CHROMAN COMPOUNDS ARE SUBSTITUTED

Abstract

The invention proposes a compound of the formula (I): where R1, X, Y, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R” are as defined in the description, and its pharmaceutical salt, is useful as an agent in the treatment of diseases and conditions mediated and regulated by CFTR, including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive pulmonary disease, and chronic obstructive airway disease. The invention also proposes a pharmaceutical composition containing one or more of the compound of the formula (I).

Description

[0001] SUBSTITUTED CHROMANES AND METHOD OF USE

[0002] BACKGROUND OF THE INVENTION

[0003] The invention relates to substituted chromane compounds that are modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, useful in treating diseases and conditions mediated and modulated by CFTR. Additionally, the invention relates to compositions containing compounds of the invention and processes for their preparation.

[0004] Cystic fibrosis (CF), one of the most common autosomal recessive genetic diseases in the Caucasian population, is caused by loss of function mutations in the Cystic Fibrosis

[0005] Transmembrane Conductance Regulator (CFTR) gene, which is located on chromosome 7 (http: / / www.cff.org / AboutCF / ; Rowe S.M et al. (2005); N Eng J Med. (352), 1992-2001).

[0006] Approximately 1 :3500 and 1 :3000 infants born in the United States and in Europe, respectively, are affected by CF, resulting in ~ 75,000 cases worldwide , -30,000 of which are in the United State. Approximately 1 ,000 new cases of CF are diagnosed each year, with more than 75% of patients being diagnosed by 2 years of age. Nearly half the CF population is currently 18 years of age and older. The CFTR protein (Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362; Riordan, j. R. et al. (1989) Science 245 : 1066-1073) is a cAMP / ATP -mediated ion channel expressed in a variety of cell types, including secretory and absorptive epithelial cells. CFTR regulates chloride and bicarbonate anion flux across the cell membrane, maintaining electro neutrality and osmolality across the epithelial membrane (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). CFTR is also responsible for regulating the activity of other ion channels and proteins (Guggino, W.B. et al. (2006), Nat Revs Molecular Cell Biology Ί , 426-436).

[0007] Aberrations in CFTR function result in imbalance of the airway surface liquid, leading to mucus dehydration, inflammation, recurrent bacterial infection and irreversible lung damage, which lead to premature death in affected patients. Besides respiratory disease, CF patients suffer from gastrointestinal problems and pancreatic insufficiency. The majority of males (95%) with cystic fibrosis are infertile as a result of azoospermia caused by altered vas deferens; which may be absent, atrophic, or fibrotic. Fertility is also decreased among females with cystic fibrosis due to abnormal cervical mucus.The F508del mutation, the most common of the approximately 1900 identified polymorphisms in CFTR, results in defective processing of CFTR in the endoplasmic reticulum (ER) (http: / / www.cftr2.org / index.php). Approximately 90% of the CF patients carry at least one copy of the F508del mutation (deletion of a phenylalanine on position 508), and 50% - 60% of the patients are homozygous for this mutation. The defective processing of CFTR results in early CFTR degradation, which leads to reduced trafficking or absence of the protein on the membrane. As there have been over 100 CF disease-causing mutations identified, they have been classified according to their phenotypic consequences and belong to synthesis, maturation, regulation, conductance, reduced number due to quantity and reduced number due to stability classifications.

[0008] Current CF drug discovery efforts focus upon developing two classes of compounds to modulate CFTR. One class, called Correctors, helps to overcome the folding defects of the mutated CFTR protein to promote its maturation resulting in higher cell surface expression. The other classes of compounds, called Potentiators, help overcome the defective regulation and / or conductance of the protein by increasing the probability of channel opening on the membrane surface.

[0009] In addition, as the modulation of CFTR protein mutations to promote proper protein folding is beneficial for CF, there are other diseases mediated by CFTR. For example, Sjogren's Syndrome (SS), an autoimmune disorder that results in symptoms of xerostomia (dry mouth) and keratoconjunctivitis sicca (KCS, dry eyes) may result from dysregulation of moisture producing glands throughout the body. Chronic obstructive lung disease (COLD), or chronic obstructive airway disease (COAD), which is a progressive and irreversible airflow limitation in the airways is result of several physiologic abnormalities, including mucus hyper secretion and impaired mucociliary secretion. Increasing the anion secretion by CFTR potentiators have been suggested to overcome these phenotypic complexities with Sjogren's Syndrome by increasing the corneal hydration and by overcoming the impaired mucociliary secretion in COAD (Bhowmik A, et al. (2009) Vol. 103(4), 496-502; Sloane P, et al. PLOS One (2012) Vol 7(6), 239809 (1-13)).

[0010] Accordingly, there is a need for novel compounds able to modulate CFTR. In particular, the present invention discloses compounds that may act as CFTR modulators for the treatment of cystic fibrosis. The present invention also provides methods for the preparation of thesecompounds, pharmaceutical compositions comprising these compounds and methods for the treatment of cystic fibrosis by administering the compounds of the invention.

[0011] SUMMARY

[0012] In one aspect the invention rovides for compounds of formula (I)

[0014] (I)

[0015] or a pharmaceutically acceptable salt thereof, wherein:

[0016] X is CR2and Y is CR3; or

[0017] X is N and Y is CR3; or

[0018] X is CR2and Y is N;

[0019] m is 0, 1, 2, or 3;

[0020] R" are optional substituents on the cyclopropyl ring, and at each occurrence, are each

[0021] independently halogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0022] R1and R2, are each independently hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR , -C(0)OR1B, -NR1AR2A, or -C(0)NR1AR2A;

[0023] R1Aand R2A, at each occurrence, are each independently hydrogen, Ci-C6haloalkyl, G1A, or Ci- C6alkyl; wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORZA, -SRZA, -S(0)2RZA, -C(0)RZA, -C(0)ORZA, -C(0)N(RZA)2, -N(RZA)2, -N(RZA)C(0)RZB, -N(RZA)S(0)2RZB, -N(RZA)C(0)ORZB, -N(RZA)C(0)N(RZA)2, -CN, and G1A; or R1Aand R2Atogether with the nitrogen atom to which they are attached form a 4-6 membered heterocycle wherein the 4-6 membered heterocycle is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci-C6alkyl, Ci-C6haloalkyl, -ORj, and N(Rj)2; wherein

[0024] RZA, at each occurrence, is independently hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, G1A, or -(Ci- C6alkylenyl)-G1A; andR , at each occurrence, is independently Ci-C6haloalkyl, Ci-C6alkyl, G , or -(Ci-C6alkylenyl)-G1A;

[0025] R1Bis hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0026] R3and R14, are each independently hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OH, or

[0027] -0-(Ci-C6alkyl);

[0028] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0029] R5is hydrogen, -C(0)R -C(0)OH, -C(0)0(Ci-C6alkyl), -C(0)N(Rh)2, Ci-C6haloalkyl, Ci-C6alkyl, or G2A; wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -OC(0)N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2R\ -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, and G2A; or

[0030] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups;

[0031] G2A, at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or

[0032] heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rqgroups;

[0033] Rpand Rq, at each occurrence, are each independently Ci-C6alkyl, halogen, Ci-C6haloalkyl,

[0034] -CN, oxo, N02, -ORh, -OCCC R1, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -C(0)N(Rh)S(0)2Rh, -N(Rh)2, - CR^C^R1, -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -OC(0)R\ -OC(0)N(Rh)2, -SRh, -S(0)2Rh,

[0035] -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -C(0)N(Rh)S(0)2Rh, -N(Rh)2,

[0036] -N(Rh)C(0)R\ -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, -CN, and GA;

[0037] Rh, at each occurrence, is independently hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRj, -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;R1, at each occurrence, is independently Ci-C6haloalkyl, Ci-C6alkyl, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRJ,

[0038] -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;

[0039] R6is hydrogen, halogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0040] R7is hydrogen, halogen, -ORj, -N(Rj)2, -N(Rj)C(0)Rk, C C6haloalkyl, C C6alkyl, C2-C6alkenyl, or -(Ci-C6alkylenyl)-G3A;

[0041] R8is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0042] R9, R10, and R13, are each independently hydrogen, halogen, -ORJ, Ci-C6haloalkyl, or Ci-C6alkyl;

[0043] R11and R12are each independently hydrogen, C1-C3 alkyl, or halogen;

[0044] G1A, G3A, and GA, at each occurrence, are each independently cycloalkyl, cycloalkenyl,

[0045] heterocycle, aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rsgroups; wherein

[0046] Rs, at each occurrence, is independently Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, Ci- C6haloalkyl, -CN, oxo, N02, -ORj, -OC(0)Rk, -OC(0)N(Rj)2, -SRj, -S(0)2Rj,

[0047] -S(0)2N(RJ)2, -C(0)RJ, -C(0)ORJ, -C(0)N(RJ)2, -N(RJ)2, -N(RJ)C(0)Rk, -N(RJ)S(0)2Rk, -N(Rj)C(0)0(Rk), -N(Rj)C(0)N(Rj)2, -(C C6alkylenyl)-ORj, -(C C6

[0048] alkylenyl)-OC(0)Rk, -(C C6alkylenyl)-OC(0)N(Rj)2, -(C C6alkylenyl)-SRj, -(C C6alkylenyl)-S(0)2Rj, -(Ci-C6alkylenyl)-S(0)2N(Rj)2, -(Ci-C6alkylenyl)-C(0)Rj, -(Ci-C6alkylenyl)-C(0)ORj, -(Ci-C6alkylenyl)-C(0)N(Rj)2, -(Ci-C6alkylenyl)-N(Rj)2, -(Ci-C6alkylenyl)-N(Rj)C(0)Rk, -(Ci-C6alkylenyl)-N(Rj)S(0)2Rk, -(Ci-C6

[0049] alkylenyl)-N(Rj)C(0)0(Rk), -(C C6alkylenyl)-N(Rj)C(0)N(Rj)2, or -(C C6

[0050] alkylenyl)-CN;

[0051] RJ, at each occurrence, is independently hydrogen, Ci-C6alkyl, or Ci-C6haloalkyl; and

[0052] Rk, at each occurrence, is independently Ci-C6alkyl or Ci-C6haloalkyl.

[0053] Another aspect of the invention relates to pharmaceutical compositions comprising compounds of the invention or pharmaceutically acceptable salts thereof, and a pharmaceutical carrier. Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator activity. In a particularaspect, the pharmaceutical compositions may additionally comprise further one or more therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of cystic fibrosis.

[0054] Moreover, the compounds of the invention or pharmaceutically acceptable salts thereof, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0055] Yet another aspect of the invention relates to a method of correcting the folding defects of the mutated CFTR protein(s) to promote its maturation resulting in higher cell surface expression. The method is useful for treating, or preventing conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator activity in mammals. More particularly, the method is useful for treating or preventing conditions and disorders related to cystic fibrosis, Sjogren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, or chronic obstructive airway disease. Accordingly, the compounds and compositions of the invention are useful as a medicament for treating or preventing Cystic Fibrosis Transmembrane Conductance Regulator modulated disease.

[0056] The compounds, compositions comprising the compounds or pharmaceutically acceptable salts thereof, methods for making the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.

[0057] In a particular aspect, the compounds of the invention or pharmaceutically acceptable salts thereof are provided for use in the treatment of cystic fibrosis. In a particular aspect, the compounds of the invention or pharmaceutically acceptable salts thereof are provided for use in the treatment of cystic fibrosis caused by class I, II, III, IV, V, and / or VI mutations.

[0058] The present invention also provides pharmaceutical compositions comprising a compound of the invention or pharmaceutically acceptable salts thereof, and a suitable pharmaceutical carrier for use in medicine. In a particular aspect, the pharmaceutical

[0059] composition is for use in the treatment of cystic fibrosis.

[0060] In an alternative embodiment, certain compounds of the invention have a corrector activity.In another particular aspect, certain compounds of the invention have improved potency, in addition to exhibiting low effects on CYP3A4 expression, which suggest low drug-drug interaction potential, and accordingly may be advantageous for patients under multiple therapies.

[0061] These and other objects of the invention are described in the following paragraphs.

[0062] These objects should not be deemed to narrow the scope of the invention.

[0063] DETAILED DESCRIPTION OF THE INVENTION

[0064] Described herein are com ounds of formula (I)

[0066] (I)

[0067] wherein R1, X, Y, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R"are defined above in the Summary of the Invention and below in the Detailed Description. Further, compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also included.

[0068] Compounds included herein may contain one or more variable(s) that occur more than one time in any substituent or in the formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds, which can be isolated from a reaction mixture.

[0069] Definitions

[0070] It is noted that, as used in this specification and the intended claims, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound as well as one or more of the same or different compounds, reference to "optionally a pharmaceutically acceptable carrier" refers to a single optional pharmaceutically acceptable carrier as well as one or more

[0071] pharmaceutically acceptable carriers, and the like.

[0072] As used in the specification and the appended claims, unless specified to the contrary, thefollowing terms have the meaning indicated:

[0073] The term "alkenyl" as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond. The term "C2-C6alkenyl" means an alkenyl group containing 2-6 carbon atoms. Non-limiting examples of C2-C6alkenyl include buta-l,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, and 5-hexenyl.

[0074] The term "alkyl" as used herein, means a saturated, straight or branched hydrocarbon chain radical. In some instances, the number of carbon atoms in an alkyl moiety is indicated by the prefix "Cx-Cy", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "Ci-C6alkyl" means an alkyl substituent containing from 1 to 6 carbon atoms and "C1-C3alkyl" refers to an alkyl substituent containing from 1 to 3 carbon atoms. Representative examples of Ci-C6alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2- dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, and 1,2,2- trimethy lpropy 1.

[0075] The term "alkylene" or "alkylenyl" means a divalent radical derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms (Ci-C6alkylenyl) or of 1 to 4 carbon atoms or of 1 to 3 carbon atoms (C1-C3alkylenyl) or of 2 to 6 carbon atoms (C2-C6alkylenyl). Examples of Ci-C6alkylenyl include, but are not limited to, -CH2-, -CH2CH2-, -C((CH3)2)-CH2CH2CH2-, -C((CH3)2)-CH2CH2,

[0076] -CH2CH2CH2CH2-, and -CH2CH(CH3)CH2-.

[0077] The term "C2-C6alkynyl" as used herein, means a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of C2-C6alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0078] The term "aryl" as used herein, means phenyl or a bicyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl. Non-limiting examples of the aryl groups include dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. The phenyl and the bicyclic aryls (including exemplary rings) are optionally substituted unless otherwise indicated. The phenyland the bicyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the bicyclic ring systems.

[0079] The term "cycloalkyl" as used herein, refers to a radical that is a monocyclic cycloalkyl or a bicyclic cycloalkyl. The monocyclic cycloalkyl is a carbocyclic ring system containing three to eight carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring. The monocyclic and the bicyclic cycloalkyl groups may further contain one or two alkylene bridges, each consisting of one, two, three, or four carbon atoms in length, and each bridge links two non- adjacent carbon atoms of the ring system. Non-limiting examples of bridged ring systems include bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[l .l . l]pentyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, tricyclo[3.3.1.03'7]nonyl

[0080] (octahydro-2,5-methanopentalene or noradamantyl), and tricyclo[3.3.1.13'7]decane (adamantyl). The monocyclic and the bicyclic cycloalkyls, including exemplary rings, are optionally substituted unless otherwise indicated. The monocyclic cycloalkyl and the bicyclic cycloalkyl are attached to the parent molecular moiety through any substitutable carbon atom contained within the ring systems.

[0081] The term "C3-C6cycloalkyl" as used herein, means cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted unless otherwise indicated.

[0082] The term "cycloalkenyl" as used herein, refers to a monocyclic or a bicyclic hydrocarbon ring radical. The monocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms and zero heteroatoms. The four-membered ring systems have one double bond, the five-or six- membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two, or three double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. The monocyclic and bicyclic cycloalkenyl ring may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, and each linking two non- adjacent carbon atoms of the ring system. Representative examples of the bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl,and 1,6-dihydro-pentalene. The monocyclic and the bicyclic cycloalkenyls, including exemplary rings, are optionally substituted unless otherwise indicated. The monocyclic cycloalkenyl and bicyclic cycloalkenyl are attached to the parent molecular moiety through any substitutable atom contained within the ring systems.

[0083] The term "halo" or "halogen" as used herein, means CI, Br, I, and F.

[0084] The term "haloalkyl" as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term "Ci-C6haloalkyl" means a Ci-C6alkyl group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen. The term "C1-C3haloalkyl" means a C1-C3alkyl group, as defined herein, in which one, two, three, four, or five hydrogen atoms are replaced by halogen. Representative examples of Ci-C6haloalkyl include, but are not limited to,

[0085] chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, f uoromethyl, 2,2,2-trif uoroethyl,

[0086] trifluoromethyl, difluoromethyl, pentaf uoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl.

[0087] The term "heterocycle" or "heterocyclic" as used herein, means a radical of a monocyclic heterocycle and a bicyclic heterocycle. A monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered carbocyclic ring wherein at least one carbon atom is replaced by heteroatom independently selected from the group consisting of O, N, and S. A three- or four- membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. A five-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of five- membered heterocyclic rings include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N. Non limiting examples of 5-membered heterocyclic groups include 1,3-dioxolanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl, and thiazolidinyl. A six- membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of six-membered heterocyclic rings include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. Examples of 6- membered heterocyclic groups include tetrahydropyranyl, dihydropyranyl, dioxanyl, 1 ,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl, piperidinyl, 1,2,3,6- tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl, and trithianyl. Seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,

[0088] tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-lH-indolyl, 3,4-dihydroisoquinolin- 2( 1 H)-yl, 2,3 ,4,6-tetrahydro- 1 H-pyrido[ 1 ,2-a]pyrazin-2-yl, hexahydropyrano[3 ,4-b] [ 1 ,4]oxazin- l(5H)-yl. The monocyclic heterocycle and the bicyclic heterocycle may further contain one or two alkylene bridges, each consisting of no more than four carbon atoms and each linking two non-adjacent atoms of the ring system. Examples of such bridged heterocycle include, but are not limited to, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 8- azabicyclo[3.2. l]oct-8-yl, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[¾]furan, hexahydro- \H- 1 ,4-methanocyclopenta[c]furan, aza-admantane (l-azatricyclo[3.3.1.13'7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13'7]decane). The monocyclic and the bicyclic heterocycles, including exemplary rings, are optionally substituted unless otherwise indicated. The monocyclic and the bicyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring systems. The nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized (e.g. 1,1-dioxidotetrahydrothienyl, l,l-dioxido-l,2-thiazolidinyl, 1,1- dioxidothiomorpholinyl)) and the nitrogen atoms may optionally be quarternized.The term "4-6 membered heterocycle" or "4-6 membered heterocyclic" as used herein, means a 4, 5, or 6 membered monocyclic heterocycle as defined herein above. Examples of 4-6 membered heterocycle include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl, thiomorpholinyl, and morpholinyl. The 4-6 membered heterocycles, including exemplary rings, are optionally substituted unless indicated otherwise.

[0089] The term "5-6 membered heterocycle" or "5-6 membered heterocyclic" as used herein, means a 5 or 6 membered monocyclic heterocycle as defined herein above. Examples of 5-6 membered heterocycle include 1,3-dioxolanyl, pyrrolidinyl, 1 ,2-thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl, thiomorpholinyl, and morpholinyl. The 5-6 membered heterocycles, including exemplary rings, are optionally substituted unless indicated otherwise.

[0090] The term "heteroaryl" as used herein, means a monocyclic heteroaryl and a bicyclic heteroaryl. The monocyclic heteroaryl is a five- or six-membered ring. The five-membered ring contains two double bonds. The five membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom. The six-membered ring contains three double bonds and one, two, three or four nitrogen atoms. Representative examples of monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle. Representative examples of bicyclic heteroaryls include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol- 5(4H)-yl, 6,7-dihydro-pyrazolo[ 1 ,5-a]pyrazin-5(4H)-yl, 6,7-dihydro- 1 ,3-benzothiazolyl, imidazo[l,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 2,4,6, 7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl, thiazolo[5,4- b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroaryls, including exemplary rings, are optionally substituted unless otherwise indicated. The monocyclic and bicyclic heteroaryls are connected to the parentmolecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the ring systems. The nitrogen atom in the heteroaryl rings may optionally be oxidized and may optionally be quarternized.

[0091] The term "5-6 membered heteroaryl" as used herein, means a 5- or 6-membered monocyclic heteroaryl as described above. Examples of 5-6 membered heteroaryl include furanyl, thienyl, pyrazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,3-thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl. The 5-6 membered heteroaryls, including exemplary rings, are optionally substituted unless indicated otherwise.

[0092] The term "heteroatom" as used herein, means a nitrogen, oxygen, and sulfur.

[0093] The term "oxo" as used herein, means a =0 group.

[0094] The term "radiolabel" refers to a compound of the invention in which at least one of the atoms is a radioactive atom or radioactive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, for example alpha particles or beta particles, or positrons. Examples of such radioactive atoms include, but are not limited to,3H

[0095] 15

[0096] O, 18 F, 35cS, 123tI, and . 125TI.

[0097] If a moiety is described as "substituted", a non-hydrogen radical is in the place of hydrogen radical of any substitutable atom of the moiety. Thus, for example, a substituted heterocycle moiety is a heterocycle moiety in which at least one non-hydrogen radical is in the place of a hydrogen radical on the heterocycle. It should be recognized that if there are more than one substitution on a moiety, each non-hydrogen radical may be identical or different (unless otherwise stated).

[0098] If a moiety is described as being "optionally substituted," the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described asbeing optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.

[0099] Unless otherwise indicated, the terms Ci-C6alkyl, C1-C3alkyl, Ci-C6haloalkyl, and Ci- C3haloalkyl are not further substituted.

[0100] The terms "treat", "treating", and "treatment" refer to a method of alleviating or abrogating a disease and / or its attendant symptoms.

[0101] The terms "prevent", "preventing", and "prevention" refer to a method of preventing the onset of a disease and / or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject's risk of acquiring a disease.

[0102] The phrase "therapeutically effective amount" means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with one or more additional therapeutic agents or treatment in a particular subject or subject population. For example in a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.

[0103] The term "subject" is defined herein to refer to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.

[0104] The term One or more' refers to one to four. In one embodiment it refers to one or three. In another embodiment it refers to one to three. In a further embodiment it refers to one to two. In yet other embodiment it refers to two. In yet other further embodiment it refers to one.

[0105] As used herein, "Class I mutation(s)" refers to mutations which interfere with protein synthesis. They result in the introduction of a premature signal of termination of translation (stop codon) in the mRNA. The truncated CFTR proteins are unstable and rapidly degraded, so, the net effect is that there is no protein at the apical membrane. In particular, Class I mutation(s) refers to p.Gly542X (G542X), W1282X, c.489+lG>T (621+lOT), or c.579+lG>T(711+1 G>T) mutation. More particularly, Class I mutation(s) refers to G542X; or W1282X mutations.

[0106] As used herein, "Class II mutation(s)" refers to mutations which affect protein

[0107] maturation. These lead to the production of a CFTR protein that cannot be correctly folded and / or trafficked to its site of function on the apical membrane. In particular, Class II mutation(s) refers to p.Phe508del (F508del), p.Ile507del, or p.Asnl303Lys (N1303K) mutations. More particularly, Class II mutation(s) refers to F508del or N1303K mutations.

[0108] As used herein, "Class III mutation(s)" refers to mutations which alter the regulation of the CFTR channel. The mutated CFTR protein is properly trafficked and localized to the plasma membrane but cannot be activated, or it cannot function as a chloride channel. In particular, Class III mutation(s) refers to p.Gly551Asp (G551D), G551S, R553G; G1349D; S 125 IN, G178R, S549N mutations. More particularly, Class III mutation(s) refers to G551D, R553G, G1349D, S 125 IN, G178R, or S549N mutations.

[0109] As used herein, "Class IV mutation(s)" refers to mutations which affect chloride conductance. The CFTR protein is correctly trafficked to the cell membrane but generates reduced chloride flow or a "gating defect" (most are missense mutations located within the membrane-spanning domain). In particular, Class IV mutation(s) refers to p.Argl 17His

[0110] (Rl 17H), R347P, or p.Arg334Trp (R334W) mutations.

[0111] As used herein, "Class V mutation(s)" refers to mutations which reduce the level of normally functioning CFTR at the apical membrane or result in a "conductance defect" (for example partially aberrant splicing mutations or inefficient trafficking missense mutations). In particular, Class V mutation(s) refers to C.1210-12T[5] (5T allele), c.S3140-26A>G (3272- 26A>G), C.3850-2477OT (3849+1 OkbOT) mutations.

[0112] As used herein, "Class VI mutation(s)" refers to mutations which decrease the stability of the CFTR which is present or which affect the regulation of other channels, resulting in inherent instability of the CFTR protein. In effect, although functional, the CFTR protein is unstable at the cell surface and it is rapidly removed and degraded by cell machinery. In particular, Class VI mutation(s) refers to Rescued F508del, 120del23, N287Y, 4326dellTC, or 4279insA mutations. More particularly, Class VI mutation(s) refers to Rescued F508del mutations.

[0113] Compounds

[0114] Compounds of the invention have the general formula (I) as described above.Particular values of variable groups are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined

[0115] hereinbefore or hereinafter.

[0116] In certain embodiments of formula (I), X is CR2and Y is CR3. Thus, included herein are compounds of formula (I-a) or harmaceutically acceptable salts thereof

[0118] (I-a)

[0119] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R", are as defined in the Summary and embodiments herein below.

[0120] In certain embodiments of formula (I), X is N and Y is CR3. Thus, included herein are compounds of formula (I-b) or pharmaceutically acceptable salts thereof

[0122] (I-b)

[0123] wherein R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R", are as defined in the Summary and embodiments herein below.

[0124] In certain embodiments of formula (I), X is CR2and Y is N. Thus, included herein are compounds of formula (I-c) or harmaceutically acceptable salts thereof

[0125] (I-c)

[0126] wherein R1, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R", are as defined in the Summary and embodiments herein below.

[0127] In certain embodiments, m is 0, 1, 2, or 3.

[0128] In certain embodiments, m is 0.

[0129] In certain embodiments, m is 2.

[0130] In certain embodiments, R", if present, is halogen. In some such embodiments, R" is F.

[0131] In certain embodiments, R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, -C(0)OR1B, -NR1AR2A, or -C(0)NR1AR2A.

[0132] In certain embodiments, R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B. In some such embodiments, R1Ais C1-C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl.

[0133] In certain embodiments, R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A. In some such embodiments, R1Ais C1-C3alkyl.

[0134] In certain embodiments, R1is hydrogen, C1-C3alkyl, or -OR1A. In some such

[0135] embodiments, R1Ais C1-C3alkyl.

[0136] In certain embodiments, R1is hydrogen, CH3, or -OCH3.

[0137] In certain embodiments, R1is hydrogen.

[0138] In certain embodiments, R1is halogen. In some such embodiments, R1is F or CI. In some such embodiments, R1is F.

[0139] In certain embodiments, R1is -OR1A. In some such embodiments, R1Ais C1-C3haloalkyl or C1-C3alkyl. In some such embodiments, R1Ais C1-C3alkyl. In some such embodiments, R1Ais CH3.

[0140] In certain embodiments, R1is Ci-C6alkyl. In some such embodiments, R1is C1-C3alkyl. In some such embodiments, R1is CH3.

[0141] In certain embodiments, R1is -C(0)OR1B. In some such embodiments, R1Bis hydrogen or C1-C3alkyl. In some such embodiments, R1Bis hydrogen or CH3. In some such

[0142] embodiments, R1Bis hydrogen. In some such embodiments, R1Bis CH3

[0143] In certain embodiments, R2is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B. In some such embodiments, R1Ais hydrogen, C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one substituent selected from the groupconsisting of -OR , -C(0)OH, and G ; and R is hydrogen or C1-C3alkyl. In some such embodiments, G1Ais phenyl optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently C1-C3alkyl, C1-C3haloalkyl, halogen, or -OCH3. In some such embodiments, G1Ais unsubstituted phenyl. In some such embodiments, RZAis C1-C3haloalkyl or C1-C3alkyl.

[0144] In certain embodiments, R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A. In some such embodiments, the halogen is Br, F or CI. In some such embodiments, R1Ais C1-C3haloalkyl or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein RZAis C1-C3alkyl.

[0145] In certain embodiments, R2is hydrogen, halogen, or -OR1Awherein R1Ais C1-C3alkyl or C1-C3haloalkyl. In some such embodiments, the halogen is F or CI.

[0146] In certain embodiments, R2is hydrogen, F, CF3, CH3, -OCH3, -OCHF2, -OCH2CH2F, or -OCH2CH2OCH3.

[0147] In certain embodiments, R2is hydrogen.

[0148] In certain embodiments, R2is halogen. In some such embodiments, the halogen is F, CI, or Br. In some such embodiments, the halogen is F or CI.

[0149] In certain embodiments, R2is Ci-C6haloalkyl. In certain embodiments, R2is C1-C3haloalkyl. In some such embodiments, R2is CF3.

[0150] In certain embodiments, R2is Ci-C6alkyl. In some such embodiments, R2is C1-C3alkyl. In some such embodiments, R2is CH3.

[0151] In certain embodiments, R2is -OR1A.

[0152] In certain embodiments, R2is -OR1Awherein R1Ais C1-C3haloalkyl or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one substituent selected from the group consisting of -ORZA, -C(0)OH, and G1A. In some such embodiments, G1Ais phenyl optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently C1-C3alkyl, C1-C3haloalkyl, halogen, or -OCH3. In some such embodiments, G1Ais unsubstituted phenyl. In some such embodiments, RZAis C1-C3haloalkyl or C1-C3alkyl. In some such embodiments, RZAis C1-C3alkyl.

[0153] In certain embodiments R2is -OR1Awherein R1Ais -CHF2, -CH2CH2F, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -OCH3.

[0154] In certain embodiments, R3is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OH, or -0-(Ci-C6alkyl).In certain embodiments, R3is hydrogen or halogen. In some such embodiments, the halogen is F or CI. In some such embodiments, the halogen is F.

[0155] In certain embodiments, R3is hydrogen.

[0156] In certain embodiments, R3is halogen. In some such embodiments, the halogen is F or CI. In some such embodiments, the halogen is F.

[0157] In certain embodiments, R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl; and R5is hydrogen, -C(0)R -C(0)OH, -C(0)0(Ci-C6alkyl), -C(0)N(Rh)2, Ci-C6haloalkyl, Ci-C6alkyl, or G2A.

[0158] In certain embodiments, R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl; and R5is hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or G2A. In some such embodiments, G2Ais phenyl, C3- C6cycloalkyl, 4-6 membered heterocycle, or 5-6 membered heteroaryl. In some such embodiments, G2Ais phenyl, cyclopropyl, cyclohexyl, azetidinyl, tetrahydrofuranyl or pyridinyl. In some such embodiments, G2Ais phenyl or cyclohexyl. In some such embodiments, G2Ais phenyl. In some such embodiments, G2Ais monocyclic cycloalkyl. In some such embodiments, G2Ais cyclopropyl, cyclobutyl, bicyclo[l .l . l]pentyl, or cyclohexyl. In some such embodiments, G2Ais C3-C6cycloalkyl. In some such embodiments, G2Ais cyclopropyl or cyclohexyl. In some such embodiments, G2Ais cyclohexyl. In some such embodiments, G2Ais 5-6 membered heteroaryl. In some such embodiments, G2Ais thiazolyl or pyridinyl. In some such

[0159] embodiments, G2Ais pyridinyl. In some such embodiments, G2Ais 4-6 membered heterocycle. In some such embodiments, G2Ais azetidinyl or tetrahydrofuranyl.

[0160] In certain embodiments, R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl; and R5is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl.

[0161] In certain embodiments, R4is hydrogen, CH2F, CHF2, CF3, CH3, or CH2CH3; and R5is hydrogen, CH2F, CHF2, CH3, or CH2CH3.

[0162] In certain embodiments, R4is hydrogen or Ci-C3alkyl; and R5is hydrogen or Ci-C3alkyl.

[0163] In certain embodiments, R4is hydrogen; and R5is hydrogen.

[0164] In certain embodiments, R4is hydrogen, Ci-C3haloalkyl, or Ci-C3alkyl; and R5is G2A. In certain embodiments, R4is hydrogen or Ci-C3alkyl; and R5is G2A.

[0165] In certain embodiments, R4is hydrogen and R5is G2A.In certain embodiments, examples of G include phenyl, monocyclic cycloalkyl (for example, cyclopropyl, cyclobutyl, bicyclo[l . l .l]pentyl, or cyclohexyl), 4-6 membered heterocycle (for example, azetidinyl or tetrahyrofuranyl), or 5-6 membered heteroaryl (for example, thiazolyl or pyridinyl).

[0166] In certain embodiments, examples of G2Ainclude phenyl, C3-C6cycloalkyl (for example, cyclopropyl, cyclohexyl), 4-6 membered heterocycle (for example, azetidinyl, tetrahyrofuranyl), or 5-6 membered heteroaryl (for example, pyridinyl).

[0167] In certain embodiments, G2Ais phenyl, cyclopropyl, cyclobutyl, cyclohexyl,

[0168] bicyclo[l .l . l]pentyl, azetidinyl, tetrahyrofuranyl, thiazolyl, or pyridinyl.

[0169] In certain embodiments, G2Ais phenyl, cyclopropyl, cyclohexyl, azetidinyl,

[0170] tetrahyrofuranyl, or pyridinyl.

[0171] In certain embodiments, G2Ais phenyl.

[0172] In certain embodiments, G2Ais monocyclic cycloalkyl.

[0173] In certain embodiments, G2Ais C3-C6cycloalkyl.

[0174] In certain embodiments, G2Ais 4-6 membered heterocycle.

[0175] In certain embodiments, G2Ais 5-6 membered heteroaryl.

[0176] In certain embodiments, G2Ais phenyl or cyclohexyl.

[0177] In certain embodiments, G2Ais cyclopropyl or cyclohexyl.

[0178] In certain embodiments, G2Ais cyclohexyl.

[0179] Each G2A, including specific examples, is optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0180] In certain embodiments, G2A, including specific examples, is unsubstituted.

[0181] In certain embodiments, G2A, including specific examples, is substituted with 1, 2, or 3 independently selected Rqgroups.

[0182] In certain embodiments, G2A, including specific examples, is substituted with one Rqgroup.

[0183] In certain embodiments, Rq, when present, is

[0184] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH group;

[0185] halogen,

[0186] Ci-C6haloalkyl;

[0187] -ORhwherein Rhis hydrogen or C1-C3alkyl,-C(0)Rhwherein Rhis GA; and GAis optionally substituted 4-6 membered heterocycle; -C(0)ORhwherein Rhis hydrogen or C C6alkyl;

[0188] -C(0)N(Rh)2; wherein Rh, at each occurrence, is independently hydrogen, optionally substituted cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci-C6alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of -OH and optionally substiuted cycloalkyl;

[0189] -C(0)N(Rh)S(0)2Rhwherein Rhis hydrogen or Ci-C6alkyl; or

[0190] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0191] In certain embodiments, Rq, when present, is

[0192] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH group;

[0193] halogen,

[0194] Ci-C6haloalkyl;

[0195] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[0196] -C(0)Rhwherein Rhis GA; and GAis optionally substituted 4-6 membered heterocycle; -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl;

[0197] -C(0)N(Rh)2; wherein Rh, at each occurrence, is independently hydrogen, optionally substituted cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci-C6alkyl are each optionally substituted with 1 or 2 -OH groups; or

[0198] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0199] In certain embodiments, Rq, when present, is -ORhwherein Rhis C1-C3alkyl, or Rqis -C(0)ORhwherein Rhis hydrogen or C C6alkyl.

[0200] In certain embodiments, one of Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl, or one of Rqis -C(0)N(H)(Rh) wherein Rhis cyclopentyl, or Rhis Ci-C6alkyl which is substituted with 1 or 2 -OH groups; and the other optional Rqgroups are independently selected from the group consisting of C1-C3alkyl, halogen, and C1-C3haloalkyl.

[0201] In certain embodiments, Rqis -C(0)ORhwherein Rhis hydrogen or C1-C3alkyl. In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0202] In certain embodiments, G2Ais; wherein Rhis hydrogen or C1-C3alkyl. In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0203] In certain embodiments, G iswherein Rhis hydrogen or C1-C3alkyl. In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0204] embodiments, G is; wherein Rhis hydrogen or C1-C3alkyl. In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0205] In certain embodiments, G is; wherein Rhis hydrogen or C1-C3alkyl. In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0206] In certain embodiments, R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl; and R5is -C(0)OH, -C(0)0(Ci-C6alkyl), -C(0)R\ or -C(0)N(Rh)2. In some such embodiments, R' is optionally substituted monocyclic heterocycle. In some such embodiments, one of Rhis hydrogen or Ci-C6alkyl which is optionally substituted with one or two -OH, and the other Rhis optionally substituted monocyclic heterocycle, optionally substituted aryl, or Ci-C6alkyl which is optionally substituted with one or two substituents independently selected from the goup consisting of -OH and optionally substituted phenyl.

[0207] In certain embodiments, R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle.

[0208] In certain embodiments R4and R5, together with the carbon atom to which they are attached, form a 4-6 membered heterocycle. In some such embodiments, the 4-6 membered heterocycle is azetidinyl or piperidinyl.

[0209] In certain embodiments R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl, optionally substituted with 1 or 2 Rpgroups.In certain embodiments, the C3-C6 cycloalkyl is unsubstituted cyclobutyl or unsubstituted cyclopentyl.

[0210] In certain embodiments, the 4-6 membered heterocycle formed by R4and R5, and the carbon atom to which they are attached, is optionally substituted with 1 or 2 Rpgroups.

[0211] In certain embodiments, Rp, when present, are each independently

[0212] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups; -C(0)Rhwherein Rhis Ci-C6alkyl;

[0213] C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl or -CH2-phenyl; or

[0214] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0215] In certain embodiments, R6is hydrogen or C1-C3alkyl; and R7is hydrogen or C1-C3alkyl.

[0216] In certain embodiments, R6is hydrogen and R7is hydrogen.

[0217] In certain embodiments, R6is hydrogen or C1-C3alkyl; and R7is -(Ci-C6alkylenyl)-G3A. In some such embodiments, R7is -(CH2)-G3A.

[0218] In certain embodiments, G3Ais phenyl which is optionally substituted with 1, 2, or 3 independently selected Rsgroups. In some such embodiments, each Rsis independently C1-C3alkyl, halogen, C1-C3haloalkyl, or -ORJwherein RJis hydrogen or C1-C3alkyl. In some such embodiments, each Rsis independently -ORJwherein RJis C1-C3alkyl.

[0219] In certain embodiments of, R8is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl.

[0220] In certain embodiments, R8is hydrogen.

[0221] In certain embodiments, R9, R10, and R13, are each independently hydrogen, halogen, -ORj, Ci-C6haloalkyl, or Ci-C6alkyl.

[0222] In certain embodiments, R9, R10, and R13, are each independently hydrogen or halogen. In certain embodiments, R9, R10, and R13are hydrogen.

[0223] In certain embodiments, R11and R12, are each independently hydrogen, C1-C3alkyl, or halogen.

[0224] In certain embodiments, R11and R12are each independently hydrogen or halogen. In some such embodiments, the halogen is F.

[0225] 11 12 11 12

[0226] In certain embodiments, R and R are hydrogen, or R and R are halogen. In some such embodiments, the halogen is F.

[0227] In certain embodiments, R11and R12are hydrogen.In certain embodiments, R11and R12are halogen.

[0228] In certain embodiments, R11and R12are F.

[0229] In certain embodiments, R14is hydrogen or halogen.

[0230] In certain embodiments, R14is hydrogen.

[0231] Various embodiments of substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R have been discussed above. These substituents embodiments can be combined to form various embodiments of the invention. All embodiments of present compounds, formed by combining the substituent embodiments discussed above are within the scope of Applicant's invention, and some illustrative embodiments of present compounds are provided below.

[0232] In one embodiment, the invention is directed to compounds of formula (I), (la), (I-b), or (I-c) wherein R8is hydrogen; and m is 0.

[0233] In one embodiment, the invention is directed to compounds of formula (I), (la), (I-b), or

[0234] (I-c) wherein R 8 is hydrogen; m is 0, and R 9 R 10 , and R 113Jare each independently hydrogen or halogen.

[0235] In one embodiment, the invention is directed to compounds of formula (I), (la), (I-b), or

[0236] (I-c) wherein R 8 is hydrogen; m is 0, and R 9 , R 10 , and R 13 are hydrogen.

[0237] In one embodiment, the invention is directed to compounds of formula (I), (la), (I-b), or

[0238] (I-c) wherein R 8 is hydrogen; m is 0, R 9 R 10 , and R 113Jare each independently hydrogen or halogen; and R 11 and R 12 are hydrogen, or R 11 and R 12 are halogen. In some such embodiment, the halogen is F.

[0239] In one embodiment, the invention is directed to compounds of formula (I), (la), (I-b), or

[0240] 8 9 10 13 11 12

[0241] (I-c) wherein R is hydrogen; m is 0, R , R , and R are hydrogen, and R and R are halogen. In some such embodiment, R11and R12are F.

[0242] In one embodiment, the invention is directed to compounds of formula (I), (la), (I-b), or

[0243] (I-c) wherein R 8 is hydrogen; m is 0, R 9 , R10 , and R 13 are hydrogen, R 11 and R 12 are halogen, and R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl. In some such embodiment, R11and R12are F.

[0244] In one embodiment, the invention is directed to compounds of formula (I), (la), or (I-c), wherein

[0245] R8is hydrogen;m is 0,

[0246] R9, R10, and R13are hydrogen,

[0247] R11and R12are halogen,

[0248] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or C1-C3 alkyl; and R1Bis hydrogen or C1-C3alkyl; and

[0249] R2is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais hydrogen, C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one substituent selected from the group consisting of -ORZA, -C(0)OH, and G1A; and R1Bis hydrogen or C1-C3alkyl.

[0250] In some such embodiment, G1Ais phenyl optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently C1-C3alkyl, C1-C3haloalkyl, halogen, or -OCH3. In some such embodiment, G1Ais unsubstituted phenyl. In some such embodiment, RZAis C1-C3haloalkyl or C1-C3alkyl.

[0251] In one embodiment, the invention is directed to compounds of formula (I), (la), or (I-b), wherein

[0252] R8is hydrogen;

[0253] m is 0,

[0254] R9, R10, and R13are hydrogen,

[0255] R11and R12are halogen,

[0256] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl; and

[0257] R3is hydrogen or halogen.

[0258] In one embodiment, the invention is directed to compounds of formula (I), (la), (I-b), or

[0259] (I-c) wherein

[0260] R8is hydrogen;

[0261] m is 0,

[0262] R9, R10, and R13are hydrogen,

[0263] R11and R12are halogen, and

[0264] R14is hydrogen or halogen.

[0265] In one embodiment, the invention is directed to compounds of formula (I), (la), (I-b), or (I-c) whereinR4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0266] R5is hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or G2A;

[0267] R6is hydrogen or C1-C3alkyl; and

[0268] R7is hydrogen or C1-C3alkyl.

[0269] In some such embodiment, G2Ais phenyl, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. In some such embodiment, G2Ais phenyl, cyclopropyl, cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some such embodiment, G2Ais phenyl or cyclohexyl. In some such embodiment, G2Ais phenyl. In some such embodiment, G2Ais cyclohexyl. Each G2Ais optionally substituted with 1, 2, or 3independently selected Rqgroups.

[0270] In one embodiment, the invention is directed to compounds of formula (I) or (la) wherein R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups;

[0271] R6is hydrogen or C1-C3alkyl; and

[0272] R7is hydrogen or C1-C3alkyl.

[0273] In some such embodiment, Rp, when present, are each independently

[0274] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups;

[0275] -C(0)Rhwherein Rhis C C6alkyl;

[0276] -C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl, or -CH2-phenyl; or

[0277] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0278] In one embodiment, the invention is directed to compounds of formula (I) or (I-a) wherein

[0279] R4is hydrogen or C1-C3alkyl;

[0280] R5is hydrogen or C1-C3alkyl;

[0281] R6is hydrogen or C1-C3alkyl; and

[0282] R7is -(Ci-C6alkylenyl)-G3A.

[0283] In some such embodiment, R7is -(CH2)-G3A. In some such embodiment, G3Ais phenyl optionally substituted with 1, 2, or 3 independently selected Rsgroups. In some such embodiment, G3Ais phenyl optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently C1-C3alkyl, C1-C3haloalkyl, halogen, or -OR wherein RJis C1-C3alkyl.In one embodiment, the invention is directed to compounds of formula (I) wherein R8is hydrogen;

[0284] m is 0,

[0285] R9, R10, and R13are hydrogen,

[0286] R11and R12are halogen,

[0287] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0288] R5is hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or G2A;

[0289] R6is hydrogen or C1-C3alkyl;

[0290] R7is hydrogen or C1-C3alkyl; and

[0291] R14and R3are each independently hydrogen or halogen.

[0292] In some such embodiment, G2Ais phenyl, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. In some such embodiment, G2Ais phenyl, cyclopropyl, cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some such embodiment, G2Ais phenyl or cyclohexyl. In some such embodiment, G2Ais phenyl. In some such embodiment, G2Ais cyclohexyl. Each G2Ais optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0293] In one embodiment, the invention is directed to compounds of formula (I) wherein R8is hydrogen;

[0294] m is 0,

[0295] R9, R10, and R13are hydrogen,

[0296] R11and R12are halogen,

[0297] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups;

[0298] R6is hydrogen or C1-C3alkyl;

[0299] R7is hydrogen or C1-C3alkyl; and

[0300] R14and R3are each independently hydrogen or halogen.

[0301] In some such embodiment, Rp, when present, are each independently

[0302] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups;

[0303] -C(0)Rhwherein Rhis Ci-C6alkyl;

[0304] -C(0)ORhwherein Rhis hydrogen, C C6alkyl, or -CH2-phenyl; or-S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0305] In one embodiment, the invention is directed to compounds of formula (I) wherein R8is hydrogen;

[0306] m is 0,

[0307] R9, R10, and R13are hydrogen,

[0308] R11and R12are halogen,

[0309] R4is hydrogen or C1-C3alkyl;

[0310] R5is hydrogen or C1-C3alkyl;

[0311] R6is hydrogen or C1-C3alkyl;

[0312] R7is -(Ci-C6alkylenyl)-G3A; and

[0313] R14and R3are each independently hydrogen or halogen.

[0314] In some such embodiment, R7is -(CH2)-G3A. In some such embodiment, G3Ais phenyl optionally substituted with 1, 2, or 3 independently selected Rsgroups. In some such

[0315] embodiment, G3Ais phenyl optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently C1-C3alkyl, C1-C3haloalkyl, halogen, or -ORJwherein RJis C1-C3alkyl.

[0316] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen; and m is 0.

[0317] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen; m is 0, and R9, R10, and R13are each independently hydrogen or halogen.

[0318] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen; m is 0, and R9, R10, and R13are hydrogen.

[0319] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen; m is 0, R9, R10, and R13are each independently hydrogen or halogen; and R11and R12are hydrogen, or R11and R12are halogen. In some such embodiment, the halogen is F.

[0320] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen; m is 0, R9, R10, and R13are hydrogen, and R11and R12are halogen. In some such embodiment, R11and R12are F.

[0321] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen; m is 0, R9, R10, and R13are hydrogen, R11and R12are halogen, and R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C1-C3 haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl. In some such embodiment, R11and R12are F.In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen;

[0322] m is 0,

[0323] R9, R10, and R13are hydrogen,

[0324] R11and R12are halogen,

[0325] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl; and

[0326] R2is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais hydrogen, C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one substituent selected from the group consisting of -ORZA, -C(0)OH, and G1A; and R1Bis hydrogen or C1-C3alkyl.

[0327] In some such embodiment, G1Ais phenyl optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently C1-C3alkyl, C1-C3haloalkyl, halogen, or -OCH3. In some such embodiments, G1Ais unsubstituted phenyl. In some such embodiments, RZAis C1-C3haloalkyl or C1-C3alkyl.

[0328] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen;

[0329] m is 0,

[0330] R9, R10, and R13are hydrogen,

[0331] R11and R12are halogen,

[0332] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl; and

[0333] R3is hydrogen or halogen.

[0334] In one embodiment, the invention is directed to compounds of formula (I-a) wherein

[0335] R8is hydrogen;

[0336] m is 0,

[0337] R9, R10, and R13are hydrogen,

[0338] R11and R12are halogen, and

[0339] R14is hydrogen or halogen.

[0340] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;R5is hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or G2A;

[0341] R6is hydrogen or C1-C3alkyl; and

[0342] R7is hydrogen or C1-C3alkyl.

[0343] In some such embodiment, G2Ais phenyl, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. In some such embodiment, G2Ais phenyl, cyclopropyl, cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some such embodiment, G2Ais phenyl or cyclohexyl. In some such embodiment, G2Ais phenyl. In some such embodiment, G2Ais cyclohexyl. Each G2Ais optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0344] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups;

[0345] R6is hydrogen or C1-C3alkyl; and

[0346] R7is hydrogen or C1-C3alkyl.

[0347] In some such embodiment, Rp, when present, are each independently

[0348] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups;

[0349] -C(0)Rhwherein Rhis C C6alkyl;

[0350] -C(0)ORhwherein Rhis hydrogen, C C6alkyl, or -CH2-phenyl; or

[0351] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0352] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R4is hydrogen or C1-C3alkyl;

[0353] R5is hydrogen or C1-C3alkyl;

[0354] R6is hydrogen or C1-C3alkyl; and

[0355] R7is -(Ci-C6alkylenyl)-G3A.

[0356] In some such embodiment, R7is -(CH2)-G3A. In some such embodiment, G3Ais phenyl optionally substituted with 1, 2, or 3 independently selected Rsgroups. In some such embodiment, G3Ais phenyl optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently C1-C3alkyl, C1-C3haloalkyl, halogen, or -OR wherein RJis C1-C3alkyl.

[0357] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen;m is 0,

[0358] R9, R10, and R13are hydrogen,

[0359] R11and R12are halogen,

[0360] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0361] R5is hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or G2A;

[0362] R6is hydrogen or C1-C3alkyl;

[0363] R7is hydrogen or C1-C3alkyl; and

[0364] R14and R3are each independently hydrogen or halogen.

[0365] In some such embodiment, G2Ais phenyl, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. In some such embodiment, G2Ais phenyl, cyclopropyl, cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some such embodiment, G2Ais phenyl or cyclohexyl. In some such embodiment, G2Ais phenyl. In some such embodiment, G2Ais cyclohexyl. Each G2Ais optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0366] In one embodiment, the invention is directed to compounds of formula (I-a) wherein R8is hydrogen;

[0367] m is 0,

[0368] R9, R10, and R13are hydrogen,

[0369] R11and R12are halogen,

[0370] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups;

[0371] R6is hydrogen or C1-C3alkyl;

[0372] R7is hydrogen or C1-C3alkyl; and

[0373] R14and R3are each independently hydrogen or halogen.

[0374] In some such embodiment, Rp, when present, are each independently

[0375] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups;

[0376] -C(0)Rhwherein Rhis Ci-C6alkyl;

[0377] -C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl, or -CH2-phenyl; or

[0378] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0379] In one embodiment, the invention is directed to compounds of formula (I-a) whereinR8is hydrogen;

[0380] m is 0,

[0381] R9, R10, and R13are hydrogen,

[0382] R11and R12are halogen,

[0383] R4is hydrogen or C1-C3alkyl;

[0384] R5is hydrogen or C1-C3alkyl;

[0385] R6is hydrogen or C1-C3alkyl;

[0386] R7is -(Ci-C6alkylenyl)-G3A; and

[0387] R14and R3are each independently hydrogen or halogen.

[0388] In some such embodiment, R7is -(CH2)-G3A. In some such embodiment, G3Ais phenyl optionally substituted with 1, 2, or 3 independently selected Rsgroups. In some such embodiment, G3Ais phenyl optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently C1-C3alkyl, C1-C3haloalkyl, halogen, or -OR wherein RJis C1-C3alkyl.

[0389] In one embodiment, the invention is directed to compounds of formula (I-b) wherein R8is hydrogen; and m is 0.

[0390] In one embodiment, the invention is directed to compounds of formula (I-b) wherein R8is hydrogen; m is 0, and R9, R10, and R13are each independently hydrogen or halogen.

[0391] In one embodiment, the invention is directed to compounds of formula (I- b) wherein R8is hydrogen; m is 0, and R9, R10, and R13are hydrogen.

[0392] In one embodiment, the invention is directed to compounds of formula (I-b) wherein R8is hydrogen; m is 0, R9, R10, and R13are each independently hydrogen or halogen; and R11and R12are hydrogen, or R11and R12are halogen. In some such embodiment, the halogen is F.

[0393] In one embodiment, the invention is directed to compounds of formula (I-b) wherein R8is hydrogen; m is 0, R9, R10, and R13are hydrogen, and R11and R12are halogen. In some such embodiment, R11and R12are F.

[0394] In one embodiment, the invention is directed to compounds of formula (I-b) wherein R8is hydrogen; m is 0, R9, R10, and R13are hydrogen, R11and R12are halogen, and R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C1-C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl. In some such embodiment, R11and R12are F.

[0395] In one embodiment, the invention is directed to compounds of formula (I-b) wherein R8is hydrogen;m is 0,

[0396] R9, R10, and R13are hydrogen,

[0397] R11and R12are halogen,

[0398] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl; and

[0399] R3is hydrogen or halogen.

[0400] In one embodiment, the invention is directed to compounds of formula (I-b) wherein

[0401] R8is hydrogen;

[0402] m is 0,

[0403] R9, R10, and R13are hydrogen,

[0404] R11and R12are halogen, and

[0405] R14is hydrogen or halogen.

[0406] In one embodiment, the invention is directed to compounds of formula (I-b) wherein R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0407] R5is hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or G2A;

[0408] R6is hydrogen or C1-C3alkyl; and

[0409] R7is hydrogen or C1-C3alkyl.

[0410] In some such embodiment, G2Ais phenyl, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. In some such embodiment, G2Ais phenyl, cyclopropyl, cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some such embodiment, G2Ais phenyl or cyclohexyl. In some such embodiment, G2Ais phenyl. In some such embodiment, G2Ais cyclohexyl. Each G2Ais optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0411] In one embodiment, the invention is directed to compounds of formula (I-b) wherein R8is hydrogen;

[0412] m is 0,

[0413] R9, R10, and R13are hydrogen,

[0414] R11and R12are halogen,

[0415] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0416] R5is hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or G2A;

[0417] R6is hydrogen or C1-C3alkyl;

[0418] R7is hydrogen or C1-C3alkyl; andR14and R3are each independently hydrogen or halogen.

[0419] In some such embodiment, G2Ais phenyl, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. In some such embodiment, G2Ais phenyl, cyclopropyl, cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some such embodiment, G2Ais phenyl or cyclohexyl. In some such embodiment, G2Ais phenyl. In some such embodiment, G2Ais cyclohexyl. Each G2Ais optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0420] In one embodiment, the invention is directed to compounds of formula (I-b) wherein R8is hydrogen;

[0421] m is 0,

[0422] R9, R10, and R13are hydrogen,

[0423] R11and R12are halogen,

[0424] R4is hydrogen or Ci-C3alkyl;

[0425] R5is G2Awherein G2Ais phenyl which is substituted with one Rq; wherein Rqis -C(0)ORh

[0426] wherein Rhis hydrogen or Ci-C3alkyl;

[0427] R6is hydrogen or Ci-C3alkyl;

[0428] R7is hydrogen or Ci-C3alkyl;

[0429] R14and R3are each independently hydrogen or halogen; and

[0430] R1is hydrogen.

[0431] In some such embodiment, Rqis -C(0)ORhwherein Rhis hydrogen. In some such embodiment, Rqis -C(0)ORhwherein Rhis Ci-C3alkyl.

[0432] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8is hydrogen; and m is 0.

[0433] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8is hydrogen; m is 0, and R9, R10, and R13are each independently hydrogen or halogen.

[0434] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8is hydrogen; m is 0, and R9, R10, and R13are hydrogen.

[0435] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8is hydrogen; m is 0, R9, R10, and R13are each independently hydrogen or halogen; and R11and R12are hydrogen, or R11and R12are halogen. In some such embodiment, the halogen is F.In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8hydrogen; m is 0, R9, R10, and R13are hydrogen, and R11and R12are halogen. In some such embodiment, R11and R12are F.

[0436] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8hydrogen; m is 0, R9, R10, and R13are hydrogen, R11and R12are halogen, and R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl. In some such embodiment, R11and R12are F.

[0437] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8is hydrogen;

[0438] m is 0,

[0439] R9, R10, and R13are hydrogen,

[0440] R11and R12are halogen,

[0441] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl; and

[0442] R2is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais hydrogen, Ci-C3haloalkyl, or Ci-C3alkyl wherein the Ci-C3alkyl is optionally substituted with one substituent selected from the group consisting of -ORZA, -C(0)OH, and G1A; and R1Bis hydrogen or C C3alkyl.

[0443] In some such embodiment, G1Ais phenyl optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently Ci-C3alkyl, Ci-C3haloalkyl, halogen, or -OCH3. In some such embodiments, G1Ais unsubstituted phenyl. In some such embodiments, RZAis Ci-C3haloalkyl or Ci-C3alkyl.

[0444] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8is hydrogen;

[0445] m is 0,

[0446] R9, R10, and R13are hydrogen,

[0447] R11and R12are halogen, and

[0448] R14is hydrogen or halogen.

[0449] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0450] R5is hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or G2A;R6is hydrogen or C1-C3alkyl; and

[0451] R7is hydrogen or C1-C3alkyl.

[0452] In some such embodiment, G2Ais phenyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. In some such embodiment, G2Ais phenyl, cyclopropyl, cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some such embodiment, G2Ais phenyl or cyclohexyl. In some such embodiment, G2Ais phenyl. In some such embodiment, G2Ais cyclohexyl. Each G2Ais optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0453] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8is hydrogen;

[0454] m is 0,

[0455] R9, R10, and R13are hydrogen,

[0456] R11and R12are halogen,

[0457] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0458] R5is hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or G2A;

[0459] R6is hydrogen or C1-C3alkyl;

[0460] R7is hydrogen or C1-C3alkyl; and

[0461] R14is hydrogen or halogen.

[0462] In some such embodiment, G2Ais phenyl, C3-C6cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. In some such embodiment, G2Ais phenyl, cyclopropyl, cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some such embodiment, G2Ais phenyl or cyclohexyl. In some such embodiment, G2Ais phenyl. In some such embodiment, G2Ais cyclohexyl. Each G2Ais optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0463] In one embodiment, the invention is directed to compounds of formula (I-c) wherein R8is hydrogen;

[0464] m is 0,

[0465] R9, R10, and R13are hydrogen,

[0466] R11and R12are halogen,

[0467] R4is hydrogen or C1-C3alkyl;

[0468] R5is G2Awherein G2Ais phenyl which is substituted with one Rq; wherein Rqis -C(0)ORhwherein Rhis hydrogen or C1-C3alkyl;

[0469] R6is hydrogen or C1-C3alkyl;R is hydrogen or C1-C3alkyl;

[0470] R14is hydrogen or halogen;

[0471] R1is hydrogen; and

[0472] R2is hydrogen, halogen, or -OR1Awherein R1Ais C1-C3alkyl or C1-C3haloalkyl.

[0473] In some such embodiment, Rqis -C(0)ORhwherein Rhis hydrogen. In some such embodiment, Rqis -C(0)ORhwherein Rhis C C3alkyl.

[0474] One embodiment is directed to compounds of formula (I-d)

[0476] (I-d)

[0477] wherein

[0478] X is CR2and Y is CR3; or

[0479] X is N and Y is CR3; or

[0480] X is CR2and Y is N;

[0481] R1and R2, at each occurrence, are each independently hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, -C(0)OR1B, -NR1AR2A, or -C(0)NR1AR2A;

[0482] R1Aand R2A, at each occurrence, are each independently hydrogen, Ci-C6haloalkyl, G1A, or Ci- C6alkyl; wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORZA, -SRZA, -S(0)2RZA, -C(0)RZA, -C(0)ORZA, -C(0)N(RZA)2, -N(RZA)2, -N(RZA)C(0)RZB, -N(RZA)S(0)2RZB, -N(RZA)C(0)ORZB, -N(RZA)C(0)N(RZA)2, -CN, and G1A; or R1Aand R2Atogether with the nitrogen atom to which they are attached form a 4-6 membered heterocycle wherein the 4-6 membered heterocycle is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci-C6alkyl, Ci-C6haloalkyl, -ORj, and N(Rj)2; wherein

[0483] RZA, at each occurrence, is independently hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, G1A, or -(Ci- C6alkylenyl)-G1A; andR , at each occurrence, is independently Ci-C6haloalkyl, Ci-C6alkyl, G , or -(Ci-C6alkylenyl)-G1A;

[0484] R1Bis hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0485] R3and R14are each independently hydrogen or halogen;

[0486] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0487] R5is hydrogen, -C(0)R -C(0)OH, -C(0)N(Rh)2, C C6haloalkyl, C C6alkyl, or G2A; wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -OC(0)N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -NCR^CCC R1, -N(Rh)S(0)2Ri,

[0488] -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, and G2A; or

[0489] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups;

[0490] G2A, at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or

[0491] heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rqgroups;

[0492] Rpand Rq, at each occurrence, are each independently Ci-C6alkyl, halogen, Ci-C6haloalkyl,

[0493] -CN, oxo, N02, -ORh, -OCCC R1, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -NCR^CCC R1, -Ν^)8(0)2^, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -00(0)^, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, -CN, and GA;

[0494] Rh, at each occurrence, is independently hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRj, -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;

[0495] R1, at each occurrence, is independently Ci-C6haloalkyl, Ci-C6alkyl, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituentsindependently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRJ,

[0496] -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;

[0497] R6is hydrogen, halogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0498] R7is hydrogen, halogen, -ORj, -N(Rj)2, -N(Rj)C(0)Rk, Ci-C6haloalkyl, Ci-C6alkyl, C2-C6

[0499] alkenyl, or -(Ci-C6alkylenyl)-G3A;

[0500] R9, R10, and R13, are each independently hydrogen or halogen;

[0501] G1A, G3A, and GA, at each occurrence, are each independently cycloalkyl, cycloalkenyl,

[0502] heterocycle, aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rsgroups; wherein

[0503] Rs, at each occurrence, is independently Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, Ci- C6haloalkyl, -CN, oxo, N02, -ORj, -OC(0)Rk, -OC(0)N(Rj)2, -SRj, -S(0)2Rj,

[0504] -S(0)2N(RJ)2, -C(0)RJ, -C(0)ORJ, -C(0)N(RJ)2, -N(RJ)2, -N(RJ)C(0)Rk, -N(RJ)S(0)2Rk, -N(Rj)C(0)0(Rk), -N(Rj)C(0)N(Rj)2, -(Ci-C6alkylenyl)-ORj, -(Ci-C6

[0505] alkylenyl)-OC(0)Rk, -(C C6alkylenyl)-OC(0)N(Rj)2, -(C C6alkylenyl)-SRj, -(C C6alkylenyl)-S(0)2Rj, -(Ci-C6alkylenyl)-S(0)2N(Rj)2, -(Ci-C6alkylenyl)-C(0)Rj, -(Ci-C6alkylenyl)-C(0)ORj, -(Ci-C6alkylenyl)-C(0)N(Rj)2, -(Ci-C6alkylenyl)-N(Rj)2, -(Ci-C6alkylenyl)-N(Rj)C(0)Rk, -(Ci-C6alkylenyl)-N(Rj)S(0)2Rk, -(Ci-C6

[0506] alkylenyl)-N(Rj)C(0)0(Rk), -(C C6alkylenyl)-N(Rj)C(0)N(Rj)2, or -(C C6

[0507] alkylenyl)-CN;

[0508] RJ, at each occurrence, is independently hydrogen, Ci-C6alkyl, or Ci-C6haloalkyl; and

[0509] Rk, at each occurrence, is independently Ci-C6alkyl or Ci-C6haloalkyl.

[0510] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen.

[0511] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C1-C3 haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl.

[0512] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen; and

[0513] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl.

[0514] In one embodiment, the invention is directed to compounds of formula (I-d), whereinR9, R10, and R13are hydrogen;

[0515] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0516] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0517] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0518] R5is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0519] R6is hydrogen or C1-C3alkyl; and

[0520] R7is hydrogen or C1-C3alkyl.

[0521] In some such embodiment, R4is hydrogen, CH2F, CHF2, CH3, or CH2CH3; and R5is hydrogen, CH2F, CHF2, CH3, or CH2CH3.

[0522] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0523] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0524] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0525] R4is hydrogen or C1-C3alkyl;

[0526] R5is G2Awherein G2Ais phenyl, C3-C6 cycloalkyl, 4-6 membered heterocycle, or 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[0527] R6is hydrogen or C1-C3alkyl; and

[0528] R7is hydrogen or C1-C3alkyl.

[0529] In one embodiment, the invention is directed to compounds of formula (I-d), wherein

[0530] R9, R10, and R13are hydrogen;

[0531] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0532] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0533] R4is hydrogen or C1-C3alkyl;

[0534] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[0535] R6is hydrogen or C1-C3alkyl; and

[0536] R7is hydrogen or C1-C3alkyl.

[0537] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0538] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0539] R4is hydrogen or C1-C3alkyl;

[0540] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 Rqgroups;

[0541] wherein each Rqis independently

[0542] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[0543] halogen;

[0544] Ci-C6haloalkyl;

[0545] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[0546] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[0547] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,

[0548] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[0549] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl;

[0550] R6is hydrogen or C1-C3alkyl; and

[0551] R7is hydrogen or C1-C3alkyl.

[0552] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0553] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0554] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0555] R4is hydrogen or C1-C3alkyl;

[0556] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 Rqgroups;wherein one of Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl, or one of Rqis

[0557] -C(0)N(H)(Rh) wherein Rhis cyclopentyl, or Rhis Ci-C6alkyl which is substituted with 1 or 2 -OH groups; and the other optional Rqgroups are independently selected from the group consisting of C1-C3alkyl, halogen, and C1-C3haloalkyl;

[0558] R6is hydrogen or C1-C3alkyl; and

[0559] R7is hydrogen or C1-C3alkyl.

[0560] In one embodiment, the invention is directed to compounds of formula (I-d), wherein

[0561] R9, R10, and R13are hydrogen;R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0562] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0563] R4is hydrogen or C1-C3alkyl;

[0564] R5is G2Awherein G2Ais phenyl which is substituted with one Rq; wherein Rqis -C(0)ORhwherein Rhis hydrogen or C1-C3alkyl;

[0565] R6is hydrogen or C1-C3alkyl; and

[0566] R7is hydrogen or C1-C3alkyl.

[0567] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0568] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0569] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0570] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0571] R4is hydrogen or C1-C3alkyl;

[0572] R5is G2Awherein G2Ais; wherein R is hydrogen or C1-C3alkyl; hydrogen or C1-C3alkyl; and

[0573] R is hydrogen or C1-C3alkyl.

[0574] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0575] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0576] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0577] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0578] R4is hydrogen or C1-C3alkyl;

[0579] R5is G2Awherein G2Ais; wherein Rhis hydrogen or C1-C3alkyl;

[0580] hydrogen or C1-C3alkyl; andR is hydrogen or C1-C3alkyl.

[0581] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0582] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0583] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0584] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0585] R4is hydrogen or C1-C3alkyl;

[0586] R5is G; wherein Rhis hydrogen or C1-C3alkyl;

[0587] R6is hydrogen or C1-C3alkyl; and

[0588] R7is hydrogen or C1-C3alkyl.

[0589] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0590] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0591] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0592] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0593] R4is hydrogen or C1-C3alkyl;

[0594] R5is G2Awherein G2Ais C3-C6cycloalkyl which is optionally substituted with 1, 2, or 3 Rqgroups; wherein each Rqis independently

[0595] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[0596] halogen;

[0597] Ci-C6haloalkyl;

[0598] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[0599] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[0600] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,

[0601] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[0602] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or-S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl;

[0603] R6is hydrogen or C1-C3alkyl; and

[0604] R7is hydrogen or C1-C3alkyl.

[0605] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0606] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0607] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0608] R4is hydrogen or C1-C3alkyl;

[0609] R5is G2Awherein G2Ais cyclopropyl or cyclohexyl, each of which is optionally substituted with one Rq; wherein Rqis

[0610] -ORhwherein Rhis C1-C3alkyl, or

[0611] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl;

[0612] R6is hydrogen or C1-C3alkyl; and

[0613] R7is hydrogen or C1-C3alkyl.

[0614] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0615] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0616] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0617] R4is hydrogen or C1-C3alkyl;

[0618] R5is G2Awherein G2Ais cyclohexyl which is substituted with one Rq; wherein Rqis -C(0)ORhwherein Rhis hydrogen or C1-C3alkyl,

[0619] R6is hydrogen or C1-C3alkyl; and

[0620] R7is hydrogen or C1-C3alkyl.

[0621] In some such embodiment, Rqis -C(0)ORhwherein Rhis hydrogen. In some such embodiment, Rqis -C(0)ORhwherein Rhis C1-C3alkyl.

[0622] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0623] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0624] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0625] R4is hydrogen or C1-C3alkyl;

[0626] R5is G2Awherein G2Ais; wherein Rhis hydrogen or C1-C3alkyl.

[0627] R6is hydrogen or C1-C3alkyl; and

[0628] R7is hydrogen or C1-C3alkyl.

[0629] In some such embodiment, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0630] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0631] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais (

[0632] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0633] R4is hydrogen or C1-C3alkyl;

[0634] R5is G2Awherein G2Ais 4-6 membered heterocycle which is optionally substituted with 1, 2,

[0635] 3 independently selected Rqgroups;

[0636] R6is hydrogen or C1-C3alkyl; and

[0637] R7is hydrogen or C1-C3alkyl.

[0638] In some such embodiment, G2Ais tetrahydrofuranyl or azetidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0639] In some such embodiments, G2Atetrahydrofuranyl or azetidinyl, each of which is optionally substituted with 1, 2, or 3 Rqgroups; wherein each Rqis independently Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[0640] halogen;

[0641] Ci-C6haloalkyl;

[0642] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[0643] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[0644] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,

[0645] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[0646] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and C C6alkyl are each optionally substituted with 1 or 2 -OH groups; or

[0647] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0648] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0649] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0650] R4is hydrogen or C1-C3alkyl;

[0651] R5is G2Awherein G2Ais 5-6 membered heteroaryl which is optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[0652] R6is hydrogen or C1-C3alkyl; and

[0653] R7is hydrogen or C1-C3alkyl.

[0654] In some such embodiment, G2Ais pyridinyl which is optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0655] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0656] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0657] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0658] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups; and

[0659] R6and R7are each independently hydrogen or C1-C3alkyl.

[0660] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0661] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0662] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0663] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl which is optionally substituted with 1 or 2 Rpgroups; and

[0664] R6and R7are each independently hydrogen or C1-C3alkyl.

[0665] In some such embodiment, the C3-C6cycloalkyl formed is cyclobutyl or cyclopentyl, each of which is optionally substituted with 1 or 2 Rpgroups. In some such embodiment, the C3- C6cycloalkyl formed is unsubstituted cyclobutyl or unsubstituted cyclopentyl.

[0666] In some such embodiments, each Rpis independently

[0667] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups; -C(0)Rhwherein Rhis C C6alkyl;-C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl, or -CH2-phenyl; or

[0668] -S02Rhwherein Rhis C C6haloalkyl or C C6alkyl.

[0669] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0670] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0671] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0672] R4and R5, together with the carbon atom to which they are attached, form a 4-6 membered

[0673] heterocycle which is optionally substituted with 1 or 2 Rpgroups; and

[0674] R6and R7are each independently hydrogen or C1-C3alkyl.

[0675] In some such embodiment, the 4-6 membered heterocycle formed is azetidinyl, piperidinyl, each of which is optionally substituted with 1 or 2 independently selected Rpgroups.

[0676] In some such embodiments, each Rpis independently

[0677] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups; -C(0)Rhwherein Rhis C C6alkyl;

[0678] -C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl, or -CH2-phenyl; or

[0679] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0680] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0681] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0682] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0683] R4hydrogen or C1-C3alkyl; and

[0684] R5is hydrogen or C1-C3alkyl;

[0685] R6is hydrogen or C1-C3alkyl; and

[0686] R7is -(Ci-C6alkylenyl)-G3A.

[0687] In one embodiment, the invention is directed to compounds of formula (I-d), wherein R9, R10, and R13are hydrogen;

[0688] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0689] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0690] R4hydrogen or C1-C3alkyl; and

[0691] R5is hydrogen or C1-C3alkyl;

[0692] R6is hydrogen or C1-C3alkyl;R is -(CH2)-G wherein G is phenyl which is optionally substituted with 1, 2, or 3 Rsgroup; and each Rsis independently C1-C3alkyl, halogen, C1-C3haloalkyl, or -ORJwherein RJis hydrogen or C1-C3alkyl.

[0693] In some such embodiments, each Rsis independently -ORJwherein RJis C1-C3alkyl. In one embodiment, the invention is directed to compounds of formula (I-e)

[0695] (I-e)

[0696] wherein R1, R2, R3, R4, R5, R6, R7, R9, R10, R13, and R14are as described in formula (I-d).

[0697] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen.

[0698] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C1-C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl.

[0699] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen; and

[0700] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0701] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl.

[0702] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0703] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0704] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0705] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0706] R5is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0707] R6is hydrogen or C1-C3alkyl; and

[0708] R7is hydrogen or C1-C3alkyl.

[0709] In some such embodiment, R4is hydrogen, CH2F, CHF2, CH3, or CH2CH3; and R5is hydrogen, CH2F, CHF2, CH3, or CH2CH3.In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0710] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0711] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0712] R4is hydrogen or C1-C3alkyl;

[0713] R5is G2Awherein G2Ais phenyl, C3-C6cycloalkyl, 4-6 membered heterocycle, or 5-6 membered heteroaryl; each G2Ais optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0714] R6is hydrogen or C1-C3alkyl; and

[0715] R7is hydrogen or C1-C3alkyl.

[0716] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0717] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0718] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0719] R4is hydrogen or C1-C3alkyl;

[0720] R5is G2Awherein G2Ais phenyl optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[0721] R6is hydrogen or C1-C3alkyl; and

[0722] R7is hydrogen or C1-C3alkyl.

[0723] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0724] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0725] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0726] R4is hydrogen or C1-C3alkyl;

[0727] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 Rqgroups;

[0728] wherein each Rqis independently

[0729] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[0730] halogen;

[0731] Ci-C6haloalkyl;

[0732] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[0733] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;-C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,

[0734] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[0735] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl;

[0736] R6is hydrogen or Ci-C3alkyl; and

[0737] R7is hydrogen or Ci-C3alkyl.

[0738] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0739] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0740] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[0741] R4is hydrogen or Ci-C3alkyl;

[0742] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 Rqgroups;

[0743] wherein one of Rqis -C(0)ORhwherein Rhis hydrogen or C C6alkyl, or one of Rqis -C(0)N(H)(Rh) wherein Rhis cyclopentyl, or Rhis Ci-C6alkyl which is substituted with 1 or 2 -OH groups; and the other optional Rqgroups are independently selected from the group consisting of Ci-C3alkyl, halogen, and Ci-C3haloalkyl;

[0744] R6is hydrogen or Ci-C3alkyl; and

[0745] R7is hydrogen or Ci-C3alkyl.

[0746] In one embodiment, the invention is directed to compounds of formula (I-e), wherein

[0747] R9, R10, and R13are hydrogen;

[0748] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0749] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[0750] R4is hydrogen or Ci-C3alkyl;

[0751] R5is G2Awherein G2Ais phenyl which is substituted with one Rq; wherein Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C3alkyl;

[0752] R6is hydrogen or Ci-C3alkyl; and

[0753] R7is hydrogen or Ci-C3alkyl.

[0754] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis Ci-C3alkyl.

[0755] In one embodiment, the invention is directed to compounds of formula (I-e), whereinR9, R10, and R13are hydrogen;

[0756] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0757] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3 alkyl;

[0758] R4is hydrogen or C1-C3alkyl;

[0759] R5is G2Awherein G2Ais; wherein Rhis hydrogen or C1-C3alkyl;

[0760] R6is hydrogen or C1-C3alkyl; and

[0761] R7is hydrogen or C1-C3alkyl.

[0762] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3 alkyl.

[0763] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0764] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0765] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3 alkyl;

[0766] R4is hydrogen or C1-C3alkyl;

[0767] R5is G2Awherein G2Ais; wherein R is hydrogen or C1-C3alkyl;

[0768] R6is hydrogen or C1-C3alkyl; and

[0769] R7is hydrogen or C1-C3alkyl.

[0770] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3 alkyl.

[0771] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0772] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0773] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3 alkyl;

[0774] R4is hydrogen or C1-C3alkyl;

[0775] R5is G2Awherein G2Ais; wherein Rhis hydrogen or C1-C3alkyl;

[0776] R6is hydrogen or C1-C3alkyl; and

[0777] R7is hydrogen or C1-C3alkyl.

[0778] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0779] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0780] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0781] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0782] R4is hydrogen or C1-C3alkyl;

[0783] R5is G2Awherein G2Ais C3-C6cycloalkyl which is optionally substituted with 1, 2, or 3 Rqgroups; wherein each Rqis independently

[0784] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[0785] halogen;

[0786] Ci-C6haloalkyl;

[0787] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[0788] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[0789] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,

[0790] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[0791] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl;

[0792] R6is hydrogen or C1-C3alkyl; and

[0793] R7is hydrogen or C1-C3alkyl.

[0794] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0795] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0796] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0797] R4is hydrogen or C1-C3alkyl;R5is G2Awherein G2Ais cyclopropyl or cyclohexyl, each of which is optionally substituted with one Rq; wherein Rqis -ORhwherein Rhis CrC3alkyl, or Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl;

[0798] R6is hydrogen or C1-C3 alkyl; and

[0799] R7is hydrogen or Ci-C3alkyl.

[0800] In one embodiment, the invention is directed to compounds of formula (I-e), wherein

[0801] R9, R10, and R13are hydrogen;

[0802] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0803] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[0804] R4is hydrogen or Ci-C3alkyl;

[0805] R5is G2Awherein G2Ais cyclohexyl which is substituted with one Rq; wherein Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C3alkyl,

[0806] R6is hydrogen or Ci-C3alkyl; and

[0807] R7is hydrogen or Ci-C3alkyl.

[0808] In some such embodiment, Rhis hydrogen. In some such embodiment, Rhis Ci-C3alkyl.

[0809] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0810] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0811] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[0812] R4is hydrogen or Ci-C3alkyl;

[0813] R5is G2Awherein G2Ais; wherein Rhis hydrogen or Ci-C3alkyl.

[0814] R6is hydrogen or Ci-C3alkyl; and

[0815] R7is hydrogen or Ci-C3alkyl.

[0816] In some such embodiment, Rhis hydrogen. In some such embodiments, Rhis Ci-C3alkyl.

[0817] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0818] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;R4is hydrogen or C1-C3alkyl;

[0819] R5is G2Awherein G2Ais 4-6 membered heterocycle optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[0820] R6is hydrogen or C1-C3alkyl; and

[0821] R7is hydrogen or C1-C3alkyl.

[0822] In some such embodiment, G2Ais tetrahydrofuranyl or azetidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0823] In some such embodiments, G2Atetrahydrofuranyl or azetidinyl, each of which is optionally substituted with 1, 2, or 3 Rqgroups; wherein each Rqis independently Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[0824] halogen;

[0825] Ci-C6haloalkyl;

[0826] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[0827] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[0828] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,

[0829] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[0830] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or

[0831] -S02Rhwherein Rhis C C6haloalkyl or C C6alkyl.

[0832] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0833] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0834] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0835] R4is hydrogen or C1-C3alkyl;

[0836] R5is G2Awherein G2Ais 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[0837] R6is hydrogen or C1-C3alkyl; and

[0838] R7is hydrogen or C1-C3alkyl.

[0839] In some such embodiment, G2Ais pyridinyl optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[0840] In one embodiment, the invention is directed to compounds of formula (I-e), whereinR9, R10, and R13are hydrogen;

[0841] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0842] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0843] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups; and

[0844] R6and R7are each independently hydrogen or C1-C3alkyl.

[0845] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0846] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0847] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0848] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl which is optionally substituted with 1 or 2 Rpgroups; and

[0849] R6and R7are each independently hydrogen or C1-C3alkyl.

[0850] In some such embodiment, the C3-C6cycloalkyl formed is cyclobutyl or cyclopentyl, each of which is optionally substituted with 1 or 2 Rpgroups. In some such embodiment, the C3- C6cycloalkyl formed is unsubstituted cyclobutyl or unsubstituted cyclopentyl.

[0851] In some such embodiment, each Rpis independently

[0852] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups; -C(0)Rhwherein Rhis Ci-C6alkyl;

[0853] -C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl, or -CH2-phenyl; or

[0854] -S02Rhwherein Rhis C C6haloalkyl or C C6alkyl.

[0855] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0856] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0857] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0858] R4and R5, together with the carbon atom to which they are attached, form a 4-6 membered

[0859] heterocycle which is optionally substituted with 1 or 2 Rpgroups; and

[0860] R6and R7are each independently hydrogen or C1-C3alkyl.In some such embodiment, the 4-6 membered heterocycle formed is azetidinyl or piperidinyl, each of which is optionally substituted with 1 or 2 Rpgroups.

[0861] In some such embodiments, each Rpis independently

[0862] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups; -C(0)Rhwherein Rhis Ci-C6alkyl;

[0863] -C(0)ORhwherein Rhis hydrogen, C C6alkyl, or -CH2-phenyl; or

[0864] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[0865] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0866] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0867] C3haloalkyl or C1-C3 alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[0868] R4hydrogen or Ci-C3alkyl; and

[0869] R5is hydrogen or Ci-C3alkyl;

[0870] R6is hydrogen or Ci-C3alkyl; and

[0871] R7is -(Ci-C6alkylenyl)-G3A.

[0872] In one embodiment, the invention is directed to compounds of formula (I-e), wherein R9, R10, and R13are hydrogen;

[0873] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0874] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[0875] R4hydrogen or Ci-C3alkyl; and

[0876] R5is hydrogen or Ci-C3alkyl;

[0877] R6is hydrogen or Ci-C3alkyl; and

[0878] R7is -(CH2)-G3Awherein G3Ais phenyl which is optionally substituted with 1, 2, or 3 Rsgroup; and each Rsis independently Ci-C3alkyl, halogen, Ci-C3haloalkyl, or -ORJwherein RJis hydrogen or Ci-C3alkyl.

[0879] In some such embodiments, each Rsis independently -ORJwherein RJis Ci-C3alkyl. One embodiment is directed to compounds of formula (I-f)

[0880] (i-f)

[0881] wherein R1, R3, R4, R5, R6, R7, R9, R10, R13, and R14are as described in formula (I-d).

[0882] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen.

[0883] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C1-C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl.

[0884] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen; and

[0885] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0886] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl.

[0887] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0888] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0889] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0890] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0891] R5is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[0892] R6is hydrogen or C1-C3alkyl; and

[0893] R7is hydrogen or C1-C3alkyl.

[0894] In some such embodiment, R4is hydrogen, CH2F, CHF2, CH3, or CH2CH3; and R5is hydrogen, CH2F, CHF2, CH3, or CH2CH3.

[0895] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0896] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0897] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0898] R4is hydrogen or C1-C3alkyl;R5is G2Awherein G2Ais phenyl, C3-C6cycloalkyl, 4-6 membered heterocycle, or 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[0899] R6is hydrogen or C1-C3alkyl; and

[0900] R7is hydrogen or C1-C3alkyl.

[0901] In one embodiment, the invention is directed to compounds of formula (I-f), wherein

[0902] R9, R10, and R13are hydrogen;

[0903] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0904] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0905] R4is hydrogen or C1-C3alkyl;

[0906] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[0907] R6is hydrogen or C1-C3alkyl; and

[0908] R7is hydrogen or C1-C3alkyl.

[0909] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0910] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0911] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0912] R4is hydrogen or C1-C3alkyl;

[0913] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 Rqgroups;

[0914] wherein each Rqis independently

[0915] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[0916] halogen;

[0917] Ci-C6haloalkyl;

[0918] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[0919] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[0920] -C(0)ORhwherein Rhis hydrogen or C C6alkyl,

[0921] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[0922] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or

[0923] -S02Rhwherein Rhis C C6haloalkyl or C C6alkyl;R6is hydrogen or C1-C3alkyl; and

[0924] R7is hydrogen or C1-C3alkyl.

[0925] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0926] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0927] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0928] R4is hydrogen or C1-C3alkyl;

[0929] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 Rqgroups;

[0930] wherein one of Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl, or one of Rqis -C(0)N(H)(Rh) wherein Rhis cyclopentyl, or Rhis Ci-C6alkyl which is substituted with 1 or 2 -OH groups; and the other optional Rqgroups are independently selected from the group consisting of C1-C3alkyl, halogen, and C1-C3haloalkyl ;

[0931] R6is hydrogen or C1-C3alkyl; and

[0932] R7is hydrogen or C1-C3alkyl.

[0933] In one embodiment, the invention is directed to compounds of formula (I-f), wherein

[0934] R9, R10, and R13are hydrogen;

[0935] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0936] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0937] R4is hydrogen or C1-C3alkyl;

[0938] R5is G2Awherein G2Ais phenyl which is substituted with one Rq; wherein Rqis -C(0)ORhwherein Rhis hydrogen or C1-C3alkyl;

[0939] R6is hydrogen or C1-C3alkyl; and

[0940] R7is hydrogen or C1-C3alkyl.

[0941] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[0942] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0943] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0944] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0945] R4is hydrogen or C1-C3alkyl;

[0946] R5is G2Awherein G2Ais; wherein R is hydrogen or C1-C3alkyl; R6is hydrogen or C1-C3alkyl; and

[0947] R7is hydrogen or C1-C3alkyl.

[0948] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3 alkyl.

[0949] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0950] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3 alkyl;

[0951] R4is hydrogen or C1-C3alkyl;

[0952] R5is G2 !AAwwhheerreeiinn GG22AAiiss; wherein Rhis hydrogen or C1-C3alkyl;

[0953] R6is hydrogen or C1-C3alkyl; and

[0954] R7is hydrogen or C1-C3alkyl.

[0955] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3 alkyl.

[0956] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0957] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais d-

[0958] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0959] R4is hydrogen or C1-C3alkyl;

[0960] R5is G2Awherein G2Ais

[0961] wherein Rhis hydrogen or C1-C3 alkyl;

[0962] R6is hydrogen or C1-C3alkyl; and

[0963] R7is hydrogen or C1-C3alkyl.

[0964] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3 alkyl.In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0965] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0966] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0967] R4is hydrogen or C1-C3alkyl;

[0968] R5is G2Awherein G2Ais C3-C6cycloalkyl which is optionally substituted with 1, 2, or 3 Rqgroups; wherein each Rqis independently

[0969] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[0970] halogen;

[0971] Ci-C6haloalkyl;

[0972] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[0973] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[0974] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,

[0975] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[0976] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl;

[0977] R6is hydrogen or C1-C3alkyl; and

[0978] R7is hydrogen or C1-C3alkyl.

[0979] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0980] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[0981] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0982] R4is hydrogen or C1-C3alkyl;

[0983] R5is G2Awherein G2Ais cyclopropyl or cyclohexyl, each of which is optionally substituted with one Rq; wherein Rqis ORhwherein Rhis C1-C3alkyl, or Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl;

[0984] R6is hydrogen or C1-C3alkyl; and

[0985] R7is hydrogen or C1-C3alkyl.

[0986] In one embodiment, the invention is directed to compounds of formula (I-f), wherein

[0987] R9, R10, and R13are hydrogen;R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0988] C3haloalkyl or C1-C3 alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0989] R4is hydrogen or C1-C3alkyl;

[0990] R5is G2Awherein G2Ais cyclohexyl which is substituted with one Rq; wherein Rqis -C(0)ORhwherein Rhis hydrogen or C1-C3alkyl,

[0991] R6is hydrogen or C1-C3alkyl; and

[0992] R7is hydrogen or C1-C3alkyl.

[0993] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[0994] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[0995] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[0996] R4is hydrogen or C1-C3alkyl;

[0997] R5is G2Awherein G2Ais

[0998] R6is hydrogen or C1-C3alkyl; and

[0999] R7is hydrogen or C1-C3alkyl.

[1000] In some such embodiment, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[1001] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[1002] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[1003] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1004] R4is hydrogen or C1-C3alkyl;

[1005] R5is G2Awherein G2Ais 4-6 membered heterocycle which is optionally substituted with 1, 2, 3 independently selected Rqgroups;

[1006] R6is hydrogen or C1-C3alkyl; and

[1007] R7is hydrogen or C1-C3alkyl.

[1008] In some such embodiment, G2Ais tetrahydrofuranyl or azetidinyl; each of which is optionally substituted with 1, 2, or 3 independently selected Rqgroups.In some such embodiments, G tetrahydrofuranyl or azetidinyl, each of which is optionally substituted with 1, 2, or 3 Rqgroups; wherein each Rqis independently Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[1009] halogen;

[1010] Ci-C6haloalkyl;

[1011] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[1012] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[1013] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,

[1014] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[1015] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or

[1016] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[1017] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[1018] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1019] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1020] R4is hydrogen or C1-C3alkyl;

[1021] R5is G2Awherein G2Ais 5-6 membered heteroaryl which is optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[1022] R6is hydrogen or C1-C3alkyl; and

[1023] R7is hydrogen or C1-C3alkyl.

[1024] In some such embodiment, G2Ais pyridinyl which is optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[1025] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[1026] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1027] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1028] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups; andR6and R7are each independently hydrogen or C1-C3alkyl.

[1029] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[1030] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1031] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1032] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl which is optionally substituted with 1 or 2 Rpgroups; and

[1033] R6and R7are each independently hydrogen or C1-C3alkyl.

[1034] In some such embodiment, the C3-C6cycloalkyl formed is cyclobutyl or cyclopentyl, each of which is optionally substituted with 1 or 2 Rpgroups. In some such embodiment, the C3- C6cycloalkyl formed is unsubstituted cyclobutyl or unsubstituted cyclopentyl.

[1035] In some such embodiment, each Rpis independently

[1036] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups; -C(0)Rhwherein Rhis C C6alkyl;

[1037] -C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl, or -CH2-phenyl; or

[1038] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[1039] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[1040] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[1041] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1042] R4and R5, together with the carbon atom to which they are attached, form a 4-6 membered

[1043] heterocycle which is optionally substituted with 1 or 2 independently selected Rpgroups; and

[1044] R6and R7are each independently hydrogen or C1-C3alkyl.

[1045] In some such embodiment, the 4-6 membered heterocycle formed is azetidinyl or piperidinyl, each of which is optionally substituted with 1 or 2 Rpgroups.

[1046] In some such embodiments, each Rpis independently

[1047] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups; -C(0)Rhwherein Rhis Ci-C6alkyl;

[1048] -C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl, or -CH2-phenyl; or

[1049] -S02Rhwherein Rhis C C6haloalkyl or C C6alkyl.In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[1050] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1051] R4hydrogen or C1-C3alkyl; and

[1052] R5is hydrogen or C1-C3alkyl;

[1053] R6is hydrogen or C1-C3alkyl; and

[1054] R' is -(Ci-C6alkylenyl)-G3A.

[1055] In one embodiment, the invention is directed to compounds of formula (I-f), wherein R9, R10, and R13are hydrogen;

[1056] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1057] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1058] R4hydrogen or C1-C3alkyl; and

[1059] R5is hydrogen or C1-C3alkyl;

[1060] R6is hydrogen or C1-C3alkyl;

[1061] R7is -(CH2)-G3Awherein G3Ais phenyl which is optionally substituted with 1, 2, or 3 Rsgroup; and each Rsis independently C1-C3alkyl, halogen, C1-C3haloalkyl, or -ORJwherein RJis hydrogen or C1-C3alkyl.

[1062] In some such embodiments, each Rsis independently -ORJwherein RJis C1-C3alkyl. One embodiment is directed to com ounds of formula (I-g)

[1064] (i-g)

[1065] wherein R1, R2, R4, R5, R6, R7, R9, R10, R13, and R14are as described in formula (I-d).

[1066] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen.In one embodiment, the invention is directed to compounds of formula (I-g), wherein R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl.

[1067] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen; and

[1068] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[1069] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl.

[1070] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1071] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[1072] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[1073] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[1074] R5is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[1075] R6is hydrogen or Ci-C3alkyl; and

[1076] R7is hydrogen or Ci-C3alkyl.

[1077] In some such embodiment, R4is hydrogen, CH2F, CHF2, CH3, or CH2CH3; and R5is hydrogen, CH2F, CHF2, CH3, or CH2CH3.

[1078] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1079] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1080] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[1081] R4is hydrogen or Ci-C3alkyl;

[1082] R5is G2Awherein G2Ais phenyl, C3-C6cycloalkyl, 4-6 membered heterocycle, or 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, or 3 independently selected Rqgroups

[1083] R6is hydrogen or Ci-C3alkyl; and

[1084] R7is hydrogen or Ci-C3alkyl.

[1085] In one embodiment, the invention is directed to compounds of formula (I-g), wherein

[1086] R9, R10, and R13are hydrogen;

[1087] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;R4is hydrogen or C1-C3alkyl;

[1088] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[1089] R6is hydrogen or C1-C3alkyl; and

[1090] R7is hydrogen or C1-C3alkyl.

[1091] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1092] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1093] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1094] R4is hydrogen or C1-C3alkyl;

[1095] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 Rqgroups;

[1096] wherein each Rqis independently

[1097] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[1098] halogen;

[1099] Ci-C6haloalkyl;

[1100] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[1101] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[1102] -C(0)ORhwherein Rhis hydrogen or C C6alkyl,

[1103] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[1104] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl;

[1105] R6is hydrogen or C1-C3alkyl; and

[1106] R7is hydrogen or C1-C3alkyl.

[1107] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1108] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[1109] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1110] R4is hydrogen or C1-C3alkyl;

[1111] R5is G2Awherein G2Ais phenyl which is optionally substituted with 1, 2, or 3 Rqgroups wherein one of Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl, or one of Rqis-C(0)N(H)(Rh) wherein Rhis cyclopentyl, or Rhis Ci-C6alkyl which is substituted with

[1112] 1 or 2 -OH groups; and the other optional Rqgroups are independently selected from the group consisting of C1-C3alkyl, halogen, and C1-C3haloalkyl;

[1113] R6is hydrogen or C1-C3alkyl; and

[1114] R7is hydrogen or C1-C3alkyl.

[1115] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1116] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1117] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1118] R4is hydrogen or C1-C3alkyl;

[1119] R5is G2Awherein G2Ais phenyl which is substituted with one Rq; wherein Rqis -C(0)ORhwherein Rhis hydrogen or C1-C3alkyl;

[1120] R6is hydrogen or C1-C3alkyl; and

[1121] R7is hydrogen or C1-C3alkyl.

[1122] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[1123] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1124] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[1125] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1126] R4is hydrogen or C1-C3alkyl;

[1127] R5is G2Awherein G2Ais; wherein Rhis hydrogen or C1-C3alkyl; R6is hydrogen or C1-C3alkyl; and

[1128] R7is hydrogen or C1-C3alkyl.

[1129] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[1130] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1131] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[1132] R4is hydrogen or Ci-C alkyl;

[1133] R5is G2Awherein G2Ais

[1134] R6is hydrogen or Ci-C3alkyl; and

[1135] R7is hydrogen or Ci-C3alkyl.

[1136] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis Ci-C3alkyl.

[1137] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1138] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1139] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[1140] R4is hydrogen or Ci-C alkyl;

[1141] R5is G2Awherein G2Ais

[1142] COORh; wherein Rhis hydrogen or Ci-C3alkyl;

[1143] R6is hydrogen or Ci-C alkyl; and

[1144] R7is hydrogen or Ci-C alkyl.

[1145] In some such embodiments, Rhis hydrogen. In some such embodiments, Rhis Ci-C3alkyl.

[1146] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1147] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1148] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[1149] R4is hydrogen or C1-C3 alkyl;

[1150] R5is G2Awherein G2Ais C3-C6cycloalkyl which is optionally substituted with 1, 2, or 3 Rqgroups; wherein each Rqis independently

[1151] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;halogen;

[1152] Ci-C6haloalkyl;

[1153] -ORhwherein Rhis hydrogen or C1-C3 alkyl,

[1154] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle;

[1155] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,

[1156] -C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6

[1157] cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and Ci- C6alkyl are each optionally substituted with 1 or 2 -OH groups; or -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl;

[1158] R6is hydrogen or C1-C3 alkyl; and

[1159] R7is hydrogen or Ci-C3alkyl.

[1160] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1161] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[1162] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[1163] R4is hydrogen or Ci-C3alkyl;

[1164] R5is G2Awherein G2Ais cyclopropyl or cyclohexyl, each of which is optionally substituted with one Rq; wherein Rqis -ORhwherein Rhis C C3alkyl, or Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl;

[1165] R6is hydrogen or Ci-C3alkyl; and

[1166] R7is hydrogen or Ci-C3alkyl.

[1167] In one embodiment, the invention is directed to compounds of formula (I-g), wherein

[1168] R9, R10, and R13are hydrogen;

[1169] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1170] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[1171] R4is hydrogen or Ci-C3alkyl;

[1172] R5is G2Awherein G2Ais cyclohexyl which is substituted with one Rq; wherein Rqis -C(0)ORhwherein Rhis hydrogen or Ci-C3alkyl,

[1173] R6is hydrogen or Ci-C3alkyl; and

[1174] R7is hydrogen or Ci-C3alkyl.

[1175] In one embodiment, the invention is directed to compounds of formula (I-g), whereinR9, R10, and R13are hydrogen;

[1176] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[1177] C3haloalkyl or C1-C3 alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1178] R4is hydrogen or C1-C3alkyl;

[1179] R5is G2Awherein G2Ais

[1180] R6is hydrogen or C1-C3alkyl; and

[1181] R7is hydrogen or C1-C3alkyl.

[1182] In some such embodiment, Rhis hydrogen. In some such embodiments, Rhis C1-C3alkyl.

[1183] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1184] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1185] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1186] R4is hydrogen or C1-C3alkyl;

[1187] R5is G2Awherein G2Ais 4-6 membered heterocycle optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[1188] R6is hydrogen or C1-C3alkyl; and

[1189] R7is hydrogen or C1-C3alkyl.

[1190] In some such embodiment, G2Ais tetrahydrofuranyl or azetidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[1191] In some such embodiments, G2Atetrahydrofuranyl or azetidinyl, each of which is optionally substituted with 1, 2, or 3 Rqgroups; wherein each Rqis independently Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with one -OH;

[1192] halogen;

[1193] Ci-C6haloalkyl;

[1194] -ORhwherein Rhis hydrogen or C1-C3alkyl,

[1195] -C(0)Rhwherein Rhis GA; wherein GAis 4-6 membered heterocycle ;

[1196] -C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl,-C(0)N(Rh)2, wherein Rhat each occurrence, is independently hydrogen, C3-C6cycloalkyl, Ci-C6haloalkyl, or Ci-C6alkyl; wherein the Ci-C6haloalkyl and C C6alkyl are each optionally substituted with 1 or 2 -OH groups; or

[1197] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[1198] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1199] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais (

[1200] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1201] R4is hydrogen or C1-C3alkyl;

[1202] R5is G2Awherein G2Ais 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 independently selected Rqgroups;

[1203] R6is hydrogen or C1-C3alkyl; and

[1204] R7is hydrogen or C1-C3alkyl.

[1205] In some such embodiment, G2Ais pyridinyl optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[1206] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1207] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais ( C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1208] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups; and

[1209] R6and R7are each independently hydrogen or C1-C3alkyl.

[1210] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1211] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais ( C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1212] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl which is optionally substituted with 1 or 2 Rpgroups; and

[1213] R6and R7are each independently hydrogen or C1-C3alkyl.In some such embodiment, the C3-C6 cycloalkyl formed is cyclobutyl or cyclopentyl, each of which is optionally substituted with 1 or 2 Rpgroups. In some such embodiment, the C3- C6cycloalkyl formed is unsubstituted cyclobutyl or unsubstituted cyclopentyl.

[1214] In some such embodiment, each Rpis independently

[1215] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups; -C(0)Rhwherein Rhis C C6alkyl;

[1216] -C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl, or -CH2-phenyl; or

[1217] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[1218] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1219] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1220] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[1221] R4and R5, together with the carbon atom to which they are attached, form a 4-6 membered

[1222] heterocycle which is optionally substituted with 1 or 2 Rpgroups; and

[1223] R6and R7are each independently hydrogen or Ci-C3alkyl.

[1224] In some such embodiment, the 4-6 membered heterocycle formed is azetidinyl or piperidinyl, each of which is optionally substituted with 1 or 2 Rpgroups.

[1225] In some such embodiments, each Rpis independently

[1226] Ci-C6alkyl wherein the Ci-C6alkyl is optionally substituted with 1 or 2 -OH groups; -C(0)Rhwherein Rhis Ci-C6alkyl;

[1227] -C(0)ORhwherein Rhis hydrogen, Ci-C6alkyl, or -CH2-phenyl; or

[1228] -S02Rhwherein Rhis Ci-C6haloalkyl or Ci-C6alkyl.

[1229] In one embodiment, the invention is directed to compounds of formula (I-g), wherein R9, R10, and R13are hydrogen;

[1230] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci-

[1231] C3haloalkyl or Ci-C3alkyl; and R1Bis hydrogen or Ci-C3alkyl;

[1232] R4hydrogen or Ci-C3alkyl; and

[1233] R5is hydrogen or Ci-C3alkyl;

[1234] R6is hydrogen or Ci-C3alkyl; and

[1235] R7is -(Ci-C6alkylenyl)-G3A.

[1236] In one embodiment, the invention is directed to compounds of formula (I-g), whereinR9, R10, and R13are hydrogen;

[1237] R1is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais C

[1238] C3haloalkyl or C1-C3alkyl; and R1Bis hydrogen or C1-C3alkyl;

[1239] R4hydrogen or C1-C3alkyl; and

[1240] R5is hydrogen or C1-C3alkyl;

[1241] R6is hydrogen or C1-C3alkyl; and

[1242] R7is -(CH2)-G3Awherein G3Ais phenyl which is optionally substituted with 1, 2, or 3 Rsgroup; wherein each Rsis independently C1-C3alkyl, halogen, C1-C3haloalkyl, or -ORJwherein RJis hydrogen or C1-C3alkyl.

[1243] In some such embodiments, each Rsis independently -ORJwherein RJis C1-C3alkyl.

[1244] Compounds described herein may contain one or more asymmetrically substituted atoms, and thus may exist as individual stereoisomers (including enantiomers and diastereomers) or mixtures thereof. For example, certain embodiments are directed to compounds of formula (I-h)

[1246] (I-h)

[1247] wherein

[1248] R1is hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais Ci- C3haloalkyl or C1-C3alkyl;

[1249] R2is hydrogen, halogen, C C6haloalkyl, C C6alkyl, -OR1A, or -C(0)OR1B; wherein R1Ais hydrogen, C1-C3haloalkyl, or C1-C3alkyl; wherein the C1-C3alkyl is optionally substituted with one substituent selected from the group consisting of -ORZA, -C(0)OH, and G1A; wherein G1Ais phenyl which is optionally substituted with 1, 2, or 3 Rsgroups wherein each Rsis independently C1-C3alkyl, C1-C3haloalkyl, halogen, or -OCH3; and RZAis C1-C3haloalkyl or C1-C3alkyl;

[1250] R1Bis hydrogen or C1-C3alkyl;

[1251] R3and R14are each independently hydrogen or halogen;

[1252] R4is hydrogen, C1-C3haloalkyl, or C1-C3alkyl;R5is G2A;

[1253] G2Ais C3-C6cycloalkyl, 4-6 membered heterocycle, phenyl, or 5-6 membered heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rqgroups;

[1254] Rq, at each occurrence, is independently Ci-C6alkyl, halogen, Ci-C6haloalkyl, -CN, oxo, N02, -ORh, -OCCC R1, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N^CCC R1, -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri),

[1255] -N(Rh)C(0)N(Rh)2, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -00(0)^, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, -CN, and GA;

[1256] Rh, at each occurrence, is independently hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRj, -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;

[1257] R1, at each occurrence, is independently Ci-C6haloalkyl, Ci-C6alkyl, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRJ,

[1258] -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;

[1259] R6is hydrogen or Ci-C3alkyl;

[1260] R7is hydrogen or Ci-C3alkyl;

[1261] R9, R10, and R13, are each independently hydrogen or halogen;

[1262] GA, at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or

[1263] heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rsgroups;

[1264] Rs, at each occurrence, is independently Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, Ci- C6haloalkyl, -CN, oxo, N02, -ORj, -OC(0)Rk, -OC(0)N(Rj)2, -SRj, -S(0)2Rj,

[1265] -S(0)2N(RJ)2, -C(0)RJ, -C(0)ORJ, -C(0)N(RJ)2, -N(RJ)2, -N(RJ)C(0)Rk, -N(RJ)S(0)2Rk, -N(Rj)C(0)0(Rk), -N(Rj)C(0)N(Rj)2, -(Ci-C6alkylenyl)-ORj, -(Ci-C6

[1266] alkylenyl)-OC(0)Rk, -(C C6alkylenyl)-OC(0)N(Rj)2, -(C C6alkylenyl)-SRj, -(C C6alkylenyl)-S(0)2Rj, -(Ci-C6alkylenyl)-S(0)2N(Rj)2, -(Ci-C6alkylenyl)-C(0)Rj, -(Ci-C6alkylenyl)-C(0)ORj, -(C C6alkylenyl)-C(0)N(Rj)2, -(C C6alkylenyl)-N(Rj)2, -(C C6alkylenyl)-N(Rj)C(0)Rk, -(Ci-C6alkylenyl)-N(Rj)S(0)2Rk, -(Ci-C6

[1267] alkylenyl)-N(Rj)C(0)0(Rk), -(Ci-C6alkylenyl)-N(Rj)C(0)N(Rj)2, or -(Ci-C6

[1268] alkylenyl)-CN;

[1269] R, at each occurrence, is independently hydrogen, Ci-C6alkyl, or Ci-C6haloalkyl; and

[1270] Rk, at each occurrence, is independently Ci-C6alkyl or Ci-C6haloalkyl.

[1271] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R3, R14, R9, R10, and R13are hydrogen.

[1272] In one embodiment, the invention is directed to compounds of formula (I-h) wherein G2Ais phenyl, cyclopropyl, cyclohexyl, pyridinyl, azetidinyl, or tetrahydrofuranyl; each of which is optionally substituted with 1, 2, or 3 independently selected Rqgroups.

[1273] In one embodiment, the invention is directed to compounds of formula (I-h) wherein G2Ais phenyl, pyridinyl, cyclopropyl, cyclohexyl, pyridinyl, azetidinyl, or tetrahydrofuranyl; each of which is optionally substituted with 1, 2, or 3 independently selected Rqgroups; and R3, R14, R9, R10, and R13are hydrogen.

[1274] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; and R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1275] RZAis C1-C3alkyl.

[1276] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1277] RZAis C1-C3alkyl; and

[1278] R3, R14, R9, R10, and R13are hydrogen.

[1279] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl;R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein RZAis C1-C3alkyl;

[1280] R4is hydrogen;

[1281] R6is hydrogen; and

[1282] R7is hydrogen.

[1283] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1284] RZAis C1-C3alkyl;

[1285] R4is hydrogen;

[1286] R6is hydrogen;

[1287] R7is hydrogen; and

[1288] R3, R14, R9, R10, and R13are hydrogen.

[1289] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, CH3, or -OCH3;

[1290] R2is hydrogen, F, CF3, CH3, -OCHF2, -OCH2CH2F, or -OCH2CH2OCH3;

[1291] R4is hydrogen;

[1292] R6is hydrogen;

[1293] R7is hydrogen; and

[1294] R3, R14, R9, R10, and R13are hydrogen.

[1295] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1296] RZAis C1-C3alkyl;

[1297] R4is hydrogen;

[1298] R6is hydrogen;

[1299] R7is hydrogen; andG2Ais phenyl substituted with 1, 2, or 3 Rqgroups; wherein one of Rqgroups is C(0)ORhwherein Rhis hydrogen or Ci-C6alkyl; or one of Rqgroups is -C(0)N(H)(Rh), wherein Rhis cyclopentyl, or Rhis Ci-C6alkyl substituted with 1 or 2 -OH groups; and the other optional Rqgroups are independently selected from the group consisting of C1-C3alkyl, halogen, and C1-C3haloalkyl.

[1300] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1301] RZAis C1-C3alkyl;

[1302] R4is hydrogen;

[1303] R6is hydrogen;

[1304] R7is hydrogen;

[1305] R3, R14, R9, R10, and R13are hydrogen; and

[1306] G2Ais phenyl substituted with 1, 2, or 3 Rqgroups; wherein one of Rqgroups is C(0)ORh

[1307] wherein Rhis hydrogen or Ci-C6alkyl; or one of Rqgroups is -C(0)N(H)(Rh), wherein Rhis cyclopentyl, or Rhis Ci-C6alkyl substituted with 1 or 2 -OH groups; and the other optional Rqgroups are independently selected from the group consisting of C1-C3alkyl, halogen, and C1-C3haloalkyl.

[1308] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1309] RZAis C1-C3alkyl;

[1310] R4is hydrogen;

[1311] R6is hydrogen;

[1312] R7is hydrogen; and

[1313] G2Ais phenyl or cyclohexyl; each of which is substituted with one C(0)ORhwherein Rhis

[1314] hydrogen or C1-C3alkyl.

[1315] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl;R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein RZAis C1-C3alkyl;

[1316] R4is hydrogen;

[1317] R6is hydrogen;

[1318] R7is hydrogen;

[1319] R3, R14, R9, R10, and R13are hydrogen; and

[1320] G2Ais phenyl or cyclohexyl; each of which is substituted with one C(0)ORhwherein Rhis

[1321] hydrogen or C1-C3alkyl.

[1322] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1323] RZAis C1-C3alkyl;

[1324] R4is hydrogen;

[1325] R6is hydrogen;

[1326] R7is hydrogen; and

[1327] G2Ais phenyl substituted with one C(0)ORhwherein Rhis hydrogen or C C3alkyl.

[1328] In some such embodiment, Rhis hydrogen. In some such embodiment, Rhis C1-C3alkyl.

[1329] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1330] RZAis C1-C3alkyl;

[1331] R4is hydrogen;

[1332] R6is hydrogen;

[1333] R7is hydrogen;

[1334] R3, R14, R9, R10, and R13are hydrogen; and

[1335] G2Ais phenyl substituted with one C(0)ORhwherein Rhis hydrogen or C1-C3alkyl.

[1336] In some such embodiment, Rhis hydrogen. In some such embodiment, Rhis C1-C3alkyl. In one embodiment, the invention is directed to compounds of formula (I-h) whereinR1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1337] RZAis C1-C3alkyl;

[1338] R4is hydrogen;

[1339] R6is hydrogen;

[1340] R7is hydrogen; and

[1341] G2Ais cyclohexyl substituted with one C(0)ORhwherein Rhis hydrogen or C1-C3alkyl.

[1342] In some such embodiment, Rhis hydrogen. In some such embodiment, Rhis C1-C3alkyl.

[1343] In one embodiment, the invention is directed to compounds of formula (I-h) wherein R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZAwherein

[1344] RZAis C1-C3alkyl;

[1345] R4is hydrogen;

[1346] R6is hydrogen;

[1347] R7is hydrogen;

[1348] R3, R14, R9, R10, and R13are hydrogen; and

[1349] G2Ais cyclohexyl substituted with one C(0)ORhwherein Rhis hydrogen or C C3alkyl.

[1350] In some such embodiment, Rhis hydrogen. In some such embodiment, Rhis C1-C3alkyl. One embodiment is directed to compounds of formula (I-i)

[1352] whereinR1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; and

[1353] R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZA, and RZAis C1-C3alkyl; and

[1354] Rhis hydrogen or C1-C3alkyl.

[1355] In one embodiment, the invention is directed to compounds of formula (I-i) wherein R1is hydrogen, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; and

[1356] Rhis hydrogen.

[1357] One embodiment is directed to com ounds of formula (I-j)

[1359] (i-j)

[1360] wherein

[1361] R1is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; and

[1362] R2is hydrogen, halogen, C1-C3haloalkyl, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3haloalkyl, or C1-C3alkyl wherein the C1-C3alkyl is optionally substituted with one -ORZA, and RZAis C1-C3alkyl; and

[1363] Rhis hydrogen or C1-C3alkyl.

[1364] In one embodiment, the invention is directed to compounds of formula (I-j) wherein R1is hydrogen, C1-C3alkyl, or -OR1A; wherein R1Ais C1-C3alkyl; and

[1365] Rhis hydrogen.

[1366] One embodiment is directed to compounds of formula (I) wherein

[1367] X is CR2and Y is CR3; or

[1368] X is N and Y is CR3; orX is CR2and Y is N;

[1369] m is 0, 1, 2, or 3;

[1370] R" are optional substituents on the cyclopropyl ring, and at each occurrence, are each

[1371] independently halogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[1372] R1and R2, are each independently hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OR , -C(0)OR1B, -NR1AR2A, or -C(0)NR1AR2A;

[1373] R1Aand R2A, at each occurrence, are each independently hydrogen, Ci-C6haloalkyl, G1A, or Ci- C6alkyl; wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORZA, -SRZA, -S(0)2RZA, -C(0)RZA, -C(0)ORZA, -C(0)N(RZA)2, -N(RZA)2, -N(RZA)C(0)RZB, -N(RZA)S(0)2RZB, -N(RZA)C(0)ORZB, -N(RZA)C(0)N(RZA)2, -CN, and G1A; or R1Aand R2Atogether with the nitrogen atom to which they are attached form a 4-6 membered heterocycle wherein the 4-6 membered heterocycle is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci-C6alkyl, Ci-C6haloalkyl, -ORj, and N(Rj)2; wherein

[1374] RZA, at each occurrence, is independently hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, G1A, or

[1375] -(Ci-Ce alkylenyl)-G1A; and

[1376] RZB, at each occurrence, is independently Ci-C6haloalkyl, Ci-C6alkyl, G1A, or -(Ci-C6alkylenyl)-G1A;

[1377] R1Bis hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[1378] R3and R14, are each independently hydrogen, halogen, Ci-C6haloalkyl, Ci-C6alkyl, -OH, or

[1379] -0-(Ci-C6alkyl);

[1380] R4is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[1381] R5is hydrogen, -C(0)R\ -C(0)OH, -C(0)N(Rh)2, Ci-C6haloalkyl, Ci-C6alkyl, or G2A; wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -OC(0)N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2Ri,

[1382] -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, and G2A; or

[1383] R4and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6cycloalkyl and the 4-6 memberedheterocycle are each optionally substituted with 1, 2, or 3 independently selected Rpgroups;

[1384] G2A, at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or

[1385] heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rqgroups;

[1386] Rpand Rq, at each occurrence, are each independently Ci-C6alkyl, halogen, Ci-C6haloalkyl,

[1387] -CN, oxo, N02, -ORh, -OCiO)^, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -NCR^CCC R1, -Ν^)8(0)2^, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -00(0)^, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, -CN, and GA;

[1388] Rh, at each occurrence, is independently hydrogen, Ci-C6haloalkyl, Ci-C6alkyl, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRj, -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;

[1389] R1, at each occurrence, is independently Ci-C6haloalkyl, Ci-C6alkyl, or GA, wherein the Ci-C6haloalkyl and the Ci-C6alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRJ,

[1390] -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;

[1391] R6is hydrogen, halogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[1392] R7is hydrogen, halogen, -ORj, -N(Rj)2, -N(Rj)C(0)Rk, C C6haloalkyl, C C6alkyl, C2-C6

[1393] alkenyl, or -(Ci-C6alkylenyl)-G3A;

[1394] R8is hydrogen, Ci-C6haloalkyl, or Ci-C6alkyl;

[1395] R9, R10, and R13, are each independently hydrogen, halogen, -ORJ, Ci-C6haloalkyl, or Ci-C6alkyl;

[1396] R11and R12are each independently hydrogen, C1-C3 alkyl, or halogen;

[1397] G1A, G3A, and GA, at each occurrence, are each independently cycloalkyl, cycloalkenyl,

[1398] heterocycle, aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rsgroups; whereinRs, at each occurrence, is independently Ci-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C C6haloalkyl, -CN, oxo, N02, -ORj, -OC(0)Rk, -OC(0)N(Rj)2, -SRj, -S(0)2RJ, -S(0)2N(RJ)2, -C(0)RJ, -C(0)ORJ, -C(0)N(RJ)2, -N(RJ)2, -N(RJ)C(0)Rk, -N(Rj)S(0)2Rk, -N(Rj)C(0)0(Rk), -N(Rj)C(0)N(Rj)2, -(Ci-C6alkylenyl)-ORj, -(Ci-C6alkylenyl)-OC(0)Rk, -(Ci-C6alkylenyl)-OC(0)N(Rj)2, -(Ci-C6alkylenyl)-SRj, -(C C6alkylenyl)-S(0)2Rj, -(C C6alkylenyl)-S(0)2N(Rj)2, -(C C6alkylenyl)-C(0)Rj, -(Ci-C6alkylenyl)-C(0)ORj, -(Ci-C6

[1399] alkylenyl)-C(0)N(Rj)2, -(Ci-C6alkylenyl)-N(Rj)2, -(Ci-C6

[1400] alkylenyl)-N(Rj)C(0)Rk, -(Ci-C6alkylenyl)-N(Rj)S(0)2Rk, -(Ci-C6alkylenyl)-N(Rj)C(0)0(Rk), -(C C6alkylenyl)-N(Rj)C(0)N(Rj)2, or -(C C6alkylenyl)-CN;

[1401] RJ, at each occurrence, is independently hydrogen, Ci-C6alkyl, or Ci-C6haloalkyl; and

[1402] Rk, at each occurrence, is independently Ci-C6alkyl or Ci-C6haloalkyl.

[1403] Exemplary compounds of formula (I) include, but are not limited to:

[1404] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1405] 3-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1406] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3,4-dimethoxyphenyl)-7-methoxy- 3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1407] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(25',45)-2-(3,4-dimethoxyphenyl)-7-methoxy- 3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1408] methyl 3-[(2i?,45)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1409] methyl 3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1410] methyl 3-[(2i?,45)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1411] methyl 3-[(2i?,4i?)-4-({[l-(2,2-difiuoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]benzoic acid;

[1412] 3-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4- dihydro-2H-chromen-2-yl]benzoic acid;

[1413] methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1414] methyl 3-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1415] 3-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1416] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1417] 3-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1418] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1419] methyl 3-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1420] methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1421] 3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6- methoxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1422] l-(2,2-difiuoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-hydroxy-2-(3-methoxyphenyl)-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1423] methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1424] rac-l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,45)-7-methoxy-2-(pyridin-3-yl)-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1425] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- hydroxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;ethyl rel-3-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate;

[1426] ethyl re / -3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate;

[1427] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (difluoromethoxy)-3 ,4-dihydro-2H-chromen-2-yl] cyclohexanecarboxylic acid;

[1428] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (difluoromethoxy)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1429] rac-3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;

[1430] rac-3-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;

[1431] methyl rac-3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 , 3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2- yljbenzoate;

[1432] rac-3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;

[1433] rac-3-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;

[1434] rac-methyl 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;

[1435] rac-methyl 3-[(2i?,45)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;

[1436] 3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;

[1437] 3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- fluoro-3,4-dihydro-2H-chromen-2-yl] cyclohexanecarboxylic acid;

[1438] methyl 3-[4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;

[1439] 3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- fluoro-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1440] rac-N-[(2i?,4i?)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro- l ,3-benzodioxol-5-yl)cyclopropanecarboxamide;

[1441] rac-N-[(2i?,45)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro- l ,3-benzodioxol-5-yl)cyclopropanecarboxamide;

[1442] 4-( { [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3 ,4-dihydro-2H- chromene-7-carboxylic acid;

[1443] 3-({3-[(2R,4R)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoyl} amino)- 1 -methylcyclopentanecarboxylic acid;

[1444] (2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-2-(3- methoxyphenyl)-3 ,4-dihydro-2H-chromene-6-carboxylic acid;

[1445] methyl 4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4- dihydro-2H-chromene-7-carboxylate;

[1446] methyl (2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 2-(3-methoxycyclohexyl)-3,4-dihydro-2H-chromene-6-carboxylate;

[1447] methyl (2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 2-(3-methoxyphenyl)-3,4-dihydro-2H-chromene-6-carboxylate;

[1448] 3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2i?)-2,3-dihydroxypropyl]benzamide;

[1449] l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3- {[(3i?)-3-hydroxypyrrolidin-l- yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1450] 3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3 ,4-dihydro-2H-chromen-2-yl] -N-(3 ,3 ,3 -trifluoro-2-hydroxypropyl)benzamide;

[1451] 3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]-N-(2-hydroxy-2-methylpropyl)benzamide;

[1452] l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3- {[3-(hydroxymethyl)piperidin-l- yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1453] l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3- {[2-(hydroxymethyl)morpholin-4- yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(l-hydroxycyclobutyl)methyl]benzamide;

[1454] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3-{[3-(hydroxymethyl)-3- methylazetidin-l-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4- y 1] cy clopropanecarboxamide ;

[1455] N-(7-bromo-3,4-dihydro-2H-chromen-4-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide;

[1456] rac-l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-methoxy-2-(pyridin-3-yl)-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1457] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-{(2i?)-2-[3-(hydroxymethyl)phenyl]-3,4-dihydro- 2H-chromen-4-yl}cyclopropanecarboxamide;

[1458] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-methoxy-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide;

[1459] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-methoxy-2-phenyl-3,4-dihydro-2H-chromen- 4-yl)cyclopropanecarboxamide;

[1460] N-[2-(3,4-dichlorophenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-i benzodioxol-5-yl)cyclopropanecarboxamide;

[1461] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1462] N-[2-(4-chlorophenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l -(2,2-difluoro- 1,3- benzodioxol-5-yl)cyclopropanecarboxamide;

[1463] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-{2-[4-(trifluoromethyl)phenyl]-3,4-dih^ chromen-4-yl}cyclopropanecarboxamide;

[1464] N-[2-(2-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3-benzodioxol^ yl)cyclopropanecarboxamide;

[1465] N-[2-(3,4-dichlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxamide;

[1466] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(2-phenyl-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide;

[1467] N-[2-(4-chlorophenyl)-3,4-dihydro-2H-ch^

[1468] yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[2-(3,4-dimethoxyphenyl)-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide;

[1469] N-[2-(3-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide;

[1470] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[2-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4- y 1] cy clopropanecarboxamide ;

[1471] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-6-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1472] N-(3-benzyl-3,4-dihydro-2H-chromen-4-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide;

[1473] N-[(4i?)-2,2-diethyl-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide;

[1474] N-[(4i?)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxamide;

[1475] N-[(4i?)-7-chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl] -(2,2-difluoro-1 benzodioxol-5-yl)cyclopropanecarboxamide;

[1476] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(4i?)-8-fluoro-2,2-bis(fluoromethyl)-3,4-dih^ 2H-chromen-4-yl]cyclopropanecarboxamide;

[1477] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(4i?)-3,4-dihydrospiro[chromene-2, - cyclopentan]-4-yl]cyclopropanecarboxamide;

[1478] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(4i?)-7-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro- 2H-chromen-4-yl]cyclopropanecarboxamide;

[1479] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(25*,4i?)-2-(fluoromethyl)-2-methyl-7- (trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1480] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(difluoromethyl)-2-methyl-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1481] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2^,4i?)-2-(difluoromethyl)-2-methyl-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1482] N-[(25',4i?)-7-chloro-2 difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl^ difluoro- 1 ,3-benzodioxol-5-yl)cyclopropanecarboxamide;N-[(2R,4R)-7-cWoro-2-(difluorom

[1483] difluoro- 1 ,3-benzodioxol-5-yl)cyclopropanecarboxamide;

[1484] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(25*,4i?)-2-methyl-2-(trifluoromethyl)-^ dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1485] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(4i?)-7-fluoro-2,2-dimethyl-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide;

[1486] N-[(4i?)-7-chloro-2,2-bis(fluoromethyl)-3,4-dm^

[1487] l,3-benzodioxol-5-yl)cyclopropanecarboxamide;

[1488] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(45)-6-fluoro-2,2-dimethyl-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide;

[1489] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(45)-6-fluoro-3,4-dihydrospiro[chromene-2, - cyclobutan]-4-yl]cyclopropanecarboxamide;

[1490] N-[(4i?)-8-chloro-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl] -(2,2-diflu^^ l,3-benzodioxol-5-yl)cyclopropanecarboxamide;

[1491] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-7-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1492] tert-butyl 4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- fluoro-3,4-dihydro- H-spiro[chromene-2,4'-piperidine]- -carboxylate;

[1493] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-fluoro-3,4-dihydrospiro[chromene-2,4'- piperidin]-4-yl)cyclopropanecarboxamide;

[1494] methyl 3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate; methyl 3-[(2i?,4i?)-7-(benzyloxy)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1495] 3-[(2i?,4i?)-7-(carboxymethoxy)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl} amino)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1496] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7-(2- methoxyethoxy)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1497] 3-[(2i?,4i?)-7-(benzyloxy)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl} amino)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-{ -[(2i?)-2,3-dihydroxypropyl]-7-fluoro-3,4- dihydrospiro[chromene-2,4'-piperidin]-4-yl}cyclopropanecarboxamide;

[1498] benzyl 4'-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7'-fluoro- 3',4'-dihydro-lH-spiro[azetidine-3,2'-chromene]-l-carboxylate;

[1499] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[7-fluoro- -(methylsulfonyl)-3,4- dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanecarboxamide;

[1500] N-( -acetyl-7-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl)- 1 -(2,2-difluoro- 1,3- benzodioxol-5-yl)cyclopropanecarboxamide;

[1501] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7'-fluoro-3',4'-dihydrospiro[azetidine-3,2'- chromen]-4'-yl)cyclopropanecarboxamide;

[1502] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[7*-fluoro-l-(methylsulfonyl)-3*,4*- dihydrospiro[azetidine-3,2'-chromen]-4'-yl]cyclopropanecarboxamide;

[1503] N-(l-acetyl-7'-fluoro-3^4'-dihydrospiro[azetidine-3,2'-chromen]-4'-yl)-l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxamide;

[1504] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7-(2- f uoroethoxy)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1505] l-(2,2-dif uoro-l,3-benzodioxol-5-yl)-N-[ -(3-hydroxy-2,2-dimethylpropanoyl)-7- methoxy-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanecarboxamide;

[1506] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (trifluoromethyl)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1507] 3- [(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (trifluoromethyl)-3 ,4-dihydro-2H-chromen-2-yl] cyclohexanecarboxylic acid;

[1508] methyl 4-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1509] 4- [(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1510] methyl rac-3-[(2i?,4i?)-7-chloro-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;

[1511] methyl rac-3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 , 3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;rac-3-[(2R,4R)-7-cMoio-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;

[1512] tert-butyl 3-[4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]azetidine- 1 -carboxylate;

[1513] N-[2-(azetidin-3-yl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l -(2,2-difluoro-l, 3- benzodioxol-5-yl)cyclopropanecarboxamide;

[1514] 1 -(2,2-difluoro-l ,3-benzodioxol-5-yl)-N- {7-methoxy-2-[ 1 -(methylsulfonyl)azetidin-3-yl]- 3 ,4-dihydro-2H-chromen-4-yl} cyclopropanecarboxamide;

[1515] methyl rac-3-[(2i?,45)-4-({[l-(2,2-dif uoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-f uoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;

[1516] 3- [(2i?,4i?)-4-( {[ 1 -(2,2-dif uoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-8- f uoro-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1517] methyl 4-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1518] 4- [(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]benzoic acid;

[1519] 4-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (difluoromethoxy)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1520] methyl 4-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate; l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-hydroxy-2,2-dimethyl-3,4-dihydro-2H- chromen-4-yl)cyclopropanecarboxamide;

[1521] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[7-(difluoromethoxy)-2,2-dimethyl-3,4-dihydro- 2H-chromen-4-yl]cyclopropanecarboxamide;

[1522] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[7-methoxy-2-(tetrahydrofuran-2-yl)-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1523] methyl 4-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-hydroxy-3,4-dihydro-2H-chromen-2-yl]benzoate;

[1524] 4-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- hydroxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7-methoxy-3 ,4- dihydrospiro[chromene-2, 1 '-cyclobutane]-3'-carboxylic acid;

[1525] ethyl rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate;

[1526] methyl rac-(2i?,45)-4-({[l-(2,2-difiuoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate;

[1527] ethyl rel-2-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-5-carboxylate;

[1528] 2-[(45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4- dihydro-2H-chromen-2-yl]- 1 ,3-thiazole-5-carboxylic acid;

[1529] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3 ,4-dihydro-2H-chromene-2-carboxylic acid;

[1530] ethyl rel-2-[(2R,4R)-H ii 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-5-carboxylate;

[1531] 2-[(4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]- 1 ,3-thiazole-5-carboxylic acid;

[1532] methyl 4-[(2i?,4i?)-4-({[l-(2,2-difiuoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoate; methyl 4-[(2i?,4i?)-4-({[l-(2,2-difiuoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-3-fluorobenzoate;

[1533] 4-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoic acid;

[1534] ethyl rel-2-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4-carboxylate; ethyl re / -2-[(2i?,45)-4-({[l-(2,2-difiuoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4-carboxylate; ethyl rel-2-[(2R,4R)-H ii 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4-carboxylate; re / -2-[(25',45)-4-({[l-(2,2-difiuoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4-carboxylic acid;rel-2-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4-carboxylic acid;

[1535] re / -2-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3,4-dihydro-2H-chromen-2-yl]-l ,3-thiazole-4-carboxylic acid;

[1536] 4-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]-3-fluorobenzoic acid;

[1537] methyl rac-3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 , 3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2- yl]bicyclo[ 1.1.1 Jpentane- 1 -carboxylate;

[1538] rac-3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 7-methoxy-3 ,4-dihydro-2H-chromen-2-yl]bicyclo[ 1.1.1 Jpentane- 1 -carboxylic acid;

[1539] ethyl rac-6-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;

[1540] ethyl rac-6-[(2R,4R)-H {[ 1 -(2,2-difluoro- 1 , 3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;

[1541] ethyl 3-[4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]cyclobutanecarboxylate;

[1542] 3-[4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro- 2H-chromen-2-yl]cyclobutanecarboxylic acid;

[1543] rac-6-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 3, 4-dihydro-2H-chromen-2-yl]pyridine-3 -carboxylic acid;

[1544] rac-6-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3, 4-dihydro-2H-chromen-2-yl]pyridine-3 -carboxylic acid;

[1545] ethyl re / -2-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4- carboxylate;

[1546] re / -2-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 7-methoxy-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4-carboxylic acid;

[1547] ethyl rel-2-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4- carboxylate;re / -2-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 7-methoxy-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4-carboxylic acid;

[1548] methyl re / -6-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3- carboxylate;

[1549] methyl re / -6-[(25,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3- carboxylate;

[1550] methyl re / -6-[(25,4S)^-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3- carboxylate;

[1551] methyl re / -6-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3- carboxylate;

[1552] ethyl rac-(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate;

[1553] rac-(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3 ,4-dihydro-2H-chromene-2-carboxylic acid;

[1554] re -6-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylic acid;

[1555] rac-(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (2-hydroxyethyl)-7-methoxy-N-propyl-3,4-dihydro-2H-chromene-2-carboxamide;

[1556] rac-(2i?,4i?)-N-benzyl-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-N-(2-hydroxyethyl)-7-methoxy-3,4-dihydro-2H-chromene-2- carboxamide;

[1557] rac-(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (2-hydroxy-2-phenylethyl)-7-methoxy-N-methyl-3,4-dihydro-2H-chromene-2-carboxamide; rac-l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2R,4R)-2-{[4-(2-hydroxyethyl)piperazin- l-yl]carbonyl}-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1558] rac-(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- ( 1 -hydroxy-2-methylpropan-2-yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (2 -hydroxy- 1 -phenylethyl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide;

[1559] rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2- carboxamide;

[1560] rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-N-[3-(trifluoromethyl)oxetan-3-yl]-3,4-dihydro-2H-chromene-2-carboxa

[1561] rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N- {(2i?,4i?)-2-[(4,4-difluoropiperidin-l- yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide;

[1562] rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-methoxy-2-(l ,4-oxazepan-4- ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1563] rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-N-methyl-N-(oxetan-3-yl)-3,4-dihydro-2H-chromene-2-carboxamide

[1564] rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-methoxy-2-(morpholin-^ ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1565] rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- [2-hydroxy-l-(2-methoxyphenyl)ethyl]-7-methox

[1566] rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- [2-(3-hydroxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;

[1567] rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (l ,3-dihydroxypropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;

[1568] rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (2 -hydroxy-2,3 -dihydro- 1 H-inden- 1 -yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide; rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2-hydroxyphenyl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;

[1569] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2-hydroxyethyl)-7-methoxy-N-propyl-3,4-dihydro-2H-chromene-2-carboxamide;

[1570] rac-(2i?,45)-N-benzyl-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-N-(2-hydroxyethyl)-7-methoxy-3,4-dihydro-2H-chromene-2- carboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2-hydroxy-2-phenylethyl)-7-methoxy-N-methyl-3,4-dihydro-2H-chromen

[1571] rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N- {(2i?,45)-2-[(4-hydroxypiperidin-l- yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide;

[1572] rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,45)-2- {[4-(2-hydroxyethyl)piperazin-l- yl]carbonyl}-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamid;

[1573] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2-hydroxy-2-methylpropyl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;

[1574] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- ( 1 -hydroxy-2-methylpropan-2-yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamid;

[1575] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2 -hydroxy- 1 -phenylethyl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide;

[1576] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2- carboxamide;

[1577] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-N-[3-(trifluoromethyl)oxetan-3-yl]-3,4-dihydro-2H-chromene-2-carboxamide;

[1578] rac- 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-N- {(2i?,45)-2-[(4,4-difluoropiperidin- 1 - yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide;

[1579] rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,45)-7-methoxy-2-(l ,4-oxazepan-4- ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1580] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-N-methyl-N-(oxetan-3-yl)-3,4-dihydro-2H-chromene-2-carboxamide;

[1581] rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,45)-7-methoxy-2-(morpholin-4- ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;

[1582] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- [2-hydroxy-l-(2-methoxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide; rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- [2-(3-hydroxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;

[1583] rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (l ,3-dihydroxypropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2-hydroxy-2,3 -dihydro- 1 H-inden- 1 -yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide; roc- 1 - { [(2R,4S)-4-( { [ 1 -(2,2-difluoro- 1 ,3 -benzodioxol-5 - yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2- y 1] carbony 1 } pyrrolidine-3 -carboxy lie acid;

[1584] 4-[(2R,4R)-4-( {[ 1 -(6-bromo-2,2-difluoro- 1 ,3 -benzodioxol-5 - yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;

[1585] methyl 4-((2R,4R)-4-(l-(6-bromo-2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarboxamido)-7-methoxychroman-2-yl)benzoate; and

[1586] 4-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]-N-(methylsulfonyl)benzamide.

[1587] Compound names are assigned by using Name 2012 naming algorithm by Advanced Chemical Development or Struct=Name naming algorithm as part of CHEMDRAW® ULTRA v. 12.0.2.1076.

[1588] Compounds of the invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are "R" or "S" depending on the configuration of substituents around the chiral carbon atom. The terms "R" and "S" used herein are

[1589] configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The invention contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical,Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.

[1590] Chiral centers, of which the relative but not the absolute configuration is known, may be labelled arbitrarily, and the whole name is prefixed by rel- (for relative). For example, ethyl rel- 3-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4-dihydro- 2H-pyrano[2,3-c]pyridin-2-yl]benzoate means

[1592] or

[1594] Certain names are prefixed by rac- (for racemic), denoting a racemic mixtures of two enantiomers in the ratio of about 1 :1.

[1595] Compounds of the invention may exist as cis or trans isomers, wherein substituents on a ring may attached in such a manner that they are on the same side of the ring (cis) relative to each other, or on opposite sides of the ring relative to each other (trans). For example, cyclobutane may be present in the cis or trans configuration, and may be present as a single isomer or a mixture of the cis and trans isomers. Individual cis or trans isomers of compounds of the invention may be prepared synthetically from commercially available starting materials using selective organic transformations, or prepared in single isomeric form by purification of mixtures of the cis and trans isomers. Such methods are well-known to those of ordinary skill in the art, and may include separation of isomers by recrystallization or chromatography.

[1596] It should be understood that the compounds of the invention may possess tautomeric forms, as well as geometric isomers, and that these also constitute an aspect of the invention.

[1597] The present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the sameatomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as2H and3H, carbon, such asUC,13C and14C, chlorine, such as36C1, fluorine, such as18F, iodine, such as123I and125I,

[1598] 13 15 15 17 18 32 nitrogen, such as N and N, oxygen, such as O, O and O, phosphorus, such as P, and sulphur, such as35S. Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon- 14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

[1599] Thus, the formula drawings within this specification can represent only one of the possible tautomeric, geometric, or stereoisomeric forms. It is to be understood that the invention encompasses any tautomeric, geometric, or stereoisomeric form, and mixtures thereof, and is not to be limited merely to any one tautomeric, geometric, or stereoisomeric form utilized within the formula drawings.

[1600] Compounds of formula (I) may be used in the form of pharmaceutically acceptable salts. The phrase "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgement, 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.

[1601] Pharmaceutically acceptable salts have been described in S. M. Berge et al. J.

[1602] Pharmaceutical Sciences, 1977, 66: 1-19.Compounds of formula (I) may contain either a basic or an acidic functionality, or both, and can be converted to a pharmaceutically acceptable salt, when desired, by using a suitable acid or base. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention.

[1603] Examples of acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

[1604] Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4- methylbenzenesulfonic acid, succinic acid and citric acid.

[1605] Basic addition salts may be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine,

[1606] dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other examples of organic amines useful for the formation of base addition salts include

[1607] ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.The term "pharmaceutically acceptable prodrug" or "prodrug"as used herein, represents those prodrugs of the compounds of the invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[1608] The invention contemplates compounds of formula (I) formed by synthetic means or formed by in vivo biotransformation of a prodrug.

[1609] Compounds described herein can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.

[1610] General Synthesis

[1611] The compounds described herein in various embodiments, including compounds of general formula (I) and specific examples can be prepared by methodologies known in the art, for example, through the reaction schemes depicted in schemes 1-9. The variables R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R", G2A, X, Y, and m used in the following schemes have the meanings as set forth in the summary and detailed description sections, unless otherwise noted.

[1612] Abbreviations used in the descriptions of the schemes and the specific examples have the following meanings: n-BuLi for n-butyllithium, DMF for Ν,Ν-dimethylformamide, DMSO for dimethyl sulfoxide, dppf for 1 , l'-bis(diphenylphosphino)ferrocene, HPLC for High Performance Liquid chromatography, LC / MS for liquid chromatography / mass spectrometry, Prep HPLC for Preparative High Performance Liquid chromatography, MeOH for methanol, MTBE for methyl tert-butyl ether, NMR is nuclear magnetic resonance, SFC for Supercritical Fluid

[1613] Chromatography, TFA for trifluoroacetic acid, and THF for tetrahydrofuran.

[1614] Compounds of general formula (I) may be prepared utilizing general procedure as described in Scheme 1. Acids of formula (1) may be reacted with amines of formula (2) in the presence of l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, and a base such as, but not limited to, diisopropylethyl amine, in a solvent such as, but not limited to, DMF, and at ambient temperature to provide amides of general formula (I).Alternatively, compounds of general formula (I) may be prepared by (a) treatment of the acids (1) with oxalyl chloride in the presence of catalytic amount of DMF, and in a solvent such as, but not limited to, dichloromethane, at ambient temperature to provide the corresponding acid chloride (3), and (b) reacting the acid chloride (3) with the amines (2) in the presence of a base such as, but not limited to, triethylamine, in a solvent such as, but not limited to,

[1615] dichloromethane, at ambient temperature.

[1617] (3)

[1618] The requisite amines of formula (2) may be prepared by any of several methods and synthetic intermediates selected by one of ordinary skill in the art as illustrated in Schemes 2-5. Racemic amines of general formula (2) may be prepared from the corresponding chromanones as shown in Scheme 2. Chromanones (4) may be treated with hydroxylamines or alkoxyamines such as methoxyamine to provide oximes of formula (5). The oxime group of (5) may be reduced using methodologies known by one skilled in the art, for example, by hydrogenoloysis in the presence of hydrogen and a catalyst such as, but not limited to, platinum on carbon, or Raney-Nickel, or platinum (IV) oxide, to provide the amines of general formula (2).

[1619] Alternatively, chromanones (4) may be treated with a reducing agent such as, but not limited to, sodium borohydride, to provide alcohols (6). Alcohols (6) may be converted to azides of general formula (7) by activation with a sulfonylating agent such as, but not limited to, methanesulfonic anhydride, followed by displacement with a nucleophilic azide source such as, but not limited to, tetrabutylammonium azide. Alternatively, alcohols (6) may be treated with diphenylphosphoryl azide in the presence of a base such as, but not limited to, 1,8- diazabicyclo[5.4.0]undec-7-ene, to provide azides (7). Amines (2) may be prepared by reduction of azides (7) by treatment with a phosphine agent such as, but not limited to triphenylphosphine with an appropriate water miscible organic co-solvent such as, but not limited to, THF.Scheme 2

[1621] (6) (7)

[1622] Chiral amines may be prepared using synthetic methods as outlined in Schemes 3 and 4. Chiral amines of formula (8), (15), and (16) may be converted to target compounds described herein using synthetic methods as outlined in Scheme 1.

[1623] Chromanones (4) may be treated with chiral hydride sources known to those skilled in the art (Corey, E.J. et al. J. Org. Chem. 1988, 53, 2861; Kawanami, S. et al. Tetrahedron 2003, 59, 8411; Corey, E.J. et al. Tetrahedron Asymm. 2002, 13, 1347) to provide chiral alcohols of general formula (9). Alcohols (9) may be converted to azides of formula (10) and subsequently to amines (8), by employing reagents and reaction conditions as described in Scheme 2.

[1624] Scheme 3

[1626] Alternatively, the hydrochloride salts of the chiral amines may be prepared according to the general procedure described by Ellman and co-workers (Tanuwidjaja, J.; Ellman, J.A. et al. J.

[1627] Org. Chem. 2007, 72, 626) as illustrated in Scheme 4. Chromanones (4) may be condensed with a chiral sulfmamide such as tert-butanesulfinamide in the presence of a Lewis acid such as titanium(IV) ethoxide to provide N-sulfmyl imine intermediates (11) and (12). The

[1628] diastereomeric mixture of (11) and (12) may be separated via chromatography. The respective

[1629] N-sulfmyl imine intermediates (11) and (12) may undergo a subsequent reduction with reagentssuch as sodium borohydride to provide sulfanamides of general formula (13) and (14).

[1630] Treatment of the sulfmamides (13) and (14) with HCl or acetyl chloride and methanol provides the hydrochloride salts of amines (15) and (16).

[1631] Scheme 4

[1633] Stereoselective hydrogenolysis of oximes of formula (17) wherein R5is G2Amay be achieved in the presence of a reducing agent such as platinum on carbon or platinum (IV) oxide / acetic acid, as illustrated in Scheme 5. The reduction provides selectively a single enantiomer of formula (18).

[1634] Scheme 5

[1636] Alcohols of general formula (6) and (9) wherein R4, R6, and R7are hydrogen, and R5is alkyl or G2A, may be prepared as shown in Scheme 6. Ethanones of general formula (20) may be treated with lithium bis(trimethylsilyl)amide in in a solvent such as THF at about -78 °C, followed by treatment with aldehydes of formula (19), to provide hydroxyketones of formula (21). Reduction of (21) with a reducing agent such as, but not limited to, sodium borohydride, optionally in presence of a complexing agent such as diethylmethoxyborane, provides the diols of formula (22). Cyclization of the diols (22) may be achieved in the presence of DBU atelevated temperature (e.g. about 60 C to about 90 C). The cis and trans isomers may be obtained via column chromatography of (23).

[1637] Scheme 6

[1639] Chromanones (4) wherein R4, R6, and R7are hydrogen, and R5is alkyl or G2A, may be prepared as shown in Scheme 7. Ethanones of general formula (20) may be reacted with lithium bis(trimethylsilyl)amide in in a solvent such as THF at about -78 °C, followed by treatment with acid chlorides of formula (24), to provide intermediates of formula (25). Cyclization of (25) in the presence of a base such as potassium carbonate in a solvent such as, but not limited to, DMF, at elevated temperature (e.g. about 90 °C to about 120 °C) provides chromenones (26).

[1640] Transformation of the chromenones (26) to chromanones (26A) may be achieved by a) reduction of (26) with a suitable reducing agent to provide the corresponding chromanol (23), and b) oxidizing the chromanol with an oxidant such as, but not limited to, Jones reagent.

[1641] Scheme 7

[1643] Chromanones (4) wherein R4, R6, and R7are hydrogen, and R5is alkyl or G2A, may be prepared as shown in Scheme 8. Hydroxyethanones (27) may be treated with aldehydes (28) in the presence of a base such as sodium hydroxide to provide intermediates (29). Cyclization of (29) to (26A) may be achieved by treatment with concentrated HC1 at elevated temperature (e.g. about 100 °C).

[1644] Alternatively, chromanones (26A) may be prepared from a) treatment of

[1645] hydroxyethanones (27) with lithium diisopropylamide and aldehydes (28) to provide

[1646] intermediate (30), and b) cyclization of (30) in the presence of trifluoroacetic anhydride and DBU.

[1647] Scheme 8

[1649] (30)

[1650] Chiral chormanones (32) wherein R5is aryl or heteroaryl may be prepared as shown in Scheme 9. Hydroxyethanones (27) may be treated with l,l-dimethoxy-N,N- dimethylmethanamine at elevated temperature (about 100 °C to about 120 °C) or under microwave irradiation to provide chromenones (31). Treatment of of (31) with aryl or heteroaryl boronic acid (or esters thereof) in the presence of (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5- dihydrooxazole, and a catalyst such as bis(2,2,2-trifluroacetoxy)palladium provides the chiral chromanones (32).

[1651] Scheme 9

[1653] (27) (31 ) (32)

[1654] Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Reactions may be further processed in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that can not be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (3rded.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[1655] Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

[1656] When an optically active form of a compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[1657] Similarly, when a pure geometric isomer of a compound is required, it can be prepared by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[1658] Pharmaceutical Compositions

[1659] This invention also provides for pharmaceutical compositions comprising a

[1660] therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, diluent, or excipient thereof. The phrase "pharmaceutical composition" refers to a composition suitable for administration in medical or veterinary use.

[1661] The pharmaceutical compositions that comprise a compound of formula (I), alone or in combination with one or more additional therapeutic agents, may be administered to the subjectsorally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally" as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

[1662] The term "pharmaceutically acceptable carrier" as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which may serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt;

[1663] gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, 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, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

[1664] Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate), and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[1665] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may beensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[1666] In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a

[1667] parenterally-administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[1668] Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. Examples of other biodegradable polymers include poly(orthoesters) and

[1669] poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[1670] The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[1671] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In certain embodiments, solid dosage forms may contain from 1% to 95% (w / w) of a compound of formula (I). In certain embodiments, the compound of formula (I) may be present in the solid dosage form in a range of from 5% to 70% (w / w). In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as

[1672] carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[1673] The pharmaceutical composition may be a unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules. Also, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the appropriate number of any of these in packaged form. The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to 95% (w / w) of a unit dose, according to the particular application and the potency of the active component. The composition may, if desired, also contain other therapeutic agents.

[1674] The dose to be administered to a subject may be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the subject to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular subject. In determining the effective amount of the compound to be administered in the treatment or prophylaxis of the disorder being treated, the physician may evaluate factors such as the circulating plasma levels of the compound, compound toxicities, and / or the progression of the disease, etc.

[1675] For administration, compounds may be administered at a rate determined by factors that may include, but are not limited to, the LD50of the compound, the pharmacokinetic profile of the compound, contraindicated drugs, and the side-effects of the compound at various

[1676] concentrations, as applied to the mass and overall health of the subject. Administration may be accomplished via single or divided doses.

[1677] The compounds utilized in the pharmaceutical method of the invention may be administered at the initial dosage of about 0.001 mg / kg to about 100 mg / kg daily. In certain embodiments, the daily dose range is from about 0.1 mg / kg to about 10 mg / kg. The dosages,however, may be varied depending upon the requirements of the subject, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Treatment may be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[1678] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[1679] The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding

[1680] compositions which can be used include polymeric substances and waxes.

[1681] The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.

[1682] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan and mixtures thereof.

[1683] Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[1684] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

[1685] Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[1686] Compounds may also be administered in the form of liposomes. Liposomes generally may be derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to a compound of the invention, stabilizers, preservatives, excipients, and the like. Examples of lipids include, but are not limited to, natural and synthetic phospholipids, and phosphatidyl cholines (lecithins), used separately or together.

[1687] Methods to form liposomes have been described, see example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

[1688] Dosage forms for topical administration of a compound described herein include powders, sprays, ointments, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

[1689] Methods of Use

[1690] The compounds and compositions using any amount and any route of administration may be administered to a subject for the treatment or prevention of cystic fibrosis, pancreatic insufficiency, Sjogren's Syndrome (SS), chronic obstructive lung disease (COLD), or chronic obstructive airway disease (CO AD).

[1691] The term "administering" refers to the method of contacting a compound with a subject. Thus, the compounds may be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, parentally, or intraperitoneally. Also, the compounds described herein may be administered by inhalation, for example, intranasally.Additionally, the compounds may be administered transdermally, topically, and via implantation. In certain embodiments, the compounds and compositions thereof may be delivered orally. The compounds may also be delivered rectally, bucally, intravaginally, ocularly, or by insufflation. CFTR-modulated disorders and conditions may be treated prophylactically, acutely, and chronically using compounds or pharmaceutically acceptable salts thereof and compositions thereof, depending on the nature of the disorder or condition. Typically, the host or subject in each of these methods is human, although other mammals may also benefit from the

[1692] administration of compounds or pharmaceutically acceptable salts thereof and compositions thereof as set forth hereinabove.

[1693] Compounds of the invention are useful as modulators of CFTR. Thus, the compounds and compositions are particularly useful for treating or lessening the severity or progression of a disease, disorder, or a condition where hyperactivity or inactivity of CFTR is involved.

[1694] Accordingly, the invention provides a method for treating cystic fibrosis, pancreatic

[1695] insufficiency, Sjogren's Syndrome (SS), chronic obstructive lung disease (COLD), or chronic obstructive airway disease (CO AD) in a subject, wherein the method comprises the step of administering to said subject a therapeutically effective amount of a compound of formula (I), (I- a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), or (I-j) or a pharmaceutically acceptable salt thereof, or a preferred embodiment thereof as set forth above, with or without a pharmaceutically acceptable carrier. Particularly, the method is for the treatment or prevention of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and / or VI mutation.

[1696] One embodiment is directed to a compound of the invention or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof for use in medicine.

[1697] One embodiment is directed to a compound according to formula (I), (I-a), (I-b), (I-c), (I- d), (I-e), (I-f), (I-g), (I-h), (I-i), or (I-j) or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions comprising a compound of the invention or pharmaceutically acceptable salt thereof, for use in the treatment of cystic fibrosis, pancreatic insufficiency, Sjogren's Syndrome (SS), chronic obstructive lung disease (COLD) or chronic obstructive airway disease (COAD). In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and / or VI mutation.In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In a particular embodiment, the additional therapeutic agent is a cystic fibrosis treatment agent other than a compound of the invention. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and / or VI mutation.

[1698] The present compounds or pharmaceutically acceptable salts thereof may be administered as the sole active agent or it may be co-administered with one or more additional therapeutic agents, including other compounds that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. The present compounds may be co-administered to a subject. The term "co-administered" means the administration of two or more different therapeutic agents to a subject by combination in the same pharmaceutical composition or in separate pharmaceutical compositions. Thus coadministration involves administration at the same time of a single pharmaceutical composition comprising two or more therapeutic agents or administration of two or more different

[1699] compositions to the same subject at the same or different times.

[1700] The compounds of the invention or pharmaceutically acceptable salts thereof may be coadministered with a therapeutically effective amount of one or more additional therapeutic agents to treat a CFTR mediated disease, where examples of the therapeutic agents include, but are not limited to, antibiotics (for example, aminoglycosides, colistin, aztreonam, ciprofloxacin, and azithromycin), expectorants (for example, hypertonic saline, acetylcysteine, dornase alfa, and denufosol), pancreatic enzyme supplements (for example, pancreatin, and pancrelipase), epithelial sodium channel blocker (ENaC) inhibitors, CFTR modulators (for example, CFTR potentiators, CFTR correctors), and CFTR amplifiers. In one embodiment, the CFTR mediated disease is cystic fibrosis. In one embodiment, the compounds of the invention or

[1701] pharmaceutically acceptable salts thereof may be co-administered with one or more additional therapeutic agents selected from the group consisting of CFTR modulators and CFTR amplifiers. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or two CFTR modulators and one CFTR amplifier. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator, one or more correctors, and one CFTR amplifier. Inone embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one CFTR modulators. In one embodiment, the compounds of the invention or

[1702] pharmaceutically acceptable salts thereof may be co-administered with two CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with three CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and one or more correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and two correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one corrector. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with two correctors.

[1703] Examples of potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, and N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H- thieno[2,3-c]pyran-2-yl)-lH-pyrazole-5-carboxamide. Examples of potentiators are also disclosed in publications: WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421, WO2008147952, WO2011072241, WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, and WO2013038390; and US Applications 14 / 271,080 and 14 / 451,619.

[1704] In one embodiment, the potentiator can be selected from the group consisting of

[1705] Ivacaftor (VX-770, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide);

[1706] CTP-656;

[1707] NVS-QBW251 ;

[1708] FD1860293;2-(2-fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3- carboxamide;

[1709] N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-lH- pyrazole-5-carboxamide;

[1710] 2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3- carboxamide

[1711] 2-(l-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H- thieno[2,3-c]pyran-3-carboxamide;

[1712] 5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thieno[2,3- c]pyran-3 -carboxamide;

[1713] 2-(2-hydroxy-2-methylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3- c]pyran-3 -carboxamide;

[1714] 2-(l-(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro- 4H-thieno [2,3 -c]pyran-3 -carboxamide;

[1715] 2-(3-hydroxy-2,2-dimethylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H- thieno[2,3-c]pyran-3-carboxamide;

[1716] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5- methyl-lH-pyrazole-3-carboxamide;

[1717] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5- cyclopropyl-lH-pyrazole-3-carboxamide;

[1718] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5- isopropyl-lH-pyrazole-3-carboxamide;

[1719] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5- (trifluoromethyl)- 1 H-pyrazole-3 -carboxamide;

[1720] 5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran- 2-yl)-lH-pyrazole-3-carboxamide;

[1721] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5- ethyl-lH-pyrazole-3-carboxamide;

[1722] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-3- ethyl-4-methyl-lH-pyrazole-5-carboxamide;2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3- carboxamide;

[1723] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4- chloro-lH-pyrazole-3-carboxamide;

[1724] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-l,4,6,7- tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;

[1725] 4- bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2- yl)- lH-pyrazole-3-carboxamide;

[1726] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4- chloro-5-methyl-lH-pyrazole-3-carboxamide;

[1727] N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4- methyl- lH-pyrazole-3-carboxamide;

[1728] 2-(2-hydroxy-3 ,3-dimethylbutanamido)-5 ,5 ,7,7-tetramethyl-5 ,7-dihydro-4H- thieno[2,3-c]pyran-3-carboxamide;

[1729] 2- [(2-hydroxy-4-methyl-pentanoyl)amino] -5 ,5 ,7 ,7-tetramethyl-4H-thieno [2,3 - c]pyran-3 -carboxamide;

[1730] 5- (2-methoxy-ethoxy)-lH-pyrazole-3-carboxylic acid (3-carbamoyl-5, 5,7,7- tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide;

[1731] N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3- methoxypropyl)-lH-pyrazole-3-carboxamide;

[1732] N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethoxyethyl)- lH-pyrazole-3-carboxamide;

[1733] 2-[[(25)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3- c]pyran-3 -carboxamide;

[1734] 2-[[(2i?)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H- thieno[2,3-c]pyran-3-carboxamide;

[1735] 2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3- c]pyran-3 -carboxamide;

[1736] [5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol- l-yl]methyl dihydrogen phosphate;[3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol- l-yl]methyl dihydrogen phosphate;

[1737] N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(l,4-dioxan-2-yl)- lH-pyrazole-3-carboxamide;

[1738] 5,5,7,7-tetramethyl-2-[[(25)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl]amino]- 4H-thieno [2 ,3 -c]pyran-3 -carboxamide;and

[1739] 2-[[(25)-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3- carboxamide.

[1740] Non limiting examples of correctors include Lumacaftor (VX-809), l-(2,2-difluoro-l,3- benzodioxol-5-yl)-N-{l-[(2i?)-2,3-dihydroxypropyl]-6-fluoro-2-(l-hydroxy-2-methylpropan-2- yl)-lH-indol-5-yl}cyclopropanecarboxamide (VX-661), VX-983, GLPG2665, VX-152, VX-440, FDL169, FDL304, FD2052160, and FD2035659. Examples of correctors are also disclosed in publications: US20140274933 and WO2014160478; and US Application 62 / 073586.

[1741] In one embodiment, the corrector(s) can be selected from the group consisting of

[1742] Lumacaftor (VX-809);

[1743] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-{l-[(2i?)-2,3-dihydroxypropyl]-6-fluoro-2-(l- hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl}cyclopropanecarboxamide (VX-661);

[1744] VX-983;

[1745] GLPG2665;

[1746] VX-152;

[1747] VX-440;

[1748] FDL169

[1749] FDL304;

[1750] FD2052160;

[1751] FD2035659;

[1752] rac-3-[(2R,4S)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

[1753] rac-4-[(2R,4S)-4-( { [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

[1754] 3-[(25,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;3-[(2R,4S)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;

[1755] rac-3-[(2R,45,6S)-4-({[l-(2,2-difluoro -benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

[1756] 3-[(25,,4i?,6i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;

[1757] 3- [(2R,4S,6S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6- phenyltetrahydro-2H-pyran-2-yl]benzoic acid; and

[1758] 4- [(2R,4S)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid.

[1759] In one embodiment, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effect of known CFTR modulators, such as potentiators and correctors. An example of a CFTR amplifier is PTI130. Examples of amplifiers are also disclosed in publications: WO2015138909 and WO2015138934.

[1760] In one embodiment, the additional therapeutic agent is an agent that reduces the activity of the epithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., seine proteases, channel-activating proteases). Exemplary of such agents include camostat (a trypsin- like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, Aerolytic, amiloride, and VX- 371. Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example, in PCT Publication No. WO2009074575 and US Patent No.

[1761] US8999976.

[1762] In one embodiment, the ENaC inhibitor is VX-371.

[1763] This invention also is directed to kits that comprise one or more compounds and / or salts of the invention, and, optionally, one or more additional therapeutic agents.

[1764] This invention also is directed to methods of use of the compounds, salts, compositions, and / or kits of the invention to,with or without one or more additional therapeutic agents, for example, modulate the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, and treat a disease treatable by modulating the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein (including cystic fibrosis, Sjogren's syndrome, pancreatic

[1765] insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease).This invention also is directed to a use of one or more compounds and / or salts of the invention in the preparation of a medicament. The medicament optionally can comprise one or more additional therapeutic agents. In some embodiments, the medicament is useful for treating cystic fibrosis, Sjogren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. In a particular embodiment, the medicament is for use in the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and / or VI mutation.

[1766] This invention also is directed to a use of one or more compounds and / or salts of the invention in the manufacture of a medicament for the treatment of cystic fibrosis, Sjogren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. The medicament optionally can comprise one or more additional therapeutic agents. In a particular embodiment, the invention is directed to the use of one or more compounds and / or salts of the invention in the manufacture of a medicament for the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and / or VI mutation.

[1767] Further benefits of Applicants' invention will be apparent to one skilled in the art from reading this patent application.

[1768] The following Examples may be used for illustrative purposes and should not be deemed to narrow the scope of the invention.

[1769] Examples

[1770] General Reverse Phase Purification Procedures:

[1771] Preparative LC / MS Method TFA1

[1772] Samples were purified by reverse phase preparative HPLC on a Phenomenex Luna C8(2) 5 μιη lOOA AXIA column (50mm x 21.2mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 30 mL / min (0-0.5 min 5% A, 0.5-6.5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0- 10 min 5% A). A sample volume of 1.0 mL was injected directly from the flow reactor stream to the HPLC system. A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV / Vis 155 detector;

[1773] Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination ofThermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

[1774] Preparative LC / MS Method TFA2

[1775] Samples were purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μιη ΙΟθΑ AXIA column (30mm x 75mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL / min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5- 100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A). Samples were injected in 1.5 mL DMSO:MeOH (1 : 1). A custom purification system was used, consisting of the following modules: Waters LC4000 preparative pump; Waters 996 diode-array detector; Waters 717+ autosampler; Waters SAT / IN module, Alltech Varex III evaporative light-scattering detector; Gilson 506C interface box; and two Gilson FC204 fraction collectors. The system was controlled using Waters Millennium32 software, automated using an Abbott developed Visual Basic application for fraction collector control and fraction tracking. Fractions were collected based upon UV signal threshold and selected fractions subsequently analyzed by flow injection analysis mass spectrometry using positive APCI ionization on a Finnigan Navigator using 70:30 MeOH: 10 mM NH40H(aqueous) at a flow rate of 0.8 mL / min. Loop-injection mass spectra were acquired using a Finnigan Navigator running Navigator 1.8 software and a Gilson 215 liquid handler for fraction injection controlled by an Abbott developed Visual Basic application.

[1776] Preparative LC / MS Method TFA4

[1777] Samples were purified by reverse phase preparative HPLC on a Phenomenex Luna C8(2) 5 μιη lOOA AXIA column (50 mm x 21.2 mm). A gradient of acetonitrile (A) and 0.1 % trifluoroacetic acid in water (B) was used, at a flow rate of 30 mL / min (0-0.1 min 5% A, 0.1 -0.5 min linear gradient 5-30% A, 0.5-6.5 min linear gradient 30-70% A, 6.5-7.0 min linear gradient 70-100% A, 7.0-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A). A sample volume of 1.0 mL was injected directly from the flow reactor stream to the HPLC system. A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0. Preparative LC / MS Method TFA6Samples were purified by reverse phase preparative HPLC on a Phenomenex Luna C8(2) 5 μιη lOOA AXIA column (50mm x 21.2mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 30 mL / min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100-15% A, 9.1-10 min 15% A). A sample volume of 1.0 mL was injected directly from the flow reactor stream to the HPLC system. A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

[1778] Preparative LC / MS Method TFA8

[1779] Samples were purified by reverse phase preparative HPLC on a Phenomenex Luna C8(2) 5 μιη lOOA AXIA column (50 mm x 21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 30 mL / min (0-0.5 min 35% A, 0.5-8.0 min linear gradient 35-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100-35% A, 9.1-10 min 35% A). A sample volume of 1.0 mL was injected directly from the flow reactor stream to the HPLC system. A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

[1780] Preparative LC / MS Method AA2

[1781] Samples were purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μιη ΙΟθΑ AXIA column (30mm x 75mm). A gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) was used, at a flow rate of 50 mL / min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5- 100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A). Samples were injected in 1.5 mL DMSO:MeOH (1 : 1). A custom purification system was used, consisting of the following modules: Waters LC4000 preparative pump; Waters 996 diode-array detector; Waters 717+ autosampler; Waters SAT / IN module, Alltech Varex III evaporative light-scatteringdetector; Gilson 506C interface box; and two Gilson FC204 fraction collectors. The system was controlled using Waters Millennium32 software, automated using an Abbott developed Visual Basic application for fraction collector control and fraction tracking. Fractions were collected based upon UV signal threshold and selected fractions subsequently analyzed by flow injection analysis mass spectrometry using positive APCI ionization on a Finnigan Navigator using 70:30 MeOH: 10 mM NH4OH(aq) at a flow rate of 0.8 mL / min. Loop-injection mass spectra were acquired using a Finnigan Navigator running Navigator 1.8 software and a Gilson 215 liquid handler for fraction injection controlled by an Abbott developed Visual Basic application.

[1782] Preparative LC / MS Method AA7

[1783] Samples were purified by reverse phase preparative HPLC on a Phenomenex Luna C8(2) 5 μιη lOOA AXIA column (50mm x 21.2mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of 30 mL / min (0-0.5 min 25% A, 0.5-8.0 min linear gradient 25-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100-25% A, 9.1-10 min 25% A). A sample volume of 1.0 mL was injected directly from the flow reactor stream to the HPLC system. A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

[1784] Preparative LC / MS Method AA8

[1785] Samples were purified by reverse phase preparative HPLC on a Phenomenex Luna C8(2) 5 μιη lOOA AXIA column (50 mm x 21.2 mm). A gradient of acetonitrile (A) and 0.1 % ammonium acetate in water (B) was used, at a flow rate of 30 mL / min (0-0.5 min 35% A, 0.5-8.0 min linear gradient 35-100% A, 8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100-35% A, 9.1-10 min 35% A). A sample volume of 1.0 mL was injected directly from the flow reactor stream to the HPLC system. A custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV / Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer. The systemwas controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.

[1786] Example 1

[1787] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7-methoxy-

[1788] 3 ,4-dihydro-2H-chromen-2-yl]benzoic acid

[1789] To a solution of Example 6 (25 mg, 0.047 mmol) in tetrahydrofuran (233 μί) was added lithium hydroxide hydrate (233 of a 0.8 M solution in water). The resulting biphasic mixture was stirred vigorously for 16 hours at room temperature, followed by addition of more lithium hydroxide hydrate (233 of a 0.8 M solution). The reaction mixture was stirred for an additional 5 hours at room temperature, acidified by the addition of 6 M HC1 (0.040 mL) and the resulting biphasic mixture loaded directly onto a 4g silica gel cartridge and eluted with 30 % ethyl acetate / heptanes over 15 minutes to give the title compound as a white solid. 1H NMR (400 MHz, CDCls) δ 8.20 (s, 1H), 8.06 (dd, J = 7.9, 1.5 Hz, 1H), 7.71 - 7.61 (m, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.13 (dd, J = 8.2, 1.7 Hz, 1H), 7.09 (d, J = 1.7 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.52 (dd, J = 8.6, 2.5 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 5.49 (td, J = 9.9, 6.0 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H), 5.33 - 5.22 (m, 1H), 3.76 (s, 3H), 2.58 (ddd, J = 13.3, 5.9, 2.0 Hz, 1H), 1.82 - 1.72 (m, 2H), 1.69 - 1.63 (m, 1H), 1.09 (q, J = 2.8 Hz, 2H); MS (ESI-) m / z 522.1 (M-H)~.

[1790] Example 2

[1791] 3-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-

[1792] 3 ,4-dihydro-2H-chromen-2-yl]benzoic acid

[1793] To a solution of Example 5E (35 mg, 0.065 mmol) in tetrahydrofuran (326 μί) was added lithium hydroxide hydrate (326 μΐ^of a 0.8 M solution). The resulting biphasic mixture was stirred vigorously for 16 hours at room temperature, followed by addition of more lithium hydroxide hydrate (326 μΐ^of a 0.8 M solution). The reaction was stirred for an additional 5 hours at room temperature, acidified by the addition of 6 M HC1 (0.050 mL) and the resulting biphasic mixture was loaded directly onto a 4g silica gel cartridge and eluted with 30 % ethyl acetate / heptanes over 15 minutes to give the title compound as a white solid. 1H NMR (400 MHz, CDCI3) δ 8.13 (t, J = 1.8 Hz, 1H), 8.12 - 8.04 (m, 1H), 7.72 - 7.61 (m, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.20 - 7.11 (m, 2H), 7.04 (dd, J = 8.4, 4.1 Hz, 2H), 6.53 (dd, J = 8.5, 2.6 Hz, 1H), 6.45 (d, J = 2.6 Hz, 1H), 5.60 (d, J = 6.6 Hz, 1H), 5.01 (dd, J = 5.5, 2.8 Hz, 1H), 4.84 (dd, J = 11.6,2.2 Hz, 1H), 3.76 (s, 3H), 2.35 (dt, J = 14.4, 2.5 Hz, 1H), 2.16 (ddd, J = 14.4, 11.4, 4.5 Hz, 1H), 1.70 (q, J = 3.7 Hz, 2H), 1.09 (q, J = 3.7 Hz, 2H); MS (ESI-) m / z 522.1 (M-H)~.

[1794] Example 3

[1795] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3,4-dimethoxyphenyl)-7-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide

[1796] To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (CAS 68015- 98-5) (120 mg, 0.496 mmol) in DMF (1239 μΐ,) was added HATU (1- [bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid

[1797] hexafluorophosphate) (245 mg, 0.644 mmol). The mixture was stirred for 5 minutes at room temperature, and then 2-(3,4-dimethoxyphenyl)-7-methoxychroman-4-amine (156 mg, 0.496 mmol) was added, followed by dropwise addition of triethylamine (276 μΐ,, 1.982 mmol). After 45 minutes, the mixture was quenched with saturated aqueous sodium bicarbonate, and the aqueous layer removed. The resulting oil was triturated with water and filtered to give 283 mg of a white solid. The solid was dissolved in dichloromethane and purified using a 24 g silica gel cartridge with a gradient of 5-50% ethyl acetate / heptanes to give 189 mg of a mixture of the two diastereomers. The mixture was subjected to preparative supercritical fluid chromatography set to maintain a backpressure at 100 bar using a CHIRALPAK IA®, 21 x 250 mm, 5 micron, with the sample at a concentration of 20 mg / mL in methanol using 16 % methanol in C02at a flow rate of 70 mL / minute with a retention time of 7.2 minutes to give the title compound (111 mg, 0.206 mmol, 41.5 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 6.98 - 6.91 (m, 4H), 6.50 (dd, J = 8.5, 2.6 Hz, 1H), 6.36 (d, J = 2.5 Hz, 1H), 5.36 - 5.24 (m, 1H), 5.15 (dd, J = 11.5, 1.9 Hz, 1H), 3.75 (d, J = 1.4 Hz, 6H), 3.68 (s, 3H), 2.10 (q, J = 11.8 Hz, 1H), 1.99 (ddd, J = 12.9, 6.2, 2.1 Hz, 1H), 1.53 - 1.46 (m, 1H), 1.37 (ddd, J = 8.4, 5.8, 2.8 Hz, 1H), 1.05 (dtdd, J = 12.7, 9.6, 6.4, 3.3 Hz, 2H); MS (ESI+) m / z 402 (M+H)+. Absolute stereochemistry was assigned by X-ray diffraction analysis.

[1798] Example 4

[1799] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(25*,45)-2-(3,4-dimethoxyphenyl)-7-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide

[1800] To l-(2,2-dif uorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (120 mg, 0.496 mmol) in DMF (1239 μί) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (245 mg, 0.644 mmol). The mixture was stirred for 5 minutes at room temperature, and then 2-(3,4-dimethoxyphenyl)-7- methoxychroman-4-amine (156 mg, 0.496 mmol) was added, followed by dropwise addition of triethylamine (276 μί, 1.982 mmol). After 45 minutes, the mixture was quenched with saturated aqueous sodium bicarbonate, the aqueous layer removed, the resulting oil triturated with water and filtered to give 283 mg of a white solid. The solid was dissolved in dichloromethane and purified using a 24 g silica gel cartridge with a gradient of 5-50% ethyl acetate / heptanes to give 189 mg of a mixture of the two diastereomers. The mixture was subjected to preparative supercritical fluid chromatography set to maintain a backpressure at 100 bar using a

[1801] CHIRALPAK ® I A, 21 x 250 mm, 5 micron, with the sample at a concentration of 20 mg / mL in methanol using 16% methanol in C02at a flow rate of 70 mL / minute with a retention time of 4.5 minutes to give the title compound (106 mg, 0.196 mmol, 39.7 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 6.98 - 6.91 (m, 4H), 6.50 (dd, J = 8.5, 2.6 Hz, 1H), 6.36 (d, J = 2.5 Hz, 1H), 5.36 - 5.24 (m, 1H), 5.15 (dd, J = 11.5, 1.9 Hz, 1H), 3.75 (d, J = 1.4 Hz, 6H), 3.68 (s, 3H), 2.10 (q, J = 11.8 Hz, 1H), 1.99 (ddd, J = 12.9, 6.2, 2.1 Hz, 1H), 1.53 - 1.46 (m, 1H), 1.37 (ddd, J = 8.4, 5.8, 2.8 Hz, 1H), 1.05 (dtdd, J = 12.7, 9.6, 6.4, 3.3 Hz, 2H); MS (ESI+) m / z 402 (M+H)+.

[1802] Example 5

[1803] methyl 3-[(2i?,45)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate

[1804] Example 5A

[1805] 7-methoxy-4H-chromen-4-one

[1806] l,l-Dimethoxy-N,N-dimethylmethanamine (1.0 mL, 7.53 mmol) and l-(2-hydroxy-4- methoxyphenyl)ethanone (1.251 g, 7.53 mmol) were heated in the microwave at 115 °C for 15 seconds to give a red solution which solidified upon cooling. The solid was triturated with heptane to give the enamine intermediate as red crystals. 1H NMR (400 MHz, DMSO-d6) δ 14.96 (s, 1H), 7.82 (dd, J = 10.6, 1.6 Hz, 2H), 6.37 (dd, J = 8.8, 2.6 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 5.84 (d, J = 12.0 Hz, 1H), 3.75 (s, 3H), 3.17 (s, 3H), 2.95 (s, 3H). The enamine was dissolved in dichloromethane (40 mL) and treated with HCl (4 mL) at reflux for one hour. The aqueous layer was removed and extracted with 3 x 40mL of dichloromethane. The combinedextracts were washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate, then filtered and the solvent removed under reduced pressure to give title compound (0.854 g, 4.85 mmol, 64.4 % yield) as pale yellow crystals. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 8.9, 2.4 Hz, 1H), 6.27 (d, J = 6.0 Hz, 1H), 3.90 (s, 3H); MS (ESI+) m / z 177 (M+H)+.

[1807] Example 5B

[1808] (i?)-methyl 3 -(7-methoxy-4-oxochroman-2-yl)benzoate A 4 mL vial was charged with bis(2,2,2-trifluoroacetoxy)palladium (9.44 mg, 0.028 mmol), (5)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (6.96 mg, 0.034 mmol), ammonium hexafluorophosphate(V) (27.8 mg, 0.170 mmol), and 3- methoxycarbonylphenylboronic acid (204 mg, 1.135 mmol) were stirred in dichloroethane (1.0 mL) for 5 minutes, and a pale yellow color was observed. To this suspension was added Example 5A (100 mg, 0.568 mmol) and water (0.051 mL, 2.84 mmol) and the sides of the vial washed with more dichloroethane (1.0 mL). The vial was capped and the mixture stirred at 60 °C overnight. The mixture was filtered through a plug of silica gel and eluted with

[1809] dichloromethane and then ethyl acetate. The solvent was removed and the crude material was chromatographed using a 12g silica gel cartridge with a gradient of 5-50 % ethyl

[1810] acetate / heptanes over 20 minutes to give the title compound (133 mg, 0.426 mmol, 75 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J = 1.8 Hz, 1H), 7.98 (dt, J = 7.8, 1.4 Hz, 1H), 7.84 (dt, J = 7.9, 1.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 6.69 (d, J = 8.6 Hz, 2H), 5.77 (dd, J = 12.9, 2.9 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.17 (dd, J = 16.8, 13.0 Hz, 1H), 2.80 (dd, J = 16.8, 3.0 Hz, 1H); MS (ESI+) m / z 313 (M+H)+.

[1811] Example 5C

[1812] (i?)-methyl 3 -(7-methoxy-4-(methoxyimino)chroman-2-yl)benzoate Example 5B (100 mg, 0.320 mmol) and O-methylhydroxylamine hydrochloride (29.4 mg, 0.352 mmol) were stirred in pyridine (640 μί) at 60 °C overnight. Added an additional 0.3 equivalent (7 mg) of amine and heated at 60 °C for 12 hours. The mixture was concentrated and then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated aqueous ammonium chloride sequentially. The solvent was removed and the crude material purified using a 12 g silica gel cartridge eluting with 5-20 % ethyl acetate / heptanes over 20 minutes to give the title compound (107 mg, 0.313 mmol) as a light pink oil. 1H NMR (400MHz, CDCI3) δ 8.15 (t, J= 1.9 Hz, 1H), 8.03 (dt, J= 7.7, 1.5 Hz, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.77 - 7.63 (m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 6.59 (dd, J= 8.8, 2.6 Hz, 1H), 6.50 (d, J= 2.5 Hz, 1H), 5.12 (dd, J= 12.5, 3.1 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.80 (s, 3H), 3.48 (dd, J= 17.2, 3.1 Hz, 1H), 2.65 (dd, J= 17.1, 12.5 Hz, 1H); MS (ESI+) m / z 342.0 (M+H)+.

[1813] Example 5D

[1814] 3-((2i?)-4-amino-7-methoxychroman-2-yl)benzoate

[1815] Example 5C (50 mg, 0.146 mmol) and methanol (10 mL) were added to Ra-Ni 2800, water slurry (150 mg, 1.150 mmol) in a 50 mL pressure bottle and stirred for 16 hours at 30 psi of hydrogen gas and at ambient temperature. The reaction was filtered and the solvent removed. The residue (44 mg) was dissolved in methyl-tert-butyl ether. HC1 (4.0 M in dioxane, 0.3 mL) was added dropwise, and the resulting suspension was filtered to give the hydrochloride salt of the title compound as a mixture of two diastereomers. 1H NMR (400 MHz, DMSO-de) δ 8.48 (s, 6H), 8.06 (dt, J= 6.1, 1.8 Hz, 2H), 7.97 (ddd, J= 9.2, 3.1, 1.4 Hz, 2H), 7.74 (dd, J= 7.7, 1.7 Hz, 2H), 7.60 (t, J= 7.7 Hz, 2H), 7.55 (d, J= 8.6 Hz, 1H), 7.45 (d, J= 8.6 Hz, 1H), 6.65 (ddd, J = 8.7, 6.3, 2.6 Hz, 2H), 6.55 (d, J= 2.6 Hz, 1H), 6.52 (d, J= 2.6 Hz, 1H), 5.51 (dd, J= 11.9, 2.3 Hz, 1H), 5.33 (dd, J= 11.8, 1.8 Hz, 1H), 4.75 (dd, J= 11.0, 6.4 Hz, 1H), 4.45 (dd, J= 5.0, 2.4 Hz, 1H), 3.89 (s, 3H), 3.89 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 2.61 (ddd, J= 13.1, 6.5, 1.9 Hz, lH), 2.46 (t, J= 2.4 Hz, 1H), 2.31 (ddd, J= 15.0, 11.9, 5.0 Hz, 1H), 2.08 (dt, J= 13.0, 11.4 Hz, 1H); MS (ESI-) m / z 297.1 (M-NH3)~.

[1816] Example 5E

[1817] methyl 3-[(2i?,45)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate

[1818] To a suspension of the product from Example 5D (90mg, 0.257mmol) in 1.3 mL of dichloromethane was added N,N-diisopropylethylamine (135 μί, 0.772 mmol). After a solution was achieved, a solution of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarbonyl chloride (prepared as described in Example 8D) (84 mg, 0.322mmol) in 1 mL of

[1819] dichloromethane was added dropwise at ambient temperature and the reaction was stirred for 1 hour. The reaction mixture was diluted with 5 mL of methyl-tert-butyl ether and quenched with saturated aqueous sodium bicarbonate. After stirring for 10 minutes, the aqueous layer was removed and the organic layer was washed twice more with saturated aqueous sodium

[1820] bicarbonate. The organics were dried over sodium sulfate then concentrated. The residue waschromatographed using a 40 g silica gel cartridge with 10-20 % methyl-tert-butyl ether / heptanes over 3 minutes then 20 % methyl-fert-butyl ether / heptanes for 17 minutes then a 20-30 % methyl-fert-butyl ether / heptanes gradient over 10 minutes to provide the title compound as the first eluting isomer and Example 6 as the second eluting isomer. 1H NMR (500 MHz, CDCI3) δ 8.06 (t, J= 1.8 Hz, 1H), 8.01 (d, J= 7.9 Hz, 1H), 7.59 (dt, J= 7.9, 1.4 Hz, 1H), 7.48 (t, J= 7.7 Hz, 1H), 7.15 (dd, J= 8.2, 1.7 Hz, 1H), 7.12 (d, J= 1.7 Hz, 1H), 7.07 - 6.99 (m, 2H), 6.52 (dd, J = 8.5, 2.6 Hz, 1H), 6.44 (d, J= 2.5 Hz, 1H), 5.58 (d, J= 6.6 Hz, 1H), 5.06 - 4.96 (m, 1H), 4.81 (dd, J= 11.5, 2.1 Hz, 1H), 3.94 (s, 3H), 3.75 (s, 3H), 2.31 (dt, J= 14.3, 2.5 Hz, 1H), 2.15 (ddd, J

[1821] = 14.4, 11.5, 4.6 Hz, 1H), 1.71 - 1.66 (m, 2H), 1.10 - 1.05 (m, 2H); MS (ESI-) m / z 536.1 (M-H)". Relative stereochemistry confirmed by H NMR NOE analysis.

[1822] Example 6

[1823] methyl 3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate

[1824] The title compound was isolated as the second eluting isomer from the column

[1825] chromatography as described in Example 5E. 1H NMR (500 MHz, CDC13) δ 8.08 (s, 1H), 8.00 (d, J= 7.7 Hz, 1H), 7.58 (dt, J= 7.8, 1.4 Hz, 1H), 7.45 (t, J= 7.7 Hz, 1H), 7.12 (dd, J= 8.2, 1.7 Hz, 1H), 7.08 (d, J= 1.7 Hz, 1H), 7.00 (d, J= 8.2 Hz, 1H), 6.96 (dd, J= 8.7, 1.0 Hz, 1H), 6.51 (dd, J= 8.6, 2.6 Hz, 1H), 6.44 (d, J= 2.6 Hz, 1H), 5.46 - 5.38 (m, 1H), 5.33 (d, J= 8.8 Hz, 1H), 5.21 (dd, J= 11.3, 1.9 Hz, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 2.51 (ddd, J= 13.3, 6.0, 2.0 Hz, 1H),

[1826] I .86 - 1.62 (m, 3H), 1.11 - 1.03 (m, 2H); MS (ESI-) m / z 536.1 (M-H)".

[1827] Example 7

[1828] methyl 3-[(2i?,45)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]benzoate

[1829] The title compound (36 mg, 0.067 mmol, 21.76 % yield) was collected as the first eluting isomer from the separation of the two isomers as described in Example 8D. 1H NMR (400 MHz, CDCI3) δ 8.05 (d, J = 2.1 Hz, 1H), 8.01 (dt, J = 7.9, 1.6 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.47 (dd, J = 8.7, 6.8 Hz, 1H), 7.22 (td, J = 7.7, 1.8 Hz, 1H), 7.18 - 7.10 (m, 3H), 7.03 (d, J = 8.3 Hz, 1H), 6.93 (t, J = 7.5 Hz, 2H), 5.63 (d, J = 6.8 Hz, 1H), 5.05 (dt, J = 6.8, 3.4 Hz, 1H), 4.84 (dd, J =

[1830] I I .3, 2.4 Hz, 1H), 3.94 (s, 3H), 2.32 (dt, J = 14.4, 2.7 Hz, 1H), 2.19 (ddd, J = 14.4, 11.3, 4.6 Hz, 1H), 1.72 - 1.66 (m, 2H), 1.12 - 1.05 (m, 2H); MS (ESI+) m / z 508 (M+H)+.

[1831] Example 8methyl 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]benzoate

[1832] Example 8A

[1833] ( ?)-methyl 3 -(4-oxochroman-2-yl)benzoate

[1834] A 20 mL vial was charged with bis(2,2,2-trifluoroacetoxy)palladium (56.9 mg, 0.171 mmol), (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (41.9 mg, 0.205 mmol), ammonium hexafluorophosphate(V) (167 mg, 1.026 mmol), and 3- methoxycarbonylphenylboronic acid (1231 mg, 6.84 mmol). The reaction was stirred in dichloroethane (5 mL) for 5 minutes, and a pale yellow color was observed. To this suspension was added 4H-chromen-4-one (CAS 11013-97-1) (500 mg, 3.42 mmol) and water (0.308 mL, 17.11 mmol) and the sides of the vial washed with more dichloroethane (5 mL). The vial was capped and the mixture stirred at 60 °C for 16 hours. The mixture was filtered through a plug of silica gel and celite and eluted with ethyl acetate to give a red solution. The solvent was removed and the crude material was chromatographed using a 40g silica gel cartridge with a gradient of 5-50 % ethyl acetate / heptanes over 40 minutes to give the title compound (329 mg, 1.165 mmol, 34.1 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (t, J = 1.8 Hz, 1H), 7.98 (dt, J = 7.7, 1.5 Hz, 1H), 7.84 (dt, J = 7.9, 1.4 Hz, 1H), 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.17 - 7.10 (m, 2H), 5.80 (dd, J = 13.1, 2.8 Hz, 1H), 3.88 (s, 3H), 3.28 (dd, J = 16.8, 13.1 Hz, 1H), 2.88 (dd, J = 16.8, 3.0 Hz, 1H); MS (ESI+) m / z 300 (M+NH4)+.

[1835] Example 8B

[1836] (i?)-methyl 3 -(4-(hydroxyimino)chroman-2-yl)benzoate Example 8A (200 mg, 0.708 mmol) was treated with hydroxylamine hydrochloride (59.1 mg, 0.850 mmol) and sodium acetate (69.7 mg, 0.850 mmol) in ethanol (3542 μί). The reaction was stirred at ambient temperature for 15 hours. The solvent was removed under a stream of nitrogen. The crude material was washed with water (2x2mL) and dried under a stream of nitrogen to provide the title compound (210 mg, 0.706 mmol, 100 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.11 (t, J = 1.8 Hz, 1H), 7.96 (dt, J = 7.8, 1.4 Hz, 1H), 7.82 (td, J = 7.7, 7.2, 1.6 Hz, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.31 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.04 - 6.97 (m, 2H), 5.32 (dd, J = 11.8, 3.2 Hz, 1H), 3.87 (s, 3H), 3.40 (dd, J = 17.0, 3.3 Hz, 1H), 2.72 (dd, J = 17.0, 11.8 Hz, 1H); MS (ESI+) m / z 298 (M+H)+.

[1837] Example 8Cmethyl 3 -((2i?)-4-aminochroman-2-yl)benzoate

[1838] Example 8B (100 mg, 0.336 mmol) and methanol (10 ml) were added to Ra-Ni 2800, water slurry (350 mg, 2.68 mmol) in a 50 mL pressure bottle and shaken for 16 hours at 30 psi of ¾ at ambient temperature. The reaction was filtered and the solvent removed under reduced pressure to provide the title compound (94 mg, 0.332mmol, 99% yield) as a tan powder. 1H NMR (400 MHz, DMSO-d6) δ 8.06 - 8.01 (m, 1H), 7.91 (ddt, J= 7.8, 2.7, 1.4 Hz, 1H), 7.71 (ddt, J= 7.1, 3.4, 1.5 Hz, 1H), 7.59 - 7.53 (m, 1.5H), 7.33 (dd, J= 7.7, 1.6 Hz, 0.5H), 7.12 (dtd, J= 13.9, 7.4, 1.7 Hz, 1H), 6.95 - 6.83 (m, 1.5H), 6.78 (dd, J= 8.2, 1.2 Hz, 0.5H), 5.41 (dd, J = 7.6, 5.7 Hz, 0.5H), 5.29 (dd, J= 11.6, 2.1 Hz, 0.5H), 4.17 (dd, J= 11.2, 5.8 Hz, 0.5H), 3.95 (t, J = 3.8 Hz, 0.5H), 3.87 (d, J= 1.6 Hz, 3H), 2.36 (ddd, J= 13.1, 5.7, 2.1 Hz, 1H), 2.09 - 2.05 (m, 1H), 1.93 - 1.84 (m, 2H)

[1839] Example 8D

[1840] methyl 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]benzoate

[1841] To a solution of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (75 mg, 0.310 mmol) in dichoromethane (774 μΕ) was added one quarter of a solution of oxalyl dichloride (108 μί, 1.239 mmol) in 200 of dichloromethane followed by 1 drop of DMF. The reaction bubbled vigorously. The remainder of the oxalyl chloride solution was added dropwise. The reaction was stirred for 30 minutes, and the solvent removed under a stream of nitrogen. The residue was chased with 2 x 0.5mL of dichloromethane, drying under a stream of nitrogen. This residue was taken up in dichloromethane (774 μΕ) and added to a mixture of the product from Example 8C (88 mg, 0.310 mmol) and triethylamine (129 μΐ, 0.929 mmol) in dichloromethane (774 μΕ). After 15 minutes, the mixture was quenched with saturated aqueous sodium bicarbonate, concentrated, and the resulting oil purified on a 12 g silica gel cartridge and eluted with a gradient of 5-100 % ethyl acetate / heptanes to give 137 mg of a mixture of the two diastereomers. The mixture of diastereomers were chromatographed again using 30 %

[1842] MTBE / heptanes to provide Example 7 as the first eluting isomer and the title compound as the second eluting isomer (36 mg, 0.066 mmol, 21.30 % yield) as a clear foam. 1H NMR (501 MHz, CDCls) δ 8.08 (t, J = 1.8 Hz, 1H), 8.00 (dt, J = 7.7, 1.5 Hz, 1H), 7.59 (dt, J = 7.8, 1.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.18 (td, J = 7.9, 1.6 Hz, 1H), 7.13 (dd, J = 8.2, 1.8 Hz, 1H), 7.10 - 7.06 (m, 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.93 (td, J = 7.6, 1.2 Hz, 1H), 6.90 (dd, J = 8.1, 1.2 Hz, 1H),5.50 (td, J = 10.6, 10.1, 6.2 Hz, 1H), 5.39 (d, J = 8.9 Hz, 1H), 5.23 (dd, J = 11.6, 1.9 Hz, 1H), 3.92 (s, 2H), 2.52 (ddd, J = 13.2, 6.0, 2.0 Hz, 1H), 1.82 (dt, J = 13.2, 11.3 Hz, 1H), 1.77 - 1.73 (m, 1H), 1.67 - 1.62 (m, 1H), 1.13 - 1.05 (m, 2H); MS (ESI+) m / z 508 (M+H)+.

[1843] Example 9

[1844] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]benzoic acid

[1845] To a suspension of Example 8D in tetrahydrofuran (164 μΕ) and water (82 μΕ) was added lithium hydroxide (2.124 mg, 0.089 mmol). The reaction mixture was stirred at room temperature. After 2 hours, additional lithium hydroxide (2.209 mg, 0.092 mmol) was added and the reaction mixture was stirred at ambient temperture for 72 hours. The reaction was quenched with 10 drops of 1 M HCl and this crude material was chromatographed directly using a 4 g silica gel cartridge with a gradient of 5-100 % ethyl acetate / heptane to give the title compound (15 mg, 0.030 mmol, 61.7 % yield) as white foam. 1H NMR (500 MHz, CDC13) δ 8.19 (t, J = 1.7 Hz, 1H), 8.06 (dt, J = 7.7, 1.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.14 (dd, J = 8.1, 1.8 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.96 - 6.89 (m, 2H), 5.56 (dd, J = 16.7, 9.4 Hz, 1H), 5.45 (d, J = 8.9 Hz, 1H), 5.29 (d, J = 11.3 Hz, 1H), 2.59 (ddd, J = 13.1, 5.9, 1.9 Hz, 1H), 1.85 - 1.76 (m, 2H), 1.71 - 1.64 (m, 2H), 1.12 - 1.08 (m, 2H); MS (ESI+) m / z 494 (M+H)+.

[1846] Example 10

[1847] 3-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-

[1848] 2H-chromen-2-yl]benzoic acid

[1849] The title compound was prepared using the conditions similar to that described in Example 1, substituting Example 7 for Example 6. 1H NMR (500 MHz, CDC13) δ 8.12 (t, J = 1.7 Hz, 1H), 8.08 (dt, J = 7.8, 1.4 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.22 (td, J = 7.7, 1.6 Hz, 1H), 7.19 - 7.12 (m, 3H), 7.03 (d, J = 8.2 Hz, 1H), 6.97 - 6.91 (m, 2H), 5.65 (d, J = 6.8 Hz, 1H), 5.06 (t, J = 6.8 Hz, 1H), 4.87 (dd, J = 11.3, 2.2 Hz, 1H), 2.35 (dt, J = 14.3, 2.6 Hz, 1H), 2.20 (ddd, J = 14.0, 11.2, 4.5 Hz, 1H), 1.71 (q, J = 3.6 Hz, 2H), 1.12 - 1.08 (m, 2H); MS (ESI+) m z 494 (M+H)+.

[1850] Example 11

[1851] methyl 3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6- methyl-3,4-dihydro-2H-chromen-2-yl]benzoateExample 11A

[1852] ( ?)-methyl 3 -(6-methyl-4-oxochroman-2-yl)benzoate

[1853] The mixture of bis(2,2,2-trifluoroacetoxy)palladium (51.9 mg, 0.156 mmol), (S)-4-(tert- butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (38.3 mg, 0.187 mmol), ammonium

[1854] hexafluorophosphate(V) (153 mg, 0.937 mmol), (3-(methoxycarbonyl) phenyl)boronic acid (1124 mg, 6.24 mmol) and dichloroethane (10 mL) in a 20 mL vial were stirred for 5 minutes at room temperature, followed by the addition of 6-methyl-4H-chromen-4-one (CAS 314041-54-8, MFCD00218598, 500 mg, 3.12 mmol) and water (0.26 mL, 14 mmol). The vial was capped and the mixture was stirred at 60 °C overnight. The reaction mixture was filtered through a plug of celite and eluted with ethyl acetate. The organics was washed with brine and dried over MgS04. The solvent was removed in vacuo and the crude material was chromatographed using a 40 g silica gel cartridge, eluting with a gradient of 5-40 % ethyl acetate in heptane to provide the title compound (410 mg, 44.3 %). 1H NMR (501 MHz, DMSO-d6) δ 8.33 (t, J= 1.7 Hz, 1H), 8.17 (dt, J= 7.7, 1.5 Hz, 1H), 8.02 (dt, J= 7.7, 1.5 Hz, 1H), 7.83 - 7.74 (m, 2H), 7.62 (dd, J= 8.5, 2.4 Hz, 1H), 7.23 (d, J= 8.4 Hz, 1H), 5.93 (dd, J= 12.9, 2.9 Hz, 1H), 4.07 (s, 3H), 3.42 (dd, J = 16.8, 13.0 Hz, 1H), 3.04 (dd, J= 16.8, 3.0 Hz, 1H), 2.49 (s, 3H); MS (ESI+) m / z 297 (M+H)+.

[1855] Example 1 IB

[1856] (i?)-methyl 3 -(4-(hydroxyimino)-6-methylchroman-2-yl)benzoate The mixture of Example 11A (390 mg, 1.316 mmol), hydroxylamine hydrochloride (183 mg, 2.63 mmol), sodium acetate (216 mg, 2.63 mmol) in methanol (10 mL) was stirred at 60 °C for 4 hours. The solvent was evaporated under pressure and the residue was dissolved in ethyl acetate, washed with brine, dried over MgS04, and filtered. The solvent was removed under reduced pressure to provide the title compound (393 mg, 95 % yield) as white solid. 1H NMR (501 MHz, DMSC / e) δ 11.51 (s, 1H), 8.32 (t, J= 1.7 Hz, 1H), 8.18 (dt, J= 7.8, 1.5 Hz, 1H), 8.02 (dt, J= 7.7, 1.3 Hz, 1H), 7.88 - 7.76 (m, 2H), 7.35 (dd, J= 8.4, 2.2 Hz, 1H), 7.12 (d, J= 8.3 Hz, 1H), 5.49 (dd, J= 11.6, 3.1 Hz, 1H), 4.10 (s, 3H), 3.60 (dd, J= 17.1, 3.3 Hz, 1H), 2.92 (dd, J = 17.0, 11.6 Hz, 1H), 2.49 (s, 3H); MS (ESI+) m / z 312 (M+H)+.

[1857] Example 11C

[1858] methyl 3 -((2i?)-4-amino-6-methylchroman-2-yl)benzoate Example 1 IB (390 mg, 1.253 mmol) was added to Ra-Ni 2800, water slurry (1.17 g) in a 100 mL pressure bottle. The mixture was charged with 30 psi of hydrogen and stirred at ambienttemperature for 16 hours. LC / MS indicated that the reaction was completed. The mixture was filtered and the solvent evaporated under reduced pressure. The residue was dissolved in tert- butyl ethyl ether, followed by the addition of 4 M HC1 in dioxane (2 ml) drop wise. The precipitated white solid was collected by filtration, washed with tert-butyl methyl ether, and dried to yield the hydrochloride salt of the title compound (355 mg, 1.063 mmol, 85 % yield). LC / MS m / z 281 (M-NH2)+.

[1859] Example 11D

[1860] methyl 3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate

[1861] To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (332 mg, 1.372 mmol) in CH2C12(6 mL) was added a few drops of DMF, followed by the drop wise addition of oxalyl dichloride (0.290 ml, 3.43 mmol). The mixture was stirred at room temperature for 30 minutes. LC / MS with methanol as solvent showed a completed methyl ester's peak. Solvent was removed in vacuo, excess oxalyl chloride removed via azeotrope with dichloroethane, and the crude material in CH2C12(4 mL) was added to the product from Example 11C (340 mg, 1.143 mmol) and pyridine (543 mg, 6.86 mmol) in CH2C12(6 mL). The mixture was stirred at room temperature for 2 hours and saturated NaHC03aqueous solution and CH2C12was added. The phases were separated and the aqueous layer was extracted with CH2C12. The combined organics were dried over MgS04, filtered, and concentrated under reduced pressure. Purification of the residue by chromatography using a 40 g silica gel cartridge, and eluting with 0-30 % ethyl acetate in hexane provide Example 12 as the first eluting isomer, and the title compound as the second eluting isomer (133 mg, 0.255 mmol, 22.30 % yield). 1H NMR (400 MHz, CDC13) δ 8.07 (t, J= 1.7 Hz, 1H), 7.99 (dt, J= 8.0, 1.4 Hz, 1H), 7.58 (dt, J= 7.8, 1.4 Hz, 1H), 7.44 (t, J= 7.7 Hz, 1H), 7.18 - 7.06 (m, 2H), 7.05 - 6.92 (m, 2H), 6.88 - 6.72 (m, 2H), 5.53 - 5.29 (m, 2H), 5.19 (dd, J= 11.5, 1.9 Hz, 1H), 3.92 (s, 3H), 2.53 (ddd, J= 13.4, 5.9, 2.0 Hz, 1H), 2.26 (s, 3H), 1.86 - 1.67 (m, 2H), 1.61 (d, J= 16.1 Hz, 1H), 1.17 - 1.00 (m, 2H); MS (ESI+) m / z 522 (M+H)+.

[1862] Example 12

[1863] methyl 3-[(2i?,45)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6- methyl-3,4-dihydro-2H-chromen-2-yl]benzoateThe title compound was isolated as the first eluting isomer from the chromatography as described in Example 1 ID (97 mg, 16.27 % yield). 1H NMR (400 MHz, CDC13) δ 8.05 (t, J = 1.7 Hz, 1H), 8.00 (d, J= 7.7 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.05 - 6.99 (m, 2H), 6.93 (d, J= 2.2 Hz, 1H), 6.81 (d, J= 8.3 Hz, 1H), 5.62 (d, J= 6.9 Hz, 1H), 5.01 (ddd, J= 7.1, 4.6, 2.8 Hz, 1H), 4.80 (dd, J= 11.2, 2.3 Hz, 1H), 3.94 (s, 3H), 2.34 - 2.23 (m, 4H), 2.17 (ddd, J= 14.4, 11.1, 4.7 Hz, 1H), 1.74 - 1.64 (m, 2H), 1.13 - 1.04 (m, 2H); MS (ESI+) m / z 522 (M+H)+.

[1864] Example 13

[1865] 3-[(2i?,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6-methyl-

[1866] 3 ,4-dihydro-2H-chromen-2-yl]benzoic acid

[1867] A mixture of Example 12 (96 mg, 0.184 mmol) and 2 M LiOH (2 mL) in methanol (6 mL) was stirred at 35 °C for 4 hours. Solvent was removed under reduced pressure and the residue dissolved in water (2 mL), and the pH was adjusted with 2 M HCl to pH 1-2. The precipitated white solid was collected by filtration, washed with water, and dried to provide the title compound (83 mg, 89 % yield). 1H NMR (400 MHz, CDC13) δ 8.10 (t, J= 1.7 Hz, 1H), 8.06 (d, J= 7.8 Hz, 1H), 7.64 (d, J= 7.7 Hz, 1H), 7.49 (t, J= 7.8 Hz, 1H), 7.20 - 7.13 (m, 2H), 7.06 - 6.99 (m, 2H), 6.93 (d, J= 2.1 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 5.65 (d, J= 6.8 Hz, 1H),

[1868] 5.01 (dt, J= 7.0, 3.5 Hz, 1H), 4.83 (dd, J= 11.2, 2.3 Hz, 1H), 2.31 (dt, J= 14.4, 2.8 Hz, 1H), 2.26 (s, 3H), 2.18 (ddd, J= 14.7, 11.1, 4.7 Hz, 1H), 1.74 - 1.66 (m, 2H), 1.14 - 1.04 (m, 2H); MS (ESI+) m / z 508(M+H)+.

[1869] Example 14

[1870] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6-methyl-

[1871] 3 ,4-dihydro-2H-chromen-2-yl]benzoic acid

[1872] The mixture of Example 1 ID (35 mg, 0.067 mmol) and 2 M LiOH (1 mL) in methanol (4 mL) was stirred at 35 °C for 4 hours. Solvent was removed under reduced pressure and the residue dissolved in water (2 mL), and the pH was adjusted with 2 M HCl to pH 1-2. The white solid precipitated was collected by filtration, washed with water, and dried to yield title compound (30 mg, 88 % yield). 1H NMR (400 MHz, CDC13) δ 8.18 (t, J= 1.7 Hz, 1H), 8.05 (dt, J= 7.9, 1.3 Hz, 1H), 7.65 (dt, J= 7.6, 1.4 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.17 - 7.10 (m, 2H),

[1873] 7.02 (d, J= 8.6 Hz, 1H), 6.98 (dd, J= 8.3, 2.1 Hz, 1H), 6.84 (d, J= 2.0 Hz, 1H), 6.80 (d, J= 8.3 Hz, 1H), 5.49 (td, J= 10.5, 9.8, 6.0 Hz, 1H), 5.42 (d, J= 8.8 Hz, 1H), 5.25 (dd, J= 11.6, 1.8 Hz,1H), 2.59 (ddd, J= 13.3, 5.9, 1.9 Hz, 1H), 2.26 (s, 3H), 1.85 - 1.75 (m, 2H), 1.68 - 1.58 (m, 1H), 1.18 - 1.04 (m, 2H); MS (ESI+) m / z 508 (M+H)+.

[1874] Example 15

[1875] 3-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-

[1876] 3 ,4-dihydro-2H-chromen-2-yl]benzoic acid

[1877] The title compound was prepared using the conditions similar to that described in

[1878] Example 1, substituting Example 17 for Example 6. 1H NMR (400 MHz, CDC13) δ 8.17 - 7.97 (m, 2H), 7.66 - 7.40 (m, 2H), 7.20 - 6.95 (m, 4H), 6.74 (t, J= 3.4 Hz, 2H), 5.64 (d, J= 6.8 Hz, 1H), 4.93 (ddd, J= 70.0, 8.8, 3.0 Hz, 2H), 2.32 (dt, J= 14.4, 2.6 Hz, 1H), 2.28 (s, 3H), 2.17 (ddd, J= 14.9, 11.1, 4.7 Hz, 1H), 1.70 (q, J= 3.9 Hz, 2H), 1.08 (q, J= 3.9 Hz, 2H) ; MS (ESI+) m / z 508 (M+H)+.

[1879] Example 16

[1880] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7-methyl-

[1881] 3 ,4-dihydro-2H-chromen-2-yl]benzoic acid

[1882] The mixture of 18E (130 mg, 0.249 mmol) and 2 M LiOH (1ml) in methanol (4 mL) was stirred at 35 °C for 4 hours, solvent was removed under pressure and the residue dissolved in water (2 mL), and adjusted with 2 M HCl to pH 1-2. The precipitated white solid was filtered, washed with water and dried to give title compound (114 mg, 90 % yield). 1H NMR (400 MHz, CDC13) δ 8.19 (s, 1H), 8.05 (d, J= 7.7 Hz, 1H), 7.64 (d, J= 7.6 Hz, 1H), 7.46 (t, J= 7.7 Hz, 1H), 7.17 - 7.04 (m, 2H), 6.97 (dd, J= 25.7, 7.9 Hz, 2H), 6.73 (d, J= 9.0 Hz, 2H), 5.60 - 5.35 (m, 2H), 5.24 (d, J= 11.3 Hz, 1H), 2.58 (dd, J= 12.9, 5.9 Hz, 1H), 2.27 (s, 3H), 1.86 - 1.70 (m, 2H), 1.66 (d, J= 11.9 Hz, 1H), 1.09 (q, J= 2.8 Hz, 2H); MS (ESI+) m / z 508 (M+H)+.

[1883] Example 17

[1884] methyl 3-[(2i?,45)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate

[1885] The title compound (290 mg, 26.5 % yield) was isolated as the first eluting isomer from the separation of the isomers as described in Example 18E. 1H NMR (400 MHz, CDC13) δ 8.05 (t, J= 1.8 Hz, 1H), 8.01 (dt, J= 7.7, 1.5 Hz, 1H), 7.58 (dt, J= 7.5, 1.4 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.19 - 7.10 (m, 2H), 7.03 (dd, J= 8.2, 1.7 Hz, 2H), 6.75 (dd, J= 6.2, 1.9 Hz, 2H), 5.61 (d, J= 6.8 Hz, 1H), 5.01 (dt, J= 7.1, 3.3 Hz, 1H), 4.81 (dd, J= 11.3, 2.3 Hz, 1H), 3.94 (s, 3H),2.34 - 2.29 (m, 1H), 2.29 (s, 3H), 2.16 (ddd, J= 14.2, 11.3, 4.6 Hz, 1H), 1.73 - 1.65 (m, 2H), 1.11 - 1.03 (m, 2H). ); MS (ESI+) m / z 522 (M+H)+.

[1886] Example 18

[1887] methyl 3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate

[1888] Example 18A

[1889] The mixture of l-(2-hydroxy-4-methylphenyl)ethanone (2 ml, 14.12 mmol) and 1,1- dimethoxy-N,N-dimethylmethanamine (2.063 ml, 15.53 mmol) was heated at 120 °C for 2 hours, and then cooled down . The precipitated orange solid was filtered, washed with heptane, and dried to give intermediate (E)-3-(dimethylamino)-l-(2-hydroxy-4-methylphenyl)prop-2-en-l- one, which was dissolved in CH2CI2(120 mL) and treated with concentrated HC1 (15 mL). The mixture was refluxed for 2 hours, and LC / MS indicated the reaction was complete. The water layer was removed and extracted with CH2CI2(10 mL x 2). The combined organics was concentrated to give a crude orange color solid. Purification by chromatography on 80 g silica gel cartridge, eluting with ethyl acetate in heptane at 5-40 % gradient gave title compound as white solid (1.82 g, 80 % yield). 1H NMR (400 MHz, CDC13) δ 8.09 (d, J= 8.1 Hz, 1H), 7.81 (d, J= 5.7 Hz, 1H), 7.24 (s, 1H), 7.23 - 7.19 (m, 1H), 6.30 (d, J= 6.1 Hz, 1H), 2.48 (s, 3H); MS (ESI+) m / z 161 (M+H)+.

[1890] Example 18B

[1891] (i?)-methyl 3 -(7-methyl-4-oxochroman-2-yl)benzoate

[1892] A 20mL vial was charged with bis(2,2,2-trifluoroacetoxy)palladium (0.353 g, 1.061 mmol), (5)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.260 g, 1.274 mmol), ammonium hexafluorophosphate(V) (1.038 g, 6.37 mmol) and (3-(methoxycarbonyl) phenyl) boronic acid (3.82 g, 21.23 mmol) were stirred in dichloroethane (10 mL) at room temperature for 5 minutes. To this suspension was added Example 18A (1.70 g, 10.61 mmol) and water (0.256 mL, 14.19 mmol). The vial was capped and the mixture was stirred at 60 °C overnight. The mixture was filtered through a plug of celite and eluted with ethyl acetate. The solvent was removed under pressure and the crude material was chromatographed using a 80 g silica gel cartridge, eluting with a gradient of 5-50 % ethyl acetate in heptane to provide the title compound (2.6 g, 83 % yield). 1H NMR (400 MHz, CDC13) δ 8.22 - 8.13 (m, 1H), 8.11 - 8.01 (m, 1H), 7.83 (d, J= 8.3 Hz, 1H), 7.77 - 7.60 (m, 1H), 7.52 (t, J= 7.7 Hz, 1H), 6.89 (d, J= 6.8 Hz, 2H), 5.51 (dd, J =13.2, 2.9 Hz, 1H), 4.13 (s, OH), 3.95 (d, J= 1.0 Hz, 3H), 3.76 (s, OH), 3.05 (ddd, J= 16.8, 13.3,

[1893] 1.0 Hz, 1H), 2.88 (ddd, J= 16.8, 2.9, 0.9 Hz, 1H), 2.38 (s, 3H); MS (ESI+) m / z 297 (M+H)+.

[1894] Example 18C

[1895] ( ?)-methyl 3 -(4-(methoxyimino)-7-methylchroman-2-yl)benzoate The mixture of Example 18B (1.2 g, 4.05 mmol), sodium acetate (0.664 g, 8.10 mmol) and O-methylhydroxylamine, hydrochloric acid (0.676 g, 8.10 mmol) in methanol (10 mL) was stirred at 60 °C overnight. The solvent was evaporated under pressure and the residue washed with water, filtered, and dried to provide the title compound (1.3g, 4.00 mmol, 99 % yield) as white solid. 1H NMR (400 MHz, CDC13) δ 8.14 (d, J= 1.9 Hz, 1H), 8.03 (dt, J= 7.7, 1.5 Hz, 1H), 7.90 - 7.76 (m, 1H), 7.67 (dt, J= 7.7, 1.5 Hz, 1H), 7.49 (t, J= 7.7 Hz, 1H), 6.81 (dd, J = 4.4, 2.6 Hz, 2H), 5.10 (dd, J= 12.5, 3.1 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.48 (dd, J= 17.3,

[1896] 3.1 Hz, 1H), 2.65 (dd, J= 17.2, 12.5 Hz, 1H), 2.32 (s, 3H); MS (ESI+) m / z 326 (M+H)+.

[1897] Example 18D

[1898] Methyl 3-((2i?)-4-amino-7-methylchroman-2-yl)benzoate Example 18C (820 mg, 2.52 mmol) was added to Ra-Ni 2800, water slurry (2.5 g) in a 100 mL pressure bottle and charged with 30 psi of hydrogen. The mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the solvent removed under pressure. The residue was dissolved in tert-butyl ethyl ether, followed by drop wise addition of 4 M HC1 in dioxane (2mL). The precipitated white solid was collected by filtration, washed with tert-butyl methyl ether, and dried to provide the hydrochloride salt of the title compound with a cis- / trans- isomer of about 1 to 1 (705 mg, 2.371 mmol, 94 % yield). LC / MS m / z 281 (M-NH2)+.

[1899] Example 18E

[1900] methyl 3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate

[1901] To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (559 mg, 2.3 mmol) in DMF (5 ml) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate ,1196 mg, 3.15 mmol). The mixture was stirred for 10 minutes at room temperature, followed by addition of the product from Example 18D (700 mg, 2.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.461 ml, 8.39 mmol) sequentially. The mixture was stirred at room temperature for 2 hours. LC / MS indicated the reaction was complete. Dichloromethane (40 mL) was added and the solution was washed withbrine (20 mL x 2). The organic layer was dried over MgSC^ and concentrated under reduced pressure. The resulting residue was purified by chromatography on a 40 g silica gel cartridge, eluting with a gradient of 0-25 % ethyl acetate in heptane to provide Example 17 as the first eluting isomer and the title compound as the second eluting isomer (400 mg, 36.6 % yield). 1H NMR (400 MHz, CDC13) δ 8.07 (d, J= 1.9 Hz, 1H), 7.99 (dt, J= 7.9, 1.4 Hz, 1H), 7.58 (dt, J = 7.8, 1.5 Hz, 1H), 7.44 (t, J= 7.7 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.97 (dd, J= 21.0, 8.0 Hz, 2H), 6.74 (d, J= 9.5 Hz, 2H), 5.49 - 5.39 (m, 1H), 5.36 (d, J= 8.7 Hz, 1H), 5.20 (dd, J= 11.3, 1.9 Hz, 1H), 3.92 (s, 3H), 2.51 (ddd, J= 13.2, 6.0, 2.0 Hz, 1H), 2.28 (s, 3H), 1.67 - 1.59 (m, 1H), 1.57 (d, J = 1.1 Hz, 2H), 1.07 (td, J= 3.6, 2.2 Hz, 2H); MS (ESI+) m / z 522(M+H)+.

[1902] Example 19

[1903] 3-[(2i?,4i?)-4-( {[ 1 -(2,2-dif uoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6-methoxy-

[1904] 3 ,4-dihydro-2H-chromen-2-yl]benzoic acid

[1905] A mixture of Example 21D (80 mg, 0.149 mmol) and aqueous LiOH (2 M, 1 mL) in methanol (4 mL) was stirred at 35 °C for 4 hours; LC / MS indicated the reaction was complete. Solvent was removed under reduced pressure and water (2 mL) was added. To the mixture was added 2 M HCl to adjust pH to 1-2. The white solid was collected by filtration, washed with water, and dried to give the title compound (55 mg, 70.6 % yield).1H NMR (400 MHz, CDC13) δ 8.18 (s, 1H), 8.05 (d, J= 7.7 Hz, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.17 - 7.11 (m, 2H), 7.02 (dd, J= 8.3, 3.7 Hz, 1H), 6.83 (d, J= 9.0 Hz, 1H), 6.75 (dd, J= 8.8, 3.0 Hz, 1H), 6.59 (d, J= 3.0 Hz, 1H), 5.49 (dt, J= 18.5, 7.4 Hz, 2H), 5.22 (d, J= 11.4 Hz, 1H), 3.74 (s, 3H), 2.66 - 2.49 (m, 1H), 1.79 (ddd, J= 11.9, 6.8, 4.0 Hz, 2H), 1.69 - 1.63 (m, 1H), 1.11 (d, J = 5.0 Hz, 2H); MS (ESI+) m / z 524 (M+H)+.

[1906] Example 20

[1907] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-hydroxy-2-(3-methoxyphenyl)-3,4-dihydro-

[1908] 2H-chromen-4-yl]cyclopropanecarboxamide

[1909] Example 20A

[1910] (i?)-7-hydroxy-2-(3-methoxyphenyl)chroman-4-one

[1911] A 250-mL round bottom flask was charged with (3-methoxyphenyl)boronic acid (1.991 g, 13.11 mmol), (5)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.094 g, 0.463 mmol), bis(2,2,2-trifluoroacetoxy)palladium (0.128 g, 0.385 mmol), and ammonium

[1912] hexafluorophosphate (0.377 g, 2.313 mmol), and dichloroethane (15.42 mL) was added. Thereaction was stirred at ambient temperature for 5 minutes, at which point a yellow color was observed in the suspension. To the reaction mixture was added 7-hydroxy-4H-chromen-4-one (CAS 59887-89-7, MFCD00209371, 1.25 g, 7.71 mmol) and water (0.694 mL, 38.5 mmol) and an additional dichloroethane (10.28 mL) was used to wash down the sides of the flask. The reaction was stirred for 18 hours at 60 °C, cooled to ambient temperature, diluted with dichloromethane, and filtered through a silica / celite filter, initially using 100% dichloromethane but then 20% ethyl acetate / 80% dichloromethane to effectively remove the boronic acid.

[1913] Combined filtrates was concentrated and the crude material loaded onto a 40 g silica gel column and eluted with 5-50 % ethyl acetate / heptanes over 25 minutes to provide the title compound as a white solid. LC / MS m / z 271 (M+H)+.

[1914] Example 20B

[1915] (i?)-7-hydroxy-2-(3-methoxyphenyl)chroman-4-one O-methyl oxime Example 20A (1 g, 3.70 mmol) was dissolved in pyridine (3.70 mL) and O- methylhydroxylamine hydrochloride (0.927 g, 11.10 mmol) was added. The resulting suspension was heated at 60 °C for 2 hours, cooled to room temperature, and concentrated under reduced pressure. The crude material was partitioned between saturated aqueous ammonium chloride and methyl-tert-butyl ether. The crude material obtained from the concentration of the organic layer was purified using a 40 g silica gel cartridge, eluting with 5-20 %> ethyl

[1916] acetate / heptanes over 30 minutes to provide the title compound (505 mg, 1.69 mmol) as a white solid. 1H NMR (400 MHz, CDCls) 5 7.80 (d, J= 8.6 Hz, 1H), 7.31 (t, J= 8.0 Hz, 1H), 7.13 - 6.96 (m, 2H), 6.98 - 6.82 (m, 1H), 6.48 (dd, J= 8.7, 2.5 Hz, 1H), 6.43 (d, J= 2.5 Hz, 1H), 5.91 (d, J= 10.3 Hz, 1H), 5.03 (dd, J= 12.4, 3.1 Hz, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 3.43 (dd, J = 17.3, 3.1 Hz, 1H), 2.66 (dd, J= 17.3, 12.4 Hz, 1H); MS (ESI+) m / z 300.1 (M+H)+.

[1917] Example 20C

[1918] (2i?,4i?)-4-amino-2-(3-methoxyphenyl)chroman-7-ol

[1919] Example 20B (430 mg, 1.437 mmol) was dissolved in acetic acid (5 mL), and platinum (IV) oxide (48.9 mg, 0.215 mmol) was added. The resulting suspension was stirred under an atmosphere of hydrogen for 2 hours at room temperature. To the reaction mixture was added 15 % more catalyst and it was stirred for 2 more hours. The solid was filtered and the filtrate concentrated. The residue was dissolved in methyl-tert-butyl ether (4 mL). To the solution was added HCl (4M solution in dioxane, 0.718 mL, 2.87 mmol). The resulting solid was collected byfiltration and dried to constant weight to provide the hydrochloride salt of the title compound (407mg, 1.32 mmol) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.67 (d, J= 5.3 Hz, 3H), 7.45 (d, J= 8.5 Hz, 1H), 7.36 (t, J= 7.8 Hz, 1H), 7.05 - 6.91 (m, 3H), 6.47 (dd, J= 8.6, 2.4 Hz, 1H), 6.31 (d, J= 2.3 Hz, 1H), 5.16 (d, J= 11.6 Hz, 1H), 4.67 (dt, J= 11.0, 5.8 Hz, 1H), 3.78 (s, 3H), 2.50 - 2.46 (m, 1H), 1.99 (q, J= 12.0 Hz, 1H); MS (ESI-) m / z 255.1 (M-NH2).

[1920] Example 20D

[1921] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-hydroxy-2-(3-methoxyphenyl)-3,4-dihydro-

[1922] 2H-chromen-4-yl]cyclopropanecarboxamide

[1923] To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (40 mg, 0.165 mmol) in DMF (1 mL) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (82 mg, 0.215 mmol). The mixture was stirred for 5 minutes, and the product from Example 20C (50.8 mg, 0.165 mmol) was added, followed by addition of N-ethyl-N-isopropylpropan-2-amine (0.115 mL, 0.661 mmol). The mixture was stirred at ambient temperature for 2 hours, then purified by chromatography on a 25 g silica gel, eluting with a gradient of 5-50 % ethyl acetatein heptanes to provide the title compound (25 mg, 0.050 mmol, 30.5 % yield). 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.38 (d, J= 1.6 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.19 (dd, J= 8.3, 1.7 Hz, 1H), 7.07 (d, J= 8.9 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.88 (dd, J= 8.1, 2.6 Hz, 1H), 6.85 - 6.80 (m, 1H), 6.34 (dd, J= 8.3, 2.4 Hz, 1H), 6.18 (d, J= 2.4 Hz, 1H), 5.27 (td, J= 9.9, 6.8 Hz, 1H), 5.16 (dd, J= 10.8, 2.7 Hz, 1H), 3.75 (s, 3H), 2.09 - 1.95 (m, 2H), 1.49 (ddd, J= 9.0, 5.4, 2.2 Hz, 1H), 1.41 - 1.30 (m, 1H), 1.10 - 0.98 (m, 2H); MS (ESI-) m / z 494 (M-H)".

[1924] Example 21

[1925] methyl 3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6- methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate

[1926] Example 21 A

[1927] (i?)-methyl 3 -(6-methoxy-4-oxochroman-2-yl)benzoate

[1928] A 20 mL vial was charged with bis(2,2,2-trifluoroacetoxy)palladium (0.377 g, 1.135 mmol), (5)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.278 g, 1.362 mmol), ammonium hexafluorophosphate(V) (1.110 g, 6.81 mmol) and (3-(methoxycarbonyl)phenyl)boronic acid (3.06 g, 17.03 mmol). The mixture was stirred in dichloroethane (5 mL) for 5 minutes at room temperature, and a pale yellow color was observed. To this suspension was added 6-methoxy-4H-chromen-4-one (CAS 117408-98-7, 2.0 g, 11.35 mmol) and water (0.256 mL, 14.19 mmol) and the sides of the vial was washed with more dichloroethane (5 mL). The vial was capped and the mixture stirred at 60 °C overnight. The reaction gradually turned black, with Pd plated out on the sides of the vial. The mixture was filtered through a plug of silica gel and celite and eluted with ethyl acetate to give a red solution. The filtrate was concentrated under reduced pressure and the crude material was chromatographed using a 40 g silica gel cartridge, eluting with a gradient of 5-50 % ethyl acetate / heptanes to provide the title compound (1.85 g, 5.92 mmol, 52.2 % yield). 1H NMR (400 MHz, CDC13) δ 8.18 (t, J= 1.7 Hz, 1H), 8.06 (dt, J= 8.0, 1.4 Hz, 1H), 7.68 (dt, J= 7.8, 1.5 Hz, 1H), 7.52 (t, J= 7.8 Hz, 1H), 7.36 (d, J= 3.1 Hz, 1H), 7.14 (dd, J= 9.1, 3.1 Hz, 1H), 7.01 (d, J= 9.0 Hz, 1H), 5.50 (dd, J= 13.4, 3.0 Hz, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 3.06 (dd, J= 16.9, 13.4 Hz, 1H), 2.90 (dd, J= 17.0, 3.0 Hz, 1H); MS (ESI+) m / z 329.9

[1929] (M+NH4)+.

[1930] Example 2 IB

[1931] (i?)-methyl 3 -(6-methoxy-4-(methoxyimino)chroman-2-yl)benzoate The mixture of 21 A (1.85 g, 5.92 mmol), sodium acetate (0.972 g, 11.85 mmol) and O- methylhydroxylamine, hydrochloric acid (0.989 g, 11.85 mmol) in methanol (10 mL) was stirred at 60 °C overnight. The solvent was evaprated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and partitioned. The organic layers was dried over MgS04, filtered, and concentrated under reduced pressure. The residue was chromatographed on a 80 g silica gel cartridge, eluting with a gradient of 5-40 % ethyl acetate / heptane to provided the title compound (1.7 g, 4.98 mmol, 84 % yield) as white solid. LC / MS: TFA m / z 342 (M+H)+.

[1932] Example 21C

[1933] methyl 3 -((2i?,4i?)-4-amino-6-methoxychroman-2-yl)benzoate To Example 21B (1.5 g, 4.39 mmol) in acetic acid (10 mL) was added 5% platinum (857 mg, 0.220 mmol) on carbon. The reaction mixture was charged with 30 psi hydrogen and stirred at ambient temperature for 24 hours, and then filtered. The solvent was evaporated under reduced pressure and the residue dissolved in t-butyl methyl ether (10 mL). HC1 (4M in dioxane, 2.5 mL) was added drop wise. The precipitated solid was collected by filtration and dried to provide the hydrochloride salt of the title compound (842 mg, 54.8 % yield). LC / MS: m z 297 (M-NH2)+.

[1934] Example 2 IDmethyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d] [1,3] dioxol-5-yl)cyclopropanecarboxamido)-6- methoxychroman-2-yl)benzoate

[1935] The mixture of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (779 mg, 3.22 mmol) and HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (1427 mg, 3.75 mmol) in DMF (4 mL) was stirred for 10 minutes at room temperature, and the product from Example 21B (840 mg, 2.68 mmol) was added, followed by the addition of N-ethyl-N-isopropylpropan-2-amine (1.868 mL, 10.72 mmol). The mixture was stirred at ambient temperature for 2 hours. LC / MS indicated the reaction was complete. Purification of the mixture by chromatography on 80 g silica gel cartridge, eluting with a gradient of 5-40 % ethyl acetate in heptane provided the title compound (835 mg, 57.9 % yield). 1H NMR (400 MHz, CDC13) δ 8.07 (t, J= 1.8 Hz, 1H), 7.99 (dt, J= 7.9, 1.5 Hz, 1H), 7.59 (d, J= 7.7 Hz, 1H), 7.44 (t, J= 7.8 Hz, 1H), 7.15 - 7.10 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.83 (d, J= 9.0 Hz, 1H), 6.75 (dd, J= 8.9, 3.0 Hz, 1H), 6.59 (d, J= 2.9 Hz, 1H), 5.49 - 5.33 (m, 2H), 5.20 - 5.13 (m, 1H), 3.92 (s, 3H), 3.74 (s, 3H), 2.52 (ddd, J= 13.4, 5.9, 1.9 Hz, 1H), 1.84 - 1.72 (m, 2H), 1.66 - 1.61 (m, 1H), 1.11 - 1.06 (m, 2H); MS (ESI+) m / z 537.9 (M+H)+.

[1936] Example 22

[1937] rac-l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,45)-7-methoxy-2-(pyridin-3-yl)-3,4-dihydro-

[1938] 2H-chromen-4-yl]cyclopropanecarboxamide

[1939] Example 22A

[1940] (E)- 1 -(2-hydroxy-4-methoxyphenyl)-3 -(pyridin-3 -yl)prop-2-en- 1 -one To a solution of l-(2-hydroxy-4-methoxyphenyl)ethanone (10 g, 60.2 mmol) in 1 M aqueous NaOH (600 mL) was added nicotinaldehyde (16.95 mL, 181 mmol). The mixture was stirred for 16 hours at room temperature. The mixture was neutralized by dropwise addition of 1 M HC1 (about 600 mL). The resulting precipitate was collected by filtration and dissolved in ethyl acetate and methanol. The solvent was removed in vacuo and the solid was then triturated with a small amount of methanol and filtered to provide the title compound (4.6 g, 18.04 mmol, 30.07 % yield) as a yellow solid.1HNMR (400MHz, CDC13) δ 13.21 (s, 1 H), 8.80 (s, 1 H), 8.57 (d, J = 4.4 Hz, 1 H), 7.73 - 7.89 (m, 3 H), 7.57 (d, J = 16 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 1 H), 6.42 - 6.45(m, 2 H), 3.80 (s, 3 H); MS (ESI+) m / z 256 (M+H)+.

[1941] Example 22B7-methoxy-2-(pyridin-3-yl)chroman-4-one

[1942] To a solution of the product from Example 22A (2.0g, 7.83 mmol) in 96% ethanol (100 mL) was added concentrated HC1 (10 mL, 120 mmol) and water (6 mL). The mixture was heated (block at 100 °C) at reflux for 72 hours, and cooled. The solvent was removed in vacuo. The crude material was purified by silica gel co...

Claims

A compound having formula (I) or a pharmaceutically acceptable salt thereof(I)whereinX is CR2 and Y is CR3; orX is N and Y is CR3; orX is CR2 and Y is N;m is 0, 1, 2, or 3;R" are optional substituents on the cyclopropyl ring, and at each occurrence, are eachindependently halogen, Ci-C6 haloalkyl, or Ci-C6 alkyl;R1 and R2, are each independently hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 alkyl, -OR , -C(0)OR1B, -NR1AR2A, or -C(0)NR1AR2A;R1A and R2A, at each occurrence, are each independently hydrogen, Ci-C6 haloalkyl, G1A, or Ci- C6 alkyl; wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORZA, -SRZA, -S(0)2RZA, -C(0)RZA, -C(0)ORZA, -C(0)N(RZA)2, -N(RZA)2, -N(RZA)C(0)RZB, -N(RZA)S(0)2RZB, -N(RZA)C(0)ORZB, -N(RZA)C(0)N(RZA)2, -CN, and G1A; or R1A and R2A together with the nitrogen atom to which they are attached form a 4-6 membered heterocycle wherein the 4-6 membered heterocycle is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORj, and N(Rj)2; whereinRZA, at each occurrence, is independently hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, G1A, or -(Ci- C6 alkylenyl)-G1A; andRZB, at each occurrence, is independently Ci-C6 haloalkyl, Ci-C6 alkyl, G1A, or -(Ci-C6alkylenyl)-G1A;R1B is hydrogen, Ci-C6 haloalkyl, or Ci-C6 alkyl; R3 and R14, are each independently hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 alkyl, -OH, or-0-(Ci-C6 alkyl);R4 is hydrogen, Ci-C6 haloalkyl, or Ci-C6 alkyl;R5 is hydrogen, -C(0)R -C(0)OH, -C(0)0(Ci-C6 alkyl), -C(0)N(Rh)2, Ci-C6 haloalkyl, Ci-C6 alkyl, or G2A; wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -OC(0)N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2R\ -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, and G2A; orR4 and R5, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6 cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rp groups;G2A, at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, orheteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rq groups;Rp and Rq, at each occurrence, are each independently Ci-C6 alkyl, halogen, Ci-C6 haloalkyl,-CN, oxo, N02, -ORh, -OCCC R1, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -C(0)N(Rh)S(0)2Rh, -N(Rh)2,-N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, or GA, wherein the C C6 haloalkyl and the C C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -OC(0)R\ -OC(0)N(Rh)2, -SRh, -S(0)2Rh,-S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -C(0)N(Rh)S(0)2Rh, -N(Rh)2,-N(Rh)C(0)R\ -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, -CN, and GA;Rh, at each occurrence, is independently hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, or GA, wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRj, -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;R1, at each occurrence, is independently Ci-C6 haloalkyl, Ci-C6 alkyl, or GA, wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRJ,-C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA; hydrogen, halogen, Ci-C6 haloalkyl, or Ci-C6 alkyl;R7 is hydrogen, halogen, -ORj, -N(Rj)2, -N(Rj)C(0)Rk, C C6 haloalkyl, C C6 alkyl, C2-C6 alkenyl, or -(Ci-C6 alkylenyl)-G3A;hydrogen, Ci-C6 haloalkyl, or Ci-C6 alkyl;R9, R10, and R13, are each independently hydrogen, halogen, -ORJ, Ci-C6 haloalkyl, or Ci-C6 alkyl;R11 and R12 are each independently hydrogen, C1-C3 alkyl, or halogen;G1A, G3A, and GA, at each occurrence, are each independently cycloalkyl, cycloalkenyl,heterocycle, aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rs groups; whereinRs, at each occurrence, is independently Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci- C6 haloalkyl, -CN, oxo, N02, -ORj, -OC(0)Rk, -OC(0)N(Rj)2, -SRj, -S(0)2Rj,-S(0)2N(RJ)2, -C(0)RJ, -C(0)ORJ, -C(0)N(RJ)2, -N(RJ)2, -N(RJ)C(0)Rk, -N(RJ)S(0)2Rk, -N(Rj)C(0)0(Rk), -N(Rj)C(0)N(Rj)2, -(C C6 alkylenyl)-ORj, -(C C6alkylenyl)-OC(0)Rk, -(Ci-C6 alkylenyl)-OC(0)N(Rj)2, -(Ci-C6 alkylenyl)-SRj, -(Ci-C6 alkylenyl)-S(0)2Rj, -(Ci-C6 alkylenyl)-S(0)2N(Rj)2, -(Ci-C6 alkylenyl)-C(0)Rj, -(Ci-C6 alkylenyl)-C(0)ORj, -(Ci-C6 alkylenyl)-C(0)N(Rj)2, -(Ci-C6 alkylenyl)-N(Rj)2, -(Ci-C6 alkylenyl)-N(Rj)C(0)Rk, -(C C6 alkylenyl)-N(Rj)S(0)2Rk, -(C C6alkylenyl)-N(Rj)C(0)0(Rk), -(C C6 alkylenyl)-N(Rj)C(0)N(Rj)2, or -(C C6 alkylenyl)-CN;RJ, at each occurrence, is independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; andRk, at each occurrence, is independently Ci-C6 alkyl or Ci-C6 haloalkyl.

2. The compound of claim 1 having formula (I-a) or a pharmaceutically acceptable salt thereof(I-a) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R", are as set forth in claim 1.

3. The compound of claim 1 having formula (I-b) or a pharmaceutically acceptable salt thereof(I-b)wherein R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R", are as set forth in claim1.

4. The compound of claim 1 having formula (I-c) or a pharmaceutically acceptable salt thereof(I-c)wherein R1, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R", are as set forth in claim1.

5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R8 is hydrogen.

6. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R8 is hydrogen; andm is 0.The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, whereinR8 is hydrogen;m is 0; andR9, R10, and R13 are each independently hydrogen or halogen.The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, whereinR8 is hydrogen;m is 0; andR9, R10, and R13 are hydrogen.The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, whereinR8 is hydrogen;m is 0;R9, R10, and R13 are each independently hydrogen or halogen; andR11 and R12 are hydrogen, or R11 and R12 are halogen.The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, whereinR8 is hydrogen;m is 0;R9, R10, and R13 are hydrogen; andR11 and R12 are halogen.The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R8 is hydrogen;m is 0;R9, R10, and R13 are hydrogen;R11 and R12 are halogen; andR1 is hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 alkyl, -OR1A, or -C(0)OR1B; wherein R1A is C1-C3 haloalkyl or C C alkyl; and R1B is hydrogen or C C3 alkyl.

12. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, whereinR8 is hydrogen;m is 0;R9, R10, and R13 are hydrogen;R11 and R12 are halogen;R1 is hydrogen, halogen, C C6 haloalkyl, C C6 alkyl, -OR1A, or -C(0)OR1B; wherein R1A is Ci-C3 haloalkyl or C1-C3 alkyl; and R1B is hydrogen or C1-C3 alkyl; andR2 is hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 alkyl, -OR1A, or -C(0)OR1B; wherein R1A is hydrogen, Ci-C3 haloalkyl, or Ci-C3 alkyl wherein the Ci-C3 alkyl is optionally substituted with one substituent selected from the group consisting of -ORZA, -C(0)OH, and G1A; and R1B is hydrogen or C C3 alkyl.

13. The compound of any one of claims 1, 2, and 3 or a pharmaceutically acceptable salt thereof, whereinR8 is hydrogen;m is 0;R9, R10, and R13 are hydrogen;R11 and R12 are halogen;R1 is hydrogen, halogen, C C6 haloalkyl, C C6 alkyl, -OR1A, or -C(0)OR1B; wherein R1A is C1-C3 haloalkyl or C1-C3 alkyl; and R1B is hydrogen or C1-C3 alkyl; and R3 is hydrogen or halogen. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, whereinR8 is hydrogen;m is 0;R9, R10, and R13 are hydrogen;R11 and R12 are halogen; andR14 is hydrogen or halogen.The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, whereinR4 is hydrogen, Ci-C6 haloalkyl, or Ci-C6 alkyl;R5 is hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, or G2A;R6 is hydrogen or C1-C3 alkyl; andR7 is hydrogen or C1-C3 alkyl.The compound of any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof, whereinR4 and R5, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6 cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rp groups;R6 is hydrogen or C1-C3 alkyl; andR7 is hydrogen or C1-C3 alkyl.The compound of any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof, whereinR4 is hydrogen or C1-C3 alkyl;R5 is hydrogen or C1-C3 alkyl;R6 is hydrogen or C1-C3 alkyl; andR7 is -(Ci-C6 alkylenyl)-G3A.

18. The compound of claim 1 having formula (I-d) or a pharmaceutically acceptable salt thereof(I-d)whereinX is CR2 and Y is CR3; orX is N and Y is CR3; orX is CR2 and Y is N;R1 and R2, are each independently hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 alkyl, -OR , -C(0)OR1B, -NR1AR2A, or -C(0)NR1AR2A;R1A and R2A, at each occurrence, are each independently hydrogen, Ci-C6 haloalkyl, G1A, or Ci- C6 alkyl; wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORZA, -SRZA, -S(0)2RZA, -C(0)RZA, -C(0)ORZA, -C(0)N(RZA)2, -N(RZA)2, -N(RZA)C(0)RZB, -N(RZA)S(0)2RZB, -N(RZA)C(0)ORZB, -N(RZA)C(0)N(RZA)2, -CN, and G1A; or R1A and R2A together with the nitrogen atom to which they are attached form a 4-6 membered heterocycle wherein the 4-6 membered heterocycle is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORj, and N(Rj)2; whereinRZA, at each occurrence, is independently hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, G1A, or-(Ci-Ce alkylenyl)-G1A; andRZB, at each occurrence, is independently Ci-C6 haloalkyl, Ci-C6 alkyl, G1A, or -(Ci-C6 alkylenyl)-G1A;R1B is hydrogen, Ci-C6 haloalkyl, or Ci-C6 alkyl;R3 and R14 are each independently hydrogen or halogen;R4 is hydrogen, Ci-C6 haloalkyl, or Ci-C6 alkyl; R5 is hydrogen, -C(0)R\ -C(0)OH, -C(0)N(Rh)2, Ci-C6 haloalkyl, Ci-C6 alkyl, or G2A; wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -OC(0)N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2Ri,-N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, and G2A; orR4 and R5, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6 cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rp groups;G2A, at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, orheteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rq groups;Rp and Rq, at each occurrence, are each independently Ci-C6 alkyl, halogen, Ci-C6 haloalkyl,-CN, oxo, N02, -ORh, -OC(0)R\ -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, or GA, wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -OC(0)R\ -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2R\ -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, -CN, and GA;Rh, at each occurrence, is independently hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, or GA, wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRj, -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;R1, at each occurrence, is independently Ci-C6 haloalkyl, Ci-C6 alkyl, or GA, wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRJ,-C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;R6 is hydrogen, halogen, Ci-C6 haloalkyl, or Ci-C6 alkyl;R7 is hydrogen, halogen, -ORj, -N(Rj)2, -N(Rj)C(0)Rk, Ci-C6 haloalkyl, Ci-C6 alkyl, C2-C6alkenyl, or -(C C6 alkylenyl)-G3A; R9, R10, and R13, are each independently hydrogen or halogen;G1A, G3A, and GA, at each occurrence, are each independently cycloalkyl, cycloalkenyl,heterocycle, aryl, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rs groups; whereinRs, at each occurrence, is independently Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,halogen, C C6 haloalkyl, -CN, oxo, N02, -ORj, -OC(0)Rk, -OC(0)N(Rj)2, -SRj, -S(0)2RJ, -S(0)2N(RJ)2, -C(0)RJ, -C(0)ORJ, -C(0)N(RJ)2, -N(RJ)2, -N(RJ)C(0)Rk, -N(Rj)S(0)2Rk, -N(Rj)C(0)0(Rk), -N(Rj)C(0)N(Rj)2, -(Ci-C6 alkylenyl)-ORj, -(Ci-C6 alkylenyl)-OC(0)Rk, -(Ci-C6 alkylenyl)-OC(0)N(Rj)2, -(Ci-C6 alkylenyl)-SRj, -(C C6 alkylenyl)-S(0)2Rj, -(C C6 alkylenyl)-S(0)2N(Rj)2, -(C C6 alkylenyl)-C(0)Rj, -(Ci-C6 alkylenyl)-C(0)ORj, -(Ci-C6alkylenyl)-C(0)N(Rj)2, -(Ci-C6 alkylenyl)-N(Rj)2, -(Ci-C6alkylenyl)-N(Rj)C(0)Rk, -(Ci-C6 alkylenyl)-N(Rj)S(0)2Rk, -(Ci-C6 alkylenyl)-N(Rj)C(0)0(Rk), -(C C6 alkylenyl)-N(Rj)C(0)N(Rj)2, or -(C C6 alkylenyl)-CN;RJ, at each occurrence, is independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; andRk, at each occurrence, is independently Ci-C6 alkyl or Ci-C6 haloalkyl.

19. The compound of claim 18 having formula (I-e) or a pharmaceutically acceptable salt thereof,(I-e)wherein R1, R2, R3, R4, R5, R6, R7, R9, R10, R13, and R14 are as set forth in claim 18.

20. The compound of claim 18 having formula (I-f) or a pharmaceutically acceptable salt thereof,(i-f)wherein R1, R3, R4, R5, R6, R7, R9, R10, R13, and R14 are as set forth in claim 18.

21. The compound of claim 18 having formula (I-g) or a pharmaceutically acceptable salt thereof,(i-g)wherein R1, R2, R4, R5, R6, R7, R9, R10, R13, and R14 are as set forth in claim 18.

22. The compound of any one of claims 18-21, or a pharmaceutically acceptable salt thereof, whereinR9, R10, and R13 are hydrogen.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, whereinR1 is hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 alkyl, -OR1A, or -C(0)OR1B; wherein R1A is C1-C3 haloalkyl or C1-C3 alkyl; and R1B is hydrogen or C1-C3 alkyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, whereinR4 is hydrogen, Ci-C6 haloalkyl, or Ci-C6 alkyl;R5 is hydrogen, Ci-C6 haloalkyl, or Ci-C6 alkyl;R6 is hydrogen or C1-C3 alkyl; and R is hydrogen or C1-C3 alkyl.

25. The compound of claim 23, or a pharmaceutically acceptable salt thereof, whereinR4 is hydrogen or C1-C3 alkyl;R5 is G2A wherein G2A is phenyl, C3-C6 cycloalkyl, 4-6 membered heterocycle, or 5-6 membered heteroaryl; each of which is optionally substituted with 1, 2, or 3 independently selected Rq groups;R6 is hydrogen or C1-C3 alkyl; andR7 is hydrogen or C1-C3 alkyl.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein G2A is phenyl which is optionally substituted with 1, 2, or 3 independently selected Rq group.

27. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein G2A is phenyl which is optionally substituted with 1, 2, or 3 Rq groups; wherein each Rq is independentlyCi-C6 alkyl wherein the Ci-C6 alkyl is optionally substituted with one -OH;halogen;Ci-C6 haloalkyl;-ORh wherein Rh is hydrogen or C1-C3 alkyl,-C(0)Rh wherein Rh is GA; wherein GA is 4-6 membered heterocycle;-C(0)ORh wherein Rh is hydrogen or Ci-C6 alkyl,-C(0)N(Rh)2, wherein Rh at each occurrence, is independently hydrogen, C3-C6cycloalkyl, Ci-C6 haloalkyl, or Ci-C6 alkyl; wherein the Ci-C6 haloalkyl and Ci- C6 alkyl are each optionally substituted with 1 or 2 -OH groups; or-S02Rh wherein Rh is Ci-C6 haloalkyl or Ci-C6 alkyl.

28. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein G2A is C3-C6 cycloalkyl which is optionally substituted with 1, 2, or 3 Rq groups; wherein each Rq is independentlyCi-C6 alkyl wherein the Ci-C6 alkyl is optionally substituted with one -OH; halogen;Ci-C6 haloalkyl;-ORh wherein Rh is hydrogen or C1-C3 alkyl,-C(0)Rh wherein Rh is GA; wherein GA is 4-6 membered heterocycle;-C(0)ORh wherein Rh is hydrogen or Ci-C6 alkyl,-C(0)N(Rh)2, wherein Rh at each occurrence, is independently hydrogen, C3-C6cycloalkyl, Ci-C6 haloalkyl, or Ci-C6 alkyl; wherein the Ci-C6 haloalkyl and Ci- C6 alkyl are each optionally substituted with 1 or 2 -OH groups; or-S02Rh wherein Rh is Ci-C6 haloalkyl or Ci-C6 alkyl.

29. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein G2A is cyclopropyl or cyclohexyl, each of which is optionally substituted with one Rq wherein Rq is-ORh wherein Rh is C C3 alkyl, or-C(0)ORh wherein Rh is hydrogen or Ci-C6 alkyl.

30. The compound of claim 25 or a pharmaceutically acceptable salt thereof, whereinG2A is cyclohexyl which is substituted with one Rq; andRq is -C(0)ORh wherein Rh is hydrogen or C C3 alkyl.

31. The compound of claim 25 or a pharmaceutically acceptable salt thereof, whereinG2A is a 4-6 membered heterocycle which is optionally substituted with 1, 2, or 3 independently selected Rq groups.

32. The compound of claim 25 or a pharmaceutically acceptable salt thereof, whereinG2A is 5-6 membered heteroaryl which is optionally substituted with 1, 2, or 3 independently selected Rq groups.

33. The compound of claim 23 or a pharmaceutically acceptable salt thereof, whereinR4 and R5, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl or a 4-6 membered heterocycle; wherein the C3-C6 cycloalkyl and the 4-6 membered heterocycle are each optionally substituted with 1, 2, or 3 independently selected Rp groups; andR6 and R7 are each independently hydrogen or C1-C3 alkyl.

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl which is optionally substituted with lor 2 Rp groups, wherein each Rp is independentlyCi-C6 alkyl wherein the Ci-C6 alkyl is optionally substituted with 1 or 2 -OH groups, -C(0)Rh wherein Rh is C C6 alkyl;-C(0)ORh wherein Rh is hydrogen, Ci-C6 alkyl, or -CH2-phenyl; or-S02Rh wherein Rh is Ci-C6 haloalkyl or Ci-C6 alkyl.

35. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the carbon atom to which they are attached, form a 4-6 membered heterocycle which is optionally substituted with 1 or 2 Rp groups, wherein each Rp is independentlyCi-C6 alkyl wherein the Ci-C6 alkyl is optionally substituted with 1 or 2 -OH groups, -C(0)Rh wherein Rh is C C6 alkyl;-C(0)ORh wherein Rh is hydrogen, Ci-C6 alkyl, or -CH2-phenyl; or-S02Rh wherein Rh is Ci-C6 haloalkyl or Ci-C6 alkyl.

36. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R4 hydrogen or C1-C3 alkyl;R5 is hydrogen or C1-C3 alkyl;R6 is hydrogen or C1-C3 alkyl; andR7 is -(Ci-C6 alkylenyl)-G3A.

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R is -(CH2)-G wherein G is phenyl which is optionally substituted with 1, 2, or 3 Rs groups; and each Rs is independently C1-C3 alkyl, halogen, C1-C3 haloalkyl, or -ORJ wherein RJ is hydrogen or C1-C3 alkyl.The compound of claim 1 having formula (I-h) or a pharmaceutically acceptable salt thereof(I-h)whereinR1 is hydrogen, halogen, C C6 haloalkyl, C C6 alkyl, -OR1A, or -C(0)OR1B; wherein R1A is C C3 haloalkyl or C1-C3 alkyl;R2 is hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 alkyl, -OR1A, or -C(0)OR1B; wherein R1A is hydrogen, C1-C3 haloalkyl, or C1-C3 alkyl; wherein the C1-C3 alkyl is optionally substituted with one substituent selected from the group consisting of -ORZA, -C(0)OH, and G1A; wherein G1A is phenyl which is optionally substituted with 1, 2, or 3 Rs groups wherein each Rs is independently C1-C3 alkyl, C1-C3 haloalkyl, halogen, or -OCH3; and RZA is C1-C3 haloalkyl or C1-C3 alkyl;R1B is hydrogen or C1-C3 alkyl;R3 and R14 are each independently hydrogen or halogen;R4 is hydrogen, C1-C3 haloalkyl, or C1-C3 alkyl;R5 is G2A;G2A is C3-C6 cycloalkyl, 4-6 membered heterocycle, phenyl, or 5-6 membered heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rq groups;Rq, at each occurrence, is independently Ci-C6 alkyl, halogen, Ci-C6 haloalkyl, -CN, oxo, N02, -ORh, -OCCC R1, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, or GA, wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORh, -00(0)^, -OC(0)N(Rh)2, -SRh, -S(0)2Rh, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)R\ -N(Rh)S(0)2Ri, -N(Rh)C(0)0(Ri), -N(Rh)C(0)N(Rh)2, -CN, and GA;Rh, at each occurrence, is independently hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, or GA, wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRj, -C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;R1, at each occurrence, is independently Ci-C6 haloalkyl, Ci-C6 alkyl, or GA, wherein the Ci-C6 haloalkyl and the Ci-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of -ORJ, -OC(0)N(RJ)2, -SRJ,-C(0)ORj, -C(0)N(Rj)2, -N(Rj)2, -CN, and GA;R6 is hydrogen or C1-C3 alkyl;R7 is hydrogen or C1-C3 alkyl;R9, R10, and R13, are each independently hydrogen or halogen;GA, at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, orheteroaryl, each of which is independently unsubstituted or substituted with 1, 2, or 3 independently selected Rs groups; wherein Rs, at each occurrence, is independently Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci-C6 haloalkyl, -CN, oxo, N02, -ORJ, -OC(0)Rk, -OC(0)N(RJ)2, -SRJ, -S(0)2RJ, -S(0)2N(RJ)2, -C(0)RJ, -C(0)ORJ,-C(0)N(Rj)2, -N(Rj)2, -N(Rj)C(0)Rk, -N(Rj)S(0)2Rk, -N(Rj)C(0)0(Rk),-N(Rj)C(0)N(Rj)2, -(Ci-C6 alkylenyl)-ORj, -(C C6 alkylenyl)-OC(0)Rk, -(C C6 alkylenyl)-OC(0)N(Rj)2, -(Ci-C6 alkylenyl)-SRj, -(Ci-C6 alkylenyl)-S(0)2Rj, -(Ci-C6 alkylenyl)-S(0)2N(Rj)2, -(Ci-C6 alkylenyl)-C(0)Rj, -(Ci-C6 alkylenyl)-C(0)ORj, -(Ci-C6 alkylenyl)-C(0)N(Rj)2, -(Ci-C6 alkylenyl)-N(Rj)2, -(Ci-C6 alkylenyl)-N(Rj)C(0)Rk, -(Ci- C6 alkylenyl)-N(Rj)S(0)2Rk, -(C C6 alkylenyl)-N(Rj)C(0)0(Rk), -(C C6alkylenyl)-N(Rj)C(0)N(Rj)2, or -(Ci-C6 alkylenyl)-CN;RJ, at each occurrence, is independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; andRk, at each occurrence, is independently Ci-C6 alkyl or Ci-C6 haloalkyl.

39. The compound of claim 38 or a pharmaceutically acceptable salt thereof, whereinG2A is phenyl, cyclopropyl, cyclohexyl, pyridinyl, azetidinyl, or tetrahydrofuranyl, each of which is optionally substituted with 1, 2, or 3 independently selected Rq groups.

40. The compound of claim 38 or a pharmaceutically acceptable salt thereof, whereinR1 is hydrogen, halogen, C1-C3 haloalkyl, C1-C3 alkyl, or -OR1A; wherein R1A is C1-C3 alkyl; andR2 is hydrogen, halogen, C1-C3 haloalkyl, C1-C3 alkyl, or -OR1A; wherein R1A is C1-C3 haloalkyl, or R1A is C1-C3 alkyl wherein the C1-C3 alkyl is optionally substituted with one -ORZA wherein RZA is C C3 alkyl.

41. The compound of claim 40 or a pharmaceutically acceptable salt thereof, whereinR4 is hydrogen;R6 is hydrogen; andR7 is hydrogen.

42. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein G2A is phenyl substituted with 1, 2, or 3 Rq groups; whereinone of Rq groups is C(0)ORh wherein Rh is hydrogen or Ci-C6 alkyl; or one of Rq groups is -C(0)N(H)(Rh), wherein Rh is cyclopentyl, or Rh is Ci-C6 alkyl substituted with 1 or 2 -OH groups; andthe other optional Rq groups are independently selected from the group consisting of Ci- C3 alkyl, halogen, and C1-C3 haloalkyl.

43. The compound of claim 41 or a pharmaceutically acceptable salt thereof, whereinG2A is phenyl or cyclohexyl; each of which is substituted with one C(0)ORh wherein Rh is hydrogen or C1-C3 alkyl.

44. The compound of claim 41 or a pharmaceutically acceptable salt thereof, whereinG2A is phenyl substituted with one C(0)ORh wherein Rh is hydrogen. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein G2A is cyclohexyl substituted with one C(0)ORh wherein Rh is hydrogen.The compound of any one of claims 38-45, or a pharmaceutically acceptable salt thereof, whereinR3, R14, R9, R10, and R13 are hydrogen.A compound having formula I-i) or a pharmaceutically acceptable salt thereof(I-i)whereinR1 is hydrogen, halogen, C1-C3 haloalkyl, C1-C3 alkyl, or -OR1A; wherein R1A is C1-C3 alkyl; andR2 is hydrogen, halogen, C1-C3 haloalkyl, C1-C3 alkyl, or -OR1A; wherein R1A is C1-C3 haloalkyl, or C1-C3 alkyl wherein the C1-C3 alkyl is optionally substituted with one -ORZA, and RZA is C1-C3 alkyl; andRh is hydrogen or C1-C3 alkyl.A compound having formula (I-j) or a pharmaceutically acceptable salt thereof(i-j)whereinR1 is hydrogen, halogen, C1-C3 haloalkyl, C1-C3 alkyl, or -OR1A; wherein R1A is C1-C3 alkyl; andR2 is hydrogen, halogen, C1-C3 haloalkyl, C1-C3 alkyl, or -OR1A; wherein R1A is C1-C3 haloalkyl, or C1-C3 alkyl wherein the C1-C3 alkyl is optionally substituted with one -ORZA, and RZA is C1-C3 alkyl; andRh is hydrogen or C1-C3 alkyl.

49. The compound of any one of claims 47 and 48, or a pharmaceutically acceptable salt thereof whereinR1 is hydrogen, C1-C3 alkyl, or -OR1A; wherein R1A is C1-C3 alkyl; andRh is hydrogen.

50. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;3-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3,4-dimethoxyphenyl)-7-methoxy- 3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(25',45)-2-(3,4-dimethoxyphenyl)-7-methoxy- 3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; methyl 3-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;methyl 3-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate;methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate;3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]benzoic acid;3-[(2R,4S)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4- dihydro-2H-chromen-2-yl]benzoic acid;methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate;methyl 3-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate;3-[(2R,4S)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;3-[(2R,4S)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;methyl 3-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate;methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate;3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6- methoxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid; l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-hydroxy-2-(3-methoxyphenyl)-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;rac-l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,45)-7-methoxy-2-(pyridin-3-yl)-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- hydroxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;ethyl re / -3-[(25,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate;ethyl re / -3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (difluoromethoxy)-3 ,4-dihydro-2H-chromen-2-yl] cyclohexanecarboxylic acid;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (difluoromethoxy)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;rac-3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;rac-3-[(2i?,4iS)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;methyl rac-3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 , 3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2- yljbenzoate;rac-3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;rac-3-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;rac-methyl 3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;rac-methyl 3-[(2R,4S)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate; 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- f uoro-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;methyl 3-[4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;3- [(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- f uoro-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;methyl 3-[(2R,4R)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoate;rac-N-[(2i?,4i?)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro- l ,3-benzodioxol-5-yl)cyclopropanecarboxamide;rac-N-[(2i?,45)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro- l ,3-benzodioxol-5-yl)cyclopropanecarboxamide;4- ( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3 ,4-dihydro-2H- chromene-7-carboxylic acid;3-({3-[(2R,4R)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methyl-3 ,4-dihydro-2H-chromen-2-yl]benzoyl} amino)- 1 -methylcyclopentanecarboxylic acid;(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-2-(3- methoxyphenyl)-3 ,4-dihydro-2H-chromene-6-carboxylic acid;methyl 4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4- dihydro-2H-chromene-7-carboxylate;methyl (2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 2-(3-methoxycyclohexyl)-3,4-dihydro-2H-chromene-6-carboxylate;methyl (2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 2-(3-methoxyphenyl)-3,4-dihydro-2H-chromene-6-carboxylate;3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2i?)-2,3-dihydroxypropyl]benzamide;l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3- {[(3i?)-3-hydroxypyrrolidin-l- yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; 3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3 ,4-dihydro-2H-chromen-2-yl] -N-(3 ,3 ,3 -trifluoro-2-hydroxypropyl)benzamide;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]-N-(2-hydroxy-2-methylpropyl)benzamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3-{[3-(hydroxymethyl)piperidin-l- yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3-{[2-(hydroxymethyl)morpho yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(l-hydroxycyclobutyl)methyl]benzamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3-{[3-(hydroxymethyl)-3- methylazetidin-l-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4- y 1] cy clopropanecarboxamide ;N-(7-bromo-3,4-dihydro-2H-chromen-4-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide;rac-l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-methoxy-2-(pyridin-3-yl)-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;l-(2,2-dif uoro-l,3-benzodioxol-5-yl)-N-{(2i?)-2-[3-(hydroxymethyl)phenyl]-3,4-dihydro- 2H-chromen-4-yl}cyclopropanecarboxamide;l-(2,2-dif uoro-l,3-benzodioxol-5-yl)-N-(7-methoxy-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide;l-(2,2-dif uoro-l,3-benzodioxol-5-yl)-N-(7-methoxy-2-phenyl-3,4-dihydro-2H-chromen- 4-yl)cyclopropanecarboxamide;N-[2-(3,4-dichlorophenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difl^ benzodioxol-5-yl)cyclopropanecarboxamide;l-(2,2-dif uoro-l,3-benzodioxol-5-yl)-N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;N-[2-(4-chlorophenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l -(2,2-difluoro- 1,3- benzodioxol-5-yl)cyclopropanecarboxamide;l-(2,2-difiuoro-l,3-benzodioxol-5-yl)-N-{2-[4-(Mchromen-4-yl}cyclopropanecarboxamide; N-[2-(2-chlorophenyl)-3,4-dihydro-2Hyl)cyclopropanecarboxamide;N-[2-(3,4-dichlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(2-phenyl-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide;N-[2-(4-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[2-(3,4-dimethoxyphenyl)-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide;N-[2-(3-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[2-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4- y 1] cy clopropanecarboxamide ;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-6-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;N-(3-benzyl-3,4-dihydro-2H-chromen-4-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide;N-[(4i?)-2,2-diethyl-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide;N-[(4i?)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxamide;N-[(4i?)-7-chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl] -(2,2-difluoro-1 benzodioxol-5-yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(4i?)-8-fluoro-2,2-bis(fluoromethyl)-3,4-dih^ 2H-chromen-4-yl]cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(4i?)-3,4-dihydrospiro[chromene-2, - cyclopentan]-4-yl]cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(4i?)-7-fluoro-2,2-bis(fluoromethyl)-3,4-dihydro- 2H-chromen-4-yl]cyclopropanecarboxamide; l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(25*,4i?)-2-(fluoromethyl)-2-methyl-7- (trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(difluoromethyl)-2-methyl-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2^,4i?)-2 difluoromethyl)-2-methyl-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;N-[(25',4i?)-7-chloro-2 difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl] difluoro- 1 ,3-benzodioxol-5-yl)cyclopropanecarboxamide;N-[(2i?,4i?)-7-chloro-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-yl^ difluoro- 1 ,3-benzodioxol-5-yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(25*,4i?)-2-methyl-2-(trifluoromedihydro-2H-chromen-4-yl]cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(4i?)-7-fluoro-2,2-dimethyl-3,4-dihydro-^ chromen-4-yl]cyclopropanecarboxamide;N-[(4i?)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-di l,3-benzodioxol-5-yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(45)-6-fluoro-2,2-dimethyl-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(45)-6-fluoro-3,4-dihydrospiro[chromene-2, cyclobutan]-4-yl]cyclopropanecarboxamide;N-[(4i?)-8-chloro-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl] -(2,2-di l,3-benzodioxol-5-yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-7-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;tert-butyl 4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- fiuoro-3,4-dihydro- H-spiro[chromene-2,4'-piperidine]- -carboxylate;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-fluoro-3,4-dihydrospiro[chromene-2,4'- piperidin]-4-yl)cyclopropanecarboxamide;methyl 3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate; methyl 3-[(2i?,4i?)-7-(benzyloxy)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate;3-[(2i?,4i?)-7-(carboxymethoxy)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl} amino)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7-(2- methoxyethoxy)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;3-[(2i?,4i?)-7-(benzyloxy)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl} amino)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-{ -[(2i?)-2,3-dihydroxypropyl]-7-fluoro-3,4- dihydrospiro[chromene-2,4'-piperidin]-4-yl}cyclopropanecarboxamide;benzyl 4'-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7'-fluoro- 3',4'-dihydro-lH-spiro[azetidine-3,2'-chromene]-l-carboxylate;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[7-fluoro- -(methylsulfonyl)-3,4- dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanecarboxamide;N-( -acetyl-7-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl)- 1 -(2,2-difluoro- 1,3- benzodioxol-5-yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7'-fluoro-3',4'-dihydrospiro[azetidine-3,2'- chromen]-4'-yl)cyclopropanecarboxamide;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[7*-fluoro-l-(methylsulfonyl)-3*,4*- dihydrospiro[azetidine-3,2'-chromen]-4'-yl]cyclopropanecarboxamide;N-(l-acetyl-7'-fluoro-3^4'-dihydrospiro[azetidine-3,2'-chromen]-4'-yl)-l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxamide;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7-(2- fluoroethoxy)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[ -(3-hydroxy-2,2-dimethylpropanoyl)-7- methoxy-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanecarboxamide;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (trifluoromethyl)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (trifluoromethyl)-3 ,4-dihydro-2H-chromen-2-yl] cyclohexanecarboxylic acid; methyl 4-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;4-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;methyl rac-3-[(2i?,4i?)-7-chloro-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;methyl rac-3-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 , 3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate; rac-3-[(2i?,4i?)-7-chloro-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic acid;tert-butyl 3-[4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]azetidine- 1 -carboxylate;N-[2-(azetidin-3-yl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l -(2,2-difluoro- 1,3- benzodioxol-5-yl)cyclopropanecarboxamide;1 -(2,2-difluoro-l ,3-benzodioxol-5-yl)-N- {7-methoxy-2-[ 1 -(methylsulfonyl)azetidin-3-yl]- 3 ,4-dihydro-2H-chromen-4-yl} cyclopropanecarboxamide;methyl rac-3-[(2i?,45)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;3- [(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-8- fluoro-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;methyl 4-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate;4- [(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]benzoic acid;4-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (difluoromethoxy)-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;methyl 4-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate; l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-hydroxy-2,2-dimethyl-3,4-dihydro-2H- chromen-4-yl)cyclopropanecarboxamide; l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[7-(difluoromethoxy)-2,2-dimethyl-3,42H-chromen-4-yl]cyclopropanecarboxamide;1- (2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[7-methoxy-2-(tetrahydrofuran-2-yl)-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;methyl 4-[(2R,4R)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-hydroxy-3,4-dihydro-2H-chromen-2-yl]benzoate;4-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- hydroxy-3 ,4-dihydro-2H-chromen-2-yl]benzoic acid;4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7-methoxy-3 ,4- dihydrospiro[chromene-2, 1 '-cyclobutane]-3'-carboxylic acid;ethyl rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate;methyl rac-(2i?,45)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate;ethyl rel-2-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l ,3-thiazole-5-carboxylate;2- [(45)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4- dihydro-2H-chromen-2-yl]- 1 ,3-thiazole-5-carboxylic acid;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3 ,4-dihydro-2H-chromene-2-carboxylic acid;ethyl rel-2-[(2R,4R)-H ii 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l ,3-thiazole-5-carboxylate;2-[(4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]- 1 ,3-thiazole-5-carboxylic acid;methyl 4-[(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoate; methyl 4-[(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-3-fluorobenzoate;4-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3 ,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoic acid; ethyl rel-2-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l ,3-thiazole-4-carboxylate; ethyl re / -2-[(2i?,45)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l ,3-thiazole-4-carboxylate; ethyl rel-2-[(2R,4R)-H ii 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-l ,3-thiazole-4-carboxylate;re / -2-[(25',45)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3,4-dihydro-2H-chromen-2-yl]-l ,3-thiazole-4-carboxylic acid;rel-2-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 3,4-dihydro-2H-chromen-2-yl]-l ,3-thiazole-4-carboxylic acid;re / -2-[(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3,4-dihydro-2H-chromen-2-yl]-l ,3-thiazole-4-carboxylic acid;4-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]-3-fluorobenzoic acid;methyl rac-3-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 , 3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2- yl]bicyclo[ 1.1.1 Jpentane- 1 -carboxylate;rac-3-[(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 7-methoxy-3 ,4-dihydro-2H-chromen-2-yl]bicyclo[ 1.1.1 Jpentane- 1 -carboxylic acid;ethyl rac-6-[(2i?,45)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;ethyl rac-6-[(2R,4R)-H ii 1 -(2,2-difluoro- 1 , 3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;ethyl 3-[4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-3,4- dihydro-2H-chromen-2-yl]cyclobutanecarboxylate;3-[4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro- 2H-chromen-2-yl]cyclobutanecarboxylic acid;rac-6-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 3, 4-dihydro-2H-chromen-2-yl]pyridine-3 -carboxylic acid;rac-6-[(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3, 4-dihydro-2H-chromen-2-yl]pyridine-3 -carboxylic acid; ethyl re / -2-[(2R,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-l,3-thicarboxylate;re / -2-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 7-methoxy-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4-carboxylic acid;ethyl rel-2-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4- carboxylate;re / -2-[(2S,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 7-methoxy-3,4-dihydro-2H-chromen-2-yl]-l,3-thiazole-4-carboxylic acid;methyl re / -6-[(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3- carboxylate;methyl re / -6-[(25,4R)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3- carboxylate;methyl re / -6-[(25,4S)^-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3- carboxylate;methyl re / -6-[(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3- carboxylate;ethyl rac-(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate;rac-(2R,4R)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3 ,4-dihydro-2H-chromene-2-carboxylic acid;re / -6-[(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylic acid;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (2-hydroxyethyl)-7-methoxy-N-propyl-3,4-dihydro-2H-chromene-2-carboxamide; rac-(2i?, R)-N-benzyl-4-( {[ 1 -(2,2-difhioro- 1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-N-(2-hydroxyethyl)-7-methoxy-3,4-dihydro-2H-chromene-2- carboxamide;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (2-hydroxy-2-phenylethyl)-7-methoxy-N-methyl-3,4-dihydro-2H-chromene-2-carboxamrac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-{[4-(2-hydroxyethyl)piperazin- l-yl]carbonyl}-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- ( 1 -hydroxy-2-methylpropan-2-yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (2 -hydroxy- 1 -phenylethyl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2- carboxamide;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-N-[3-(trifluoromethyl)oxetan-3-yl]-3,4-dihydro-2H-chromene-2-carboxarac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N- {(2i?,4i?)-2-[(4,4-difluoropiperidin-l- yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide;rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-methoxy-2-(l ,4-oxazepan-4- ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-N-methyl-N-(oxetan-3-yl)-3,4-dihydro-2H-chromene-2-carboxamiderac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-methoxy-2-(morpholin-^ ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxoL[2-hydroxy-l-(2-methoxyphenyl)ethyl]-7-mrac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- [2-(3-hydroxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (l ,3-dihydroxypropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide; rac-(2i?,4i?)-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-N- (2 -hydroxy-2,3 -dihydro- 1 H-inden- 1 -yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide; rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2-hydroxyphenyl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2-hydroxyethyl)-7-methoxy-N-propyl-3,4-dihydro-2H-chromene-2-carboxamide;rac-(2i?,45)-N-benzyl-4-({[l-(2,2-difluoro-l ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-N-(2-hydroxyethyl)-7-methoxy-3,4-dihydro-2H-chromene-2- carboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2-hydroxy-2-phenylethyl)-7-methoxy-N-methyl-3,4-dihydro-2H-chromene-2-carboxamide;rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N- {(2i?,45)-2-[(4-hydroxypiperidin-l- yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide;rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,45)-2- {[4-(2-hydroxyethyl)piperazin-l- yl]carbonyl}-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamid;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2-hydroxy-2-methylpropyl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- ( 1 -hydroxy-2-methylpropan-2-yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamid;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2 -hydroxy- 1 -phenylethyl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2- carboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-N-[3-(trifluoromethyl)oxetan-3-yl]-3,4-dihydro-2H-chromene-2-carboxamide;rac- 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-N- {(2i?,45)-2-[(4,4-difluoropiperidin- 1 - yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide;rac-l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-N-[(2i?,45)-7-methoxy-2-(l ,4-oxazepan-4- ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-N-methyl-N-(oxetan-3-yl)-3,4-dihydro-2H-chromene-2-carboxamide;rac-l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,45)-7-methoxy-2-(morpholin-4- ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- [2-hydroxy-l-(2-methoxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide; rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- [2-(3-hydroxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (l,3-dihydroxypropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamide;rac-(2R,4S)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-N- (2 -hydroxy-2,3 -dihydro- 1 H-inden- 1 -yl)-7-methoxy-3 ,4-dihydro-2H-chromene-2-carboxamide; roc- 1 - { [(2R,4S)-4-( { [ 1 -(2,2-difluoro- 1 ,3 -benzodioxol-5 - yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2- y 1] carbony 1 } pyrrolidine-3 -carboxy lie acid;4-[(2R,4R)-4-( {[ 1 -(6-bromo-2,2-difluoro- 1 ,3 -benzodioxol-5 - yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;methyl 4-((2R,4R)-4-(l-(6-bromo-2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarboxamido)-7-methoxychroman-2-yl)benzoate; and4-[(2i?,4i?)-4-( {[ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- (difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]-N-(methylsulfonyl)benzamide.

51. A pharmaceutical composition comprising a therapeutically effective amount of acompound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

52. A method for treating cystic fibrosis in a subject comprising administering atherapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

53. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

54. The pharmaceutical composition of claim 53 wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers.

55. The pharmaceutical composition of claim 53 wherein the additional therapeutic agents are CFTR modulators.

56. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, one potentiator, and one or more correctors.

57. A method for treating cystic fibrosis in a subject comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

58. The method of claim 57 wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers.

59. The method of claim 57 the wherein the additional therapeutic agents are CFTRmodulators.

60. A method for treating cystic fibrosis in a subject comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, one potentiator, and one or more correctors.