or ureter cancer (e.g., renal cell carcinoma, renal pelvis cancer), penile cancer, small intestine cancer, thyroid cancer, urethral cancer, blood cancer such as acute myeloid leukemia, tongue cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer or vulvar cancer, chronic myeloid leukemia, chronic or acute leukemia, chronic pain, classical Bartter's syndrome, common cold conjunctivitis , coronary heart disease, cutaneous or intraocular melanoma, dermatitis, dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis, fibromyalgia, fungal infections, gout, gynecological tumors, uterine sarcoma, fallopian tube cancer, headache, hemophilic arthropathy, Parkinson's disease, acquired immune deficiency syndrome, shingles, Hodgkin's disease, Huntington's disease, hyperprostaglandin E syndrome, influenza, iritis, juvenile arthritis, juvenile onset rheumatoid arthritis, juvenile rheumatoid arthritis, lower back pain and neck pain, lymphocytic lymphoma, fascial disorders, myositis, neuralgia, neurodegenerative disorders such as Alzheimer's disease, neuroinflammatory disorders, neuropathic pain, vulvar cancer, Parkinson's disease, pediatric malignancies, pulmonary fibrosis, rectal cancer, rhinitis, sarcoidosis, soft tissue sarcoma, scleritis, skin cancer, pediatric solid tumors, spinal axis tumors, sprains, and These include contusions, gastric cancer, stroke, subacute and chronic musculoskeletal pain syndromes such as bursitis, surgical or dental procedures, symptoms associated with influenza or other viral infections, synovitis, toothache, ulcers, uterine cancer, uterine sarcoma, uveitis, vasculitis, viral infections, viral infections (e.g., influenza), and wound healing.

[0125] Criteria useful for assessing disease activity in subjects with ulcerative colitis can be found, for example, in Truelove et al. (1955) Br Med J 2:1041-1048.Using these criteria, disease activity can be characterized as mild disease activity or severe disease activity in subjects with IBD.Subjects that do not meet all the criteria for severe disease activity and subjects that exceed the criteria for mild disease activity are classified as having moderate disease activity.

[0126] The disclosed treatment methods can also be applied at any point in the course of the disease. In certain embodiments, the methods are applied to subjects suffering from IBD in remission (i.e., inactive disease). In such embodiments, the methods provide benefit by extending the period of remission (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In other embodiments, the methods may be applied to subjects suffering from IBD during the active disease stage. Such methods provide benefit by shortening the duration of the active disease stage, reducing or ameliorating one or more symptoms of IBD, or treating IBD.

[0127] Measures for determining the effectiveness of IBD treatment in clinical practice have been described, including, for example, fistula closure, the required level of corticosteroid therapy, and improvement in quality of life. Health-related quality of life (HRQL) can be assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is widely used in clinical practice to assess quality of life in subjects with IBD. (See Guyatt et al. (1989) Gastroenterology 96:804-810.) In some embodiments, the disease or condition is an immune-mediated liver injury, disease, or condition. Tpl2 can mediate immune-related liver diseases or conditions. (Vyrla et al., The Journal of Immunology, 2016, 196; Perugorria et al., Hepatology, 2013; 57:1238-1249).

[0128] In some embodiments, the disease or condition mediated by Cot is alcoholic hepatitis. Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver failure that develops in subjects with chronic and active alcohol abuse. (See Akriviadis E. et al., Ann Gastroenterol. 2016 Apr-Jun;29(2):236-237.) Alcoholic hepatitis can cause liver cirrhosis and hepatocellular fibrosis. Glucocorticoids (e.g., prednisolone) and phosphodiesterase inhibitors (e.g., pentoxifylline) can be used to treat alcoholic hepatitis. The compounds herein can be used as an independent treatment or in combination with existing treatments for alcoholic hepatitis.

[0129] In some embodiments, the Cot-mediated disease or condition is systemic lupus erythematosus (SLE), lupus nephritis, a lupus-related disorder or other autoimmune disorder, or symptoms of SLE. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, mouth sores, swollen lymph nodes, photosensitivity, skin rash, headache, numbness, tingling, seizures, vision problems, personality changes, abdominal pain, nausea, vomiting, irregular heartbeat, vomiting blood and difficulty breathing, mottled skin color, and Raynaud's phenomenon.

[0130] In some embodiments, the Cot-mediated disease or condition is acute or chronic liver failure, acute intrahepatic cholestatic states of obstructive or chronic inflammatory disorders resulting from inadequate bile composition, alcohol-induced cirrhosis and related cholestasis, cholestatic or fibrotic effects associated with alcohol-induced cirrhosis or virally transmitted forms of hepatitis, chemotherapy-associated steatohepatitis (CASH), chronic intrahepatic or extrahepatic cholestatic states, chronic or obstructive inflammatory disorders of the liver, congenital hepatic fibrosis, lipid or lipoprotein disorders. , liver fibrosis, liver cirrhosis, liver failure or ischemia after major liver resection, fatty liver or related syndromes, liver ischemia after major liver resection, neoplastic disease of the gastrointestinal tract or liver, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obstructive or chronic inflammatory disorders of the liver, obesity, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive familial cholestasis, or metabolic syndrome selected from the group consisting of dyslipidemia, diabetes mellitus, and an abnormally high body mass index.

[0131] In some embodiments, the Cot-mediated disease or condition is diabetic kidney disease (DKD).

[0132] Improvement in any of the above response criteria is specifically provided by the methods of the present disclosure.

[0133] Combination therapy In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents.

[0134] In some embodiments, the additional therapeutic agent is in use and / or in development to treat an inflammatory disorder (eg, IBD).The one or more additional therapeutic agents may be selected from the group consisting of beta-adrenergic receptor antagonists, beta-glucuronidase inhibitors, bradykinin receptor modulators, calcineurin inhibitors, calcium channel inhibitors, cathepsin S inhibitors, CCR3 chemokine antagonists, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors, cytochrome P450 3A4 inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, GATA3 transcription factor inhibitors, glucagon-like peptide 2 agonists, glucocorticoid agonists, guanylate cyclase receptor agonists, histone deacetylase inhibitors, HLA class II antigen modulators, IL-12 antagonists, IL-13 antagonists, IL-23 antagonists, IL-6 antagonists, IL-6 receptor modulators, interleukin-7 receptor modulators, IL-7 antagonists, IL-8 antagonists, integrin α-4 / β-1 antagonists, integrin α-4 / β-7 antagonists, integrin α-E antagonists, integrin antagonists, integrin β-7 antagonists, interleukin ligand inhibitors, interleukin receptor 17A antagonists, interleukin-1β ligands, interleukin-1β ligand modulators, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, LanC-like protein 2 modulators, lipoxygenase modulators, MAdCAM inhibitors, matrix metalloproteinase inhibitors, melanocortin agonists, metalloproteinase 9 inhibitors, natriuretic peptide receptor C agonists, neuregulin 4 ligands, NKG2 D-activated NK receptor antagonists, opioid receptor antagonists, opioid receptor delta antagonists, oxidoreductase inhibitors, P2X7 purinergic receptor agonists, PDE4 inhibitors, phagocytosis-stimulating peptide modulators, potassium channel inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, fimH protein. The inhibitor may be a protein inhibitor, a P-selectin glycoprotein ligand 1 inhibitor, an RNA polymerase inhibitor, a sphingosine 1 phosphate phosphatase 1 stimulator, a sphingosine 1 phosphate phosphatase modulator, a sphingosine-1-phosphate receptor 1 agonist, a sphingosine-1-phosphate receptor 1 antagonist, a sphingosine-1-phosphate receptor 1 modulator, a sphingosine-1-phosphate receptor 5 modulator, a STAT3 gene inhibitor, a stem cell antigen 1 inhibitor, a superoxide dismutase modulator, a superoxide dismutase stimulator, a TGFβ1 ligand inhibitor, a thymulin agonist, a TLR antagonist, a TLR agonist, a TNFα ligand inhibitor, a TNF antagonist, a tumor necrosis factor 14 ligand modulator, a type II TNF receptor modulator, or a zonulin inhibitor.

[0135] Exemplary additional therapeutic agents include ABX-464, adalimumab; alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast; Alequel; AMG-139; amiselimod, ASD-003, ASP-3291, AX-1505, BBT-401, balsalazide; beclomethasone dipropionate; BI-655130, BMS-986184; budesonide; CEQ-508; certolizumab; Clostridium butyricum; ChAdOx2-HAV, dexamethasone sodium phosphate, DNVX-078, etanercept; ETX-201, golimumab; infliximab; mesalazine, HLD-400, LYC-30937 EC; IONIS-JBI1-2.5Rx, JNJ-64304500, naltrexone; natalizumab; neihulizumab, olsalazine; PH-46-A, propionyl-L-carnitine; PTG-100; remestemcel-L; tacrolimus ;Teduglutide;Tofacitinib;ASP-1002;Ustekinumab;Vedolizumab;AVX-470;INN-108;SGM-1019;PF-06480605;PF-06651600;PF-06687234;RBX-8225, SER-287;Thetanix;TOP-1288;VBY-129;99mTc-Annexin V-128;Bertilimumab;DLX-105;Dolcanatide;E-6011;FFP-104;Filgotinib;Foralumab;GED-0507-34-Levo;Gibinostat;GLPG -0974; Iberogast; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; Larazotide acetate; LY-3074828, Midismase; Olokizumab; OvaSave; P-28-GST; PF-547659; Prednisolone; QBECO; RBX-2660, JKB-122; SB-012; STNM-01; Debio-0512; TRK-170; Zucapsaicin; ABT-494; Ampion; BI-655066; Carotegast methyl methyl); cobitolimod; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; peficitinib; RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod; plecanatide; or AZD-058.

[0136] In some embodiments, the additional therapeutic agents include one or more alpha-fetoprotein modulators, such as ACT-101; beta-adrenergic receptor antagonists, such as NM-001; calcineurin inhibitors, such as tacrolimus; carbohydrate metabolism modulators, such as ASD-003; cathepsin S inhibitors, such as VBY-129; CD40 ligand receptor antagonists, such as FFP-104, BI-655064; chemokine CXC ligand inhibitors, such as LY-3041658; STNM CHST15 gene inhibitors such as -01; collagen modulators such as ECCS-50 (DCCT-10); CSF-1 antagonists such as JNJ-40346527 (PRV-6527); CX3CR1 chemokine modulators such as E-6130; ecobiotics such as SER-287; eotaxin ligand inhibitors such as bertilimumab; EP4 prostanoid receptor agonists such as KAG-308; and F1F0 ATP synthase inhibitors such as LYC-30937EC. fructose-dependent cyclase modulators; fructose-dependent cyclase inhibitors such as E-6011; free fatty acid receptor 2 antagonists such as GLPG-0974; GATA3 transcription factor inhibitors such as SB-012; glucagon-like peptide 2 agonists such as teduglutide; glucocorticoid agonists such as budesonide, beclomethasone dipropionate, and dexamethasone sodium phosphate; guanylate cyclase receptor agonists such as dolucanatide; HIF prolyl hydroxylase inhibitors such as DS-1093 and AKB-4924; and histamine-dependent cyclase inhibitors such as gibinostat. Tondeacetylase inhibitors; HLA class II antigen modulators such as HLA class II protein modulators; IL-12 antagonists such as ustekinumab (IL12 / IL23); IL-13 antagonists such as tralokinumab; IL-22 agonists such as RG-7880; IL-23 antagonists such as tildrakizumab, risankizumab (BI-655066), mirikizumab (LY-3074828), brazikumab (AMG-139), and PGT-200; IL-6 antagonists such as olokizumab; clotrimazole IL-8 receptor antagonists such as IL-8 receptor antagonists; integrin α4 / β1 antagonists such as natalizumab; integrin α-4 / β-7 antagonists such as etrolizumab (α4β7 / αEβ7), vedolizumab, carotegast methyl, TRK-170 (α4β7 / α4β1), and PTG-100; integrin antagonists such as E-6007; interleukin ligand inhibitors such as bimekizumab (IL-17A / IL-17E); interleukin receptor 17A antagonists such as brodalumab; interleukin receptor 17A antagonists such as K(D)PT. Interleukin-1β ligands; interleukin-1-like receptor 2 inhibitors such as BI-655130; IL-6 receptor modulators such as olamkicept; JAK tyrosine kinase inhibitors such as tofacitinib (1 / 3), peficitinib (1 / 3), TD-3504, and TD-1473; Jak1 tyrosine kinase inhibitors such as upadacitinib (ABT-494), filgotinib, GLPG-0555, and PF-06700841 (JAK1 / Tyk2); and Jak3 tyrosine kinase inhibitors such as PF-06651600.LanC-like protein 2 modulators such as BT-11; MAdCAM inhibitors such as SHP-647 (PF-547659); melanin-concentrating hormone (MCH-1) antagonists such as CSTI-100; melanocortin agonists such as ASP-3291 and PL-8177; metalloproteinase 9 inhibitors such as GS-5745; natriuretic peptide receptor C agonists such as plecanatide; neuregulin 4 ligands such as NRG-4; NKG2D-activating NK receptor antagonists such as JNJ-4500; naltrexate opioid receptor antagonists such as IRT-103; OX40 ligand inhibitors such as KHK-4083; oxidoreductase inhibitors such as olsalazine; P2X7 purinergic receptor modulators such as SGM-1019; PDE4 inhibitors such as apremilast; PPARα / δ agonists such as elafibranor (GFT-1007); PPARγ agonists such as GED-0507-34-Levo; fimH protein inhibitors such as EB-8018, SEL-K2, and P-anticoagulants such as neihulizumab Selectin glycoprotein ligand 1 inhibitors; Ret tyrosine kinase receptor inhibitors such as GSK-3179106; RIP-1 kinase inhibitors such as GSK-2982772; RIP-2 kinase inhibitors such as GSK-2983559; sphingosine-1-phosphate phosphatase 1 stimulators such as etrasimod; sphingosine-1-phosphate receptor 1 agonists such as ozanimod, moclavimod (KRP-203), and BMS-986166; and sphingosine-1-phosphate receptor 1 antagonists such as amiselimod (MT-1303). stem cell antigen 1 inhibitors such as Ampion (DMI-9523); superoxide dismutase modulators such as midismase; TLR-4 antagonists such as JKB-122; TLR-9 agonists such as cobitolimod; TNFα ligand inhibitors such as adalimumab, ceratolizumab, infliximab, golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb, and V-565; TNF inhibitors such as AVX-470, tulinercept, and etanercept; antagonists; TPL2 inhibitors such as GS-4875; tumor necrosis factor 14 ligand modulators such as AEVI-002; tumor necrosis factor 15 ligands such as PF-06480605 type I IL-1 receptor antagonists such as anakinra; and / or zonulin inhibitors such as larazotide acetate.

[0137] In some embodiments, the one or more additional therapeutic agents can be an α4β7 integrin inhibitor or an agent that inhibits the expression and / or activity of α4β7 integrin. The inhibitor can be a small molecule or a biologic. For example, the α4β7 integrin inhibitor can be natalizumab or vedolizumab.

[0138] In some embodiments, the one or more additional therapeutic agents may be steroids, including but not limited to corticosteroids, which may be administered by various routes, including intravenously (i.e., methylprednisolone, hydrocortisone), orally (i.e., prednisone, prednisolone, budesonide, dexamethasone), or topically (i.e., enema, suppository, or foam preparation).

[0139] In some embodiments, the one or more additional therapeutic agents can be an MMP9 inhibitor or an agent that inhibits the expression and / or activity of MMP9. A representative protein sequence for MMP9 is GenBank Accession No. NP_004985. The inhibitor can be a small molecule or a biologic. For example, Gu et al., The Journal of Neuroscience, 25(27):6401-6408 (2005), discloses the specific MMP9 inhibitor SB-3CT (CAS292605-14-2). Furthermore, siRNA, antisense RNA, and antibodies have also been demonstrated to inhibit MMP9 expression or activity and are within the scope of the present disclosure. In one embodiment, the MMP9 inhibitor is a monoclonal anti-MMP9 antibody. In some embodiments, the one or more additional therapeutic agents include an MMP9 inhibitor and a nucleoside analog, such as gemcitabine.

[0140] In some embodiments, the one or more additional therapeutic agents can be a sphingosine 1-phosphate receptor (S1P1) inhibitor, or an agent that inhibits the expression and / or activity of S1P1. The inhibitor can be a small molecule or a biologic. For example, the S1P1 inhibitor can be RPC1063.

[0141] In some embodiments, the one or more additional therapeutic agents can be a TNF inhibitor or an agent that inhibits the expression and / or activity of TNF. The inhibitor can be a small molecule or a biologic. For example, the TNF inhibitor can be golimumab.

[0142] In some embodiments, the one or more additional therapeutic agents are in use and / or development for treating ulcerative colitis (UC) and / or Crohn's disease (CD). The agent may be a biologic or a small molecule. In some embodiments, the agent is a modulator (e.g., an agonist or antagonist) of alpha-fetoprotein, beta-adrenergic receptor, calcineurin, carbohydrate metabolism, cathepsin S, S1P1, IL-6, CX3CL1, DHODH, alpha4, beta7, JAK, TNF, CB, IL-12 / IL-23, CCL20, TLR9, MAdCAM, CCR9, CXCL10, Smad7, PDE4, MC, VLA-1, GC, GATA-3, eotaxin, FFA2, LIGHT, FMS, MMP9, CD40, steroids, 5-ASA, immunomod, STAT3, and / or EP4.

[0143] In some embodiments, the additional therapeutic agent is in use and / or in development to treat IBD. Non-limiting examples of agents in use and / or in development to treat IBD include ABX-464, adlimumab; alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast; Alequel; AMG-139; Cerimod, ASD-003, ASP-3291, AX-1505, BBT-401, balsalazide; beclomethasone dipropionate; BI-655130, BMS-986184; budesonide; CEQ-508; certolizumab; Clostridium butyricum; ChAdOx2-HAV, dexamethasone sodium phosphate, DNVX-078, etanercept; ETX-201, golimumab; infliximab; mesalazine, HLD-400, LYC-30937 EC; IONIS-JBI1-2.5Rx, JNJ-64304500, naltrexone; natalizumab; neihulizumab, olsalazine; PH-46-A, propionyl-L-carnitine; PTG-100; remestemcel-L; tacrolimus; teduglutide; tofu Acitinib; ASP-1002; ustekinumab; vedolizumab; AVX-470; INN-108; SGM-1019; PF-06480605; PF-06651600; PF-06687234; RBX-8225, SER-287; Thetanix; TOP-1288; VBY-129; 99mTc-annexin V-128; bertilimumab; DLX-105; dolucanatide; E-6011; FFP-104; filgotinib; foralumab; GED-0507-34-Levo; gibinostat; GLPG-0974 ; Iberogast; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; Larazotide acetate; LY-3074828, Midismase; Olokizumab; OvaSave; P-28-GST; PF-547659; Prednisolone; QBECO; RBX-2660, JKB-122; SB-012; STNM-01; Debio-0512; TRK-170; Zucapsaicin; ABT-494; Ampion; BI-655066; Carotegast methyl methyl); cobitolimod; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; peficitinib; RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod; plecanatide, and AZD-058.

[0144] Non-limiting examples of agents in use and / or development for treating ulcerative colitis (UC) and Crohn's disease (CD) include PF-06410293 (Pfizer), SAN-300 (VLA-1 modulator, Salix), SAR252067 (LIGHT modulator, Sanofi), PF-00547659 (MAdCAM modulator, Pfizer), Eldelumab (Smad7 modulator, BMS), AMG181 / MEDI-7183 (β7 modulator, Amgen / AstraZeneca), etrolizumab (β7 modulator, Roche), ustekinumab (IL-12 / IL-23 modulator, J&J), Remicade (TNF modulator, , manufactured by J&J and Merck), Entyvio (beta7 modulator, manufactured by Takeda), Humira (TNF modulator, manufactured by Abbvie), infliximab (manufactured by Celtrion), PF-06651600 (manufactured by Pfizer), GSK2982772 (manufactured by GSK), GLPG1205 (FFA2 modulator, manufactured by Galapagos), AG014 (manufactured by Intrexon), and Vidofludimus (DHODH modulator, manufactured by 4SC).

[0145] In some embodiments, the one or more additional therapeutic agents can be a JAK inhibitor, such as a JAK-1 selective inhibitor. The inhibitor can be a small molecule or a biological agent. For example, the JAK inhibitor can be filgotinib, GLPG0634 (JAK modulator, manufactured by Galapagos).

[0146] In some embodiments, the one or more additional therapeutic agents are an ACE inhibitor, an acetaldehyde dehydrogenase inhibitor, an acetyl-CoA carboxylase inhibitor, an acetyl-CoA carboxylase inhibitor, a diacylglycerol O-acyltransferase 2 inhibitor, an adenosine A3 receptor agonist, an adiponectin receptor agonist, an aldehyde dehydrogen ... agonist-2 stimulators, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), AMP kinase activators, ATP citrate lyase inhibitors, AMP-activated protein kinase stimulators, endothelial nitric oxide synthase stimulators, NAD-dependent deacetylase sirtuin 1 stimulators, androgen receptor agonists, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, autophagy protein modulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase 3 stimulators, cathepsin inhibitors, caveolin-1 inhibitors, CCR2 chemokine antagonists, angiotensin II AT-1 receptor antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulators, CNR1 inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, DGAT1 / 2 inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT1), cytochrome P450 2E1 inhibitors (CYP2E1), CXCR4 chemokine antagonists, dipeptidyl peptidase IV inhibitors, endosialin modulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, galectin-3 inhibitors, glucagon receptor agonists, glucagon-like peptide 1 agonists, G protein-coupled bile acid receptor 1 agonists, G protein-coupled receptor 84 antagonists, hedgehog (Hh) modulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4α modulators (HNF4A), hepatocyte growth factor modulators, histone deacetylase inhibitors, STAT3 modulators, HMGCoA reductase inhibitors, hypoxia-inducible factor 2α inhibitors, IL-10 agonists, IL-17 antagonists, ileal bile acid sodium cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, IL-6 receptor agonists, Jak2 tyrosine kinase inhibitors, ketohexokinase (KHK) inhibitors, Klotho-β stimulators, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptors, LPL gene Gene stimulators, lysophosphatidate 1 receptor antagonists, lysyl oxidase homolog 2 inhibitors, macrophage mannose receptor 1 modulators, matrix metalloproteinase (MMP) inhibitors, MEKK5 protein kinase inhibitors, MCH receptor 1 antagonists, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase 2 inhibitors, methyl-CpG binding protein 2 modulators, microRNA 21 (miR-21) inhibitors, mitochondrial uncouplers, mixed lineage kinase 3 inhibitors, myelin basic protein stimulators, NACHT LRRPYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin stimulators, NADPH oxidase inhibitors (NOX), nicotinic acid receptor 1 agonists, P2Y13 purinergic receptor stimulators, nuclear receptor modulators, P2X7 purinergic receptor modulators, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor beta modulators, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, PPAR alpha agonists, PPAR delta agonists, PPAR gamma agonists, peptidyl-prolyl cis-trans isomerase A inhibitors, PPAR gamma modulators, protease-activated receptor 2 antagonists, protein kinase modulators, Rho-associated protein kinase inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter 2 inhibitors, SREBP transcription factor inhibitors, STAT1 inhibitors, stearoyl-CoA desaturase 1 inhibitors, STK25 inhibitors, inhibitors of stimulators of cytokine signaling 1, inhibitors of stimulators of cytokine signaling 3, transforming growth factor β (TGF-β), transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor β agonists, TLR4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators, or YAP / TAZ modulators and zonulin inhibitors.

[0147] For example, additional therapeutic agents include A-4250, AC-3174, acetylsalicylic acid, AK-20, lipogen tiparvovec, AMX-342, AN-3015, aramchol, ARI-3037MO, ASP-8232, AZD-2693, bertilimumab, betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, celicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dapagliflozin, and DCR-LIV. 1, Deuterated pioglitazone R enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, fulasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201, hydrochlorothiazide, icosabutate (PRC-40 16), icosapent ethyl ester, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, Irbesarta, propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452, LM-011, LM-002 (CVI-LM-002) , LMB-763, LYN-100, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namatizumab, NC-101, NDI-010976, ND-L02-s0201, NGM-282, NGM-313, NGM-386, NGM-395, NP-160, norursodeoxycholic acid, NVP-022, O-304, obeticholic acid, 25HC3S, olesoxime, PAT-505, PAT-048, PB-4 547, peg-ilodecaquin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, remogliflozin etabonate, RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) chin), TCM-606F, TEV-45478, TQA-3526, tipelukast (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, vorixibat potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007 may also be included.

[0148] kit Also provided herein are kits comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of Formula I (or any other formula described herein), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and / or instructions for use of the compound in treating an indication, including a disease or condition described herein.

[0149] Also provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, in a suitable container, which may be a vial, jar, ampoule, pre-filled syringe, or intravenous bag.

[0150] Pharmaceutical Compositions and Modes of Administration The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions containing one or more of the compounds described herein, or their pharmaceutically acceptable salts, tautomers, stereoisomers, stereoisomeric mixtures, prodrugs, or deuterated analogs, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients, are also provided herein. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts. For example, see Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0151] The pharmaceutical composition may be administered in either a single dose or multiple doses. The pharmaceutical composition may be administered by a variety of methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0152] One mode of administration is parenterally, e.g., by injection. Forms into which the pharmaceutical compositions described in this disclosure can be incorporated for administration by injection include, for example, aqueous or oily suspensions, or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, or elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0153] Oral administration may be another route for administering the compounds described herein. Administration may be, for example, via capsules or enteric-coated tablets. In preparing pharmaceutical compositions containing at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingredient is typically diluted with an excipient and / or enclosed within a carrier, such as may be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0154] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents, and flavoring agents.

[0155] Compositions containing at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by employing procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and solution-based systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are described in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods disclosed herein employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0156] To prepare solid compositions such as tablets, the primary active ingredient may be mixed with pharmaceutical excipients to form a solid preformulation composition containing a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. These preformulation compositions are referred to as homogeneous, meaning that the active ingredient may be dispersed evenly throughout the composition, so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0157] Tablets or pills of the compounds described herein may be coated or otherwise formulated to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0158] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be atomized by use of an inert gas. The atomized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing device. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0159] dosage The specific dosage level of the compounds of the present application for any given subject will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, number of doses, route of administration, as well as excretion rate in the subject undergoing therapy, drug combination, and the severity of a given disease. For example, dosages may be expressed as milligrams of the compounds described herein per kilogram of subject body weight (mg / kg). Doses between 0.1 and 150 mg / kg may be appropriate. In some embodiments, between about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses between 0.5 and 60 mg / kg may be appropriate. Normalizing by subject weight may be useful when adjusting dosages between subjects of widely differing sizes, such as occurs when using drugs in both children and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages appropriate for human subjects.

[0160] A daily dose may also be described as the total amount of a compound described herein administered per administration or per day. The daily dose of a compound of Formula I may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day. In some embodiments, the daily dose of a compound, i.e., a compound of Formula I or another formula described herein, is about 150 mg / day to 1000 mg / day.

[0161] When administered orally, the total daily dose for a human subject may be 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day.

[0162] The compounds of the present application or compositions thereof may be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compounds may also continue for several days. For example, treatment will typically continue for at least 7, 14, or 28 days per treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. In other embodiments, the treatment cycle may also be continuous.

[0163] In some embodiments, the method includes administering to a subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice weekly, or weekly.

[0164] Compound synthesis The compounds disclosed herein may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may also be used. The synthesis of exemplary compounds described herein may be achieved as illustrated in the following examples. Where available, reagents may be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0165] General Synthesis Exemplary embodiments of the compounds described herein may be synthesized using the general reaction schemes set forth below. Given the description herein, it will be apparent that the general schemes may be modified by substituting starting materials with other materials having similar structures, resulting in correspondingly different products. The synthetic description then provides numerous examples of how starting materials may be varied to provide the corresponding products. Given a desired product with defined substituents, the necessary starting materials can generally be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. To synthesize a compound that is an embodiment described in this disclosure, inspection of the structure of the compound to be synthesized provides the identity of each substituent. The identity of the final product is In general, in view of the examples herein, the identity of the necessary starting materials will be apparent by a simple inspection process. In general, the compounds described herein are typically stable and isolatable at room temperature and pressure.

[0166] Synthesis reaction parameters The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0167] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in T.W. Greene and G.M.Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0168] Additionally, compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents 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.

[0169] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chem or Sigma (St. Louis, Missouri, USA). Others are described in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, Inc., and They may be prepared by procedures or obvious modifications thereof described in standard reference texts such as 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).

[0170] The term "solvent" generally refers to solvents such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, etc. " refers to a solvent that is inert under the conditions of the reaction (including: (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) (j) (k ...

[0171] The term "qs" means adding a quantity sufficient to achieve a stated function, for example, to bring a solution to the desired volume (ie, 100%).

[0172] Compounds of Formula I can be prepared by first providing a substituted quinoline core and, optionally, further modifying the core as desired to provide the substituents disclosed herein. Scheme 1 illustrates the preparation of the quinoline core to provide compounds of Formula 1-e, where m, R 5 and R 15 is a functional group that is as defined herein or can be converted thereto using standard reaction conditions. [ka]

[0173] In Scheme 1, appropriately substituted 1-a and 1-b are condensed in a suitable solvent (e.g., DMF, etc.) at elevated temperatures (e.g., about 40-50°C) in the presence of a catalyst (e.g., CsCO, etc.) to provide 1-c. Compound 1-c is then converted to 1-d under thermal cyclization conditions (e.g., about 250°C) or under microwave conditions. Chlorination of 1-d to provide 1-e is accomplished using a suitable chlorinating agent (e.g., POCl, SOCl, etc.) at elevated temperatures (e.g., about 110-120°C) in the presence of a base (e.g., pyridine, dimethylaniline, diethylaniline, etc.) or a catalyst (e.g., DMF, DEF, etc.) in a suitable solvent (e.g., chlorobenzene, CHCN, etc.) or under solvent-free conditions (i.e., neat).

[0174] Scheme 2 shows the synthesis of compounds of formula 2-c and 2-d, where m, R 1 , R 2 , R 5 and R 15 is as defined herein. [ka]

[0175] In Scheme 2, 1-e is reacted with an appropriate amine under standard nucleophilic aromatic substitution conditions in the presence of a base (e.g., NEt) at elevated temperature (e.g., 150 °C) to give 2-a. 5 and / or R 15 Compounds of formula I, where is cyano, are provided by reacting 2-a with a suitable cyanating agent (e.g., CuCN, Zn(CN), etc.) in the presence of a catalyst. Compounds 2-c and 2-d are then provided via reduction of the nitro group of compound 2-a or compound 2-b, respectively (e.g., using Fe, SnCl, etc.).

[0176] Scheme 3 shows the synthesis of compounds 3-d and 3-e, where R 4 is as defined herein. [ka]

[0177] In Scheme 3, deuterated 3-c is obtained by reducing appropriately substituted aldehyde 3-a with a deuterium-containing reducing agent (e.g., NaBD), followed by oxidation of 3-b to the corresponding aldehyde 3-c under standard oxidation conditions (e.g., MnO2, Fe2O3, NiO, CuO, ZnO, ZrO2, La2O3, Sm2O3, Eu2O3, Yb2O3, etc.). Compound 3-d is obtained by reacting 3-c with an ethynyl Grignard followed by acylation of the resulting alcohol with acetic anhydride in the presence of a base (e.g., pyridine, TEA, etc.). Compound 3-e can be obtained in two steps by reacting the appropriately substituted aldehyde 3-a with an ethynyl Grignard followed by acylation of the resulting alcohol with acetic anhydride in a similar two-step process.

[0178] Scheme 4 illustrates the synthesis of appropriately protected azide compounds of formula 4-b, where Lg is a leaving group and R 3a is as defined herein. [ka]

[0179] In Scheme 4, appropriately substituted amine 4-a is treated with a diazo transfer agent (e.g., imidazole-1-sulfonyl azide hydrochloride) to give the corresponding 4-b. Alternatively, 4-b can be obtained in two steps from alcohol 4-c by conversion of the hydroxyl moiety to a suitable leaving group (Lg) (e.g., TsO-, MsO-, NsO-, TfO-, etc.), followed by nucleophilic substitution with azide.

[0180] Scheme 5 illustrates the synthesis of intermediate compounds of formula 5-c, where R50 is alkyl, and R 3a is as defined herein. [ka]

[0181] In Scheme 5, appropriately substituted triazole 5-b is obtained by reacting 4-b with 5-a using standard 1,3 dipolar cycloaddition conditions. The acetal 5-b is converted to the corresponding aldehyde 5-c under standard carbonyl deprotection conditions (e.g., aqueous acid).

[0182] Scheme 6 shows an exemplary synthesis of compounds 6b and 6c, where R 3a , m, R 1 , R 2 , R 4 , R 5 and R 15 is as defined herein. [ka]

[0183] In Scheme 6, compounds of formula 6-c can be provided via N-alkylation of amine 2-d with 3-d (or 3-e), followed by cyclization with azide 4-b under standard 1,3-dipolar cycloaddition conditions. Separation of the isomers of formula 6-a to provide compounds of formula 6-b can be carried out using standard chiral separation / resolution techniques (e.g., chiral chromatography, crystallization, etc.). Alternatively, compounds of formula 6-b can be provided via enantioselective N-alkylation of 2-d with 3-d (or 3-e) using a chiral metal complex (e.g., with a chiral ligand, such as [Cu(CHCN)PF]PF, CuOTf benzene, Cu(OAc) or Cu(I)I). Suitable reaction conditions and exemplary chiral ligands / complexes can be found in the literature (see, for example, Detz, et al. Angew. Chem. Int. Ed. 2008, 47, 3777-3780). Contacting compound 6-c with azide 4-b under standard 1,3-dipolar cycloaddition conditions provides compound 6-b. 6-c may or may not be isolated prior to the addition of compound 4-b.

[0184] Scheme 7 shows an alternative synthesis leading to compound 7-g via imine formation and subsequent nucleophilic addition, where R 3a , m, R 1 , R 2 , R 3 , R 4 , R 5 and R 15 is as defined herein. [ka]

[0185] In Scheme 7, amine 2-d is reacted with aldehyde 7-a to give the corresponding imine 7-b under standard imine-forming conditions. Compound 7-b is then reacted with Grignard reagent 7-c to provide Formula I. Alternatively, 2-d can be reacted with aldehyde 7-d to give imine 7-e, which can then be reacted with an ethynyl Grignard to provide compound 7-f. Compound 7-f can then be converted to compound 7-g under standard 1,3-dipolar cycloaddition conditions with 4-b, as shown in Scheme 6. Furthermore, resolution of isomers of Formula I or compound 7-g can be carried out using standard chiral separation / resolution conditions (e.g., chiral chromatography, crystallization, etc.).

[0186] Scheme 8 shows an alternative synthesis leading to compound 8-c, where m, R 1 , R 2 , R 3 , R 4 , R 5 and R 15 is as defined herein. [ka]

[0187] In Scheme 8, amine 2-d is reacted with appropriately substituted 8-a under nucleophilic substitution conditions, where Lg is a suitable leaving group that is a halide (e.g., fluoro, chloro, bromo, iodo) or an activated alcohol (e.g., AcO-, TsO-, TfO-, MsO-, etc.), in the presence of a base to provide compounds of Formula I. Alternatively, amine 2-d is reacted with ketone 8-b to provide 8-c, which is subsequently reduced to provide compounds of Formula I. Resolution of isomers of Formula I can be carried out using standard chiral separation / resolution conditions (e.g., chiral chromatography, crystallization, etc.).

[0188] Scheme 9 shows the synthesis leading to compound 9-e, where m, R 1 , R 2 , R 3 , R 4 , R 5 and R15 is as defined herein. [ka]

[0189] In Scheme 9, amine 6-b is reacted with an appropriately substituted chloroformate 9-a using a suitable solvent (e.g., DCM) and a base (e.g., proton sponge) to give compound 9-b. Compound 9-b is then reacted with a suitable nucleophile 9-c (e.g., acetate, phosphate, etc.) and an iodide salt (e.g., tetrabutylammonium iodide, etc.), followed by an optional deprotection step, to give compound 9-e. Amine 6-b can also be reacted with 1,1'-carbonyldiimidazole in a suitable solvent (e.g., DMF), an excess of a base (e.g., NaH), and a suitable substituted alcohol to give compound 9-g. [Example]

[0190] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent well-functioning techniques in the practice of the present disclosure and can therefore be considered to constitute specific modes for its practice. However, those skilled in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments disclosed that still achieve similar or similar results without departing from the spirit and scope of the present disclosure.

[0191] [Table A-1] [Table A-2]

[0192] Synthetic cyanoquinoline core Ethyl (Z)-3-((2-chloro-4-nitrophenyl)amino)-2-cyanoacrylate [ka] 2-Chloro-4-nitroaniline (1 equivalent), (Z)-ethyl 2-cyano-3-ethoxyacrylate (1.3 equivalents), and CsCO (1.3 equivalents) in DMF were heated at 45° C. overnight. After cooling to room temperature, the mixture was poured into water. The solid formed was filtered, washed with water, and dried to give the above-mentioned compound as a solid, which was used in the next step without further purification. 1 H NMR (DMSO-d6,300MHz): δ11.28(d,J=12.9Hz,1H),8.84(d,J=12.9Hz,1H),8.42(d,J=2.4Hz, 1H),8.26-8.22(m,1H),8.02(d,J=9.3Hz,1H),4.27(q,J=7.2Hz,2H),1.27(t,J=7.2Hz,3H).

[0193] 8-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile [ka] (Z)-Ethyl 3-((2-chloro-4-nitrophenyl)amino)-2-cyanoacrylate in diphenyl ether under nitrogen was heated to reflux in a sand bath in a heating mantle for 24 hours. After cooling to room temperature, the reaction mixture was poured into hexane and stirred for 2 hours. The mixture was filtered, and the filter cake was washed twice with hexane to give the title compound as a solid. 1 H NMR (DMSO-d6, 300MHz): δ12.86 (br s, 1H), 8.73-8.71 (m, 3H).

[0194] 4,8-Dichloro-6-nitroquinoline-3-carbonitrile [ka] A suspension of 8-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile and 5 drops of DMF in POCl was heated at 115° C. overnight. The solution was cooled to room temperature and excess POCl was removed. The residue was dissolved in DCM, washed with saturated NaHCO, brine, and dried over NaSO. The solution was filtered and concentrated to give the crude product. The residue was triturated with hexane and EtOAc to give the title compound as a solid. 1 H NMR (DMSO-d6, 300MHz): d 9.50 (s, 1H), 8.98 (d, J = 2.4 Hz, 1 H), 8.89 (d, J = 2.4 Hz, 1 H).

[0195] 8-chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile: [ka] 4,8-Dichloro-6-nitroquinoline-3-carbonitrile (615 mg, 2.29 mmol), neopentylamine (220 mg, 0.25 mmol), and triethylamine (278 mg, 2.75 mmol) in isopropanol (4 mL) were heated at 150° C. for 45 minutes under microwave conditions. The reaction was cooled to room temperature. Water was added, and the resulting precipitate was collected by filtration. The crude product was used in the next step without further purification. ES / MS 319.1 (M+H) + ).

[0196] Alternatively, 4,8-dichloro-6-nitroquinoline-3-carbonitrile (3000 mg, 11.2 mmol), neopentylamine (1073 mg, 12.3 mmol), and triethylamine (1246 mg, 12.3 mmol) in isopropanol (60 mL) were heated at 80° C. for 4 hours. The reaction was cooled to room temperature. The solvent was removed, and the crude reaction was purified via chromatography on silica gel (eluent: EtOAc / hexanes) to give the product. ES / MS (M+H) + )319.1.

[0197] Synthesis of (S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile [ka] 6-amino-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile: [ka] 8-Chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile (699 mg, 2.2 mmol), calcium chloride (483.6 mg, 3.28 mmol), and iron powder (612.3 mg, 10.96 mmol) were heated in ethanol (22 mL) / water (2.2 mL) at 60° C. for 1 hour. The reaction was cooled to room temperature and the solid was removed by filtration. The solid was washed with EtOAc, and the combined organic layers were washed with aqueous sodium bicarbonate, brine, and dried over sodium sulfate. Filtration and evaporation of all volatiles afforded the product. ES / MS 289.1 (M+H + ).

[0198] Alternatively, 8-chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile (2,000 mg, 6.2 mmol) and tin chloride (7079 mg, 31.3 mmol) were heated at 70° C. for 4 hours. Additional tin chloride (2832 mg, 12.6 mmol) was added. After 5 hours, the reaction was allowed to cool to room temperature. Half of the ethanol was removed under reduced pressure. This mixture was added to NaHCO (200 mL) and EtOAc (50 mL). The mixture was diluted with 100 mL of DMSO-d6 (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 5.74 (s, 2H), 3.66 (d, J = 6.6 Hz, 2H), 0.96 (s, 9H). The organic phase was washed with brine (200 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to provide the desired material. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 5.74 (s, 2H), 3.66 (d, J = 6.6 Hz, 2H), 0.96 (s, 9H).

[0199] (R)-8-chloro-6-((1-(6-fluoro-2-methylpyridin-3-yl)prop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile: [ka] A mixture of acetonitrile (800 mL) and methanol (800 mL) was degassed with argon and added to Cu(I) iodide (3.3 g, 17.3 mmol) and bis-oxazoline ligand (10.8 g, 20.7 mmol). The mixture was stirred at ambient temperature for 90 minutes under an inert atmosphere. The mixture was cooled to 5°C. A 5 L reactor was charged with 6-amino-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile (100 g, 346 mmol), 1-(6-fluoro-2-methylpyridin-3-yl)prop-2-yl-1-yl acetate (86 g, 415 mmol), and sodium acetate (35.6 g, 434 mmol). The reactor was charged with a mixture of acetonitrile (800 mL) and methanol (800 mL) and degassed with argon. The reactor was cooled to -5°C and a solution containing Cu(I) iodide and a bis-oxazoline ligand was introduced via cannulation over 20 minutes. After stirring at -5°C for 48 hours, the mixture was warmed to 5°C, and 4M NH4Cl (2 L) was added to the mixture over 1 hour. The mixture was warmed to 20°C, and the resulting solid was filtered and washed with water (500 mL). The wet cake was transferred to a reactor and heated with a 1:1 mixture of isopropyl acetate and ethyl acetate (3 L) and heated to 40°C. The solid was filtered through Celite, the aqueous layer was removed from the filtrate, and the organic layer was concentrated under reduced pressure. The resulting solid was suspended in dichloromethane (1.5 L), heated to reflux, and hexane (750 mL) was slowly added. The resulting suspension was warmed to 5°C over 4 hours. The precipitated solid was filtered (95 g) and recrystallized from dichloromethane and hexane to give the title compound. 1H NMR(400MHz,Methanol-d4)δ 8.27(s,1H),8.24(t,J=8.1Hz,1H),7.50(d,J=2.4Hz,1H),7.17(d,J=2.4Hz,1H),6.97(dd,J=8.4,2.8Hz,1H),5.76 (d,J=2.2Hz,1H),3.94(d,J=13.9Hz,1H),3.71(d,J=13.9Hz,1H),3.06(d,J=2.3Hz,1H),2.60(s,3H),1.02(s,9H). ES / MS 436.34(M+H + ).

[0200] (S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile: [ka] A 500 mL round-bottom flask was charged with 1-(difluoromethyl)cyclopropanamine hydrochloride (8.2 g, 57.4 mmol). The round-bottom flask was placed in a water bath and charged with acetonitrile (34 mL), followed by N,N-diisopropylethylamine (10.3 mL, 59.6 mmol). The mixture was stirred until homogeneous, and a solution of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (16.4 g, 57.4 mmol) in acetonitrile (32 mL) was added to the mixture over 10 minutes. The mixture was stirred at 30° C. for 8 hours, N,N-diisopropylethylamine (1.98 mL, 11.47 mmol) was added, and the mixture was stirred at 30° C. for 18 hours. A 500 mL jacketed flask was charged with (R)-8-chloro-6-((1-(6-fluoro-2-methylpyridin-3-yl)prop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile (20 g, 45.9 mmol) and maintained at 20 °C using a circulating condenser. Tetrahydrofuran (40 mL), copper(II) sulfate pentahydrate (1.2 g, 4.6 mmol), sodium ascorbate (2.7 g, 13.8 mmol), and water (16 mL) were added to the flask. The azide solution was added overhead in quarter portions over 10 minutes. The mixture was stirred at 22 °C for 18 hours. The reaction was quenched with tributylphosphine (3.4 mL, 13.8 mmol). After stirring for 20 minutes, the mixture was diluted with ethyl acetate (160 mL) and washed with 0.5 M aqueous HCl (160 mL). The organic layer was stirred with 0.5 M ammonium hydroxide (160 mL) for 3 hours. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was diluted with ethyl acetate (15 mL), and the mixture was heated to 50°C. To the mixture was added methyl tert-butyl ether (150 mL). The solution was cooled to 20°C and stirred for 18 hours. The solid was filtered, washed with (10:1 MTBE:EtOAc), and dried under reduced pressure. The filtrate was concentrated and purified by silica chromatography, and the purified product was precipitated from ethyl acetate and methyl tert-butyl ether. The products were combined to give the title compound.

[0201] (S)-6-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile [ka] (S)-8-chloro-6-(((1-(1-difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6- A mixture of (fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile (95 mg, 0.14 mmol), zinc powder (1.2 mg, 0.02 mmol), Zn(CN), and Pd(dppf)Cl was degassed with argon for 2 minutes. The mixture was heated in a microwave reactor at 200 °C for 15 minutes. The mixture was diluted with ethyl acetate (10 mL) and washed with saturated NaHCO (5 mL aqueous solution) and brine (5 mL). The organic phase was dried over sodium sulfate and treated with thiol-functionalized silica to remove residual palladium. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography using ethyl acetate and hexane. The product-containing fractions were combined, and the solvent was removed under reduced pressure. The residue was taken up in methanol (1 mL) and water (1 mL) with 2 drops of TFA and purified by preparative HPLC using acetonitrile and water with 0.5% trifluoroacetic acid to give the title compound as the trifluoroacetic acid salt. 1H NMR(400MHz,Methanol-d4)δ 8.36(s,1H),8.05(d,J=1.3Hz,1H),7.84-7.75(m,2H),7.11(t,J=2.1Hz,1H),6.86(dd,J=8.5,2.7Hz,1H),6.24(s,1H),5 .94(t,J=54.7Hz,1H),3.89(d,J=13.8Hz,1H),3.70(dd,J=13.8,1.6Hz,1H),2.50(s,3H),1.55-1.50(m,4H),0.89(s,9H). ES / MS 560.24(M+H+).

[0202] Example 1 (Phosphonoxy)methyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate [ka] Synthesis of chloromethyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate: DCE of (S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile hydrochloride salt (100 mg, 0.159 mmol) To a solution of 1 mL of HCl at room temperature was added DIPEA (616 mg, 4.77 mmol) followed by chloromethyl carbonochloridate (1024 mg, 7.94 mmol). After heating at 50° C. overnight, the reaction was cooled to room temperature and extracted with ethyl acetate (100 mL). The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 85 mg of the desired product, MS (m / z): 685.261 [M+H]. + obtained.

[0203] Synthesis of ((di-tert-butoxyphosphoryl)oxy)methyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate: To a solution of chloromethyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate (85 mg, 0.124 mmol) in DMF (5 mL) was added potassium di-tert-butylphosphate (77 mg, 0.37 mmol) and tetrabutylammonium iodide (22.9 mg, 0.06 mmol) at room temperature. After heating to 70° C. for 4 hours, the reaction was cooled to room temperature and extracted with ethyl acetate (100 mL), and the extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 93 mg of the desired product MS (m / z): 858.956 [M+H] + obtained.

[0204] Synthesis of (phosphonoxy)methyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate: To a solution of ((di-tert-butoxyphosphoryl)oxy)methyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate (93 mg, 0.108 mmol) in ACN:water (4 mL, 1:1) was added AcOH (2 mL). After heating to 55° C. for 4 h, the reaction was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to give 10 mg of (phosphonooxy)methyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate trifluoroacetate MS (m / z): 858.956 [M+H] + obtained.

[0205] Example 2 ((((S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl L-alaninate [ka] Synthesis of ((((S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl(tert-butoxycarbonyl)-L-alaninate: To a solution of chloromethyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate (73 mg, 0.43 mmol) in DMF (1 mL) was added potassium bicarbonate (37 mg, 0.43 mmol), potassium iodide (22.9 mg, 0.06 mmol), and BOC-L-alanine (55 mg, 0.29 mmol) and stirred at room temperature for 16 hours. The reaction was poured onto aqueous brine solution (approximately 50 mL), extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 100 mg of the desired product MS (m / z): 839.0 [M+H] + obtained.

[0206] Synthesis of ((((S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl L-alaninate: A solution of ((((S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl (tert-butoxycarbonyl)-L-alaninate (100 mg, 0.12 mmol) in DCM:TFA (4 mL, 1:1) was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and purified by reverse phase HPLC to give 80 mg of the title compound as the trifluoroacetate salt. MS (m / z): 739.2 [M+H] + was obtained as.

[0207] Example 3 ((((S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl L-valinate [ka] The title compound was produced in the same manner as in Example 2, except that BOC-L-valine was used instead of BOC-L-alanine. MS (m / z): 767.1 [M+H] + .

[0208] Example 4 3-(Phosphonoxy)propyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate [ka] Synthesis of 3-chloropropyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate: To a solution of (S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile (630 mg, 1.1 mmol) in DCM (3 mL) was added proton sponge (683 mg, 3.2 mmol) followed by 3-chloropropyl carbonochloridate (417 mg, 2.6 mmol) at room temperature. After stirring for 24 hours at room temperature, the reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give 233 mg of the desired product. MS (m / z): 714.3 [M+H] + obtained.

[0209] Synthesis of 3-((di-tert-butoxyphosphoryl)oxy)propyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate: To a solution of 3-chloropropyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate (100 mg, 0.14 mmol) in THF (2 mL) was added potassium di-tert-butylphosphate (52 mg, 0.2 mmol) and tetrabutylammonium iodide (21 mg, 0.06 mmol) at room temperature. After heating to 50° C. for 16 hours, the reaction was cooled to room temperature and extracted with ethyl acetate (100 mL), and the extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 25 mg of the desired product MS.(m / z): 887.9 [M+H] + obtained.

[0210] Synthesis of 3-(phosphonoxy)propyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate: A solution of 3-((di-tert-butoxyphosphoryl)oxy)propyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate (25 mg, 0.28 mmol) in DCM:TFA (4 mL, 1:1) was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and the resulting residue was purified by reverse phase HPLC to afford 15 mg of the title compound as the trifluoroacetic acid salt. MS (m / z): 776.1 [M+H] + .

[0211] Example 5 3-Hydroxypropyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate [ka] To a suspension of (S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile in DMF (0.5 mL) was added NaH (60% in mineral oil). (60%, 12.14 mg, 0.3 mmol) was added. After stirring for 10 minutes, di(imidazol-1-yl)methanone (24.6 mg, 0.15 mmol) was added and the mixture was stirred at room temperature for 1 hour. To this mixture was added 1,3-propanediol (0.25 mL) and the reaction was stirred for 1 hour. The mixture was acidified with 5% TFA in water and the product was purified via reverse phase HPLC (eluent: water / MeCN 0.1% TFA) to give the product as the trifluoroacetate salt. ES / MS: 695.3 (M+H + ).

[0212] Example 6 (Phosphonooxy)methyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamate [ka] The title compound was produced in the same manner as in Example 1, except that (S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile was used in place of (S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile hydrochloride salt. MS (m / z): 689.968 [M+H] + .

[0213] Example 7 (S)-((((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl acetate [ka] To a suspension of chloromethyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamate (63 mg, 0.1 mmol) in DMF (3 mL) was added tetrabutylammonium iodide (18 mg, 0.05 mmol) followed by potassium acetoxy (20 mg, 0.2 mmol). After heating to 60° C. for 2 h, the reaction was cooled to room temperature, extracted with ethyl acetate (30 mL), and the extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was acidified with 5% TFA in water, and the product was purified via reverse-phase HPLC (eluent: water / MeCN 0.1% TFA) to give the product as the trifluoroacetate salt. MS(m / z):652.1[M+H] +

[0214] Example 8 (S)-((((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl 1-methylpiperidine-4-carboxylate [ka] To a suspension of 1-methylpiperidine-4-carboxylic acid (13.68 mg, 0.096 mmol) in DMF (3 mL) was added KHMDS (1 M solution in THF, 0.08 mL), and after 15 minutes, chloromethyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3 triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamate (20 mg, 0.032 mmol) was added, followed by tetrabutylammonium iodide (5.88 mg, 0.016 mmol). After heating at 60° C. for 2 hours, the reaction was extracted with ethyl acetate, washed with brine, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give 13.2 mg of the title compound as a trifluoroacetate salt MS. (m / z): 735.29 [M+H] + was obtained as.

[0215] Example 9 (R)-1-Methoxypropan-2-yl((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro- 2-Methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamate [ka] To a solution of (S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile (69 mg, 0.12 mmol) in pyridine (1 mL) was added (R)-1-methoxypropan-2-ylcarbonochloridate (200 mg, 1 mmol) at 0° C. The reaction was warmed to room temperature and heated to 50° C. for 16 hours. Upon cooling to room temperature, the reaction was extracted with ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to provide 84 mg of the title compound as the trifluoroacetate salt. MS (m / z): 652.16 [Mt-Bu] +

[0216] Example 10 (Phosphonooxy)methyl((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)carbamate [ka] Instead of 6-(((S)-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile hydrochloride salt, 6-(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(((R The title compound was prepared in the same manner as in Example 1 using (3,3-dimethylbutan-2-yl)amino)quinoline-3,8-dicarbonitrile. MS (m / z): 704.028 [M+H] + .

[0217] Example 11 (((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyl dihydrogen phosphate [ka] Synthesis of (((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyl di-tert-butyl phosphate: To a solution of 6-(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinoline-3,8-dicarbonitrile (60 mg, 0.109 mmol) in DCE (2 ml) was added DIPEA (141.8 mg, 1.09 mmol) and di-tert-butyl(chloromethyl)phosphate (112.96 g, 0.437 mmol) at room temperature. After heating to 50° C. overnight, the reaction was cooled to room temperature and extracted with ethyl acetate (100 mL), and the extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was applied to a silica gel column for purification to give 22 mg of (((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyl di-tert-butyl phosphate. MS (m / z): 715.68 [Mt-Bu] + .

[0218] Synthesis of (((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyl dihydrogen phosphate: A solution of (((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyl di-tert-butyl phosphate (22 mg, 0.1 mmol) in a mixture of ACN (2 mL) and water (2 mL) was added AcOH (2 mL) and heated to 70° C. for 4 h. The reaction was cooled, concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to provide 28.5 mg of (((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino. (amino)methyl dihydrogen phosphate trifluoroacetate MS (m / z): 659.935 [M+H] + obtained.

[0219] Example 12 (R)-1-Methoxypropan-2-yl((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)carbamate [ka] To a solution of 6-(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinoline-3,8-dicarbonitrile (25 mg, 0.045 mmol) in DCE (1 ml) was added DIPEA (117.6 mg, 0.9 mmol) and (R)-1-methoxypropan-2-ylcarbonochloridate (69.4 mg, 0.46 mmol) at room temperature. After heating to 50° C. for 16 hours, the reaction was cooled to room temperature, extracted with ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to give 7.2 mg of the title compound. MS(m / z):666.17[Mt-Bu] +

[0220] Example 13 2-(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)-2-oxoacetic acid [ka] To a solution of 6-(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3 triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinoline-3,8-dicarbonitrile (50 mg, 0.095 mmol) in THF (5 mL) was added DMAP (56 mg, 0.45 mmol) followed by oxalyl dichloride (23 mg, 0.18 mmol) at room temperature. After heating to 50° C. for 4 h, the reaction was cooled to room temperature, extracted with ethyl acetate (100 mL), washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to give 27 mg of methylaminopropanol. The title compound was obtained. MS (m / z): 621.9 [Mt-Bu] + .

[0221] Example 14 3-Hydroxypropyl (S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate [ka] To a solution of (S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile (150 mg, 0.26 mmol) and di(imidazol-1-yl)methanone (106.86 mg, 0.66 mmol) in DMF (1.0 mL) was added NaH (15.82 mg, 0.66 mmol) in four portions. After stirring for 30 min, 1,3-propanediol (0.5 mL) was added and the mixture was stirred at ambient temperature for 2 h. The mixture was extracted with EtOAc (3 mL) and washed three times with 5% LiCl (aq, 3 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was carried to the next step without further purification. ES / MS: 671.20 (M+H + ).

[0222] Example 15 3-(Phosphonooxy)propyl (S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate [ka] To 3-hydroxypropyl (S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate (0.11 g, 0.17 mmol) was added acetonitrile (2 mL) and EtN(i-Pr) (145.48 μL, 0.84 mmol). To the stirred mixture was added phosphorus(V) oxychloride (47.13 μl, 0.5 mmol) and the mixture was stirred for 30 minutes. To the reaction was added 1 M HCl (0.5 mL). After stirring for 1 minute, the mixture was partially concentrated, diluted with DMF, and purified by reverse phase HPLC (eluent: water / MeCN * 0.1% TFA) to give the product as the trifluoroacetate salt (30 mg). ES / MS: 751.20 (M+H + ).

[0223] Example 16 2-Hydroxyethyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate [ka] To a suspension of (S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile (100 mg, 0.17 mmol) in DMF (0.5 mL) was added NaH (12.14 mg, 0.51 mmol). After stirring for 1 minute, di(imidazol-1-yl)methanone (41.01 mg, 0.25 mmol) in DMF (0.2 mL) was added dropwise and the mixture was stirred at ambient temperature for 1 hour. Additional CDI (1 equivalent) and NaH (1 equivalent) were added and the reaction was stirred for 30 minutes. To this mixture was added ethylene glycol (0.2 mL) and the reaction was stirred for 1 h. The mixture was extracted with EtOAc (20 mL) and washed three times with 5% LiCl (aq, 15 mL). The organic layer was dried over Na2SO4, filtered and concentrated. ES / MS: 681.22 (M+H + ).

[0224] Example 17 2-(Phosphonoxy)ethyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate [ka] To 2-hydroxyethyl (S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate (0.11 g, 0.17 mmol) was added acetonitrile (2 mL) and EtN(i-Pr)2 (145.48 μL, 0.84 mmol). To this stirred mixture was added phosphorus(V) oxychloride (47.13 μL, 0.5 mmol) and the mixture was stirred for 30 minutes. To the reaction was added 1 M HCl (0.5 mL). After stirring for 1 minute, the mixture was partially concentrated, diluted with DMF, and purified by reverse-phase HPLC (eluent: water / MeCN). * 0.1% TFA) to give the product as the trifluoroacetate salt (40 mg). ES / MS: 723.20 (M+H + ).

[0225] Example 18 Chloromethyl (S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate [ka] A solution of (S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile (0.3 g, 0.53 mmol), chloromethyl carbonochloridate (0.09 mL, 1.05 mmol), and proton sponge (0.25 g, 1.16 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 15 h. The product was purified by silica chromatography using EtOAc (0-100%) in hexanes. ES / MS: 661.20 (M+H + ).

[0226] Example 19 ((di-tert-butoxyphosphoryl)oxy)methyl(S)-(8-chloro-3- Cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate [ka] Chloromethyl (S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate (30.03 mg, 0.12 mmol) and tetrabutylammonium iodide (1 mg) in MeTHF (0.5 mL) were stirred at 60° C. for 1 h. The mixture was diluted with EtOAc (3 mL) and extracted twice with water (3 mL) followed by 0.1 M NaCl (aq, 10 mL). The organic layer was dried over NaSO, filtered, and concentrated. ES / MS: 661.20 (M+H). + ).

[0227] Example 20 (Phosphonooxy)methyl (S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate [ka] A solution of ((di-tert-butoxyphosphoryl)oxy)methyl (S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate (50 mg, 0.06 mmol) in dichloromethane (0.1 mL) and trifluoroacetic acid (0.1 mL) was stirred at 20° C. for 1 hour. The mixture was concentrated and purified by reverse-phase HPLC (eluent: water / MeCN). * 0.1% TFA) to give the product as the trifluoroacetate salt. ES / MS: 761.20 (M+H + ).

[0228] Compound example The following compounds were prepared according to the examples and procedures described herein (and shown in Table 1 under Examples / Procedures), using appropriate starting materials and appropriate protecting group chemistries where necessary.

[0229] [Table 1-1] [Table 1-2] [Table 1-3]

[0230] Biological assays Example 21 Human and canine gastrointestinal S9 stability A gastrointestinal S9 stability assay was performed. Generally, a substrate concentration of 2 μM, a protein concentration of 1.0 mg / mL of intestinal S9, and a reaction buffer of 1× phosphate-buffered saline (PBS) were used. Intestinal S9 was provided by BioIVT (dogs) or Xenotech (humans). The reaction composition contained 5 μL of the compound of interest (prepared as a 100 μM stock solution, 1:1 ACN:HO) and 245 μL of intestinal S9 solution (S9 diluted with 1×PBS to a protein concentration of 1.02 mg / mL), provided in a total volume of 250 μL per well. At 0, 10, 20, 30, 60, and 120 minutes, 25 μL of each time point was added to the plate with 225 μL of quenching solution (10% MeOH, 90% ACN, and 200 nM labetalol as an internal standard). The plate was vortexed and then centrifuged at 3000xG for 30 minutes. 150 μL of the supernatant was transferred to a new plate and 150 μL of water was added. The new plate was vortexed to mix.

[0231] Samples were analyzed using a Leap HTC autosampler and a Dionex UltiMate 3000 HPLC system interfaced to a Thermo Q-Exactive mass spectrometer operating in positive ion electrospray mode. Thermo Scientific Hypersil GOLD (1.9 μM particle size, 50× A 2.1 mm HPLC column was used, and the mobile phase was pumped at 0.5 mL / min. Elution of the analytes was achieved with a linear gradient series of acetonitrile in water containing 0.1% (v / v) formic acid. Quantitation was by analyte / internal standard peak area ratio (PAR). The results are shown in Table 2 below.

[0232] [Table 2]

[0233] Example 22 Solubility in FASSIF and FESSIF The aqueous solubility of the compounds was assessed over a 2.5-hour period. Solubility was determined at ambient temperature in fasted-state simulated buffered intestinal fluid (FaSSIF, pH 6.5) and fasted-state simulated buffered intestinal fluid (FeSSIF, pH 5.0), both prepared in the laboratory using BioRelevant Simulated Intestinal Fluid (SIF) powder. The solids were added to FaSSIF or FeSSIF in 1.5 mL Eppendorf tubes, sonicated for 1 minute, and then mixed in an Eppendorf ThermoMixer C for 2.5 hours. To determine the concentration in solution, the suspensions were centrifuged at 14,800 rpm for 10 minutes, and the supernatants were diluted to a volume of 1 mL with 1:1 v / v acetonitrile:water. All diluted supernatants were analyzed by UPLC using a Waters Acquity UPLC with a PDA UV detector. The results are shown in Table 3.

[0234] [Table 3]

[0235] Example 23 Human and dog plasma stability Plasma stability assays were performed in humans and dogs. Duplicate sets were run using a Tecan liquid handler or using cluster tubes in a heat block. Generally, a substrate concentration of 2 μM was used. Plasma in sodium EDTA was provided by BioIVT as whole plasma with K2EDA as the anticoagulant. Reaction compositions were prepared by combining 6 μL of compound (100 μM stock solution, 1:1 ACN:HO) with 294 μL of plasma in the incubation wells of the plate. Samples were incubated for 3 min, 30 min, and 4 min. The assay was performed at 1 minute, 1 hour, 2 hours, 3 hours, and 4 hours. At each time point, 25 μL was added to a plate containing 225 μL of quenching solution (100% ACN containing 200 nM propranolol as an internal standard). After vortexing, the plate was centrifuged at 3000 rpm for 30 minutes. 150 μL of the supernatant was transferred to a new plate, and 150 μL of water was added. The new plate was vortexed to mix.

[0236] Samples were analyzed using a Leap HTC autosampler and a Dionex UltiMate 3000 HPLC system interfaced to a Thermo Q-Exactive mass spectrometer operating in positive ion electrospray mode. A Thermo Scientific Hypersil GOLD (1.9 μM particle size, 50 × 2.1 mm) HPLC column was used, with the mobile phase pumped at 0.5 mL / min. Elution of the analytes was achieved with a linear gradient series of acetonitrile in water containing 0.1% (v / v) formic acid. Quantitation was by analyte / internal standard peak area ratio (PAR). Results are shown in Table 4 below.

[0237] [Table 4]

[0238] Example 24 In vivo pharmacokinetic studies in dogs In vivo dog pharmacokinetic studies of Compounds B and C were evaluated as follows. [ka] Compound B was administered as a powder in capsules to beagle dogs (N=3) using the following formulation: 57.5% amorphous Compound B (9.7 mg-eq / kg), 4.7% crospovidone, 18.7% lactose monohydrate, 0.4% magnesium stearate, and 18.7% microcrystalline cellulose. Compound A was administered separately as a powder in capsules to beagle dogs (N=3) using the following formulation: 20% amorphous Compound A, 0.75% magnesium stearate, 3% hydroxypropyl cellulose, 5% tocopheryl polyethylene glycol succinate, 20% hydroxypropyl methylcellulose, and 51.25% microcrystalline cellulose. Samples were evaluated for the presence of Compound B, proposed intermediate A, and Compound A. Figure 1 shows the plasma concentration of Compound A (nM) over a 72-hour period after dosing with either Compound B or Compound A using the above-described powder in capsule formulation. The area under the curve measured for Compound A in plasma was 0.75% magnesium stearate, 3% hydroxypropyl cellulose, 5% tocopheryl polyethylene glycol succinate, 20% hydroxypropyl methylcellulose, and 51.25% microcrystalline cellulose, as shown in Table 5. 0~72時間 was higher after dosing with Compound B than after dosing with an equivalent dose of Compound A.

[0239] [Table 5]

[0240] [ka] Compound C was dosed to beagle dogs (N=3) as a 3 mg / mL solution using the following formulation: 3 mg / kg Compound C, 5% ethanol, 55% polyethylene glycol 300, and 40% (5% dextrose in water). Samples were evaluated for the presence of Compound C, intermediate Compound D, and Compound A. Figure 2 shows the plasma concentrations of Compound A and Compound D (nM) over a 72-hour period following dosing with Compound C using the solution formulation previously described. As can be seen in Figure 2 and reported in Table 6, Compound C was converted in vivo to both Compound D and Compound A in measurable amounts.

[0241] [Table 6]

[0242] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Formula I below: [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 1 But hydrogen, -OR 7 , -N(R 8 )(R 9 ), -C(O)-R 7 , -S(O)2-R 7 , -C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 S chloroalkyl, heterocyclyl, aryl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, and heteroaryl each optionally have 1 to 4 Z 1 may be substituted with R 2 is hydrogen, -C(O)-R 7 , -C(O)OR 7 , -C(O)N(R 7 )2, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 2 may be substituted with or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains 1 to 4 Z 2 is replaced by R 3 is heterocyclyl or heteroaryl, wherein each heterocyclyl or each heteroaryl is optionally joined to one to four Z 3 is replaced by R 4 is aryl, heterocyclyl, or heteroaryl, wherein each aryl, each heterocyclyl, or each heteroaryl is optionally joined to one to four Z 4 is replaced by R 5 But hydrogen, halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R 7 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 5 may be substituted with R 6 But -C(O)OR 16 -OP(O)(OR 12 )2-C(O)-R 16 -OP(O)(OR 12 )2, -R 16 -OP(O)(OR 12 )2, -C(O)OR 16 -OR 17 ;-C(O)OR 16 -OH;-C(O)OR 16 -OC(O)R 17 ;-C(O)-C(O)OR 12 ; or -C(O)OR 16 -OC(O)R 17 NH2, Each R 7 are independently hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 7 may be substituted with R 8 and R 9 independently at each occurrence, hydrogen, -S(O)R 10 , -C(O)-R 10 , -C(O)OR 10 , -C(O)N(R 10 )(R11 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl each optionally having 1 to 4 Z 8 may be substituted with R 10 and R 11 independently at each occurrence: hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 1b is replaced by Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR12 、-C(O)-R 12 、-C(O)O-R 12 、-C(O)-N(R 13 )(R 14 )、-N(R 13 )(R 14 )、-N(R 13 )2(R 14 ) + 、-N(R 12 )C(O)-R 12 、-N(R 12 )C(O)O-R 12 、-N(R 12 )C(O)N(R 13 )(R 14 )、-N(R 12 )S(O)2(R 12 )、-NR 12 S(O)2N(R 13 )(R 14 )、-NR 12 S(O)2O(R 12 )、-OC(O)R 12 、-OC(O)-N(R 13 )(R 14 )、-P(O)(OR 12 )2、-OP(O)(OR 12 )2、-CH2P(O)(OR 12 )2、-OCH2P(O)(OR 12 )2、-C(O)OCH2P(O)(OR 12 )2、-P(O)(R 12 )(OR 12 )、-OP(O)(R 12 )(OR 12 )、-CH2P(O)(R 12 )(OR 12 )、-OCH2P(O)(R 12 )(OR 12 )、-C(O)OCH2P(O)(R 12 )(OR 12 )、-P(O)(N(R 12 )2)2、-OP(O)(N(R 12 )2)2、-CH2P(O)(N(R 12 )2)2、-OCH2P(O)(N(R 12 )2)2、-C(O)OCH2P(O)(N(R 12)2)2, -P(O)(N(R 12 )2)(OR 12 ), -OP(O)(N(R 12 )2)(OR 12 ), -CH2P(O)(N(R 12 )2)(OR 12 ), -OCH2P(O)(N(R 12 )2)(OR 12 ), -C(O)OCH2P(O)(N(R 12 )2)(OR 12 ), -P(O)(R 12 )(N(R 12 )2), -OP(O)(R 12 )(N(R 12 )2), -CH2P(O)(R 12 )(N(R 12 )2), -OCH2P(O)(R 12 )(N(R 12 )2), -C(O)OCH2P(O)(R 12 )(N(R 12 )2), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 13 )(R 14), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR 12 , -OC(O)-N(R 13 )(R 14 ), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, Each R 12 are independently hydrogen, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, R 13 and R 14 each occurrence independently represents hydrogen, C 1~9 Alkyl, C2~6 Al Kenil, C. 2~6 Alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b or R 13 and R 14 together with the nitrogen to which they are attached form a heterocyclyl, wherein said heterocyclyl optionally contains 1 to 4 Z 1b is replaced by Each R 15 are independently halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R 7 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; R 16 However, in some cases, 1 to 4 C 1~3 alkyl- or cyclopropyl-substituted, -C 1~3 alkyl or cyclopropyl; R 17 However, in some cases, 1 to 3 R 16 Replaced by C 1~9alkyl, cycloalkyl, or heterocyclyl; and Z 1 , Z 2 , Z 4 , Z 5 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -NR 12 S(O)2N(R 13 )(R 14 ), -NR 12 S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)-N(R 13 )(R 14 ), -P(O)(OR 12 )2, -OP(O)(OR 12 )2, -CH2P(O)(OR 12 )2, -OCH2P(O)(OR 12 )2, -C(O)OCH2P(O)(OR 12 )2, -P(O)(R 12 )(OR 12 ), -OP(O)(R12 )(OR 12 )、 -CH2P(O)(R 12 )(OR 12 )、 -OCH2P(O)(R 12 )(OR 12 )、 -C(O)OCH2P(O)(R 12 )(OR 12 )、 -P(O)(N(R 12 )2)2、 -OP(O)(N(R 12 )2)2、 -CH2P(O)(N(R 12 )2)2、 -OCH2P(O)(N(R 12 )2)2、 -C(O)OCH2P(O)(N(R 12 )2)2、 -P(O)(N(R 12 )2)(OR 12 )、 -OP(O)(N(R 12 )2)(OR 12 )、 -CH2P(O)(N(R 12 )2)(OR 12 )、 -OCH2P(O)(N(R 12 )2)(OR 12 )、 -C(O)OCH2P(O)(N(R 12 )2)(OR 12 )、 -P(O)(R 12 )(N(R 12 )2)、 -OP(O)(R 12 )(N(R 12 )2)、 -CH2P(O)(R 12 )(N(R 12 )2)、 -OCH2P(O)(R 12 )(N(R 12 )2)、 -C(O)OCH2P(O)(R[[ID=6​​​​​​​​​​​​​​​​​​wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, Z 9 is hydrogen, halo, -CN, or -OR 12 and each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C( O)R 12 , -C(O)OR 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR 12 , -OC(O)-N(R 13 )(R 14 ), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, each Z 1b are independently oxo, thioxo, hydroxy, halo, -NO2, -N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(C 1~8 haloalkyl), -N(aryl), -N(heteroaryl), -N(heterocyclyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8haloalkyl), -N(C 1~9 alkyl)(aryl), -N(C 1~9 alkyl)(heteroaryl), -N(C 1~9 alkyl)(heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl), -C(O)N(aryl), -C(O)N(heteroaryl), -C(O)N(heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl optionally contains 1 to 4 halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9alkyl), -S(O)N(C 1~9 alkyl) 2、 -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or -O(C 1~9 alkyl), a compound wherein m is 0, 1, or 2; or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Section 2) Formula II: [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, according to item 1 above, having a structure according to the formula: R 1 But hydrogen, -OR 7 , -N(R 8 )(R 9 ), -C(O)-R 7 , -S(O)2-R 7 , -C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, heterocyclyl, aryl, and heteroaryl each optionally have 1 to 4 Z 1 may be substituted with R 2 is hydrogen, -C(O)-R 7 , -C(O)OR 7 , -C(O)N(R 7 )2, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 2 may be substituted with or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains 1 to 4 Z 2 is replaced by R 3a However, hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -NR 12 S(O)2N(R 13 )(R 14 ), -NR 12S(O)2O(R 12 )、-OC(O)R 12 、-OC(O)-N(R 13 )(R 14 )、-P(O)(OR 12 )2、-OP(O)(OR 12 )2、-CH2P(O)(OR 12 )2、-OCH2P(O)(OR 12 )2、-C(O)OCH2P(O)(OR 12 )2、-P(O)(R 12 )(OR 12 )、-OP(O)(R 12 )(OR 12 )、-CH2P(O)(R 12 )(OR 12 )、-OCH2P(O)(R 12 )(OR 12 )、-C(O)OCH2P(O)(R 12 )(OR 12 )、-P(O)(N(R 12 )2)2、-OP(O)(N(R 12 )2)2、-CH2P(O)(N(R 12 )2)2、-OCH2P(O)(N(R 12 )2)2、-C(O)OCH2P(O)(N(R 12 )2)2、-P(O)(N(R 12 )2)(OR 12 )、-OP(O)(N(R 12 )2)(OR 12 )、-CH2P(O)(N(R 12 )2)(OR 12 )、-OCH2P(O)(N(R 12 )2)(OR 12 )、-C(O)OCH2P(O)(N(R 12 )2)(OR 12 )、-P(O)(R 12 )(N(R 12 )2)、-OP(O)(R 12 )(N(R 12 )2)、-CH2P(O)(R 12 )(N(R 12 )2)、-OCH2P(O)(R 12 )(N(R 12)2), -C(O)OCH2P(O)(R 12 )(N(R 12 )2), -Si(R 12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, R 4 is aryl, heterocyclyl, or heteroaryl, wherein each aryl, each heterocyclyl, or each heteroaryl is optionally joined to one to four Z 4 is replaced by R 5 But hydrogen, halo, -CN, -NO2, -OR 7 , -N(R 8 )(R 9 ), -S(O)-R 7 , -S(O)2R 7 , -S(O)2N(R 7 )2, -C(O)R 7 , -OC(O)-R 7 , -C(O)OR 7 , -OC(O)OR 7 , -OC(O)N(R 10 )(R 11 ), -C(O)N(R 7 )2, -N(R 7 )C(O)(R 7 ), C 1~9 Alkyl , C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 1~9 Alkylthio, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 5 may be substituted with R 6 But -C(O)OR 16 -OP(O)(OR 12 )2, Each R 7 are independently hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 7 may be substituted with R 8 and R 9 independently at each occurrence, hydrogen, -S(O)R 10 , -C(O)-R 10 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15cycloalkyl, aryl, heterocyclyl, or heteroaryl each optionally having 1 to 4 Z 8 may be substituted with R 10 and R 11 independently at each occurrence: hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, or heteroaryl; Among these, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~15 cycloalkyl, aryl, heterocyclyl, and heteroaryl each optionally have 1 to 4 Z 1b is replaced by Each R 12 are independently hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, R 13 and R 14 each occurrence independently represents hydrogen, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b or R 13 and R 14together with the nitrogen to which they are attached form a heterocyclyl, wherein said heterocyclyl optionally contains 1 to 4 Z 1b is replaced by R 16 However, in some cases, 1 to 4 C 1~2 alkyl- or cyclopropyl-substituted, -C 1~2 is alkyl, and Z 1 , Z 2 , Z 4 , Z 5 , Z 7 , and Z 8 are each independently hydrogen, oxo, halo, -NO2, -N3, -CN, thioxo, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )C(O)-R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N R 12 S(O)2N(R 13 )(R 14 ), -NR 12 S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)-N(R 13 )(R 14 ), -P(O)(OR12 )2、-OP(O)(OR 12 )2、-CH2P(O)(OR 12 )2、-OCH2P(O)(OR 12 )2、-C(O)OCH2P(O)(OR 12 )2、-P(O)(R 12 )(OR 12 )、-OP(O)(R 12 )(OR 12 )、-CH2P(O)(R 12 )(OR 12 )、-OCH2P(O)(R 12 )(OR 12 )、-C(O)OCH2P(O)(R 12 )(OR 12 )、-P(O)(N(R 12 )2)2、-OP(O)(N(R 12 )2)2、-CH2P(O)(N(R 12 )2)2、-OCH2P(O)(N(R 12 )2)2、-C(O)OCH2P(O)(N(R 12 )2)2、-P(O)(N(R 12 )2)(OR 12 )、-OP(O)(N(R 12 )2)(OR 12 )、-CH2P(O)(N(R 12 )2)(OR 12 )、-OCH2P(O)(N(R 12 )2)(OR 12 )、-C(O)OCH2P(O)(N(R 12 )2)(OR 12 )、-P(O)(R 12 )(N(R 12 )2)、-OP(O)(R 12 )(N(R 12 )2)、-CH2P(O)(R 12 )(N(R 12 )2)、-OCH2P(O)(R 12 )(N(R 12 )2)、-C(O)OCH2P(O)(R 12 )(N(R 12 )2)、-Si(R 12 )3、-S-R 12 、-S(O)R 12, -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclyl may optionally be joined by 1 to 4 Z 1a is substituted with a group, Z 9 is hydrogen, halo, -CN, or -OR 12 and each Z 1a are independently oxo, halo, thioxo, -NO2, -CN, -N3, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -N(R 12 )-C(O)R 12 , -N(R 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 13 )(R 14 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 13 )(R 14 ), -N(R 12 )S(O)2O(R 12 ), -OC(O)R 12 , -OC(O)OR 12 , -OC(O)-N(R 13 )(R 14 ), -Si(R12 )3, -SR 12 , -S(O)R 12 , -S(O)(NH)R 12 , -S(O)2R 12 or -S(O)N(R 13 )(R 14 ) and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally has 1 to 4 Z 1b is substituted with a group, each Z 1b are independently oxo, thioxo, hydroxy, halo, -NO2, -N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(C 1~8 haloalkyl), -N(aryl), -N(heteroaryl), -N(heterocyclyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 alkyl)(aryl), -N(C 1~9 alkyl)(heteroaryl), -N(C 1~9 alkyl)(heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl), -C(O)N(aryl), -C(O)N(heteroaryl), -C(O)N(heterocyclyl), -NHC(O)(C 1~9alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C1~8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl optionally contains 1 to 4 halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH (C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 3~15cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl) 2、 -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or -O(C 1~9 alkyl), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. (Section 3) R 1 But -C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, or C 3~15 A compound according to any of the preceding clauses which is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1 to 4 halo. (Section 4) R 1 optionally substituted with 1 to 4 halo -C 1~9 The compound of any of the preceding clauses, wherein the aryl group is alkyl. (Section 5) R 2 The compound of any of the preceding clauses, wherein is hydrogen. (Section 6) 2. A compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R 3a But hydrogen, C 1~9 Alkyl, C 3~15 cycloalkyl, heterocyclyl, aryl, or heteroaryl; Said C 1~9 Alkyl, C 3~15 The cycloalkyl, aryl, or heterocyclyl is selected from the group consisting of cyano, halo, -OR 12 , -C(O)-R 12 , -OC(O)-R12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -S(O)2-R 12 , -Si(R 12 )3, C 1~9 Alkyl, C 1~8 Haloalkyl, C 3~15 optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl; and Said C 1~9 Alkyl, C 3~15 The cycloalkyl, heterocyclyl, or aryl may be selected from halo, -O(C 1~9 alkyl), -C(O)N(C 1~9 Alkyl)2, C 1~9 A compound or a pharmaceutically acceptable salt thereof, which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and heterocyclyl. (Section 7) 2. A compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen or C 1~9 is alkyl, Said C 1~9 Alkyl is cyano, halo, -OR 12 , -C(O)-R 12 , -OC(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -S(O)2-R 12 , -Si(R 12 )3, C 1~8 Haloalkyl, C 3~15optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl; and Said C 3~15 The cycloalkyl, aryl, heterocyclyl, or heteroaryl may be selected from the group consisting of halo, —O(C 1~9 alkyl), -C(O)N(C 1~9 Alkyl)2, C 1~9 A compound or a pharmaceutically acceptable salt thereof, which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and heterocyclyl. (Section 8) 2. A compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R 3a But C 3~15 cycloalkyl, heterocyclyl, aryl, or heteroaryl It is Said C 1~9 Alkyl, C 3~15 The cycloalkyl, aryl, or heterocyclyl is selected from the group consisting of cyano, halo, -OR 12 , -C(O)-R 12 , -OC(O)-R 12 , -C(O)OR 12 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , -S(O)2-R 12 , -Si(R 12 )3, C 1~9 Alkyl, C 1~8 Haloalkyl, C 3~15 optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl; and Said C 1~9 Alkyl, C 3~15 The cycloalkyl, heterocyclyl, or aryl may be selected from halo, -O(C 1~9 alkyl), -C(O)N(C 1~9 Alkyl)2, C1~9 A compound or a pharmaceutically acceptable salt thereof, which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and heterocyclyl. (Section 9) 2. A compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R 3a But, cyano, halo, -OR 12 , -C(O)OR 12 , -OC(O)-R 12 , -N(R 13 )(R 14 ), -N(R 13 )2(R 14 ) + , C 1~9 Alkyl, C 1~8 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl, heterocyclyl, and heteroaryl 3~15 2. The compound or a pharmaceutically acceptable salt thereof, wherein: (Section 10) A compound according to any of the preceding paragraphs, wherein R 4 But, -CN, Halo, -OR 12 , -C(O)-R 12 , -C(O)OR 12 , -S(O)2-R 12 , -N(R 12 )C(O)-R 12 , -N(R 12 )S(O)2R 12 , -C(O)N(R 13 )(R 14 ), -N(R 13 )(R 14 ), C 1~9 Alkyl, C 3~15 aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; Said C 1~9 Alkyl, C 3~15 The cycloalkyl or heteroaryl may optionally be selected from halo, -CN, -OR 12 , -N(R 13 )(R14 ), C 1~9 A compound which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and heterocyclyl. (Section 11) A compound according to any of the preceding paragraphs, wherein R 4 but, [ka] [ka] [ka] A compound. (Section 12) The compound according to item 1 or 2 above or a pharmaceutically acceptable salt thereof, wherein R 4 Cyano, halo, and C 1~9 A compound or a pharmaceutically acceptable salt thereof, wherein the compound is heterocyclyl or heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl. (Section 13) The compound according to item 1 or 2 above or a pharmaceutically acceptable salt thereof, wherein R 4 is heterocyclyl or heteroaryl, and said heterocyclyl or heteroaryl is optionally selected from -CN, halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 A compound or a pharmaceutically acceptable salt thereof, which is substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl and heterocyclyl. (Section 14) The compound according to item 1 or 2 above or a pharmaceutically acceptable salt thereof, wherein R 4 but, -CN, Halo, -OR 12 , -C(O)-R 12 , -N(R 13)(R 14 ), C 1~9 Alkyl, C 1~8 A compound or a pharmaceutically acceptable salt thereof, which is heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl, and heterocyclyl. (Section 15) The compound according to item 1 or 2 above or a pharmaceutically acceptable salt thereof, wherein R 4 But, -CN, Halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 A compound or a pharmaceutically acceptable salt thereof, which is heterocyclyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl and heterocyclyl. (Section 16) The compound according to item 1 or 2 above or a pharmaceutically acceptable salt thereof, wherein R 4 but, [ka] [ka] and q is 0, 1, 2, 3, or 4; In the formula, Z 4 But, -CN, Halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 independently selected from the group consisting of haloalkyl, and heterocyclyl; A compound or a pharmaceutically acceptable salt thereof. (Section 17) The compound according to item 1 or 2 above or a pharmaceutically acceptable salt thereof, wherein R 4 but, [ka] and q is 0, 1, 2, 3, or 4; In the formula, Z 4 But, -CN, Halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 A compound, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of haloalkyl, and heterocyclyl. (Section 18) The compound according to item 1 or 2 above or a pharmaceutically acceptable salt thereof, wherein R 4 but, [ka] and In the formula, Z 4 But, -CN, Halo, -OR 12 , -C(O)-R 12 , -N(R 13 )(R 14 ), C 1~9 Alkyl, C 1~8 A compound, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of haloalkyl, and heterocyclyl. (Section 19) The compound according to item 1 or 2, wherein R 4 but, [ka] [ka] [ka] [ka] A compound. (Section 20) A compound according to any preceding paragraph or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, cyano, or halo, or a pharmaceutically acceptable salt thereof. (Section 21) A compound according to any preceding paragraph or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, cyano, chloro, or bromo, or a pharmaceutically acceptable salt thereof. (Section 22) The compound according to item 1 or 2, wherein R 6 But -C(O)OR 16 -OP(O)(OH)2. (Section 23) The compound according to item 1 or 2, wherein R 16 But C 1~3 A compound that is alkyl. (Section 24) The compound according to item 1 or 2, wherein R 6 but, [ka] A compound. (Section 25) The compound according to item 1 or 2, wherein R 6 but, [ka] A compound. (Section 26) The compound according to item 1 or 2, wherein R 6 but, [ka] A compound. (Section 27) The compound according to item 1 or 2, wherein Z 9 is hydrogen, compound. (Section 28) Item 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] or a pharmaceutically acceptable salt thereof. (Section 29) Item 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] or a pharmaceutically acceptable salt thereof. (Section 30) Item 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] or a pharmaceutically acceptable salt thereof. (Section 31) Item 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] or a pharmaceutically acceptable salt thereof. (Section 32) A composition comprising a compound according to any of the preceding clauses. (Section 33) A method for treating a disease or condition mediated by Osaka-type thyroid carcinoma (Cot) in a human patient in need thereof, comprising administering to the patient an effective amount of the composition described in paragraph 32 above. (Section 34) Item 34. The method according to item 33 above, wherein the disease or condition is cancer. (Section 35) Item 34. The method according to item 33 above, wherein the disease or condition is diabetes. (Section 36) Item 34. The method according to item 33, wherein the disease or condition is an inflammatory disease. (Section 37) Item 34. The method according to item 33, wherein the disease or condition is inflammatory bowel disease (IBD). (Section 38) Item 34. The method according to item 33 above, wherein the disease or condition is a liver disease. (Section 39) 34. The method according to claim 33, wherein the disease or condition is selected from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain tumor (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, and soft tissue sarcoma. The method of claim 1, wherein the tumor is a solid tumor. (Section 40) Item 34. The method according to item 33, wherein the disease or condition is selected from type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting glucose, and impaired glucose tolerance. (Section 41) Item 34. The method according to Item 33, wherein the disease or condition is systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated cerebrospinal fluid syndrome (ACS), or the like. myelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis, Sjogren's syndrome, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD), ankylosing spondylitis, reactive arthritis, monoarthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile onset rheumatoid arthritis, juvenile rheumatoid and psoriatic arthritis. (Section 42) Item 34. The method according to item 33, wherein the disease or condition is selected from diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enteritis, unclassifiable colitis, Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, colonic Crohn's disease (granulomatous colitis), irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, pouchitis, proctitis, and chronic diarrhea, Crohn's disease, or ulcerative colitis. (Section 43) 34. The method according to paragraph 33, wherein the disease or condition is selected from systemic lupus erythematosus (SLE), lupus nephritis, lupus-related disorders, and autoimmune disorders, or symptoms of SLE. (Section 44) Item 34. The method according to item 33, wherein the symptoms of SLE are selected from joint pain, joint swelling, arthritis, fatigue, hair loss, stomatitis, swollen lymph nodes, photosensitivity, skin rash, headache, numbness, tingling, seizures, visual problems, personality changes, abdominal pain, nausea, vomiting, arrhythmia, hematemesis and difficulty breathing, mottled skin color, and Raynaud's phenomenon. (Section 45) 34. The method according to paragraph 33, wherein the disease or condition is selected from chronic intrahepatic or extrahepatic cholestatic conditions, hepatic fibrosis, chronic or obstructive inflammatory disorders of the liver, cirrhosis, fatty liver or related syndromes, cholestatic or fibrotic effects associated with alcohol-induced cirrhosis or virally transmitted forms of hepatitis, acute or chronic liver failure, hepatic ischemia after major liver resection, chemotherapy-associated steatohepatitis (CASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or neoplastic diseases of the gastrointestinal tract or liver, diabetic kidney disease (DKD), non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH). (Section 46) 33. Use of the compound or composition according to any one of items 1 to 32 in the manufacture of a medicament. (Section 47) Use of the compound or composition according to any one of items 1 to 32 in the manufacture of a medicament for the treatment of a disease or condition mediated by Osaka-type thyroid carcinoma (Cot) in a human patient. (Item 48) 48. The use according to item 47, wherein the disease or condition is selected from cancer, diabetes, inflammatory diseases, and inflammatory bowel disease (IBD). (Section 49) Item 49. The use according to item 48, wherein the disease or condition is pancreatic cancer, bladder cancer, colorectal cancer, The solid tumor is selected from breast cancer, prostate cancer, renal cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain tumor (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, and soft tissue sarcoma. (Section 50) Item 49. The use according to item 48, wherein the disease or condition is selected from type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting glucose, and impaired glucose tolerance. (Section 51) 49. The use according to the above paragraph 48, wherein the disease or condition is selected from systemic lupus erythematosus (SLE), myasthenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis, Sjogren's syndrome, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD), ankylosing spondylitis, reactive arthritis, monoarthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile-onset rheumatoid arthritis, juvenile rheumatoid and psoriatic arthritis. (Section 52) Item 49. The use according to item 48, wherein the disease or condition is selected from diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enteritis, unclassifiable colitis, Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, colonic Crohn's disease (granulomatous colitis), irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, pouchitis, proctitis, and chronic diarrhea. (Section 53) The use according to the above item 48, wherein the disease or condition is systemic lupus erythematosus (SLE), lupus nephritis, lupus-related disorders, autoimmune disorders, or symptoms of SLE. (Item 54) 49. The use according to paragraph 48, wherein the disease or condition is a chronic intrahepatic or extrahepatic cholestatic condition, hepatic fibrosis, chronic or obstructive inflammatory disorders of the liver, cirrhosis, fatty liver or related syndromes, cholestatic or fibrotic effects associated with alcohol-induced cirrhosis or virally transmitted forms of hepatitis, acute or chronic liver failure, hepatic ischemia after major liver resection, chemotherapy-associated steatohepatitis (CASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), neoplastic diseases of the gastrointestinal tract or liver, diabetic kidney disease (DKD), non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

Claims

[Claim 1] A disease or condition mediated by Osaka-type thyroid cancer.

Images