Modulators of cystic fibrosis transmembrane conductance regulator

The application is a national stage application under 35 U.S.C. § 371 of international application number PCT/US2017/025381, filed Mar. 31, 2017, which designated the U.S. and claims the benefit of priority under 35 U.S.C. § 119 to U.S. provisional application Ser. No. 62/316,043, filed Mar. 31, 2016, the entire contents of which incorporated herein by reference.

The present disclosure features modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions, methods of treatment, and kits thereof.

Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.

In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea—perhaps explaining the relatively high frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 1000 disease causing mutations in the CF gene have been identified (http://cftr2.org). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as F508del. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.

The deletion of residue 508 in F508del prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies have shown, however, that the reduced numbers of F508del in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.

Accordingly, there is a need for novel treatments of CFTR mediated diseases.

The disclosure features a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is a C 6 -C 10 aryl ring; a C 3 -C 10 cycloalkyl ring; or a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; W is O, S, or NR; X is O or NR; Z is NR or C(R) 2 ; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 ; C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; p is 0, 1, 2, or 3; and

Provided that 1) when R 1 is adjacent to the C═W attached to Ring A, R 1 does not contain a ring moiety, 2) at least one R 1 is adjacent to the C═W attached to Ring A, and at least one R 1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; 3) when Ring A is phenyl or six-membered mono-heteroaryl wherein anywhere from 1 to 3 ring atoms are N, R 1 is not 4,5-dihydroisoxazole; 4) when Ring A is phenyl, R 1 is not

ureido, or aminocarbonyl; 5) when Ring A and the at least one R 1 is pyridine, R 1 (pyridine) is not further substituted by —CONHSO 2 —; and 6) when Ring A is pyridine or thiazole, and C═W wherein W is O in formula I is adjacent to the N on the pyridine or thiazole, R 1 which is adjacent to the N on the pyridine or on the thiazole is not

The present disclosure also features pharmaceutical compositions thereof, which may include additional agents, and methods of treating CFTR mediated diseases, such as cystic fibrosis, comprising administering compounds of formula I to a subject in need thereof. The present disclosure also features kits comprising compounds of formula I.

FIG. 1 discloses a list of CFTR mutations by name, protein name, and legacy name that in one aspect of the disclosure a patient may possess and be treatable by the compounds and compositions of the present disclosure.

As used herein, “CFTR” stands for cystic fibrosis transmembrane conductance regulator.

As used herein, “mutations” can refer to mutations in the CFTR gene or the CFTR protein. A “CFTR mutation” refers to a mutation in the CFTR gene, and a “CFTR mutation” refers to a mutation in the CFTR protein. A genetic defect or mutation, or a change in the nucleotides in a gene in general results in a mutation in the CFTR protein translated from that gene.

As used herein, a “F508del mutation” or “F508del” is a specific mutation within the CFTR protein. The mutation is a deletion of the three nucleotides that comprise the codon for amino acid phenylalanine at position 508, resulting in CFTR protein that lacks this phenylalanine residue.

The term “CFTR gating mutation” as used herein means a CFTR mutation that results in the production of a CFTR protein for which the predominant defect is a low channel open probability compared to normal CFTR (Van Goor, F., Hadida S. and Grootenhuis P., “Pharmacological Rescue of Mutant CFTR function for the Treatment of Cystic Fibrosis”, Top. Med. Chem. 3: 91-120 (2008)). Gating mutations include, but are not limited to, G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D.

As used herein, a patient who is “homozygous” for a particular mutation, e.g. F508del, has the same mutation on each allele.

As used herein, a patient who is “heterozygous” for a particular mutation, e.g. F508del, has this mutation on one allele, and a different mutation on the other allele.

As used herein, the term “modulator” refers to a compound that increases the activity of a biological compound such as a protein. For example, a CFTR modulator is a compound that increases the activity of CFTR. The increase in activity resulting from a CFTR modulator includes but is not limited to compounds that correct, potentiate, stabilize and/or amplify CFTR.

As used herein, the term “CFTR corrector” refers to a compound that increases the amount of functional CFTR protein to the cell surface, resulting in enhanced ion transport.

As used herein, the term “CFTR potentiator” refers to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport.

As used herein, the term “stabilize” or “stabilizer,” as in a CFTR stabilizer, results in an elongated presence of CFTR in the epithelial cell membrane.

As used herein, the term “amplify” or “amplifier,” as in a CFTR amplifier, enhances the effect of other CFTR modulators such as potentiators, correctors, or stabilizer.

As used herein, the term “active pharmaceutical ingredient” or “API” refers to a biologically active compound.

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.

The terms “effective dose” or “effective amount” are used interchangeably herein and refer to that amount that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF or lessening the severity of CF or a symptom of CF). The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

As used herein, the terms “treatment,” “treating,” and the like generally mean the improvement of CF or its symptoms or lessening the severity of CF or its symptoms in a subject. “Treatment,” as used herein, includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and/or liver function, reduced cases of chest infections, and/or reduced instances of coughing or shortness of breath. Improvements in or lessening the severity of any of these conditions can be readily assessed according to standard methods and techniques known in the art.

As used herein, the term “in combination with” when referring to two or more compounds or agents means that the order of administration includes the compounds or agents being administered prior to, concurrent with, or subsequent to each other to the patient.

As used herein, the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”

As described herein, compounds within the compositions of the disclosure can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the disclosure (such as the compounds listed in Table 1). As described herein in formulas I to IIa-ii-2, the variables R 1 to R 3 in formulas I to IIa-ii-2 encompass specific groups, such as, for example, alkyl, alkenyl, alkynyl, alkoxy, heteroaryl, heterocyclic, cycloalkyl, and aryl, etc. Unless otherwise noted, each of the specific groups for the variables R 1 to R 3 can be optionally substituted with one or more groups selected from halo, phospho, OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fluoroalkyl, alkyl, alkenyl, alkynyl, nitro, CN, hydroxyl, and (C 1 -C 9 alkylene)-E wherein up to 4 CH 2 units are independently replaced with O, S, SO 2 , SO, CO, NH, N-alkyl, N-alkenyl, or N-alkynyl, and E is H, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, CN, or CF 3 , further wherein each of the aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with one or more group selected from halo, alkyl, amino, CN, alkenyl, alkynyl, and alkoxy.

In some embodiments, each of the specific groups for the variables R 1 to R 3 can be optionally substituted with one or more groups selected from halo, phospho, OH, C 3 -C 6 cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, nitro, CN, hydroxyl, and (C 1 -C 9 alkylene)-E wherein up to 4 CH 2 units are independently replaced with O, S, SO 2 , SO, CO, NH, N—C 1 -C 4 alkyl, N—C 2 -C 4 alkenyl, or N—C 2 -C 4 alkynyl, and wherein E is H, phenyl, C 3 -C 6 cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, C 1 -C 6 alkoxy, CN, or CF 3 , further wherein each of the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with one or more group selected from halo, C 1 -C 6 alkyl, amino, CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkoxy.

As used herein, the phrase “formulas I to IIa-ii-2” includes any one of formula I, I-i, Ia, Ia-i, Ia-i-1, Ia-i-2, Ia-ii, Ia-ii-1, Ia-ii-2, II, II-i, IIa, IIa-i, IIa-i-1, IIa-i-2, IIa-ii, IIa-ii-1, and IIa-ii-2, or any combinations thereof.

In some embodiments, each of the specific groups for the variables R 1 to R 3 can be optionally substituted with one or more groups selected from halo, C 3 -C 6 cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CN, hydroxyl, and (C 1 -C 9 alkylene)-E wherein up to 4 CH 2 units are independently replaced with O, S, SO 2 , SO, CO, NH, N—C 1 -C 4 alkyl, N—C 2 -C 4 alkenyl, or N—C 2 -C 4 alkynyl, and wherein E is H, phenyl, C 3 -C 6 cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, C 1 -C 6 alkoxy, CN, or CF 3 , further wherein each of the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with one or more group selected from halo, C 1 -C 4 alkyl, —NH 2 , CN, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, and C 1 -C 4 alkoxy.

In some embodiments, each of the specific groups for the variables R 1 to R 3 can be optionally substituted with one or more groups selected from halo, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CN, hydroxyl, and (C 1 -C 9 alkylene)-E wherein up to 4 CH 2 units are independently replaced with O, S, SO 2 , SO, CO, NH, N—C 1 -C 4 alkyl, N—C 2 -C 4 alkenyl, or N—C 2 -C 4 alkynyl, and wherein E is H, phenyl, C 3 -C 6 cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, C 1 -C 6 alkoxy, CN, or CF 3 , further wherein each of the phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with one or more group selected from halo, C 1 -C 4 alkyl, —NH 2 , CN, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, and C 1 -C 4 alkoxy.

In some embodiments, each of the specific groups for the variables R 1 to R 3 can be optionally substituted with one or more groups selected from halo, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CN, hydroxyl, and (C 1 -C 9 alkylene)-E wherein up to 4 CH 2 units are independently replaced with O, S, SO 2 , SO, CO, NH, N—C 1 -C 4 alkyl, N—C 2 -C 4 alkenyl, or N—C 2 -C 4 alkynyl, and wherein E is H, CN, or CF 3 .

In some embodiments, each of the specific groups for the variables R 1 to R 3 can be optionally substituted with one or more groups selected from halo, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CN, hydroxyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl), and C 1 -C 6 alkoxy.

In some embodiments, each of the specific groups for the variables R 1 to R 3 can be optionally substituted with one or more groups selected from halo, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CN, hydroxyl, and C 1 -C 6 alkoxy.

In some embodiments, each of the specific groups for the variables R 1 to R 3 can be optionally substituted with one or more groups selected from halo, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkoxy.

In some embodiments, each of the specific groups for the variables R 1 and R 3 can be optionally substituted with one or more groups selected from halo, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkoxy.

As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atom(s) to which they are bound.

As disclosed herein, substituents or variables (such as R 1 to R 3 in formula I to IIa-ii-2) can be selected from more than one specific group. To the extent that one specific group for a variable may include or overlap with another specific group for the same variable, the narrower specific group is provisoed out from the broader specific group. In other words, double inclusion cannot exist.

In general, the term “substituted,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below 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 one of ordinary skill in the art will recognize, combinations of substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds.

The phrase “up to”, as used herein, refers to zero or any integer number that is equal or less than the number following the phrase. For example, “up to 3” means any one of 0, 1, 2, and 3.

The terms “about” and “approximately”, when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

The term “adjacent” as used herein refers to positions on the ring wherein the two ring atoms are bonded to each other. Two ring atoms with an intervening ring atom are not considered adjacent even when that intervening atom does not allow substitution due to valency.

The term “aliphatic”, “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups.

The term “spiro” as used herein, means a two-ring system wherein both rings share only one common atom.

The term “cycloaliphatic” or “cycloalkyl” mean a monocyclic, bicyclic (fused or spiro), tricyclic (fused or spiro), or propellane hydrocarbon that has a single point of attachment to the rest of the molecule, and that is completely saturated or contains one or more units of unsaturation, but none of the individual rings in the monocyclic, bicyclic, or tricyclic hydrocarbon is aromatic. The single point of attachment can be on the saturated or unsaturated carbon. In some embodiments, “cycloaliphatic” or “cycloalkyl” refers to a monocyclic C 3 -C 8 hydrocarbon or bicyclic C 8 -C 12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but none of the individual ring in the monocyclic C 3 -C 8 hydrocarbon or fused bicyclic C 8 -C 12 hydrocarbon is aromatic, and that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.

As used herein, an “alkyl” group refers to a saturated hydrocarbon group containing 1-20 (e.g., 1-6 or 1-12) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl.

As used herein, an “alkenyl” group refers to a hydrocarbon group that contains 2-20 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. The point of attachment can be on a saturated carbon or unsaturated carbon. Examples of an alkenyl group include, but are not limited to allyl, isoprenyl, 2-butenyl, and 2-hexenyl.

As used herein, an “alkynyl” group refers to a hydrocarbon group that contains 2-20 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has at least one triple bond. An alkynyl group can be straight or branched. The point of attachment can be on a saturated carbon or unsaturated carbon. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl.

As used herein, an “alkoxy” group refers to —O-alkyl, O-alkenyl, or O-alknyl, wherein alkyl, alkenyl, and alkynyl are as defined above.

As used herein, “fluoroalkyl” or “fluoroalkoxy” refers to alkyl or alkoxy wherein one or more hydrogen is substituted with a fluoro.

As used herein, an “amino” refers to NH 2 which is optionally substituted with one or two groups independently selected from alkyl, cycloalkyl, and heterocycloalkyl.

The term “electron withdrawing group”, as used herein means an atom or a group that is electronegative relative to hydrogen. See, e.g., “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,” Jerry March, 4 th Ed., John Wiley & Sons (1992), e.g., pp. 14-16, 18-19, etc. Exemplary such substituents include halo such as Cl, Br, or F, CN, COOH, CF 3 , etc.

Unless otherwise specified, the term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, “heterocycloalkyl” or “heterocyclic” as used herein means monocyclic, bicyclic (fused or spiro), tricyclic (fused or spiro), or propellane ring systems in which one or more ring atoms in one or more ring members is an independently selected heteroatom and none of the individual rings in the system is aromatic. Heterocyclic rings can be saturated or can contain one or more unsaturated bonds. In some embodiments, the “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, “heterocycloalkyl” or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains 3 to 7 ring members. The point of attachment can be on the carbon or heteroatom.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation but is not aromatic.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic (fused), and tricyclic (fused or spiro) hydrocarbon ring systems having a total of five to fourteen ring carbon atoms, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring carbon atoms. The term “aryl” may be used interchangeably with the term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic (fused), and tricyclic (fused or spiro) ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

The term “alkylene” refers to a straight or branched hydrocarbon chain that may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.

The term “prodrug,” as used herein, represents a compound that is transformed in vivo into a compound according to any one of the formulae listed herein. Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue. Prodrugs of the compounds of the disclosure may be, for example, amides. Amides that may be utilized as prodrugs in the present disclosure are phenyl amides, aliphatic (C 1 -C 24 ) amides, acyloxymethyl amides, ureas, carbamates, and amino acid amides. For example, a compound of the disclosure that contains an NH group may be acylated at this position in its prodrug form. Other prodrug forms include esters, such as, for example phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro - drugs as Novel Delivery Systems , Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press, 1987, and Judkins et al., Synthetic Communications 26(23):4351-4367, 1996, each of which is incorporated in its entirety herein by reference. In some embodiments, the present disclosure features a prodrug of any one of the formulas or compounds listed herein.

The term “isosteres” or “bioisosteres,” as used herein, refers to compounds resulting from the exchange of an atom or group of atoms to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. For example, an isosteric replacement for a carboxylic acid is CONHSO 2 (alkyl or aryl)) such as CONHSO 2 Me. A further discussion of isosterism is provided in R. Silverman, The Organic Chemistry of Drug Design and Drug Action , second edition, Elsevier Academic Press, 2004, incorporated in its entirety herein by reference. In some embodiments, the present disclosure features a isostere of any one of the formulas or compounds listed herein.

In the formulas and drawings, a line transversing a ring and bonded to an R group such as, for example, R 1 or R 2 in the following formula

means that the R group can be bonded to any carbon, or if applicable, heteroatom such as N, of that ring, including any fused ring, as valency allows.

Within a term definition as, for example, R 1 to R 3 when a CH 2 unit or, interchangeably, a methylene unit may be replaced by O, CO, S, SO, SO 2 , or NR; it is meant to include any CH 2 unit, including a CH 2 within a terminal methyl or methylene group. For example, —CH 2 CH 2 CH 2 SH is within the definition of C 1 -C 9 alkylene-R 3 wherein up to four CH 2 units are independently replaced by O, CO, S, SO, SO 2 , or NR because the CH 2 unit of the terminal methyl group has been replaced by S. The analogous applies to such definitions as —CH 2 CH 2 OH, —CH 2 CH 2 CN, or —CH 2 CH 2 NH 2 .

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Where the enantiomers of a racemic mixture have been separated, but the absolute chemistry has not yet been determined, the compound's structure is depicted with a wavy line.

Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Thus, included within the scope of the disclosure are tautomers of compounds of formulas I to IIa-ii-2.

To the extent that a definition in the present application differs from any definition in an application incorporated by reference, the definition in the present application supercedes.

CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

In patients with cystic fibrosis, mutations in endogenously expressed CFTR lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea-perhaps explaining the relatively high frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 1000 disease-causing mutations in the CF gene have been identified as reported by the scientific and medical literature. The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as F508del. This mutation occurs in approximately 70 percent of the cases of cystic fibrosis and is associated with a severe disease. A more complete list of identified mutations can be found at www.cftr2.org.

These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell. Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na + —K + -ATPase pump and Cl− channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl − channels, resulting in a vectorial transport. Arrangement of Na + /2Cl − /K + co-transporter, Na + —K + -ATPase pump and the basolateral membrane K + channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

Compounds of Formula I

Disclosed is a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is a C 6 -C 10 aryl ring; a C 3 -C 10 cycloalkyl ring; or a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; W is O, S, or NR; X is O or NR; Z is NR or C(R) 2 ; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 ; C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; p is 0, 1, 2, or 3; and

Provided that 1) when R 1 is adjacent to the C═W attached to Ring A, R 1 does not contain a ring moiety, 2) at least one R 1 is adjacent to the C═W attached to Ring A, and at least one R 1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; 3) when Ring A is phenyl or six-membered mono-heteroaryl wherein anywhere from 1 to 3 ring atoms are N, R 1 is not 4,5-dihydroisoxazole; 4) when Ring A is phenyl, R 1 is not

ureido, or aminocarbonyl; 5) when Ring A and the at least one R 1 is pyridine, R 1 (pyridine) is not further substituted by —CONHSO 2 —; and 6) when Ring A is pyridine or thiazole, and C═W wherein W is O in formula I is adjacent to the N on the pyridine or thiazole, R 1 which is adjacent to the N on the pyridine or on the thiazole is not

In some embodiments, Ring A is a C 3 -C 10 cycloalkyl ring, such as cyclopentane, cyclopentene, cyclohexane, or cyclohexene. In some embodiments, Ring A is a C 6 -C 10 aryl ring, such as a phenyl, indane, 1,2,3,4-tetrahydronaphthalene, or naphthalene. In some embodiments, Ring A is a C3-C11 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR, such as pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, 1,2,3,4-tetrahydroquinoline, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole, thiophene, oxazole, pyrazine, triazole, thiazole, indazole, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, 1H-benzo[d]imidazole, imidazo[1,2-a]pyridine, or imidazole ring.

In some embodiments, Ring A is

wherein the wavy line indicates point of attachment of Ring A to the C═W.

In some embodiments, Ring B is a cycloalkyl ring, such as a cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In some embodiments, Ring B is a C 6 -C 10 aryl ring, such as a phenyl or naphthalene. In some embodiments, ring B is a heroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR, such as pyridyl, pyridine-2(1H)-one, pyrazole, indole, pyrrole, indoline, thiophene, dihydrobenzofuran, tetrahydrofuran, furan, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, 3-azabicyclo[3.1.0]hexane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, pyrrolidine, azetidine, piperidine, piperazine, imidazo[1,2-a]pyridine, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the group of (X═)S(═O) of formula I.

In some embodiments, X is O. In some embodiments, Z is NH.

In some embodiments, R 1 is independently halo, amino, OH, C 2 -C 6 alkenyl; C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH 2 O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O—, CH 3 OCH 2 CH(CH 3 )O—, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O—, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O—, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O—, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O—, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O—, CH 3 C≡CCH 2 CH 2 O—, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O—, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O—, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O—, (CH 3 CH 2 ) 2 CHO—, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH, or (CH 3 ) 3 C.

In some embodiments, R 1 is CH 3 , Cl, F, CN, CH 2 CH 3 , CH(CH 3 ) 2 , OCH 2 CH 2 OCH 2 CH 3 ,

In some embodiments, R 2 is halo, OH, CN, amino, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 2. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, W is O. In some embodiments, Z is NH. In some embodiments, X is O

In some embodiments, Ring A is

and n is 2. In some embodiments, Ring A is

and n is 2. In some embodiments, Ring A is

and at least one R 1 is phenyl. In some embodiments, Ring A is

and at least one R 1 is tert-butyl. In some embodiments, Ring A is

and at least one R 1 is pyridinyl. In some embodiments, Ring A is

one R 1 is phenyl, and one R 1 is alkenyl, amino, or C 1 -C 8 alkoxy or C 1 -C8 fluoroalkoxy. In some embodiments, Ring A is

and Ring B is

In some embodiments, Ring A is

and Ring B is

In some embodiments, Ring A is

Ring B is

one R 1 is phenyl, and one R 1 is alkenyl, amino, or C 1 -C8 alkoxy or C 1 -C8 fluoroalkoxy.

In some embodiments, in the compound of formula I, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments of formula I, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula I-i:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; X is O or NR; Z is NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; and p is 0, 1, 2, or 3.

In some embodiments, ring A is a pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole, oxazole, pyrazine, triazole, indazole, imidazo[1,2-a]pyridine, or imidazole ring.

In some embodiments, Ring A is

wherein the wavy line indicates point of attachment of Ring A to the carbonyl (CO).

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

In some embodiments, X is O. In some embodiments, Z is NH.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C6 alkyl, C 2 -C 6 alkenyl; C 2 -C 6 alkynyl, C 1 -C8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH, or (CH 3 ) 3 C.

In some embodiments, R 1 is CH 3 , Cl, F, CN, CH 2 CH 3 , CH(CH 3 ) 2 , OCH 2 CH 2 OCH 2 CH 3 ,

In some embodiments, R 2 is halo, CN, OH, amino, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 2. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula I-i, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, disclosed is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; X is O or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 ; C 1 -C 6 alkyl; C 1 -C6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; p is 0, 1, 2, or 3; and

Provided that 1) when R 1 is adjacent to the carbonyl attached to Ring A, R 1 does not contain a ring moiety, 2) at least one R 1 is adjacent to the C═W attached to Ring A, and at least one R 1 is C 1 -C6 alkyl or C 1 -C6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; 3) R 1 is not 4,5-dihydroisoxazole; and 4) when the at least one R 1 is pyridine, R 1 is not further substituted by —CONHSO 2 —.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the group of (X═)S(═O) of formula Ia.

In some embodiments, X is O.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C6 fluoroalkyl, CN, C 1 -C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH, or (CH 3 ) 3 C.

In some embodiments, R 1 is CH 3 , Cl, F, CN, CH 2 CH 3 , CH(CH 3 ) 2 , OCH 2 CH 2 OCH 2 CH 3 ,

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 2. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula Ia, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula Ia or a pharmaceutically acceptable salt thereof is a compound of formula Ia-i

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 C 2 -C 6 alkenyl; C 2 -C 6 C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 C 2 -C 6 alkenyl; C 2 -C 6 C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 1. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula Ia-i, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula Ia-i or a pharmaceutically acceptable salt thereof is a compound of formula Ia-i-1

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 ; C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 1. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula Ia-i-1, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula Ia-i-1 or a pharmaceutically acceptable salt thereof is a compound of formula Ia-i-2

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a pyridinyl; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 1. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula Ia-i-2, one or more hydrogen atoms may be replaced by a deuterium atom

In some embodiments, the compounds of formula Ia or a pharmaceutically acceptable salt thereof is a compound of formula Ia-ii

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

In some embodiments, R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1-1 is

In some embodiments, R 1 -2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula Ia-ii, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula Ia-ii or a pharmaceutically acceptable salt thereof is a compound of formula Ia-ii-1

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

In some embodiments, R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 5 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1-1 is

In some embodiments, R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula Ia-ii-1, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula Ia-ii-1 or a pharmaceutically acceptable salt thereof is a compound of formula Ia-ii-2

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a pyridinyl; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

In some embodiments, R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1-1 is

In some embodiments, R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula Ia-ii-2, one or more hydrogen atoms may be replaced by a deuterium atom.

In another embodiment, the present disclosure provides compounds of formulas I to IIa-ii-2 that contain isotope-labelled forms thereof. An isotope-labelled form of a compound of formulas I to IIa-ii-2 is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs in greater natural abundance. Examples of isotopes which are readily commercially available and which can be incorporated into a compound of formulas I to IIa-ii-2 by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively. A compound of formulas I to IIa-ii-2, a prodrug thereof, or a pharmaceutically acceptable salt of either which contains one or more of the above-mentioned isotopes and/or other iso-topes of other atoms is intended to be part of the present disclosure. An isotope-labelled compound of formulas I to IIa-ii-2 can be used in a number of beneficial ways. For example, an isotope-labelled compound of formula I to IIa-ii-2 into which, for example, a radioisotope, such as 3 H or 14 C, has been incorporated is suitable for medicament and/or substrate tissue distribution assays. These radioisotopes, i.e. tritium ( 3 H) and carbon-14 ( 14 C), are particularly preferred owing to simple preparation and excellent detectability. Incorporation of heavier isotopes, for example deuterium ( 2 H), into a compound of formulas I to IIa-ii-2 has therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present disclosure. An isotope-labelled compound of formulas I to IIa-ii-2 can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

Deuterium ( 2 H) can also be incorporated into a compound of formulas I to IIa-ii-2 for the purpose in order to manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of k M /k D =2-7 are typical. If this rate difference is successfully applied to a compound of formulas I to IIa-ii-2 that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development , Ann. Rep. Med. Chem. 2011, 46, 403-417, incorporated in its entirety herein by reference.

The concentration of the isotope(s) (e.g., deuterium) incorporated into the isotope-labelled compounds of the invention may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In some embodiments, if a substituent in a compound of the invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

In some embodiments, the isotope-labelled compounds of the invention are deuterium ( 2 H)-labelled compounds. In some specific embodiments, the isotope-labelled compounds of Formula I to IIa-ii-2 or pharmaceutically acceptable salts thereof are deuterium ( 2 H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium.

When discovering and developing therapeutic agents, the person skilled in the art attempts to improve pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available provide valuable information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of formulas I to IIa-ii-2 with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profiles of compounds of formulas I to IIa-ii-2 are thereby obtained, and can be expressed quantitatively in terms of increases in the in vivo half-life (t 1/2 ), concentration at maximum therapeutic effect (C max ), area under the dose response curve (AUC), and bioavailability; and in terms of reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of formulas I to IIa-ii-2 which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favourable and accurate determination of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of formulas I to IIa-ii-2 can also be used to achieve a favorable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange may be found, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993.

In some embodiments, the compound of formula I is selected from Table 1:

In some embodiments, the compound of formula I is a pharmaceutical salt of a compound selected from Table 1.

In some embodiments, the compound of formula I is selected from the group consisting of Compounds 1, 16, 17, 31, 42, 61, 63, 64, 66, 67, 69, 74, and 75:

In some embodiments, the compound of formula I is a pharmaceutical salt of a compound selected from the group consisting of Compounds 1, 16, 17, 31, 42, 61, 63, 64, 66, 67, 69, 74, and 75.

In some embodiments, the compound of formula I is selected from the group consisting of Compounds 85 and 86:

In some embodiments, the compound of formula I is a pharmaceutical salt of a compound selected from the group consisting of Compounds 85 and 86.

Disclosed is a method of treating cystic fibrosis in a patient comprising administering to the patient in need thereof an effective amount of

1) a compound of formula II or a pharmaceutically acceptable salt thereof, or

2) a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula II or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

Ring A is a C 6 -C 10 aryl ring; C 3 -C 10 cycloalkyl ring; or a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; W is O, S, or NR; X is O or NR; Z is NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; p is 0, 1, 2, or 3; and

Provided that 1) when R 1 is adjacent to C═W attached to Ring A, R 1 does not contain a ring moiety, and 2) at least one R 1 is adjacent to the C═W attached to Ring A.

In some embodiments, Ring A is a C 3 -C 10 cycloalkyl ring, such as cyclopentane, cyclopentene, cyclohexane, or cyclohexene. In some embodiments, Ring A is a C 6 -C 10 aryl ring, such as a phenyl, indane, 1,2,3,4-tetrahydronaphthalene, or naphthalene. In some embodiments, Ring A is a C 3 -C 11 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR, such as pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, 1,2,3,4-tetrahydroquinoline, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole, thiophene, oxazole, pyrazine, triazole, thiazole, indazole, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, 1H-benzo[d]imidazole, imidazo[1,2-a]pyridine, or imidazole ring.

In some embodiments, Ring A is

wherein the wavy line indicates point of attachment of Ring A to C═W.

In some embodiments, Ring B is a cycloalkyl ring, such as a cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In some embodiments, Ring B is a C 6 -C 10 aryl ring, such as a phenyl or naphthalene. In some embodiments, ring B is a heroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR, such as pyridyl, pyridine-2(1H)-one, pyrazole, indole, pyrrole, indoline, thiophene, dihydrobenzofuran, tetrahydrofuran, furan, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, 3-azabicyclo[3.1.0]hexane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, pyrrolidine, azetidine, piperidine, piperazine, imidazo[1,2-a]pyridine, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the (X═)S(═O) group of formula II.

In some embodiments, X is O. In some embodiments, Z is NH.

In some embodiments, R 1 is independently halo, amino, OH, C 2 -C 6 alkenyl; C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH, or (CH 3 ) 3 C.

In some embodiments, R 1 is CH 3 , Cl, F, CN, CH 2 CH 3 , CH(CH 3 ) 2 , OCH 2 CH 2 OCH 2 CH 3 ,

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 2. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, W is O. In some embodiments, Z is NH. In some embodiments, X is O

In some embodiments, Ring A is

and n is 2. In some embodiments, Ring A is

and n is 2. In some embodiments, Ring A is

and at least one R 1 is phenyl. In some embodiments, Ring A is

and at least one R 1 is tert-butyl. In some embodiments, Ring A is

and at least one R 1 is pyridinyl. In some embodiments, Ring A is

one R 1 is phenyl, and one R 1 is alkenyl, amino, or C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy. In some embodiments, Ring A is

and Ring B is

In some embodiments, Ring A is

and Ring B is

In some embodiments, Ring A is

Ring B is

one R 1 is phenyl, and one R 1 is alkenyl, amino, or C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy.

In some embodiments, in the compound of formula II, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments of formula II, the compound of formula II or a pharmaceutically acceptable salt thereof is a compound of formula II-i:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; X is O or NR; Z is NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; and p is 0, 1, 2, or 3.

In some embodiments, ring A is a pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole, oxazole, pyrazine, triazole, indazole, imidazo[1,2-a]pyridine, or imidazole ring.

In some embodiments, Ring A is

wherein the wavy line indicates point of attachment of Ring A to the carbonyl (CO).

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

In some embodiments, X is O. In some embodiments, Z is NH.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl; C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH, or (CH 3 ) 3 C.

In some embodiments, R 1 is CH 3 , Cl, F, CN, CH 2 CH 3 , CH(CH 3 ) 2 , OCH 2 CH 2 OCH 2 CH 3 ,

In some embodiments, R 2 is halo, CN, OH, amino, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 2. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula II-i, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compound of formula II or a pharmaceutically acceptable salt thereof is a compound of formula IIa:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; X is O or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; p is 0, 1, 2, or 3; and

Provided that 1) when R 1 is adjacent to the carbonyl attached to Ring A, R 1 does not contain a ring moiety, 2) at least one R 1 is adjacent to the carbonyl attached to Ring A, and 3) at least one R 1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of

In some embodiments, X is O.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH, or (CH 3 ) 3 C.

In some embodiments, R 1 is CH 3 , Cl, F, CN, CH 2 CH 3 , CH(CH 3 ) 2 , OCH 2 CH 2 OCH 2 CH 3 ,

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 , or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH, CH 2 H, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 2. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula IIa, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula IIa or a pharmaceutically acceptable salt thereof is a compound of formula IIa-i

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 1. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula IIa-i, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula IIa-i or a pharmaceutically acceptable salt thereof is a compound of formula IIa-i-1

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 1. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula IIa-i-1, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula IIa-i-1 or a pharmaceutically acceptable salt thereof is a compound of formula IIa-i-2

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a pyridinyl; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

In some embodiments, R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, n is 1. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula IIa-i-2, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula IIa or a pharmaceutically acceptable salt thereof is a compound of formula IIa-ii

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

In some embodiments, R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1-1 is

In some embodiments, R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula IIa-ii, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula IIa-ii or a pharmaceutically acceptable salt thereof is a compound of formula IIa-ii-1

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

In some embodiments, R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1-1 is

In some embodiments, R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula IIa-ii-1, one or more hydrogen atoms may be replaced by a deuterium atom.

In some embodiments, the compounds of formula IIa-ii-1 or a pharmaceutically acceptable salt thereof is a compound of formula IIa-ii-2

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a pyridinyl; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

In some embodiments, Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

In some embodiments, R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

In some embodiments, R 1-1 is tert-butyl,

In some embodiments, R 1-1 is or

In some embodiments, R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

In some embodiments, R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

In some embodiments, R 2 is Cl, F, OH, CN, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , NHCH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , ═O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,

or CO 2 H.

In some embodiments, R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in the compound of formula IIa-ii-2, one or more hydrogen atoms may be replaced by a deuterium atom.

Disclosed is a method of treating cystic fibrosis in a patient comprising administering to the patient in need thereof an effective amount of

1) a compound of any of formulas I, I-i, Ia, Ia-i and Ia-ii, including all embodiments disclosed herein, or a pharmaceutically acceptable salt thereof, or

2) a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formulae any of formulas I, I-i, Ia, Ia-i and Ia-ii, including all embodiments disclosed herein, or a pharmaceutically acceptable salt thereof.

In one embodiment, the present disclosure features any of the below numerated embodiments.

1. In one embodiment, the present disclosure features a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is a C 6 -C 10 aryl ring; a C 3 -C 10 cycloalkyl ring; or a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; W is O, S, or NR; X is O or NR; Z is NR or C(R) 2 ; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; p is 0, 1, 2, or 3; and

Provided that 1) when R 1 is adjacent to the C═W attached to Ring A, R 1 does not contain a ring moiety, 2) at least one R 1 is adjacent to the C═W attached to Ring A, and at least one R 1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; 3) when Ring A is phenyl or six-membered mono-heteroaryl wherein anywhere from 1 to 3 ring atoms are N, R 1 is not 4,5-dihydroisoxazole; 4) when Ring A is phenyl, R 1 is not

ureido, or aminocarbonyl; 5) when Ring A and the at least one R 1 is pyridine, R 1 (pyridine) is not further substituted by —CONHSO 2 —; and 6) when Ring A is pyridine or thiazole, and C═W wherein W is 0 in formula I is adjacent to the N on the pyridine or thiazole, R 1 which is adjacent to the N on the pyridine or on the thiazole is not

2. In another embodiment, the present disclosure features the compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, 1,2,3,4-tetrahydroquinoline, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole, thiophene, oxazole, pyrazine, triazole, thiazole, indazole, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, 1H-benzo[d]imidazole, imidazo[1,2-a]pyridine, or imidazole ring.

3. In another embodiment, the present disclosure features the compound of embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Ring A is

wherein the wavy line indicates point of attachment of Ring A to the C═W.

4. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Ring B is a pyridyl, pyridine-2(1H)-one, pyrazole, indole, pyrrole, indoline, thiophene, dihydrobenzofuran, tetrahydrofuran, furan, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, 3-azabicyclo[3.1.0]hexane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, pyrrolidine, azetidine, piperidine, piperazine, imidazo[1,2-a]pyridine, or quinoline.

5. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 4 or a pharmaceutically acceptable salt thereof, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the X═S═O.

6. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is independently halo, amino, OH, C 2 -C 6 alkenyl; C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

7. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH,

or (CH 3 ) 3 C.

8. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 2 is halo, OH, CN, amino, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

9. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

10. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 9 or a pharmaceutically acceptable salt thereof, wherein n is 2.

11. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 10 or a pharmaceutically acceptable salt thereof, wherein p is 0.

12. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 10 or a pharmaceutically acceptable salt thereof, wherein p is 1.

13. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 12 or a pharmaceutically acceptable salt thereof, wherein W is O.

14. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 13 or a pharmaceutically acceptable salt thereof, wherein Z is NH.

15. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, wherein X is O.

16. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Ring A is

and n is 2.

17. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Ring A is

and n is 2.

18. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Ring A is

and at least one R 1 is phenyl.

19. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Ring A is

and at least one R 1 is tert-butyl.

20. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 19 or a pharmaceutically acceptable salt thereof, wherein Ring A is

and at least one R 1 is pyridinyl. In some embodiments, Ring A is

one R 1 is phenyl, and one R 1 is alkenyl, amino, or C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy. In some embodiments, Ring A is

and Ring B is

In some embodiments, Ring A is

and Ring B is

In some embodiments, Ring A is

Ring B is

one R 1 is phenyl, and one R 1 is alkenyl, amino, or C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy.

21. In another embodiment, the present disclosure features the compound of any one of embodiments 1 to 20 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms is replaced by a deuterium atom.

22. In another embodiment, the present disclosure features the compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula I-i:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; X is O or NR; Z is NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; and p is 0, 1, 2, or 3.

23. In another embodiment, the present disclosure features the compound of embodiment 22 or a pharmaceutically acceptable salt thereof, wherein ring A is a pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole, oxazole, pyrazine, triazole, indazole, imidazo[1,2-a]pyridine, or imidazole ring.

24. In another embodiment, the present disclosure features the compound of embodiment 22 or 23 or a pharmaceutically acceptable salt thereof, wherein Ring A is

wherein the wavy line indicates point of attachment of Ring A to the carbonyl (CO).

25. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 24 or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

26. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 25 or a pharmaceutically acceptable salt thereof, wherein Ring B

wherein the wavy line indicates point of attachment of Ring B to X═S═O.

27. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 26 or a pharmaceutically acceptable salt thereof, wherein X is O.

28. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 27 or a pharmaceutically acceptable salt thereof, wherein Z is NH.

29. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 28 or a pharmaceutically acceptable salt thereof, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl; C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

30. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 29 or a pharmaceutically acceptable salt thereof, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH,

or (CH 3 ) 3 C.

31. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 30 or a pharmaceutically acceptable salt thereof, wherein R 2 is halo, CN, OH, amino, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

32. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 31 or a pharmaceutically acceptable salt thereof, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

33. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 32 or a pharmaceutically acceptable salt thereof, wherein n is 2.

34. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 33 or a pharmaceutically acceptable salt thereof, wherein p is 0.

35. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 33 or a pharmaceutically acceptable salt thereof, wherein p is 1.

36. In another embodiment, the present disclosure features the compound of any one of embodiments 22 to 35 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by a deuterium atom.

37. In another embodiment, the present disclosure features the compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; X is O or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; and p is 0, 1, 2, or 3.

38. In another embodiment, the present disclosure features the compound of embodiment 37 or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

39. In another embodiment, the present disclosure features the compound of embodiment 37 or 38 or a pharmaceutically acceptable salt thereof, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to X═S═O.

40. In another embodiment, the present disclosure features the compound of any one of embodiments 37 to 39 or a pharmaceutically acceptable salt thereof, wherein X is O.

41. In another embodiment, the present disclosure features the compound of any one of embodiments 37 to 40 or a pharmaceutically acceptable salt thereof, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

42. In another embodiment, the present disclosure features the compound of any one of embodiments 37 to 41 or a pharmaceutically acceptable salt thereof, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , (R)—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH,

or (CH 3 ) 3 C.

43. In another embodiment, the present disclosure features the compound of any one of embodiments 37 to 42 or a pharmaceutically acceptable salt thereof, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

44. In another embodiment, the present disclosure features the compound of any one of embodiments 37 to 43 or a pharmaceutically acceptable salt thereof, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

45. In another embodiment, the present disclosure features the compound of any one of embodiments 37 to 44 or a pharmaceutically acceptable salt thereof, wherein n is 2.

46. In another embodiment, the present disclosure features the compound of any one of embodiments 37 to 45 or a pharmaceutically acceptable salt thereof, wherein p is 0.

47. In another embodiment, the present disclosure features the compound of any one of embodiments 37 to 45 or a pharmaceutically acceptable salt thereof, wherein p is 1.

48. In another embodiment, the present disclosure features the compound of any one of embodiments 37 to 47 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by a deuterium atom.

49. In another embodiment, the present disclosure features the compound of embodiment 37 or a pharmaceutically acceptable salt thereof, wherein the compounds of formula Ia or a pharmaceutically acceptable salt thereof is a compound of formula Ia-i

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

50. In another embodiment, the present disclosure features the compound of embodiment 49 or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

51. In another embodiment, the present disclosure features the compound of embodiment 49 or 50 or a pharmaceutically acceptable salt thereof, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

52. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 51 or a pharmaceutically acceptable salt thereof, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

53. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 52 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

54. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 53 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is tert-butyl,

55. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 54 or a pharmaceutically acceptable salt thereof, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

56. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 55 or a pharmaceutically acceptable salt thereof, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

57. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 56 or a pharmaceutically acceptable salt thereof, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

58. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 57 or a pharmaceutically acceptable salt thereof, wherein n is 1.

59. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 58 or a pharmaceutically acceptable salt thereof, wherein p is 0.

60. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 58 or a pharmaceutically acceptable salt thereof, wherein p is 1.

61. In another embodiment, the present disclosure features the compound of any one of embodiments 49 to 60 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by a deuterium atom.

62. In another embodiment, the present disclosure features the compound of embodiment 49 or a pharmaceutically acceptable salt thereof, wherein the compounds of formula Ia-i or a pharmaceutically acceptable salt thereof is a compound of formula Ia-i-1

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

63. In another embodiment, the present disclosure features the compound of embodiment 62 or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

64. In another embodiment, the present disclosure features the compound of embodiment 62 or 63 or a pharmaceutically acceptable salt thereof, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

65. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 64 or a pharmaceutically acceptable salt thereof, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

66. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 65 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

67. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 66 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is tert-butyl,

68. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 67 or a pharmaceutically acceptable salt thereof, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH 2 O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

69. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 68 or a pharmaceutically acceptable salt thereof, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

70. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 69 or a pharmaceutically acceptable salt thereof, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

71. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 70 or a pharmaceutically acceptable salt thereof, wherein n is 1.

72. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 71 or a pharmaceutically acceptable salt thereof, wherein p is 0.

73. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 71 or a pharmaceutically acceptable salt thereof, wherein p is 1.

74. In another embodiment, the present disclosure features the compound of any one of embodiments 62 to 73 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by a deuterium atom.

75. In another embodiment, the present disclosure features the compound of embodiment 62 or a pharmaceutically acceptable salt thereof, wherein the compound of formula Ia-i-1 or a pharmaceutically acceptable salt thereof is a compound of formula Ia-i-2

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a pyridinyl; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

76. In another embodiment, the present disclosure features the compound of embodiment 75 or a pharmaceutically acceptable salt thereof, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

77. In another embodiment, the present disclosure features the compound of embodiment 75 or 76 or a pharmaceutically acceptable salt thereof, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

78. In another embodiment, the present disclosure features the compound of any one of embodiments 75 to 77 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

79. In another embodiment, the present disclosure features the compound of any one of embodiments 75 to 78 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is tert-butyl,

80. In another embodiment, the present disclosure features the compound of any one of embodiments 75 to 79 or a pharmaceutically acceptable salt thereof, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

81. In another embodiment, the present disclosure features the compound of any one of embodiments 75 to 80 or a pharmaceutically acceptable salt thereof, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

82. In another embodiment, the present disclosure features the compound of any one of embodiments 75 to 81 or a pharmaceutically acceptable salt thereof, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

83. In another embodiment, the present disclosure features the compound of any one of embodiments 75 to 82 or a pharmaceutically acceptable salt thereof, wherein n is 1.

84. In another embodiment, the present disclosure features the compound of any one of embodiments 75 to 83 or a pharmaceutically acceptable salt thereof, wherein p is 0.

85. In another embodiment, the present disclosure features the compound of any one of embodiments 75 to 83 or a pharmaceutically acceptable salt thereof, wherein p is 1.

86. In another embodiment, the present disclosure features the compound of any one of embodiments 75 to 85 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by a deuterium atom

87. In another embodiment, the present disclosure features the compound of embodiment 37 or a pharmaceutically acceptable salt thereof, wherein the compounds of formula Ia or a pharmaceutically acceptable salt thereof is a compound of formula Ia-ii

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

88. In another embodiment, the present disclosure features the compound of embodiment 87 or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

89. In another embodiment, the present disclosure features the compound of embodiment 87 or 88 or a pharmaceutically acceptable salt thereof, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

90. In another embodiment, the present disclosure features the compound of any one of embodiments 87 to 89 or a pharmaceutically acceptable salt thereof, wherein R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

91. In another embodiment, the present disclosure features the compound of any one of embodiments 87 to 90 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

92. In another embodiment, the present disclosure features the compound of any one of embodiments 87 to 91 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is tert-butyl,

93. In another embodiment, the present disclosure features the compound of any one of embodiments 87 to 92 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is

94. In another embodiment, the present disclosure features the compound of any one of embodiments 87 to 93 or a pharmaceutically acceptable salt thereof, wherein R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

95. In another embodiment, the present disclosure features the compound of any one of embodiments 87 to 94 or a pharmaceutically acceptable salt thereof, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

96. In another embodiment, the present disclosure features the compound of any one of embodiments 87 to 95 or a pharmaceutically acceptable salt thereof, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

97. In another embodiment, the present disclosure features the compound of any one of embodiments 87 to 96 or a pharmaceutically acceptable salt thereof, wherein p is 0. In some embodiments, p is 1.

98. In another embodiment, the present disclosure features the compound of any one of embodiments 87 to 97 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by a deuterium atom.

99. In another embodiment, the present disclosure features the compound of embodiment 87 or a pharmaceutically acceptable salt thereof, wherein the compounds of formula Ia-ii or a pharmaceutically acceptable salt thereof is a compound of formula Ia-ii-1

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

100. In another embodiment, the present disclosure features the compound of embodiment 99 or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

101. In another embodiment, the present disclosure features the compound of embodiment 99 or 100 or a pharmaceutically acceptable salt thereof, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

102. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 101 or a pharmaceutically acceptable salt thereof, wherein R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

103. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 102 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

104. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 103 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is tert-butyl,

105. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 104 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is

106. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 105 or a pharmaceutically acceptable salt thereof, wherein R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

107. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 106 or a pharmaceutically acceptable salt thereof, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

108. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 107 or a pharmaceutically acceptable salt thereof, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

109. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 108 or a pharmaceutically acceptable salt thereof, wherein p is 0.

110. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 108 or a pharmaceutically acceptable salt thereof, wherein p is 1.

111. In another embodiment, the present disclosure features the compound of any one of embodiments 99 to 110 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced by a deuterium atom.

112. In another embodiment, the present disclosure features the compound of embodiment 99 or a pharmaceutically acceptable salt thereof, wherein the compounds of formula Ia-ii-1 or a pharmaceutically acceptable salt thereof is a compound of formula Ia-ii-2

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a pyridinyl; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

113. In another embodiment, the present disclosure features the compound of embodiment 112 or a pharmaceutically acceptable salt thereof, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

114. In another embodiment, the present disclosure features the compound of embodiment 112 or 113 or a pharmaceutically acceptable salt thereof, wherein R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

115. In another embodiment, the present disclosure features the compound of any one of embodiments 112 to 114 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

116. In another embodiment, the present disclosure features the compound of any one of embodiments 112 to 115 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is tert-butyl,

117. In another embodiment, the present disclosure features the compound of any one of embodiments 112 to 116 or a pharmaceutically acceptable salt thereof, wherein R 1-1 is

118. In another embodiment, the present disclosure features the compound of any one of embodiments 112 to 117 or a pharmaceutically acceptable salt thereof, wherein R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

119. In another embodiment, the present disclosure features the compound of any one of embodiments 112 to 118 or a pharmaceutically acceptable salt thereof, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

120. In another embodiment, the present disclosure features the compound of any one of embodiments 112 to 119 or a pharmaceutically acceptable salt thereof, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

121. In another embodiment, the present disclosure features the compound of any one of embodiments 112 to 120 or a pharmaceutically acceptable salt thereof, wherein p is 0.

122. In another embodiment, the present disclosure features the compound of any one of embodiments 112 to 121 or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms may be replaced by a deuterium atom.

123. In another embodiment, the present disclosure features a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

124. In another embodiment, the present disclosure features a pharmaceutical composition comprising the compound of any one of embodiments 1-123 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

125. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 124, further comprising one or more additional therapeutic agent(s).

126. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, a CFTR modulator, or an anti-inflammatory agent.

127. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agent is a CFTR modulator.

128. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agent is a CFTR corrector.

129. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

130. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

131. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

132. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agent is a CFTR potentiator.

133. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agent is

or pharmaceutically acceptable salt thereof.

134. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agents are a CFTR corrector and a CFTR potentiator.

135. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

136. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

137. In another embodiment, the present disclosure features the pharmaceutical composition of embodiment 125, wherein the additional therapeutic agents are

or pharmaceutically acceptable salts thereof.

138. In another embodiment, the present disclosure features a method of treating cystic fibrosis in a patient comprising administering to the patient in need thereof an effective amount of

1) a compound of formula II or a pharmaceutically acceptable salt thereof, or

2) a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula II or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

Ring A is a C 6 -C 10 aryl ring; C 3 -C 10 cycloalkyl ring; or a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; W is O, S, or NR; X is O or NR; Z is NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; p is 0, 1, 2, or 3; and

Provided that 1) when R 1 is adjacent to C═W attached to Ring A, R 1 does not contain a ring moiety, and 2) at least one R 1 is adjacent to the C═W attached to Ring A.

139. In another embodiment, the present disclosure features a method of embodiment 138, wherein Ring A is a pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, 1,2,3,4-tetrahydroquinoline, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole, thiophene, oxazole, pyrazine, triazole, thiazole, indazole, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, 1H-benzo[d]imidazole, imidazo[1,2-a]pyridine, or imidazole ring.

140. In another embodiment, the present disclosure features a method of embodiment 138 or 139, wherein Ring A is

wherein the wavy line indicates point of attachment of Ring A to C═W.

141. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 140, wherein Ring B is a pyridyl, pyridine-2(1H)-one, pyrazole, indole, pyrrole, indoline, thiophene, dihydrobenzofuran, tetrahydrofuran, furan, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, 3-azabicyclo[3.1.0]hexane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, pyrrolidine, azetidine, piperidine, piperazine, imidazo[1,2-a]pyridine, or quinoline.

142. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 141, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to X═S═O.

143. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 142, wherein R 1 is independently halo, amino, OH, C 2 -C 6 alkenyl; C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

144. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 143, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH,

or (CH 3 ) 3 C.

145. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 144, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

146. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 145, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

147. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 146, wherein n is 2.

148. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 147, wherein p is 0.

149. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 147, wherein p is 1.

150. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 149, wherein W is O.

151. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 150, wherein Z is NH.

152. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 151, wherein X is O.

152. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 152, wherein Ring A is

and n is 2.

154. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 152, wherein Ring A is

and n is 2.

155. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 152, wherein Ring A is

and at least one R 1 is phenyl.

156. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 152, wherein Ring A is

and at least one R 1 is tert-butyl.

157. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 152, wherein Ring A is

and at least one R 1 is pyridinyl.

158. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 152, wherein Ring A is

one R 1 is phenyl, and one R 1 is alkenyl, amino, or C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy.

159. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 152, wherein Ring A is

and Ring B is

160. In another embodiment, the present disclosure features a method of embodiment 138, wherein Ring A is

and Ring B is

161. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 152, wherein Ring A is

Ring B is

one R 1 is phenyl, and one R 1 is alkenyl, amino, or C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy.

162. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 161, wherein one or more hydrogen atoms are replaced by a deuterium atom.

163. In another embodiment, the present disclosure features a method of embodiment 138, wherein the compound of formula II or a pharmaceutically acceptable salt thereof is a compound of formula II-i:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring A is a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; X is O or NR; Z is NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; and p is 0, 1, 2, or 3.

164. In another embodiment, the present disclosure features a method of embodiment 163, wherein ring A is a pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole, oxazole, pyrazine, triazole, indazole, imidazo[1,2-a]pyridine, or imidazole ring.

165. In another embodiment, the present disclosure features a method of embodiment 163 or 164, wherein Ring A is

wherein the wavy line indicates point of attachment of Ring A to the carbonyl (CO).

166. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 165, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

167. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 166, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the X═S═O.

168. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 167, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl; C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

169. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 168, wherein R 1 is CF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH,

or (CH 3 ) 3 C.

170. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 169, wherein R 2 is halo, CN, OH, amino, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

171. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 170, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

172. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 171, wherein n is 2.

173. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 172, wherein p is 0.

174. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 172, wherein p is 1.

175. In another embodiment, the present disclosure features a method of any one of embodiments 163 to 174, wherein in the compound of formula II-i, one or more hydrogen atoms are replaced by a deuterium atom.

176. In another embodiment, the present disclosure features a method of embodiment 138, wherein the compound of formula II or a pharmaceutically acceptable salt thereof is a compound of formula IIa:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; X is O or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 2 or 3; and p is 0, 1, 2, or 3.

177. In another embodiment, the present disclosure features a method of embodiment 176, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

178. In another embodiment, the present disclosure features a method of embodiment 176 or 177, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to X═S═O.

179. In another embodiment, the present disclosure features a method of any one of embodiments 176 to 178, wherein X is O.

180. In another embodiment, the present disclosure features a method of any one of embodiments 176 to 179, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

181. In another embodiment, the present disclosure features a method of any one of embodiments 176 to 180, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH,

or (CH 3 ) 3 C.

182. In another embodiment, the present disclosure features a method of any one of embodiments 176 to 181, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

183. In another embodiment, the present disclosure features a method of any one of embodiments 176 to 182, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

184. In another embodiment, the present disclosure features a method of any one of embodiments 176 to 183, wherein n is 2.

185. In another embodiment, the present disclosure features a method of any one of embodiments 176 to 184, wherein p is 0.

186. In another embodiment, the present disclosure features a method of any one of embodiments 176 to 184, wherein p is 1.

187. In another embodiment, the present disclosure features a method of any one of embodiments 176 to 186, wherein in the compound of formula IIa, one or more hydrogen atoms are replaced by a deuterium atom.

188. In another embodiment, the present disclosure features a method of embodiment 176, wherein the compounds of formula IIa or a pharmaceutically acceptable salt thereof is a compound of formula IIa-i

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

189. In another embodiment, the present disclosure features a method of embodiment 188, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

190. In another embodiment, the present disclosure features a method of embodiment 188 or 189, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

191. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 190, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

192. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 191, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

193. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 192, wherein R 1-1 is tert-butyl,

194. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 193, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

195. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 194, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

196. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 195, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

197. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 196, wherein n is 1.

198. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 197, wherein p is 0.

199. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 197, wherein p is 1.

200. In another embodiment, the present disclosure features a method of any one of embodiments 188 to 199, wherein in the compound of formula IIa-i, one or more hydrogen atoms are replaced by a deuterium atom.

201. In another embodiment, the present disclosure features a method of embodiment 188, wherein the compounds of formula IIa-i or a pharmaceutically acceptable salt thereof is a compound of formula IIa-i-1

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

202. In another embodiment, the present disclosure features a method of embodiment 201, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

203. In another embodiment, the present disclosure features a method of embodiment 201 or 202, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

204. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 203, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

205. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 204, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

206. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 205, wherein R 1-1 is tert-butyl,

207. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 206, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

208. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 207, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

208. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 207, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

209. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 208, wherein n is 1.

210. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 209, wherein p is 0.

211. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 209, wherein p is 1.

212. In another embodiment, the present disclosure features a method of any one of embodiments 201 to 211, wherein in the compound of formula IIa-i-1, one or more hydrogen atoms are replaced by a deuterium atom.

213. In another embodiment, the present disclosure features a method of embodiment 201, wherein the compound of formula IIa-i-1 or a pharmaceutically acceptable salt thereof is a compound of formula IIa-i-2

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a pyridinyl; R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; n is 1 or 2; and p is 0, 1, 2, or 3.

214. In another embodiment, the present disclosure features a method of embodiment 213, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl.

215. In another embodiment, the present disclosure features a method of embodiment 213 or 214, wherein R 1 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

216. In another embodiment, the present disclosure features a method of any one of embodiments 213 to 215, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

217. In another embodiment, the present disclosure features a method of any one of embodiments 213 to 216, wherein R 1-1 is tert-butyl,

218. In another embodiment, the present disclosure features a method of any one of embodiments 213 to 217, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

219. In another embodiment, the present disclosure features a method of any one of embodiments 213 to 218, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

220. In another embodiment, the present disclosure features a method of any one of embodiments 213 to 219, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

221. In another embodiment, the present disclosure features a method of any one of embodiments 213 to 220, wherein n is 1.

222. In another embodiment, the present disclosure features a method of any one of embodiments 213 to 221, wherein p is 0.

223. In another embodiment, the present disclosure features a method of embodiment 213, wherein p is 1.

224. In another embodiment, the present disclosure features a method of any one of embodiments 213 to 223, wherein in the compound of formula IIa-i-2, one or more hydrogen atoms are replaced by a deuterium atom.

225. In another embodiment, the present disclosure features a method of embodiment 176, wherein the compounds of formula IIa or a pharmaceutically acceptable salt thereof is a compound of formula IIa-ii

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

226. In another embodiment, the present disclosure features a method of embodiment 225, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

227. In another embodiment, the present disclosure features a method of embodiment 225 or 226, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

228. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 227, wherein R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

229. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 228, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

230. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 229, wherein R 1-1 is tert-butyl,

231. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 230, wherein R 1-1 is

232. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 231, wherein R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH. 234. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 233, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

235. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 234, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

236. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 235, wherein p is 0.

237. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 235, wherein p is 1.

238. In another embodiment, the present disclosure features a method of any one of embodiments 225 to 237, wherein in the compound of formula IIa-ii, one or more hydrogen atoms are replaced by a deuterium atom.

239. In another embodiment, the present disclosure features a method of embodiment 225, wherein the compounds of formula IIa-ii or a pharmaceutically acceptable salt thereof is a compound of formula IIa-ii-1

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

240. In another embodiment, the present disclosure features a method of embodiment 239, wherein Ring B is pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, thiazole, pyrrolidinone, or quinoline.

241. In another embodiment, the present disclosure features a method of embodiment 239 or 240, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

242. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 241, wherein R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

243. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 242, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

244. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 243, wherein R 1-1 is tert-butyl,

245. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 244, wherein R 1-1 is

246. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 245, wherein R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

247. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 246, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

248. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 247, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

249. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 248, wherein p is 0.

250. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 248, wherein p is 1.

251. In another embodiment, the present disclosure features a method of any one of embodiments 239 to 250, wherein in the compound of formula IIa-ii-1, one or more hydrogen atoms are replaced by a deuterium atom.

252. In another embodiment, the present disclosure features a method of embodiment 239, wherein the compound of formula IIa-ii-1 or a pharmaceutically acceptable salt thereof is a compound of formula IIa-ii-2

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

Ring B is a pyridinyl; R 1-2 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; or (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR; or two R 2 may form a ═CH 2 or ═O group; R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R; R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl; and p is 0, 1, 2, or 3.

253. In another embodiment, the present disclosure features a method of embodiment 252, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the sulfonyl (SO 2 ).

254. In another embodiment, the present disclosure features a method of embodiment 252 or 253, wherein R 1-2 is independently halo, amino, OH, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

255. In another embodiment, the present disclosure features a method of any one of embodiments 252 to 254, wherein R 1-1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, a phenyl, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring.

256. In another embodiment, the present disclosure features a method of any one of embodiments 252 to 255, wherein R 1-1 is tert-butyl,

257. In another embodiment, the present disclosure features a method of any one of embodiments 252 to 256, wherein R 1-1 is

258. In another embodiment, the present disclosure features a method of any one of embodiments 252 to 257, wherein R 1-2 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH2O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO—, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , ( R )—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, or CH 3 CH 2 CH 2 CH 2 CH 2 NH.

259. In another embodiment, the present disclosure features a method of any one of embodiments 252 to 258, wherein R 2 is halo, CN, amino, OH, C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy, C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 carbon atoms are independently O, S, N, or NR; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR.

260. In another embodiment, the present disclosure features a method of any one of embodiments 252 to 259, wherein R 2 is NH 2 , or NHCH 2 CH 2 CH 3 .

261. In another embodiment, the present disclosure features a method of any one of embodiments 252 to 260, wherein p is 0.

262. In another embodiment, the present disclosure features a method of any one of embodiments 252 to 260, wherein p is 1.

263. In another embodiment, the present disclosure features a method of any one of embodiments 252 to 262, wherein in the compound of formula IIa-ii-2, one or more hydrogen atoms are replaced by a deuterium atom.

264. In another embodiment, the present disclosure features a method of any one of embodiments 138-263, further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to

1) the compound of any one of embodiments 1 to or a pharmaceutically acceptable salt thereof, or

2) the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula II or a pharmaceutically acceptable salt thereof.

265. In another embodiment, the present disclosure features a method of embodiment 264, wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, a CFTR modulator, or an anti-inflammatory agent.

266. In another embodiment, the present disclosure features a method of embodiment 264, wherein the additional therapeutic agent is a CFTR modulator.

267. In another embodiment, the present disclosure features a method of embodiment 264, wherein the additional therapeutic agent is a CFTR corrector.

268. In another embodiment, the present disclosure features a method of embodiment 264, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

269. In another embodiment, the present disclosure features a method of embodiment 264, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

270. In another embodiment, the present disclosure features a method of embodiment 264, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

271. In another embodiment, the present disclosure features a method of embodiment 264, wherein the additional therapeutic agent is a CFTR potentiator.

272. In another embodiment, the present disclosure features a method of embodiment 264, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

273. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 272, wherein the patient is homozygous in the ΔF508 CFTR mutation.

274. In another embodiment, the present disclosure features a method of any one of embodiments 138 to 272, wherein the patient is heterozygous in the ΔF508 CFTR mutation.

275. In another embodiment, the present disclosure features a method of treating cystic fibrosis in a patient comprising administering to the patient in need thereof an effective amount of

1) the compound of any one of embodiments 1 to 123 or a pharmaceutically acceptable salt thereof, or

2) the pharmaceutical composition of embodiment 124.

276. In another embodiment, the present disclosure features a method of embodiment 275, further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound of any one of embodiments 1 to 123 or the pharmaceutical composition of embodiment 124.

277. In another embodiment, the present disclosure features a method of embodiment 275, wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, a CFTR modulator, or an anti-inflammatory agent.

278. In another embodiment, the present disclosure features a method of embodiment 275, wherein the additional therapeutic agent is a CFTR modulator.

279. In another embodiment, the present disclosure features a method of embodiment 275, wherein the additional therapeutic agent is a CFTR corrector.

280. In another embodiment, the present disclosure features a method of embodiment 275, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

281. In another embodiment, the present disclosure features a method of embodiment 275, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

282. In another embodiment, the present disclosure features a method of embodiment 275, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

283. In another embodiment, the present disclosure features a method of embodiment 275, wherein the additional therapeutic agent is a CFTR potentiator.

284. In another embodiment, the present disclosure features a method of embodiment 275, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

285. In another embodiment, the present disclosure features a method of any one of embodiments 275 to 284, wherein the patient is homozygous in the ΔF508 CFTR mutation.

286. In another embodiment, the present disclosure features a method of any one of embodiments 275 to 284, wherein the patient is heterozygous in the ΔF508 CFTR mutation.

289. In another embodiment, the present disclosure features a kit comprising

1) the compound of any one of embodiments 1 to 123 or a pharmaceutically acceptable salt thereof, or

2) the pharmaceutical composition of any one of embodiments 124 to 137, and instructions for use thereof.

290. In another embodiment, the present disclosure features the kit of embodiment 289, further comprising one or more additional therapeutic agent(s).

291. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, a CFTR modulator, or an anti-inflammatory agent.

292. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agent is a CFTR modulator.

293. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agent is a CFTR corrector.

294. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

295. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

296. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

297. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agent is a CFTR potentiator.

298. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agent is

or a pharmaceutically acceptable salt thereof.

299. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agents are a CFTR corrector and a CFTR potentiator.

300. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agents are

pharmaceutically acceptable salts thereof.

301. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agents are

pharmaceutically acceptable salts thereof.

302. In another embodiment, the present disclosure features the kit of embodiment 290, wherein the additional therapeutic agents are

pharmaceutically acceptable salts thereof.

303. In another embodiment, the present disclosure features the kit of any one of embodiments 289 to 302, wherein the compound of any one of embodiments 1 to 123 or the pharmaceutical composition of any one of embodiments 124 to 137 and the one or more additional therapeutic agent(s) are in separate containers.

304. In another embodiment, the present disclosure features the kit of any one of embodiments 289 to 303, wherein the compound of any one of embodiments 1 to 123 or the pharmaceutical composition of any one of embodiments 124 to 137 and the one or more additional therapeutic agent(s) are in the same container.

305. In another embodiment, the present disclosure features the kit of embodiment 303 or 304, wherein the container is a bottle, vial, or blister pack, or combination thereof.

Methods of Preparing Compounds of Formula I

Compounds of the disclosure may be prepared by known methods and as illustrated in Schemes I-III. R 1 , R 2 , n, p, and rings A and B are as defined in the Specification unless noted otherwise below for each individual scheme.

a) HATU or CDI, Et 3 N or (i-Pr) 2 NEt or K 2 CO 3 or NaH, DMF or CH 2 Cl 2

a) X=halogen (F or Cl or Br), HATU or CDI, Et 3 N or (i-Pr) 2 NEt or K 2 CO 3 or NaH, DMF or CH 2 Cl 2

a) X=halogen (F or Cl or Br), Z═H: NaH or Cs 2 CO 3 or K 2 CO 3 or DIEA or Et 3 N, CsF, DMF or DMSO or dioxane or NMP.

Pharmaceutically Acceptable Salts and Prodrugs

It will also be appreciated that certain compounds of the compositions of the present disclosure can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof. According to the present disclosure, a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 -C 4 alkyl) 4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

Pharmaceutical Compositions

Pharmaceutically Acceptable Vehicle, Adjuvant, or Carrier

In one aspect, the present disclosure features a pharmaceutical composition comprising a compound of formulas I to IIa-ii-2 or pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable vehicle, adjuvant, or carrier.

As described above, the pharmaceutical compositions of the present disclosure additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology , eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which is incorporated by reference herein, disclose various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Additional Therapeutic Agent(s)

In another embodiment, the pharmaceutical compositions of the present disclosure further comprise one or more additional therapeutic agent(s). In one embodiment, the additional therapeutic agent is a CFTR modulator. In one embodiment, the additional therapeutic agent is a CFTR corrector. In one embodiment, the additional therapeutic agent is a CFTR potentiator. In another embodiment, the pharmaceutical composition comprises a compound of Formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof and one or more of the following additional therapeutic agents.

In another embodiment, the additional therapeutic agent is selected from:

3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof;

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-yl)cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof; or

4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of Table 1, or pharmaceutically acceptable salt thereof and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of Table 1, or pharmaceutically acceptable salt thereof and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof and 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of Table 1, or pharmaceutically acceptable salt thereof and 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of Table 1, or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-difluoroethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 1), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopentyloxy-pyridine-3-carboxamide (Compound 2), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 3), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 4), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopropoxy-pyridine-3-carboxamide (Compound 5), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,3,3-tetrafluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 6), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-isobutoxy-phenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine-8-carboxamide (Compound 7), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,3-trifluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 9), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-methoxy-pyridine-3-carboxamide (Compound 10), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pentoxy-pyridine-3-carboxamide (Compound 11), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 12), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 13), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(isopropyl)amino]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 14), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethylpropoxy)pyridine-3-carboxamide (Compound 15), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-[ethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 16), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1 S)-2,2,2-trifluoro-1-methyl-ethyl]amino]pyridine-3-carboxamide (Compound 17), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[1-(methoxymethyl)propoxy]pyridine-3-carboxamide (Compound 18), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(dimethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 19), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 20), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxypropoxy)pyridine-3-carboxamide (Compound 21), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxy-3-methyl-butoxy)pyridine-3-carboxamide (Compound 22), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 24), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,2,2-trimethylpropoxy)pyridine-3-carboxamide (Compound 25), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2-methyl-propoxy)pyridine-3-carboxamide (Compound 26), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-propoxy-pyridine-3-carboxamide (Compound 27), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[(E)-but-2-enoxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 28), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-1-methylpropoxy]pyridine-3-carboxamide (Compound 29), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-ethoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 30), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isopropyl(methyl)amino]pyridine-3-carboxamide (Compound 31), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 32), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]pyridine-3-carboxamide (Compound 33), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 34), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pent-3-ynoxy-pyridine-3-carboxamide (Compound 35), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,3,3-trimethylbutoxy)pyridine-3-carboxamide (Compound 36), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylprop-1-enyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 37), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 6-(3-fluoro-5-isobutoxy-phenyl)-2-(propylamino)-N-[[6-(propylamino)-2-pyridyl]sulfonyl]pyridine-3-carboxamide (Compound 39), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethyl-2-methyl-propoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 40), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diisopropylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 41), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylallyloxy)pyridine-3-carboxamide (Compound 42), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-allyloxy-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 43), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,1-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 44), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 46), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 47), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylallyloxy)pyridine-3-carboxamide (Compound 49), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxy-1,1-dimethyl-ethoxy)pyridine-3-carboxamide (Compound 51), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 52), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 53), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-isopropoxyethoxy)pyridine-3-carboxamide (Compound 55), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylbutoxy)pyridine-3-carboxamide (Compound 56), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-difluoropropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 57), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(tert-butylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 58), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-1-methylpropoxy]pyridine-3-carboxamide (Compound 59), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxyethoxy)pyridine-3-carboxamide (Compound 60), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isobutyl(methyl)amino]pyridine-3-carboxamide (Compound 61), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylpentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 62), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-butoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 63), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(propyl)amino]pyridine-3-carboxamide (Compound 64), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 65), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(2,2,2-trifluoroethyl)amino]pyridine-3-carboxamide (Compound 66), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 67), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2,2-dimethyl-propoxy)pyridine-3-carboxamide (Compound 68), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-ethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 69), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxy-1-methyl-ethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 71), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,2-trifluoro-1-methyl-ethoxy)pyridine-3-carboxamide (Compound 73), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 74), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]pyridine-3-carboxamide (Compound 75), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylpropyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 76), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylpentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 77), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-methoxypropoxy]pyridine-3-carboxamide (Compound 78), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 6-(3-fluoro-5-isobutoxy-phenyl)-2-[isopropyl(methyl)amino]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 79), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,3-trifluoropropoxy)pyridine-3-carboxamide (Compound 81), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4,4,4-trifluorobutoxy)pyridine-3-carboxamide (Compound 82), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(E)-4,4,4-trifluorobut-2-enoxy]pyridine-3-carboxamide (Compound 83), or pharmaceutically acceptable salt thereof; and a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

In one embodiment, the above recited pharmaceutical compositions contain a pharmaceutically acceptable prodrug of the compound of the present disclosure.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of Table 1, or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-difluoroethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 1), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopentyloxy-pyridine-3-carboxamide (Compound 2), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 3), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 4), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopropoxy-pyridine-3-carboxamide (Compound 5), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,3,3-tetrafluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 6), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-isobutoxy-phenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine-8-carboxamide (Compound 7), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,3-trifluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 9), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-methoxy-pyridine-3-carboxamide (Compound 10), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pentoxy-pyridine-3-carboxamide (Compound 11), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 12), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 13), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(isopropyl)amino]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 14), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethylpropoxy)pyridine-3-carboxamide (Compound 15), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-[ethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 16), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1 S)-2,2,2-trifluoro-1-methyl-ethyl]amino]pyridine-3-carboxamide (Compound 17), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[1-(methoxymethyl)propoxy]pyridine-3-carboxamide (Compound 18), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(dimethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 19), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 20), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxypropoxy)pyridine-3-carboxamide (Compound 21), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxy-3-methyl-butoxy)pyridine-3-carboxamide (Compound 22), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 24), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,2,2-trimethylpropoxy)pyridine-3-carboxamide (Compound 25), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2-methyl-propoxy)pyridine-3-carboxamide (Compound 26), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-propoxy-pyridine-3-carboxamide (Compound 27), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[(E)-but-2-enoxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 28), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-1-methylpropoxy]pyridine-3-carboxamide (Compound 29), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-ethoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 30), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isopropyl(methyl)amino]pyridine-3-carboxamide (Compound 31), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 32), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]pyridine-3-carboxamide (Compound 33), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 34), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pent-3-ynoxy-pyridine-3-carboxamide (Compound 35), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,3,3-trimethylbutoxy)pyridine-3-carboxamide (Compound 36), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylprop-1-enyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 37), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 6-(3-fluoro-5-isobutoxy-phenyl)-2-(propylamino)-N-[[6-(propylamino)-2-pyridyl]sulfonyl]pyridine-3-carboxamide (Compound 39), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethyl-2-methyl-propoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 40), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diisopropylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 41), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylallyloxy)pyridine-3-carboxamide (Compound 42), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-allyloxy-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 43), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,1-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 44), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-yl sulfonyl)pyridine-3-carboxamide (Compound 46), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 47), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylallyloxy)pyridine-3-carboxamide (Compound 49), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxy-1,1-dimethyl-ethoxy)pyridine-3-carboxamide (Compound 51), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 52), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 53), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-isopropoxyethoxy)pyridine-3-carboxamide (Compound 55), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylbutoxy)pyridine-3-carboxamide (Compound 56), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-difluoropropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 57), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(tert-butylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 58), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-1-methylpropoxy]pyridine-3-carboxamide (Compound 59), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxyethoxy)pyridine-3-carboxamide (Compound 60), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isobutyl(methyl)amino]pyridine-3-carboxamide (Compound 61), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylpentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 62), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-butoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 63), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(propyl)amino]pyridine-3-carboxamide (Compound 64), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 65), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(2,2,2-trifluoroethyl)amino]pyridine-3-carboxamide (Compound 66), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 67), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2,2-dimethyl-propoxy)pyridine-3-carboxamide (Compound 68), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-ethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 69), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxy-1-methyl-ethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 71), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,2-trifluoro-1-methyl-ethoxy)pyridine-3-carboxamide (Compound 73), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 74), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]pyridine-3-carboxamide (Compound 75), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylpropyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 76), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylpentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 77), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-methoxypropoxy]pyridine-3-carboxamide (Compound 78), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 6-(3-fluoro-5-isobutoxy-phenyl)-2-[isopropyl(methyl)amino]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 79), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,3-trifluoropropoxy)pyridine-3-carboxamide (Compound 81), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4,4,4-trifluorobutoxy)pyridine-3-carboxamide (Compound 82), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(E)-4,4,4-trifluorobut-2-enoxy]pyridine-3-carboxamide (Compound 83), or pharmaceutically acceptable salt thereof; and 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In one embodiment, the above recited pharmaceutical compositions contain a pharmaceutically acceptable prodrug of the compound of the present disclosure.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of Table 1, or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-difluoroethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 1), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopentyloxy-pyridine-3-carboxamide (Compound 2), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 3), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 4), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopropoxy-pyridine-3-carboxamide (Compound 5), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,3,3-tetrafluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 6), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-isobutoxy-phenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine-8-carboxamide (Compound 7), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,3-trifluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 9), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-methoxy-pyridine-3-carboxamide (Compound 10), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pentoxy-pyridine-3-carboxamide (Compound 11), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 12), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 13), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(isopropyl)amino]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 14), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethylpropoxy)pyridine-3-carboxamide (Compound 15), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-[ethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 16), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1 S)-2,2,2-trifluoro-1-methyl-ethyl]amino]pyridine-3-carboxamide (Compound 17), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[1-(methoxymethyl)propoxy]pyridine-3-carboxamide (Compound 18), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(dimethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 19), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 20), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxypropoxy)pyridine-3-carboxamide (Compound 21), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxy-3-methyl-butoxy)pyridine-3-carboxamide (Compound 22), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 24), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,2,2-trimethylpropoxy)pyridine-3-carboxamide (Compound 25), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2-methyl-propoxy)pyridine-3-carboxamide (Compound 26), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-propoxy-pyridine-3-carboxamide (Compound 27), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[(E)-but-2-enoxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 28), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-1-methylpropoxy]pyridine-3-carboxamide (Compound 29), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-ethoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 30), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isopropyl(methyl)amino]pyridine-3-carboxamide (Compound 31), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 32), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]pyridine-3-carboxamide (Compound 33), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 34), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pent-3-ynoxy-pyridine-3-carboxamide (Compound 35), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,3,3-trimethylbutoxy)pyridine-3-carboxamide (Compound 36), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylprop-1-enyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 37), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 6-(3-fluoro-5-isobutoxy-phenyl)-2-(propylamino)-N-[[6-(propylamino)-2-pyridyl]sulfonyl]pyridine-3-carboxamide (Compound 39), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethyl-2-methyl-propoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 40), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diisopropylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 41), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylallyloxy)pyridine-3-carboxamide (Compound 42), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-allyloxy-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 43), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,1-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 44), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-yl sulfonyl)pyridine-3-carboxamide (Compound 46), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 47), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylallyloxy)pyridine-3-carboxamide (Compound 49), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxy-1,1-dimethyl-ethoxy)pyridine-3-carboxamide (Compound 51), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 52), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 53), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-isopropoxyethoxy)pyridine-3-carboxamide (Compound 55), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylbutoxy)pyridine-3-carboxamide (Compound 56), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-difluoropropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 57), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(tert-butylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 58), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-1-methylpropoxy]pyridine-3-carboxamide (Compound 59), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxyethoxy)pyridine-3-carboxamide (Compound 60), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isobutyl(methyl)amino]pyridine-3-carboxamide (Compound 61), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylpentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 62), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-butoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 63), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(propyl)amino]pyridine-3-carboxamide (Compound 64), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 65), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(2,2,2-trifluoroethyl)amino]pyridine-3-carboxamide (Compound 66), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 67), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2,2-dimethyl-propoxy)pyridine-3-carboxamide (Compound 68), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-ethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 69), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxy-1-methyl-ethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 71), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,2-trifluoro-1-methyl-ethoxy)pyridine-3-carboxamide (Compound 73), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 74), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]pyridine-3-carboxamide (Compound 75), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylpropyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 76), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylpentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 77), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-methoxypropoxy]pyridine-3-carboxamide (Compound 78), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 6-(3-fluoro-5-isobutoxy-phenyl)-2-[isopropyl(methyl)amino]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 79), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,3-trifluoropropoxy)pyridine-3-carboxamide (Compound 81), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4,4,4-trifluorobutoxy)pyridine-3-carboxamide (Compound 82), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(E)-4,4,4-trifluorobut-2-enoxy]pyridine-3-carboxamide (Compound 83), or pharmaceutically acceptable salt thereof; and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the above recited pharmaceutical compositions contain a pharmaceutically acceptable prodrug of the compound of the present disclosure.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a compound of Table 1, or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-difluoroethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 1), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopentyloxy-pyridine-3-carboxamide (Compound 2), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 3), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 4), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopropoxy-pyridine-3-carboxamide (Compound 5), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,3,3-tetrafluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 6), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-isobutoxy-phenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine-8-carboxamide (Compound 7), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,3-trifluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 9), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-methoxy-pyridine-3-carboxamide (Compound 10), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pentoxy-pyridine-3-carboxamide (Compound 11), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 12), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 13), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(isopropyl)amino]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 14), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethylpropoxy)pyridine-3-carboxamide (Compound 15), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-[ethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 16), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1 S)-2,2,2-trifluoro-1-methyl-ethyl]amino]pyridine-3-carboxamide (Compound 17), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[1-(methoxymethyl)propoxy]pyridine-3-carboxamide (Compound 18), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(dimethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 19), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 20), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxypropoxy)pyridine-3-carboxamide (Compound 21), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxy-3-methyl-butoxy)pyridine-3-carboxamide (Compound 22), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 24), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,2,2-trimethylpropoxy)pyridine-3-carboxamide (Compound 25), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2-methyl-propoxy)pyridine-3-carboxamide (Compound 26), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-propoxy-pyridine-3-carboxamide (Compound 27), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[(E)-but-2-enoxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 28), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-1-methylpropoxy]pyridine-3-carboxamide (Compound 29), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-ethoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 30), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isopropyl(methyl)amino]pyridine-3-carboxamide (Compound 31), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 32), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]pyridine-3-carboxamide (Compound 33), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 34), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pent-3-ynoxy-pyridine-3-carboxamide (Compound 35), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,3,3-trimethylbutoxy)pyridine-3-carboxamide (Compound 36), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylprop-1-enyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 37), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 6-(3-fluoro-5-isobutoxy-phenyl)-2-(propylamino)-N-[[6-(propylamino)-2-pyridyl]sulfonyl]pyridine-3-carboxamide (Compound 39), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethyl-2-methyl-propoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 40), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diisopropylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 41), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylallyloxy)pyridine-3-carboxamide (Compound 42), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-allyloxy-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 43), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,1-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 44), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-yl sulfonyl)pyridine-3-carboxamide (Compound 46), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 47), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylallyloxy)pyridine-3-carboxamide (Compound 49), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxy-1,1-dimethyl-ethoxy)pyridine-3-carboxamide (Compound 51), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 52), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 53), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-isopropoxyethoxy)pyridine-3-carboxamide (Compound 55), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylbutoxy)pyridine-3-carboxamide (Compound 56), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-difluoropropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 57), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(tert-butylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 58), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-1-methylpropoxy]pyridine-3-carboxamide (Compound 59), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxyethoxy)pyridine-3-carboxamide (Compound 60), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isobutyl(methyl)amino]pyridine-3-carboxamide (Compound 61), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylpentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 62), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-butoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 63), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(propyl)amino]pyridine-3-carboxamide (Compound 64), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 65), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(2,2,2-trifluoroethyl)amino]pyridine-3-carboxamide (Compound 66), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 67), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2,2-dimethyl-propoxy)pyridine-3-carboxamide (Compound 68), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-ethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 69), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxy-1-methyl-ethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 71), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,2-trifluoro-1-methyl-ethoxy)pyridine-3-carboxamide (Compound 73), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 74), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]pyridine-3-carboxamide (Compound 75), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylpropyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 76), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylpentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 77), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(2S)-2-methoxypropoxy]pyridine-3-carboxamide (Compound 78), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 6-(3-fluoro-5-isobutoxy-phenyl)-2-[isopropyl(methyl)amino]-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 79), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4,4,4-trifluorobutoxy)pyridine-3-carboxamide (Compound 82), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(4,4,4-trifluorobutoxy)pyridine-3-carboxamide (Compound 82), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(E)-4,4,4-trifluorobut-2-enoxy]pyridine-3-carboxamide (Compound 83), or pharmaceutically acceptable salt thereof; and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the above recited pharmaceutical compositions contain a pharmaceutically acceptable prodrug of the compound of the present disclosure.

In another embodiment, the additional therapeutic agent is selected from the following table:

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

In one embodiment, the additional therapeutic agent is selected from the following table:

Compounds disclosed in U.S. Pat. No. 7,407,976 (Col 13, ln 35- col 66,

ln 67; Compounds 1-100 in Table 1 at col 67, ln 1-col 127, ln 42)

Compounds disclosed in U.S. Pat. No. 7,645,789 (Col 16, ln 52-col 50,

ln 22; Compounds 1-322 in Table 1 at col 50, ln 24-col 167, ln 42)

Compounds disclosedin U.S. Pat. No. 7,659,268 (Col 16, ln 20-col 70,

ln 52; Compounds 1-528 in Table 1 at col 70, ln 53-col 331, ln 34)

Compounds disclosed in U.S. Pat. No. 7,671,221 (Col 16, ln 12-col 54,

ln 48; Compounds 1-1216 in Table 1 at col 54, ln 49-col 699, ln 27)

Compounds disclosed in U.S. Pat. No. 7,691,902 (Col 16, ln 11-col 54,

ln 29; Compounds 1-959 in Table 1 at col 54, ln 29-col 683, ln 44)

Compounds disclosed in U.S. Pat. No. 7,741,321 (Col 16, ln 25-col 72,

ln 17; Compounds 1-422 in Table 1 at col 72, ln 20-col 279, ln 15)

Compounds disclosed in U.S. Pat. No. 7,754,739 (Col 16, ln 1-col 22,

ln 47; Compounds 1-2 in Table 1 at col 18, ln 26-65)

Compounds disclosed in U.S. Pat. No. 7,776,905 (Col 16, ln 23-col 38,

ln 40; Compounds 1-306 in Table 1 at col 38, ln 45-col 96, ln 40)

Compounds disclosed in U.S. Pat. No. 7,973,169 (Col 9, ln 16-col 40,

ln 40; Compounds 1-289 in Table 1 at col. 40, ln 41-col 289, ln 39)

Compounds disclosed in U.S. Pat. No. 7,977,322 (Col 6, ln 26-col 37,

ln 47; Compounds 1-498 in Table 1 at col 37, ln 50-col 141, ln 40)

Compounds disclosed in U.S. Pat. No. 7,999,113 (Col 6, ln 13-col 10,

ln 67; Compounds 1-13 in Table 1 at col 11, ln 5-col 13, ln 65)

Compounds disclosed in U.S. Pat. No. 8,227,615 (Col 6, ln 10-col 29,

ln 66; Compounds 1-78 in Table 1 at col 30, ln 1-col 46, ln 48)

Compounds disclosed in U.S. Pat. No. 8,299,099 (Col 6, ln 10-col 34,

ln 18; Compounds 1-47 in Table 1 at col 34, ln 20-col 42, ln 35)

Compounds disclosed in US Published Application No. 2006-0052358

(Paragraphs [0034]-[0056]; [0077]-[0240]; Compounds 1-320 in Table

1 at paragraph [0241])

Compounds disclosed in US Published Application No. 2009-0143381

(Paragraphs [0102]-[0263]; Compounds 1-28 in Table 1 at

paragraph [0264])

Compounds disclosed in US Published Application No. 2009-0170905

(Paragraphs [0012]-[0013]; [0030]-[0051])

Compounds disclosed in US Published Application No. 2009-0253736

(Paragraphs [0031]-[0162]; Compounds 1-15 in Table 1 at paragraph

[0163])

Compounds disclosed in US Published Application No. 2011-0263654

(Paragraphs [0012]-[0013]; [0066]-[0141])

Compounds disclosed in US Published Application No. 2011-0251253

(Paragraphs [0012]-[0013]; [0054]-[0079])

Compounds disclosed in PCT application WO2008141119

(Paragraphs [0100]-[0339]; Compounds 1-117 in Table 1 at paragraph

[0340])

Compounds disclosed in U.S. application Ser. No. 11/047,361

Compounds disclosed in US Published Application No. 2013-0116238

(Paragraphs [0028]-[0044]; [0117]-[0128]), or combinations thereof.

In another embodiment, the additional therapeutic agent is selected from

N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; or

N-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, or pharmaceutically acceptable salt thereof.

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; b) a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid; and c) a compound selected from N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide or N-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide.

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of Table 1, or pharmaceutically acceptable salt thereof; b) a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid; and c) a compound selected from N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide or N-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide.

In another embodiment, the above recited pharmaceutical compositions contain a pharmaceutically acceptable prodrug of the compound of the present disclosure.

In another embodiment, the additional therapeutic agent is selected from the following table:

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; b) a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid; and c) a compound selected from N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide or N-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide.

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of Table 1, or pharmaceutically acceptable salt thereof; b) a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid; and c) a compound selected from N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide or N-(4-(7-azabicyclo[2.21]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide.

In another embodiment, the above recited pharmaceutical compositions contain a pharmaceutically acceptable prodrug of the compound of the present disclosure.

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; b) a compound selected from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, or 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid; and c) a compound selected from certain flavones and isoflavones, such as genistein, which are capable of stimulating CFTR-mediated chloride transport in epithelial tissues in a cyclic-AMP independent manner (See U.S. Pat. No. 6,329,422, incorporated herein by reference in its entirety); phenylglycine-01 (2-[(2-1H-indol-3-yl-acetyl)-methylamino]-N-(4-isopropylphenyl)-2-phenylacetamide); felodipine (Ethyl methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate); sulfonamide SF-01 (6-(ethylphenylsulfamoyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid cycloheptylamide); and UCCF-152 (3-[2-(benzyloxy)phenyl]-5-(chloromethyl)isoxazole).

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; b) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of Table 1, or pharmaceutically acceptable salt thereof; b) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid; and c) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; b) (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide; and c) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of Table 1, or pharmaceutically acceptable salt thereof; b) (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide; and c) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of formulas I to IIa-ii-2, or pharmaceutically acceptable salt thereof; b) 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid; and c) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the disclosure features a pharmaceutical composition comprising a) a compound of Table 1, or pharmaceutically acceptable salt thereof; b) 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid; and c) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

In another embodiment, the above recited pharmaceutical compositions contain a pharmaceutically acceptable prodrug of the compound of the present disclosure.

In another embodiment, the pharmaceutical composition of the present disclosure comprises a) N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-difluoroethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 1), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopentyloxy-pyridine-3-carboxamide (Compound 2), b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(3,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 3), b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-tert-butoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 4), b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-isopropoxy-pyridine-3-carboxamide (Compound 5), b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,3,3-tetrafluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 6), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-5-(3-fluoro-5-isobutoxy-phenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine-8-carboxamide (Compound 7), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3,3,3-trifluoro-1-methyl-propoxy)pyridine-3-carboxamide (Compound 9), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-methoxy-pyridine-3-carboxamide (Compound 10), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pentoxy-pyridine-3-carboxamide (Compound 11), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 12), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxyethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 13), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(isopropyl)amino]-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 14), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-tert-butyl-2-(2,2-dimethylpropoxy)pyridine-3-carboxamide (Compound 15), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-[ethyl(isopropyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-ylsulfonyl)pyridine-3-carboxamide (Compound 16), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl-[(1 S)-2,2,2-trifluoro-1-methyl-ethyl]amino]pyridine-3-carboxamide (Compound 17), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[1-(methoxymethyl)propoxy]pyridine-3-carboxamide (Compound 18), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(dimethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 19), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 20), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxypropoxy)pyridine-3-carboxamide (Compound 21), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(3-methoxy-3-methyl-butoxy)pyridine-3-carboxamide (Compound 22), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,3-dimethylbutoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 24), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,2,2-trimethylpropoxy)pyridine-3-carboxamide (Compound 25), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2-methyl-propoxy)pyridine-3-carboxamide (Compound 26), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-propoxy-pyridine-3-carboxamide (Compound 27), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[(E)-but-2-enoxy]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 28), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1S)-1-methylpropoxy]pyridine-3-carboxamide (Compound 29), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-ethoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 30), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isopropyl(methyl)amino]pyridine-3-carboxamide (Compound 31), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 32), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]pyridine-3-carboxamide (Compound 33), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(6-isopropoxy-3-pyridyl)pyridine-3-carboxamide (Compound 34), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-pent-3-ynoxy-pyridine-3-carboxamide (Compound 35), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1,3,3-trimethylbutoxy)pyridine-3-carboxamide (Compound 36), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylprop-1-enyl)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 37), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 6-(3-fluoro-5-isobutoxy-phenyl)-2-(propylamino)-N-[[6-(propylamino)-2-pyridyl]sulfonyl]pyridine-3-carboxamide (Compound 39), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethyl-2-methyl-propoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 40), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diisopropylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 41), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylallyloxy)pyridine-3-carboxamide (Compound 42), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-allyloxy-N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 43), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,1-dimethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 44), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises 2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)-N-(1H-pyrazol-5-yl sulfonyl)pyridine-3-carboxamide (Compound 46), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1-ethylpropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 47), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methylallyloxy)pyridine-3-carboxamide (Compound 49), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxy-1,1-dimethyl-ethoxy)pyridine-3-carboxamide (Compound 51), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[2,2-dimethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 52), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(diethylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 53), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-isopropoxyethoxy)pyridine-3-carboxamide (Compound 55), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-methylbutoxy)pyridine-3-carboxamide (Compound 56), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2,2-difluoropropoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 57), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(tert-butylamino)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 58), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-1-methylpropoxy]pyridine-3-carboxamide (Compound 59), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2-methoxyethoxy)pyridine-3-carboxamide (Compound 60), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[isobutyl(methyl)amino]pyridine-3-carboxamide (Compound 61), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(1,2-dimethylpentoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 62), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-butoxy-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 63), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(propyl)amino]pyridine-3-carboxamide (Compound 64), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(1R)-2-methoxy-1-methyl-ethoxy]pyridine-3-carboxamide (Compound 65), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[methyl(2,2,2-trifluoroethyl)amino]pyridine-3-carboxamide (Compound 66), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[ethyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 67), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(1-isopropyl-2,2-dimethyl-propoxy)pyridine-3-carboxamide (Compound 68), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-[1-ethylpropyl(methyl)amino]-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 69), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-2-(2-ethoxy-1-methyl-ethoxy)-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3-carboxamide (Compound 71), or pharmaceutically acceptable salt thereof; b) N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, or pharmaceutically acceptable salt thereof; and c) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, or pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition of the present disclosure comprises N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-(2,2,2-trifluoro-1-methyl-ethoxy)pyridine-3-carboxamide (Compound 73), or pharmaceutically acceptable salt thereof