INHIBITORS OF RNA HELICASE DHX9 AND USES THEREOF

RELATED APPLICATIONS

This application claims the benefit of the filing date, under 35 U.S.C. § 119(e), to U.S. Provisional Application No. 63/311,649, filed on February 18, 2022. The entire contents of the foregoing application are expressly incorporated herein by reference.

FIELD OF THE INVENTION

The present disclosure relates to inhibitors of RNA helicase DHX9, and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, and their use in the treatment of diseases.

BACKGROUND OF THE INVENTION

DHX9, also known as RNA Helicase A (RHA) or Nuclear DNA Helicase II (NDH II), is a DExH-box RNA helicase, which shuttles between nucleus and cytoplasm, and can use all four NTPs to power cycles of directional movement from 3’ to 5’. Functionally, DHX9 can bind to and unwind or resolve dsDNA/RNA, ssDNA/RNA, DNA:RNA hybrids (such as R-loops), circular RNA, and DNA/RNA G quadruplexes. As such, DHX9 has regulatory roles in various RNA and DNA related cellular processes, such as transcription, translation, RNA splicing, editing, RNA transport and processing, microRNA genesis, and maintenance of genomic stability (Pan et al., 2021, Current Protein & Peptide Science (22), 29-40).

Due to its regulatory role in processes such as transcription and maintenance of genomic stability, DHX9 has shown to be a key regulator in a variety of cancer types (Gulliver et al., 2020, Future Science OA (2), FSO650). DHX9 has been shown to be involved in the regulation of genes associated with sustained proliferative signaling, evasion of growth suppressors, evasion of apoptosis, angiogenesis, and metastasis, all of which are hallmarks of cancer. Specifically, micro satellite instable cancers, such as Micro satellite Instable (MSI) colorectal cancer, and tumors with defective MisMatch Repair (MMR) exhibit a strong dependence on DHX9.

In addition to its role in cancer, DHX9 has been implicated in other diseases involving gene replication, translation or regulation. These diseases include viral infections and autoimmune disease. Thus, there is a need for DHX9 inhibitors as potential therapeutic agents for treating diseases or disorders that are responsive to DHX9 inhibition.

SUMMARY OF THE INVENTION

The present disclosure provides compounds that are DHX9 inhibitors. In a first aspect, the present disclosure relates to compounds having the Formula I: or a pharmaceutically acceptable salt thereof, wherein:

X is H, Ci-4alkyl, C2-4haloalkyl, or C(O)R ^X ;

R ^x is H, -OH, -OCi-4alkyl, or Ci-4alkyl;

Y is O or NR ^y ;

R ^y is H or Ci-4alkyl;

R ¹ is Ci-4alkyl or Cs-ecycloalkyl; wherein the Cwalkyl or Cs-ecycloalkyl are each optionally and independently substituted with 1 to 3 halo;

Ring A is a C3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 10 membered bicyclic heterocyclyl, phenyl, 5 to 6-membered monocyclic heteroaryl, or 8 to 10- membered bicyclic heteroaryl; m is 0 to 3; each R ² is independently selected from Ci-4alkyl, Cs-ecycloalkyl, halo, OR ^2a , cyano, - NR ^2b R ^2c , -SO2R ^2a , -C(O)R ^2d , and -C(O)NR ^2b R ^2c , wherein the Ci-4alkyl and Cs-ecycloalkyl are optionally substituted with 1 to 4 R ^2e ; or 2 R ² together form oxo;

R ^2a is H, Ci^alkyl, Ci-4haloalkyl, Ci-4alkoxyCi-4alkyl, or benzyl;

R ^2d is H, Ci-4alkyl, Cs-ecycloalkyl; OR ^2a , phenyl, 4 to 6-membered monocyclic heterocyclyl or 5 to 6-membered monocyclic heteroaryl, wherein the Cl-4alkyl is optionally substituted with 1 to 3 halo;

R ^2b and R ^2c are each independently selected from H, Ci-4alkyl, Cs-ecycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl; or R ^2b and R ^2c , together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R ^2d ; each R ^2e is independently selected from halo, cyano, NR ^2b R ^2c , OR ^2a , phenyl, and 4 to

6 membered monocyclic heterocyclyl;

Z is a bond, -CH2-, -O-, -O-Ci-4alkylene-*, -Ci-4alkylene-O-*, -C(O)-, -C(O)O-*, - OC(O)-*, -S(O) ₂ -, -S(O) ₂ N(Z ^a )-*, -N(Z ^a )S(O) ₂ -*, -N(Z ^a )-, -N(Z ^a )-Ci- ₄ alkylene-*, -Ci- ₄ alkylene-N(Z ^a )-*, -C(O)N(Z ^a )-*, -N(Z ^a )C(O)-*, or -C(O)N(Z ^a )-Ci- ₃ alkylene-*, wherein * indicates the attachment point to R ³ ;

Z ^a is H or Ci-4alkyl; provided when X is H and Z is a bond, ring A is phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, or 1, 4,5,6- tetrahydrocyclopenta[c]pyrazolyl;

R ³ is C3-6cycloalkyl, 7 to 10-membered bicyclic carbocyclyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 10-membered bicyclic heterocyclyl, phenyl, 5 to 6-membered monocyclic heteroaryl, or 8 to 10-membered bicyclic heteroaryl, wherein the Cs ecycloalkyl,

7 to 10-membered bicyclic carbocyclyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 10- membered bicyclic heterocyclyl, phenyl, 5 to 6-membered monocyclic heteroaryl, or 8 to 10- membered bicyclic heteroaryl are each optionally and independently substituted with 1 to 4 R ⁴ ; each R ⁴ is independently selected from Cwalkyl, halo, OR ^4a , cyano, -NR ^4b R ^4c , - C(O)R ^4a , -C(O)OR ^4a , -C(O)NR ^4b R ^4c , -NR ^4b C(O)R ^4a -NR ^4b C(O)OR ^4a , -SR ^4a , -SO ₂ R ^4a , - SO2NR ^4b R ^4c , -P(O)R ^4b R ^4c , phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl, and 6 to 10-membered bicyclic heterocyclyl, wherein the Ci-4alkyl is optionally substituted with 1 to 4 R ^4d , and wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl and 6 to 10-membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R ^4e ; or two R ⁴ together form oxo;

R ^4a is H, Ci^alkyl optionally substituted with 1 to 4 R ^4d , Cs ecycloalkyl, 4 to 6- membered monocyclic heterocyclyl, phenyl, or 5 to 6-membered monocyclic heteroaryl; wherein the Cs ecycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl or 5 to 6- membered monocyclic heteroaryl are each optinally and independently substituted with 1 to 3 R ^4e ; R ^4b and R ^4c are each independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclyl, 5 to 6-membered monocyclic heteroaryl, and Ci-4alkyl optionally substituted with 1 to 4 R ^4d ; each R ^4d is independently selected from halo, OR ^4f , -C(O)Ci-4alkyl, -C(O)NR ^4b R ^4c , - C(O)Ci-4haloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, and 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R ^4g ; each R ^4e is independently selected from halo, Ci-4alkyl optionally substituted with 1 to 3 halo, cyano, OR ^4f , -NR ^4b R ^4c , -C(O)H, -C(O)Ci- ₄ alkyl, -Ci- ₄ alkylene-C(O)NR ^4b R ^4c , and - C(O)NR ^4b R ^4c ; or two R ^4e together form oxo;

R ^4f is H, Ci-4alkyl, Cwhaloalkyl, phenyl or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with one to three halo; each R ^4g is independently selected from halo, OR ^4f , Cwalkyl, halo, cyano, -NR ^4b R ^4c , - C(O)H, and -C(O)OR ^4f . In some embodiments, the compound of Formula (I) is not any one of the compounds listed in Table I below.

Another aspect of the disclosure relates to pharmaceutical compositions comprising compounds of Formula (I) or pharmaceutically acceptable salts thereof, and a pharmaceutical carrier.

In yet another aspect, the present disclosure provides a method of treating a disease or disorder that is responsive to inhibition of DHX9 in a subject comprising administering to said subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for the treatment of cancer.

Another aspect of the present disclosure relates to the use of at least one compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder responsive to inhibition of DHX9. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder responsive to inhibition of DHX9.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful in the treatment of diseases or disorders through mediation of DHX9 function/activity. In some embodiments, the compounds of present disclosure are DHX9 inhibitors.

COMPOUNDSAND COMPOSITIONS

In a first embodiment, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

X is H, Ci-4alkyl, C2-4haloalkyl, or C(O)R ^X ;

R ^x is H, -OH, -OCi-4alkyl, or Cwalkyl;

Y is O or NR ^y ;

R ^y is H or Ci-4alkyl;

R ¹ is Ci^alkyl or Cs-ecycloalkyl; wherein the Cwalkyl or Cs-ecycloalkyl are each optionally and independently substituted with 1 to 3 halo;

Ring A is a C3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 10 membered bicyclic heterocyclyl, phenyl, 5 to 6-membered monocyclic heteroaryl, or 8 to 10- membered bicyclic heteroaryl; m is 0 to 3; each R ² is independently selected from Ci-4alkyl, Cs-ecycloalkyl, halo, OR ^2a , cyano, - NR ^2b R ^2c , -SO2R ^2a , -C(O)R ^2d , and -C(O)NR ^2b R ^2c , wherein the Ci-4alkyl and Cs-ecycloalkyl are optionally substituted with 1 to 4 R ^2e ; or 2 R ² together form oxo;

R ^2a is H, Ci^alkyl, Ci-4haloalkyl, Ci-4alkoxyCi-4alkyl, or benzyl;

R ^2d is H, Ci-4alkyl, Cs-ecycloalkyl; OR ^2a , phenyl, 4 to 6-membered monocyclic heterocyclyl or 5 to 6-membered monocyclic heteroaryl, wherein the Ci-4alkyl is optionally substituted with 1 to 3 halo;

R ^2b and R ^2c are each independently selected from H, Ci-4alkyl, Cs-ecycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl; or R ^2b and R ^2c , together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R ^2d ; each R ^2e is independently selected from halo, cyano, NR ^2b R ^2c , OR ^2a , phenyl, and 4 to

6 membered monocyclic heterocyclyl;

Z is a bond, -CH2-, -O-, -O-Ci-4alkylene-*, -Ci-4alkylene-O-*, -C(O)-, -C(O)O-*, - OC(O)-*, -S(O) ₂ -, -S(O) ₂ N(Z ^a )-*, -N(Z ^a )S(O) ₂ -*, -N(Z ^a )-, -N(Z ^a )-Ci- ₄ alkylene-*, -Ci- ₄ alkylene-N(Z ^a )-*, -C(O)N(Z ^a )-*, -N(Z ^a )C(O)-*, or -C(O)N(Z ^a )-Ci- ₃ alkylene-*, wherein * indicates the attachment point to R ³ ;

Z ^a is H or Ci-4alkyl; provided when X is H and Z is a bond, ring A is phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, or 1, 4,5,6- tetrahydrocyclopenta[c]pyrazolyl;

R ³ is C3-6cycloalkyl, 7 to 10-membered bicyclic carbocyclyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 10-membered bicyclic heterocyclyl, phenyl, 5 to 6-membered monocyclic heteroaryl, or 8 to 10-membered bicyclic heteroaryl, wherein the Cs ecycloalkyl,

7 to 10-membered bicyclic carbocyclyl, 4 to 6-membered monocyclic heterocyclyl, 6 to 10- membered bicyclic heterocyclyl, phenyl, 5 to 6-membered monocyclic heteroaryl, or 8 to 10- membered bicyclic heteroaryl are each optionally and independently substituted with 1 to 4 R ⁴ ; each R ⁴ is independently selected from Cwalkyl, halo, OR ^4a , cyano, -NR ^4b R ^4c , - C(O)R ^4a , -C(O)OR ^4a , -C(O)NR ^4b R ^4c , -NR ^4b C(O)R ^4a -NR ^4b C(O)OR ^4a , -SR ^4a , -SO ₂ R ^4a , - SO2NR ^4b R ^4c , -P(O)R ^4b R ^4c , phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl, and 6 to 10-membered bicyclic heterocyclyl, wherein the Ci-4alkyl is optionally substituted with 1 to 4 R ^4d , and wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl and 6 to 10-membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R ^4e ; or two R ⁴ together form oxo;

R ^4a is H, Ci^alkyl optionally substituted with 1 to 4 R ^4d , Cs ecycloalkyl, 4 to 6- membered monocyclic heterocyclyl, phenyl, or 5 to 6-membered monocyclic heteroaryl; wherein the Cs ecycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl or 5 to 6- membered monocyclic heteroaryl are each optinally and independently substituted with 1 to 3 R ^4e ; R ^4b and R ^4c are each independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclyl, 5 to 6-membered monocyclic heteroaryl, and Ci-4alkyl optionally substituted with 1 to 4 R ^4d ; each R ^4d is independently selected from halo, OR ^4f , -C(O)Ci-4alkyl, -C(O)NR ^4b R ^4c , - C(O)Ci-4haloalkyl, phenyl, and 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R ^4g ; each R ^4e is independently selected from halo, Ci-4alkyl optionally substituted with 1 to 3 halo, cyano, OR ^4f , -NR ^4b R ^4c , -C(O)H, -C(O)Ci- ₄ alkyl, -Ci- ₄ alkylene-C(O)NR ^4b R ^4c , and - C(O)NR ^4b R ^4c ; or two R ^4e together form oxo;

R ^4f is H, Ci-4alkyl, Cwhaloalkyl, phenyl or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with one to three halo; each R ^4g is independently selected from halo, OR ^4f , Cwalkyl, halo, cyano, -NR ^4b R ^4c , - C(O)H, and -C(O)OR ^4f .

In some embodiments, the compound of Formula (I) is not any one of the compounds listed in Table I below.

In a second embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ¹ is -CH3 or -CH2CH3; and the remaining variables are as described in the first aspect or the first embodiment.

In a third embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, X is H; and the remaining variables are as described in the first aspect or the first or second embodiment.

In a fourth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, X is Cwalkyl, C2-4haloalkyl, or C(O)R ^X ; and the remaining variables are as described in the first aspect or the first or second embodiment.

In a fifth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, X is -CH3 or -C(O)H; and the remaining variables are as described in the first aspect or the first or second embodiment.

In a sixth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is phenyl, thiophenyl, pyrrolyl, pyrazoyl, furanyl, isothiazoyl, thiazoyl, imidazoyl, cyclobutyl, benzofuranyl, 2-oxo-2,3-dihydro-lH- benzo[d] imidazolyl, imidazo[l,2-a]pyridin-6-yl, l,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2- oxo-2, 3 -dihydro- IH-imidazolyl, indolizinyl, pyrrolo[l,2-a]pyrimidinyl, pyrrolo[l,2- c]pyrimidinyl, pyrrolo[l,2-a]pyrazinly, 5-oxo-5H-thiazolo[3,2-a]pyridinyl, thieno[3,2- b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, benzothiophenyl, thieno[3,2- d]pyrimidinyl, pyrrolo[l,2-b]pyridazinyl, pyrrolo[l,2-a]pyrazinyl, pyrrolo[l,2-a]pyrimidinyl, pyrrolo[ 1 ,2-b]pyridazinyl, pyrrolo[ 1 ,2-c]pyrimidinyl, 1-oxo- 1 ,2-dihydropyrrolo[ 1,2- a]pyrazinyl, pyrrolo[2,l-f][l,2,4]triazinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6- dihydro-4H-cyclopenta[b]thiophenyl, or 4,7-dihydro-5H-thieno[2,3-c]pyranyl; and the remaining variables are as described in first aspect or the first, second, third, fourth, or fifth embodiment.

In a seventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, or 1 ,4,5,6- tetrahydrocyclopenta[c]pyrazolyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

In an eighth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is ; each of which is optionally substituted with 1 to 2 R ² ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

In a ninth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring

the first aspect or the first, second, third, fourth, or fifth embodiment.

In a tenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

In an eleventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is phenyl, thiophenyl, pyrazolyl, isothiazolyl, or imidazolyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment. In a twelfth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is ; each of which is substituted with 0 to 1 R ² ; and the remaining variables are as described in the first aspect the first, second, third, fourth, or fifth embodiment.

In a thirteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond and ring A is remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

In a fourteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond and ring A is ; the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

In a fifteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -CH2-, -O-, -O-Ci-4alkylene-*, -Ci- ₄ alkylene-O-*, -C(O)-, -C(O)O-*, -OC(O)-*, -S(O) ₂ -, -S(O) ₂ N(Z ^a )-*, -N(Z ^a )S(O) ₂ -*, -N(Z ^a )-, -N(Z ^a )-Ci- ₄ alkylene-*, -Ci- ₄ alkylene-N(Z ^a )-*, -C(O)N(Z ^a )-*, -N(Z ^a )C(O)-*, or -C(O)N(Z ^a )- Ci-3alkylene-*, wherein * indicates the attachment point to R ³ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, or twelfth embodiment.

In a sixteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -C(O)NH-* or -C(O)NH-Ci- salkylene-*, wherein * indicates the attachment point to R ³ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, or twelfth embodiment. In a seventeenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is C(O)NH-*, wherein * indicates the attachment point to R ³ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, or twelfth embodiment.

In an eighteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth, fifteenth, sixteenth, or seventeenth embodiment.

In a nineteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ² is Ci-4alkyl, halo, cyano, -C(O)R ^2d , or -C(O)NR ^2b R ^2c , wherein the Ci-4alkyl is optionally substituted with 1 to 4 R ^2e ; R ^2b and R ^2c are each independently selected from H or Cwalkyl optionally substituted with Ci-3alkoxy; R ^2d is OH or Ci-3alkoxy; and R ^2e is halo, -OH or Ci-3alkoxy; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

In a twentieth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ² is -CH3, -CF3, -CH2OH, halo, cyano,

-C(O)OH, -C(0)NHCH3, or ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

In a twenty-first embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ³ is cyclopropyl, cyclobutyl, cyclohexyl, piperidinyl, phenyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, thiophenyl, tetrahydropyranyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro- IH-pyrazoly, benzamidazolyl, indazolyl, indoyl, 2,3-dihydrobenzofuranyl, imidazo[l,2- a]pyridinyl, 2,3-dihydro-lH-indenyl, 2-oxo-2,3-dihydro-lH-benzo[d]imidazolyl, and 2- azaspiro[3.3]heptanyl, or 2-oxaspiro[3.3]heptanyl, each of which is optionally substituted with 1 to 3 R ⁴ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment. In a twenty- second embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ³ is

3 R ⁴ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a twenty-third embodiment, for the compounds of Formula (I) described in the first

remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a twenty-fourth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R ³ is phenyl, pyridyl, pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, pyrazoyl, isothiazoyl, triazoyl, tetrazoyl, or oxadiazoyl, each of which is optionally substituted with 1 to 2 R ⁴ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a twenty-fifth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R ³ is ; each of which is optionally substituted with 1 to 2 R ⁴ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a twenty- sixth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R ³ is variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a twenty- seventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R ³ is phenyl, pyridyl, or pyrimidyl, each of which is optionally substituted with 1 to 2 R ⁴ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a twenty-eighth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R ³ is each of which is optionally substituted with 1 to 2 R ⁴ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a twenty-ninth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R ³ is variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a thirtieth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -CH2-, -O-, -O-Ci-4alkylene-*, -Ci- ₄ alkylene-O-*, -C(O)-, -C(O)O-*, -OC(O)-*, -S(O) ₂ -, -S(O) ₂ N(Z ^a )-*, -N(Z ^a )S(O) ₂ -*, -N(Z ^a )-, -N(Z ^a )-Ci- ₄ alkylene-*, -Ci- ₄ alkylene-N(Z ^a )-*, -C(O)N(Z ^a )-*, -N(Z ^a )C(O)-*, or -C(O)N(Z ^a )- Ci-3alkylene-*, wherein * indicates the attachment point to R ³ , R ³ is cyclopropyl, cyclohexyl, piperidinyl, phenyl, pyridyl, pyrazoyl, isothiazoyl, 2-oxo-2,3-dihydro-lH-pyrazoly, benzamidazoyl, indazoyl, indoyl, 2,3-dihydrobenzofuranyl, imidazo[ 1 ,2-a]pyridinyl, 2,3- dihydro- 177- indenyl, or 2-oxo-2,3-dihydro-l 77-benzo[<7] imidazolyl, each of which is optionally substituted with 1 to 3 R ⁴ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a thirty-first embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -CH2-, -O-, -O-Ci-4alkylene-*, -Ci-

₄ alkylene-O-*, -C(O)-, -C(O)O-*, -OC(O)-*, -S(O) ₂ -, -S(O) ₂ N(Z ^a )-*, -N(Z ^a )S(O) ₂ -*, -N(Z ^a )-,

-N(Z ^a )-Ci- ₄ alkylene-*, -Ci- ₄ alkylene-N(Z ^a )-*, -C(O)N(Z ^a )-*, -N(Z ^a )C(O)-*, or -C(O)N(Z ^a )-

Ci-3alkylene-*, wherein * indicates the attachment point to R ³ , R ³ is the remaining variables are as described in the first aspect of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a thirty-second embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -CH ₂ -, -O-, -O-Ci- ₄ alkylene-*, -Ci- ₄ alkylene-O-*, -C(O)-, -C(O)O-*, -OC(O)-*, -S(O) ₂ -, -S(O) ₂ N(Z ^a )-*, -N(Z ^a )S(O) ₂ -*, - N(Z ^a )-, -N(Z ^a )-Ci- ₄ alkylene-*, -Ci- ₄ alkylene-N(Z ^a )-*, -C(O)N(Z ^a )-*, -N(Z ^a )C(O)-*, or -

C(O)N(Z ^a )-Ci-3alkylene-*, wherein * indicates the attachment point to R ³ , R ³ is ;

variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a thirty-third embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -C(O)NH-*, wherein * indicates the attachment point to R ³ , R ³ is benzamidazolyl or 2-oxo-2,3-dihydro-l /7-bcnzo[<7| imidazolyl, each of which is optionally substituted with 1 to 2 R ⁴ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a thirty-fourth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -C(O)NH-*, wherein * indicates the attachment point t ; each of which is optionally substituted with 1 to 2 R ⁴ ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a thirty-fifth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -C(O)NH-*, wherein * indicates the attachment point t the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

In a thirty- sixth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ⁴ is independently selected from Ci- ₄ alkyl, halo, OR ^4a , cyano, -NR ^4b R ^4c , -C(O)OH, -C(O)NR ^4b R ^4c , -NR ^4b C(O)R ^4a , - NR ^4b C(O)OR ^4a , 4 to 6-membered monocyclic heterocyclyl, phenyl, and 4 to 6-membered monocyclic heteroaryl, wherein the Cwalkyl is optionally substituted with 1 to 3 substituents selected from OR ^4f , cyano, or 4 to 6-membered monocyclic heterocyclyl; and wherein the 4 to 6-membered monocyclic heterocyclyl, phenyl, and to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R ^4e ; or two R ⁴ together form oxo; R ^4a is H, phenyl, or Ci-4alkyl optionally substituted with 1 to 3 substituents independently selected from halo, phenyl and 4 to 6-membered monocyclic heterocyclyl; R ^4b and R ^4c are each independently selected from H andCi-4alkyl; each R ^4e is independently selected from Cwalkyl or -C(O)Ci- 4alkyl; R ^4f is H or Cwalkyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twentyseventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty- second, thirty-third, thirtyfourth, or thirty-fifth embodiment. In an alternative thirty-sixth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ⁴ is independently selected from Ci-4alkyl, halo, OR ^4a , cyano, -NR ^4b R ^4c , -C(O)OH, - C(O)NR ^4b R ^4c , -NR ^4b C(O)R ^4a , -NR ^4b C(O)OR ^4a , 4 to 6-membered monocyclic heterocyclyl, phenyl, and 4 to 6-membered monocyclic heteroaryl, wherein the Ci-4alkyl is optionally substituted with 1 to 3 substituents selected from OR ^4f , cyano, or 4 to 6-membered monocyclic heterocyclyl; and wherein the 4 to 6-membered monocyclic heterocyclyl, phenyl, and to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R ^4e ; or two R ⁴ together form oxo; R ^4a is H, phenyl, or Ci-4alkyl optionally substituted with 1 to 3 substituents independently selected from halo, phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl, wherein the phenyl, 5 to 6- membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R ^4g ; R ^4b and R ^4c are each independently selected from H and Ci-4alkyl; each R ^4e is independently selected from Ci-4alkyl, halo, or -C(O)Ci-4alkyl; R ^4f is H or Ci-4alkyl; and each R ^4g is independently halo or -OH.

In a thirty- seventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ⁴ is each of which is optionally substituted with 1 to 2 R ^4e ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty- third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty- second, thirty-third, thirty-fourth, thirty-fifth, or thirty-sixth embodiment or any alternative embodiments described therein. In an alternative thirtyseventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ⁴ is represented by the following structural formula: , each of which is optionally substituted with 1 to 2 R ^4e ; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twentysixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty- third, thirty-fourth, thirty-fifth, or thirty- sixth embodiment or any alternative embodiments described therein.

In a thirty-eighth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, or thirty- sixth embodiment or any alternative embodiments described therein. In an alternative thirty-eighth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ⁴ is represented by the following structural formula: the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, or thirty-sixth embodiment or any alternative embodiments described therein.

In a thirty-ninth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ^4e is -CH3 or -C(O)CH3; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty- third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty- second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirtyseventh, or thirty-eighth embodiment or any alternative embodiments described therein. In an alternative thirty-ninth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ^4e is -F, -CH3, or -C(O)CH3; the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty- third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty- second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirtyseventh, or thirty-eighth embodiment or any alternative embodiments described therein.

In a fortieth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ⁴ is -CH3, -CH2OCH3, -CH2CN, - CH2CH2OH, halo, cyano, -OH, -OCH3, -OCH2CH3, -OCH(CH ₃ ) ₂ , -OCF3, -NH ₂ , - NHC(O)CH ₃ , -C(O)OH, -C(O)NH ₂ , -C(O)NHCH ₃ , -C(O)N(CH ₃ ) ₂ , -C(O)NC(CH ₃ ) ₃ , as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment. In an alternative fortieth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ⁴ is - CH ₃ , -CH2OCH3, -CH2CN, -CH2CH2OH, halo, cyano, -OH, -OCH3, -OCH2CH3, - OCH(CH ₃ ) ₂ , -OCF3, -NH ₂ , -NHC(O)CH ₃ , -C(O)OH, -C(O)NH ₂ , -C(O)NHCH ₃ , - C(O)N(CH3)2, -C(O)NC(CH3)3, or R ⁴ is represented by the following formula: variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty- second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirtyseventh, thirty-eighth, or thirty-ninth embodiment.

In a forty-first embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ⁴ is -CH3, halo, cyano, -OH, -OCH3, - d, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twentyeighth, twenty-ninth, thirtieth, thirty-first, thirty- second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment or any alternative embodiments described therein.

In a forty- second embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R ⁴ is -CH3, -NH ₂ , -OH, halo, or - aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twentysixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty- third, thirty-fourth, thirty-fifth, thirty- sixth, thirty- seventh, thirty-eighth, or thirty-ninth embodiment or any alternative embodiments describe therein.

In a forty-third embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -CH ₂ -, -OCH ₂ -*, -S(O) ₂ , - S(O) ₂ N(H)-*, -N(H)-, -N(H)CH ₂ -*, -C(O)NH-*, or -C(O)NH-Ci- ₃ alkylene-*, wherein * indicates the attachment point to R ³ , R ⁴ is -CH3, -CH ₂ OCH3, -CH ₂ CN, -CH ₂ CH ₂ OH, halo, - remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth, fifteenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, thirtieth, thirty-first, thirty-second, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment or any alternative embodiments.

In a forty-fourth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is -CH ₂ -, -OCH ₂ -*, -S(O) ₂ , - S(O) ₂ N(H)-*, -N(H)-, -N(H)CH ₂ -*, -C(O)NH-*, or -C(O)NH-Ci- ₃ alkylene-*, wherein * indicates the attachment point to R ³ , R ⁴ is -CH3; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth, fifteenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, thirtieth, thirty-first, thirty-second, thirty-sixth, thirty- seventh, thirty-eighth, or thirty-ninth embodiment or any alternative embodiments described therein.

In a forty-fifth embodiment, the compound of the present disclosure is represented by Formula (IIA), (IIB) or (IIC): or a pharmaceutically acceptable salt thereof; where the variables X, R ¹ , R ² and R ³ depicted in Formula (IIA), (IIB) or (IIC) are as described in the first aspect or the first, second, third, fourth, fifth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirty- sixth, thirtyseventh, thirty-eighth, thirty-ninth, fortieth, forty-first, or forty-second embodiment or any alternative embodiments described therein.

In a forty-sixth embodiment, the compound of the present disclosure is represented by Formula (IIIA) or (IIIB): or a pharmaceutically acceptable salt thereof; where the variables X, R ¹ , and R ³ depicted in Formula (IIIA) or (IIIB) are as described in the first aspect or the first, second, third, fourth, fifth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twentyfifth, twenty-sixth, twenty- seventh, twenty-eighth, twenty-ninth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, or forty-second embodiment or any alternative embodiments described therein.

In a forty-seventh embodiment, the compound of the present disclosure is represented by Formula (IVA), (IVB), (IVC), or (IVD): or a pharmaceutically acceptable salt thereof; where m is 0 or 1, and where the variables X, R ¹ , R ² and R ³ depicted in Formula (IVA), (IVB), (IVC), or (IVD) are as described in the first aspect or the first, second, third, fourth, fifth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty- eighth, twenty-ninth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty- first, or forty-second embodiment or any alternative embodiments described therein.

In a forty-eighth embodiment, the compound of the present disclosure is represented by Formula (V): or a pharmaceutically acceptable salt thereof; where the variables X, R ¹ , and R ³ depicted in Formula (V) are as described in the first aspect or the first, second, third, fourth, fifth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, thirtieth, thirty-first, thirty- second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirtyninth, fortieth, forty-third, or forty-fourth embodiment or any alternative embodiments described therein.

In a forty-ninth embodiment, the compound of the present disclosure is represented by Formula (VI): or a pharmaceutically acceptable salt thereof, wherein;

R ¹ is Ci-2alkyl;

Ring A is selected from phenyl, thiophenyl, pyrazolyl, isothiazolyl, and imidazolyl; m is 0 to 1 ; each R ² is independently selected from Ci-4alkyl and -C(O)OH;

Z is a bond or -C(O)NH-*, wherein * indicates the attachment point to R ³ ;

R ³ is selected from phenyl, pyridyl, pyrimidyl, benzimidazolyl and 2-oxo-2,3- dihydro-1 //-benzo [d] imidazolyl, each of which is optionally substituted with 1 to 2 R ⁴ ; each R ⁴ is independently selected from Ci-4alkyl, halo, -OH, -O-benzyl, cyano, -NR ^4b R ^4c , -C(O)NR ^4b R ^4c , or 4 to 6-membered monocyclic heterocyclyl;

R ^4b and R ^4c are each independently selected from H and Ci-4alkyl.

In a fiftieth embodiment, for the compounds of Formula (VI) described in the fortyninth embodiment, or a pharmaceutically acceptable salt thereof, Z is a bond, ring A is with 1 R ³ and optionally substituted with 1 R ² ; and the remaining variables are as described in the forty-ninth embodiment.

In a fifty-first embodiment, for the compounds of Formula (VI) described in the fortyninth embodiment, or a pharmaceutically acceptable salt thereof, Z is a bond, ring A is ; and the remaining variables are as described in the forty-ninth embodiment.

In a fifty- second embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, Z is a bond, ring A is variables are as described in the forty-ninth embodiment.

In a fifty-third embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R ² is -CH3 or - C(O)OH; and the remaining variables are as described in the forty-ninth, fiftieth, fifty-first, or fifty- second embodiment.

In a fifty-fourth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R ³ is phenyl, pyridyl, or pyrimidyl, each of which is optionally substituted with 1 to 2 R ⁴ ; and the remaining variables are as described in the forty-ninth, fiftieth, fifty-first, fifty-second, or fifty-third embodiment. In a fifty-fifth embodiment, for the compounds of Formula (VI) described in the forty- ninth embodiment, or a pharmaceutically acceptable salt thereof, R ³ is ; each of which is optionally substituted with 1 to 2 R ⁴ ; and the remaining variables are as described in the forty-ninth, fiftieth, fifty-first, fifty- second, or fifty-third embodiment.

In a fifty- sixth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R ³ is remaining variables are as described in the forty-ninth, fiftieth, fifty-first, fifty-second, or fifty-third embodiment.

In a fifty- seventh embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R ⁴ is -CH3, -NH2, -

OH, halo, the remaining variables are as described in the forty-ninth, fiftieth, fifty-first, fifty- second, fifty-third, fifty-fourth, fifty-fifth, or fifty- sixth embodiment.

In a fifty-eighth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, Z is -C(O)NH-*, wherein * indicates the attachment point to R ³ , ring A is , which is substituted with 1

R ³ ; and the remaining variables are as described in the forty-ninth embodiment.

In a fifty-ninth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, Z is -C(O)NH-*, wherein * indicates the attachment point to R 3 , ring A is ; and the remaining variables are as described in the forty-ninth embodiment.

In a sixtieth embodiment, for the compounds of Formula (VI) described in the fortyninth embodiment, or a pharmaceutically acceptable salt thereof, R ³ is benzamidazolyl or 2- oxo-2, 3 -dihydro- lH-benzo[d] imidazolyl, each of which is optionally substituted with 1 to 2 R ⁴ ; and the remaining variables are as described in the forty-ninth, fifth-eighth, or fifth-ninth embodiment.

In a sixty-first embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, the remaining variables are as described in the forty-ninth, fifth-eighth, or fifth-ninth embodiment.

In a sixty-second embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R ⁴ is -CH3; and the remaining variables are as described in the forty-ninth, fifth-eighth, fifth-ninth, sixtieth, or sixty-first embodiment.

In a sixty-third embodiment, the present disclosure provides a compound described herein (e.g., a compound of any one of Examples 1-162), or a pharmaceutically acceptable salt thereof.

In a sixty-fourth embodiment, the present disclosure provides a compound selected from the group consisting of:

N-(3-(methylsulfonamido)phenyl)-l-phenyl-lH-pyrazole-4-ca rboxamide;

N-(3-(methylsulfonamido)phenyl)-4-phenylpicolinamide;

4-(benzyloxy)-N-(3-(methylsulfonamido)phenyl)benzamide;

3-(benzyloxy)-N-(3-(methylsulfonamido)phenyl)benzamide;

N-(3-(methylsulfonamido)phenyl)-5-phenylthiophene-2-carbo xamide;

N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carbo xamide;

4-(5-methyl-l,3,4-oxadiazol-2-yl)-N-(3-(methylsulfonamido )phenyl)benzamide; N-(3-(methylsulfonamido)phenyl)-4-(lH-tetrazol-5-yl)benzamid e;

N-(3-(methylsulfonamido)phenyl)-2-(4H-l,2,4-triazol-3-yl) thiazole-4-carboxamide; l-benzyl-N-(3-(methylsulfonamido)phenyl)-lH-pyrazole-4-carbo xamide;

N-(3 -(methylsulfonamido)phenyl)- [1,1 '-biphenyl] -3 -carboxamide;

N-(3 -(methylsulfonamido)phenyl)- [1,1 '-biphenyl] -4-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(lH-pyrazol-l-yl)benzam ide;

N-(3-(methylsulfonamido)phenyl)-3-(lH-pyrazol-l-yl)benzam ide;

N-(3-(methylsulfonamido)phenyl)-l-(pyridin-2-yl)-lH-pyraz ole-4-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-phenylthiazole-2-carbox amide;

N-(3-(methylsulfonamido)phenyl)-l-(pyrimidin-2-yl)-lH-pyr azole-4-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(thiophen-2-yl)picolina mide;

4-(3-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophe ne-2-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(o-tolyl)thiophene-2-ca rboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(m-tolyl)thiophene-2-ca rboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(p-tolyl)thiophene-2-ca rboxamide;

5-methyl-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophen e-2-carboxamide;

4-(3-carbamoylphenyl)-N-(3-(methylsulfonamido)phenyl)thio phene-2-carboxamide;

4-(3-cyanophenyl)-N-(3-(methylsulfonamido)phenyl)thiophen e-2-carboxamide;

4-(2-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophe ne-2-carboxamide;

4-(4-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophe ne-2-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene -2-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(pyridin-4-yl)thiophene -2-carboxamide;

4-(3-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)thioph ene-2-carboxamide;

4-(2-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)thioph ene-2-carboxamide;

4-(3-aminophenyl)-N-(3-(methylsulfonamido)phenyl)thiophen e-2-carboxamide;

4-(2-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)thioph ene-2-carboxamide;

4-(2-methylpyridin-3-yl)-N-(3-(methylsulfonamido)phenyl)t hiophene-2-carboxamide;

4-(4-methylpyridin-3-yl)-N-(3-(methylsulfonamido)phenyl)t hiophene-2-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(pyrimidin-5-yl)thiophe ne-2-carboxamide;

4-(2-ethoxypyrimidin-5-yl)-N-(3-(methylsulfonamido)phenyl )thiophene-2- carboxamide;

5-(4-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)-lH-py razole-3-carboxamide;

4-(6-methylpyridin-3-yl)-N-(3-(methylsulfonamido)phenyl)t hiophene-2-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(pyridazin-3-yl)thiophe ne-2-carboxamide; 4-(3-methoxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl) thiophene-2- carboxamide;

4-(5-methoxy-2-methylphenyl)-N-(3-(methylsulfonamido)phen yl)thiophene-2- carboxamide;

4-(3-hydroxypyridin-2-yl)-N-(3-(methylsulfonamido)phenyl) thiophene-2- carboxamide;

4-(2-fluoro-6-hydroxyphenyl)-N-(3-(methylsulfonamido)phen yl)thiophene-2- carboxamide;

4-benzyl-N-(3-(methylsulfonamido)phenyl)thiophene-2-carbo xamide; tert-butyl (3-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3- yl)phenyl)carbamate;

4-(3-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)thioph ene-2-carboxamide;

4-(3-hydroxy-2-methylphenyl)-N-(3-(methylsulfonamido)phen yl)thiophene-2- carboxamide;

4-(5-hydroxy-2-methylphenyl)-N-(3-(methylsulfonamido)phen yl)thiophene-2- carboxamide;

4-(2,6-difluorophenyl)-N-(3-(methylsulfonamido)phenyl)thi ophene-2-carboxamide;

4-(2-(benzyloxy)phenyl)-N-(3-(methylsulfonamido)phenyl)th iophene-2-carboxamide;

5-(4-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)-lH-py razole-3-carboxamide;

5-(4-hydroxyphenyl)- 1 -methyl-N -(3 -(methylsulfonamido)phenyl)- 1 H-pyrazole-3 - carboxamide;

5-methyl-N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl) thiophene-2- carboxamide;

N-(3-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)-lH-pyraz ole-5-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene -2-carboxamide;

4-(3-methylpyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)t hiophene-2-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(pyrimidin-2-yl)thiophe ne-2-carboxamide;

4-(6-aminopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)th iophene-2-carboxamide;

4-(4-aminopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)th iophene-2-carboxamide;

2-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-y l)isonicotinic acid;

4-(2-aminophenyl)-N-(3-(methylsulfonamido)phenyl)thiophen e-2-carboxamide;

4-(3-aminopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)th iophene-2-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)-lH-imida zole-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(5-(piperazin-l-yl)pyridin -2-yl)thiophene-2- carboxamide;

2-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-y l)isonicotinamide;

4-(2-acetamidophenyl)-N-(3-(methylsulfonamido)phenyl)thio phene-2-carboxamide;

4-(3-acetamidopyridin-2-yl)-N-(3-(methylsulfonamido)pheny l)thiophene-2- carboxamide;

4-(5-(4-acetylpiperazin-l-yl)pyridin-2-yl)-N-(3-

(methylsulfonamido)phenyl)thiophene-2-carboxamide;

N-(3-(ethylsulfonamido)phenyl)-4-phenylthiophene-2-carbox amide;

N-(3-(ethylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene- 2-carboxamide;

5-bromo-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene -2-carboxamide;

N-(3-(methylsulfonamido)phenyl)-4-phenyl-5-(trifluorometh yl)thiophene-2- carboxamide;

5-cyano-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene -2-carboxamide;

5-((3-(methylsulfonamido)phenyl)carbamoyl)-3-phenylthioph ene-2-carboxylic acid;

N2-(3-(methylsulfonamido)phenyl)-N4-phenylthiophene-2,4-d icarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(2-(pyridin-3-yl)ethy l)thiophene-2,4- dicarboxamide;

N4-(3-chloro-4-methylphenyl)-N2-(3-(methylsulfonamido)phe nyl)thiophene-2,4- dicarboxamide;

N4-((l-hydroxycyclohexyl)methyl)-N2-(3-(methylsulfonamido )phenyl)thiophene- 2,4-dicarboxamide;

N4-(6-methoxypyridin-3-yl)-N2-(3-(methylsulfonamido)pheny l)thiophene-2,4- dicarboxamide;

N4-(l,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-lH-pyrazol-4- yl)-N2-(3- (methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(4-(trifluoromethoxy) phenyl)thiophene-2,4- dicarboxamide;

N4-(5-fluoro-2-methoxyphenyl)-N2-(3-(methylsulfonamido)ph enyl)thiophene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(l-phenylethyl)thioph ene-2,4-dicarboxamide;

N4-((5-fluoropyridin-3-yl)methyl)-N2-(3-(methylsulfonamid o)phenyl)thiophene-2,4- dicarboxamide; N4-(2,3-dihydro-lH-inden-2-yl)-N2-(3-(methylsulfonamido)phen yl)thiophene-2,4- dicarboxamide;

N4-(4-chloro-3-methylphenyl)-N2-(3-(methylsulfonamido)phe nyl)thiophene-2,4- dicarboxamide;

N4-(4-(dimethylcarbamoyl)phenyl)-N2-(3-(methylsulfonamido )phenyl)thiophene-

2,4-dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(2-phenoxyphenyl)thio phene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(4-morpholinobenzyl)t hiophene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(4-phenoxyphenyl)thio phene-2,4- dicarboxamide;

N4-(4-isopropoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)t hiophene-2,4- dicarboxamide;

N4-(cyclopropylmethyl)-N2-(3-(methylsulfonamido)phenyl)th iophene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(4-(morpholinomethyl) phenyl)thiophene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(3-(trifluoromethoxy) phenyl)thiophene-2,4- dicarboxamide;

N4-(3-isopropoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)t hiophene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(4-(2-morpholinoethox y)phenyl)thiophene-

2,4-dicarboxamide;

N4-(2,3-dihydrobenzofuran-4-yl)-N2-(3-(methylsulfonamido) phenyl)thiophene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(4-(morpholinomethyl) benzyl)thiophene-2,4- dicarboxamide;

N4-(3-chloro-5-methoxyphenyl)-N2-(3-(methylsulfonamido)ph enyl)thiophene-2,4- dicarboxamide;

N4-(4-(tert-butylcarbamoyl)phenyl)-N2-(3-(methylsulfonami do)phenyl)thiophene-

2,4-dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(4-(pyridin-4-yl)phen yl)thiophene-2,4- dicarboxamide; N4-(imidazo[l,2-a]pyridin-3-yl)-N2-(3-(methylsulfonamido)phe nyl)thiophene-2,4- dicarboxamide;

N4-(4-methoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thio phene-2,4- dicarboxamide;

N4-(l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5- yl)-N2-(3- (methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide;

N4-(l-methyl-lH-benzo[d]imidazol-6-yl)-N2-(3- (methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(3-(pyridin-3-yl)phen yl)thiophene-2,4- dicarboxamide;

N4-(3-(methoxymethyl)phenyl)-N2-(3-(methylsulfonamido)phe nyl)thiophene-2,4- dicarboxamide;

N4-(2-isopropoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)t hiophene-2,4- dicarboxamide;

N4-(2,3-dihydro-lH-inden-l-yl)-N2-(3-(methylsulfonamido)p henyl)thiophene-2,4- dicarboxamide;

N4-(4-chlorophenyl)-N2-(3-(methylsulfonamido)phenyl)thiop hene-2,4- dicarboxamide;

N4-(2-(cyanomethyl)phenyl)-N2-(3-(methylsulfonamido)pheny l)thiophene-2,4- dicarboxamide;

N4-(4-(methylcarbamoyl)phenyl)-N2-(3-(methylsulfonamido)p henyl)thiophene-2,4- dicarboxamide;

N4-(2-(lH-indol-3-yl)ethyl)-N2-(3-(methylsulfonamido)phen yl)thiophene-2,4- dicarboxamide;

N4-(( 1 H-benzo [d] imidazol-2-yl)methyl)-N2-(3 - (methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide;

N4-(2,5-dimethoxyphenethyl)-N2-(3-(methylsulfonamido)phen yl)thiophene-2,4- dicarboxamide;

N4-(2-(2-hydroxyethyl)phenyl)-N2-(3-(methylsulfonamido)ph enyl)thiophene-2,4- dicarboxamide;

N4-((lH-indazol-3-yl)methyl)-N2-(3-(methylsulfonamido)phe nyl)thiophene-2,4- dicarboxamide;

N4-((lH-indol-5-yl)methyl)-N2-(3-(methylsulfonamido)pheny l)thiophene-2,4- dicarboxamide; N4-(lH-benzo[d]imidazol-2-yl)-N2-(3-(methylsulfonamido)pheny l)thiophene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(3-(2-methylthiazol-4 -yl)phenyl)thiophene- 2,4-dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(5-phenyl-lH-pyrazol- 3-yl)thiophene-2,4- dicarboxamide;

N4-(4-(2-hydroxyethyl)phenyl)-N2-(3-(methylsulfonamido)ph enyl)thiophene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(2-(piperidin-l-yl)et hyl)thiophene-2,4- dicarboxamide;

N2-(3-(methylsulfonamido)phenyl)-N4-(3-(piperidin-l-ylmet hyl)phenyl)thiophene- 2,4-dicarboxamide;

N2-methyl-N5-(3-(methylsulfonamido)phenyl)-3-phenylthioph ene-2,5- dicarboxamide;

5-(hydroxymethyl)-N-(3-(methylsulfonamido)phenyl)-4-pheny lthiophene-2- carboxamide; l-benzyl-5-methyl-N-(3-(methylsulfonamido)phenyl)-lH-pyrazol e-3-carboxamide;

4-(benzylamino)-N-(3-(methylsulfonamido)phenyl)thiophene- 2-carboxamide;

N-(6-(methylsulfonamido)pyridin-2-yl)-4-phenylthiophene-2 -carboxamide;

N-(3-(methylsulfonoamidimidamido)phenyl)-4-phenylthiophen e-2-carboxamide;

N-(3-methyl-5-(methylsulfonamido)phenyl)-4-phenylthiophen e-2-carboxamide;

N-(3-formyl-5-(methylsulfonamido)phenyl)-4-phenylthiophen e-2-carboxamide;

5-(5-(3 ,3 -difluoroazetidin- 1 -yl)pyridin-2-yl)- 1 -methyl-N -(3- (methylsulfonamido)phenyl)-lH-pyrrole-3-carboxamide;

5-(3,5-difluoropyridin-2-yl)-l-methyl-N-(3-(methylsulfona mido)phenyl)-lH-pyrrole-

3-carboxamide; and

N4-(2-cyclopropylethyl)-N2-(3-(methylsulfonamido)phenyl)t hiophene-2,4- dicarboxamide; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of Table I are excluded from the compounds of the prent disclosure (e.g., compounds of Formula (I)). Table I.

The compounds and intermediates described herein may be isolated and used as the compound per se. Alternatively, when a moiety is present that is capable of forming a salt, the compound or intermediate may be isolated and used as its corresponding salt. As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound described herein. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds described herein and, which typically are not biologically or otherwise undesirable. In many 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.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids or organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfomate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The salts can be synthesized by conventional chemical methods from a compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed. In one embodiment, the present disclosure provides deuterated compounds described herein or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de-acetone, de-DMSO.

It will be recognized by those skilled in the art that the compounds of the present disclosure may contain chiral centers and as such may exist in different stereoisomeric forms. As used herein, the term “an optical isomer” or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound.

“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “racemic” or “rac” is used to designate a racemic mixture where appropriate. When designating the stereochemistry for the compounds of the present disclosure, a single stereoisomer with known relative and absolute configuration of the two chiral centers is designated using the conventional RS system (e.g., (1S,2S)). “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R- S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the respective retention times for the corresponding enantiomers/diastereomers via chiral HPLC.

Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

Unless specified otherwise, the compounds of the present disclosure are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAK ^R ™ and CHIRALCEL ^R ™ available from DAICEL Corp, using the appropriate solvent or mixture of solvents to achieve good separation). If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

The present disclosure also provides a pharmaceutical composition comprising a compound described herein (e.g., a compound according to any one of the preceding embodiments), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

METHODS OF USE

The compounds described herein have DHX9 inhibitory activity. As used herein, “DHX9 inhibitory activity” refers to the ability of a compound or composition to induce a detectable decrease in DHX9 activity in vivo or in vitro (e.g., at least 10% decrease in DHX9 activity as measured by a given assay such as the bioassay described in the examples and known in the art).

In certain embodiments, the present disclosure provides a method of treating a disease or disorder responsive to inhibition of DHX9 activity (referred herein as “DHX9 mediated disease or disorder”) in a subject in need of the treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to sixty-fourth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to sixty-fourth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a DHX9 mediated disorder or disease in a subject in need of the treatment.

In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixty-fourth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of a DHX9 mediated disorder or disease in a subject in need of the treatment. In certain embodiments, the DHX9 mediated disease or disorder is selected from cancer, viral infections, and autoimmune disease.

In some embodiments, the present disclosure provides a method of treating cancer. In some embodiments, the cancer is selected from colorectal, endometrial, ovarian, gastric, hematopoietic, breast, brain, skin, lung, blood, prostate, head and neck, pancreatic, bladder, bone, soft-tissue, kidney, and liver cancer. In some embodiments the cancer is selected from colorectal, endometrial, ovarian, hematopoietic, and gastric cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is Ewing’s sarcoma.

In some embodiments, the cancer is a microsatellite instable (MSI) cancer. In some embodiments, the cancer is MSI-high cancer. In other embodiments, the cancer is MSI-low cancer. MSI is determined by PCR analysis of 5 different nucleotide repeats, which is dependent on the cancer type. MSI-low cancers are characterized by instability at only 1 of the 5 sites; while MSI-high cancers are characterized by instability at 2 or more of the 5 sites (G. Yang et al. Correlations between micro satellite instability and the biological behavior of tumors. Journal of Cancer Research and Clinical Oncology, 2019).

MSI-high cancer is additionally characterized by defective mismatch repair (dMMR) (M. Lorenzi, et al. Epidemiology of Microsatellite Instability High (MSLH) and Deficient Mismatch Repair (dMMR) in Solid Tumors: A Structured Literature Review. Journal of Oncology, Volume 2020, Article ID 1897929). For example, dMMR in colorectal cancer can be determined by MLH1 promoter hypermethylation, rendering MLH1 inactive, which comprises about 80-90% of MSI-high colorectal cancers. MSI-high colorectal cancer with inactivated MLH1 is also named sporadic MSI-high colorectal cancer. Alternatively, dMMR can be determined by immunohistochemistry mutation status of MLH1, MSH2, MSH6, MSH3, PMS1 and/or PMS2 mismatch repair (MMR) proteins. In MSI-high colorectal cancer, MLH1 and MSH2 are the 2 predominantly mutated MMR proteins. They are mutated in about 10-20% of MSI-high colorectal cancers. MSI-high colorectal cancers with these mutations are also known as Lynch Syndrome cancers.

In some embodiments, the cancer is a MSI cancer and/or has mutations or defects in DNA mis-match repair (MMR), and/or mutations or defects in RNA splicing and the kinetochore complex.

The compounds, or pharmaceutically acceptable salts thereof described herein may be used to decrease the expression or activity of DHX9, or to otherwise affect the properties and/or behavior of DHX9 in a cell. One embodiment of the present disclosure includes a method of decreasing the expression or activity of DHX9, or to otherwise affect the properties and/or behavior of DHX9 in a subject comprising administering to said subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a mammal.

In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a primate.

In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a human.

As used herein, an “effective amount” and a “therapeutically effective amount” can used interchangeably. It means an amount effective for treating or lessening the severity of one or more of the diseases, disorders or conditions as recited herein. In some embodiments, the effective dose can be between 10 pg and 500 mg.

The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders or conditions recited above.

In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered parenterally.

In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically or intranasally.

In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered systemically.

The compounds of the present disclosure are typically used as a pharmaceutical composition (e.g., a compound of the present disclosure and at least one pharmaceutically acceptable carrier). As used herein, the term “pharmaceutically acceptable carrier” includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. For purposes of this disclosure, solvates and hydrates are considered pharmaceutical compositions comprising a compound of the present disclosure and a solvent (i.e., solvate) or water (i.e., hydrate).

The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present disclosure or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present disclosure is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

The pharmaceutical composition comprising a compound of the present disclosure is generally formulated for use as a parenteral or oral administration or alternatively suppositories.

For example, the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methods known in the art.

Suitable compositions for oral administration include a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

The parenteral compositions (e.g, intravenous (IV) formulation) are aqueous isotonic solutions or suspensions. The parenteral compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1- 75%, or contain about 1-50%, of the active ingredient.

The compound of the present disclosure or pharmaceutical composition thereof for use in a subject (e.g., human) is typically administered orally or parenterally at a therapeutic dose. When administered intravenously via infusion, the dosage may depend upon the infusion rate at which an IV formulation is administered. In general, the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, pharmacist, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10’ ³ molar and 10’ ⁹ molar concentrations.

DEFINITIONS

As used herein, a “patient,” “subject” or “individual” are used interchangeably and refer to either a human or non-human animal. The term includes mammals such as humans. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of any disease, condition or disorder, refers to the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present disclosure to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, condition or disorder; ameliorating or improving a clinical symptom, complications or indicator associated with the disease, condition or disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or disorder; or eliminating the disease, condition or disorder. In certain embodiments, the effect can be to prevent the onset of the symptoms or complications of the disease, condition or disorder.

As used herein the term “cancer” has the meaning normally accepted in the art. The term can broadly refer to abnormal cell growth.

As used herein, a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (in some embodiments, a human).

As used herein, the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general the term “optionally substituted” refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.

As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety. The term “Ci-4alkyl” refers to an alkyl having 1 to 4 carbon atoms. The terms “Ci-3alkyl” and “Ci-2alkyl” are to be construed accordingly. Representative examples of “Ci-4alkyl” include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, secbutyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy have the same definition as above. When indicated as being “optionally substituted”, the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls).

As used herein, the term “alkylene” refers to a fully saturated branched or unbranched divalent hydrocarbon radical. The term “Ci-4alkylene” refers to an alkylene having 1 to 4 carbon atoms. The terms “Ci-3alkylene” and “Ci-2alkylene” are to be construed accordingly. Representative examples of “Ci-4alkylene” include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, and tertbutylene.

As used herein, the term “alkoxy” refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e. a — O— C1-4 alkyl group wherein C1-4 alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy and the like. In some embodiments, alkoxy groups have about 1-4 carbons, and in some embodiments about 1-2 carbons. The term “ C1-2 alkoxy” is to be construed accordingly.

As used herein, the term “C1-4 alkoxyCi-4 alkyl” refers to a C1-4 allkyl group as defined herein, wherein at least of the hydrogen atoms is replaced by an C1-4 alkoxy. The Ci- 4alkoxyCi-4 alkyl group is connected through the rest of the molecule described herein through the alkyl group.

The number of carbon atoms in a group is specified herein by the prefix “C _x.xx ”, wherein x and xx are integers. For example, “C1-3 alkyl” is an alkyl group which has from 1 to 3 carbon atoms.

“Halogen” or “halo” may be fluorine, chlorine, bromine or iodine.

As used herein, the term “halo-substituted-Ci-4alkyl” or “ Ci-4haloalkyl” refers to a Ci-4alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The Ci-4haloalkyl group can be monohalo-Ci-4alkyl, dihalo-Ci-4alkyl or polyhalo- C1-4 alkyl including perhalo-Ci-4alkyl. A monohalo-Ci-4alkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihalo-Ci-4alkyl and polyhalo-Ci-4alkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhalo-Ci-4alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. Non-limiting examples of Ci-4haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhalo-Ci-4alkyl group refers to a Cwalkyl group having all hydrogen atoms replaced with halo atoms.

The term “aryl” refers to an aromatic carbocyclic single ring or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl.

The term “heteroaryl” refers to a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some instances, nitrogen atoms in a heteroaryl may be quaternized. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, and the like. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, indazoyl, benzofuranyl, benzimidazolyl, and imidazo[l,2-a]pyridine.

The term “carbocyclic ring” or “carbocyclyl” refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring and may exist as a single ring, bicyclic ring (including fused , spiral or bridged carbocyclic rings) or a spiral ring. Bi-cyclic carbocyclyl groups include, e.g., unsaturated carbocyclic radicals fused to another unsaturated carbocyclic radical, cycloalkyl, or aryl, such as, for example, cyclohexyl, cyclohexenyl, 2,3- dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless specified otherwise, the carbocyclic ring generally contains 4- to 10- ring members.

The term “C 3-6 cycloalkyl” refers to a carbocyclic ring which is fully saturated (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

The term “heterocycle” or “heterocyclyl” refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. A heterocyclyl group may be mono- or bicyclic (e.g., a bridged, fused, or spiro bicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, piperdinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and pyrrolidinyl. Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as, for example, 2-oxo-2,3-dihydro-l/Z-benzo[<7]imidazolyl, 1, 4,5,6- tetrahydrocyclopenta[c]pyrazolyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H- cyclopenta[b] thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl. In some embodiments, the heterocyclyl group is a 4 to 6 membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 8 to 10 membered bicyclic heterocyclyl group.

As used herein the term “spiral” ring means a two-ring system wherein both rings share one common atom. Examples of spiral rings include 5-oxaspiro[2.3]hexane, oxaspiro[2.4]heptanyl, 5-oxaspiro[2.4]heptanyl, 4-oxaspiro[2.4]heptane, 4- oxaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[bicyclo[2.1.1]hexane-2,3'-oxetan]-l-yl, oxaspiro[bicyclo[3.2.0]heptane-6,l'- eye lobutan] -7-yl, 2,6-diazaspiro[3.3]heptanyl, -oxa-6-azaspiro[3.3]heptane, 2,2,6- diazaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, 7- azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, 8-azaspiro[4.5]decane, 1,6- diazaspiro[3.3]heptane, 5-azaspiro[2.5]octane, 4,7-diazaspiro[2.5]octane, 5-oxa-2- azaspiro[3.4]octane, 6-oxa-l-azaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9- diazaspiro[5.5]undecanyl, and the like.

The term “fused” ring refers to two ring systems share two adjacent ring atoms. Fused heterocycles have at least one the ring systems contain a ring atom that is a heteroatom selected from O, N and S (e.g., 3-oxabicyclo[3.1.0]hexane).

As used herein the term “bridged” refers to a 5 to 10 membered cyclic moiety connected at two non-adjacent ring atoms (e.g. bicyclo[l.l.l]pentane, bicyclo [2.2.1] heptane and bicyclo [3.2.1] octane).

The phrase “pharmaceutically acceptable” indicates that the substance, composition or dosage form must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

Unless specified otherwise, the term “compounds of the present disclosure” refers to compounds of Formula (I), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). When a moiety is present that is capable of forming a salt, then salts are included as well, in particular pharmaceutically acceptable salts.

As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed.

It is also possible that the intermediates and compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

In one embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in free form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in salt form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in acid addition salt form. In a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable salt form. In yet a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in free form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in pharmaceutically acceptable salt form. In still another embodiment, the present disclosure relates to any one of the compounds of the Examples in pharmaceutically acceptable acid addition salt form.

Compounds of the present disclosure may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma- Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967- 1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. EXEMPLIFICATION

Abbreviation:

PE = petroleum ether

EtOAc = EA = ethyl acetate

ESI = electrospray ionisation

MeOH = methanol

EtOH = ethanol

DCM = dichloromethane

DIAD = Diisopropyl azodicarboxylate

DMF = dimethylformamide

DPP A = Diphenylphosphoryl azide

EDCI = l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

HATU = Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium

HC1 = hydrochloric acid

H2O = water

NBS = N-bromosuccinimide

LCMS = liquid chromatography mass spectrometry

HPLC = high pressure liquid chromatography

THF = tetrahydrofuran

MeCN = ACN = acetonitrile

DMSO = dimetylsulfoxide

AcOH = acetic acid

CDI = carbonyldiimidazole

TFA = trifluoroacetic acid

FA = formic acid

DIPEA = diisopropylethyl amine

TLC = Thin Layer Chromatography

N2 = Nitrogen

KOH = Potassium Hydroxide

NH4HCO3 = Ammonium Bicarbonate t-BuOH = tert-butanol

NH4CI = ammonium chloride t-BuOK = potassium tert-butoxide NaH = sodium hydride

Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Na2SO4= sodium sulfate

K2CO3 = potassium carbonate

NaHCCh = sodium bicarbonate

Pd(OAc)2 = Palladium (II) Acetate

NaOH = Sodium Hydroxide

TCFH = N '-tetramethylformamidinium hexafluorophosphate

NMI = 1 -Methylimidazole

XantPhosPdGs = [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-ami no-

1,1 '-biphenyl)]palladium(II) methanesulfonate

Pd/C = Palladium on Carbon

Pd(dppf)Ch DCM = [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane

Pd(dppf)Ch = [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Pd(PPhs)4 = Tetrakis(triphenylphosphine)palladium(0)

Pd(PPh3)Ch = Bis(triphenylphosphine)palladium(II) dichloride

PPh3 = triphenylphosphine

AlMes = A1(CH ₃ ) ₃ = trimethylaluminum

Et2O = diethyl ether

C2CI6 = hexachloroethane

PEPPSI IHept-Cl = (SP-4-l)-[l,3-Bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro -l,3- dihydro-2H-imidazol-2-ylidene] dichloro(3 -chlorop yridine-KN)palladium ( ACI)

Br2 = bromine

B2PHI2 = bis(pinacoloto)diboron

GENERAL METHODS

1. ¹ H NMR spectra were recorded on :

NMR10 Bruker AVANCE III HD 300MHz

NMR 16 Bruker AVANCE III HD 300MHz

NMR 19 Bruker AVANCE III HD 400MHz NMR24 Bruker AVANCE NEO 400MHz

NMR30 Bruker AVANCE NEO 400MHz

2. LCMS measurement was run on SHIMADZU LCMS-2020 using the follow conditions:

Method A: Mobile Phase: A: Water (0.05%TFA) B: Acetonitrile (0.05%TFA);

Gradient Phase: 5%B to 100%B within 2.0 min, 100%B with 0.7 min (total runtime:

2.8 min); Flow Rate: 1.5 mL/min; Column: HALO Cl 8, 3.0*30mm, 2.0|am; Column Temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

Method B: Mobile Phase: A: Water (0.1%FA) B: Acetonitrile (0.1%FA);

Gradient Phase: 5%B to 100%B within 2.0 min, 100%B with 0.7 min (total runtime:

2.8 min); Flow Rate: 1.5 mL/min; Column: HALO Cl 8, 3.0*30mm, 2.0pm; Column Temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

Method C: Mobile Phase: A: Water (5mM NH4HCO3) B: Acetonitrile;

Gradient Phase: 10%B to 95%B within 2.0 min, 100%B with 0.6 min (total runtime:

2.8 min); Flow Rate: 1.5 mL/min; Column: Poroshell HPH-C18, 3.0*50mm, 4.0pm;

Column Temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

The observed molecular ion for all compounds listed below is for [M+H] ⁺ , unless otherwise indicated.

PREPARATION OF INTERMEDIATES

Intermediate A: N-(3-amino-5-bromophenyl) methanesulfonamide

Step 1: A mixture of l-bromo-3-fluoro-5-nitrobenzene (50.00 g, 227.27 mmol, 1.00 equiv) and methanesulfonamide (21.62 g, 2 1.27 mmol, 1.00 equiv) and CS2CO3 (222.15 g, 681.83 mmol, 3.00 equiv) in 500 mL of DMSO, the resulted solution was stirred for 1 hour at 60 °C. The mixture was cooled then quenched with 1000 mL of water. The aqueous layer was extracted with 3 x 500 mL of ethyl acetate. Dried over anhydrous Na2SO4 and concentrated and the residue was purified onto silica gel column eluted with 35% of ethyl acetate in petroleum ether to afford N-(3-bromo-5-nitrophenyl)methanesulfonamide (35.2 g, 52.5%) as a yellow solid. LCMS (ESI) [M + H] ⁺ : 295

Step 2: A mixture of N-(3-bromo-5-nitrophenyl)methanesulfonamide (35.2 g, 119.28 mmol, 1.00 equiv) and Fe (66.61 g, 1192.78 mmol, 10 equiv) and NH4CI (63.80 g, 1192.78 mmol, 10.00 equiv) in 200 mL of ethanol and 50 mL of water and this was stirred for 2 hours at 90 ⁰ C. The resulting mixture was filtered, the filter cake was washed with 6 x 50 mL of methanol. The filtrate was concentrated under reduced pressure. The residue was purified onto silica gel column eluted with 50% of ethyl acetate in petroleum ether to afford N-(3-amino-5- bromophenyl)methanesulfonamide (25.1 g, 81.2%) as a yellow solid. LCMS (ESI) [M + H] ⁺ : 265. ¹ H NMR (300 MHz, DMSO- ₆ ) 6 9.63 (s, 1H), 6.58 - 6.36 (m, 3H), 5.53 (s, 2H), 2.98 (s, 3H).

Intermediate B: l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrr ole-3- carboxylate

Step 1: To a stirred solution of methyl lH-pyrrole-3-carboxylate (100 g, 800 mmol, 1 equiv) and NaH (60%) (64 g, 1.6 mol, 2 equiv) in DMF (1 L) was added iodomethane (227.2 g, 1.6 mol, 2 equiv) dropwise at 0 °C. The resulting mixture was stirred for additional 3 hours at room temperature. The reaction was quenched by the addition of water (5 L) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 5 L). The combined organic layers were washed with brine (3x5 L), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 1 -methyip yrrole-3 -carboxylate (95g, 85.6%) as a white solid

LCMS (ESI) [M+H] ⁺ : 140

Step 2: A solution of methyl l-methylpyrrole-3-carboxylate (95 g, 683. 5mmol, 1 equiv), ELPi (138.9 g, 546.7 mmol, 0.8 equiv), Di-mu-methoxobis(l,5-cyclooctadiene)diiridium(I) (6.7g, 10.3 mmol, 0.015 equiv)and 4,4’ -Di-tert-butyl-2, 2’ -bipyridine (5.49 g, 20.5 mmol, 0.03 equiv) in 1,4-dioxane (IL) was stirred for 3 hours at 100°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2/1). The residue was triturated with PE for 12 hours at room temperature and filtered to afford l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrrole-3-carboxylate(105 g, 57.8% yield) as a white solid.

LCMS (ESI) [M+H] ⁺ : 266

’ H NMR (300 MHz, Chloroform-^) 8 7.37 (d, J = 1.6 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 1.31 (s, 12H).

Example 1: l-(cyclohex-2-en-l-yl)-N-(5-(methylsulfonamido)cyclohexa-l,5 -dien-l-yl)- lH-pyrazole-4-carboxamide

Into an 8-mL sealed tube, was placed N-(3-aminophenyl)methanesulfonamide (100.0 mg, 0.54 mmol, 1.00 equiv) and 1 -phenyl- lH-pyrazole-4-carboxylic acid (100 mg, 0.54 mmol, 1.00 equiv), DIEA (109.1 mg, 1.62 mmol, 3.00 equiv) in 4 mL of DMF, to this was added HATU (266.7 mg, 0.7 mmol, 1.30 equiv) and this was stirred for 1 h at room temperature. The mixture was then quenched with 10 mL of water and extracted with 3 x 20 mL of ethyl acetate and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified onto silica gel column chromatography, eluted with 50% of ethyl acetate in petroleum ether to afford N-(3-methanesulfonamidophenyl)-l- phenyl-lH-pyrazole-4-carboxamide (28.8 mg, 14.9%) as a white solid. LCMS (ESI) [M+H] ⁺ : 357.09. ’ H NMR (300 MHz, DMSO-d6) 8 10.05 (s, 1H), 9.80 (s, 1H), 9.11 (s, 1H), 8.32 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.68 (s, 1H), 7.55 (q, J = 6.9, 6.1 Hz, 3H), 7.40 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 3.02 (s, 3H). The compounds listed in the following table were prepared using a procedure similar to that described for Example 1 : Example 35 : l-benzyl-N-(3-methanesulfonamidophenyl)pyrazole-4-carboxamid e

The solution of l-benzylpyrazole-4-carboxylic acid (130.3 mg, 0.644 mmol, 1.20 equiv), NMI (88.2 mg, 1.074 mmol, 2.00 equiv) in ACN (3 mL) was added TCFH (226 mg, 0.805 mmol, 1.50 equiv) at room temperature. The reaction mixture was stirred for 10 min, then N- (3-aminophenyl)methanesulfonamide (100 mg, 0.537 mmol, 1 equiv) was added and stirred for another one hour. The reaction mixture was purified by HPLC to afford l-benzyl-N-(3- methanesulfonamidophenyl)pyrazole-4-carboxamide (85.7 mg, 42.96%) as a white solid. LCMS (ESI) [M+H] ⁺ =371. ’ H NMR (300 MHz, DMSO-d6) 8 9.90 (s, 1H), 9.76 (s, 1H), 8.45 (d, J = 0.8 Hz, 1H), 8.06 (d, J = 0.8 Hz, 1H), 7.64 (t, J = 2.1 Hz, 1H), 7.53 - 7.44 (m,

1H), 7.42 - 7.23 (m, 6H), 6.90 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 5.40 (s, 2H), 3.00 (s, 3H).

The compounds listed in the following table were prepared using a procedure similar to that described for Example 36: Example 45 : 4-(3-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene- 2- carboxamide

A solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamid e (100 mg, 0.266 mmol), Pd(dppf)Ch (19.4 mg, 0.0266 mmol), K2CO3 (110 mg, 0.798 mmol) and (3- fluorophenyl)boronic acid (74.4 mg, 0.532 mmol) in dioxane (4 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (0-100%) to afford 4-(3-fluorophenyl)-N-(3- methanesulfonamidophenyl)thiophene-2-carboxamide (62.8 mg, 0.160 mmol) as a white solid. LCMS (ESI) [M+H] ⁺ : 391. ’ H NMR (300 MHz, DMSO-d6) 8 10.32 (s, 1H), 9.83 (s, 1H), 8.52 (d, J = 1.5 Hz, 1H), 8.30 (d, J = 1.4 Hz, 1H), 7.69 (t, J = 2.0 Hz, 1H), 7.66 - 7.46 (m, 4H), 7.33 (t, J = 8.1 Hz, 1H), 7.26 - 7.13 (m, 1H), 6.96 (dd, J = 7.7, 2.2 Hz, 1H), 3.03 (s, 3H). The compounds listed in the following table were prepared using a procedure similar to that described for example 45 :

Example 72: tert-butyl (3-(5-((5-(methylsulfonamido)cyclohex-2-en-l- yl)carbamoyl)thiophen-3-yl)phenyl)carbamate

A mixture of 4-(3-aminophenyl)-N-(3-methanesulfonamidophenyl) thiophene-2-carboxamide (30 mg, 0.077 mmol, 1 equiv), (Boc O (20.28 mg, 0.092 mmol, 1.2 equiv) and DIEA (30.02 mg, 0.231 mmol, 3 equiv) in DCM (3 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (Water: ACN = 2:3) to afford tert-butyl N-(3-{5-[(3-methanesulfonamidophenyl) carbamoyl] thiophen-3-yl}phenyl) carbamate (25.2 mg, 66.75%) as a white solid. LCMS (ESI) [M+H] ⁺ : 488. ¹ H NMR (300 MHz, DMSO-d6) 8 10.42 (s, 1H), 9.81 (s, 1H), 9.46 (s, 1H), 8.39 (d, J = 1.4 Hz, 1H), 8.05 (d, J = 1.3 Hz, 1H), 7.92 (s, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 6.5 Hz, 4H), 6.96 (d, J = 7.9 Hz, 1H), 3.02 (s, 3H), 1.50 (s, 9H).

Example 73: 4-(5-hydroxycyclohexa-2,4-dien-l-yl)-N-(3- (methylsulfonamido)phenyl)thiophene-2-carboxamide

To a stirred solution of N-(3-methanesulfonamidophenyl)-4-(3-methoxyphenyl) thiophene-2- carboxamide (125 mg, 0.310 mmol) in DCM was added BBn (388.53 mg, 1.55 mmol, 5 equiv) dropwise. The reaction was stirred for 3 h at room temperature under nitrogen atmosphere. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (5-95%, acidic system) to afford 4-(3- hydroxyphenyl)-N-(3- methanesulfonamidophenyl)thiophene-2-carboxamide (35.5 mg, 99.876%) as a white solid. LCMS (ESI) [M+H] ⁺ : 389. ¹ H NMR (300 MHz, DMSO-d6) 8 10.33 (s, 1H), 9.82 (s, 1H), 9.58 (s, 1H), 8.44 (d, J = 1.5 Hz, 1H), 8.11 (d, J = 1.3 Hz, 1H), 7.70 (t, J = 2.1 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.30 (dt, J = 15.8, 8.0 Hz, 2H), 7.21 - 7.08 (m, 2H), 7.01 - 6.91 (m, 1H), 6.77 (ddd, J = 7.9, 2.5, 1.0 Hz, 1H), 3.02 (s, 3H).

Example 74: 4-(3-hydroxy-2-methylphenyl)-N-(3- (methylsulfonamido)phenyl)thiophene-2-carboxamide

Step 1: To a stirred solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2- carboxamide (300 mg, 0.799 mmol), (3-methoxy-2-methylphenyl)boronic acid (197 mg, 1.19 mmol) and Pd(dppf)Ch (58.4 m g, 0.07 99 mmol), K2CO3 (332 mg, 2.39 mmol) was added dioxane (10 mL). Then the mixture was stirred for 2 h at 80 °C. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (0- 100%, acidic system) to afford N-(3-methan esulfonamidophenyl)-4-(3-methoxy-2- methylphenyl)thiophene-2-carboxamide (87.0 mg, 0.208 mmol) as an off-white solid. LCMS (ESI) [M+H] ⁺ : 417.09

Step 2: To a stirred solution of N-(3-methanesulfonamidophenyl)-4-(3-methoxy-2- methylphenyl)thiophene-2-carboxamide (87 mg, 0.208 mmol), BCI3 (72.3 mg, 0.624 mmol) was added DCM (5 mL ) dropwise. Then the mixture was stirred for 2 h at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (0-100%, acidic system) to afford 4-(3-hydroxy-2-methylphenyl)-N-(3- methanesulfonamidophenyl)thiophene-2-carboxamide (25.7 mg, 0.0629 mmol) as a white solid. LCMS (ESI) [M+H] ⁺ : 403.07. ’ H NMR (300 MHz, DMSO-d6) 8 10.26 (s, 1H), 9.81 (s, 1H), 9.48 (s, 1H), 8.12 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 1.3 Hz, 1H), 7.67 (t, J = 2.1 Hz, 1H), 7.56 - 7.46 (m, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.95 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 6.82 (ddd, J = 11.6, 7.8, 1.3 Hz, 2H), 3.01 (s, 3H), 2.15 (s, 3H).

The compounds listed in the following table were prepared using a procedure similar to that described for Example 74:

Example 76: 4-(2,6-difluorophenyl)-N-(3-(methylsulfonamido)phenyl)thioph ene-2- carboxamide A solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamid e (100 mg, 0.266 mmol), XPhos Pd G3 (22.5 mg, 0.0266 mmol), K3PO4 (169 mg, 0.798 mmol) and 2- (2,6-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (191 mg, 0.798 mmol) in dioxane (5 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (0-100%) to afford 4-(2,6- difluorophenyl)-N-(3-methanesulfonamidophenyl)thiophene-2-ca rboxamide (69.5 mg, 0.169 mmol) as a white solid. LCMS (ESI) [M+H] ⁺ : 409. ¹ H NMR (300 MHz, DMSO-d6) 8 10.39 (s, 1H), 9.81 (s, 1H), 8.31 (q, J = 1.5 Hz, 1H), 8.12 (q, J = 1.3 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.58 - 7.42 (m, 2H), 7.30 (dt, J = 10.7, 8.2 Hz, 3H), 6.96 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H). The compounds listed in the following table were prepared using a procedure similar to that described for Example 76: Example 80: 5-methyl-N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thi ophene-2- carboxamide

A solution of 4-bromo-N-(3-methanesulfonamidophenyl)-5-methylthiophene-2-c arboxamide (300 mg, 0.770 mmol), 2-(tributylstannyl)pyridine (563 mg, 1.53 mmol) and Pd(PPh3)4 (177 mg, 0.154 mmol) in Toluene (5 mL) was stirred for 2 h at 120 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (0-100%) to afford N- (3-methanesulfonamidophenyl)-5-methyl-4-(pyridin-2-yl)thioph ene-2-carboxamide (28.8 mg, 0.0740 mmol) as a yellow solid. LCMS (ESI) [M+H] ⁺ : 388 ¹ H NMR (300 MHz, DMSO-d6)

8 10.31 (s, 1H), 9.79 (s, 1H), 8.69 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 8.40 (s, 1H), 7.93 (td, J = 7.7, 1.9 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.57 - 7.47 (m, 1H), 7.37 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H), 6.93 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 3.01 (s, 3H), 2.71 (s, 3H). The compounds listed in the following table were prepared using a procedure similar to that described for Example 80: Example 82: N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2- carboxamide

Step 1: A solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamid e (400 mg, 1.066 mmol, 1 equiv) and bis(pinacolato)diboron (2706.82 mg, 10.660 mmol, 10 equiv) and Pd(dppf)Ch (77.99 mg, 0.107 mmol, 0.1 equiv) and KOAc (313.84 mg, 3.198 mmol, 3 equiv) in Dioxane (5 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford N-(3-methanesulfonamidophenyl)- 4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)thiophene-2-carboxamide (352 mg, 78.19%) as a yellow oil. LCMS (ES, m/z): LCMS (ESI) [M+H] ⁺ : 423.

Step 2: A solution of N-(3-methanesulfonamidophenyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)thio phene-2-carboxamide (352 mg, O.833mmol, 1.5 equiv) and 2- bromopyridine (87.79 mg, 0.555 mmol, 1 equiv) and Pd(dppf)Ch (40.66 mg, 0.056 mmol, 0.1 equiv) and K2CO3 (230.39 mg, 1.666 mmol, 3 equi v) in Dioxane (3 mL) and H2O (1 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254nm. This resulted in N-(3-methanesulfonamidophenyl)-4-(pyridin-2-yl)thiophene-2-c ar boxamide (68.8 mg, 33.15%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H] ⁺ : 374. ’ H NMR (300 MHz, DMSO-d6) 8 10.48 (s, 1H), 9.81 (s, 1H), 8.75 (d, J = 1.4 Hz, 1H), 8.65 (m, J = 4.8, 1.4 Hz, 1H), 8.49 (d, J = 1.3 Hz, 1H), 7.96 - 7.88 (m, 2H), 7.73 (t, J = 2.0 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.42 - 7.28 (m, 2H), 6.95 (m, J = 8.1, 2.1, 1.0 Hz, 1H), 3.02 (s, 3H). The compounds listed in the following table were prepared using a procedure similar to that described for Example 82:

Example 91: N-(3-(methylsulfonamido)phenyl)-4-(5-(piperazin-l-yl)pyridin -2- yl)thiophene-2-carboxamide Step 1: To a stirred solution of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-l -carboxylate (300 mg, 1.07 mmol) and CuBr2 (119 mg, 0.535 mmol) in CthBn (5 mL) was added 3- methylbutyl nitrite (137 mg, 1.17 mmol) dropwise at 0 °C. Then the mixture was stirred for 5 h at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc/Petroleum ether (0-100%) to afford tert-butyl 4-(6- bromopyridin-3-yl)piperazine-l-carboxylate (188 mg, 0.549 mmol) as a yellow solid. LCMS (ESI) [M+H] ⁺ : 342.

Step 2: A solution of tert-butyl 4-(6-bromopyridin-3-yl)piperazine-l-carboxylate (190 mg, 0.555 mmol), Pd(PPh3)2Ch (77.2 mg, 0.110 mmol), Na2COs (175 mg, 1.66 mmol) and N-(3- methanesul fonamidophenyl)-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2- carboxamide (257 mg, 0.610 mmol) in EtOH (4 mL) and H2O (1 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0-100%) to afford tert-butyl 4-(6-{5-[(3-methanesulfonamido phenyl)carbamoyl] thiophen-3-yl}pyridin-3-yl)piperazine-l-carboxylate (178 mg, 0.319 mmol) as a yellow solid. LCMS (ESI) [M+H] ⁺ : 558

Step 3: To a stirred solution of tert-butyl 4-(6-{5-[(3-methanesulfonamidophenyl) carbamoyl]thiophen-3-yl} pyridin-3-yl)piperazine-l-carboxylate (180 mg, 0.322 mmol) in DCM (10 mL) was added TFA (365 mg, 3.21 mmol) dropwise at 0 °C for 1 h. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 9 with NaOH. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc/Petroleum ether (0-100%) to afford N-(3-methanesulfonamidophenyl)-4-[5- (piperazin-l-yl) pyridin-2-yl] thiophene-2-carboxamide (19.9 mg, 0.0419 mmol) as a yellow solid. LCMS (ESI) [M+H] ⁺ : 458. ’ H NMR (300 MHz, DMSO-d6) 8 8.61 (d, J = 1.4 Hz, 1H), 8.37 - 8.28 (m, 2H), 8.23 (d, J = 1.4 Hz, 1H), 7.80 - 7.69 (m, 2H), 7.57 - 7.40 (m, 2H), 7.31 (t, J = 8.1 Hz, 1H), 6.94 (dd, J = 8.2, 2.3 Hz, 1H), 3.34 (t, J = 5.1 Hz, 4H), 3.07 (dd, J = 6.3, 3.7 Hz, 4H), 3.01 (s, 3H).

Example 92: 2-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)- l,4- dihydropyridine-4-carboxamide

To a stirred solution of 2-{5-[(3-methanesulfonamidophenyl)carbamoyl]thiophen-3- yl}pyridine-4-carboxylic acid (100 mg, 0.240 mmol, 1 equiv) and NH4CI (12.81 mg, 0.240 mmol, 1 equiv) in DMF (3 mL) were added DIEA (92.88 mg, 0.720 mmol, 3 equiv) and HATU (136.63 mg, 0.360 mmol, 1.5 equiv) in portions at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 2-{5-[(3-methanesulfonamido phenyl)carbamoyl] thiophen-3-yl}pyridine-4- carboxamide (11.3 mg, 11.33%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H] ⁺ : 417. ’ H NMR (300 MHz, DMSO-d6) 8 10.51 (s, 1H), 9.76 (s, 1H), 8.84 - 8.73 (m, 2H), 8.53 (d, J = 1.3 Hz, 1H), 8.39 - 8.26 (m, 2H), 7.83 (s, 1H), 7.73 (m, J = 3.3, 1.4 Hz, 2H), 7.55 (m, J = 8.4, 1.2 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 6.95 (m, J = 8.1, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H).

Example 93 : 4- (2-acetamidophenyl) -N - (3- (methylsulfonamido)phenyl)thiophene-2- carboxamide

To a mixture of 4-(2-aminophenyl)-N-(3-methanesulfonamidophenyl)thiophene-2- carboxamide (80 m g, 0.206 mmol) and Et3N (62.4 mg, 0.618 mmol) in DCM (1 mL)was added CH3COCI (19.3 mg, 0.247 mmol). The resulting mixture was stirred for two hours at room temperature. Then it was concentrated, The residue was purified by flash chromatography on silica gel eluting with 35% of ethyl acetate in petroleum ether to afford 4- (2-acetamidophenyl)-N-(3-methanesulfonamidophenyl)thiophene- 2-carboxamide (39.5 mg, 44.4% ) as a white solid. LCMS [M+H] ⁺ : 430. ¹ H NMR (300 MHz, DMSO-d6) 8 10.34 (s, 1H), 9.82 (s, 1H), 9.39 (s, 1H), 8.27 (d, J = 1.4 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.68 (t, J =

2.1 Hz, 1H), 7.61 - 7.43 (m, 3H), 7.41 - 7.22 (m, 3H), 6.95 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H),

3.02 (s, 3H), 2.00 (s, 3H).

The compounds listed in the following table were prepared using a procedure similar to that described for Example 93:

Example 96: N-(3-(ethylsulfonamido)phenyl)-4-phenylthiophene-2-carboxami de Step 1: A solution of phenyl boronic acid (5 g, 41.007 mmol, 1 equiv) and 4- bromothiophene-2-carboxylic acid (8.49 g, 41.007 mmol, 1 equiv) and Pd(PPh3)2Ch (2.88 g, 4.101 mmol, 0.1 equiv) and Na2COs (13.04 g, 123.021 mmol, 3 equiv) in EtOH (20 mL) and H2O (5 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was acidified to pH 6 with HC1 (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 4-phenylthiophene-2-carboxylic acid (4.5g, 53.73%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H] ⁺ : 205

Step 2: To a stirred solution of 4-phenylthiophene-2-carboxylic acid (100 mg, 0.490 mmol, 1.0 equiv) and benzene- 1,3 -diamine (52.95 mg, 0.490 mmol, 1 equiv) in ACN (3 mL) were added TCFH (206.07 mg, 0.735 mmol, 1.5 equiv) and NMI (120.60 mg, 1.470 mmol, 3 equiv) in portions at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254nm. This resulted in N-(3- aminophenyl)-4-phenylthiophene-2-carboxamide (130 mg, 90.20%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H] ⁺ : 295.

Step 3: A solution of N-(3-aminophenyl)-4-phenylthiophene-2-carboxamide (70 mg, 0.238 mmol, 1.0 equi v) and ethanesulfonyl chloride (36.69 mg, 0.286 mmol, 1.2 equiv) in pyridine (3 mL) was stirred for 1 h at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254nm. This resulted in N-(3- ethanesulfonamidophenyl)-4-phenyl thiophene-2-carboxamide (15.0 mg, 16.32%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H] ⁺ : 387. ¹ H NMR (300 MHz, DMSO-d6) 8 10.33 (s, 1H), 9.86 (s, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.20 (d, J = 1.4 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.70 (t, J = 2.1 Hz, 1H), 7.56 - 7.43 (m, 3H), 7.41 - 7.21 (m, 2H), 7.01 - 6.92 (m, 1H), 3.13 (m, J = 7.3 Hz, 2H), 1.22 (t, J = 7.3 Hz, 3H).

The compounds listed in the following table were prepared using a procedure similar to that described for Example 96, using a synthesized or commercial carboxylic acid: Example 98: 5-bromo-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2- carboxamide

Step 1: To a solution of 4-phenylthiophene-2-carboxylic acid (1.5 g, 7.344 mmol, 1 equiv) and NBS (1.57 g, 8.813 mmol, 1.2 equiv) in CHCI3 (20 mL) was added AcOH (1.32 g, 22.032 mmol, 3 equiv) at room temperature. The resulting solution was stirred for 4 hours at room temperature. The resulting solution was concentrated under vacuum. The residue was purified by flash chromatography on C18 column gel eluting with ACN/water (0.05%FA) (28%) to afford 5-bromo-4-phenylthiophene-2-carboxylic acid (850 mg, 39.04%) as a yellow solid. LCMS : (ES, m/z): [M+H] ⁺ :283 Step 2: To a solution of 5-bromo-4-phenylthiophene-2-carboxylic acid (850 mg, 3.002 mmol, 1 equiv), NMI (492.9 mg, 6.003 mmol, 2.00 equiv) and TCFH (1.3 g, 4.633 mmol, 1.54 equiv) in ACN (10 mL) at room temperature. The resulting solution was stirred for 10 minus at room temperature. Then N-(3-aminophenyl)methanesulfonamide (838.6 mg, 4.503 mmol, 1.50 equiv) was added and stirred at room temperature for one hours. The residue was purified by flash chromatography on C18 Column gel eluting with ACN/water (0.05%NH4HC03) (56%) to afford 5-bromo-N-(3-methanesulfonamidophenyl)-4- phenylthiophene-2-carboxamide (1.0 g, 67.90%) as a yellow solid and crude product (100 mg) was purify by Pre-HPLC on condition Column: XBridge Prep C18 OBD Column, 19*150 mm, 5pm; Mobile Phase A: Water (lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 41% B to 77% B in 8 min, 77% B; Wave Length: 220 nm; RTl(min): 6.88 to afford 5-bromo-N-(3-methanesulfonamidophenyl)-4-phenylthio phene-2- carboxamide (29.2 mg, 50%) as a yellow solid. LCMS : (ES, m/z): [M+H] ⁺ : 451. ^X H NMR (400 MHz, DMSO-d6) 8 10.34 (s, 1H), 9.81 (s, 1H), 8.15 (s, 1H), 7.68 - 7.59 (m, 3H), 7.57 - 7.41 (m, 4H), 7.31 (t, J = 8.1 Hz, 1H), 6.95 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 3.00 (s, 3H).

Example 99: N-(3-(methylsulfonamido)phenyl)-4-phenyl-5-(trifluoromethyl) thiophene- 2-carboxamide

Step 1: To a solution of 5-bromo-N-(3-methanesulfonamidophenyl)-4-phenylthiophene-2- carboxamide (200 mg, 0.443 mmol, 1 equiv), Cui (8.4 mg, 0.044 mmol, 0.10 equiv), NMP (5 mL) in NMP (5 mL) was added methyl 2,2-difluoro-2-sulfoacetate (127.7 mg, 0.665 mmol, 1.50 equiv) at room temperature under nitrogen. The resulting solution was stirred for two hours at 135 °C. The residue was purified by Pre-HPLC on condition: Column: Xselect CSH C18 OBD Column 30*150mm 5pm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 66% B in 11 min, 66% B; Wave Length: 254/220 nm; RTl(min): 8.47 to afford N-(3-methanesulfonamidophenyl)-4-phenyl-5- (trifluoromethyl) thiophene-2-carboxamide (7.5 mg, 3.82%) as a white solid. LCMS : (ES, m/z): [M+l] =441.^ NMR (300 MHz, DMSO-d6) 8 10.55 (s, 1H), 9.86 (s, 1H), 8.12 (s, 1H), 7.69 - 7.53 (m, 6H), 7.36 - 7.30 (m, 1H), 6.97 (t, J = 8.1 Hz, 1H), 3.02 (s, 3H). Example 100: 5-cyano-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2- carboxamide

To a solution of 5-bromo-N-(3-methanesulfonamidophenyl)-4-phenylthiophene-2- carboxamide (120 mg, 0.266 mmol, 1 equiv) and CuCN (47.6 mg, 0.531 mmol, 2.00 equiv) in NMP (5 mL) at room temperature under nitrogen. The resulting solution was stirred overnight at 160 °C. The residue was purified by Pre-HPLC on condition: Column: YMC- Actus Triart C18 ExRS, 30*150 mm, 5pm; Mobile Phase A: Water (lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 52% B to 60% B in 8 min, 60% B; Wave Length: 220 nm; RTl(min): 7.58 to afford 5-cyano-N-(3 -methane sulfonamidophenyl)- 4- phenylthiophene-2-carboxamide (24.7 mg, 23.31%) as a yellow solid. LCMS : (ES, m/z): [M+l] =398. ¹ H NMR (300 MHz, DMSO-d6) 8 10.65 (s, 1H), 9.88 (s, 1H), 8.45 (s, 1H), 7.89 - 7.73 (m, 2H), 7.71 - 7.45 (m, 5H), 7.35 (t, J = 8.1 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 3.02 (s, 3H).

Example 101: 5-[(3-methanesulfonamidophenyl) carbamoyl] -3 -phenylthiophene-2- carboxylic add

To a solution of 5-bromo-N-(3-methanesulfonamidophenyl)-4-phenylthiophene-2- carboxamide (100 mg, 0.222 mmol, 1 equiv), acetic anhydride (45.3 mg, 0.444 mmol, 2.00 equiv), oxalic acid (39.9 mg, 0.443 mmol, 2.00 equiv), Pd(OAc)2 (5 mg, 0.022 mmol, 0.10 equiv), and Xantphos (25.6 mg, 0.044 mmol, 0.20 equiv) in DMF (5 mL) was added DIEA (85.9 mg, 0.665 mmol, 3.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 2 hours at 100 °C. The mixture was purified by Prep-HPLC to afford 5-[(3-methanesulfona midophenyl) carbamoyl]-3-phenylthiophene-2-carboxylic acid (30.5 mg, 33.05%) as a yellow solid.

LCMS (ESI) [M+H] ⁺ = 417 ’ H NMR (300 MHz, DMSO-d6) 8 10.42 (s, 1H), 9.83 (s, 1H), 8.09 (s, 1H), 7.68 (t, J = 2.1 Hz, 1H), 7.53 (ddd, J = 7.2, 6.1, 2.0 Hz, 3H), 7.48 - 7.39 (m, 3H), 7.32 (t, J = 8.1 Hz, 1H), 6.97 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 3.01 (s, 3H).

Example 102: N2-(3-(methylsulfonamido)phenyl)-N4-phenylthiophene-2,4- dicarboxamide

Step 1: To a stirred solution of 4-bromothiophene-2-carboxylic acid (500 mg, 2.41 mmol), TCFH (1.024 g, 3.615 mmol) and NMI (0.598 mg, 7.23 mmol) in ACN (4.00 mL) was added N-(3-aminophenyl)methanesulfonamide (448 mg, 24.1 mmol). Then the mixture was stirred for 4 hours at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (5-95%, acidic system) to afford 4-bromo-N- (3-methanesulfonamidophenyl)thiophene-2-carboxamide (850 mg, 95%) as a brown solid. Step 2: A solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamid e (100 mg, 0.266 mmol, 1 equiv), acetic anhydride (54.41 mg, 0.532 mmol, 2 equiv), Pd(OAc)2 (11.97 mg, 0.053 mmol, 0.2 equiv), Xantphos (30.84 mg, 0.053 mmol, 0.2 equiv), oxalic acid (47.99 mg, 0.532 mmol, 2 equiv) and DIEA (103.32 mg, 0.798 mmol, 3 equiv) in DMSO (3 mL) was stirred for 2 hours at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc=2:3, to afford 5-[(3- methanesulfonamidophenyl)carbamoyl]thiophene-3-carboxylic acid (63 mg, 69.46%) as white solid.

Step 3: A solution of 5-[(3-methanesulfonamidophenyl)carbamoyl]thiophene-3-carboxy lic acid (50 mg, 0.147 mmol, 1 equiv), aniline (15.05 mg, 0.162 mmol, 1.1 equiv), TCFH (82.43 mg, 0.294 mmol, 2 equiv) and NMI (36.18 mg, 0.441 mmol, 3 equiv) in ACN (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase Flash Chromatography with the following conditions (water/ ACN=2:3) to afford N2-(3- (methylsulfonamido)phenyl)-N4-phenylthiophene-2,4-dicarboxam ide (13.2 mg, 21.63%) as a white solid. LCMS (ESI) [M+H] ⁺ = 416

’ H NMR (300 MHz, DMSO-d6) 8 10.50 (s, 1H), 10.24 (s, 1H), 9.80 (s, 1H), 8.63 (d, J = 1.3 Hz, 1H), 8.53 (d, J = 1.4 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.71 (t, J = 2.1 Hz, 1H), 7.59 - 7.51 (m, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.31 (t, J = 8.1 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.00 - 6.91 (m, 1H), 3.02 (s, 3H). The compounds listed in the following table were prepared using a procedure similar to that described for Example 102:

Example 153: 5-(hydroxymethyl)-N-(3-(methylsulfonamido)phenyl)-4-phenylth iophene-

2-carboxamide Step 1: To a solution of 5-[(3-methanesulfonamidophenyl)carbamoyl]-3-phenylthiophene- 2- carboxylic acid (60 mg, 0.144 mmol, 1 equiv), HATU (82.2 mg, 0.216 mmol, 1.50 equiv) and DIEA (55.8 mg, 0.432 mmol, 3.00 equiv) in DMF (2 mL) was added methanol (9.2 mg, 0.287 mmol, 1.99 equiv) at room temperature. The resulting solution was stirred for two hours at room temperature. The residue was purified by Cis Column on condition: ACN/water(0.05%FA)(45%) to afford methyl 5-[(3-methanesulfonamidophenyl) carbamoyl]-

3-phenylthiophene-2-carboxylate (40 mg, 58.37%) as a yellow solid.

Step 2: To a solution of methyl 5-[(3-methanesulfonamidophenyl)carbamoyl]-3- phenylthiophene-2-carboxylate (40 mg, 0.093 mmol, 1 equiv) in EtOH (5 mF, 86.067 mmol, 926.27 equiv) was added NaBPL (7.03 mg, 0.186 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred for 2 hours at room temperature. The residue was purified by Pre-HPLC on condition: Column: XBridge Prep C18 OBD Column, 19*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 29% B to 45% B in 8 min, 45% B; Wave Length: 220 nm; RTl(min): 7.3 to afford 5-(hydroxymethyl)-N-(3-methanesulfonamidophenyl)-4-phenylthi ophene-2- carboxamide (8.8 mg, 23.34%) as a yellow solid. LCMS : (ES, m/z): [M+l] =403. ’ H NMR (300 MHz, DMSO-d6) 8 10.24 (s, 1H), 9.79 (s, 1H), 8.14 (s, 1H), 7.69 (t, J = 2.1 Hz, 1H), 7.51 (q, J = 4.1, 3.1 Hz, 5H), 7.39 (ddd, J = 8.6, 5.3, 2.5 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H), 6.94 (dd, J = 8.0, 2.1 Hz, 1H), 5.85 (t, J = 5.4 Hz, 1H), 4.73 (d, J = 5.3 Hz, 2H), 3.01 (s, 3H).

Example 154: l-benzyl-N-(3-methane sulfonamidophenyl)-5-methyl-lH-pyrazole-3- carboxamide

Step 1: To a stirred solution of ethyl 5 -methyl- lH-pyrazole-3 -carboxylate (500 mg, 3.24 mmol) and CS2CO3 (3.15 g, 9.72 mmol), (bromomethyl)benzene (554 mg, 3.24 mmol) was added in DMSO (10 mL) dropwise. The mixture was stirred for 2 hours at 80 °C. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (0-100%, acidic system) to afford ethyl l-benzyl-5-methyl-lH-pyrazole-3-carboxylate (420 mg, 1.71 mmol) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 245.

Step 2: To a stirred mixture of ethyl l-benzyl-5-methyl-lH-pyrazole-3-carboxylate (420 mg, 1.71 mmo 1) and LiOH (123 mg, 5.13 mmol) was added THF (6 mL) and H2O (2 mL) dropwise. The mixture was stirred for 2 hours at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (0- 100%, acidic system) to afford l-benzyl-5-methyl-lH-pyrazole-3-carboxylic acid (300 mg, 1.38 mmol) as a yellow solid. LCMS (ESI) [M + H]+: 217.

Step 3: To a stirred mixture of l-benzyl-5-methyl-lH-pyrazole-3-carboxylic acid (60 mg, 0.277 mmol), TCFH (116 mg, 0.415 mmol), N-(3-aminophenyl)methanesulfonamide (51.5 mg, 0.277 mmol) and NMI (113 mg, 1.38 mmol) was added ACN (5 mL). Then the mixture was stirred for 2 hours at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (0-100%, acidic system) to afford l-benzyl-N-(3-methane sulfonamidophenyl)-5-methyl-lH-pyrazole-3-carboxamide (58.7 mg, 0.152 mmol) as a white solid. LCMS (ESI) [M + H]+: 385. ’ H NMR (300 MHz, DMSO-d6) 8 10.04 (s, 1H), 9.78 (s, 1H), 7.81 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.31 (dq, J = 21.2, 7.7 Hz, 4H), 7.17 (d, J = 7.4 Hz, 2H), 6.93 (d, J = 8.1 Hz, 1H), 6.66 (s, 1H), 5.45 (s, 2H), 3.03 (s, 3H), 2.25 (s, 3H).

Example 155 : 4-(benzylamino)-N-(3-(methylsulfonamido)phenyl)thiophene-2- carboxamide

Step 1: A solution of methyl 4-aminothiophene-2-carboxylate (100 mg, 0.636 mmol, 1 equiv) and benzyl bromide (119.69 mg, 0.700 mmol, 1.1 equiv) and CS2CO3 (621.83 mg, 1.908 mmol, 3 equiv) in DMSO (3 mL) was stirred for 1 h at 60 °C. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 4-(benzylamino)thiophene-2-carboxylate (130 mg, 82.63%) as a yellow solid. LCMS (ESI) [M+H] ⁺ : 248.

Step 2: A solution of methyl 4-(benzylamino) thiophene-2-carboxylate (130 mg, 0.526 mmol, 1 equiv) an d LiOH (37.77 mg, 1.578 mmol, 3 equiv) in EtOH (3 mL) and H2O (1 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 6 with HC1 (aq.). The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 4-(benzylamino) thiophene-2-carboxylic acid (90 mg, 73.39%) as a yellow solid. LCMS (ESI) [M+H] ⁺ : 234. Step 3: To a stirred solution of 4-(benzylamino) thiophene-2-carboxylic acid (90 mg, 0.386 mmol, 1 equiv) and N-(3-aminophenyl) methanesulfonamide (71.84 mg, 0.386 mmol, 1 equiv) in ACN (3 mL) were added NMI (95.02 mg, 1.158 mmol, 3 equiv) and TCFH (162.37 mg, 0.579 mmol, 1.5 equiv) in portions at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 4-(benzylamino)-N-(3-methanesulfonamidophenyl) thiophene-2-carboxamide (66.2 mg, 42.74%) as a light yellow solid. LCMS (ES, m/z): LCMS (ESI) [M+H] ⁺ : 402. ¹ H NMR (300 MHz, DMSO-d6) 8 10.21 (s, 1H), 9.75 (s, 1H), 7.65 (t, J = 2.1 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.42 - 7.20 (m, 6H), 6.92 (m J = 8.0, 2.2, 1.0 Hz, 1H), 6.35 - 6.12 (m, 2H), 4.23 (d, J = 6.0 Hz, 2H), 3.01 (s, 3H).

Example 156: N-(6-methanesulfonamidopyridin- 2-yl)-4-phenylthiophene-2- carboxamide

Step 1: To a stirred solution of 4-phenylthiophene-2-carboxylic acid (150 mg, 0.734 mmol), TCFH (309.381 mg, 1.101 mmol) and NMI (180.5 mg, 2.202 mmol) in ACN (10.00 mL) was added 6-bromopyridin-2-amine (126 mg, 0.734 mmol). Then the mixture was stirred for 8 hours at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (5-95%, acidic system) to afford N-(6-bromopyridin- 2-yl)-4-phenylthiophene-2-carboxamide (120 mg, 95%) as a yellow solid. LCMS (ESI) [M + H]+: 359.

Step 2: To a stirred solution of N-(6-bromopyridin-2-yl)-4-phenylthiophene-2-carboxamide (100 mg, 0.278 mmol), Cui (10 mg, 0.0556 mmol) and K2CO3 (115.092 mg, 0.834 mmol) in DMSO (5.0 mL) was added methanesulfonamide (132 mg, 1.39 mmol) at 0 °C. Then the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc/Petroleum ether (0-100%) to afford N-(6-methanesulfonamidopyridin- 2-yl)-4-phenylthiophene-2-carboxamide (26.8 mg, 98.887 %) as a yellow solid. LCMS (ESI) [M + H]+: 374. ¹ H NMR (400 MHz, DMSO- d6) 8 10.54 (d, J = 11.1 Hz, 2H), 8.61 (d, J = 1.5 Hz, 1H), 8.24 (d, J = 1.5 Hz, 1H), 7.80 -

7.69 (m, 4H), 7.48 (t, J = 7.7 Hz, 2H), 7.40 - 7.31 (m, 1H), 6.69 (dd, J = 7.3, 1.4 Hz, 1H), 3.52 (s, 3H).

Example 157 : N-(3-(methylsulfonoamidimidamido)phenyl)-4-phenylthiophene-2 - carboxamide

Step 1: To a stirred solution of methanesulfonamide (500 mg, 5.25 mmol) and EtsN (1.58 g, 15.7 mmol) in DCM (10 mL) was added TBS-C1 (869 mg, 5.77 mmol) dropwise at 0 °C.

Then the mixture was stirred for 1 h at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc/Petroleum ether (0-100%) to afford N-(tert-butyldimethylsilyl)methanesulfonamide (752 mg, 3.59 mmol) as a yellow solid. LCMS (ESI) [M+H] ⁺ : 210 Step 2: PPhs (962 mg, 3.67 mmol) and C2CI6 (868 mg, 3.67 mmol) were dissolved in dry CHC13 (10 mL) under argon atmosphere. The resulting solution was heated at 70 °C for 6 h, and the formation of a white suspension was observed. The reaction mixture was cooled to room temperature and EtsN (439 mg, 4.34 mmol) was added. After stirring for additional 10 min, the formation of a yellow suspension was observed. The reaction mixture was cooled to 0 °C and a solution of N-(tert-butyldimethylsilyl)methanesulfonamide (700 mg, 3.34 mmol) was added dropwise. The mixture was stirred for 30 min and a solution of IH-imidazole (249 mg, 3.67 mmol) and EtsN (371 mg, 3.67 mmol) in THF (3 mL) was added dropwise. After stirring at 0 °C for an additional 30 min, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, the obtained solids were extracted with hexanes (200 ml), and the hexane solution was evaporated under vacuum. The residue was dissolved in CH2CI2 (150 mL) and washed with H2O (3x200 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc/hexane (3:2) as eluent, Rf=0.50) to afford (tert- butyldimethylsilyl)[(lH-imidazol-l-yl)(methyl) oxo-Z/’-sulfanylidcnc] amine (390 mg, 1.50 mmol) as a yellow solid. LCMS (ESI) [M+H] ⁺ : 260.

Step 3: A solution of (tert-butyldimethylsilyl)[(lH-imidazol-l-yl)(methyl)oxo-X ⁶ - sulf any lidene] amine (370 mg, 1.42 mmol) in dry Et20 (10 mL) was cooled to 0 °C in an argon atmosphere, methyl trifluoromethanesulfonate (255 mg, 1.56 mmol) was added dropwise and the reaction mixture was stirred at 0 °C for 1 h. The obtained solids were filtered, washed with dry Et20 (2x200 mL), and dried under vacuum to afford l-{ [(tert- butyldimethylsilyl)imino](methyl)oxo-X ⁶ -sulfanyl}-3-methyl- lH-imidazol-3-ium (300 mg, 1.09 mmol) as white solid. LCMS (ESI) [M+H] ⁺ : 275

Step 4: To a stirred solution of benzene- 1,3-diamine (150 mg, 1.38 mmol), TCFH (502 mg, 1.79 mmol) and NMI (339 mg, 4.14 mmol) in ACN (3 mL) was added 4-phenylthiophene-2- carboxylic acid (308 mg, 1.51 mmol). Then the mixture was stirred for 1 h at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (5-95%, acidic system) to afford N- (3 -aminophenyl) - 4-phenylthiophene-2-carboxamide (247 mg, 0.840 mmol) as a yellow solid. LCMS (ESI) [M+H] ⁺ : 295

Step 5: A solution of l-{ [(tert-butyldimethylsilyl)imino](methyl)oxo-X ⁶ -sulfanyl}-3-methyl- lH-imidazol-3-ium (300 mg, 1.09 mmol) and N-(3-aminophenyl)-4-phenylthiophene-2- carboxamide (350 mg, 1.19 mmol) in ACN (10 mL) was stirred for 0.5 hours at 80 °C. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H2O (5-95%, acidic system) to afford N-{3-[N-(tert- butyldimethylsilyl)methanesulfonoimidamido]phenyl}-4-phenylt hiophene-2-carboxamide (178 mg, 0.366 mmol) as a white solid. LCMS (ESI) [M + H]+: 486

Step 6: HC1 (3.08 mmol) in dioxane (5 mL) was added portion- wise to a stirred solution of N- { 3-[N- (tert-butyldimethylsilyl)methanesulfonoimidamido]phenyl}-4-p henylthiophene-2- carboxamide (150 mg, 0.308 mmol) in dry dioxane (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for an additional 10 min and then it was allowed to warm to room temperature. The obtained mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0-100%) to afford N-(3-methanesulfonoimidamidophenyl)-4-phenylthiophene-2-carb oxamide (26.8 mg, 0.0713 mmol) as a white solid. LCMS (ESI) [M+H] ⁺ : 372. ’ H NMR (300 MHz, DMSO-d6) 8 10.12 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.17 (d, J = 1.4 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.50 - 7.23 (m, 5H), 7.14 (t, J = 8.0 Hz, 1H), 6.77 (d, J = 9.9 Hz, 3H), 3.14 (s, 3H).

Example 158: N-(3-methyl-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2 - carboxamide

Step 1: To a mixture of 4-phenylthiophene-2-carboxylic acid (110 mg, 0.538 mmol) and 3- methyl-5-nitroaniline (98.1 mg, 0.645 mmol) in CAN (2 mL) was added TCFH (225 mg, 0.807 mmol) and NMI (132 mg, 1.61 mmol) at room temperature for two hours. Then it was concentrated, the residue was purified by reverse phase flash chromatography eluting with 50% of acetonitrile in water (0.1% NH4HCO3) to afford N-(3-methyl-5-nitrophenyl)-4- phenylthiophene-2-carboxamide (112 mg, 61.2%) as a white solid. LCMS [M+H] ⁺ : 339. Step 2: To a mixture of N-(3-methyl-5-nitrophenyl)-4-phenylthiophene-2-carboxamide (110 mg, 0.325 mmol), Pd/C (13.0 mg, 0.325 mmol) was added MeOH (1 mL). The resulting mixture was stirred for 1 hours at room temperature under H2 atmosphere. The reaction mixture filter and washed with Methanol, then the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 35% of ethyl acetate in petroleum ether to afford N-(3-amino-5-methylphenyl)-4-phenylthiophene-2- carboxamide (82 mg, 81.7% ) as a light yellow solid. LCMS [M+H] ⁺ : 309.

Step 3: To a mixture of N-(3-amino-5-methylphenyl)-4-phenylthiophene-2-carboxamide (82 mg, 0.265 mmol) and methanesulfonyl methanesulfonate (55.3 mg, 0.318 mmol) in ACN (1 mL) was added TCFH (111 mg, 0.397 mmol) and NMI (65.1 mg, 0.795 mmol). The resulting mixture was stirred at room temperature for two hours. Then it was concentrated, the residue was purified by reverse phase flash chromatography eluting with 55% of acetonitrile in water (0.1% NH4HCO3) to afford N-(3-methanesulfonamido-5-methylphenyl)-4-phenylthiophene- 2-carboxamide (34.0 mg, 33.1% ) as a white solid. LCMS [M+H] ⁺ : 387. ’ H NMR (300 MHz, DMSO-d6) 8 10.26 (s, 1H), 9.76 (s, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.19 (d, J = 1.4 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.55 - 7.43 (m, 3H), 7.42 - 7.30 (m, 2H), 6.79 (d, J = 2.3 Hz, 1H), 3.01 (s, 3H), 2.30 (s, 3H).

Example 159: N-(3-formyl-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2 - carboxamide

Step 1: To a mixture of methyl 4-bromothiophene-2-carboxylate (30 g, 135 mmol), phenylboronic acid (32.9 g, 270 mmol), Pd(dppf)Ch (11.0 g, 13.5 mmol) and K3PO4 (85.8 g, 405 mmol) was added dioxane (300 mL) and H2O (30 mL). The resulting mixture was stirred for 2 hours at 80 °C under N2 atmosphere. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% of ethyl acetate in petroleum ether to afford methyl 4-phenylthiophene-2-carboxylate (27.1 g, 124 mmol) as a light yellow solid.

Step 2: To a stirred solution of methyl 4-phenylthiophene-2-carboxylate (26.1 g, 119 mmol) in 260 mL of THF and 260 mL of water was added LiOH (24.9 g, 595 mmol). The resulting mixture was stirred overnight at room temperature. Then it was concentrated, and the pH value of the residue solution was adjusted to 3 with IM HC1 (aq). The product was precipitated from the solution. After filtration, obtained 4-phenylthiophene-2-carboxylic acid (24.4 g, 119 mmol) as a white solid.

Step 3: To a mixture of 4-phenylthiophene-2-carboxylic acid (10.1 g, 49.6 mmol) and N-(3- amino-5-bromophenyl) methanesulfonamide (11 g, 41.4 mmol) in ACN (110 mL ) was added TCFH (17.3 g, 62.1 mmol) and NMI (10.1 g, 124 mmol) at room temperature. The resulting mixture was stirred overnight, Then it was concentrated, the residue was purified by reverse phase flash chromatography eluting with 60% of acetonitrile in water (0.1 %FA) to afford N- (3-bromo-5-methanesulfonamidophenyl)-4-phenylthiophene-2-car boxamide ( 11.0519 g, 24.486 mmol) as a light yellow solid. LCMS (ESI) [M - H]“: 449. ¹ H NMR (300 MHz, DMSO-d6) 8 10.46 (s, 1H), 10.09 (s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 8.23 (d, J = 1.4 Hz, 1H), 7.96 - 7.60 (m, 4H), 7.57 - 7.24 (m, 3H), 7.11 (t, J = 1.9 Hz, 1H), 3.08 (s, 3H).

Step 4: A solution of N-(3-bromo-5-methanesulfonamidophenyl)-4-phenylthiophene-2- carboxamide (100 mg, 0.222 mmol, 1 equiv) and HCOOH (20.39 mg, 0.444 mmol, 2 equiv) and Pd(OAc)2 (9.95 mg, 0.044 mmol, 0.2 equiv) and AC2O (45.24 mg, 0.444 mmol, 2 equiv) and HCOONa (75.33 mg, 1.110 mmol, 5 equiv) in EtsN (44.84 mg, 0.444 mmol, 2 equiv) was stirred overnight at 90 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 0% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in N-(3- formyl-5-methanesulfonamidophenyl)-4-phenylthiophene-2-carbo xamide (11.1 mg, 12.51%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H] ⁺ : 401. ’ H NMR (300 MHz, DMSO- d6) 8 10.59 (s, 1H), 9.96 (s, 1H), 8.53 (d, J = 1.5 Hz, 1H), 8.23 (d, J = 1.4 Hz, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.81 - 7.71 (m, 2H), 7.55 - 7.44 (m, 3H), 7.41 - 7.34 (m, 1H), 3.07 (d, J = 1.2 Hz, 3H).

Example 160: 5-[5-(3,3-difluoroazetidin-l-yl)pyridin-2-yl]-A-(3- methanesulfonamidophenyl)-l-methylpyrrole-3-carboxamide Step 1: To a mixture of 5-bromo-2-iodopyridine (5.1 g, 17.9 mmol), methyl l-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l/Z-pyrrole-3- carboxylate (5.67 g, 21.4 mmol), Pd(dppf)Ch (1.45 g,1.78 mmol) and KaPCL Q LS g, 53.6 mmol) was added 1,4-dioxane (60 ml) and H2O (6 ml). The resulting mixture was stirred for 2 hours at 70 °C under N2 atmosphere. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 15% of ethyl acetate in petroleum ether to afford methyl 5-(5- bromopyridin-2-yl)-l-methyl-l/Z-pyrrole-3-carboxylate (5.10 g, 96.5%) as a white solid. LCMS [M+H] ⁺ : 295

Step 2: To a mixture of methyl 5-(5-bromopyridin-2-yl)- 1 -methyl- 1 /7-pyrrolc-3-carboxylatc (3.1g, 10.5 mmol),3,3-difluoroazetidine hydrochloride (4.08 g, 31.5 mmol), CS2CO3 (10.28 g, 31.6 mmol) and PEPPSI IHept-Cl (510 mg, 525 pmol) was added dioxane (30mL ). The resulting mixture was stirred for 1 hours at 120 °C under N2 atmosphere. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 30% of ethyl acetate in petroleum ether to afford methyl 5-[5-(3,3-difluoroazetidin-l-yl)pyridin-2- yl]-l-methyl-l/Z-pyrrole-3-carboxylate (2.20 g, 68.3%) as a yellow solid. LCMS [M+H] ⁺ : 308

Step 3: A solution of methyl 5-[5-(3,3-difluoroazetidin-l-yl)pyridin-2-yl]-l-methylpyrrol e-3- carboxylate (140 mg, 0.456 mmol, 1 equiv) and A-(3-aminophenyl)methanesulfonamide (102 mg, 0.547 mmol, 1.2 equiv) in toluene (4 mL) was stirred for 10 min at 0 °C under nitrogen atmosphere. To the above mixture was added AIMcs (0.14 mL, 1.368 mmol, 3 equiv) dropwise over 1 min at 0 °C. The resulting mixture was stirred for additional 1 hour at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue (120 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*150 mm, 5pm; Mobile Phase A: Water(0.1% formic acid), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 21% B to 52% B in 7 min, 52% B; Wave Length: 254/220 nm; RTl(min): 7.20) to afford 5-[5-(3,3- difluoroazetidin-l-yl)pyridin-2-yl]-A-(3 -methanesulfonamidophenyl)- 1 -methyip yrrole-3- carboxamide (104.9 mg, 49.9% yield) as a white solid. LCMS (ESI) [M + H] ⁺ : 462.15 ’ H NMR (400 MHz, DMSO- ₆ ) 6 9.73 (s, 1H), 9.64 (s, 1H), 7.98 (d, J = 2.9 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.61 - 7.44 (m, 3H), 7.25 (t, J = 8.1 Hz, 1H), 7.14 - 6.98 (m, 2H), 6.95 - 6.82 (m, 1H), 4.39 (t, J = 12.3 Hz, 4H), 3.92 (s, 3H), 3.00 (s, 3H).

Example 161: 5-(3,5-difluoropyridin-2-yl)-2V- (3-fhioro-5-methanesulfonamidophenyl)- 1 -methyl- lH-pyrrole-3-carboxamide

Step 1: A solution of 2-bromo-3,5-difluoropyridine (1.5 g, 7.73 mmol), methyl l-methyl-5- (4,4,5,5-tetramethyl -1, 3, 2-dioxaborolan-2-yl)-lH-pyrrole-3 -carboxylate (2.04 g, 7.73 mmol), Pd(dppf)Ch (630 mg, 773 pmol) and K2CO3 (3.18 g, 23.1 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred for 1 hour at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (20-80% acetonitrile in water) to afford methyl 5-(3,5-difluoropyridin-2-yl)-l-methyl-lH-pyrrole-3-carboxyla te (1.20 g, 4.75 mmol) as white solid.

LCMS (ESI) [M+H] ⁺ : 253.00.

Step 2: A solution of methyl 5-(3,5-difluoropyridin-2-yl)-l-methyl-l TZ-pyrrole-3- carboxylate (150 mg, 594 pmol) and lithium hydroxide (113 mg, 4.75 mmol) in H2O (0.4 mL) and EtOH (2 mL) was stirred for Ih at room temperature under nitrogen atmosphere. The mixture was acidified to pH 7 with HC1 (aq.). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 5-(3,5-difluoropyridin-2-yl)-l- methyl-lH-pyrrole-3-carboxylic acid (120 mg, 503 pmol) as a white solid. LCMS (ESI) [M+H] ⁺ : 239.00. Step 3: A solution of 5-(3,5-difluoropyridin-2-yl)-l-methyl-l/Z-pyrrole-3-carboxyl ic acid (120 mg, 503 pmol), A-(3-amino-5-fluorophenyl)methanesulfonamide (102 mg, 503 pmol), TCFH (140 mg, 503 pmol) and NMI (41 mg, 503 pmol) in ACN (2 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-(3,5- difluoropyridin-2-yl)-A- (3-fl uoro-5-methanesul fonamidophenyl)-l -methyl- l /7-pyrrolc-3- carboxamide (135.6 mg, 321 pmol) as a light yellow solid. LCMS (ESI) [M+H] ⁺ : 407.10. ’ H NMR (400 MHz, DMSO-7 ₆ ) 6 9.74 (d, J = 8.4 Hz, 2H), 8.59 (d, J = 2.4 Hz, 1H), 8.08 (ddd, J = 11.2, 8.9, 2.5 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.69 (t, J = 2.1 Hz, 1H), 7.52 (dd, J = 7.8, 2.2 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.21 (dd, 7 = 3.7, 1.9 Hz, 1H), 6.92 - 6.85 (m, 1H), 3.88 (s, 3H), 3.00 (s, 3H).

ASSAYS

Compounds of the disclosure were assessed for their ability to inhibit DHX9 activity. The inhibitory properties of the compounds of the disclosure described herein can be evidenced by testing in any one of the following assays.

1. Biochemical Assay

Materials and methods

Recombinant DHX9 - Human recombinant DHX9 protein was custom ordered from Viva.

RNA substrate - Oligos for double-stranded RNA substrate were custom ordered from IDT Technologies. (Oligo 1 - GCCUGGUCCCUGUCCUUGUUAUUUUCCUUGGUUAAUU (SEQ ID NO:1). Oligo2 - GAAUUAACCAAGGAAAAUAACAAGGACAGGGACCAGG (SEQ ID NO:2)). Each oligo was reconstituted in RNAse/DNAse-free water to achieve a lOOuM solution. The two oligo solutions were mixed in 1:1 ratio and and annealed by heating at 70 °C for 5 minutes and cooling gradually to room temperature on the benchtop. Chemicals and Assay Components - Aurintricarboxylic Acid and dimethyl sulfoxide were purchased from Sigma-Aldrich (St. Louis, MO). White 384-well assay plates (Catalog #781075) were obtained from Greiner Bio-One (Frickenhausen, Germany). The ADP-Glo™ kinase assay kit from Promega Corporation is composed of ADP-Glo reagent, kinase detection reagent (made by mixing kinase detection buffer with a lyophilized kinase detection substrate), Ultra Pure ATP and ADP.

ATPase Assay

DHX9 ATPase assay was performed in small-volume, nonbinding, 384-well white plates at a final volume of 10 pL/well. Test compounds (10 mM solution in DMSO; 100 nL/well) were serially diluted on Bravo (Agilent, Santa Clara, CA) and dispensed into wells of columns 3-22 of the plates using an Echo 555 acoustic dispenser (Labcyte, Sunnyvale, CA). lOOnL of Aurintricarboxylic acid was dispensed into low control wells and 100 nL of DMSO was dispensed into high control wells. Then, a Multidrop Combi Reagent Dispenser (Thermo Fisher Scientific, Waltham, MA) was used to add a solution of DHX9 (1.25 nM, 5 pL/well) in assay buffer (40 mM HEPES [pH 7.5], 0.01% Tween 20, 0.01%BSA, 1 mM DTT, 5 mM MgCh, 0.004U/ml RNAseOUT). The reaction was initiated by the addition of 5 pL of substrate solution (30 nM double-stranded RNA substrate, 10 pM Ultra Pure ATP in assay buffer) into the wells. The plates were incubated at room temperature for 1 h. After the indicated incubation times, 10 pL ADP-Glo reagent was added to the reactions and the plate was incubated at room temperature for 40 min. Then, 20 pL of kinase detection reagent was added and after an incubation time of 40 min, luminescence was recorded on Envision plate reader (Perkin-Elmer, Billerica, MA).

Data Processing and Analysis

All data was analyzed by Accent Therapeutics internal data analysis software developed by Scigilian (Montreal, Canada). The percentage inhibition was calculated based on the high control (DMSO) as 0% inhibition, and low control (lOpM Aurintricarboxylic acid) control as 100% inhibition and used for the calculation of IC50 and IP (inflection point) values by fitting the dose-response curves to a four-parameter logistic model. Assay results reported IP values instead of IC50 values since several compounds did not reach 100% inhibition at higher compound concentrations. 2. DHX9 Cellular Proliferation Assay

The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.

The following cell lines were obtained from ATCC: HCT116 (CCL-247) and Colo205 (CCL-222). HCT116 cells were grown and assayed in McCoy’s 5a growth media supplemented with 10%FBS, and Colo205 cells were grown in RPMI 1640 media supplemented with 10%FBS.

The cells are plated at pre-determined cell densities in 384-well solid white cell culture plates and incubated overnight in 37°C at 5% CO2. In a separate plate, reference and test compounds were prepared in DMSO stock solution and serially diluted 3 -fold for 10 points. Compound (0.1% final DMSO concentration) was transferred to the cell plate in designated wells, and incubated 37°C at 5% CO2for 120 hours. CellTiter-Glo reagent was prepared fresh according to manufacturer’s (Promega) directions and added to each well. The plate is then shaken at 300rpm for 10 minutes at RT, and then read on an Envision plate reader using a Luminescence protocol.

Data analysis was performed by normalizing the raw data (raw luminescence units or Rsampie) to an average of the positive control values for wells containing culture media only (100% cell death or RLC) and the negative control values for 0.1% DMSO (0% cell death or RHC). An IC50 was calculated using a 4-parameter logistic nonlinear regression model in Scigilian Analyzer or GraphPad Prism, constraining the top parameter to 100 and the bottom parameter to 0. ICso Fit formula = (A+((B-A)/(l+((x/C) ^A D)))) ... whereas A:Bottom; B:Top; CJC50; D: Slope

3. DHX9 circBRIPl Cellular Target Engagement SYBR Green Assay

Evaluation of the circular and linear format of BRIP1 mRNA in HCT116 cells by Quantitative Polymerase Chain Reaction (qPCR). Upon DHX9 inhibition circBRIPl levels are increased and linear BRIP1 mildly decreases or remains unchanged. HCT116 cells were obtained from ATCC (CCL-247) and were grown and assayed in McCoy’s 5a growth media supplemented with 10%FBS.

The cells are plated at pre-determined cell densities in 384-well cell culture plates and incubated overnight in 37°C at 5% CO2. In a separate plate, reference and test compounds were prepared in DMSO stock solution and serially diluted 3 -fold for 10 points. Compound (0.1% final DMSO concentration) was transferred to the cell plate in designated wells, and incubated 37°C at 5% CO2for 72 hours.

RNA is extracted from the cells using the SYBR Green Fast Advanced Cell-to-CT kit according to manufacturer’s (Invitrogen) protocol, and cDNA is reverse transcribed using the High Capacity RNA-to-cDNA Kit according to the manufacturer’s (Invitrogen) protocol. Using SYBR Green Master Mix and thermal cycler conditions for the QuantStudio Thermocycler, qPCR is carried out using the below custom primer sequences:

• BRIP1 -Circular-Forward (TCT GTG TGC CAG ACT GTG AG (SEQ ID NO:3))

• BRIP1 -Circular-Reverse (ACA CCA AGT TCT GAC GAA AAG G (SEQ ID NO:4))

• BRIP1 -Linear-Forward (GTC CAT CCT GAG GTA GTC GG (SEQ ID NO:5))

• BRIP1 -Linear-Reverse (TTC CCC AGG CTG ACA AGT TC (SEQ ID NO:6))

• GAPDH-Forward (GTCTCCTCTGACTTCAACAGCG (SEQ ID NO:7))

• GAPDH-Reverse (ACCACCCTGTTGCTGTAGCCAA (SEQ ID NO:8))

Note: Forward and Reverse primers are combined per gene, and each sample has to be run on a separate plate for each gene.

Data analysis was performed by using the QuantStudio Thermocycler software to determine threshold Ct values. ACt for circBRIPl or linBRIPl is calculated by normalizing the target gene Ct to the GAPDH housekeeping gene Ct for each sample. The inhibition activity is calculated by the following formula, whereas:

• ACts: Mean of Ct(target gene) - Mean of Ct( GAPDH) for each sample

• ACtc: Mean of Ct( target gene) - Mean of Ct(GAPDH) for DMSO control. An EC50 was then calculated using a 4-parameter logistic nonlinear regression model in Scigilian Analyzer or GraphPad Prism, floating both the top and bottom parameters. ECso Fit formula = (A+((B-A)/(l+((x/C) ^A D)))) ... whereas A:Bottom; B:Top; CJC50; D: Slope

4. DHX9 circBRIPl Cellular Target Engagement TaqMan Multiplex Assay:

Evaluation of the circular and linear format of BRIP1 mRNA in HCT116 cells by Quantitative Polymerase Chain Reaction (qPCR). Upon DHX9 inhibition circBRIPl levels are increased and linear BRIP1 mildly decreases or remains unchanged.

HCT116 cells were obtained from ATCC (CCL-247) and were grown and assayed in McCoy’s 5a growth media supplemented with 10% FBS.

The cells are plated at pre-determined cell densities in 384-well cell culture plates and incubated overnight in 37 °C at 5% CO2. In a separate plate, reference and test compounds were prepared in DMSO stock solution and serially diluted 3 -fold for 10 points. Compound (0.1% final DMSO concentration) was transferred to the cell plate in designated wells, and incubated 37 °C at 5% CO2 for 72 hours.

RNA is extracted from the cells using the TaqMan Gene Expression Cells-to-CT™ kit according to manufacturer’s (Invitrogen) protocol, and cDNA is reverse transcribed using the High Capacity RNA-to-cDNA Kit according to the manufacturer’s (Invitrogen) protocol. Using TaqMan Multiplex Mastermix and thermal cycler conditions for the QuantStudio Thermocycler, qPCR is carried out using TaqMan Gene Expression Assay with VIC Dye for Linear BRIP1 (Assay ID: Hs00908156_ml), TaqMan GAPDH primer limited assay with JUN dye/QSY probe, and the below custom TaqMan Gene Expression Assay with FAM Dye for circBRIPl:

• Forward Primer: GTGAGCCAAGGAATTTTGTGTTT (SEQ ID NO:9)

• Reverse Primer: GGTCTGAACTTTGCCATTAATATCTG (SEQ ID NO: 10)

• Probe: CCATCTTACAAGGCCTTT (SEQ ID NO: 11) Note: All target genes can be combined in one well per sample.

Data analysis was performed by using the QuantStudio Thermocycler software to determine threshold Ct values. ACt for circBRIPl or linBRIPl is calculated by normalizing the target gene Ct to the GAPDH housekeeping gene Ct for each sample. The inhibition activity is calculated by the following formula, whereas:

• ACts: Mean of Ct(target gene) - Mean of Ct( GAPDH) for each sample • ACtc: Mean of Ct( target gene) - Mean of Ct(GAPDH) for DMSO control.

2 ACts

%Inhibition = 100% x

2 ACtc

An EC50 was then calculated using a 4-parameter logistic nonlinear regression model in Scigilian Analyzer or GraphPad Prism, floating both the top and bottom parameters. IC50 Fit formula = (A+((B-A)/(l+((x/C) ^A D)))) ... whereas A:Bottom; B:Top; C:IC50; D: Slope

5. DHX9 Cellular Proliferation Assay

The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.

The following cell lines were obtained from ATCC: LS411N (CRL-2159) and NCI- H747 (CCL-252). LS41 IN and NCI-H747 cells were grown in RPMI-1640 media supplemented with 10%FBS. The cells are plated at pre-determined cell densities in 384-well solid white cell culture plates and incubated overnight in 37 °C at 5% CO2. In a separate plate, reference and test compounds were prepared in DMSO stock solution and serially diluted 3-fold for 10 points. Compound (0.1% final DMSO concentration) was transferred to the cell plate in designated wells, and incubated 37 °C at 5% CO2 for 120 hours. CellTiter- Glo reagent was prepared fresh according to manufacturer’s (Promega) directions and added to each well. The plate is then shaken at 300rpm for 10 minutes at RT, and then read on an Envision plate reader using a Luminescence protocol. Data analysis was performed by normalizing the raw data (raw luminescence units or RSample) to an average of the positive control values for wells containing culture media only (100% cell death or RLC) and the negative control values for 0.1% DMSO (0% cell death or RHC). An IC50 was calculated using a 4-parameter logistic nonlinear regression model in Scigilian Analyzer or GraphPad Prism, constraining the top parameter to 100 and the bottom parameter to 0.

ICso Fit formula = (A+((B-A)/(l+((x/C) ^A D)))) ... whereas A:Bottom; B:Top; CJC50;

D: Slope DATA FOR EXAMPLES * Compounds of examples 160 and 161 were tested using TaqMan Multiplex Assay; the rest of the compounds were tested using SYBR Green Assay.